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3074e24becffe7bd71e3889dd4bdaf2956070284 | wikidoc | Wrap rage | Wrap rage
Wrap rage (or wrapping rage or package rage) is the common name for heightened levels of anger, frustration and violence resulting from the inability to open hard-to-remove packaging.
In 2006, Consumer Reports magazine officially recognized the "wrap rage" phenomenon when it created the Oyster Awards for the products with the hardest-to-open packaging. A story in the Pittsburgh Post-Gazette about "wrap rage" was featured on The Colbert Report when host Stephen Colbert (character)|Stephen Colbert tried to use a knife to remove a new calculator from its packaging, to no avail.
Tools and implements used in attempts to open packages while under the influence of wrap rage are typically applied in a reckless and unsafe manner, and with the use of excessive force.
Wrap rage may result in minor injuries, such as cuts, sprains and bruises to the fingers and hands or strains to the shoulder muscle caused by exerting excessive efforts in attempting to open packages. In addition to personal injuries, wrap rage can result in damages to the goods (e.g. to instruction manuals, CDs or warranty cards) or other items nearby at the product’s eventual opening. Merely opening some blister packs will render the contents un-returnable as stores insist on receiving returned goods in a packaged condition - impossible if the blister pack has to be opened by force. | Wrap rage
Wrap rage (or wrapping rage or package rage) is the common name for heightened levels of anger, frustration and violence resulting from the inability to open hard-to-remove packaging.[1]
In 2006, Consumer Reports magazine officially recognized the "wrap rage" phenomenon when it created the Oyster Awards for the products with the hardest-to-open packaging.[2] A story in the Pittsburgh Post-Gazette about "wrap rage" was featured on The Colbert Report when host Stephen Colbert (character)|Stephen Colbert tried to use a knife to remove a new calculator from its packaging, to no avail.
Tools and implements used in attempts to open packages while under the influence of wrap rage are typically applied in a reckless and unsafe manner, and with the use of excessive force.
Wrap rage may result in minor injuries, such as cuts, sprains and bruises to the fingers and hands or strains to the shoulder muscle caused by exerting excessive efforts in attempting to open packages. In addition to personal injuries, wrap rage can result in damages to the goods (e.g. to instruction manuals, CDs or warranty cards) or other items nearby at the product’s eventual opening. Merely opening some blister packs will render the contents un-returnable as stores insist on receiving returned goods in a packaged condition - impossible if the blister pack has to be opened by force. | https://www.wikidoc.org/index.php/Wrap_rage | |
9e4ec519f64775ad28d5fde89bb3f0af029b8a5a | wikidoc | Yohimbine | Yohimbine
Yohimbine, also known under the antiquated names quebrachin, aphrodin, corynine, yohimvetol and hydroergotocin, is a purported aphrodisiac.
# Function
## Aphrodisiac
The NIH states that Yohimbine hydrochloride is the standardized form of yohimbine that is available as a prescription medicine in the United States, and has been shown in human studies to be effective in the treatment of male impotence.
Yohimbine chloride—a standardized form of yohimbine—is a prescription medicine that has been used to treat erectile dysfunction. Controlled studies suggest that it is not always an effective treatment for impotence, and evidence of increased sex drive (libido) is anecdotal only.
It cannot be excluded that orally administered yohimbine can have a beneficial effect in some patients with ED. The conflicting results available may be attributed to differences in drug design, patient selection, and definitions of positive response. However, generally, available results of treatment are not impressive.
Yohimbine has been shown to be effective in the reversal of sexual satiety and exhaustion in male rats.
## Other uses
Yohimbine hydrochloride has also been used for the treatment of sexual side effects caused by some antidepressants (SSRIs), female hyposexual disorder, as a blood pressure boosting agent in autonomic failure, xerostomia, and as a probe for noradrenergic activity.
Yohimbine has been used to facilitate recall of traumatic memories in the treatment of post-traumatic stress disorder (PTSD).. Use of yohimbine outside therapeutic settings may not be appropriate for persons suffering from PTSD.
Some internet shops sell expensive formulations of yohimbine for transdermal delivery to effect a local reduction of adipose tissue, although there is no evidence that it is effective. Demand for products of this kind is frequently found in the bodybuilding community.
In veterinary medicine, yohimbine is used to reverse anesthesia from the drug xylazine in small and large animals.
# Mechanism
Yohimbine Hydrochloride is a selective competitive alpha2-adrenergic receptor antagonist. The alpha2 receptor is responsible for sensing adrenaline and noradrenaline and telling the body to decrease its production as part of a negative feedback loop.
Yohimbine also antagonizes several serotonin receptor subtypes: 1A (inhibitory, behavioral control), 1B (inhibitory, vasoconstriction), 1D (inhibitory, vasoconstriction), and 2B (smooth muscle contraction). Since yohimbine is an antagonist, it will decrease the effects of these receptors, thus causing excitation, vasodilation, and smooth muscle relaxation.
Yohimbine is also said to increase dopamine and have some actions as an MAOI, although these mechanisms are unknown. Yohimbine and Yohimbine bark may also cause vasodilation through endothelin B receptor stimulation and nitric oxide (NO) release.
# Production
Yohimbine is the principal alkaloid of the bark of the West-African evergreen Pausinystalia yohimbe Pierre (formerly Corynanthe yohimbe), family Rubiaceae (Madder family). There are 31 other yohimbane alkaloids found in Yohimbe. In Africa, yohimbine has traditionally been used as an aphrodisiac. However it is very important to note that while the terms yohimbine, yohimbine hydrochloride, and yohimbe bark extract are related, they are not interchangeable.
The active chemical present in yohimbe bark is Yohimbine HCl (indole alkaloid) found in the bark of the Pausinystalia yohimbe tree.
However, the levels of yohimbine that are present in yohimbe bark extract are variable and often very low. Therefore, although yohimbe bark has been used traditionally to reduce male erectile dysfunction, there is not enough scientific evidence to form a definitive conclusion in this area.
# Adverse effects
Yohimbine has significant side effects such as anxiety reactions. According to the Mayo Clinic, yohimbine can be dangerous if used in excessive amounts.
Higher doses of oral yohimbine may create numerous side effects such as rapid heart rate, high blood pressure, and overstimulation. It causes insomnia and sleeplessness. | Yohimbine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6]
Yohimbine, also known under the antiquated names quebrachin, aphrodin, corynine, yohimvetol and hydroergotocin, is a purported aphrodisiac.
# Function
## Aphrodisiac
The NIH states that Yohimbine hydrochloride is the standardized form of yohimbine that is available as a prescription medicine in the United States, and has been shown in human studies to be effective in the treatment of male impotence.[1]
Yohimbine chloride—a standardized form of yohimbine—is a prescription medicine that has been used to treat erectile dysfunction.[2] Controlled studies suggest that it is not always an effective treatment for impotence, and evidence of increased sex drive (libido) is anecdotal only.[3]
It cannot be excluded that orally administered yohimbine can have a beneficial effect in some patients with ED. The conflicting results available may be attributed to differences in drug design, patient selection, and definitions of positive response. However, generally, available results of treatment are not impressive.
Yohimbine has been shown to be effective in the reversal of sexual satiety and exhaustion in male rats. [4]
## Other uses
Yohimbine hydrochloride has also been used for the treatment of sexual side effects caused by some antidepressants (SSRIs), female hyposexual disorder, as a blood pressure boosting agent in autonomic failure, xerostomia, and as a probe for noradrenergic activity.
Yohimbine has been used to facilitate recall of traumatic memories in the treatment of post-traumatic stress disorder (PTSD).[5]. Use of yohimbine outside therapeutic settings may not be appropriate for persons suffering from PTSD.[6]
Some internet shops sell expensive formulations of yohimbine for transdermal delivery to effect a local reduction of adipose tissue, although there is no evidence that it is effective. Demand for products of this kind is frequently found in the bodybuilding community.
In veterinary medicine, yohimbine is used to reverse anesthesia from the drug xylazine in small and large animals.
# Mechanism
Yohimbine Hydrochloride is a selective competitive alpha2-adrenergic receptor antagonist. The alpha2 receptor is responsible for sensing adrenaline and noradrenaline and telling the body to decrease its production as part of a negative feedback loop.
Yohimbine also antagonizes several serotonin receptor subtypes: 1A (inhibitory, behavioral control), 1B (inhibitory, vasoconstriction), 1D (inhibitory, vasoconstriction), and 2B (smooth muscle contraction). Since yohimbine is an antagonist, it will decrease the effects of these receptors, thus causing excitation, vasodilation, and smooth muscle relaxation.
Yohimbine is also said to increase dopamine and have some actions as an MAOI, although these mechanisms are unknown. Yohimbine and Yohimbine bark may also cause vasodilation through endothelin B receptor stimulation and nitric oxide (NO) release.
# Production
Yohimbine is the principal alkaloid of the bark of the West-African evergreen Pausinystalia yohimbe Pierre (formerly Corynanthe yohimbe), family Rubiaceae (Madder family). There are 31 other yohimbane alkaloids found in Yohimbe. In Africa, yohimbine has traditionally been used as an aphrodisiac.[7] However it is very important to note that while the terms yohimbine, yohimbine hydrochloride, and yohimbe bark extract are related, they are not interchangeable.[8]
The active chemical present in yohimbe bark is Yohimbine HCl (indole alkaloid) found in the bark of the Pausinystalia yohimbe tree.
However, the levels of yohimbine that are present in yohimbe bark extract are variable and often very low.[1] Therefore, although yohimbe bark has been used traditionally to reduce male erectile dysfunction, there is not enough scientific evidence to form a definitive conclusion in this area.
# Adverse effects
Yohimbine has significant side effects such as anxiety reactions. According to the Mayo Clinic, yohimbine can be dangerous if used in excessive amounts.[9]
Higher doses of oral yohimbine may create numerous side effects such as rapid heart rate, high blood pressure, and overstimulation. It causes insomnia and sleeplessness. | https://www.wikidoc.org/index.php/Yohimbe | |
15de5a0845754402f9ffc9caa3e1df6602b06db1 | wikidoc | Zomepirac | Zomepirac
# Overview
Zomepirac is an orally effective NSAID that has antipyretic actions. It was developed by McNeil Pharmaceutical and approved by the FDA in 1980 and sold as the sodium salt, zomepirac sodium, under the brand name Zomax. Due to its clinical effectiveness, it was preferred by doctors in many situations and obtained a large share of the analgesics market; however, it was subsequently withdrawn in March 1983 due to its tendency to cause serious anaphylaxis in an unpredictable subset of the patient population.
# Indications
Zomepirac was indicated for the management of mild to severe pain. Multiple clinical trials demonstrated zomepirac to be more effective than aspirin or codeine alone and to be as effective as analgesic combinations containing codeine or other opioids. Zomepirac provided analgesia comparable with usual intramuscular doses of morphine in postoperative pain and that with long-term use, neither tolerance to its analgesic effect nor psychological or physical dependence had been demonstrated.
# Chemical structure
Zomepirac is the sodium salt of 5-(4-chlorobenzoyl)-1,4 dimethyl-1H-pyrrole-2-acetate dihydrate. It is a pyrrole-acetic acid which is structurally related to tolmetin.
# Mechanism of action
It is a prostaglandin synthetase inhibitor.
# Toxicity
Zomepirac does not cause anaphylaxis directly, but it is metabolised by UGT to a reactive glucuronide, which binds irreversibly to plasma albumin. | Zomepirac
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Zomepirac is an orally effective NSAID that has antipyretic actions. It was developed by McNeil Pharmaceutical and approved by the FDA in 1980 and sold as the sodium salt, zomepirac sodium, under the brand name Zomax. Due to its clinical effectiveness, it was preferred by doctors in many situations and obtained a large share of the analgesics market; however, it was subsequently withdrawn in March 1983 due to its tendency to cause serious anaphylaxis in an unpredictable subset of the patient population.[1][2]
# Indications
Zomepirac was indicated for the management of mild to severe pain.[3] Multiple clinical trials demonstrated zomepirac to be more effective than aspirin or codeine alone and to be as effective as analgesic combinations containing codeine or other opioids.[4][5][6][7][8][9][10] Zomepirac provided analgesia comparable with usual intramuscular doses of morphine in postoperative pain and that with long-term use, neither tolerance to its analgesic effect nor psychological or physical dependence had been demonstrated.[3][11]
# Chemical structure
Zomepirac is the sodium salt of 5-(4-chlorobenzoyl)-1,4 dimethyl-1H-pyrrole-2-acetate dihydrate. It is a pyrrole-acetic acid which is structurally related to tolmetin.
# Mechanism of action
It is a prostaglandin synthetase inhibitor.[12]
# Toxicity
Zomepirac does not cause anaphylaxis directly, but it is metabolised by UGT to a reactive glucuronide, which binds irreversibly to plasma albumin.[13] | https://www.wikidoc.org/index.php/Zomepirac | |
06044812721d6599f50a3b61005275cc9300e9a9 | wikidoc | Zone diet | Zone diet
The Zone diet is a diet popularized in books by Barry Sears. It advocates balancing protein and carbohydrate in 3:4 ratios. It is not primarily a weight-loss "diet", though it can be used quite successfully for that purpose .
# 'The Zone'
The diet centers on a "40:30:30" ratio of calories obtained daily from carbohydrates, proteins, and fats, respectively. The exact formula is always under debate, but studies over the past several years (including a non-scientific study by the PBS documentary show Scientific American Frontiers) have shown that it can produce weight loss at reasonable rates. The Scientific American Frontiers study compared the effectiveness of several popular 'diet' regimes including the Zone; somewhat to the surprise of the show's staff, the participants on the Zone experienced the greatest fat loss while simultaneously gaining muscle mass. Participants also reported the Zone as the easiest regime to adjust to, i.e. having the fewest adverse affects such as fatigue or hunger.
"The Zone" is Sears' term for proper hormone balance. When insulin levels are neither too high nor too low, and glucagon levels are not too high, then specific anti-inflammatory chemicals (types of eicosanoids) are released, which have similar effects to aspirin, but without downsides such as gastric bleeding. Sears claims that a 30:40 ratio of protein to carbohydrates triggers this effect, and this is called 'The Zone.' Sears claims that these natural anti-inflammatories are heart and health friendly.
Additionally, the human body in caloric balance is more efficient and does not have to store excess calories as fat. The human body cannot store fat and burn fat at the same time, and Sears believes it takes time (significant time if insulin levels were high because of unbalanced eating) to switch from the former to the latter. Using stored fat for energy causes weight loss.
Another key feature of the Zone diet, introduced in his later books, is an intake of the proper ratio of Omega-3 to Omega-6 fatty acids. Dr. Sears is believed to have popularized the taking of pharmaceutical grade Omega 3 fish oils.
# Hormonal paradoxes
Sears emphasizes a hormonal paradox of which "low-fat" advocates were unaware, namely that low-fat diets increase the production of the hormone insulin, causing the body to store more fat. He points to the cattle ranching practice of fattening livestock efficiently by feeding them lots of low-fat grain. He and others have noted the irony that human diets in the West for the last twenty years have been full of low-fat carbohydrates, yet people are more obese.
Additionally, Sears describes fat consumption as essential for "burning" fat. Monounsaturated fats in a meal contribute to a feeling of fullness and decreases the rate at which carbohydrates are absorbed into the bloodstream. Slower carbohydrate absorption means lower insulin levels which means less stored fat and a faster transition to fat burning. If the body needs energy and can't burn fat because of high insulin levels, a person feels tired as their brain starves and metabolism slows to compensate. This occurs because the brain runs on glucose and high insulin levels deplete blood glucose levels. Such condition, rebound hypoglycemia causes sweet cravings (which just starts the high-insulin cycle all over again).
Sears describes a Zone meal as follows: Eat as much protein as the palm of your hand, as much nonstarchy raw vegetables as you can stand for the vitamins, enough carbohydrates to maintain mental clarity because the brain runs on glucose, and enough monounsaturated oils to keep feelings of hunger away.
# The Zone and low-carb diets
Low-carbohydrate diets like the Atkins diet became extremely popular throughout the United States in 2003 and 2004, but Sears claims that they miss the point. According to him, they ignore the importance of hormonal balance, as well as the influence of dietary balance on digestion and hormone production.
# The Zone in Italy
The introduction of the Zone in Italy began in 1997 by a physician, Aronne Romano M.D. who applied this nutritional style to patients and athletes. Since the 2nd edition of the book "Come Raggiungere la Zona" (The Zone), in 1999, the Chef Memo Romano and his brother Aronne modified the original recipes and menu to suit the local food and habits. The diffusion of the Zone continues with the efforts of many people including Paolo Perucci, Gigliola Braga, Simone Masci and Daniela Morandi.
# Famous obesity case
Possibly the most famous case of someone using the diet effectively has been Mexican Manuel Uribe. After weighing in at around 560 kg (1234 lbs or over 88 stone) but within a year had lost about 180 kg..
# Criticism
The American Heart Association does not recommend the Zone Diet due to high-protein, lack of essential nutrients and little information on long-term effects. It should be noted that AMA's characterization of the Zone diet as 'high-protein' is false, or at least a serious exaggeration, given that 70% of the calories in the Zone diet come from non-protein sources(i.e. carbohydrates, 40%, and fats 30%). The Zone does not emphasize an increase of protein intake in the standard American diet, but rather, a reduction in the intake of unhealthy carbohydrates (i.e. refined breads, starches, sugars, etc.) and an increase in healthy carbohydrates from high-fiber vegetables and fruits and healthy monounsaturated fats.
A vegetarian diet, according to Sears, is as far as you can get from The Zone. Individuals who promote a vegetarian diet are critical of Zone and similar diets.
# "Zone" books by Sears
(Partial list)
- Sears, Barry (1995). The Zone: A Dietary Road Map. HarperCollins Publishers. ISBN 0060987065..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} Sears's initial book on the Zone diet.
- Sears, Barry (1997). Mastering the Zone. HarperCollins Publishers. ISBN 006101124X. Sears urges substitution of raw vegetables for pastas, breads and refined sugars. More diagrams and flowcharts than in The Zone.
- Sears, Barry (1999). The Anti-Aging Zone. Regan Books. ISBN 0060392436. Information on meditation, relaxation and exercise in addition to diet.
- Sears, Barry (2000). A Week in the Zone: A Quick Course in the Healthiest Diet for You. Regan Books. ISBN 0060741902. Unknown parameter |coauthors= ignored (help)
- Sears, Barry (2000). The Soy Zone. Regan Books. ISBN 0060393106. Discusses Sears preference for soy protein as part of his balanced eating program. "The longest-living people in the world" living in Okinawa, Japan consume much greater amounts of soy protein and eat smaller meals than most other people.
- Sears, Barry (2002). The Omega Rx Zone: The Miracle of the New High-Dose Fish Oil. Regan Books. ISBN 0060393130. Discusses "high-dose fish oil;" a newly introduced invented pharmaceutical grade fish oil that Sears touts as a medical miracle that will put the eicasonids in balance and reduce inflammation. Extra virgin olive oil is also promoted for its phytochemicals.
- Sears, Barry (2005). The Anti-Inflammation Zone: Reversing the Silent Epidemic That's Destroying Our Health. Regan Books. ISBN 0060834145. | Zone diet
The Zone diet is a diet popularized in books by Barry Sears. It advocates balancing protein and carbohydrate in 3:4 ratios. It is not primarily a weight-loss "diet", though it can be used quite successfully for that purpose [1].
# 'The Zone'
The diet centers on a "40:30:30" ratio of calories obtained daily from carbohydrates, proteins, and fats, respectively. The exact formula is always under debate, but studies over the past several years (including a non-scientific study by the PBS documentary show Scientific American Frontiers) have shown that it can produce weight loss at reasonable rates. The Scientific American Frontiers study compared the effectiveness of several popular 'diet' regimes including the Zone; somewhat to the surprise of the show's staff, the participants on the Zone experienced the greatest fat loss while simultaneously gaining muscle mass. Participants also reported the Zone as the easiest regime to adjust to, i.e. having the fewest adverse affects such as fatigue or hunger.
"The Zone" is Sears' term for proper hormone balance. When insulin levels are neither too high nor too low, and glucagon levels are not too high, then specific anti-inflammatory chemicals (types of eicosanoids) are released, which have similar effects to aspirin, but without downsides such as gastric bleeding. Sears claims that a 30:40 ratio of protein to carbohydrates triggers this effect, and this is called 'The Zone.' Sears claims that these natural anti-inflammatories are heart and health friendly.
Additionally, the human body in caloric balance is more efficient and does not have to store excess calories as fat. The human body cannot store fat and burn fat at the same time, and Sears believes it takes time (significant time if insulin levels were high because of unbalanced eating) to switch from the former to the latter. Using stored fat for energy causes weight loss.
Another key feature of the Zone diet, introduced in his later books, is an intake of the proper ratio of Omega-3 to Omega-6 fatty acids. Dr. Sears is believed to have popularized the taking of pharmaceutical grade Omega 3 fish oils.[2]
# Hormonal paradoxes
Sears emphasizes a hormonal paradox of which "low-fat" advocates were unaware, namely that low-fat diets increase the production of the hormone insulin, causing the body to store more fat. He points to the cattle ranching practice of fattening livestock efficiently by feeding them lots of low-fat grain. He and others have noted the irony that human diets in the West for the last twenty years have been full of low-fat carbohydrates, yet people are more obese.
Additionally, Sears describes fat consumption as essential for "burning" fat. Monounsaturated fats in a meal contribute to a feeling of fullness and decreases the rate at which carbohydrates are absorbed into the bloodstream. Slower carbohydrate absorption means lower insulin levels which means less stored fat and a faster transition to fat burning. If the body needs energy and can't burn fat because of high insulin levels, a person feels tired as their brain starves and metabolism slows to compensate. This occurs because the brain runs on glucose and high insulin levels deplete blood glucose levels. Such condition, rebound hypoglycemia causes sweet cravings (which just starts the high-insulin cycle all over again).
Sears describes a Zone meal as follows: Eat as much protein as the palm of your hand, as much nonstarchy raw vegetables as you can stand for the vitamins, enough carbohydrates to maintain mental clarity because the brain runs on glucose, and enough monounsaturated oils to keep feelings of hunger away.
# The Zone and low-carb diets
Low-carbohydrate diets like the Atkins diet became extremely popular throughout the United States in 2003 and 2004, but Sears claims that they miss the point. According to him, they ignore the importance of hormonal balance, as well as the influence of dietary balance on digestion and hormone production.
# The Zone in Italy
The introduction of the Zone in Italy began in 1997 by a physician, Aronne Romano M.D. who applied this nutritional style to patients and athletes. Since the 2nd edition of the book "Come Raggiungere la Zona" (The Zone), in 1999, the Chef Memo Romano and his brother Aronne modified the original recipes and menu to suit the local food and habits. The diffusion of the Zone continues with the efforts of many people including Paolo Perucci, Gigliola Braga, Simone Masci and Daniela Morandi.
# Famous obesity case
Possibly the most famous case of someone using the diet effectively has been Mexican Manuel Uribe. After weighing in at around 560 kg (1234 lbs or over 88 stone) but within a year had lost about 180 kg.[3].
# Criticism
The American Heart Association does not recommend the Zone Diet due to high-protein, lack of essential nutrients and little information on long-term effects.[4] It should be noted that AMA's characterization of the Zone diet as 'high-protein' is false, or at least a serious exaggeration, given that 70% of the calories in the Zone diet come from non-protein sources(i.e. carbohydrates, 40%, and fats 30%). The Zone does not emphasize an increase of protein intake in the standard American diet, but rather, a reduction in the intake of unhealthy carbohydrates (i.e. refined breads, starches, sugars, etc.) and an increase in healthy carbohydrates from high-fiber vegetables and fruits and healthy monounsaturated fats.
A vegetarian diet, according to Sears, is as far as you can get from The Zone. Individuals who promote a vegetarian diet are critical of Zone and similar diets.
# "Zone" books by Sears
(Partial list)
- Sears, Barry (1995). The Zone: A Dietary Road Map. HarperCollins Publishers. ISBN 0060987065..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} Sears's initial book on the Zone diet.
- Sears, Barry (1997). Mastering the Zone. HarperCollins Publishers. ISBN 006101124X. Sears urges substitution of raw vegetables for pastas, breads and refined sugars. More diagrams and flowcharts than in The Zone.
- Sears, Barry (1999). The Anti-Aging Zone. Regan Books. ISBN 0060392436. Information on meditation, relaxation and exercise in addition to diet.
- Sears, Barry (2000). A Week in the Zone: A Quick Course in the Healthiest Diet for You. Regan Books. ISBN 0060741902. Unknown parameter |coauthors= ignored (help)
- Sears, Barry (2000). The Soy Zone. Regan Books. ISBN 0060393106. Discusses Sears preference for soy protein as part of his balanced eating program. "The longest-living people in the world" living in Okinawa, Japan consume much greater amounts of soy protein and eat smaller meals than most other people.
- Sears, Barry (2002). The Omega Rx Zone: The Miracle of the New High-Dose Fish Oil. Regan Books. ISBN 0060393130. Discusses "high-dose fish oil;" a newly introduced invented pharmaceutical grade fish oil that Sears touts as a medical miracle that will put the eicasonids in balance and reduce inflammation. Extra virgin olive oil is also promoted for its phytochemicals.
- Sears, Barry (2005). The Anti-Inflammation Zone: Reversing the Silent Epidemic That's Destroying Our Health. Regan Books. ISBN 0060834145. | https://www.wikidoc.org/index.php/Zone_diet | |
d3865f4e48fef14cc4d37cc1a2b700b122226e1c | wikidoc | Zopiclone | Zopiclone
# Disclaimer
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# Overview
Zopiclone is a central nervous system agent , nonbarbiturate hypnotic that is FDA approved for the treatment of insomnia. Common adverse reactions include unpleasant taste, headache, somnolence, respiratory infection, dizziness, dry mouth, rash, anxiety, hallucinations, and viral infections..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zopiclone are indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, Zopiclone administered at bedtime decreased sleep latency and improved sleep maintenance.
- The clinical trialsperformed in support of efficacy were up to 6 months in duration. The final formal assessments of sleep latency and maintenance were performed at 4 weeks in the 6-week study (adults only), at the end of both 2-week studies (elderly only) and at the end of the 6-month study (adults only).
- Use the lowest effective dose for the patient.
- Dosage in Adults:
- The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated. In some patients, the higher morning blood levels of Zopiclone following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness. The total dose of Zopiclone should not exceed 3 mg, once daily immediately before bedtime.
- Geriatric or Debilitated Patients:
- The total dose of Zopiclone should not exceed 2 mg in elderly or debilitated patients.
- Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors
- In patients with severe hepatic impairment, or in patients co-administered Zopiclone with potent CYP3A4inhibitors, the total dose of Zopiclone should not exceed 2 mg.
- Use with CNS Depressants:
- Dosage adjustments may be necessary when Zopiclone is combined with other CNS Depressant drugs because of the potentially additive effects.
- Administration with Food:
- Taking Zopiclone with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of Zopiclone on ]
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zopiclone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zopiclone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Zopiclone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zopiclone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zopiclone in pediatric patients.
# Contraindications
- Zopiclone is contraindicated in patients with known hypersensitivity to Zopiclone. Hypersensitivity reactions include anaphylaxis and angioedema.
# Warnings
## CNS Depressant Effects and Next-Day Impairment==
- Zopiclone is a central nervous system depressant and can impair daytime function in some patients at the higher doses (2 mg or 3 mg), even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of symptoms (or even with subjective improvement), and impairment may not be reliably detected by ordinary clinical exam (i.e., less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Zopiclone may develop, patients using 3 mg Zopiclone should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.
- Additive effects occur with concomitant use of other CNS Depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Zopiclone and concomitant CNS Depressants should be considered.
- The use of Zopiclone with other sedative-hypnotics at bedtime or the middle of the night is not recommended.
- The risk of next-day psychomotor impairment is increased if Zopiclone is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co- administered with other CNS Depressants; or co-administered with other drugs that increase the blood levels of Zopiclone.
- Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric disorders or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including Zopiclone. Because some of the important adverse effects of Zopiclone appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly.
- Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including Zopiclone. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with Zopiclone should not be rechallenged with the drug.
- A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS Depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
- Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with Zopiclone alone at therapeutic doses, the use of alcohol and other CNS Depressants with Zopiclone appears to increase the risk of such behaviors, as does the use of Zopiclone at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zopiclone should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
- It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric disorders or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
- Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs.
- Zopiclone should be taken immediately before bedtime. Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.
- Use in Elderly and/or Debilitated Patients:
- Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients.
- Use in Patients with concomitant illness:
- Clinical experience with Zopiclone in patients with concomitant illness is limited. Zopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
- A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of Zopiclone. adverse effects is advised, however, if Zopiclone is prescribed to patients with compromised respiratory function.
- The dose of Zopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of Zopiclone is excreted unchanged in the urine.
- The dose of Zopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking Zopiclone. Downward dose adjustment is also recommended when Zopiclone is administered with agents having known CNS-depressant effects.
- Use in Patients with Depression:
- sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trialsare 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 trialsof another drug and may not reflect the rates observed in clinical practice
- The premarketing development program for Zopiclone included Zopiclone exposures in patients and/or normal subjects from two different groups of studies: approximately 400 normal subjects in clinical pharmacology/pharmacokinetic studies, and approximately 1550 patients in placebo-controlled clinical effectiveness studies, corresponding to approximately 263 patient-exposure years. The conditions and duration of treatment with Zopiclone varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, and short-term and longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while the patient was receiving therapy following baseline evaluation.
- Adverse Reactions Resulting in Discontinuation of Treatment:
- In placebo-controlled, parallel-group clinical trialsin the elderly, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who received 2 mg Zopiclone, and 1.4% of 72 patients who received 1 mg Zopiclone discontinued treatment due to an adverse reaction. In the 6‑week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse reaction. In the long-term 6-month study in adult insomnia patients, 7.2% of 195 patients who received placebo and 12.8% of 593 patients who received 3 mg Zopiclone discontinued due to an adverse reaction. No reaction that resulted in discontinuation occurred at a rate of greater than 2%.
- Adverse Reactions Observed at an Incidence of ≥2% in Controlled Trials:
- Table 1 shows the incidence of adverse reactions from a Phase 3 placebo-controlled study of Zopiclone at doses of 2 or 3 mg in non-elderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with Zopiclone 2 mg or 3 mg in which the incidence in patients treated with Zopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste.
- Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of Zopiclone at doses of 1 or 2 mg in elderly adults (ages 65 to 86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with Zopiclone 1 mg or 2 mg in which the incidence in patients treated with Zopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste.
- These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence rate in the population studied.
- Other Reactions Observed During the Premarketing Evaluation of Zopiclone
- Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1550 subjects treated with Zopiclone at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trialsthroughout the United States and Canada. All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug-related. Although the reactions reported occurred during treatment with Zopiclone, they were not necessarily caused by it.
- Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; rare adverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender.
- Frequent:
- Chest pain
- Infrequent:
- Allergic reaction, cellulitis, face edema, fever, halitosis, heat stroke, hernia, malaise, neck rigidity, photosensitivity.
- Frequent:
- Migraine
- Infrequent:
- Hypertension
- Rare:
- Thrombophlebitis
- Infrequent:
- Aorexia,cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis;
- Rare:
- Colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage.
- Infrequent:
- Anemia, lymphadenopathy.
- Frequent:
- Peripheral edema
- Infrequent:
- Hypercholesteremia, weight gain, weight loss;
- Rare:
- Dehydration, gout, hyperlipemia, hypokalemia.
- Infrequent:
- Arthritis, bursitis, joint disorder (mainly swelling, stiffness, and pain), leg cramps, myasthenia, twitching
- Rare:
- Arthrosis, myopathy, ptosis.
- Infrequent:
- Agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo
- Rare:
- Abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor.
- Infrequent:
- Asthma, bronchitis, dyspnea, epistaxis, hiccup, laryngitis
- Infrequent:
- Acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria
- Rare:
- Erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash
- Infrequent:
- Conjunctivitis, dry eyes, ear pain, otitis externa, otitis media, tinnitus, vestibular disorder
- Rare:
- Hyperacusis, iritis, mydriasis, photophobia.
- Infrequent:
- Amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis;
- Rare:
- Oliguria, pyelonephritis, urethritis.
## Postmarketing Experience
- In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during post-marketing surveillance with Zopiclone. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.
# Drug Interactions
- Ethanol:
- An additive effect on psychomotor performance was seen with coadministration of Zopiclone and ethanol.
- Olanzapine:
- Coadministration of Zopiclone and olanzapine produced a decrease in DSST scores. The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug.
- Drugs That Inhibit CYP3A4 (Ketoconazole):
- CYP3A4 is a major metabolic pathway for elimination of Zopiclone. The exposure of Zopiclone was increased by coadministration of ketoconazole, a potent inhibitor of CYP3A4. Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. Dose reduction of Zopiclone is needed for patient co-administered Zopiclone with potent CYP3A4 inhibitors.
- Drugs that Induce CYP3A4 (Rifampicin):
- Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4. A similar effect would be expected with Zopiclone. Combination use with CYP3A4 inducer may decrease exposure and effects of Zopiclone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pregnancy Category
- There are no adequate and well-controlled studies in pregnant women. Zopiclone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of Zopiclone to pregnant rats (62.5, 125, or 250 mg/kg/day) and rabbits (4, 8, or 16 mg/kg/day) throughout organogenesis showed no evidence of teratogenicity up to the highest doses tested. In rats, reduced fetal weight and increased incidences of skeletal variations and/or delayed ossification were observed at the mid and high doses. The no-observed-effect dose for adverse effects on embryofetal development is 200 times the maximum recommended human dose (MRHD) of 3 mg/day on a mg/m2 basis. No effects on embryofetal development were observed in rabbits; the highest dose tested is approximately 100 times the MRHD on a mg/m2 basis.
- Oral administration of Zopiclone (60, 120, or 180 mg/kg/day) to pregnant rats throughout the pregnancy and lactation resulted in increased post-implantation loss, decreased postnatal pup weights and survival, and increased pup startle response at all doses. The lowest dose tested is approximately 200 times the MRHD on a mg/m2 basis. Zopiclone had no effects on other developmental measures or reproductive function in the offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zopiclone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zopiclone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Zopiclone with respect to nursing mothers.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
- The labeling for Sunovion Pharmaceutical Inc.’s Zopiclone tablets includes additional information from a clinical study in which efficacy was not demonstrated in pediatric patients. However, due to Sunovion Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- In studies in which Zopiclone (2 to 300 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, neurobehavioral impairment (altered auditory startle response) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were observed at doses ≥ 5 mg/kg/day. Delayed sexual maturation was noted in males and females at ≥ 10 mg/kg/day. The no-effect dose (2 mg/kg) was associated with plasma exposures (AUC) for Zopiclone and metabolite (S)-desmethylzopiclone approximately 2 times plasma exposures in humans at the maximum recommended dose (MRHD) in adults (3 mg/day).
- When Zopiclone (doses from 1 to 50 mg/kg/day) was orally administered to young dogs from weaning through sexual maturity, neurotoxicity (convulsions) was observed at doses ≥ 5 mg/kg/day. Hepatotoxicity (elevated liver enzymes and hepatocellular vacuolation and degeneration) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were noted at dose ≥ 10 mg/kg/day. The no-effect dose (1 mg/kg) was associated with plasma exposures (AUC) to Zopiclone and (S)-DMZ approximately 3 and 2 times, respectively, plasma exposures in humans at the MRHD in adults.
### Geriatic Use
- A total of 287 subjects in double-blind, parallel-group, placebo-controlled clinical trialswho received Zopiclone were 65 to 86 years of age. The overall pattern of adverse events for elderly subjects (median age = 71 years) in 2-week studies with nighttime dosing of 2 mg Zopiclone was not different from that seen in younger adults. Zopiclone 2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance in the elderly population. Compared with non-elderly adults, subjects 65 years and older had longer elimination and higher total exposure to Zopiclone. Therefore, dose reduction is recommended in the elderly patients.
### Gender
There is no FDA guidance on the use of Zopiclone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zopiclone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zopiclone in patients with renal impairment.
### Hepatic Impairment
- No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Exposure was increased in severely impaired patients compared with the healthy volunteers. The dose of Zopiclone should not exceed 2 mg in patients with severe Hepatic Impairment. Zopiclone should be used with caution in patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zopiclone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zopiclone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Zopiclone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Zopiclone in the drug label.
# Overdosage
- In clinical trialswith Zopiclone, one case of overdose with up to 36 mg of Zopiclone was reported in which the subject fully recovered. Since commercial marketing began, spontaneous cases of Zopiclone overdoses up to 270 mg (90 times the maximum recommended dose of Zopiclone) have been reported, in which patients have recovered. Fatalities related to Zopiclone overdoses were reported only in combination with other CNS drugs or alcohol.
- Signs and symptoms of overdose effects of CNS Depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Impairment of consciousness ranging from somnolence to coma has been described. Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents.
- General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. The value of dialysis in the treatment of overdosage has not been determined.
- As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.
## Chronic Overdose
- There is limited information regarding Chronic Overdose of Zopiclonein the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism of action of Zopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Zopiclone is a nonbenzodiazepine hypnotic that is a pyrrolopyrazine derivative of the cyclopyrrolone class with a chemical structure unrelated to pyrazolopyrimidines, imidazopyridines, benzodiazepines, barbiturates, or other drugs with known hypnotic properties.
## Structure
- Zopiclone are a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of Zopiclone is (+)-(5S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo pyrazin-5-yl 4-methylpiperazine-1-carboxylate. Its molecular weight is 388.81, and its empirical formula is C17H17ClN6O3. Zopiclone has a single chiral center with an (S)-configuration. It has the following chemical structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Zopiclone in the drug label.
## Pharmacokinetics
- The pharmacokinetics of Zopiclone have been investigated in healthy subjects (adult and elderly) and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Zopiclone is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) of approximately 6 hours. In healthy adults, Zopiclone does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg.
- Zopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Zopiclone is weakly bound to plasma protein (52 to 59%). The large free fraction suggests that Zopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for Zopiclone is less than one, indicating no selective uptake by red blood cells.
- Following oral administration, Zopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than Zopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of Zopiclone. Zopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.
- After oral administration, Zopiclone is eliminated with a mean t1/2 of approximately 6 hours. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for Zopiclone, the S-isomer of racemic zopiclone. Less than 10% of the orally administered Zopiclone dose is excreted in the urine as parent drug.
- In healthy adults, administration of a 3 mg dose of Zopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour. The half-life remained unchanged, approximately 6 hours. The effects of Zopiclone on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.
- Age
- Compared with non-elderly adults, subjects 65 years and older had an increase of 41% in total exposure (AUC) and a slightly prolonged elimination of Zopiclone (t1/2 approximately 9 hours). Cmax was unchanged. Therefore, in elderly patients the dose should not exceed 2 mg.
- Gender
- The pharmacokinetics of Zopiclone in men and women are similar.
- Race
- In an analysis of data on all subjects participating in Phase 1 studies of Zopiclone, the pharmacokinetics for all races studied appeared similar.
- Hepatic Impairment
- Pharmacokinetics of a 2 mg Zopiclone dose were assessed in 16 healthy volunteers and in 8 subjects with mild, moderate, and severe liver disease. Exposure was increased 2-fold in severely impaired patients compared with the healthy volunteers. Cmax and tmax were unchanged. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Dose reduction is recommended for patients with severe hepatic impairment. Zopiclone should be used with caution in patients with hepatic impairment.
- Renal Impairment
- The pharmacokinetics of Zopiclone were studied in 24 patients with mild, moderate, or severe renal impairment. AUC and Cmax were similar in the patients compared with demographically matched healthy control subjects. No dose adjustment is necessary in patients with renal impairment, since less than 10% of the orally administered Zopiclone dose is excreted in the urine as parent drug.
- Zopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation. There were no pharmacokinetic or pharmacodynamic interactions between Zopiclone and paroxetine. When Zopiclone was coadministered with olanzapine, no pharmacokinetic interaction was detected in levels of Zopiclone or olanzapine, but a pharmacodynamic interaction was seen on a measure of psychomotor function. Zopiclone and lorazepam decreased each other’s Cmax by 22%. Coadministration of Zopiclone 3 mg to subjects receiving ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days, resulted in a 2.2-fold increase in exposure to Zopiclone. Cmax and t1/2 were increased 1.4-fold and 1.3-fold, respectively. Zopiclone would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes.
- Paroxetine
- Coadministration of single dose of Zopiclone and paroxetine produced no pharmacokinetic or pharmacodynamic interaction. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Lorazepam
- Coadministration of single doses of Zopiclone and lorazepam did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Drugs with a Narrow Therapeutic Index:
- Digoxin
A single dose of Zopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.
- A single dose of Zopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.
- Warfarin
Zopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of (R)- or (S)-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.
- Zopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of (R)- or (S)-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.
- Drugs Highly Bound to Plasma Protein:
- Zopiclone is not highly bound to plasma proteins (52 to 59% bound); therefore, the disposition of Zopiclone is not expected to be sensitive to alterations in protein binding. Administration of Zopiclone 3 mg to a patient taking another drug that is highly protein-bound would not be expected to cause an alteration in the free concentration of either drug.
## Nonclinical Toxicology
- Carcinogenesis:
- In a carcinogenicity study in rats, oral administration of Zopiclone for 97 (males) or 104 (females) weeks resulted in no increases in tumors; plasma levels (AUC) of Zopiclone at the highest dose tested (16 mg/kg/day) are approximately 80 (females) and 20 (males) times those in humans at the maximum recommended human dose (MRHD) of 3 mg/day. However, in a 2-year carcinogenicity study in rats, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) resulted in increases in mammary gland adenocarcinomas (females) and thyroid gland follicular cell adenomas and carcinomas (males) at the highest dose tested. Plasma levels of Zopiclone at this dose are approximately 150 (females) and 70 (males) times those in humans at the MRHD of Zopiclone. The mechanism for the increase in mammary adenocarcinomas is unknown. The increase in thyroid tumors is thought to be due to increased levels of TSH secondary to increased metabolism of circulating thyroid hormones, a mechanism not considered relevant to humans.
- In a 2-year carcinogenicity study in mice, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) produced increases in pulmonary carcinomas and carcinomas plus adenomas (females) and skin fibromas and sarcomas (males) at the highest dose tested. The skin tumors were due to skin lesions induced by aggressive behavior, a mechanism not relevant to humans. A carcinogenicity study of Zopiclone was conducted in mice at oral doses up to 100 mg/kg/day. Although this study did not reach a maximum tolerated dose, and was thus inadequate for overall assessment of carcinogenic potential, no increases in either pulmonary or skin tumors were seen at doses producing plasma levels of Zopiclone approximately 90 times those in humans at the MRHD of Zopiclone (and 12 times the exposure in the racemate study).
- Zopiclone did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.
- Mutagenesis:
- Zopiclone was clastogenic in in vitro (mouse lymphoma and chromosomal aberration) assays in mammalian cells. Zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo micronucleus assay.
- (S)-N-desmethyl zopiclone, a metabolite of Zopiclone, was positive in in vitro chromosomal aberration assays in mammalian cells. (S)-N-desmethyl zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo chromosomal aberration and micronucleus assay.
- Impairment of Fertility:
- Oral administration of Zopiclone to rats prior to and during mating, and continuing in females to day 7 of gestation (doses up to 45 mg/kg/day to males and females or up to 180 mg/kg/day to females only) resulted in decreased fertility, with no pregnancy at the highest dose tested when both males and females were treated. In females, there was an increase in abnormal estrus cycles at the highest dose tested. In males, decreases in sperm number and motility and increases in morphologically abnormal sperm were observed at the mid and high doses. The no-effect dose for adverse effects on fertility (5 mg/kg/day) is 16 times the MRHD on a mg/m2 basis.
# Clinical Studies
- The effect of Zopiclone on reducing sleep latency and improving sleep maintenance was established in studies with 2100 subjects (ages 18 to 86) with chronic and transient insomnia in six placebo-controlled trials of up to 6 months’ duration. Two of these trials were in elderly patients (n=523). Overall, at the recommended adult dose (2 to 3 mg) and elderly dose (1 to 2 mg), Zopiclone significantly decreased sleep latency and improved measures of sleep maintenance(objectively measured as wake time after sleep onset WASO and subjectively measured as total sleep time).
- Healthy adults were evaluated in a model of transient insomnia (n=436) in a sleep laboratory in a double-blind, parallel-group, single-night trial comparing two doses of Zopiclone and placebo. Zopiclone 3 mg was superior to placebo on measures of sleep latency and sleep maintenance, including polysomnographic (PSG) parameters of latency to persistent sleep (LPS) and WASO.
- The effectiveness of Zopiclone was established in five controlled studies in chronic insomnia. Three controlled studies were in adult subjects, and two controlled studies were in elderly subjects with chronic insomnia.
- Adults
- In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks’ duration comparing Zopiclone 2 mg and 3 mg with placebo. Objective endpoints were measured for 4 weeks. Both 2 mg and 3 mg were superior to placebo on LPS at 4 weeks. The 3 mg dose was superior to placebo on WASO.
- In the second study, adults with chronic insomnia (n=788) were evaluated using subjective measures in a double-blind, parallel-group trial comparing the safety and efficacy of Zopiclone 3 mg with placebo administered nightly for 6 months. Zopiclone was superior to placebo on subjective measures of sleep latency, total sleep time, and WASO.
- In addition, a 6-period cross-over PSG study evaluating Zopiclone doses of 1 to 3 mg, each given over a 2-day period, demonstrated effectiveness of all doses on LPS, and of 3 mg on WASO. In this trial, the response was dose-related.
- Elderly
- Elderly subjects (ages 65 to 86) with chronic insomnia were evaluated in two double-blind, parallel-group trials of 2 weeks duration. One study (n=231) compared the effects of Zopiclone with placebo on subjective outcome measures, and the other (n=292) on objective and subjective outcome measures. The first study compared 1 mg and 2 mg of Zopiclone with placebo, while the second study compared 2 mg of Zopiclone with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of Zopiclone was superior to placebo on measures of sleep maintenance.
- Next Day Residual Effects
- In a double-blind study of 91 healthy adults age 25- to 40 years, the effects of Zopiclone 3 mg on psychomotor function were assessed between 7.5 and 11.5 hours the morning after dosing. Measures included tests of psychomotor coordination that are correlated with ability to maintain a motor vehicle in the driving lane, tests of working memory, and subjective perception of sedation and coordination. Compared with placebo, Zopiclone 3 mg was associated with next- morning psychomotor and memory impairment that was most severe at 7.5 hours, but still present and potentially clinically meaningful at 11.5 hours. Subjective perception of sedation and coordination from Zopiclone 3 mg was not consistently different from placebo, even though subjects were objectively impaired.
- In a 6-month double-blind, placebo-controlled trial of nightly administered Zopiclone 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with Zopiclone 3 mg compared to 0% (0/195) of subjects treated with placebo. In a 6-week adult study of nightly administered Zopiclone confusion was reported by 3% of patients treated with Zopiclone 3 mg, compared to 0% of subjects treated with placebo. In the same study, memory impairment was reported by 1% of patents treated with either 2 mg or 3 mg Zopiclone, compared to 0% treated with placebo.
- In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with Zopiclone 2 mg reported memory impairment compared to 0% treated with placebo. In another 2-week study of 231 elderly insomniacs, 2.5% of patients treated with Zopiclone 2 mg reported confusion compared to 0% treated with placebo.
- A study of normal subjects exposed to single fixed doses of Zopiclone from 1 to 7.5 mg using the DSST to assess sedation and psychomotor function at fixed times after dosing (hourly up to 16 hours) found the expected sedation and reduction in psychomotor function. This was maximal at 1 hour and present up to 4 hours, but was no longer present by 5 hours.
- In another study, patients with insomnia were given 2 or 3 mg doses of Zopiclone nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and Zopiclone 3 mg groups showed an improvement in DSST scores relative to baseline the following morning (presumably due to a learning effect), the improvement in the placebo group was greater and reached statistical significance on night 1, although not on nights 15 and 29. For the Zopiclone 2 mg group, DSST change scores were not significantly different from placebo at any time point.
- Withdrawal-Emergent Anxiety and insomnia
- During nightly use for an extended period, pharmacodynamic tolerance or adaptation has been observed with other hypnotics. If a drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.
- In a 6-month double-blind, placebo-controlled study of nightly administration of Zopiclone 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the Zopiclone arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1% of the placebo, 2 mg, and 3 mg treatment arms, respectively. In this study, single-blind placebo was administered on nights 45 and 46, the first and second days of withdrawal from study drug. New adverse events were recorded during the withdrawal period, beginning with day 45, up to 14 days after discontinuation. During this withdrawal period, 105 subjects previously taking nightly Zopiclone 3 mg for 44 nights spontaneously reported anxiety (1%), abnormal dreams (1.9%), hyperesthesia (1%), and neurosis (1%), while none of 99 subjects previously taking placebo reported any of these adverse events during the withdrawal period.
- Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of Zopiclone relative to placebo and baseline was examined objectively in a 6-week adult study on the first 2 nights of discontinuation (nights 45 and 46) following 44 nights of active treatment with 2 mg or 3 mg. In the Zopiclone 2 mg group, compared with baseline, there was a significant increase in WASO and a decrease in sleep efficiency, both occurring only on the first night after discontinuation of treatment. No changes from baseline were noted in the Zopiclone 3 mg group on the first night after discontinuation, and there was a significant improvement in LPS and sleep efficiency compared with baseline following the second night of discontinuation. Comparisons of changes from baseline between Zopiclone and placebo were also performed. On the first night after discontinuation of Zopiclone 2 mg, LPS and WASO were significantly increased and sleep efficiency was reduced; there were no significant differences on the second night. On the first night following discontinuation of Zopiclone 3 mg, sleep efficiency was significantly reduced. No other differences from placebo were noted in any other sleep parameter on either the first or second night following discontinuation. For both doses, the discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after Zopiclone discontinuation.
# How Supplied
- Zopiclone tablets are round, white, film-coated tablets and are supplied as follows:
- The 1 mg tablets are debossed with product identification “54 746” on one side and plain on the other side.
- NDC 0054-0290-13 1 mg, bottle of 30
- NDC 0054-0290-25 1 mg, bottle of 100
- The 2 mg tablets are debossed with product identification “54 029” on one side and plain on the other side.
- NDC 0054-0291-25 2 mg, bottle of 100
- The 3 mg tablets are debossed with product identification “54 396” on one side and plain on the other side.
- NDC 0054-0292-25 3 mg, bottle of 100
## Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients and their families about the benefits and risks of treatment with Zopiclone. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Zopiclone and with each prescription refill. Review the Zopiclone Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that Zopiclone should be taken only as prescribed.
- CNS depressant effects and next-day impairment: Tell patients that Zopiclone can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed. Caution patients taking the 3 mg dose against driving and other activities requiring complete mental alertness the day after use. Inform patients that impairment can be present despite feeling fully awake.
- Severe anaphylactic and anaphylactoid reactions: Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with Zopiclone. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.
- “sleep-Driving” and other complex behaviors: Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including "sleep driving" and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.
- Suicide: Tell patients to immediately report any suicidal thoughts.
- Alcohol and Other Drugs: Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use Zopiclone if they drank alcohol that evening or before bed.
- Tolerance, Abuse, and Dependence: Tell patients not to increase the dose of Zopiclone on their own, and to inform you if they believe the drug "does not work".
- Administration Instructions: Patients should be counseled to take Zopiclone right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again. Zopiclone tablets should not be taken with or immediately after a meal. Advise patients NOT to take Zopiclone if they drank alcohol that evening.
- Roxane Laboratories, Inc.
- Columbus, Ohio 43216
- 10005923/02 Revised May 2014
- ©RLI, 2014
# Precautions with Alcohol
- Additive effects occur with concomitant use of other CNS Depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Zopiclone and concomitant CNS Depressants should be considered
- Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use Zopiclone if they drank alcohol that evening or before bed.
- A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS Depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
- Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with Zopiclone alone at therapeutic doses, the use of alcohol and other CNS Depressants with Zopiclone appears to increase the risk of such behaviors, as does the use of Zopiclone at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zopiclone should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
- It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
- The clinical trial experience with Zopiclone revealed no evidence of a serious withdrawal syndrome. Nevertheless, the following adverse events included in DSM-IV criteria for uncomplicated sedative/hypnotic withdrawal were reported during clinical trialsfollowing placebo substitution occurring within 48 hours following the last Zopiclone treatment: anxiety, abnormal dreams, nausea, and upset stomach. These reported adverse events occurred at an incidence of 2% or less. Use of benzodiazepines and similar agents may lead to physical and psychological dependence. The risk of abuse and dependence increases with the dose and duration of treatment and concomitant use of other psychoactive drugs. The risk is also greater for patients who have a history of alcohol or drug abuse or history of psychiatric disorders. These patients should be under careful surveillance when receiving Zopiclone or any other hypnotic.
- In clinical trialswith Zopiclone, one case of overdose with up to 36 mg of Zopiclone was reported in which the subject fully recovered. Since commercial marketing began, spontaneous cases of Zopiclone overdoses up to 270 mg (90 times the maximum recommended dose of Zopiclone) have been reported, in which patients have recovered. Fatalities related to Zopiclone overdoses were reported only in combination with other CNS drugs or alcohol.
# Brand Names
There is limited information regarding Zopiclone Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Zopiclone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Zopiclone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
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# Overview
Zopiclone is a central nervous system agent , nonbarbiturate hypnotic that is FDA approved for the treatment of insomnia. Common adverse reactions include unpleasant taste, headache, somnolence, respiratory infection, dizziness, dry mouth, rash, anxiety, hallucinations, and viral infections..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zopiclone are indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, Zopiclone administered at bedtime decreased sleep latency and improved sleep maintenance.
- The clinical trialsperformed in support of efficacy were up to 6 months in duration. The final formal assessments of sleep latency and maintenance were performed at 4 weeks in the 6-week study (adults only), at the end of both 2-week studies (elderly only) and at the end of the 6-month study (adults only).
- Use the lowest effective dose for the patient.
- Dosage in Adults:
- The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated. In some patients, the higher morning blood levels of Zopiclone following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness. The total dose of Zopiclone should not exceed 3 mg, once daily immediately before bedtime.
- Geriatric or Debilitated Patients:
- The total dose of Zopiclone should not exceed 2 mg in elderly or debilitated patients.
- Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors
- In patients with severe hepatic impairment, or in patients co-administered Zopiclone with potent CYP3A4inhibitors, the total dose of Zopiclone should not exceed 2 mg.
- Use with CNS Depressants:
- Dosage adjustments may be necessary when Zopiclone is combined with other CNS Depressant drugs because of the potentially additive effects.
- Administration with Food:
- Taking Zopiclone with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of Zopiclone on [[sleep latency]]
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zopiclone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zopiclone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Zopiclone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zopiclone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zopiclone in pediatric patients.
# Contraindications
- Zopiclone is contraindicated in patients with known hypersensitivity to Zopiclone. Hypersensitivity reactions include anaphylaxis and angioedema.
# Warnings
## CNS Depressant Effects and Next-Day Impairment==
- Zopiclone is a central nervous system depressant and can impair daytime function in some patients at the higher doses (2 mg or 3 mg), even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of symptoms (or even with subjective improvement), and impairment may not be reliably detected by ordinary clinical exam (i.e., less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Zopiclone may develop, patients using 3 mg Zopiclone should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.
- Additive effects occur with concomitant use of other CNS Depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Zopiclone and concomitant CNS Depressants should be considered.
- The use of Zopiclone with other sedative-hypnotics at bedtime or the middle of the night is not recommended.
- The risk of next-day psychomotor impairment is increased if Zopiclone is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co- administered with other CNS Depressants; or co-administered with other drugs that increase the blood levels of Zopiclone.
- Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric disorders or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including Zopiclone. Because some of the important adverse effects of Zopiclone appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly.
- Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including Zopiclone. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with Zopiclone should not be rechallenged with the drug.
- A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS Depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
- Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with Zopiclone alone at therapeutic doses, the use of alcohol and other CNS Depressants with Zopiclone appears to increase the risk of such behaviors, as does the use of Zopiclone at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zopiclone should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
- It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric disorders or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
- Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs.
- Zopiclone should be taken immediately before bedtime. Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.
- Use in Elderly and/or Debilitated Patients:
- Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients.
- Use in Patients with concomitant illness:
- Clinical experience with Zopiclone in patients with concomitant illness is limited. Zopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
- A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of Zopiclone. adverse effects is advised, however, if Zopiclone is prescribed to patients with compromised respiratory function.
- The dose of Zopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of Zopiclone is excreted unchanged in the urine.
- The dose of Zopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking Zopiclone. Downward dose adjustment is also recommended when Zopiclone is administered with agents having known CNS-depressant effects.
- Use in Patients with Depression:
- sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trialsare 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 trialsof another drug and may not reflect the rates observed in clinical practice
- The premarketing development program for Zopiclone included Zopiclone exposures in patients and/or normal subjects from two different groups of studies: approximately 400 normal subjects in clinical pharmacology/pharmacokinetic studies, and approximately 1550 patients in placebo-controlled clinical effectiveness studies, corresponding to approximately 263 patient-exposure years. The conditions and duration of treatment with Zopiclone varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, and short-term and longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while the patient was receiving therapy following baseline evaluation.
- Adverse Reactions Resulting in Discontinuation of Treatment:
- In placebo-controlled, parallel-group clinical trialsin the elderly, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who received 2 mg Zopiclone, and 1.4% of 72 patients who received 1 mg Zopiclone discontinued treatment due to an adverse reaction. In the 6‑week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse reaction. In the long-term 6-month study in adult insomnia patients, 7.2% of 195 patients who received placebo and 12.8% of 593 patients who received 3 mg Zopiclone discontinued due to an adverse reaction. No reaction that resulted in discontinuation occurred at a rate of greater than 2%.
- Adverse Reactions Observed at an Incidence of ≥2% in Controlled Trials:
- Table 1 shows the incidence of adverse reactions from a Phase 3 placebo-controlled study of Zopiclone at doses of 2 or 3 mg in non-elderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with Zopiclone 2 mg or 3 mg in which the incidence in patients treated with Zopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste.
- Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of Zopiclone at doses of 1 or 2 mg in elderly adults (ages 65 to 86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with Zopiclone 1 mg or 2 mg in which the incidence in patients treated with Zopiclone was greater than the incidence in placebo-treated patients.
- Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste.
- These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence rate in the population studied.
- Other Reactions Observed During the Premarketing Evaluation of Zopiclone
- Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1550 subjects treated with Zopiclone at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trialsthroughout the United States and Canada. All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug-related. Although the reactions reported occurred during treatment with Zopiclone, they were not necessarily caused by it.
- Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; rare adverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender.
- Frequent:
- Chest pain
- Infrequent:
- Allergic reaction, cellulitis, face edema, fever, halitosis, heat stroke, hernia, malaise, neck rigidity, photosensitivity.
- Frequent:
- Migraine
- Infrequent:
- Hypertension
- Rare:
- Thrombophlebitis
- Infrequent:
- Aorexia,cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis;
- Rare:
- Colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage.
- Infrequent:
- Anemia, lymphadenopathy.
- Frequent:
- Peripheral edema
- Infrequent:
- Hypercholesteremia, weight gain, weight loss;
- Rare:
- Dehydration, gout, hyperlipemia, hypokalemia.
- Infrequent:
- Arthritis, bursitis, joint disorder (mainly swelling, stiffness, and pain), leg cramps, myasthenia, twitching
- Rare:
- Arthrosis, myopathy, ptosis.
- Infrequent:
- Agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo
- Rare:
- Abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor.
- Infrequent:
- Asthma, bronchitis, dyspnea, epistaxis, hiccup, laryngitis
- Infrequent:
- Acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria
- Rare:
- Erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash
- Infrequent:
- Conjunctivitis, dry eyes, ear pain, otitis externa, otitis media, tinnitus, vestibular disorder
- Rare:
- Hyperacusis, iritis, mydriasis, photophobia.
- Infrequent:
- Amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis;
- Rare:
- Oliguria, pyelonephritis, urethritis.
## Postmarketing Experience
- In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during post-marketing surveillance with Zopiclone. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.
# Drug Interactions
- Ethanol:
- An additive effect on psychomotor performance was seen with coadministration of Zopiclone and ethanol.
- Olanzapine:
- Coadministration of Zopiclone and olanzapine produced a decrease in DSST scores. The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug.
- Drugs That Inhibit CYP3A4 (Ketoconazole):
- CYP3A4 is a major metabolic pathway for elimination of Zopiclone. The exposure of Zopiclone was increased by coadministration of ketoconazole, a potent inhibitor of CYP3A4. Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. Dose reduction of Zopiclone is needed for patient co-administered Zopiclone with potent CYP3A4 inhibitors.
- Drugs that Induce CYP3A4 (Rifampicin):
- Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4. A similar effect would be expected with Zopiclone. Combination use with CYP3A4 inducer may decrease exposure and effects of Zopiclone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pregnancy Category
- There are no adequate and well-controlled studies in pregnant women. Zopiclone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of Zopiclone to pregnant rats (62.5, 125, or 250 mg/kg/day) and rabbits (4, 8, or 16 mg/kg/day) throughout organogenesis showed no evidence of teratogenicity up to the highest doses tested. In rats, reduced fetal weight and increased incidences of skeletal variations and/or delayed ossification were observed at the mid and high doses. The no-observed-effect dose for adverse effects on embryofetal development is 200 times the maximum recommended human dose (MRHD) of 3 mg/day on a mg/m2 basis. No effects on embryofetal development were observed in rabbits; the highest dose tested is approximately 100 times the MRHD on a mg/m2 basis.
- Oral administration of Zopiclone (60, 120, or 180 mg/kg/day) to pregnant rats throughout the pregnancy and lactation resulted in increased post-implantation loss, decreased postnatal pup weights and survival, and increased pup startle response at all doses. The lowest dose tested is approximately 200 times the MRHD on a mg/m2 basis. Zopiclone had no effects on other developmental measures or reproductive function in the offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zopiclone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zopiclone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Zopiclone with respect to nursing mothers.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
- The labeling for Sunovion Pharmaceutical Inc.’s Zopiclone tablets includes additional information from a clinical study in which efficacy was not demonstrated in pediatric patients. However, due to Sunovion Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- In studies in which Zopiclone (2 to 300 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, neurobehavioral impairment (altered auditory startle response) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were observed at doses ≥ 5 mg/kg/day. Delayed sexual maturation was noted in males and females at ≥ 10 mg/kg/day. The no-effect dose (2 mg/kg) was associated with plasma exposures (AUC) for Zopiclone and metabolite (S)-desmethylzopiclone [(S)-DMZ] approximately 2 times plasma exposures in humans at the maximum recommended dose (MRHD) in adults (3 mg/day).
- When Zopiclone (doses from 1 to 50 mg/kg/day) was orally administered to young dogs from weaning through sexual maturity, neurotoxicity (convulsions) was observed at doses ≥ 5 mg/kg/day. Hepatotoxicity (elevated liver enzymes and hepatocellular vacuolation and degeneration) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were noted at dose ≥ 10 mg/kg/day. The no-effect dose (1 mg/kg) was associated with plasma exposures (AUC) to Zopiclone and (S)-DMZ approximately 3 and 2 times, respectively, plasma exposures in humans at the MRHD in adults.
### Geriatic Use
- A total of 287 subjects in double-blind, parallel-group, placebo-controlled clinical trialswho received Zopiclone were 65 to 86 years of age. The overall pattern of adverse events for elderly subjects (median age = 71 years) in 2-week studies with nighttime dosing of 2 mg Zopiclone was not different from that seen in younger adults. Zopiclone 2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance in the elderly population. Compared with non-elderly adults, subjects 65 years and older had longer elimination and higher total exposure to Zopiclone. Therefore, dose reduction is recommended in the elderly patients.
### Gender
There is no FDA guidance on the use of Zopiclone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zopiclone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zopiclone in patients with renal impairment.
### Hepatic Impairment
- No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Exposure was increased in severely impaired patients compared with the healthy volunteers. The dose of Zopiclone should not exceed 2 mg in patients with severe Hepatic Impairment. Zopiclone should be used with caution in patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zopiclone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zopiclone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Zopiclone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Zopiclone in the drug label.
# Overdosage
- In clinical trialswith Zopiclone, one case of overdose with up to 36 mg of Zopiclone was reported in which the subject fully recovered. Since commercial marketing began, spontaneous cases of Zopiclone overdoses up to 270 mg (90 times the maximum recommended dose of Zopiclone) have been reported, in which patients have recovered. Fatalities related to Zopiclone overdoses were reported only in combination with other CNS drugs or alcohol.
- Signs and symptoms of overdose effects of CNS Depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Impairment of consciousness ranging from somnolence to coma has been described. Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents.
- General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. The value of dialysis in the treatment of overdosage has not been determined.
- As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.
## Chronic Overdose
- There is limited information regarding Chronic Overdose of Zopiclonein the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism of action of Zopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Zopiclone is a nonbenzodiazepine hypnotic that is a pyrrolopyrazine derivative of the cyclopyrrolone class with a chemical structure unrelated to pyrazolopyrimidines, imidazopyridines, benzodiazepines, barbiturates, or other drugs with known hypnotic properties.
## Structure
- Zopiclone are a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of Zopiclone is (+)-(5S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methylpiperazine-1-carboxylate. Its molecular weight is 388.81, and its empirical formula is C17H17ClN6O3. Zopiclone has a single chiral center with an (S)-configuration. It has the following chemical structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Zopiclone in the drug label.
## Pharmacokinetics
- The pharmacokinetics of Zopiclone have been investigated in healthy subjects (adult and elderly) and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Zopiclone is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) of approximately 6 hours. In healthy adults, Zopiclone does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg.
- Zopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Zopiclone is weakly bound to plasma protein (52 to 59%). The large free fraction suggests that Zopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for Zopiclone is less than one, indicating no selective uptake by red blood cells.
- Following oral administration, Zopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than Zopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of Zopiclone. Zopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.
- After oral administration, Zopiclone is eliminated with a mean t1/2 of approximately 6 hours. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for Zopiclone, the S-isomer of racemic zopiclone. Less than 10% of the orally administered Zopiclone dose is excreted in the urine as parent drug.
- In healthy adults, administration of a 3 mg dose of Zopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour. The half-life remained unchanged, approximately 6 hours. The effects of Zopiclone on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.
- Age
- Compared with non-elderly adults, subjects 65 years and older had an increase of 41% in total exposure (AUC) and a slightly prolonged elimination of Zopiclone (t1/2 approximately 9 hours). Cmax was unchanged. Therefore, in elderly patients the dose should not exceed 2 mg.
- Gender
- The pharmacokinetics of Zopiclone in men and women are similar.
- Race
- In an analysis of data on all subjects participating in Phase 1 studies of Zopiclone, the pharmacokinetics for all races studied appeared similar.
- Hepatic Impairment
- Pharmacokinetics of a 2 mg Zopiclone dose were assessed in 16 healthy volunteers and in 8 subjects with mild, moderate, and severe liver disease. Exposure was increased 2-fold in severely impaired patients compared with the healthy volunteers. Cmax and tmax were unchanged. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Dose reduction is recommended for patients with severe hepatic impairment. Zopiclone should be used with caution in patients with hepatic impairment.
- Renal Impairment
- The pharmacokinetics of Zopiclone were studied in 24 patients with mild, moderate, or severe renal impairment. AUC and Cmax were similar in the patients compared with demographically matched healthy control subjects. No dose adjustment is necessary in patients with renal impairment, since less than 10% of the orally administered Zopiclone dose is excreted in the urine as parent drug.
- Zopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation. There were no pharmacokinetic or pharmacodynamic interactions between Zopiclone and paroxetine. When Zopiclone was coadministered with olanzapine, no pharmacokinetic interaction was detected in levels of Zopiclone or olanzapine, but a pharmacodynamic interaction was seen on a measure of psychomotor function. Zopiclone and lorazepam decreased each other’s Cmax by 22%. Coadministration of Zopiclone 3 mg to subjects receiving ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days, resulted in a 2.2-fold increase in exposure to Zopiclone. Cmax and t1/2 were increased 1.4-fold and 1.3-fold, respectively. Zopiclone would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes.
- Paroxetine
- Coadministration of single dose of Zopiclone and paroxetine produced no pharmacokinetic or pharmacodynamic interaction. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Lorazepam
- Coadministration of single doses of Zopiclone and lorazepam did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.
- Drugs with a Narrow Therapeutic Index:
- Digoxin
A single dose of Zopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.
- A single dose of Zopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.
- Warfarin
Zopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of (R)- or (S)-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.
- Zopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of (R)- or (S)-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.
- Drugs Highly Bound to Plasma Protein:
- Zopiclone is not highly bound to plasma proteins (52 to 59% bound); therefore, the disposition of Zopiclone is not expected to be sensitive to alterations in protein binding. Administration of Zopiclone 3 mg to a patient taking another drug that is highly protein-bound would not be expected to cause an alteration in the free concentration of either drug.
## Nonclinical Toxicology
- Carcinogenesis:
- In a carcinogenicity study in rats, oral administration of Zopiclone for 97 (males) or 104 (females) weeks resulted in no increases in tumors; plasma levels (AUC) of Zopiclone at the highest dose tested (16 mg/kg/day) are approximately 80 (females) and 20 (males) times those in humans at the maximum recommended human dose (MRHD) of 3 mg/day. However, in a 2-year carcinogenicity study in rats, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) resulted in increases in mammary gland adenocarcinomas (females) and thyroid gland follicular cell adenomas and carcinomas (males) at the highest dose tested. Plasma levels of Zopiclone at this dose are approximately 150 (females) and 70 (males) times those in humans at the MRHD of Zopiclone. The mechanism for the increase in mammary adenocarcinomas is unknown. The increase in thyroid tumors is thought to be due to increased levels of TSH secondary to increased metabolism of circulating thyroid hormones, a mechanism not considered relevant to humans.
- In a 2-year carcinogenicity study in mice, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) produced increases in pulmonary carcinomas and carcinomas plus adenomas (females) and skin fibromas and sarcomas (males) at the highest dose tested. The skin tumors were due to skin lesions induced by aggressive behavior, a mechanism not relevant to humans. A carcinogenicity study of Zopiclone was conducted in mice at oral doses up to 100 mg/kg/day. Although this study did not reach a maximum tolerated dose, and was thus inadequate for overall assessment of carcinogenic potential, no increases in either pulmonary or skin tumors were seen at doses producing plasma levels of Zopiclone approximately 90 times those in humans at the MRHD of Zopiclone (and 12 times the exposure in the racemate study).
- Zopiclone did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.
- Mutagenesis:
- Zopiclone was clastogenic in in vitro (mouse lymphoma and chromosomal aberration) assays in mammalian cells. Zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo micronucleus assay.
- (S)-N-desmethyl zopiclone, a metabolite of Zopiclone, was positive in in vitro chromosomal aberration assays in mammalian cells. (S)-N-desmethyl zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo chromosomal aberration and micronucleus assay.
- Impairment of Fertility:
- Oral administration of Zopiclone to rats prior to and during mating, and continuing in females to day 7 of gestation (doses up to 45 mg/kg/day to males and females or up to 180 mg/kg/day to females only) resulted in decreased fertility, with no pregnancy at the highest dose tested when both males and females were treated. In females, there was an increase in abnormal estrus cycles at the highest dose tested. In males, decreases in sperm number and motility and increases in morphologically abnormal sperm were observed at the mid and high doses. The no-effect dose for adverse effects on fertility (5 mg/kg/day) is 16 times the MRHD on a mg/m2 basis.
# Clinical Studies
- The effect of Zopiclone on reducing sleep latency and improving sleep maintenance was established in studies with 2100 subjects (ages 18 to 86) with chronic and transient insomnia in six placebo-controlled trials of up to 6 months’ duration. Two of these trials were in elderly patients (n=523). Overall, at the recommended adult dose (2 to 3 mg) and elderly dose (1 to 2 mg), Zopiclone significantly decreased sleep latency and improved measures of sleep maintenance(objectively measured as wake time after sleep onset WASO and subjectively measured as total sleep time).
- Healthy adults were evaluated in a model of transient insomnia (n=436) in a sleep laboratory in a double-blind, parallel-group, single-night trial comparing two doses of Zopiclone and placebo. Zopiclone 3 mg was superior to placebo on measures of sleep latency and sleep maintenance, including polysomnographic (PSG) parameters of latency to persistent sleep (LPS) and WASO.
- The effectiveness of Zopiclone was established in five controlled studies in chronic insomnia. Three controlled studies were in adult subjects, and two controlled studies were in elderly subjects with chronic insomnia.
- Adults
- In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks’ duration comparing Zopiclone 2 mg and 3 mg with placebo. Objective endpoints were measured for 4 weeks. Both 2 mg and 3 mg were superior to placebo on LPS at 4 weeks. The 3 mg dose was superior to placebo on WASO.
- In the second study, adults with chronic insomnia (n=788) were evaluated using subjective measures in a double-blind, parallel-group trial comparing the safety and efficacy of Zopiclone 3 mg with placebo administered nightly for 6 months. Zopiclone was superior to placebo on subjective measures of sleep latency, total sleep time, and WASO.
- In addition, a 6-period cross-over PSG study evaluating Zopiclone doses of 1 to 3 mg, each given over a 2-day period, demonstrated effectiveness of all doses on LPS, and of 3 mg on WASO. In this trial, the response was dose-related.
- Elderly
- Elderly subjects (ages 65 to 86) with chronic insomnia were evaluated in two double-blind, parallel-group trials of 2 weeks duration. One study (n=231) compared the effects of Zopiclone with placebo on subjective outcome measures, and the other (n=292) on objective and subjective outcome measures. The first study compared 1 mg and 2 mg of Zopiclone with placebo, while the second study compared 2 mg of Zopiclone with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of Zopiclone was superior to placebo on measures of sleep maintenance.
- Next Day Residual Effects
- In a double-blind study of 91 healthy adults age 25- to 40 years, the effects of Zopiclone 3 mg on psychomotor function were assessed between 7.5 and 11.5 hours the morning after dosing. Measures included tests of psychomotor coordination that are correlated with ability to maintain a motor vehicle in the driving lane, tests of working memory, and subjective perception of sedation and coordination. Compared with placebo, Zopiclone 3 mg was associated with next- morning psychomotor and memory impairment that was most severe at 7.5 hours, but still present and potentially clinically meaningful at 11.5 hours. Subjective perception of sedation and coordination from Zopiclone 3 mg was not consistently different from placebo, even though subjects were objectively impaired.
- In a 6-month double-blind, placebo-controlled trial of nightly administered Zopiclone 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with Zopiclone 3 mg compared to 0% (0/195) of subjects treated with placebo. In a 6-week adult study of nightly administered Zopiclone confusion was reported by 3% of patients treated with Zopiclone 3 mg, compared to 0% of subjects treated with placebo. In the same study, memory impairment was reported by 1% of patents treated with either 2 mg or 3 mg Zopiclone, compared to 0% treated with placebo.
- In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with Zopiclone 2 mg reported memory impairment compared to 0% treated with placebo. In another 2-week study of 231 elderly insomniacs, 2.5% of patients treated with Zopiclone 2 mg reported confusion compared to 0% treated with placebo.
- A study of normal subjects exposed to single fixed doses of Zopiclone from 1 to 7.5 mg using the DSST to assess sedation and psychomotor function at fixed times after dosing (hourly up to 16 hours) found the expected sedation and reduction in psychomotor function. This was maximal at 1 hour and present up to 4 hours, but was no longer present by 5 hours.
- In another study, patients with insomnia were given 2 or 3 mg doses of Zopiclone nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and Zopiclone 3 mg groups showed an improvement in DSST scores relative to baseline the following morning (presumably due to a learning effect), the improvement in the placebo group was greater and reached statistical significance on night 1, although not on nights 15 and 29. For the Zopiclone 2 mg group, DSST change scores were not significantly different from placebo at any time point.
- Withdrawal-Emergent Anxiety and insomnia
- During nightly use for an extended period, pharmacodynamic tolerance or adaptation has been observed with other hypnotics. If a drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night’s use. This is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.
- In a 6-month double-blind, placebo-controlled study of nightly administration of Zopiclone 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the Zopiclone arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1% of the placebo, 2 mg, and 3 mg treatment arms, respectively. In this study, single-blind placebo was administered on nights 45 and 46, the first and second days of withdrawal from study drug. New adverse events were recorded during the withdrawal period, beginning with day 45, up to 14 days after discontinuation. During this withdrawal period, 105 subjects previously taking nightly Zopiclone 3 mg for 44 nights spontaneously reported anxiety (1%), abnormal dreams (1.9%), hyperesthesia (1%), and neurosis (1%), while none of 99 subjects previously taking placebo reported any of these adverse events during the withdrawal period.
- Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of Zopiclone relative to placebo and baseline was examined objectively in a 6-week adult study on the first 2 nights of discontinuation (nights 45 and 46) following 44 nights of active treatment with 2 mg or 3 mg. In the Zopiclone 2 mg group, compared with baseline, there was a significant increase in WASO and a decrease in sleep efficiency, both occurring only on the first night after discontinuation of treatment. No changes from baseline were noted in the Zopiclone 3 mg group on the first night after discontinuation, and there was a significant improvement in LPS and sleep efficiency compared with baseline following the second night of discontinuation. Comparisons of changes from baseline between Zopiclone and placebo were also performed. On the first night after discontinuation of Zopiclone 2 mg, LPS and WASO were significantly increased and sleep efficiency was reduced; there were no significant differences on the second night. On the first night following discontinuation of Zopiclone 3 mg, sleep efficiency was significantly reduced. No other differences from placebo were noted in any other sleep parameter on either the first or second night following discontinuation. For both doses, the discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after Zopiclone discontinuation.
# How Supplied
- Zopiclone tablets are round, white, film-coated tablets and are supplied as follows:
- The 1 mg tablets are debossed with product identification “54 746” on one side and plain on the other side.
- NDC 0054-0290-13 1 mg, bottle of 30
- NDC 0054-0290-25 1 mg, bottle of 100
- The 2 mg tablets are debossed with product identification “54 029” on one side and plain on the other side.
- NDC 0054-0291-25 2 mg, bottle of 100
- The 3 mg tablets are debossed with product identification “54 396” on one side and plain on the other side.
- NDC 0054-0292-25 3 mg, bottle of 100
## Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients and their families about the benefits and risks of treatment with Zopiclone. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Zopiclone and with each prescription refill. Review the Zopiclone Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that Zopiclone should be taken only as prescribed.
- CNS depressant effects and next-day impairment: Tell patients that Zopiclone can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed. Caution patients taking the 3 mg dose against driving and other activities requiring complete mental alertness the day after use. Inform patients that impairment can be present despite feeling fully awake.
- Severe anaphylactic and anaphylactoid reactions: Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with Zopiclone. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.
- “sleep-Driving” and other complex behaviors: Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including "sleep driving" and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.
- Suicide: Tell patients to immediately report any suicidal thoughts.
- Alcohol and Other Drugs: Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use Zopiclone if they drank alcohol that evening or before bed.
- Tolerance, Abuse, and Dependence: Tell patients not to increase the dose of Zopiclone on their own, and to inform you if they believe the drug "does not work".
- Administration Instructions: Patients should be counseled to take Zopiclone right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again. Zopiclone tablets should not be taken with or immediately after a meal. Advise patients NOT to take Zopiclone if they drank alcohol that evening.
- Roxane Laboratories, Inc.
- Columbus, Ohio 43216
- 10005923/02 Revised May 2014
- ©RLI, 2014
# Precautions with Alcohol
- Additive effects occur with concomitant use of other CNS Depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of Zopiclone and concomitant CNS Depressants should be considered
- Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use Zopiclone if they drank alcohol that evening or before bed.
- A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS Depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.
- Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with Zopiclone alone at therapeutic doses, the use of alcohol and other CNS Depressants with Zopiclone appears to increase the risk of such behaviors, as does the use of Zopiclone at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Zopiclone should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
- It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
- The clinical trial experience with Zopiclone revealed no evidence of a serious withdrawal syndrome. Nevertheless, the following adverse events included in DSM-IV criteria for uncomplicated sedative/hypnotic withdrawal were reported during clinical trialsfollowing placebo substitution occurring within 48 hours following the last Zopiclone treatment: anxiety, abnormal dreams, nausea, and upset stomach. These reported adverse events occurred at an incidence of 2% or less. Use of benzodiazepines and similar agents may lead to physical and psychological dependence. The risk of abuse and dependence increases with the dose and duration of treatment and concomitant use of other psychoactive drugs. The risk is also greater for patients who have a history of alcohol or drug abuse or history of psychiatric disorders. These patients should be under careful surveillance when receiving Zopiclone or any other hypnotic.
- In clinical trialswith Zopiclone, one case of overdose with up to 36 mg of Zopiclone was reported in which the subject fully recovered. Since commercial marketing began, spontaneous cases of Zopiclone overdoses up to 270 mg (90 times the maximum recommended dose of Zopiclone) have been reported, in which patients have recovered. Fatalities related to Zopiclone overdoses were reported only in combination with other CNS drugs or alcohol.
# Brand Names
There is limited information regarding Zopiclone Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Zopiclone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Zopiclone | |
0b13d972f85ffd86bac93d86401897edc8c8ddd9 | wikidoc | Retinene | Retinene
# Overview
The Retinenes (Retinene1 and Retinene2) are chemical derivatives of the dietary supplement vitamin A (see retinol) formed through oxidation reactions.
Retinene1 is better known as retinaldehyde or simply retinal and is fundamental in the transduction of light into visual signals in the photoreceptor level of the retina (known as the visual cycle). Retinene2 is more formally known as dehydroretinaldehyde.
The energy of impinging photons will convert retinaldehyde from an 11-cis isomer into an all-trans form. In the retina, this conversion induces a conformational change in the surrounding photopsin protein pigment, leading to signaling through the G protein transducin. Retinaldehyde also forms a part of bacteriorhodopsin, a light-induced proton pump found in some archaea.
Experimentally, it is possible to replace 11-cis retinaldehyde by perfusing retinal tissue preparations with retinaldehyde derivatives. Selective modification of the retinaldehyde structure, particularly the density of electrons in the π-orbitals, can lead to insights into the interaction between the retinaldehyde moiety and the surrounding pigment protein. | Retinene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Retinenes (Retinene1 and Retinene2) are chemical derivatives of the dietary supplement vitamin A (see retinol) formed through oxidation reactions.
Retinene1 is better known as retinaldehyde or simply retinal and is fundamental in the transduction of light into visual signals in the photoreceptor level of the retina (known as the visual cycle). Retinene2 is more formally known as dehydroretinaldehyde.
The energy of impinging photons will convert retinaldehyde from an 11-cis isomer into an all-trans form. In the retina, this conversion induces a conformational change in the surrounding photopsin protein pigment, leading to signaling through the G protein transducin. Retinaldehyde also forms a part of bacteriorhodopsin, a light-induced proton pump found in some archaea.
Experimentally, it is possible to replace 11-cis retinaldehyde by perfusing retinal tissue preparations with retinaldehyde derivatives. Selective modification of the retinaldehyde structure, particularly the density of electrons in the π-orbitals, can lead to insights into the interaction between the retinaldehyde moiety and the surrounding pigment protein. | https://www.wikidoc.org/index.php/11-cis_retinal | |
9c97e19eae4239a6d55ef624fa9e244908905610 | wikidoc | 14C-Urea | 14C-Urea
# 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
14C-Urea is a diagnostic agent that is FDA approved for the diagnosis of H. pylori infection in the human stomach. Common adverse reactions include none.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- 14C-Urea breath test is indicated for use in the detection of gastric urease as an aid in the diagnosis of H. pylori infection in the human stomach. The test utilizes a liquid scintillation counter for the measurement of 14CO2 in breath samples.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of 14C-Urea in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of 14C-Urea in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding 14C-Urea 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 14C-Urea in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of 14C-Urea in pediatric patients.
# Contraindications
None
# Warnings
None
# Adverse Reactions
## Clinical Trials Experience
None
## Postmarketing Experience
None
# Drug Interactions
- Antibiotics, proton pump inhibitors, sucralfate, and bismuth preparations are known to suppress H. pylori. Ingestion of antibiotics or bismuth within 4 weeks and proton pump inhibitors or sucralfate within 2 weeks prior to performing the test may give false negative results.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with 14C-urea. It is also not known whether 14C-urea can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of 14C-Urea in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of 14C-Urea 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 14C-urea is administered to a nursing woman.
### Pediatric Use
- Clinical studies in children have not been conducted. However, 14C-urea is expected to work the same in children as in adults. While the dose (1 capsule) does not need to be adjusted, the child must be able to swallow the intact capsule and blow into a straw.
### Geriatic Use
There is no FDA guidance on the use of 14C-Urea in geriatric settings.
### Gender
There is no FDA guidance on the use of 14C-Urea with respect to specific gender populations.
### Race
There is no FDA guidance on the use of 14C-Urea with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of 14C-Urea in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of 14C-Urea in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of 14C-Urea in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of 14C-Urea in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- The performance characteristics of the test have not been established for monitoring the efficacy of antimicrobial therapies for the treatment of H. pylori infection.
# IV Compatibility
There is limited information regarding the compatibility of 14C-Urea and IV administrations.
# Overdosage
- Risk from radiation is negligible even with a 1000 capsule overdose (0.3 rem). If overdose occurs, the patient may drink one glass of water (150 ml) every hour to hasten excretion of the isotope. Maximum excretion of urea is achieved at a urine output of ≥ 2.0 ml/min.
# Pharmacology
There is limited information regarding 14C-Urea Pharmacology in the drug label.
## Mechanism of Action
- The urease enzyme is not present in mammalian cells, so the presence of urease in the stomach is evidence that bacteria are present. The presence of urease is not specific for H. pylori, but other bacteria are not usually found in the stomach. The principle of the breath test is shown in Figure 1.
- To detect H. pylori, urea labeled with 14C is swallowed by the patient. If gastric urease from H. pylori is present, urea is split to form CO2 and NH3 at the interface between the gastric epithelium and lumen and 14CO2 is absorbed into the blood and exhaled in the breath.
- Following ingestion of the capsule by a patient with H. pylori, 14CO2 excretion in the breath peaks between 10 and 15 minutes and declines thereafter with a biological half-life of about 15 minutes. 14C-urea that is not hydrolyzed by H. pylori is excreted in the urine with a half-life of approximately 12 hours. About 10% of the 14C remains in the body at 72 hours and is gradually excreted with a biological half-life of 40 days.
- Two studies were performed. In both studies, patients with gastrointestinal symptoms underwent the breath test and an endoscopy. During the endoscopy, biopsy samples were taken from the antral gastric mucosa for histological analysis (2 samples, Giemsa stain) and rapid urease test (1 sample, CLOtest1). Breath samples were mailed to the TRI-MED lab where they were read in a liquid scintillation counter.
- Results were reported as disintegrations per minute (DPM). Analysis for accuracy used the ten minute breath sample. A breath sample DPM <50 was defined as a negative result. DPM ≥ 200 was defined as a positive result. DPM in the range of 50–199 was classified as indeterminate.
- Of 186 patients who had histopathology and CLOtest1 (80 men, 106 women), 53 were infected with H. pylori as determined by agreement between histology and CLOtest1. The study results are summarized below:
## Structure
- 14C-urea is intended for use in the detection of gastric urease as an aid in the diagnosis of Helicobacter pylori (H. pylori) infection in the human stomach. The test utilizes a liquid scintillation counter for the measurement of 14CO2 in breath samples. The capsules are to be used when analysis is planned at the site where the sample is taken.
- 14C-urea capsule is a gelatin capsule for oral administration containing 1 µCi of 14C labeled urea. The urea is adsorbed on sugar spheres and colored yellow with fluorescein.
- 1 Registered Trademark or Trademark of Kimberly-Clark Worldwide, Inc.
- Data on 14C-urea
- Structural Formula (14C-urea): NH2 14CONH2
- Radiation emission: beta-emission, 49 keVmean, 156 keVmax, no other emissions
- External emission: No external radiation hazard. Low-energy beta emissions only.
Maximum range of 0.3 mm in water.
- Radiological Half-life: 5730 years
- Maximum effective dose equivalent (EDE) : 0.3 mrem/µCi.
## Pharmacodynamics
There is limited information regarding 14C-Urea Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding 14C-Urea Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding 14C-Urea Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding 14C-Urea Clinical Studies in the drug label.
# How Supplied
- 14C-urea Capsules, clear gelatin capsules each containing 1 μCi of 14C-urea in unit dose packages of 1, 10 and 100.
- 14C-urea Kit (14C-urea breath test) is also supplied as a kit containing a 14C-urea Capsule and breath collection equipment.
- The 14C-urea Capsule has a shelf life of two years. The expiration date is printed on the capsule label.
## Storage
- 14C-urea Capsules and Kit should be stored at 15–30 °C (59–86 °F) in an area designated by each individual institution's regulations.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding 14C-Urea Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-14C-Urea interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PYTEST®
# Look-Alike Drug Names
There is limited information regarding 14C-Urea Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | 14C-Urea
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
14C-Urea is a diagnostic agent that is FDA approved for the diagnosis of H. pylori infection in the human stomach. Common adverse reactions include none.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- 14C-Urea breath test is indicated for use in the detection of gastric urease as an aid in the diagnosis of H. pylori infection in the human stomach. The test utilizes a liquid scintillation counter for the measurement of 14CO2 in breath samples.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of 14C-Urea in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of 14C-Urea in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding 14C-Urea 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 14C-Urea in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of 14C-Urea in pediatric patients.
# Contraindications
None
# Warnings
None
# Adverse Reactions
## Clinical Trials Experience
None
## Postmarketing Experience
None
# Drug Interactions
- Antibiotics, proton pump inhibitors, sucralfate, and bismuth preparations are known to suppress H. pylori. Ingestion of antibiotics or bismuth within 4 weeks and proton pump inhibitors or sucralfate within 2 weeks prior to performing the test may give false negative results.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with 14C-urea. It is also not known whether 14C-urea can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of 14C-Urea in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of 14C-Urea 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 14C-urea is administered to a nursing woman.
### Pediatric Use
- Clinical studies in children have not been conducted. However, 14C-urea is expected to work the same in children as in adults. While the dose (1 capsule) does not need to be adjusted, the child must be able to swallow the intact capsule and blow into a straw.
### Geriatic Use
There is no FDA guidance on the use of 14C-Urea in geriatric settings.
### Gender
There is no FDA guidance on the use of 14C-Urea with respect to specific gender populations.
### Race
There is no FDA guidance on the use of 14C-Urea with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of 14C-Urea in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of 14C-Urea in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of 14C-Urea in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of 14C-Urea in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- The performance characteristics of the test have not been established for monitoring the efficacy of antimicrobial therapies for the treatment of H. pylori infection.
# IV Compatibility
There is limited information regarding the compatibility of 14C-Urea and IV administrations.
# Overdosage
- Risk from radiation is negligible even with a 1000 capsule overdose (0.3 rem). If overdose occurs, the patient may drink one glass of water (150 ml) every hour to hasten excretion of the isotope. Maximum excretion of urea is achieved at a urine output of ≥ 2.0 ml/min.
# Pharmacology
There is limited information regarding 14C-Urea Pharmacology in the drug label.
## Mechanism of Action
- The urease enzyme is not present in mammalian cells, so the presence of urease in the stomach is evidence that bacteria are present. The presence of urease is not specific for H. pylori, but other bacteria are not usually found in the stomach. The principle of the breath test is shown in Figure 1.
- To detect H. pylori, urea labeled with 14C is swallowed by the patient. If gastric urease from H. pylori is present, urea is split to form CO2 and NH3 at the interface between the gastric epithelium and lumen and 14CO2 is absorbed into the blood and exhaled in the breath.
- Following ingestion of the capsule by a patient with H. pylori, 14CO2 excretion in the breath peaks between 10 and 15 minutes and declines thereafter with a biological half-life of about 15 minutes. 14C-urea that is not hydrolyzed by H. pylori is excreted in the urine with a half-life of approximately 12 hours. About 10% of the 14C remains in the body at 72 hours and is gradually excreted with a biological half-life of 40 days.
- Two studies were performed. In both studies, patients with gastrointestinal symptoms underwent the breath test and an endoscopy. During the endoscopy, biopsy samples were taken from the antral gastric mucosa for histological analysis (2 samples, Giemsa stain) and rapid urease test (1 sample, CLOtest1). Breath samples were mailed to the TRI-MED lab where they were read in a liquid scintillation counter.
- Results were reported as disintegrations per minute (DPM). Analysis for accuracy used the ten minute breath sample. A breath sample DPM <50 was defined as a negative result. DPM ≥ 200 was defined as a positive result. DPM in the range of 50–199 was classified as indeterminate.
- Of 186 patients who had histopathology and CLOtest1 (80 men, 106 women), 53 were infected with H. pylori as determined by agreement between histology and CLOtest1. The study results are summarized below:
## Structure
- 14C-urea is intended for use in the detection of gastric urease as an aid in the diagnosis of Helicobacter pylori (H. pylori) infection in the human stomach. The test utilizes a liquid scintillation counter for the measurement of 14CO2 in breath samples. The capsules are to be used when analysis is planned at the site where the sample is taken.
- 14C-urea capsule is a gelatin capsule for oral administration containing 1 µCi of 14C labeled urea. The urea is adsorbed on sugar spheres and colored yellow with fluorescein.
- 1 Registered Trademark or Trademark of Kimberly-Clark Worldwide, Inc.
- Data on 14C-urea
- Structural Formula (14C-urea): NH2 14CONH2
- Radiation emission: beta-emission, 49 keVmean, 156 keVmax, no other emissions
- External emission: No external radiation hazard. Low-energy beta emissions only.
Maximum range of 0.3 mm in water.
- Radiological Half-life: 5730 years
- Maximum effective dose equivalent (EDE) : 0.3 mrem/µCi.
## Pharmacodynamics
There is limited information regarding 14C-Urea Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding 14C-Urea Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding 14C-Urea Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding 14C-Urea Clinical Studies in the drug label.
# How Supplied
- 14C-urea Capsules, clear gelatin capsules each containing 1 μCi of 14C-urea in unit dose packages of 1, 10 and 100.
- 14C-urea Kit (14C-urea breath test) is also supplied as a kit containing a 14C-urea Capsule and breath collection equipment.
- The 14C-urea Capsule has a shelf life of two years. The expiration date is printed on the capsule label.
## Storage
- 14C-urea Capsules and Kit should be stored at 15–30 °C (59–86 °F) in an area designated by each individual institution's regulations.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding 14C-Urea Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-14C-Urea interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PYTEST®[1]
# Look-Alike Drug Names
There is limited information regarding 14C-Urea Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/14C-Urea | |
7c655f400d97fde949f5398eb7dea294417cf901 | wikidoc | 2-Pyrone | 2-Pyrone
# Overview
2-Pyrone (α-pyrone or pyran-2-one) is an unsaturated cyclic chemical compound with the molecular formula C5H4O2. It is isomeric with 4-pyrone.
2-Pyrone is used in organic synthesis as a building block for more complex chemical structures because it may participate in a variety of cycloaddition reactions to form bicyclic lactones. For example, it readily undergoes Diels-Alder reactions with alkynes producing, upon loss of carbon dioxide, substituted benzenes.. The Gogte Synthesis (1938) is a method for the alkylation of certain pyrones with acid chlorides.
2-Pyrone also forms the the core structure of a variety of natural organic compounds. For example, the coumarins are an important class of compounds which are benzo-fused derivatives of 2-pyrone.
- 4-Pyrone
- Coumarin | 2-Pyrone
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
2-Pyrone (α-pyrone or pyran-2-one) is an unsaturated cyclic chemical compound with the molecular formula C5H4O2. It is isomeric with 4-pyrone.
2-Pyrone is used in organic synthesis as a building block for more complex chemical structures because it may participate in a variety of cycloaddition reactions to form bicyclic lactones. For example, it readily undergoes Diels-Alder reactions with alkynes producing, upon loss of carbon dioxide, substituted benzenes.[1]. The Gogte Synthesis (1938) is a method for the alkylation of certain pyrones with acid chlorides.
2-Pyrone also forms the the core structure of a variety of natural organic compounds. For example, the coumarins are an important class of compounds which are benzo-fused derivatives of 2-pyrone.
- 4-Pyrone
- Coumarin | https://www.wikidoc.org/index.php/2-Pyrone | |
d77b67381636fb16c12687ca14f5429355442429 | wikidoc | 2C-B-BZP | 2C-B-BZP
2C-B-BZP is a research chemical and stimulant of the piperazine family.
# Chemistry
2C-B-BZP is 2-bromo-4,5-dimethoxy-benzylpiperazine. It is related to BZP and shares the ring-substitution pattern of the psychedelic phenethylamine 2C-B, although 2C-B-BZP is not a phenethylamine itself.
# Dosage
Reported doses are mainly in the 100-200 mg range.
# Effects
2C-B-BZP produces stimulant effects that last 3-6 hours, depending on the dose. Despite its structural similarity to 2C-B it does not produce psychedelic effects as the binding groups are in the wrong position to activate the 5HT2A receptor. 2C-B-BZP is also said by several sources to increase the effects of other compounds when combined. Side effects include headaches and nausea, similar to other piperazine derivatives used recreationally.
# Legality
2C-B-BZP is unscheduled and uncontrolled in the United States, but possession and sales of 2C-B-BZP could possibly be prosecuted under the Federal Analog Act because of its structural similarities to 2C-B or BZP. 2C-B-BZP is said to be illegal to posses, use or sale in Japan where it used to be sold in local smartshops.
# Pharmacology
The pharmacology of 2C-B-BZP is unknown.
# Dangers
The toxicity of 2C-B-BZP is not known, although Benzylpiperazine (BZP), which is chemically related, has known toxicity.
# Popularity
2C-B-BZP is unknown on the black market, though it is available from research chemical vendors that operate on the internet. It is more common in South Africa than Europe and North America. | 2C-B-BZP
Template:Unsourced
2C-B-BZP is a research chemical and stimulant of the piperazine family.
# Chemistry
2C-B-BZP is 2-bromo-4,5-dimethoxy-benzylpiperazine. It is related to BZP and shares the ring-substitution pattern of the psychedelic phenethylamine 2C-B, although 2C-B-BZP is not a phenethylamine itself.
# Dosage
Reported doses are mainly in the 100-200 mg range.
# Effects
2C-B-BZP produces stimulant effects that last 3-6 hours, depending on the dose. Despite its structural similarity to 2C-B it does not produce psychedelic effects as the binding groups are in the wrong position to activate the 5HT2A receptor. 2C-B-BZP is also said by several sources to increase the effects of other compounds when combined. Side effects include headaches and nausea, similar to other piperazine derivatives used recreationally.
# Legality
2C-B-BZP is unscheduled and uncontrolled in the United States, but possession and sales of 2C-B-BZP could possibly be prosecuted under the Federal Analog Act because of its structural similarities to 2C-B or BZP. 2C-B-BZP is said to be illegal to posses, use or sale in Japan where it used to be sold in local smartshops.
# Pharmacology
The pharmacology of 2C-B-BZP is unknown.
# Dangers
The toxicity of 2C-B-BZP is not known, although Benzylpiperazine (BZP), which is chemically related, has known toxicity.
# Popularity
2C-B-BZP is unknown on the black market, though it is available from research chemical vendors that operate on the internet. It is more common in South Africa than Europe and North America. | https://www.wikidoc.org/index.php/2C-B-BZP | |
1789135d1d53b684936e5122d2843ed59fd6a5b4 | wikidoc | 2C-B-FLY | 2C-B-FLY
2C-B-FLY is a psychedelic phenethylamine of the 2C family. It was first synthesized by Aaron P. Monte, and sometimes used as an entheogen.
# Chemistry
2C-B-FLY is 8-bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine. The full name of the chemical is 2-(8-bromo-2,3,6,7-tetrahydrofurobenzofuran-4-yl)ethanamine.
In theory, dihydrodifuran analogues of any of the 2Cx / DOx family of drugs could be made, and would be expected to show similar activity to the parent compound. So in the same way that 2C-B-FLY is the dihydrodifuran analogue of 2C-B, the 8-iodo equivalent 2C-I-FLY would be the dihydrodifuran analogue of 2C-I, and the 8-methyl equivalent 2C-M-FLY would be the dihydrodifuran analogue of 2C-D.
Other related compounds can also be produced, where the alpha carbon of the ethylamine chain is methylated, the amphetamine derivative 3C-B-FLY would be made, this compound being the dihydrodifuran analogue of DOB, and would also be the unsaturated equivalent of Bromo-DragonFLY.
Where only one methoxy group of a 2Cx drug is cyclised into a dihydrofuran ring, the resulting compound is known as a "hemifly", and when an unsaturated furan ring is used the compound is known as a "hemi-dragonfly". A large family of compounds can thus be derived, many of which can be predicted to be active hallucinogens based on the known structure-activity relationships of these drugs, although most of these compounds have not yet been made and tested.
File:2C-B-FLY SAR.png
# Dosage
Alexander Shulgin lists a dosage of 2C-B-FLY at 10 mg orally.
However, various other information reveals that 2C-B-FLY is active as low as 1 mg.
# Effects
2C-B-FLY produces psychedelic effects that last 6-8 hours, or up to 12 hours in larger doses.
# Legality
2C-B-FLY is unscheduled and uncontrolled in the United States, but possession and sales of 2C-B-FLY could probably be prosecuted under the Federal Analog Act because of its structural similarities to 2C-B.
# Pharmacology
The hallucinogenic effect of 2C-B-FLY is mediated by its partial agonistic activity at the 5-HT2A serotonin receptor, but 2C-B-FLY also has a high binding affinity for the 5-HT2B and 5-HT2C serotonin receptor.
# Dangers
The toxicity of 2C-B-FLY is not known.
# Popularity
2C-B-FLY is unknown on the black market, though it is available from research chemical vendors that operate on the internet. | 2C-B-FLY
2C-B-FLY is a psychedelic phenethylamine of the 2C family. It was first synthesized by Aaron P. Monte, and sometimes used as an entheogen.
# Chemistry
2C-B-FLY is 8-bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine. The full name of the chemical is 2-(8-bromo-2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)ethanamine.
In theory, dihydrodifuran analogues of any of the 2Cx / DOx family of drugs could be made, and would be expected to show similar activity to the parent compound. So in the same way that 2C-B-FLY is the dihydrodifuran analogue of 2C-B, the 8-iodo equivalent 2C-I-FLY would be the dihydrodifuran analogue of 2C-I, and the 8-methyl equivalent 2C-M-FLY would be the dihydrodifuran analogue of 2C-D.
Other related compounds can also be produced, where the alpha carbon of the ethylamine chain is methylated, the amphetamine derivative 3C-B-FLY would be made, this compound being the dihydrodifuran analogue of DOB, and would also be the unsaturated equivalent of Bromo-DragonFLY.
Where only one methoxy group of a 2Cx drug is cyclised into a dihydrofuran ring, the resulting compound is known as a "hemifly", and when an unsaturated furan ring is used the compound is known as a "hemi-dragonfly". A large family of compounds can thus be derived, many of which can be predicted to be active hallucinogens based on the known structure-activity relationships of these drugs, although most of these compounds have not yet been made and tested.
File:2C-B-FLY SAR.png
# Dosage
Alexander Shulgin lists a dosage of 2C-B-FLY at 10 mg orally.
However, various other information reveals that 2C-B-FLY is active as low as 1 mg[citation needed].
# Effects
2C-B-FLY produces psychedelic effects that last 6-8 hours, or up to 12 hours in larger doses.
# Legality
2C-B-FLY is unscheduled and uncontrolled in the United States, but possession and sales of 2C-B-FLY could probably be prosecuted under the Federal Analog Act because of its structural similarities to 2C-B.
# Pharmacology
The hallucinogenic effect of 2C-B-FLY is mediated by its partial agonistic activity at the 5-HT2A serotonin receptor, but 2C-B-FLY also has a high binding affinity for the 5-HT2B and 5-HT2C serotonin receptor.
# Dangers
The toxicity of 2C-B-FLY is not known.
# Popularity
2C-B-FLY is unknown on the black market, though it is available from research chemical vendors that operate on the internet.
# External links
- 2C-B-FLY Entry at Erowid
- 2C-B-FLY page at www.bluelight.ru
- 2C-B-FLY User survey
Template:Hallucinogenic phenethylamines
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/2C-B-FLY | |
6977e6ec453be1d77b1a3afdae614d71b3a89db6 | wikidoc | 4-HO-DET | 4-HO-DET
4-HO-DET, also known as 4-hydroxy-diethyl-tryptamine, CZ-74, or ethocin, is a hallucinogenic drug and psychedelic compound of moderate duration. 4-HO-DET is a substituted tryptamine, structurally related to psilocin and 4-HO-DIPT.
# Analogs
The acetic acid ester of 4-HO-DET is known as 4-AcO-DET or ethacetin. The phosphoric acid ester of 4-HO-DET is known as 4-phosphoryloxy-DET, CEY-19, or ethocybin.
# History
4-HO-DET received the lab code CZ-74 in the late 1950s by the inventors of the substance, Albert Hofmann and Franz Troxler. The substance was used together with its phosporyloxy-analog CEY-19 in human clinical trials in the 1960s by the German researchers Hanscarl Leuner and G. Baer.
# Dosage
10-25mg is the usual oral dosage for 4-HO-DET, while the acetate and phosphate esters are said to require a slightly higher dosage.
# Effects
Ethocin produces entheogenic effects similar to LSD and psilocybin. Some users have reported unpleasant anxiety and stimulation with this drug, while other accounts label the experience as being much milder than LSD or psilocybin. | 4-HO-DET
4-HO-DET, also known as 4-hydroxy-diethyl-tryptamine, CZ-74, or ethocin, is a hallucinogenic drug and psychedelic compound of moderate duration. 4-HO-DET is a substituted tryptamine, structurally related to psilocin and 4-HO-DIPT.
# Analogs
The acetic acid ester of 4-HO-DET is known as 4-AcO-DET or ethacetin. The phosphoric acid ester of 4-HO-DET is known as 4-phosphoryloxy-DET, CEY-19, or ethocybin.
# History
4-HO-DET received the lab code CZ-74 in the late 1950s by the inventors of the substance, Albert Hofmann and Franz Troxler. The substance was used together with its phosporyloxy-analog CEY-19 in human clinical trials in the 1960s by the German researchers Hanscarl Leuner and G. Baer.
# Dosage
10-25mg is the usual oral dosage for 4-HO-DET, while the acetate and phosphate esters are said to require a slightly higher dosage.
# Effects
Ethocin produces entheogenic effects similar to LSD and psilocybin. Some users have reported unpleasant anxiety and stimulation with this drug, while other accounts label the experience as being much milder than LSD or psilocybin. | https://www.wikidoc.org/index.php/4-HO-DET | |
0bd9ec2e858aba3b5e33d9d44d171e2cd567b0cf | wikidoc | Psilocin | Psilocin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Psilocin,(4-HO-DMT) sometimes called psilocine or psilotsin, is a psychedelic (hallucinogenic) mushroom alkaloid. It is found in most psychedelic mushrooms together with its close congener psilocybin. Psilocin is a Schedule I drug under the Convention on Psychotropic Substances.
Psilocin is almost identical to the chemical structure of the chemical of another known hallucinogen, bufotenin. The only difference is the position of the hydroxyl (OH-) group on the benzene ring — in psilocin, the hydroxyl group is at the 4-position, while in bufotenin it is at the 5-position.
# History
The Swiss chemist Albert Hofmann and the laboratory assistant Hans Tscherter from Sandoz isolated psilocin and its phosphate ester psilocybin from Psilocybe mushrooms in 1959 guided by self-administration.
# Chemistry
Psilocin can be obtained by dephosphorylation of natural psilocybin under strongly acidic or under alkaline conditions (hydrolysis). One synthetic route uses the Speeter-Anthony tryptamine synthesis starting from 4-hydroxyindole.
Psilocin is relatively unstable in solution due to its phenolic OH group. Under alkaline conditions in the presence of oxygen it immediately forms bluish and dark black degradation products. Similar products are also formed under acidic conditions in the presence of oxygen and Fe3+ ions (Keller's reagent, FeCl3 / MeOH / HCl). Psilocin is an amine and forms salts with acids that are usually more stable upon storage. Psilocin base can be evaporated by heating.
# Pharmacology
Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as a partial agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin (5-HT). Psilocin is an 5-HT1A and 5-HT2A/2C agonist. | Psilocin
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Psilocin,(4-HO-DMT) sometimes called psilocine or psilotsin, is a psychedelic (hallucinogenic) mushroom alkaloid. It is found in most psychedelic mushrooms together with its close congener psilocybin. Psilocin is a Schedule I drug under the Convention on Psychotropic Substances.[1]
Psilocin is almost identical to the chemical structure of the chemical of another known hallucinogen, bufotenin. The only difference is the position of the hydroxyl (OH-) group on the benzene ring — in psilocin, the hydroxyl group is at the 4-position, while in bufotenin it is at the 5-position.
# History
The Swiss chemist Albert Hofmann and the laboratory assistant Hans Tscherter from Sandoz isolated psilocin and its phosphate ester psilocybin from Psilocybe mushrooms in 1959 guided by self-administration.
# Chemistry
Psilocin can be obtained by dephosphorylation of natural psilocybin under strongly acidic or under alkaline conditions (hydrolysis). One synthetic route uses the Speeter-Anthony tryptamine synthesis starting from 4-hydroxyindole.
Psilocin is relatively unstable in solution due to its phenolic OH group. Under alkaline conditions in the presence of oxygen it immediately forms bluish and dark black degradation products. Similar products are also formed under acidic conditions in the presence of oxygen and Fe3+ ions (Keller's reagent, FeCl3 / MeOH / HCl). Psilocin is an amine and forms salts with acids [citation needed] that are usually more stable upon storage. Psilocin base can be evaporated by heating.
# Pharmacology
Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as a partial agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin (5-HT). Psilocin is an 5-HT1A and 5-HT2A/2C agonist. | https://www.wikidoc.org/index.php/4-HO-DMT | |
bad1f969f2aa1ad1878e988ce9bc6b03d5b47133 | wikidoc | 48, XXXX | 48, XXXX
# Overview
XXXX syndrome (also called tetrasomy X, quadruple X, or 48, XXXX) is a rare chromosomal disorder caused by the presence of four X chromosomes instead of two X chromosomes, which are normally found in females. This condition occurs only in females, as there are no Y chromosomes present. Tetrasomy X was first described in 1961, and since then approximately 100 cases have been reported worldwide. Approximately 60 females have been described in medical literature with this condition.
# Etiology
Tetrasomy X is a chromosomal aneuploidy, meaning it arises from a defect in meiosis. This can occur when homologous X chromosomes fail to separate in the formation of the egg or sperm. Tetrasomy X is usually suspected based on symptoms present in the individual and is confirmed via karyotyping, which reveals the extra X chromosomes.
# Symptoms
Symptoms of tetrasomy X are highly variable, ranging from relatively mild to severe. Physically, tetrasomy X patients tend to have distinctive facial features such as epicanthal folds, flat nasal bridges, upslanting palpebral fissures, midface hypoplasia, small mouths, cleft or high arched palates, delayed or absent teeth, or enamel defects. The majority have also been reported as being longer and taller. Many also show joint and muscle tone abnormalities, including hypotonia and joint looseness in the hips. Skeletal problems may also be present, including abnormal curvatures of the spine. An informal study conducted by Tetrasomy & Pentasomy X Syndrome Information and Support found that 10% of girls had joint laxity in the hips and 20% had joint limitations in a sample size of 20 tetrasomy and pentasomy patients.
In terms of intelligence, clinical findings suggest that IQ decreases 10 to 15 points per extra X chromosome. Consequently, the average IQ scores of tetrasomy X patients are between 60 and 70.
Developmentally, tetrasomy X patients frequently show mild delays in the areas of speech development and articulation, language expression and understanding, and reading skills. Delays in motor development are also present, with walking ages ranging from 16 months to 4.5 years. About 50% of patients undergo puberty normally, whereas the other 50% experiences no puberty, partial puberty without secondary sexual characteristics, or complete puberty with menstrual irregularities and/or early menopause (possibly as early as the teens). Medical literature reports four tetra-X pregnancies, two healthy, one with trisomy 21, one stillborn with omphalocele.
In terms of internal organ systems, tetrasomy X patients may have abnormal vision, hearing, circulatory systems, kidneys, or nervous systems. Disorders of the eye include myopia, nystagmus, coloboma, microphthalmus, or optic nerve hypoplasia. In terms of hearing, patients are more prone to ear infections, sound blockage, or nerve abnormalities. Several cardiac defects have also been reported, including ventricular/atrial septal defects, atresia, hypoplastic right heart syndrome, patent ductus arteriosus, and conotruncal or valvular cardiac defects. Tetrasomy X patients also appear to be more prone to seizure activity, although there is no documented abnormalities in brain function or structure when analyzed using an ECG or MRI.
# Treatment and Prognosis
The general prognosis for girls with tetrasomy X is relatively good. Due to the variability of symptoms, some tetrasomy X girls are able to function normally, whereas others will need medical attention throughout their lives. Traditionally, treatment for tetrasomy X has been management of the symptoms and support for learning. Most girls are placed on estrogen treatment to induce breast development, arrest longitudinal growth, and stimulate bone formation to prevent osteoporosis. Speech, occupational, and physical therapy may also be needed depending on the severity of the symptoms. | 48, XXXX
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
XXXX syndrome (also called tetrasomy X, quadruple X, or 48, XXXX) is a rare chromosomal disorder caused by the presence of four X chromosomes instead of two X chromosomes, which are normally found in females. This condition occurs only in females, as there are no Y chromosomes present. Tetrasomy X was first described in 1961, and since then approximately 100 cases have been reported worldwide. Approximately 60 females have been described in medical literature with this condition.
# Etiology
Tetrasomy X is a chromosomal aneuploidy, meaning it arises from a defect in meiosis. This can occur when homologous X chromosomes fail to separate in the formation of the egg or sperm. Tetrasomy X is usually suspected based on symptoms present in the individual and is confirmed via karyotyping, which reveals the extra X chromosomes.
# Symptoms
Symptoms of tetrasomy X are highly variable, ranging from relatively mild to severe. Physically, tetrasomy X patients tend to have distinctive facial features such as epicanthal folds, flat nasal bridges, upslanting palpebral fissures, midface hypoplasia, small mouths, cleft or high arched palates, delayed or absent teeth, or enamel defects. The majority have also been reported as being longer and taller. Many also show joint and muscle tone abnormalities, including hypotonia and joint looseness in the hips. Skeletal problems may also be present, including abnormal curvatures of the spine. An informal study conducted by Tetrasomy & Pentasomy X Syndrome Information and Support found that 10% of girls had joint laxity in the hips and 20% had joint limitations in a sample size of 20 tetrasomy and pentasomy patients.
In terms of intelligence, clinical findings suggest that IQ decreases 10 to 15 points per extra X chromosome. Consequently, the average IQ scores of tetrasomy X patients are between 60 and 70.
Developmentally, tetrasomy X patients frequently show mild delays in the areas of speech development and articulation, language expression and understanding, and reading skills. Delays in motor development are also present, with walking ages ranging from 16 months to 4.5 years. About 50% of patients undergo puberty normally, whereas the other 50% experiences no puberty, partial puberty without secondary sexual characteristics, or complete puberty with menstrual irregularities and/or early menopause (possibly as early as the teens). Medical literature reports four tetra-X pregnancies, two healthy, one with trisomy 21, one stillborn with omphalocele.
In terms of internal organ systems, tetrasomy X patients may have abnormal vision, hearing, circulatory systems, kidneys, or nervous systems. Disorders of the eye include myopia, nystagmus, coloboma, microphthalmus, or optic nerve hypoplasia. In terms of hearing, patients are more prone to ear infections, sound blockage, or nerve abnormalities. Several cardiac defects have also been reported, including ventricular/atrial septal defects, atresia, hypoplastic right heart syndrome, patent ductus arteriosus, and conotruncal or valvular cardiac defects. Tetrasomy X patients also appear to be more prone to seizure activity, although there is no documented abnormalities in brain function or structure when analyzed using an ECG or MRI.
# Treatment and Prognosis
The general prognosis for girls with tetrasomy X is relatively good. Due to the variability of symptoms, some tetrasomy X girls are able to function normally, whereas others will need medical attention throughout their lives. Traditionally, treatment for tetrasomy X has been management of the symptoms and support for learning. Most girls are placed on estrogen treatment to induce breast development, arrest longitudinal growth, and stimulate bone formation to prevent osteoporosis. Speech, occupational, and physical therapy may also be needed depending on the severity of the symptoms. | https://www.wikidoc.org/index.php/48,_XXXX | |
da05b8773624fcf697d64a098bb2755016aaef8e | wikidoc | 48, XXYY | 48, XXYY
# Overview
48, XXYY syndrome is a sex chromosome anomaly.
It was previously considered to be a variation of Klinefelter's syndrome. It is still considered a part of the syndrome by some definitions.
# Incidence
It affects one in every 18,000-40,000 male births.
# Presentation
Common features include tall stature, gynecomastia, truncal obesity, skin ulcers, and a craniofacial dysmorphism described as a "pugilistic" facial appearance.
# History
The first published report of a boy with a 48,XXYY karyotype was by Sylfest Muldal and Charles H. Ockey in Manchester, England in 1960.
It was found in a 15-year-old mentally challenged boy who had signs of Klinefelter syndrome; eventually, it appeared that he didn't have the Klinefelter Syndrome but, as shown above, the XXYY syndrome. | 48, XXYY
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
48, XXYY syndrome is a sex chromosome anomaly.
It was previously considered to be a variation of Klinefelter's syndrome. It is still considered a part of the syndrome by some definitions.[1]
# Incidence
It affects one in every 18,000-40,000 male births. [2]
# Presentation
Common features include tall stature, gynecomastia, truncal obesity, skin ulcers, and a craniofacial dysmorphism described as a "pugilistic" facial appearance.
# History
The first published report of a boy with a 48,XXYY karyotype was by Sylfest Muldal and Charles H. Ockey in Manchester, England in 1960.[3]
It was found in a 15-year-old mentally challenged boy who had signs of Klinefelter syndrome; eventually, it appeared that he didn't have the Klinefelter Syndrome but, as shown above, the XXYY syndrome. | https://www.wikidoc.org/index.php/48,_XXYY | |
c33d2ce63aec9ed197c3cd0fa1d75647ffde89dc | wikidoc | 4S Trial | 4S Trial
# Objective
The Scandinavian Simvastatin Survival Study (4S) is a multicenter clinical trial that was performed in 1990s in Scandinavia. The objective of the study was to assess effect of a cholesterol-lowering drug called simvastatin on mortality and morbidity in a group of 4444 patients with coronary heart disease, aged between 35 and 70 years.
# Methods
The Scandinavian Simvastatin Survival Study (4S) enrolled 4444 patients with known CAD (angina pectoris or previous myocardial infarction) and serum cholesterol levels between 212 and 309 mg/dL. Patients were randomly assigned to either simvastatin (20 to 40 mg/day) or placebo and were followed-up for a median period of 5.4 years.
# Results
- Total cholesterol reduced by 25%
- LDL-C levels reduced by 35%
- Mean HDL-C improved by 8%
- Mortality rate was lower in the simvastatin group compared with that in the placebo group (8% vs 12%)
- Significant reductions in major coronary events (19 versus 28 percent)
The patients exhibited moderate hypercholesterolemia, between 5.5 and 8.0 mmol/l.
The trial showed that treatment of patients suffering from coronary heart disease with simvastatin had a lowering effect on mortality and morbidity.
2223 patients were assigned placebo and 2221 were assigned simvastatin treatment for a mean period of 5.4 years. There was a 30% relative reduction in the risk of death with simvastatin treatment. The absolute CHD-mortality was reduced from 8.5% to 5.0%, making the number needed to treat around 30 (thirty patients would need to be treated to prevent one death). Additionally there was no excess morbidity of non-cardiac deaths from causes like cancer or suicide, a concern that has occasionally arisen in respect to the statins.
The treatment of 100 patients for six years would prevent four deaths of the disease and seven non-fatal myocardial infarcts.
The 4S study turned out to be a milestone in cardiology and evidence-based medicine - it was clearly proven that treatment with statins saved lives of patients with coronary heart disease. A host of other large multicenter clinical trials followed that paved way to widespread use of this class of pharmaceuticals.
However, it should be noted that no trial of statin in primary prevention (people without symptomatic coronary artery disease or diabetes) has shown an overall health benefit.
# Conclusion
The study showed that long-term treatment with simvastatin is safe and improves survival in CAD patients. | 4S Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Click here to download slides for 4S Trial.
# Objective
The Scandinavian Simvastatin Survival Study (4S) is a multicenter clinical trial that was performed in 1990s in Scandinavia. The objective of the study was to assess effect of a cholesterol-lowering drug called simvastatin on mortality and morbidity in a group of 4444 patients with coronary heart disease, aged between 35 and 70 years.
# Methods
The Scandinavian Simvastatin Survival Study (4S) enrolled 4444 patients with known CAD (angina pectoris or previous myocardial infarction) and serum cholesterol levels between 212 and 309 mg/dL. Patients were randomly assigned to either simvastatin (20 to 40 mg/day) or placebo and were followed-up for a median period of 5.4 years.
# Results
- Total cholesterol reduced by 25%
- LDL-C levels reduced by 35%
- Mean HDL-C improved by 8%
- Mortality rate was lower in the simvastatin group compared with that in the placebo group (8% vs 12%)
- Significant reductions in major coronary events (19 versus 28 percent)
The patients exhibited moderate hypercholesterolemia, between 5.5 and 8.0 mmol/l.
The trial showed that treatment of patients suffering from coronary heart disease with simvastatin had a lowering effect on mortality and morbidity.
2223 patients were assigned placebo and 2221 were assigned simvastatin treatment for a mean period of 5.4 years. There was a 30% relative reduction in the risk of death with simvastatin treatment. The absolute CHD-mortality was reduced from 8.5% to 5.0%, making the number needed to treat around 30 (thirty patients would need to be treated to prevent one death). Additionally there was no excess morbidity of non-cardiac deaths from causes like cancer or suicide, a concern that has occasionally arisen in respect to the statins.
The treatment of 100 patients for six years would prevent four deaths of the disease and seven non-fatal myocardial infarcts.
The 4S study turned out to be a milestone in cardiology and evidence-based medicine - it was clearly proven that treatment with statins saved lives of patients with coronary heart disease. A host of other large multicenter clinical trials followed that paved way to widespread use of this class of pharmaceuticals.
However, it should be noted that no trial of statin in primary prevention (people without symptomatic coronary artery disease or diabetes) has shown an overall health benefit.
# Conclusion
The study showed that long-term treatment with simvastatin is safe and improves survival in CAD patients.[1] | https://www.wikidoc.org/index.php/4S_Trial | |
e51d7da55fbc573652598b3f59dd7bc33de03e85 | wikidoc | Retinoid | Retinoid
# Overview
The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth.
Retinoids have many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes.
Research is also being done into their ability to treat skin cancers. Currently 9-cis retinoic acid may be used topically to help treat skin lesions from Kaposi's sarcoma.
# Types
There are three generations of Retinoids:
- First generation retinoids: which include retinol, retinal, tretinoin (Retin-A), isotretinoin and alitretinoin.
- Second generation retinoids: which include etretinate and its metabolite acitretin.
- Third generation retinoids: which include tazarotene and bexarotene.
# Structure
The basic structure of the retinoid molecule consist of a cyclic end group, a polyene side chain and a polar end group. The conjugated system formed by alternating C=C double bonds in the polyene side chain are responsible for the color of retinoids (typically yellow, orange, or red). Hence, many retinoids are chromophores. Alternation of side chains and end groups creates the various classes of retinoids.
First and Second generation retinoids are able to bind with several retinoid receptors due to the flexibility imparted by their alternating single and double bonds.
Third generation retinoids are less flexible than First and Second generation retinoids and therefore, interact with fewer retinoid receptors.
# Uses
Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of a number of dermatological conditions such as inflammatory skin disorders, skin cancers, disorders of increased cell turnover(e.g. psoriasis), and photoaging.
Common skin conditions treated by retinoids include acne and psoriasis.
# Toxicity
Toxic effects occur with prolonged high intake (in children 25,000-500,000 IU daily). A medical sign of chronic poisoning is the presence of painful tender swellings on the long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding, general malaise, pseudotumor cerebri, and death may also occur.
Chronic overdose also causes an increased liability of biological membranes and of the outer layer of the skin to peel.
Recent research has suggested a role for retinoids in cutaneous adverse effects for a variety of drugs including the Antimalarial drug proguanil. It is proposed that drugs such as proguanil act to disrupt retinoid homeostasis. | Retinoid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth.
Retinoids have many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes.
Research is also being done into their ability to treat skin cancers. Currently 9-cis retinoic acid may be used topically to help treat skin lesions from Kaposi's sarcoma.
# Types
There are three generations of Retinoids:
- First generation retinoids: which include retinol, retinal, tretinoin (Retin-A), isotretinoin and alitretinoin.
- Second generation retinoids: which include etretinate and its metabolite acitretin.
- Third generation retinoids: which include tazarotene and bexarotene.
# Structure
The basic structure of the retinoid molecule consist of a cyclic end group, a polyene side chain and a polar end group. The conjugated system formed by alternating C=C double bonds in the polyene side chain are responsible for the color of retinoids (typically yellow, orange, or red). Hence, many retinoids are chromophores. Alternation of side chains and end groups creates the various classes of retinoids.
First and Second generation retinoids are able to bind with several retinoid receptors due to the flexibility imparted by their alternating single and double bonds.
Third generation retinoids are less flexible than First and Second generation retinoids and therefore, interact with fewer retinoid receptors.
# Uses
Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of a number of dermatological conditions such as inflammatory skin disorders, skin cancers, disorders of increased cell turnover(e.g. psoriasis), and photoaging.
Common skin conditions treated by retinoids include acne and psoriasis.
# Toxicity
Toxic effects occur with prolonged high intake (in children 25,000-500,000 IU daily). A medical sign of chronic poisoning is the presence of painful tender swellings on the long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding, general malaise, pseudotumor cerebri, and death may also occur.
Chronic overdose also causes an increased liability of biological membranes and of the outer layer of the skin to peel.
Recent research has suggested a role for retinoids in cutaneous adverse effects for a variety of drugs including the Antimalarial drug proguanil. It is proposed that drugs such as proguanil act to disrupt retinoid homeostasis. | https://www.wikidoc.org/index.php/9-cis_retinoic_acid | |
27fa6fbfde54dcaef0667406ff58bb02d5fee5a1 | wikidoc | Cortisol | Cortisol
Cortisol is a corticosteroid hormone produced by the adrenal cortex (in the adrenal gland). It is a vital hormone that is often referred to as the "stress hormone" as it is involved in the response to stress. It increases blood pressure, blood sugar levels and has an immunosuppressive action. In pharmacology, the synthetic form of cortisol is referred to as hydrocortisone, and is used to treat allergies and inflammation as well as cortisol production deficiencies. When first introduced as a treatment for rheumatoid arthritis, it was referred to as Compound E.
# Physiology
## Diurnal variation
The amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning, and the lowest levels present around midnight, 3-5 hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months.)
Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature.
There is also significant individual variation, although a given person tends to have consistent rhythms.
## Effects
In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.)
- It acts as a physiological antagonist to insulin by promoting glycogenolysis (breakdown of glycogen), breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood). There is a decreased glycogen formation in the liver . Prolonged cortisol secretion causes hyperglycemia.
- It can weaken the activity of the immune system . Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor. It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution.
- It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium into cells in exchange for an equal number of sodium ions. This can cause a major problem with the hyperkalemia of metabolic shock from surgery.
- It may help to create memories when exposure is short-term; this is the proposed mechanism for storage of flash bulb memories. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning.
- It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs.
- It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress.
- It increases the effectiveness of catecholamines.
- It allows for the kidneys to produce hypotonic urine.
- It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues.
- It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body).
In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. (It binds with less affinity to it than aldosterone does, but the concentration of blood cortisol is higher than that of blood aldosterone.)
## Binding
Most serum cortisol, all but about 4%, is bound to proteins including corticosteroid binding globulin (CBG), and serum albumin. Only free cortisol is available to most receptors.
# Diseases and disorders
- Hypercortisolism: Excessive levels of cortisol in the blood result in Cushing's syndrome.
- Hypocortisolism, or adrenal insufficiency: If on the other hand the adrenal glands do not produce sufficient amounts of cortisol, Addison's disease is the consequence.
The relationship between cortisol and ACTH is as follows:
# Pharmacology
Hydrocortisone is the chemical form of cortisol used for oral administration or intravenous injection. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients who need steroid treatment but cannot take oral medication, and peri-operatively in patients on long-term steroid treatment to prevent an Addisonian crisis.
It is given by topical application for its anti-inflammatory effect in allergic rashes, eczema, psoriasis and certain other inflammatory conditions.
It may also be injected into inflamed joints resulting from diseases such as gout.
Compared to prednisolone, hydrocortisone is about 1/4th the strength (for the anti-inflammatory effect only). Dexamethasone is about 40 times stronger than hydrocortisone. For side effects, see corticosteroid and prednisolone. Non prescription 1% hydrocortisone cream or ointment are available; stronger forms are prescription only.
# Biochemistry
## Biosynthesis
Cortisol is synthesized from cholesterol. The synthesis takes place in the zona fasciculata of the cortex of the adrenal glands. (The name cortisol comes from cortex.) While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex and mainly secretes the catecholamines, adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation (more epinephrine is produced than norepinephrine, in a ratio 4:1).
The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); production of ACTH is in turn stimulated by corticotropin-releasing hormone (CRH), released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane (via regulation of STAR (steroidogenic acute regulatory) protein). The cholesterol is converted to pregnenolone, catalysed by Cytochrome P450SCC (side chain cleavage).
## Metabolism
Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.
- 11-beta HSD1 utilizes the cofactor NADPH to convert biologically inert cortisone to biologically active cortisol.
- 11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone.
Overall the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue, while 11-beta HSD2 serves to decrease the local concentrations of biologically active cortisol.
An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance, sometimes referred to the metabolic syndrome.
An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME). | Cortisol
…
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
Cortisol is a corticosteroid hormone produced by the adrenal cortex (in the adrenal gland). It is a vital hormone that is often referred to as the "stress hormone" as it is involved in the response to stress. It increases blood pressure, blood sugar levels and has an immunosuppressive action. In pharmacology, the synthetic form of cortisol is referred to as hydrocortisone, and is used to treat allergies and inflammation as well as cortisol production deficiencies. When first introduced as a treatment for rheumatoid arthritis, it was referred to as Compound E.
# Physiology
## Diurnal variation
The amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning, and the lowest levels present around midnight, 3-5 hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months.[1])
Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature.
There is also significant individual variation, although a given person tends to have consistent rhythms.
## Effects
In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.)
- It acts as a physiological antagonist to insulin by promoting glycogenolysis (breakdown of glycogen), breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood). There is a decreased glycogen formation in the liver . [2] Prolonged cortisol secretion causes hyperglycemia.
- It can weaken the activity of the immune system . Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor.[3] It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution.
- It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium into cells in exchange for an equal number of sodium ions.[4] This can cause a major problem with the hyperkalemia of metabolic shock from surgery.
- It may help to create memories when exposure is short-term; this is the proposed mechanism for storage of flash bulb memories. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning.
- It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs.
- It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress.
- It increases the effectiveness of catecholamines.
- It allows for the kidneys to produce hypotonic urine.
- It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues.
- It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body).
In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. (It binds with less affinity to it than aldosterone does, but the concentration of blood cortisol is higher than that of blood aldosterone.)
## Binding
Most serum cortisol, all but about 4%, is bound to proteins including corticosteroid binding globulin (CBG), and serum albumin. Only free cortisol is available to most receptors.
# Diseases and disorders
- Hypercortisolism: Excessive levels of cortisol in the blood result in Cushing's syndrome.
- Hypocortisolism, or adrenal insufficiency: If on the other hand the adrenal glands do not produce sufficient amounts of cortisol, Addison's disease is the consequence.
The relationship between cortisol and ACTH is as follows:
# Pharmacology
Hydrocortisone is the chemical form of cortisol used for oral administration or intravenous injection. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients who need steroid treatment but cannot take oral medication, and peri-operatively in patients on long-term steroid treatment to prevent an Addisonian crisis.
It is given by topical application for its anti-inflammatory effect in allergic rashes, eczema, psoriasis and certain other inflammatory conditions.
It may also be injected into inflamed joints resulting from diseases such as gout.
Compared to prednisolone, hydrocortisone is about 1/4th the strength (for the anti-inflammatory effect only). Dexamethasone is about 40 times stronger than hydrocortisone. For side effects, see corticosteroid and prednisolone. Non prescription 1% hydrocortisone cream or ointment are available; stronger forms are prescription only.[2]
# Biochemistry
## Biosynthesis
Cortisol is synthesized from cholesterol. The synthesis takes place in the zona fasciculata of the cortex of the adrenal glands. (The name cortisol comes from cortex.) While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex and mainly secretes the catecholamines, adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation (more epinephrine is produced than norepinephrine, in a ratio 4:1).
The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); production of ACTH is in turn stimulated by corticotropin-releasing hormone (CRH), released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane (via regulation of STAR (steroidogenic acute regulatory) protein). The cholesterol is converted to pregnenolone, catalysed by Cytochrome P450SCC (side chain cleavage).
## Metabolism
Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.
- 11-beta HSD1 utilizes the cofactor NADPH to convert biologically inert cortisone to biologically active cortisol.
- 11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone.
Overall the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue, while 11-beta HSD2 serves to decrease the local concentrations of biologically active cortisol.
An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance, sometimes referred to the metabolic syndrome.
An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME). | https://www.wikidoc.org/index.php/A-Hydrocort | |
26897eb53b019365cce8b0af5e2f1239aab8b4ad | wikidoc | Abl gene | Abl gene
# Overview
Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene (previous symbol ABL) located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene.
# Function
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The t(9;22) translocation results in the head-to-tail fusion of the BCR and ABL1 genes, leading to a fusion gene present in many cases of chronic myelogenous leukemia. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function for ABL1. The ABL1 gene is expressed as either a 6- or a 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2-11.
# Clinical significance
Mutations in the ABL1 gene are associated with chronic myelogenous leukemia (CML). In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.
This gene is a partner in a fusion gene with the BCR gene in the Philadelphia chromosome, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms. The BCR-ABL transcript encodes a tyrosine kinase, which activates mediators of the cell cycle regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the cell cycle. Second generation BCR-ABL tyrosine-kinase inhibitors are also under development
to inhibit BCR-ABL mutants resistant to imatinib. | Abl gene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene (previous symbol ABL) located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene.
# Function
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The t(9;22) translocation results in the head-to-tail fusion of the BCR and ABL1 genes, leading to a fusion gene present in many cases of chronic myelogenous leukemia. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function for ABL1. The ABL1 gene is expressed as either a 6- or a 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2-11.[1]
# Clinical significance
Mutations in the ABL1 gene are associated with chronic myelogenous leukemia (CML). In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.
This gene is a partner in a fusion gene with the BCR gene in the Philadelphia chromosome, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms. The BCR-ABL transcript encodes a tyrosine kinase, which activates mediators of the cell cycle regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the cell cycle. Second generation BCR-ABL tyrosine-kinase inhibitors are also under development
to inhibit BCR-ABL mutants resistant to imatinib. | https://www.wikidoc.org/index.php/ABL | |
1ea8f5308830b70caf98dbedaffbe8b793a5c1c5 | wikidoc | ADAMTS13 | ADAMTS13
ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)—also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting. It is secreted in blood and degrades large vWf multimers, decreasing their activity.
# Genetics
The ADAMTS13 gene maps to the ninth chromosome (9q34).
# Discovery
Since 1982 it had been known that thrombotic thrombocytopenic purpura (TTP), one of the microangiopathic hemolytic anemias (see below), was characterized in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).
In 1994, vWF was shown to be cleaved between a tyrosine at position 1605 and a methionine at 1606 by a plasma metalloprotease enzyme when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized this enzyme. In the next two years, the same two groups showed that the congenital deficiency of a vWF-cleaving protease was associated with formation of platelet microthrombi in the small blood vessels. In addition, they reported that IgG antibodies directed against this same enzyme caused TTP in a majority of non-familial cases.
# Proteomics
Genomically, ADAMTS13 shares many properties with the 19 member ADAMTS family, all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent disintegrin domain and one or more thrombospondin domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it is not anchored in the cell membrane.
# Role in disease
Deficiency of ADAMTS13 was originally discovered in Upshaw Schulman Syndrome, the recurring familial form of thrombotic thrombocytopenic purpura. By that time it was already suspected that TTP occurred in the autoimmune form as well, owing to its response to plasmapheresis and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific epitopes on its surface have been shown to be the target of inhibitory antibodies.
Low levels of ADAMTS13 are also associated with an increased risk of arterial thrombosis, including myocardial infarction and cerebrovascular disease.
Finally, since the link between aortic valve stenosis and angiodysplasia was proven to be due to high shear stress (Heyde's syndrome), it has been accepted that increased exposure of vWf to ADAMTS13 due to various reasons would predispose to bleeding by causing increased degradation of vWf. This phenomenon is characterised by a form of von Willebrand disease (type 2a). | ADAMTS13
ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)—also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting. It is secreted in blood and degrades large vWf multimers, decreasing their activity.[1]
# Genetics
The ADAMTS13 gene maps to the ninth chromosome (9q34).[1]
# Discovery
Since 1982 it had been known that thrombotic thrombocytopenic purpura (TTP), one of the microangiopathic hemolytic anemias (see below), was characterized in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).[1]
In 1994, vWF was shown to be cleaved between a tyrosine at position 1605 and a methionine at 1606 by a plasma metalloprotease enzyme when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized this enzyme. In the next two years, the same two groups showed that the congenital deficiency of a vWF-cleaving protease was associated with formation of platelet microthrombi in the small blood vessels. In addition, they reported that IgG antibodies directed against this same enzyme caused TTP in a majority of non-familial cases.[1]
# Proteomics
Genomically, ADAMTS13 shares many properties with the 19 member ADAMTS family, all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent disintegrin domain and one or more thrombospondin domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it is not anchored in the cell membrane.[1]
# Role in disease
Deficiency of ADAMTS13 was originally discovered in Upshaw Schulman Syndrome, the recurring familial form of thrombotic thrombocytopenic purpura. By that time it was already suspected that TTP occurred in the autoimmune form as well, owing to its response to plasmapheresis and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific epitopes on its surface have been shown to be the target of inhibitory antibodies.[1][2][3]
Low levels of ADAMTS13 are also associated with an increased risk of arterial thrombosis,[4] including myocardial infarction[5] and cerebrovascular disease.[6][7]
Finally, since the link between aortic valve stenosis and angiodysplasia was proven to be due to high shear stress (Heyde's syndrome), it has been accepted that increased exposure of vWf to ADAMTS13 due to various reasons would predispose to bleeding by causing increased degradation of vWf. This phenomenon is characterised by a form of von Willebrand disease (type 2a).[1] | https://www.wikidoc.org/index.php/ADAMTS-13 | |
73f2a556bffeb6f4119e360a56f24f22256924f8 | wikidoc | ADAMTS17 | ADAMTS17
ADAM metallopeptidase with thrombospondin type 1 motif, 17 is a protein that in humans is encoded by the ADAMTS17 gene.
# Function
This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene has a high sequence similarity to the protein encoded by ADAMTS19, another family member. The function of this protein has not been determined. .
# Clinical significance
Mutations in ADAMTS17 are associated with Weill-Marchesani syndrome . | ADAMTS17
ADAM metallopeptidase with thrombospondin type 1 motif, 17 is a protein that in humans is encoded by the ADAMTS17 gene.[1]
# Function
This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene has a high sequence similarity to the protein encoded by ADAMTS19, another family member. The function of this protein has not been determined. [provided by RefSeq, Jul 2008].
# Clinical significance
Mutations in ADAMTS17 are associated with Weill-Marchesani syndrome .[2] | https://www.wikidoc.org/index.php/ADAMTS17 | |
6c10fdbe673b7fa96c3cab0d1a099e1a1cd304cc | wikidoc | Atenolol | Atenolol
The initial dose of atenolol is 50 mg given as one tablet a day either alone or added to diuretic therapy. The full effect of this dose will usually be seen within one to two weeks. If an optimal response is not achieved, the dosage should be increased to atenolol 100 mg given as one tablet a day. Increasing the dosage beyond 100 mg a day is unlikely to produce any further benefit.
Atenolol may be used alone or concomitantly with other antihypertensive agents including thiazide-type diuretics, hydralazine, prazosin, and alpha-methyldopa.
# Angina Pectoris
The initial dose of atenolol is 50 mg given as one tablet a day. If an optimal response is not achieved within one week, the dosage should be increased to atenolol 100 mg given as one tablet a day. Some patients may require a dosage of 200 mg once a day for optimal effect.
Twenty-four hour control with once daily dosing is achieved by giving doses larger than necessary to achieve an immediate maximum effect. The maximum early effect on exercise tolerance occurs with doses of 50 to 100 mg, but at these doses the effect at 24 hours is attenuated, averaging about 50% to 75% of that observed with once a day oral doses of 200 mg.
# Acute Myocardial Infarction
In patients with definite or suspected acute myocardial infarction, treatment with atenolol I.V. Injection should be initiated as soon as possible after the patient's arrival in the hospital and after eligibility is established. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized. Treatment should begin with the intravenous administration of 5 mg atenolol over 5 minutes followed by another 5 mg intravenous injection 10 minutes later. atenolol I.V. Injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram. Dilutions of atenolol I.V. Injection in Dextrose Injection USP, Sodium Chloride Injection USP, or Sodium Chloride and Dextrose Injection may be used. These admixtures are stable for 48 hours if they are not used immediately.
In patients who tolerate the full intravenous dose (10 mg), atenolol Tablets 50 mg should be initiated 10 minutes after the last intravenous dose followed by another 50 mg oral dose 12 hours later. Thereafter, atenolol can be given orally either 100 mg once daily or 50 mg twice a day for a further 6-9 days or until discharge from the hospital. If bradycardia or hypotension requiring treatment or any other untoward effects occur, atenolol should be discontinued. (See full prescribing information prior to initiating therapy with atenolol Tablets.)
Data from other beta blocker trials suggest that if there is any question concerning the use of IV beta blocker or clinical estimate that there is a contraindication, the IV beta blocker may be eliminated and patients fulfilling the safety criteria may be given atenolol Tablets 50 mg twice daily or 100 mg once a day for at least seven days (if the IV dosing is excluded).
Although the demonstration of efficacy of atenolol is based entirely on data from the first seven postinfarction days, data from other beta blocker trials suggest that treatment with beta blockers that are effective in the postinfarction setting may be continued for one to three years if there are no contraindications.
Atenolol is an additional treatment to standard coronary care unit therapy.
Atenolol is excreted by the kidneys; consequently dosage should be adjusted in cases of severe impairment of renal function. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Evaluation of patients with hypertension or myocardial infarction should always include assessment of renal function. Atenolol excretion would be expected to decrease with advancing age.
No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73m2. Accumulation of atenolol and prolongation of its half-life were studied in subjects with creatinine clearance between 5 and 105 mL/min. Peak plasma levels were significantly increased in subjects with creatinine clearances below 30 mL/min.
The following maximum oral dosages are recommended for elderly, renally-impaired patients and for patients with renal impairment due to other causes:
Some renally-impaired or elderly patients being treated for hypertension may require a lower starting dose of atenolol: 25 mg given as one tablet a day. If this 25 mg dose is used, assessment of efficacy must be made carefully. This should include measurement of blood pressure just prior to the next dose ("trough" blood pressure) to ensure that the treatment effect is present for a full 24 hours.
Although a similar dosage reduction may be considered for elderly and/or renally-impaired patients being treated for indications other than hypertension, data are not available for these patient populations.
Patients on hemodialysis should be given 25 mg or 50 mg after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.
If withdrawal of atenolol therapy is planned, it should be achieved gradually and patients should be carefully observed and advised to limit physical activity to a minimum.
- Dosing Information
- 5 mg IV pre-surgery, followed by 50 mg (HR of 55-65 bpm) or 100 mg PO (HR over 65 bpm).
- Dosing Information
- 0.3 and 1.3 mg/kg/day.
- Dosing Information
- Initiation dose of 1 mg/kg/day, if tachycardia perists increase to 2 mg/kg/day.
- Dosing Information
- 1.5 mg/kg/day.
- Second degree heart block and third degree heart block
- Cardiogenic shock
- Overt cardiac failure
- Hypersensitivity to the atenolol or any of the drug product’s components.
Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure.
In patients with acute myocardial infarction, cardiac failure which is not promptly and effectively controlled by 80 mg of intravenous furosemide or equivalent therapy is a contraindication to beta-blocker treatment.
Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, and the response observed closely. If cardiac failure continues despite adequate treatment, atenolol should be withdrawn.
## Concomitant Use of Calcium Channel Blockers
Bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta-blockers are administered with verapamil or diltiazem. Patients with pre-existing conduction abnormalities or left ventricular dysfunction are particularly susceptible.
## Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1selectivity, however, TENORMIN may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1 selectivity is not absolute, the lowest possible dose of atenolol should be used with therapy initiated at 50 mg and a beta2-stimulating agent (bronchodilator) should be made available. If dosage must be increased, dividing the dose should be considered in order to achieve lower peak blood levels.
## Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
## Diabetes and Hypoglycemia
Atenolol should be used with caution in diabetic patients if a beta-blocking agent is required. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses atenolol does not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, does not delay recovery of blood glucose to normal levels.
## Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom atenolol therapy is to be withdrawn should be monitored closely.
## Untreated Pheochromocytoma
Atenolol should not be given to patients with untreated pheochromocytoma.
## Pregnancy and Fetal Injury
Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in cord blood. Administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. 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.
Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding.
Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum recommended human antihypertensive dose1. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose1.
The frequency estimates in the following table were derived from controlled studies in hypertensive patients in which adverse reactions were either volunteered by the patient (US studies) or elicited, eg, by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects of atenolol and placebo is similar, causal relationship to atenolol is uncertain.
# Acute Myocardial Infarction
In a series of investigations in the treatment of acute myocardial infarction, bradycardia and hypotension occurred more commonly, as expected for any beta blocker, in atenolol-treated patients than in control patients. However, these usually responded to atropine and/or to withholding further dosage of atenolol. The incidence of heart failure was not increased by atenolol. Inotropic agents were infrequently used. The reported frequency of these and other events occurring during these investigations is given in the following table.
In a study of 477 patients, the following adverse events were reported during either intravenous and/or oral atenolol administration:
In the subsequent International Study of Infarct Survival (ISIS-1) including over 16,000 patients of whom 8,037 were randomized to receive atenolol treatment, the dosage of intravenous and subsequent oral atenolol was either discontinued or reduced for the following reasons:
# Potential Adverse Effects
In addition, a variety of adverse effects have been reported with other beta-blockers, and may be considered potential adverse effects of atenolol.
- Hematologic: Agranulocytosis.
- Allergic: Fever, combined with aching and sore throat, laryngospasm, and respiratory distress.
- Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation of time and place; short-term memory loss; emotional lability with slightly clouded sensorium; and, decreased performance on neuropsychometrics.
- Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
- Other: Erythematous rash.
- Miscellaneous: There have been reports of skin rashes and/or dry eyes associated with the use of beta-blockers. The reported incidence is small, and in most cases, the symptoms have cleared when treatment was withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with atenolol. Furthermore, a number of patients who had previously demonstrated established practolol reactions were transferred to atenolol therapy with subsequent resolution or quiescence of the reaction.
- Calcium channel blockers may also have an additive effect when given with atenolol.
- Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects.
- Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta-blockers.
- Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta-blockers.
- Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta-blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.
- Concomitant use of prostaglandin synthase inhibiting drugs, eg, indomethacin, may decrease the hypotensive effects of beta-blockers.
- Information on concurrent usage of atenolol and aspirin is limited. Data from several studies, ie, TIMI-II, ISIS-2, currently do not suggest any clinical interaction between aspirin and beta-blockers in the acute myocardial infarction setting.
- While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.
- Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding.
Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum recommended human antihypertensive dose. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose.
Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding.
Clinical studies of atenolol did not include sufficient number of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
## Acute Myocardial Infarction
Of the 8,037 patients with suspected acute myocardial infarction randomized to atenolol in the ISIS-1 trial, 33% (2,644) were 65 years of age and older. It was not possible to identify significant differences in efficacy and safety between older and younger patients; however, elderly patients with systolic blood pressure < 120 mmHg seemed less likely to benefit.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Evaluation of patients with hypertension or myocardial infarction should always include assessment of renal function.
Injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram.
The predominant symptoms reported following atenolol overdose are lethargy, disorder of respiratory drive, wheezing, sinus pause and bradycardia. Additionally, common effects associated with overdosage of any beta-blocking agent and which might also be expected in atenolol overdose are congestive heart failure, hypotension, bronchospasm and/or hypoglycemia.
Treatment of overdose should be directed to the removal of any unabsorbed drug by induced emesis, gastric lavage, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Other treatment modalities should be employed at the physician's discretion and may include:
- BRADYCARDIA: Atropine intravenously. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated.
- HEART BLOCK (SECOND OR THIRD DEGREE): Isoproterenol or transvenous cardiac pacemaker.
- CARDIAC FAILURE: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful.
- HYPOTENSION: Vasopressors such as dopamine or norepinephrine (levarterenol). Monitor blood pressure continuously.
- BRONCHOSPASM: A beta2 stimulant such as isoproterenol or terbutaline and/or aminophylline.
- HYPOGLYCEMIA: Intravenous glucose.
Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support.
Atenolol (free base) has a molecular weight of 266. It is a relatively polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37°C and a log partition coefficient (octanol/water) of 0.23. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at 25°C).
Atenolol is available as 25, 50 and 100 mg tablets for oral administration.
Inactive Ingredients: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate
A significant beta-blocking effect of atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. This effect is maximal at about 2 to 4 hours, and persists for at least 24 hours. Maximum reduction in exercise tachycardia occurs within 5 minutes of an intravenous dose. For both orally and intravenously administered drug, the duration of action is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. The effect on exercise tachycardia of a single 10 mg intravenous dose is largely dissipated by 12 hours, whereas beta-blocking activity of single oral doses of 50 mg and 100 mg is still evident beyond 24 hours following administration. However, as has been shown for all beta-blocking agents, the antihypertensive effect does not appear to be related to plasma level.
In normal subjects, the beta1 selectivity of atenolol has been shown by its reduced ability to reverse the beta2-mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of atenolol producing a greater effect on resting heart rate than propranololresulted in much less increase in airway resistance. In a placebo controlled comparison of approximately equipotent oral doses of several beta blockers, atenolol produced a significantly smaller decrease of FEV1 than nonselective beta blockers such as propranololand, unlike those agents, did not inhibit bronchodilation in response to isoproterenol.
Consistent with its negative chronotropic effect due to beta blockade of the SA node, atenolol increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged. atenolol is devoid of membrane stabilizing activity, and increasing the dose well beyond that producing beta blockade does not further depress myocardial contractility. Several studies have demonstrated a moderate (approximately 10%) increase in stroke volume at rest and during exercise.
In controlled clinical trials, atenolol, given as a single daily oral dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. atenolol has been studied in combination with thiazide-type diuretics, and the blood pressure effects of the combination are approximately additive. Atenolol is also compatible with methyldopa, hydralazine, and prazosin, each combination resulting in a larger fall in blood pressure than with the single agents. The dose range of atenolol is narrow and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. The mechanisms of the antihypertensive effects of beta-blocking agents have not been established. Several possible mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery, and (3) suppression of renin activity. The results from long-term studies have not shown any diminution of the antihypertensive efficacy of atenolol with prolonged use.
By blocking the positive chronotropic and inotropic effects of catecholamines and by decreasing blood pressure, atenolol generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, atenolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.
In a multicenter clinical trial (ISIS-1) conducted in 16,027 patients with suspected myocardial infarction, patients presenting within 12 hours (mean = 5 hours) after the onset of pain were randomized to either conventional therapy plus atenolol (n = 8,037), or conventional therapy alone (n = 7,990). Patients with a heart rate of < 50 bpm or systolic blood pressure < 100 mm Hg, or with other contraindications to beta blockade were excluded. Thirty-eight percent of each group were treated within 4 hours of onset of pain. The mean time from onset of pain to entry was 5.0 ± 2.7 hours in both groups. Patients in the atenolol group were to receive atenolol I.V. Injection 5-10 mg given over 5 minutes plus atenolol Tablets 50 mg every 12 hours orally on the first study day (the first oral dose administered about 15 minutes after the IV dose) followed by either atenolol Tablets 100 mg once daily or atenolol Tablets 50 mg twice daily on days 2-7. The groups were similar in demographic and medical history characteristics and in electrocardiographic evidence of myocardial infarction, bundle branch block, and first degree atrioventricular block at entry.
During the treatment period (days 0-7), the vascular mortality rates were 3.89% in the atenolol group (313 deaths) and 4.57% in the control group (365 deaths). This absolute difference in rates, 0.68%, is statistically significant at the P < 0.05 level. The absolute difference translates into a proportional reduction of 15% (3.89-4.57/4.57 = -0.15). The 95% confidence limits are 1%-27%. Most of the difference was attributed to mortality in days 0-1 (atenolol - 121 deaths; control - 171 deaths).
Despite the large size of the ISIS-1 trial, it is not possible to identify clearly subgroups of patients most likely or least likely to benefit from early treatment with atenolol. Good clinical judgment suggests, however, that patients who are dependent on sympathetic stimulation for maintenance of adequate cardiac output and blood pressure are not good candidates for beta blockade. Indeed, the trial protocol reflected that judgment by excluding patients with blood pressure consistently below 100 mm Hg systolic. The overall results of the study are compatible with the possibility that patients with borderline blood pressure (less than 120 mm Hg systolic), especially if over 60 years of age, are less likely to benefit.
The mechanism through which atenolol improves survival in patients with definite or suspected acute myocardial infarction is unknown, as is the case for other beta blockers in the postinfarction setting. Atenolol, in addition to its effects on survival, has shown other clinical benefits including reduced frequency of ventricular premature beats, reduced chest pain, and reduced enzyme elevation.
The elimination half-life of oral atenolol is approximately 6 to 7 hours, and there is no alteration of the kinetic profile of the drug by chronic administration. Following intravenous administration, peak plasma levels are reached within 5 minutes. Declines from peak levels are rapid (5- to 10-fold) during the first 7 hours; thereafter, plasma levels decay with a half-life similar to that of orally administered drug. Following oral doses of 50 mg or 100 mg, both beta-blocking and antihypertensive effects persist for at least 24 hours. When renal function is impaired, elimination of atenolol is closely related to the glomerular filtration rate; significant accumulation occurs when the creatinine clearance falls below 35 mL/min/1.73m2.
In general, elderly patients present higher atenolol plasma levels with total clearance values about 50% lower than younger subjects. The half-life is markedly longer in the elderly compared to younger subjects. The reduction in atenolol clearance follows the general trend that the elimination of renally excreted drugs is decreased with increasing age.
Fertility of male or female rats (evaluated at dose levels as high as 200 mg/kg/day or 100 times the maximum recommended human dose) was unaffected by atenolol administration.
Chronic studies employing oral atenolol performed in animals have revealed the occurrence of vacuolation of epithelial cells of Brunner's glands in the duodenum of both male and female dogs at all tested dose levels of atenolol (starting at 15 mg/kg/day or 7.5 times the maximum recommended human antihypertensive dose11, respectively).
In controlled clinical trials, TENORMIN given as a single daily dose was an effective antihypertensive agent providing 24-hour reduction of blood pressure. TENORMIN has been studied in combination with thiazide-type diuretics, and the blood pressure effects of the combination are approximately additive. TENORMIN is also compatible with methyldopa, hydralazine, and prazosin, each combination resulting in a larger fall in blood pressure than with the single agents. The dose range of TENORMIN is narrow and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. The mechanisms of the antihypertensive effects of beta-blocking agents have not been established. Several possible mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery, and (3) suppression of renin activity. The results from long-term studies have not shown any diminution of the antihypertensive efficacy of TENORMIN with prolonged use.
In a multicenter clinical trial (ISIS-1) conducted in 16,027 patients with suspected myocardial infarction, patients presenting within 12 hours (mean = 5 hours) after the onset of pain were randomized to either conventional therapy plus TENORMIN (n = 8,037), or conventional therapy alone (n = 7,990). Patients with a heart rate of < 50 bpm or systolic blood pressure < 100 mm Hg, or with other contraindications to beta blockade, were excluded. Thirty-eight percent of each group were treated within 4 hours of onset of pain. The mean time from onset of pain to entry was 5.0 ± 2.7 hours in both groups. Patients in the TENORMIN group were to receive TENORMIN I.V. Injection 5-10 mg given over 5 minutes plus TENORMIN Tablets 50 mg every 12 hours orally on the first study day (the first oral dose administered about 15 minutes after the IV dose) followed by either TENORMIN Tablets 100 mg once daily or TENORMIN Tablets 50 mg twice daily on days 2-7. The groups were similar in demographic and medical history characteristics and in electrocardiographic evidence of myocardial infarction, bundle branch block, and first degree atrioventricular block at entry.
During the treatment period (days 0-7), the vascular mortality rates were 3.89% in the TENORMIN group (313 deaths) and 4.57% in the control group (365 deaths). This absolute difference in rates, 0.68%, is statistically significant at the P < 0.05 level. The absolute difference translates into a proportional reduction of 15% (3.89-4.57/4.57 = -0.15). The 95% confidence limits are 1%-27%. Most of the difference was attributed to mortality in days 0-1 (TENORMIN - 121 deaths; control - 171 deaths).
- Tablets of 25 mg atenolol, NDC 0310-0107 (round, flat, uncoated white tablets identified with "T" debossed on one side and 107 debossed on the other side) are supplied in bottles of 100 tablets.
- Tablets of 50 mg atenolol, NDC 0310-0105 (round, flat, uncoated white tablets identified with "TENORMIN" debossed on one side and 105 debossed on the other side, bisected) are supplied in bottles of 100 tablets.
- Tablets of 100 mg atenolol, NDC 0310-0101 (round, flat, uncoated white tablets identified with "TENORMIN" debossed on one side and 101 debossed on the other side) are supplied in bottles of 100 tablets.
- TENORMIN I.V. Injection, NDC 0310-0108, is supplied as 5 mg atenolol in 10 mL ampules of isotonic citrate-buffered aqueous solution.
- Store at controlled room temperature, 20-25°C (68-77°F) . Dispense in well-closed, light-resistant containers.
- Protect from light.
- Keep ampules in outer packaging until time of use.
- Store at controlled room temperature, 20-25°C (68-77°F).
- ↑ Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W; et al. (1998). "Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group". Anesthesiology. 88 (1): 7–17. PMID 9447850.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}
- ↑ Mehta AV, Subrahmanyam AB, Anand R (1996). "Long-term efficacy and safety of atenolol for supraventricular tachycardia in children". Pediatr Cardiol. 17 (4): 231–6. PMID 8662045.CS1 maint: Multiple names: authors list (link)
- ↑ Ko JK, Ban JE, Kim YH, Park IS (2004). "Long-term efficacy of atenolol for atrioventricular reciprocating tachycardia in children less than 5 years old". Pediatr Cardiol. 25 (2): 97–101. doi:10.1007/s00246-003-0536-x. PMID 14648002.CS1 maint: Multiple names: authors list (link)
- ↑ Trippel DL, Gillette PC (1990). "Atenolol in children with ventricular arrhythmias". Am Heart J. 119 (6): 1312–6. PMID 2353617. | Atenolol
The initial dose of atenolol is 50 mg given as one tablet a day either alone or added to diuretic therapy. The full effect of this dose will usually be seen within one to two weeks. If an optimal response is not achieved, the dosage should be increased to atenolol 100 mg given as one tablet a day. Increasing the dosage beyond 100 mg a day is unlikely to produce any further benefit.
Atenolol may be used alone or concomitantly with other antihypertensive agents including thiazide-type diuretics, hydralazine, prazosin, and alpha-methyldopa.
## Angina Pectoris
The initial dose of atenolol is 50 mg given as one tablet a day. If an optimal response is not achieved within one week, the dosage should be increased to atenolol 100 mg given as one tablet a day. Some patients may require a dosage of 200 mg once a day for optimal effect.
Twenty-four hour control with once daily dosing is achieved by giving doses larger than necessary to achieve an immediate maximum effect. The maximum early effect on exercise tolerance occurs with doses of 50 to 100 mg, but at these doses the effect at 24 hours is attenuated, averaging about 50% to 75% of that observed with once a day oral doses of 200 mg.
## Acute Myocardial Infarction
In patients with definite or suspected acute myocardial infarction, treatment with atenolol I.V. Injection should be initiated as soon as possible after the patient's arrival in the hospital and after eligibility is established. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized. Treatment should begin with the intravenous administration of 5 mg atenolol over 5 minutes followed by another 5 mg intravenous injection 10 minutes later. atenolol I.V. Injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram. Dilutions of atenolol I.V. Injection in Dextrose Injection USP, Sodium Chloride Injection USP, or Sodium Chloride and Dextrose Injection may be used. These admixtures are stable for 48 hours if they are not used immediately.
In patients who tolerate the full intravenous dose (10 mg), atenolol Tablets 50 mg should be initiated 10 minutes after the last intravenous dose followed by another 50 mg oral dose 12 hours later. Thereafter, atenolol can be given orally either 100 mg once daily or 50 mg twice a day for a further 6-9 days or until discharge from the hospital. If bradycardia or hypotension requiring treatment or any other untoward effects occur, atenolol should be discontinued. (See full prescribing information prior to initiating therapy with atenolol Tablets.)
Data from other beta blocker trials suggest that if there is any question concerning the use of IV beta blocker or clinical estimate that there is a contraindication, the IV beta blocker may be eliminated and patients fulfilling the safety criteria may be given atenolol Tablets 50 mg twice daily or 100 mg once a day for at least seven days (if the IV dosing is excluded).
Although the demonstration of efficacy of atenolol is based entirely on data from the first seven postinfarction days, data from other beta blocker trials suggest that treatment with beta blockers that are effective in the postinfarction setting may be continued for one to three years if there are no contraindications.
Atenolol is an additional treatment to standard coronary care unit therapy.
Atenolol is excreted by the kidneys; consequently dosage should be adjusted in cases of severe impairment of renal function. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Evaluation of patients with hypertension or myocardial infarction should always include assessment of renal function. Atenolol excretion would be expected to decrease with advancing age.
No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73m2. Accumulation of atenolol and prolongation of its half-life were studied in subjects with creatinine clearance between 5 and 105 mL/min. Peak plasma levels were significantly increased in subjects with creatinine clearances below 30 mL/min.
The following maximum oral dosages are recommended for elderly, renally-impaired patients and for patients with renal impairment due to other causes:
Some renally-impaired or elderly patients being treated for hypertension may require a lower starting dose of atenolol: 25 mg given as one tablet a day. If this 25 mg dose is used, assessment of efficacy must be made carefully. This should include measurement of blood pressure just prior to the next dose ("trough" blood pressure) to ensure that the treatment effect is present for a full 24 hours.
Although a similar dosage reduction may be considered for elderly and/or renally-impaired patients being treated for indications other than hypertension, data are not available for these patient populations.
Patients on hemodialysis should be given 25 mg or 50 mg after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.
If withdrawal of atenolol therapy is planned, it should be achieved gradually and patients should be carefully observed and advised to limit physical activity to a minimum.
- Dosing Information
- 5 mg IV pre-surgery, followed by 50 mg (HR of 55-65 bpm) or 100 mg PO (HR over 65 bpm).[1]
- Dosing Information
- 0.3 and 1.3 mg/kg/day.[2]
- Dosing Information
- Initiation dose of 1 mg/kg/day, if tachycardia perists increase to 2 mg/kg/day.[3]
- Dosing Information
- 1.5 mg/kg/day.[4]
- Second degree heart block and third degree heart block
- Cardiogenic shock
- Overt cardiac failure
- Hypersensitivity to the atenolol or any of the drug product’s components.
Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure.
In patients with acute myocardial infarction, cardiac failure which is not promptly and effectively controlled by 80 mg of intravenous furosemide or equivalent therapy is a contraindication to beta-blocker treatment.
Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, and the response observed closely. If cardiac failure continues despite adequate treatment, atenolol should be withdrawn.
### Concomitant Use of Calcium Channel Blockers
Bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta-blockers are administered with verapamil or diltiazem. Patients with pre-existing conduction abnormalities or left ventricular dysfunction are particularly susceptible.
### Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1selectivity, however, TENORMIN may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1 selectivity is not absolute, the lowest possible dose of atenolol should be used with therapy initiated at 50 mg and a beta2-stimulating agent (bronchodilator) should be made available. If dosage must be increased, dividing the dose should be considered in order to achieve lower peak blood levels.
### Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
### Diabetes and Hypoglycemia
Atenolol should be used with caution in diabetic patients if a beta-blocking agent is required. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses atenolol does not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, does not delay recovery of blood glucose to normal levels.
### Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom atenolol therapy is to be withdrawn should be monitored closely.
### Untreated Pheochromocytoma
Atenolol should not be given to patients with untreated pheochromocytoma.
### Pregnancy and Fetal Injury
Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in cord blood. Administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. 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.
Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding.
Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum recommended human antihypertensive dose1. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose1.
The frequency estimates in the following table were derived from controlled studies in hypertensive patients in which adverse reactions were either volunteered by the patient (US studies) or elicited, eg, by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects of atenolol and placebo is similar, causal relationship to atenolol is uncertain.
## Acute Myocardial Infarction
In a series of investigations in the treatment of acute myocardial infarction, bradycardia and hypotension occurred more commonly, as expected for any beta blocker, in atenolol-treated patients than in control patients. However, these usually responded to atropine and/or to withholding further dosage of atenolol. The incidence of heart failure was not increased by atenolol. Inotropic agents were infrequently used. The reported frequency of these and other events occurring during these investigations is given in the following table.
In a study of 477 patients, the following adverse events were reported during either intravenous and/or oral atenolol administration:
In the subsequent International Study of Infarct Survival (ISIS-1) including over 16,000 patients of whom 8,037 were randomized to receive atenolol treatment, the dosage of intravenous and subsequent oral atenolol was either discontinued or reduced for the following reasons:
## Potential Adverse Effects
In addition, a variety of adverse effects have been reported with other beta-blockers, and may be considered potential adverse effects of atenolol.
- Hematologic: Agranulocytosis.
- Allergic: Fever, combined with aching and sore throat, laryngospasm, and respiratory distress.
- Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation of time and place; short-term memory loss; emotional lability with slightly clouded sensorium; and, decreased performance on neuropsychometrics.
- Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
- Other: Erythematous rash.
- Miscellaneous: There have been reports of skin rashes and/or dry eyes associated with the use of beta-blockers. The reported incidence is small, and in most cases, the symptoms have cleared when treatment was withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with atenolol. Furthermore, a number of patients who had previously demonstrated established practolol reactions were transferred to atenolol therapy with subsequent resolution or quiescence of the reaction.
- Calcium channel blockers may also have an additive effect when given with atenolol.
- Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects.
- Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta-blockers.
- Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta-blockers.
- Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta-blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.
- Concomitant use of prostaglandin synthase inhibiting drugs, eg, indomethacin, may decrease the hypotensive effects of beta-blockers.
- Information on concurrent usage of atenolol and aspirin is limited. Data from several studies, ie, TIMI-II, ISIS-2, currently do not suggest any clinical interaction between aspirin and beta-blockers in the acute myocardial infarction setting.
- While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.
- Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding.
Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum recommended human antihypertensive dose. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose.
Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding.
Clinical studies of atenolol did not include sufficient number of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Acute Myocardial Infarction
Of the 8,037 patients with suspected acute myocardial infarction randomized to atenolol in the ISIS-1 trial, 33% (2,644) were 65 years of age and older. It was not possible to identify significant differences in efficacy and safety between older and younger patients; however, elderly patients with systolic blood pressure < 120 mmHg seemed less likely to benefit.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Evaluation of patients with hypertension or myocardial infarction should always include assessment of renal function.
Injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram.
The predominant symptoms reported following atenolol overdose are lethargy, disorder of respiratory drive, wheezing, sinus pause and bradycardia. Additionally, common effects associated with overdosage of any beta-blocking agent and which might also be expected in atenolol overdose are congestive heart failure, hypotension, bronchospasm and/or hypoglycemia.
Treatment of overdose should be directed to the removal of any unabsorbed drug by induced emesis, gastric lavage, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Other treatment modalities should be employed at the physician's discretion and may include:
- BRADYCARDIA: Atropine intravenously. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated.
- HEART BLOCK (SECOND OR THIRD DEGREE): Isoproterenol or transvenous cardiac pacemaker.
- CARDIAC FAILURE: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful.
- HYPOTENSION: Vasopressors such as dopamine or norepinephrine (levarterenol). Monitor blood pressure continuously.
- BRONCHOSPASM: A beta2 stimulant such as isoproterenol or terbutaline and/or aminophylline.
- HYPOGLYCEMIA: Intravenous glucose.
Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support.
Atenolol (free base) has a molecular weight of 266. It is a relatively polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37°C and a log partition coefficient (octanol/water) of 0.23. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at 25°C).
Atenolol is available as 25, 50 and 100 mg tablets for oral administration.
Inactive Ingredients: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate
A significant beta-blocking effect of atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. This effect is maximal at about 2 to 4 hours, and persists for at least 24 hours. Maximum reduction in exercise tachycardia occurs within 5 minutes of an intravenous dose. For both orally and intravenously administered drug, the duration of action is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. The effect on exercise tachycardia of a single 10 mg intravenous dose is largely dissipated by 12 hours, whereas beta-blocking activity of single oral doses of 50 mg and 100 mg is still evident beyond 24 hours following administration. However, as has been shown for all beta-blocking agents, the antihypertensive effect does not appear to be related to plasma level.
In normal subjects, the beta1 selectivity of atenolol has been shown by its reduced ability to reverse the beta2-mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of atenolol producing a greater effect on resting heart rate than propranololresulted in much less increase in airway resistance. In a placebo controlled comparison of approximately equipotent oral doses of several beta blockers, atenolol produced a significantly smaller decrease of FEV1 than nonselective beta blockers such as propranololand, unlike those agents, did not inhibit bronchodilation in response to isoproterenol.
Consistent with its negative chronotropic effect due to beta blockade of the SA node, atenolol increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged. atenolol is devoid of membrane stabilizing activity, and increasing the dose well beyond that producing beta blockade does not further depress myocardial contractility. Several studies have demonstrated a moderate (approximately 10%) increase in stroke volume at rest and during exercise.
In controlled clinical trials, atenolol, given as a single daily oral dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. atenolol has been studied in combination with thiazide-type diuretics, and the blood pressure effects of the combination are approximately additive. Atenolol is also compatible with methyldopa, hydralazine, and prazosin, each combination resulting in a larger fall in blood pressure than with the single agents. The dose range of atenolol is narrow and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. The mechanisms of the antihypertensive effects of beta-blocking agents have not been established. Several possible mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery, and (3) suppression of renin activity. The results from long-term studies have not shown any diminution of the antihypertensive efficacy of atenolol with prolonged use.
By blocking the positive chronotropic and inotropic effects of catecholamines and by decreasing blood pressure, atenolol generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, atenolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.
In a multicenter clinical trial (ISIS-1) conducted in 16,027 patients with suspected myocardial infarction, patients presenting within 12 hours (mean = 5 hours) after the onset of pain were randomized to either conventional therapy plus atenolol (n = 8,037), or conventional therapy alone (n = 7,990). Patients with a heart rate of < 50 bpm or systolic blood pressure < 100 mm Hg, or with other contraindications to beta blockade were excluded. Thirty-eight percent of each group were treated within 4 hours of onset of pain. The mean time from onset of pain to entry was 5.0 ± 2.7 hours in both groups. Patients in the atenolol group were to receive atenolol I.V. Injection 5-10 mg given over 5 minutes plus atenolol Tablets 50 mg every 12 hours orally on the first study day (the first oral dose administered about 15 minutes after the IV dose) followed by either atenolol Tablets 100 mg once daily or atenolol Tablets 50 mg twice daily on days 2-7. The groups were similar in demographic and medical history characteristics and in electrocardiographic evidence of myocardial infarction, bundle branch block, and first degree atrioventricular block at entry.
During the treatment period (days 0-7), the vascular mortality rates were 3.89% in the atenolol group (313 deaths) and 4.57% in the control group (365 deaths). This absolute difference in rates, 0.68%, is statistically significant at the P < 0.05 level. The absolute difference translates into a proportional reduction of 15% (3.89-4.57/4.57 = -0.15). The 95% confidence limits are 1%-27%. Most of the difference was attributed to mortality in days 0-1 (atenolol - 121 deaths; control - 171 deaths).
Despite the large size of the ISIS-1 trial, it is not possible to identify clearly subgroups of patients most likely or least likely to benefit from early treatment with atenolol. Good clinical judgment suggests, however, that patients who are dependent on sympathetic stimulation for maintenance of adequate cardiac output and blood pressure are not good candidates for beta blockade. Indeed, the trial protocol reflected that judgment by excluding patients with blood pressure consistently below 100 mm Hg systolic. The overall results of the study are compatible with the possibility that patients with borderline blood pressure (less than 120 mm Hg systolic), especially if over 60 years of age, are less likely to benefit.
The mechanism through which atenolol improves survival in patients with definite or suspected acute myocardial infarction is unknown, as is the case for other beta blockers in the postinfarction setting. Atenolol, in addition to its effects on survival, has shown other clinical benefits including reduced frequency of ventricular premature beats, reduced chest pain, and reduced enzyme elevation.
The elimination half-life of oral atenolol is approximately 6 to 7 hours, and there is no alteration of the kinetic profile of the drug by chronic administration. Following intravenous administration, peak plasma levels are reached within 5 minutes. Declines from peak levels are rapid (5- to 10-fold) during the first 7 hours; thereafter, plasma levels decay with a half-life similar to that of orally administered drug. Following oral doses of 50 mg or 100 mg, both beta-blocking and antihypertensive effects persist for at least 24 hours. When renal function is impaired, elimination of atenolol is closely related to the glomerular filtration rate; significant accumulation occurs when the creatinine clearance falls below 35 mL/min/1.73m2.
In general, elderly patients present higher atenolol plasma levels with total clearance values about 50% lower than younger subjects. The half-life is markedly longer in the elderly compared to younger subjects. The reduction in atenolol clearance follows the general trend that the elimination of renally excreted drugs is decreased with increasing age.
Fertility of male or female rats (evaluated at dose levels as high as 200 mg/kg/day or 100 times the maximum recommended human dose) was unaffected by atenolol administration.
Chronic studies employing oral atenolol performed in animals have revealed the occurrence of vacuolation of epithelial cells of Brunner's glands in the duodenum of both male and female dogs at all tested dose levels of atenolol (starting at 15 mg/kg/day or 7.5 times the maximum recommended human antihypertensive dose11, respectively).
In controlled clinical trials, TENORMIN given as a single daily dose was an effective antihypertensive agent providing 24-hour reduction of blood pressure. TENORMIN has been studied in combination with thiazide-type diuretics, and the blood pressure effects of the combination are approximately additive. TENORMIN is also compatible with methyldopa, hydralazine, and prazosin, each combination resulting in a larger fall in blood pressure than with the single agents. The dose range of TENORMIN is narrow and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. The mechanisms of the antihypertensive effects of beta-blocking agents have not been established. Several possible mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery, and (3) suppression of renin activity. The results from long-term studies have not shown any diminution of the antihypertensive efficacy of TENORMIN with prolonged use.
In a multicenter clinical trial (ISIS-1) conducted in 16,027 patients with suspected myocardial infarction, patients presenting within 12 hours (mean = 5 hours) after the onset of pain were randomized to either conventional therapy plus TENORMIN (n = 8,037), or conventional therapy alone (n = 7,990). Patients with a heart rate of < 50 bpm or systolic blood pressure < 100 mm Hg, or with other contraindications to beta blockade, were excluded. Thirty-eight percent of each group were treated within 4 hours of onset of pain. The mean time from onset of pain to entry was 5.0 ± 2.7 hours in both groups. Patients in the TENORMIN group were to receive TENORMIN I.V. Injection 5-10 mg given over 5 minutes plus TENORMIN Tablets 50 mg every 12 hours orally on the first study day (the first oral dose administered about 15 minutes after the IV dose) followed by either TENORMIN Tablets 100 mg once daily or TENORMIN Tablets 50 mg twice daily on days 2-7. The groups were similar in demographic and medical history characteristics and in electrocardiographic evidence of myocardial infarction, bundle branch block, and first degree atrioventricular block at entry.
During the treatment period (days 0-7), the vascular mortality rates were 3.89% in the TENORMIN group (313 deaths) and 4.57% in the control group (365 deaths). This absolute difference in rates, 0.68%, is statistically significant at the P < 0.05 level. The absolute difference translates into a proportional reduction of 15% (3.89-4.57/4.57 = -0.15). The 95% confidence limits are 1%-27%. Most of the difference was attributed to mortality in days 0-1 (TENORMIN - 121 deaths; control - 171 deaths).
- Tablets of 25 mg atenolol, NDC 0310-0107 (round, flat, uncoated white tablets identified with "T" debossed on one side and 107 debossed on the other side) are supplied in bottles of 100 tablets.
- Tablets of 50 mg atenolol, NDC 0310-0105 (round, flat, uncoated white tablets identified with "TENORMIN" debossed on one side and 105 debossed on the other side, bisected) are supplied in bottles of 100 tablets.
- Tablets of 100 mg atenolol, NDC 0310-0101 (round, flat, uncoated white tablets identified with "TENORMIN" debossed on one side and 101 debossed on the other side) are supplied in bottles of 100 tablets.
- TENORMIN I.V. Injection, NDC 0310-0108, is supplied as 5 mg atenolol in 10 mL ampules of isotonic citrate-buffered aqueous solution.
- Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in well-closed, light-resistant containers.
- Protect from light.
- Keep ampules in outer packaging until time of use.
- Store at controlled room temperature, 20-25°C (68-77°F).
- ↑ Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W; et al. (1998). "Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group". Anesthesiology. 88 (1): 7–17. PMID 9447850.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}
- ↑ Mehta AV, Subrahmanyam AB, Anand R (1996). "Long-term efficacy and safety of atenolol for supraventricular tachycardia in children". Pediatr Cardiol. 17 (4): 231–6. PMID 8662045.CS1 maint: Multiple names: authors list (link)
- ↑ Ko JK, Ban JE, Kim YH, Park IS (2004). "Long-term efficacy of atenolol for atrioventricular reciprocating tachycardia in children less than 5 years old". Pediatr Cardiol. 25 (2): 97–101. doi:10.1007/s00246-003-0536-x. PMID 14648002.CS1 maint: Multiple names: authors list (link)
- ↑ Trippel DL, Gillette PC (1990). "Atenolol in children with ventricular arrhythmias". Am Heart J. 119 (6): 1312–6. PMID 2353617. | https://www.wikidoc.org/index.php/APO-Atenol | |
7d00023e09d700fe4e6e9414b7659a0a9c1dda14 | wikidoc | APOBEC3C | APOBEC3C
DNA dC->dU-editing enzyme APOBEC-3C is a protein that in humans is encoded by the APOBEC3C gene.
A3C belong to the A3 family of cytidine deaminases that act as restriction factors against diverse retroviruses. A3C was reported to inhibit simian immunodeficiency deficiency virus potently rather than HIV-1, in absence of viral infectivity factor, Vif. Enhancing A3C's catalytic activity had only a marginal effect on HIV-1 replication (in absence of Vif), the counteractive viral mechanism is unclear. A3C was also shown to inhibit other viruses.
# Function
This gene is a member of the cytidine deaminase gene family. It is one of seven related genes or pseudogenes found in a cluster thought to result from gene duplication, on chromosome 22. Members of the cluster encode proteins that are structurally and functionally related to the C to U RNA-editing cytidine deaminase APOBEC1. Conversely, A3 proteins enzymatically convert cytidine to uridine present in the single stranded DNA.
# Structure
The crystal structure of A3C suggests a putative HIV-1 vif binding region. A3C was found to inhibit LINE-1 elements by directly interacting with ORF1p proteins, in a deaminase-independent manner. | APOBEC3C
DNA dC->dU-editing enzyme APOBEC-3C is a protein that in humans is encoded by the APOBEC3C gene.[1][2]
A3C belong to the A3 family of cytidine deaminases that act as restriction factors against diverse retroviruses. A3C was reported to inhibit simian immunodeficiency deficiency virus potently rather than HIV-1, in absence of viral infectivity factor, Vif.[3] Enhancing A3C's catalytic activity had only a marginal effect on HIV-1 replication (in absence of Vif), the counteractive viral mechanism is unclear.[4] A3C was also shown to inhibit other viruses.[5][6][7][8][9]
# Function
This gene is a member of the cytidine deaminase gene family. It is one of seven related genes or pseudogenes found in a cluster thought to result from gene duplication, on chromosome 22. Members of the cluster encode proteins that are structurally and functionally related to the C to U RNA-editing cytidine deaminase APOBEC1. Conversely, A3 proteins enzymatically convert cytidine to uridine present in the single stranded DNA.[10][11][12][13][14]
# Structure
The crystal structure of A3C suggests a putative HIV-1 vif binding region.[15][16] A3C was found to inhibit LINE-1 elements by directly interacting with ORF1p proteins, in a deaminase-independent manner.[17] | https://www.wikidoc.org/index.php/APOBEC3C | |
aab1fd689cc94ba2950c7b068ee380d2709ca96a | wikidoc | APOBEC3G | APOBEC3G
APOBEC3G is a human protein belonging to the APOBEC superfamily of proteinsthat interferes with the replication of HIV and other retroviruses. This family of proteins has been suggested to play an important role in innate anti-viral immunity.
APOBEC3G and other proteins in the same family are able to act as a cytidine deaminase, inducing numerous C to U mutations in the negative strand of the HIV DNA. This results in many inviable virions. HIV appears to have evolved the Vif gene in order to counteract this effect. Vif does not halt APOBEC activity: it only down-regulates it, perhaps increasing overall HIV success by elevating the mutation rate. It is also able to function as anti-viral protein when its active site has been mutated so it can no longer mutate retroviral DNA.
It was first identified in 2002 as a cellular factor able to restrict replication of HIV-1 lacking the viral accessory protein Vif. Soon after, it was shown that APOBEC3G belonged to a family of proteins grouped together due to their homology with the cytidine deaminase APOBEC1. | APOBEC3G
APOBEC3G is a human protein belonging to the APOBEC superfamily of proteins[1]that interferes with the replication of HIV and other retroviruses. This family of proteins has been suggested to play an important role in innate anti-viral immunity.[2]
APOBEC3G and other proteins in the same family are able to act as a cytidine deaminase, inducing numerous C to U mutations in the negative strand of the HIV DNA. This results in many inviable virions. HIV appears to have evolved the Vif gene in order to counteract this effect. Vif does not halt APOBEC activity: it only down-regulates it, perhaps increasing overall HIV success by elevating the mutation rate. It is also able to function as anti-viral protein when its active site has been mutated so it can no longer mutate retroviral DNA.
It was first identified in 2002 as a cellular factor able to restrict replication of HIV-1 lacking the viral accessory protein Vif. Soon after, it was shown that APOBEC3G belonged to a family of proteins grouped together due to their homology with the cytidine deaminase APOBEC1. | https://www.wikidoc.org/index.php/APOBEC3G | |
c376b60df8c0bbb09a33a3f2136facbf6d6a0574 | wikidoc | ARHGAP25 | ARHGAP25
Rho GTPase activating protein 25 is a protein that in humans is encoded by the ARHGAP25 gene. The gene is also known as KAIA0053. ARHGAP25 belongs to a family of Rho GTPase-modulating proteins that are implicated in actin remodeling, cell polarity, and cell migration.
# Model organisms
Model organisms have been used in the study of ARHGAP25 function. A conditional knockout mouse line, called Arhgap25tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty-one tests were carried out on homozygous-mutant mice and one significant abnormality was observed: abnormal retina morphology and pigmentation. | ARHGAP25
Rho GTPase activating protein 25 is a protein that in humans is encoded by the ARHGAP25 gene.[1] The gene is also known as KAIA0053.[1] ARHGAP25 belongs to a family of Rho GTPase-modulating proteins that are implicated in actin remodeling, cell polarity, and cell migration.[2]
# Model organisms
Model organisms have been used in the study of ARHGAP25 function. A conditional knockout mouse line, called Arhgap25tm1a(KOMP)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty-one tests were carried out on homozygous-mutant mice and one significant abnormality was observed: abnormal retina morphology and pigmentation.[7] | https://www.wikidoc.org/index.php/ARHGAP25 | |
268d8bb1ee63dc9707fed38106cb8ffe4e5afc2a | wikidoc | ARHGAP29 | ARHGAP29
ARHGAP29 is a gene located on chromosome 1p22 that encodes Rho GTPase activating protein (GAP) 29, a protein that mediates the cyclical regulation of small GTP binding proteins such as RhoA.
# Function
ARHGAP29 is expressed in the developing face and may act downstream of IRF6 in craniofacial development.
# Structure
ARHGAP29 contains four domains including a coiled-coil region known to interact with Rap2, a C1 domain, the Rho GTPase domain, and a small C-terminal region that interacts with PTPL1.
# Clinical Significance
The 1p22 locus containing ARHGAP29 was associated with nonsydromic cleft lip/palate by genome wide association and meta-analysis. A follow-up study identified rare coding variants including a nonsense and a frameshift variant in patients with nonsydromic cleft lip/palate. The finding of ARHGAP29's role in craniofacial development was discovered after the adjacent ABCA4 gene lacked functional or expression data to support it as the etiologic gene for nonsydromic cleft lip/palate even though SNPs in the ABCA4 gene were associated with cleft lip/palate. | ARHGAP29
ARHGAP29 is a gene located on chromosome 1p22 that encodes Rho GTPase activating protein (GAP) 29,[1] a protein that mediates the cyclical regulation of small GTP binding proteins such as RhoA.[2]
# Function
ARHGAP29 is expressed in the developing face and may act downstream of IRF6 in craniofacial development.[3]
# Structure
ARHGAP29 contains four domains including a coiled-coil region known to interact with Rap2,[4] a C1 domain, the Rho GTPase domain, and a small C-terminal region that interacts with PTPL1.[2]
# Clinical Significance
The 1p22 locus containing ARHGAP29 was associated with nonsydromic cleft lip/palate by genome wide association[5] and meta-analysis.[6] A follow-up study[3] identified rare coding variants including a nonsense and a frameshift variant in patients with nonsydromic cleft lip/palate. The finding of ARHGAP29's role in craniofacial development was discovered after the adjacent ABCA4 gene lacked functional or expression data to support it as the etiologic gene for nonsydromic cleft lip/palate even though SNPs in the ABCA4 gene were associated with cleft lip/palate. | https://www.wikidoc.org/index.php/ARHGAP29 | |
115d84bf81c9d4610301439f5eaf94f5f63b3c52 | wikidoc | ARHGAP31 | ARHGAP31
The Rho GTPase activating protein 31 is encoded in humans by the ARHGAP31 gene. It is a Cdc42/Rac1 GTPase regulator.
# Function
ARHGAP31 encodes a GTPase-activating protein (GAP). A variety of cellular processes are regulated by Rho GTPases which cycle between an inactive form bound to GDP and an active form bound to GTP. This cycling between inactive and active forms is regulated by guanine nucleotide exchange factors and GAPs. The encoded protein is a GAP shown to regulate two GTPases involved in protein trafficking and cell growth.
# Clinical relevance
ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures, causing syndromic cutis aplasia and limb anomalies. | ARHGAP31
The Rho GTPase activating protein 31 is encoded in humans by the ARHGAP31 gene. It is a Cdc42/Rac1 GTPase regulator.[1]
# Function
ARHGAP31 encodes a GTPase-activating protein (GAP). A variety of cellular processes are regulated by Rho GTPases which cycle between an inactive form bound to GDP and an active form bound to GTP. This cycling between inactive and active forms is regulated by guanine nucleotide exchange factors and GAPs. The encoded protein is a GAP shown to regulate two GTPases involved in protein trafficking and cell growth.[1]
# Clinical relevance
ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures, causing syndromic cutis aplasia and limb anomalies.[2] | https://www.wikidoc.org/index.php/ARHGAP31 | |
7dc70999488c5d771ebd248bd349ee6422fd6720 | wikidoc | ARHGEF11 | ARHGEF11
Rho guanine nucleotide exchange factor 11 is a protein that in humans is encoded by the ARHGEF11 gene.
# Function
Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. A similar protein in rat interacts with glutamate transporter EAAT4 and modulates its glutamate transport activity. Expression of the rat protein induces the reorganization of the actin cytoskeleton and its overexpression induces the formation of membrane ruffling and filopodia. Two alternative transcripts encoding different isoforms have been described.
# Interactions
ARHGEF11 has been shown to interact with PLXNB3, PLXNB1, PLXNB2 and RHOA. | ARHGEF11
Rho guanine nucleotide exchange factor 11 is a protein that in humans is encoded by the ARHGEF11 gene.[1][2][3]
# Function
Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. A similar protein in rat interacts with glutamate transporter EAAT4 and modulates its glutamate transport activity. Expression of the rat protein induces the reorganization of the actin cytoskeleton and its overexpression induces the formation of membrane ruffling and filopodia. Two alternative transcripts encoding different isoforms have been described.[3]
# Interactions
ARHGEF11 has been shown to interact with PLXNB3,[4][5] PLXNB1,[4][5][6][7] PLXNB2[4][5] and RHOA.[1] | https://www.wikidoc.org/index.php/ARHGEF11 | |
9921ed3cf3c1b5335b0c36b408018fcc2e542c96 | wikidoc | ARHGEF12 | ARHGEF12
Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene.
# Function
Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptor . The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals.
# Clinical significance
This protein is observed to form myeloid/lymphoid fusion partner in acute myeloid leukemia.
# Interactions
ARHGEF12 has been shown to interact with:
- GNA12,
- GNA13,
- IGF1R,
- PLXNB1,
- RHOA, and
- TEC. | ARHGEF12
Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene.[1][2][3]
# Function
Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptor . The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals.[3]
# Clinical significance
This protein is observed to form myeloid/lymphoid fusion partner in acute myeloid leukemia.[3]
# Interactions
ARHGEF12 has been shown to interact with:
- GNA12,[4][5]
- GNA13,[4][5]
- IGF1R,[6]
- PLXNB1,[7]
- RHOA,[5][8] and
- TEC.[5] | https://www.wikidoc.org/index.php/ARHGEF12 | |
83c2036c7daf403b6d1098f921582207035d0271 | wikidoc | ATP6V0A2 | ATP6V0A2
V-type proton ATPase 116 kDa subunit a isoform 2 also known as V-ATPase 116 kDa isoform a2 is an enzyme that in humans is encoded by the ATP6V0A2 gene.
# Function
V-ATPase 116 kDa isoform a2 is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase consists of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain.
# Clinical significance
Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. | ATP6V0A2
V-type proton ATPase 116 kDa subunit a isoform 2 also known as V-ATPase 116 kDa isoform a2 is an enzyme that in humans is encoded by the ATP6V0A2 gene.[1][2][3]
# Function
V-ATPase 116 kDa isoform a2 is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase consists of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain.[3]
# Clinical significance
Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome.[3] | https://www.wikidoc.org/index.php/ATP6V0A2 | |
fda00730d944e19675e28fd5bf661820688e636e | wikidoc | ATP6V1B2 | ATP6V1B2
V-type proton ATPase subunit B, brain isoform is an enzyme that in humans is encoded by the ATP6V1B2 gene.
This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts.
In melanocytic cells ATP6V1B2 gene expression may be regulated by MITF. | ATP6V1B2
V-type proton ATPase subunit B, brain isoform is an enzyme that in humans is encoded by the ATP6V1B2 gene.[1][2][3]
This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts.[3]
In melanocytic cells ATP6V1B2 gene expression may be regulated by MITF.[4] | https://www.wikidoc.org/index.php/ATP6V1B2 | |
7836cea6917ac4415192d006e020ae1a8d7d06fb | wikidoc | ATP6V1C1 | ATP6V1C1
V-type proton ATPase subunit C 1 is an enzyme that in humans is encoded by the ATP6V1C1 gene.
This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This gene is one of two genes that encode the V1 domain C subunit proteins and is found ubiquitously. This C subunit is analogous but not homologous to gamma subunit of F-ATPases. Previously, this gene was designated ATP6D.
In melanocytic cells ATP6V1C1 gene expression may be regulated by MITF. | ATP6V1C1
V-type proton ATPase subunit C 1 is an enzyme that in humans is encoded by the ATP6V1C1 gene.[1][2][3]
This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This gene is one of two genes that encode the V1 domain C subunit proteins and is found ubiquitously. This C subunit is analogous but not homologous to gamma subunit of F-ATPases. Previously, this gene was designated ATP6D.[3]
In melanocytic cells ATP6V1C1 gene expression may be regulated by MITF.[4] | https://www.wikidoc.org/index.php/ATP6V1C1 | |
2b366ef5b782c44a3c09bf2db9901bf734534a3a | wikidoc | ATP6V1G2 | ATP6V1G2
V-type proton ATPase subunit G 2 is an enzyme that in humans is encoded by the ATP6V1G2 gene.
This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c double prime, and d.
Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes, or alternatively spliced transcript variants. This encoded protein is one of three V1 domain G subunit proteins. This gene had previous gene symbols of ATP6G and ATP6G2. Alternatively spliced transcript variants encoding different isoforms have been described. | ATP6V1G2
V-type proton ATPase subunit G 2 is an enzyme that in humans is encoded by the ATP6V1G2 gene.[1][2]
This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c double prime, and d.
Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes, or alternatively spliced transcript variants. This encoded protein is one of three V1 domain G subunit proteins. This gene had previous gene symbols of ATP6G and ATP6G2. Alternatively spliced transcript variants encoding different isoforms have been described.[2] | https://www.wikidoc.org/index.php/ATP6V1G2 | |
c5d19dd66d404e22da9f1fa4c1e6c9a5b893f760 | wikidoc | Ataxin 1 | Ataxin 1
Ataxin-1 is a DNA-binding protein which in humans is encoded by the ATXN1 gene.
Mutations in ataxin-1 cause spinocerebellar ataxia type 1, an inherited neurodegenerative disease characterized by a progressive loss of cerebellar neurons, particularly Purkinje neurons.
# Genetics
ATXN1 is conserved across multiple species, including humans, mice, and Drosophila.
In humans, ATXN1 is located on the short arm of chromosome 6. The gene contains 9 exons, two of which are protein-coding. There is a CAG repeat in the coding sequence which is longer in humans than other species (6-38 uninterrupted CAG repeats in healthy humans versus 2 in the mouse gene). This repeat is prone to errors in DNA replication and can vary widely in length between individuals.
# Structure
Notable features of the Ataxin-1 protein structure include:
- A polyglutamine tract of variable length, encoded by the CAG repeat in ATXN1.
- A region which mediates protein-protein interactions, known as the AXH domain
- A nuclear localization sequence
- A phosphorylation site which regulates the protein's stability and interactions with its binding partners
# Function
The function of Ataxin-1 is not completely understood. It appears to be involved in regulating gene expression based on its location in the nucleus of the cell, its association with promoter regions of several genes, and its interactions with transcriptional regulators and parts of the RNA splicing machinery.
# Interactions
Ataxin 1 has been shown to interact with:
- C2orf27,
- Coilin,
- Glyceraldehyde 3-phosphate dehydrogenase,
- UBE2E1, and
- USP7.
# Role in disease
ATXN1 is the gene mutated in spinocerebellar ataxia type 1 (SCA1), a dominantly-inherited, fatal genetic disease in which neurons in the cerebellum and brain stem degenerate over the course of years or decades. SCA1 is a trinucleotide repeat disorder caused by expansion of the CAG repeat in ATXN1; this leads to an expanded polyglutamine tract in the protein. This elongation is variable in length, with as few as 6 and as many as 81 repeats reported in humans. Repeats of 39 or more uninterrupted CAG triplets cause disease, and longer repeat tracts are correlated with earlier age of onset and faster progression.
How polyglutamine expansion in Ataxin-1 causes neuronal dysfunction and degeneration is still unclear. Disease likely occurs through the combination of several processes.
## Aggregation
Mutant Ataxin-1 protein spontaneously misfolds and forms aggregates in cells, much like other disease-associated proteins such as tau, Aβ, and huntingtin. This led to the hypothesis that the aggregates are toxic to neurons, but it has been shown in mice that aggregation is not required for pathogenesis. Other neuronal proteins can modulate the formation of Ataxin-1 aggregates and this in turn may affect aggregate-induced toxicity.
## Altered protein-protein interactions
Soluble Ataxin-1 interacts with many other proteins. Polyglutamine expansion in Ataxin-1 can affect these interactions, sometimes causing loss of function (where the protein fails to perform one of its normal functions) and sometimes causing toxic gain of function (where the protein binds too strongly or to an inappropriate target). This, in turn, could alter the expression of the genes ataxin-1 regulates, leading to disease.
## HMGB1 interaction
Mutant ataxin1 causes the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). In a mouse model of SCA1, mutant ataxin1 mediates the reduction or inhibition of the high mobility group box1 protein (HMGB1) in neuron mitochondria. HMGB1 is a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. The impairment of HMGB1 function leads to increased mitochondrial DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitates repair of the mitochondrial DNA damage, ameliorates the neuropathology and the motor deficits, and extends the lifespan of these mutant ataxin1 mice. | Ataxin 1
Ataxin-1 is a DNA-binding protein which in humans is encoded by the ATXN1 gene.[1][2]
Mutations in ataxin-1 cause spinocerebellar ataxia type 1, an inherited neurodegenerative disease characterized by a progressive loss of cerebellar neurons, particularly Purkinje neurons.
# Genetics
ATXN1 is conserved across multiple species, including humans, mice, and Drosophila.[3]
In humans, ATXN1 is located on the short arm of chromosome 6. The gene contains 9 exons, two of which are protein-coding. There is a CAG repeat in the coding sequence which is longer in humans than other species (6-38 uninterrupted CAG repeats in healthy humans versus 2 in the mouse gene). This repeat is prone to errors in DNA replication and can vary widely in length between individuals.[4]
# Structure
Notable features of the Ataxin-1 protein structure[5] include:
- A polyglutamine tract of variable length, encoded by the CAG repeat in ATXN1.
- A region which mediates protein-protein interactions, known as the AXH domain
- A nuclear localization sequence
- A phosphorylation site which regulates the protein's stability and interactions with its binding partners
# Function
The function of Ataxin-1 is not completely understood. It appears to be involved in regulating gene expression based on its location in the nucleus of the cell, its association with promoter regions of several genes, and its interactions with transcriptional regulators[6] and parts of the RNA splicing machinery.[7]
# Interactions
Ataxin 1 has been shown to interact with:
- C2orf27,[8]
- Coilin,[9][10]
- Glyceraldehyde 3-phosphate dehydrogenase,[11]
- UBE2E1,[10] and
- USP7.[12]
# Role in disease
ATXN1 is the gene mutated in spinocerebellar ataxia type 1 (SCA1), a dominantly-inherited, fatal genetic disease in which neurons in the cerebellum and brain stem degenerate over the course of years or decades.[4] SCA1 is a trinucleotide repeat disorder caused by expansion of the CAG repeat in ATXN1; this leads to an expanded polyglutamine tract in the protein. This elongation is variable in length, with as few as 6 and as many as 81 repeats reported in humans.[13][4] Repeats of 39 or more uninterrupted CAG triplets cause disease, and longer repeat tracts are correlated with earlier age of onset and faster progression.[14]
How polyglutamine expansion in Ataxin-1 causes neuronal dysfunction and degeneration is still unclear. Disease likely occurs through the combination of several processes.
## Aggregation
Mutant Ataxin-1 protein spontaneously misfolds and forms aggregates in cells,[15] much like other disease-associated proteins such as tau, Aβ, and huntingtin. This led to the hypothesis that the aggregates are toxic to neurons, but it has been shown in mice that aggregation is not required for pathogenesis.[16] Other neuronal proteins can modulate the formation of Ataxin-1 aggregates and this in turn may affect aggregate-induced toxicity.[17]
[18]
[19]
[20]
[21]
[22]
[23]
## Altered protein-protein interactions
Soluble Ataxin-1 interacts with many other proteins. Polyglutamine expansion in Ataxin-1 can affect these interactions, sometimes causing loss of function (where the protein fails to perform one of its normal functions) and sometimes causing toxic gain of function (where the protein binds too strongly or to an inappropriate target).[24] This, in turn, could alter the expression of the genes ataxin-1 regulates, leading to disease.
## HMGB1 interaction
Mutant ataxin1 causes the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). In a mouse model of SCA1, mutant ataxin1 mediates the reduction or inhibition of the high mobility group box1 protein (HMGB1) in neuron mitochondria.[25] HMGB1 is a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. The impairment of HMGB1 function leads to increased mitochondrial DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitates repair of the mitochondrial DNA damage, ameliorates the neuropathology and the motor deficits, and extends the lifespan of these mutant ataxin1 mice.[25] | https://www.wikidoc.org/index.php/ATXN1 | |
21933f5ae255b0d4dc7aa4ab01eb8681f05afe54 | wikidoc | Ataxin 3 | Ataxin 3
Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.
# Clinical significance
Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by the ATXN3 gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 13-36 to 68-79 is the cause of Machado-Joseph disease. There is an inverse correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.
# Interactions
Ataxin 3 has been shown to interact with:
- RAD23A,
- RAD23B, and
- VCP.
# Model organisms
Model organisms have been used in the study of ATXN3 function. A conditional knockout mouse line called Atxn3tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | Ataxin 3
Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.[1][2]
# Clinical significance
Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by the ATXN3 gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 13-36 to 68-79 is the cause of Machado-Joseph disease. There is an inverse correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[2]
# Interactions
Ataxin 3 has been shown to interact with:
- RAD23A,[3]
- RAD23B,[3] and
- VCP.[4][5]
# Model organisms
Model organisms have been used in the study of ATXN3 function. A conditional knockout mouse line called Atxn3tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[6] Male and female animals underwent a standardized phenotypic screen[7] to determine the effects of deletion.[8][9][10][11] Additional screens performed: - In-depth immunological phenotyping[12] - in-depth bone and cartilage phenotyping[13] | https://www.wikidoc.org/index.php/ATXN3 | |
5b8da63c79aa5b3b7b6d5f31fda47e988ca4d4eb | wikidoc | Ribosome | Ribosome
Ribosomes (from ribonucleic acid and "greek: soma (meaning body)") are complexes of RNA and protein that are found in all cells. Prokaryotic ribosomes from archaea and bacteria are smaller than most of the ribosomes from eukaryotes such as plants and animals. However, the ribosomes in the mitochondrion of eukaryotic cells resemble those in bacteria, reflecting the evolutionary origin of this organelle.
The function of ribosomes is the assembly of proteins, in a process called translation. Ribosomes do this by catalysing the assembly of individual amino acids into polypeptide chains; this involves binding a messenger RNA and then using this as a template to join together the correct sequence of amino acids. This reaction uses adapters called transfer RNA molecules, which read the sequence of the messenger RNA and are attached to the amino acids.
# Description
Ribosomes are about 20nm (200 Ångström) in diameter and are composed of 65% ribosomal RNA and 35% ribosomal proteins (known as a Ribonucleoprotein or RNP). They translate messenger RNA (mRNA) to build polypeptide chains (e.g., proteins) using amino acids delivered by transfer RNA (tRNA). Their active sites are made of RNA, so ribosomes are now classified as "ribozymes".
Ribosomes build proteins from the genetic instructions held within messenger RNA. Free ribosomes are suspended in the cytosol (the semi-fluid portion of the cytoplasm); others are bound to the rough endoplasmic reticulum, giving it the appearance of roughness and thus its name, or to the nuclear envelope. As ribozymes, partly constituted from RNA, it is thought that they might be remnants of the RNA world. Catalysis of the peptide bond involves the C2 hydroxyl of RNA's P-site adenosine in a protein shuttle mechanism. The full function (i.e. translocation) of the ribosome is reliant on changes in protein conformations. Ribosomes are sometimes referred to as organelles, but the use of the term organelle is contested and is falling from favor.
Ribosomes are an extremely important structure in the cell. Ribosomes were first observed in the mid-1950s by Romanian cell biologist George Palade using an electron microscope as dense particles or granules for which he would win the Nobel Prize. The term "ribosome" was proposed by scientist Richard B. Roberts in 1958:
During the course of the symposium a semantic difficulty became apparent. To some of the participants, "microsomes" mean the ribonucleoprotein particles of the microsome fraction contaminated by other protein and lipid material; to others, the microsomes consist of protein and lipid contaminated by particles. The phrase “microsomal particles” does not seem adequate, and “ribonucleoprotein particles of the microsome fraction” is much too awkward. During the meeting the word "ribosome" was suggested; this seems a very satisfactory name, and it has a pleasant sound. The present confusion would be eliminated if “ribosome” were adopted to designate ribonucleoprotein particles in sizes ranging from 35 to 100S.
The structure and function of the ribosomes and associated molecules, known as the translational apparatus, has been of research interest since the mid-twentieth century and is a very active field of study today.
Ribosomes consist of two subunits (Figure 1) that fit together (Figure 2) and work as one to translate the mRNA into a polypeptide chain during protein synthesis (Figure 3). Prokaryotic subunits consist of one or two and eukaryotic of one or three very large RNA molecules (known as ribosomal RNA or rRNA) and multiple smaller protein molecules. Crystallographic work has shown that there are no ribosomal proteins close to the reaction site for polypeptide synthesis. This suggests that the protein components of ribosomes act as a scaffold that may enhance the ability of rRNA to synthesize protein rather than directly participating in catalysis (See: Ribozyme).
# Biogenesis
In prokaryotic cells, ribosomes synthesize with cytoplasm to enable the transcription of multiple ribosome gene operons. In eukaryotes and some prokaryotic cells, the process takes place both in the cell cytoplasm and in the nucleolus of eukaryotic cells. It involves the coordinated function of over 200 proteins in the synthesis and processing of the four rRNAs, as well as assembly of those rRNAs with the ribosomal proteins.
# Ribosome locations
Ribosomes are classified as being either "free" or "membrane-bound".
## Free ribosomes
Free ribosomes are "free" to move about anywhere in the cytoplasm (within the cell membrane). Proteins formed from free ribosomes are used within the cell. Proteins containing disulfide bonds using cysteine amino acids cannot be produced outside of the lumen of the endoplasmic reticulum.
## Membrane-bound ribosomes
When certain proteins are synthesized by a ribosome they can become "membrane-bound". The newly produced polypeptide chains are inserted directly into the endoplasmic reticulum by the ribosome and are then transported to their destinations. Bound ribosomes usually produce proteins that are used within the cell membrane or are expelled from the cell via exocytosis.
Free and membrane-bound ribosomes differ only in their spatial distribution; they are identical in structure and function. Whether the ribosome exists in a free or membrane-bound state depends on the presence of a ER-targeting signal sequence on the protein being synthesized.
# Structure
The ribosomal subunits of prokaryotes and eukaryotes are quite similar.
Prokaryotes have 70S ribosomes, each consisting of a small (30S) and a large (50S) subunit. Their large subunit is composed of a 5S RNA subunit (consisting of 120 nucleotides), a 23S RNA subunit (2900 nucleotides) and 34 proteins. The 30S subunit has a 1540 nucleotide RNA subunit bound to 21 proteins.
Eukaryotes have 80S ribosomes, each consisting of a small (40S) and large (60S) subunit. Their large subunit is composed of a 5S RNA (120 nucleotides), a 28S RNA (4700 nucleotides), a 5.8S subunit (160 nucleotides) and ~49 proteins. The 40S subunit has a 1900 nucleotide (18S) RNA and ~33 proteins.
The ribosomes found in chloroplasts and mitochondria of eukaryotes also consist of large and small subunits bound together with proteins into one 70S particle. These organelles are believed to be descendants of bacteria (see Endosymbiotic theory) and as such their ribosomes are similar to those of prokaryotes.
The various ribosomes share a core structure which is quite similar despite the large differences in size. The extra RNA in the larger ribosomes is in several long continuous insertions, such that they form loops out of the core structure without disrupting or changing it. All of the catalytic activity of the ribosome is carried out by the RNA, the proteins reside on the surface and seem to stabilize the structure.
The differences between the prokaryotic and eukaryotic ribosomes are exploited by pharmaceutical chemists to create antibiotics that can destroy a bacterial infection without harming the cells of the infected person. Due to the differences in their structures, the bacterial 70S ribosomes are vulnerable to these antibiotics while the eukaryotic 80S ribosomes are not. Even though mitochondria possess ribosomes similar to the bacterial ones, mitochondria are not affected by these antibiotics because they are surrounded by a double membrane that does not easily admit these antibiotics into the organelle.
## Atomic structure
The general molecular structure of the ribosome has been known since the early 1970s. In the early 2000s the structure has been achieved at high resolutions, in the order of a few Ångströms.
The first papers giving the structure of the ribosome at atomic resolution, were published in rapid succession in late 2000. First, the 50S (large prokaryotic) subunit from the archea, Haloarcula marismortui was published. Soon after the structure of the 30S subunit from Thermus thermophilus was published. Shortly thereafter a more detailed structure was published. Early the next year (May 2001) these coordinates were used to reconstruct the entire T. thermophilus 70S particle at 5.5 Ångström resolution.
Two papers were published in November 2005 with structures of the Escherichia coli 70S ribosome. The structures of vacant ribosome were determined at 3.5 Ångström resolution using x-ray crystallography. Then, two weeks later, a structure based on cryo-electron microsopy was published, which depicts the ribosome at 11-15 Ångström resolution in the act of passing a newly synthesized protein strand into the protein-conducting channel.
First atomic structures of the ribosome complexed with tRNA and mRNA molecules were solved by using X-ray crystallography by two groups independently, at 2.8 Ångström and at 3.7 Ångström. These structures allow one to see the details of interactions of the Thermus thermophilus ribosome with mRNA and with tRNAs bound at classical ribosomal sites. Interactions of the ribosome with long mRNAs containing Shine-Dalgarno sequences were visualized soon after that at 4.5 to 5.5 Ångström resolution.
# Function
Ribosomes are the workhorses of protein biosynthesis, the process of translating RNA into protein. The mRNA comprises a series of codons that dictate to the ribosome the sequence of the amino acids needed to make the protein. Using the mRNA as a template, the ribosome traverses each codon of the mRNA, pairing it with the appropriate amino acid. This is done using molecules of transfer RNA (tRNA) containing a complementary anticodon on one end and the appropriate amino acid on the other.
Protein synthesis begins at a start codon near the 5' end of the mRNA. The small ribosomal subunit, typically bound to a tRNA containing the amino acid methionine, binds to an AUG codon on the mRNA and recruits the large ribosomal subunit. The large ribosomal subunit contains three tRNA binding sites, designated A, P, and E. The A site binds an aminoacyl-tRNA (a tRNA bound to an amino acid); the P site binds a peptidyl-tRNA (a tRNA bound to the peptide being synthesized); and the E site binds a free tRNA before it exits the ribosome.
In Figure 3, both ribosomal subunits (small and large) assemble at the start codon (towards the 5' end of the mRNA). The ribosome uses tRNA which matches the current codon (triplet) on the mRNA to append an amino acid to the polypeptide chain. This is done for each triplet on the mRNA, while the ribosome moves towards the 3' end of the mRNA. Usually in bacterial cells, several ribosomes are working parallel on a single mRNA, forming what we call a polyribosome or polysome. | Ribosome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Ribosomes (from ribonucleic acid and "greek: soma (meaning body)") are complexes of RNA and protein that are found in all cells. Prokaryotic ribosomes from archaea and bacteria are smaller than most of the ribosomes from eukaryotes such as plants and animals. However, the ribosomes in the mitochondrion of eukaryotic cells resemble those in bacteria, reflecting the evolutionary origin of this organelle.
The function of ribosomes is the assembly of proteins, in a process called translation. Ribosomes do this by catalysing the assembly of individual amino acids into polypeptide chains; this involves binding a messenger RNA and then using this as a template to join together the correct sequence of amino acids. This reaction uses adapters called transfer RNA molecules, which read the sequence of the messenger RNA and are attached to the amino acids.
# Description
Ribosomes are about 20nm (200 Ångström) in diameter and are composed of 65% ribosomal RNA and 35% ribosomal proteins (known as a Ribonucleoprotein or RNP). They translate messenger RNA (mRNA) to build polypeptide chains (e.g., proteins) using amino acids delivered by transfer RNA (tRNA). Their active sites are made of RNA, so ribosomes are now classified as "ribozymes".[1]
Ribosomes build proteins from the genetic instructions held within messenger RNA. Free ribosomes are suspended in the cytosol (the semi-fluid portion of the cytoplasm); others are bound to the rough endoplasmic reticulum, giving it the appearance of roughness and thus its name, or to the nuclear envelope. As ribozymes, partly constituted from RNA, it is thought that they might be remnants of the RNA world.[2] Catalysis of the peptide bond involves the C2 hydroxyl of RNA's P-site adenosine in a protein shuttle mechanism. The full function (i.e. translocation) of the ribosome is reliant on changes in protein conformations. Ribosomes are sometimes referred to as organelles, but the use of the term organelle is contested and is falling from favor.
Ribosomes are an extremely important structure in the cell. Ribosomes were first observed in the mid-1950s by Romanian cell biologist George Palade using an electron microscope as dense particles or granules[3] for which he would win the Nobel Prize. The term "ribosome" was proposed by scientist Richard B. Roberts in 1958:
During the course of the symposium a semantic difficulty became apparent. To some of the participants, "microsomes" mean the ribonucleoprotein particles of the microsome fraction contaminated by other protein and lipid material; to others, the microsomes consist of protein and lipid contaminated by particles. The phrase “microsomal particles” does not seem adequate, and “ribonucleoprotein particles of the microsome fraction” is much too awkward. During the meeting the word "ribosome" was suggested; this seems a very satisfactory name, and it has a pleasant sound. The present confusion would be eliminated if “ribosome” were adopted to designate ribonucleoprotein particles in sizes ranging from 35 to 100S.
The structure and function of the ribosomes and associated molecules, known as the translational apparatus, has been of research interest since the mid-twentieth century and is a very active field of study today.
Ribosomes consist of two subunits (Figure 1) that fit together (Figure 2) and work as one to translate the mRNA into a polypeptide chain during protein synthesis (Figure 3). Prokaryotic subunits consist of one or two and eukaryotic of one or three very large RNA molecules (known as ribosomal RNA or rRNA) and multiple smaller protein molecules. Crystallographic work has shown that there are no ribosomal proteins close to the reaction site for polypeptide synthesis. This suggests that the protein components of ribosomes act as a scaffold that may enhance the ability of rRNA to synthesize protein rather than directly participating in catalysis (See: Ribozyme).
# Biogenesis
In prokaryotic cells, ribosomes synthesize with cytoplasm to enable the transcription of multiple ribosome gene operons. In eukaryotes and some prokaryotic cells, the process takes place both in the cell cytoplasm and in the nucleolus of eukaryotic cells. It involves the coordinated function of over 200 proteins in the synthesis and processing of the four rRNAs, as well as assembly of those rRNAs with the ribosomal proteins.
# Ribosome locations
Ribosomes are classified as being either "free" or "membrane-bound".
## Free ribosomes
Free ribosomes are "free" to move about anywhere in the cytoplasm (within the cell membrane). Proteins formed from free ribosomes are used within the cell. Proteins containing disulfide bonds using cysteine amino acids cannot be produced outside of the lumen of the endoplasmic reticulum.
## Membrane-bound ribosomes
When certain proteins are synthesized by a ribosome they can become "membrane-bound". The newly produced polypeptide chains are inserted directly into the endoplasmic reticulum by the ribosome and are then transported to their destinations. Bound ribosomes usually produce proteins that are used within the cell membrane or are expelled from the cell via exocytosis.
Free and membrane-bound ribosomes differ only in their spatial distribution; they are identical in structure and function. Whether the ribosome exists in a free or membrane-bound state depends on the presence of a ER-targeting signal sequence on the protein being synthesized.
# Structure
The ribosomal subunits of prokaryotes and eukaryotes are quite similar.[6]
Prokaryotes have 70S ribosomes, each consisting of a small (30S) and a large (50S) subunit. Their large subunit is composed of a 5S RNA subunit (consisting of 120 nucleotides), a 23S RNA subunit (2900 nucleotides) and 34 proteins. The 30S subunit has a 1540 nucleotide RNA subunit bound to 21 proteins.[6]
Eukaryotes have 80S ribosomes, each consisting of a small (40S) and large (60S) subunit. Their large subunit is composed of a 5S RNA (120 nucleotides), a 28S RNA (4700 nucleotides), a 5.8S subunit (160 nucleotides) and ~49 proteins. The 40S subunit has a 1900 nucleotide (18S) RNA and ~33 proteins.[6]
The ribosomes found in chloroplasts and mitochondria of eukaryotes also consist of large and small subunits bound together with proteins into one 70S particle.[6] These organelles are believed to be descendants of bacteria (see Endosymbiotic theory) and as such their ribosomes are similar to those of prokaryotes.[7]
The various ribosomes share a core structure which is quite similar despite the large differences in size. The extra RNA in the larger ribosomes is in several long continuous insertions, such that they form loops out of the core structure without disrupting or changing it.[6] All of the catalytic activity of the ribosome is carried out by the RNA, the proteins reside on the surface and seem to stabilize the structure.[6]
The differences between the prokaryotic and eukaryotic ribosomes are exploited by pharmaceutical chemists to create antibiotics that can destroy a bacterial infection without harming the cells of the infected person. Due to the differences in their structures, the bacterial 70S ribosomes are vulnerable to these antibiotics while the eukaryotic 80S ribosomes are not.[8] Even though mitochondria possess ribosomes similar to the bacterial ones, mitochondria are not affected by these antibiotics because they are surrounded by a double membrane that does not easily admit these antibiotics into the organelle.[9]
## Atomic structure
The general molecular structure of the ribosome has been known since the early 1970s. In the early 2000s the structure has been achieved at high resolutions, in the order of a few Ångströms.
The first papers giving the structure of the ribosome at atomic resolution, were published in rapid succession in late 2000. First, the 50S (large prokaryotic) subunit from the archea, Haloarcula marismortui was published.[10] Soon after the structure of the 30S subunit from Thermus thermophilus was published.[5] Shortly thereafter a more detailed structure was published.[11] Early the next year (May 2001) these coordinates were used to reconstruct the entire T. thermophilus 70S particle at 5.5 Ångström resolution.[12]
Two papers were published in November 2005 with structures of the Escherichia coli 70S ribosome. The structures of vacant ribosome were determined at 3.5 Ångström resolution using x-ray crystallography.[13] Then, two weeks later, a structure based on cryo-electron microsopy was published,[14] which depicts the ribosome at 11-15 Ångström resolution in the act of passing a newly synthesized protein strand into the protein-conducting channel.
First atomic structures of the ribosome complexed with tRNA and mRNA molecules were solved by using X-ray crystallography by two groups independently, at 2.8 Ångström[15] and at 3.7 Ångström.[16] These structures allow one to see the details of interactions of the Thermus thermophilus ribosome with mRNA and with tRNAs bound at classical ribosomal sites. Interactions of the ribosome with long mRNAs containing Shine-Dalgarno sequences were visualized soon after that at 4.5 to 5.5 Ångström resolution.[17]
# Function
Ribosomes are the workhorses of protein biosynthesis, the process of translating RNA into protein. The mRNA comprises a series of codons that dictate to the ribosome the sequence of the amino acids needed to make the protein. Using the mRNA as a template, the ribosome traverses each codon of the mRNA, pairing it with the appropriate amino acid. This is done using molecules of transfer RNA (tRNA) containing a complementary anticodon on one end and the appropriate amino acid on the other.
Protein synthesis begins at a start codon near the 5' end of the mRNA. The small ribosomal subunit, typically bound to a tRNA containing the amino acid methionine, binds to an AUG codon on the mRNA and recruits the large ribosomal subunit. The large ribosomal subunit contains three tRNA binding sites, designated A, P, and E. The A site binds an aminoacyl-tRNA (a tRNA bound to an amino acid); the P site binds a peptidyl-tRNA (a tRNA bound to the peptide being synthesized); and the E site binds a free tRNA before it exits the ribosome.
In Figure 3, both ribosomal subunits (small and large) assemble at the start codon (towards the 5' end of the mRNA). The ribosome uses tRNA which matches the current codon (triplet) on the mRNA to append an amino acid to the polypeptide chain. This is done for each triplet on the mRNA, while the ribosome moves towards the 3' end of the mRNA. Usually in bacterial cells, several ribosomes are working parallel on a single mRNA, forming what we call a polyribosome or polysome. | https://www.wikidoc.org/index.php/A_site | |
b8bb00a3af4c77a6bcb4a77fd5636420b7a001b8 | wikidoc | Abacavir | Abacavir
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# Black Box Warning
# Overview
Abacavir is a nucleoside analogue that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ZIAGEN Tablets and Oral Solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.
- Additional important information on the use of ZIAGEN for treatment of HIV-1 infection:
- ZIAGEN is one of multiple products containing abacavir. Before starting ZIAGEN, review medical history for prior exposure to any abacavir-containing product in order to avoid reintroduction in a patient with a history of hypersensitivity to abacavir
### Dosage
- A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.
- ZIAGEN may be taken with or without food.
- The recommended oral dose of ZIAGEN for adults is 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.
- The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child-Pugh score 5 to 6) is 200 mg twice daily. To enable dose reduction, ZIAGEN Oral Solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients.
### DOSAGE FORMS AND STRENGTHS
- ZIAGEN Tablets contain 300 mg of abacavir as abacavir sulfate. The tablets are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides.
- ZIAGEN Oral Solution contains 20 mg/mL of abacavir as abacavir sulfate. The solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abacavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abacavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The recommended oral dose of ZIAGEN Oral Solution in HIV-1-infected pediatric patients aged 3 months and older is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents.
- ZIAGEN is also available as a scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing ZIAGEN Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow ZIAGEN Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of ZIAGEN Tablets for HIV-1-infected pediatric patients is presented in Table 1.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abacavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abacavir in pediatric patients.
# Contraindications
- ZIAGEN is contraindicated in patients with:
- previously demonstrated hypersensitivity to abacavir or any other component of the products. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
- moderate or severe hepatic impairment
# Warnings
### Hypersensitivity Reaction
- Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.
- HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients.
- Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.
- Important information on signs and symptoms of hypersensitivity, as well as clinical management, is presented below. Signs and Symptoms of
- Hypersensitivity: Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups.
- Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported infrequently.
- Hypersensitivity to abacavir was reported in approximately 8% of 2,670 subjects (n = 206) in 9 clinical trials (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. The frequencies of symptoms are shown in Figure 1. Symptoms usually appeared within the first 6 weeks of treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset was 9 days; 89% appeared within the first 6 weeks; 95% of subjects reported symptoms from 2 or more of the 5 groups listed above.
- Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions. In one trial, 4 subjects (11%) receiving ZIAGEN 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 subjects receiving ZIAGEN 300 mg twice daily.
Physical findings associated with hypersensitivity to abacavir in some patients include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash.
- Laboratory abnormalities associated with hypersensitivity to abacavir in some patients include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia.
- Clinical Management of Hypersensitivity: Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. To minimize the risk of a life-threatening hypersensitivity reaction, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
- Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
- When therapy with ZIAGEN has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of ZIAGEN or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of ZIAGEN to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of ZIAGEN.
- If hypersensitivity cannot be ruled out, DO NOT reintroduce ZIAGEN or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of ZIAGEN or any other abacavir-containing product and that reintroduction of ZIAGEN or any other abacavir-containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.
- Risk Factor: HLA-B*5701 Allele: Trials have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.
- CNA106030 (PREDICT-1), a randomized, double-blind trial, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this trial, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this trial, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.
Screening for carriage of the HLA -B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.
- Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
### Lactic Acidosis/Severe Hepatomegaly With Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering ZIAGEN to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Treatment with ZIAGEN should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
### Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZIAGEN. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
### Fat Redistribution
- Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
### Myocardial Infarction
- In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI).1 In a sponsor-conducted pooled analysis of clinical trials, no excess risk of myocardial infarction was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Serious and sometimes fatal hypersensitivity reaction. In one trial, once-daily dosing of abacavir was associated with more severe hypersensitivity reactions .
- Lactic acidosis and severe hepatomegaly .
- Immune reconstitution syndrome .
- Fat redistribution.
- Myocardial infarction .
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adults:Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2.
- Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3.
- Five subjects receiving ZIAGEN in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.
- ZIAGEN Once Daily Versus ZIAGEN Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving ZIAGEN twice daily. However, subjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event.
- Laboratory Abnormalities: Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4.
- The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.
- Pediatric Trials: Therapy-Experienced Pediatric Subjects: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 8 mg/kg twice daily, lamivudine 4 mg/kg twice daily, and zidovudine 180 mg/m2 twice daily compared with lamivudine 4 mg/kg twice daily and zidovudine 180 mg/m2 twice daily from CNA3006 are listed in Table 6.
- Laboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving ZIAGEN (CNA3006) as compared with adult subjects (CNA30024).
- Other Adverse Events: In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT.
## Postmarketing Experience
- In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of ZIAGEN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ZIAGEN.
- Body as a Whole: Redistribution/accumulation of body fat.
- Cardiovascular: Myocardial infarction.
- Hepatic: Lactic acidosis and hepatic steatosis.
- Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.
- There have also been reports of erythema multiforme with abacavir use.
# Drug Interactions
- Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure .
- The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC.
- There are no adequate and well-controlled studies in pregnant women. ZIAGEN should be used during pregnancy only if the potential benefits outweigh the risk.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ZIAGEN, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 FREE
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abacavir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abacavir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
- Although it is not known if abacavir is excreted in human milk, abacavir is secreted into the milk of lactating rats. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving ZIAGEN.
### Pediatric Use
- The safety and effectiveness of ZIAGEN have been established in pediatric patients 3 months to 13 years of age. Use of ZIAGEN in these age-groups is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of ZIAGEN in adults and pediatric patients
### Geriatic Use
- Clinical studies of ZIAGEN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Abacavir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abacavir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Abacavir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Abacavir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
- oral
### Monitoring
There is limited information regarding Monitoring of Abacavir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Abacavir in the drug label.
# Overdosage
- There is no known antidote for ZIAGEN. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
# Pharmacology
## Mechanism of Action
- Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3′-OH group in the incorporated nucleotide analogue prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.
## Structure
- ZIAGEN is the brand name for abacavir sulfate, a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1. The chemical name of abacavir sulfate is (1S,cis)-4--2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2H2SO4 and a molecular weight of 670.76 daltons. It has the following structural formula:
- Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled water at 25°C. It has an octanol/water (pH 7.1 to 7.3) partition coefficient (log P) of approximately 1.20 at 25°C.
- ZIAGEN Tablets are for oral administration. Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir as active ingredient and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.
- ZIAGEN Oral Solution is for oral administration. Each milliliter (1 mL) of ZIAGEN Oral Solution contains abacavir sulfate equivalent to 20 mg of abacavir (i.e., 20 mg/mL) as active ingredient and the following inactive ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water.
- In vivo, abacavir sulfate dissociates to its free base, abacavir. All dosages for ZIAGEN are expressed in terms of abacavir.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Abacavir in the drug label.
## Pharmacokinetics
- The pharmacokinetic properties of abacavir have been studied in asymptomatic, HIV-1-infected adult subjects after administration of a single intravenous (IV) dose of 150 mg and after single and multiple oral doses. The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg/day.
- Abacavir was rapidly and extensively absorbed after oral administration. The geometric mean absolute bioavailability of the tablet was 83%. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (Cmax) was 3.0 ± 0.89 mcg/mL (mean ± SD) and AUC(0-12 hr) was 6.02 ± 1.73 mcghr/mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcghr/mL.
- The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L/kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC(0-6 hr) to plasma abacavir AUC(0-6 hr) ratio ranged from 27% to 33%.
- Binding of abacavir to human plasma proteins is approximately 50%. Binding of abacavir to plasma proteins was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes.
- In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase (to form the 5′-carboxylic acid) and glucuronyl transferase (to form the 5′-glucuronide). The metabolites do not have antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.
- Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose.
- In single-dose trials, the observed elimination half-life (t1/2) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L/hr/kg (mean ± SD).
- Bioavailability of abacavir tablets was assessed in the fasting and fed states. There was no significant difference in systemic exposure (AUC∞) in the fed and fasting states; therefore, ZIAGEN Tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of ZIAGEN Oral Solution and ZIAGEN Tablets. Therefore, these products may be used interchangeably.
- The pharmacokinetic properties of ZIAGEN have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.
- The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh score 5 to 6). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased. A dose of 200 mg (provided by 10 mL of ZIAGEN Oral Solution) administered twice daily is recommended for patients with mild liver disease. The safety, efficacy, and pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients.
- The pharmacokinetics of abacavir have been studied after either single or repeat doses of ZIAGEN in 68 pediatric subjects. Following multiple-dose administration of ZIAGEN 8 mg/kg twice daily, steady-state AUC(0-12 hr) and Cmax were 9.8 ± 4.56 mcghr/mL and 3.71 ± 1.36 mcg/mL (mean ± SD), respectively . In addition, to support dosing of ZIAGEN scored tablet (300 mg) for pediatric patients 14 kg to greater than 30 kg, analysis of actual and simulated pharmacokinetic data indicated comparable exposures are expected following administration of 300 mg scored tablet and the 8 mg/kg dosing regimen using oral solution.
- The pharmacokinetics of ZIAGEN have not been studied in patients over 65 years of age.
- A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.
- There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.
- In human liver microsomes, abacavir did not inhibit cytochrome P450 isoforms (2C9, 2D6, 3A4). Based on these data, it is unlikely that clinically significant drug interactions will occur between abacavir and drugs metabolized through these pathways.
- Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.
- Due to the common metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was studied in 24 HIV-1-infected male subjects. Each subject received the following treatments on separate occasions: a single 600-mg dose of abacavir, 0.7 g/kg ethanol (equivalent to 5 alcoholic drinks), and abacavir 600 mg plus 0.7 g/kg ethanol. Coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC∞ and a 26% increase in abacavir t1/2. In males, abacavir had no effect on the pharmacokinetic properties of ethanol, so no clinically significant interaction is expected in men. This interaction has not been studied in females.
- In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir.
### Microbiology
- Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3′-OH group in the incorporated nucleotide analogue prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.
- The antiviral activity of abacavir against HIV-1 was evaluated against a T-cell tropic laboratory strain HIV-1IIIB in lymphoblastic cell lines, a monocyte/macrophage tropic laboratory strain HIV-1BaL in primary monocytes/macrophages, and clinical isolates in peripheral blood mononuclear cells. The concentration of drug necessary to effect viral replication by 50 percent (EC50) ranged from 3.7 to 5.8 μM (1 μM = 0.28 mcg/mL) and 0.07 to 1.0 μM against HIV-1IIIB and HIV-1BaL, respectively, and was 0.26 ± 0.18 μM against 8 clinical isolates. The EC50 values of abacavir against different HIV-1 clades (A-G) ranged from 0.0015 to 1.05 μM, and against HIV-2 isolates, from 0.024 to 0.49 μM. The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. Ribavirin (50 μM) had no effect on the anti–HIV-1 activity of abacavir in cell culture.
- HIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture and were also obtained from subjects treated with abacavir. Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I in RT contributed to abacavir resistance. In a trial of therapy-naive adults receiving ZIAGEN 600 mg once daily (n = 384) or 300 mg twice daily (n = 386), in a background regimen of lamivudine 300 mg once daily and efavirenz 600 mg once daily (CNA30021), the incidence of virologic failure at 48 weeks was similar between the 2 groups (11% in both arms). Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this trial showed that the RT substitutions that emerged during abacavir once-daily and twice-daily therapy were K65R, L74V, Y115F, and M184V/I. The substitution M184V/I was the most commonly observed substitution in virologic failure isolates from subjects receiving abacavir once daily (56%, 10/18) and twice daily (40%, 8/20).
- Thirty-nine percent (7/18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a greater than 2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).
- Cross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in cell culture and in subjects. The K65R substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V substitution can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine. An increasing number of thymidine analogue mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.
## Nonclinical Toxicology
- Carcinogenicity: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose. It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
- Mutagenicity: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay.
- Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.
- Impairment of Fertility: Abacavir had no adverse effects on the mating performance or fertility of male and female rats at a dose approximately 8 times the human exposure at the recommended dose based on body surface area comparisons.
- Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.
# Clinical Studies
- Therapy-Naive Adults: CNA30024 was a multicenter, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Trial participants were male (81%), Caucasian (51%), black (21%), and Hispanic (26%). The median age was 35 years; the median pretreatment CD4+ cell count was 264 cells/mm3, and median plasma HIV-1 RNA was 4.79 log10 copies/mL. The outcomes of randomized treatment are provided in Table 7.
- After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells/mm3 in the group receiving ZIAGEN and 155 cells/mm3 in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving ZIAGEN (5 CDC classification C events and 3 deaths) and 5 subjects (2%) on the zidovudine arm (3 CDC classification C events and 2 deaths) experienced clinical disease progression.
- CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR® (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies/mL and plasma HIV-1 RNA greater than 100,000 copies/mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells/mm3, and median baseline plasma HIV-1 RNA was 4.8 log10 copies/mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies/mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8.
- In subjects with baseline viral load greater than 100,000 copies/mL, percentages of subjects with HIV-1 RNA levels less than 50 copies/mL were 31% in the group receiving abacavir versus 45% in the group receiving indinavir.
- Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells/mm3 was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir sulfate (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.
- CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), Caucasian (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells/mm3 (range 21 to 918 cells/mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies/mL (range: 2.60 to 6.99 log10 copies/mL).
- The outcomes of randomized treatment are provided in Table 10.
- After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm3 in the group receiving abacavir 600 mg once daily and 200 cells/mm3 in the group receiving abacavir 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.
- Therapy-Experienced Pediatric Subjects: CNA3006 was a randomized, double-blind trial comparing ZIAGEN 8 mg/kg twice daily plus lamivudine 4 mg/kg twice daily plus zidovudine 180 mg/m2 twice daily versus lamivudine 4 mg/kg twice daily plus zidovudine 180 mg/m2 twice daily. Two hundred and five therapy-experienced pediatric subjects were enrolled: female (56%), Caucasian (17%), black (50%), Hispanic (30%), median age of 5.4 years, baseline CD4+ cell percent greater than 15% (median = 27%), and median baseline plasma HIV-1 RNA of 4.6 log10 copies/mL. Eighty percent and 55% of subjects had prior therapy with zidovudine and lamivudine, respectively, most often in combination. The median duration of prior nucleoside analogue therapy was 2 years. At 16 weeks the proportion of subjects responding based on plasma HIV-1 RNA less than or equal to 400 copies/mL was significantly higher in subjects receiving ZIAGEN plus lamivudine plus zidovudine compared with subjects receiving lamivudine plus zidovudine, 13% versus 2%, respectively. Median plasma HIV-1 RNA changes from baseline were -0.53 log10 copies/mL in the group receiving ZIAGEN plus lamivudine plus zidovudine compared with -0.21 log10 copies/mL in the group receiving lamivudine plus zidovudine. Median CD4+ cell count increases from baseline were 69 cells/mm3 in the group receiving ZIAGEN plus lamivudine plus zidovudine and 9 cells/mm3 in the group receiving lamivudine plus zidovudine.
# How Supplied
- ZIAGEN Tablets, containing abacavir sulfate equivalent to 300 mg abacavir are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides. They are packaged as follows:
- Bottles of 60 tablets (NDC 49702-221-18).
- Unit dose blister packs of 60 tablets (NDC 49702-221-44). Each pack contains 6 blister cards of 10 tablets each.
- ZIAGEN Oral Solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows:
- Bottles of 240 mL (NDC 49702-222-48) with child-resistant closure. This product does not require reconstitution.
## Storage
- Store at controlled room temperature of 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 49702-221-18
ZIAGEN ®
(abacavir sulfate)
TABLETS
300 mg
Rx only
60 Tablets
Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir.
Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP).
See prescribing information for dosage information.
Notice to Authorized Dispenser:
Each time ZIAGEN is dispensed, give the patient a Medication Guide and Warning Card from the carton.
Manufactured for:
ViiV Healthcare
Research Triangle Park, NC 27709
by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in UK
10000000095110 Rev. 5/11
NDC 49702-222-48
ZIAGEN®
(abacavir sulfate)
ORAL SOLUTION
20 mg/mL
Rx only
240 mL
Each mL contains abacavir sulfate equivalent to 20 mg of abacavir.
Store at controlled room temperature of 20° to 25°C (68° to 77°F)
(see USP). DO NOT FREEZE.
See prescribing information for dosage information.
Notice to Authorized Dispenser:
Each time ZIAGEN is dispensed, give the patient a Medication Guide and Warning Card from the carton.
Manufactured for:
ViiV Healthcare
Research Triangle Park, NC 27709
by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in UK
©2011, ViiV Healthcare
Rev. 4/11 A094812
### Ingredients and Appearance
# Patient Counseling Information
- See FDA-approved patient labeling (Medication Guide)
- Hypersensitivity Reaction: Inform patients:
- that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of ZIAGEN, and encourage the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about ZIAGEN. (The complete text of the Medication Guide is reprinted at the end of this document.)
- to carry the Warning Card with them.
- how to identify a hypersensitivity reaction .
- that if they develop symptoms consistent with a hypersensitivity reaction they should call their doctor right away to determine if they should stop taking ZIAGEN.
- that a hypersensitivity reaction can worsen and lead to hospitalization or death if ZIAGEN is not immediately discontinued.
- that in one trial, more severe hypersensitivity reactions were seen when ZIAGEN was dosed 600 mg once daily.
- to not restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
- that a hypersensitivity reaction is usually reversible if it is detected promptly and ZIAGEN is stopped right away.
- that if they have interrupted ZIAGEN for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
- to not restart ZIAGEN or any other abacavir-containing product without medical consultation and that restarting abacavir needs to be undertaken only if medical care can be readily accessed by the patient or others.
- ZIAGEN should not be coadministered with EPZICOM ® (abacavir sulfate and lamivudine) Tablets or TRIZIVIR ® (abacavir sulfate, lamivudine, and zidovudine) Tablets.
- Lactic Acidosis/Hepatomegaly: Inform patients that some HIV medicines, including ZIAGEN, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).
- Redistribution/Accumulation of Body Fat: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
- Information About HIV-1 Infection: ZIAGEN is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using ZIAGEN.
- Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if ZIAGEN can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- Patients should be informed to take all HIV medications exactly as prescribed.
### MEDICATION GUIDE
(abacavir sulfate)
- Read this Medication Guide before you start taking ZIAGEN 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 your treatment. Be sure to carry your ZIAGEN Warning Card with you at all times.
1.Serious allergic reaction (hypersensitivity reaction). ZIAGEN contains abacavir (also contained in EPZICOM® and TRIZIVIR®). Patients taking ZIAGEN may have a serious allergic reaction (hypersensitivity reaction) that can cause death. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.
- If you get a symptom from 2 or more of the following groups while taking ZIAGEN, call your healthcare provider right away to find out if you should stop taking ZIAGEN.
- A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times.
- If you stop ZIAGEN because of an allergic reaction, never take ZIAGEN (abacavir sulfate) or any other abacavir-containing medicine (EPZICOM and TRIZIVIR) again. If you take ZIAGEN or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death. If you stop ZIAGEN, for any other reason, even for a few days, and you are not allergic to ZIAGEN, talk with your healthcare provider before taking it again. Taking ZIAGEN again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.
- If your healthcare provider tells you that you can take ZIAGEN again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.
2. Lactic Acidosis (buildup of acid in the blood). Some human immunodeficiency virus (HIV) medicines, including ZIAGEN, can cause a rare but serious condition called lactic acidosis. Lactic acidosis is a serious medical emergency that can cause death and must be treated in the hospital.
- Call your healthcare provider right away if you get any of the following signs or symptoms of lactic acidosis:
- you feel very weak or tired
- you have unusual (not normal) muscle pain
- you have trouble breathing
- you have stomach pain with nausea and vomiting
- you feel cold, especially in your arms and legs
- you feel dizzy or light-headed
- you have a fast or irregular heartbeat
3. Serious liver problems. Some people who have taken medicines like ZIAGEN have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Hepatomegaly with steatosis is a serious medical emergency that can cause death.Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:
- your skin or the white part of your eyes turns yellow (jaundice)
- your urine turns dark
- your bowel movements (stools) turn light in color
- you don’t feel like eating food for several days or longer
- you feel sick to your stomach (nausea)
- you have lower stomach area (abdominal) pain
- You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight, or have been taking nucleoside analogue medicines for a long time.
- ZIAGEN is a prescription medicine used to treat HIV infection. ZIAGEN is a medicine called a nucleoside analogue reverse transcriptase inhibitor (NRTI). ZIAGEN is always used with other anti-HIV medicines. When used in combination with these other medicines, ZIAGEN helps lower the amount of HIV in your blood.
- ZIAGEN does not cure HIV infection or AIDS.
- It is not known if ZIAGEN will help you live longer or have fewer of the medical problems that people get with HIV or AIDS.
- Do not take ZIAGEN if you:
- are allergic to abacavir or any of the ingredients in ZIAGEN. See the end of this Medication Guide for a complete list of ingredients in ZIAGEN.
- have certain liver problems.
- Before you take ZIAGEN, tell your healthcare provider if you:
- have been tested and know whether or not you have a particular gene variation called HLA-B*5701.
- have hepatitis B virus infection or have other liver problems.
- have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.
- are pregnant or plan to become pregnant. It is not known if ZIAGEN will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
- Pregnancy Registry. If you take ZIAGEN while you are pregnant, talk to your healthcare provider about how you can take part in the Pregnancy Registry for ZIAGEN. The purpose of the pregnancy registry is to collect information about the health of you and your baby.
- are breastfeeding or plan to breastfeed. Do not breastfeed. We do not know if ZIAGEN can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
- Especially tell your healthcare provider if you take:
- Ask your healthcare provider if you are not sure if you take one of the medicines listed above.
- ZIAGEN may affect the way other medicines work, and other medicines may affect how ZIAGEN works.
- Know the medicines you take. Keep a list of your medicines with you to show to your healthcare provider and pharmacist when you get a new medicine.
- Take ZIAGEN exactly as your healthcare provider tells you to take it.
- ZIAGEN is taken by mouth as a tablet or a strawberry- and banana-flavored liquid.
- ZIAGEN may be taken with or without food.
- Do not skip doses.
- Children aged 3 months and older can also take ZIAGEN. The child’s healthcare provider will decide the right dose and whether the child should take the tablet or liquid, based on the child’s weight. The dose should not be more than the recommended adult dose.
- Do not let your ZIAGEN run out.
- If you stop your anti-HIV medicines, even for a short time, the amount of virus in your blood may increase and the virus may become harder to treat. If you take too much ZIAGEN, call your healthcare provider or poison control center or go to the nearest hospital emergency room right away.
- ZIAGEN can cause serious side effects including allergic reactions, lactic acidosis, and liver problems. See “What is the most important information I should know about ZIAGEN?”
- Changes in immune system (Immune Reconstitution Syndrome). Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking ZIAGEN.
- Changes in body fat (fat redistribution). Changes in body fat (lipoatrophy or lipodystrophy) can happen in some people taking antiretroviral medicines including ZIAGEN.
- These changes may include:
- more fat in or around your trunk, upper back and neck (buffalo hump), breast, or chest
- loss of fat in your legs, arms, or face
- Heart attack (myocardial infarction). Some HIV medicines including ZIAGEN may increase your risk of heart attack.
- The most common side effects of ZIAGEN in adults include:
- bad dreams or sleep problems
- nausea
- headache
- tiredness
- vomiting
- The most common side effects of ZIAGEN in children include:
- fever and chills
- nausea
- vomiting
- rash
- ear, nose, or throat infections
- 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 ZIAGEN. 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 FREE.
- Store ZIAGEN at room temperature, between 68°F to 77°F (20°C to 25°C).
- Do not freeze ZIAGEN.
- Keep ZIAGEN and all medicines out of the reach of children.
- General information for safe and effective use of ZIAGEN
- Avoid doing things that can spread HIV infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZIAGEN for a condition for which it was not prescribed. Do not give ZIAGEN 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 ZIAGEN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information that is written for healthcare professionals.
- For more information go to www.ZIAGEN.com or call 1-877-844-8872 FREE.
- Tablets
- Active ingredient: abacavir sulfate
- Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate, and afilm‑coating made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.
- Oral Solution
- Active ingredient: abacavir sulfate
- Inactive ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water.
- This Medication Guide has been approved by the US Food and Drug Administration.
# Precautions with Alcohol
Alcohol-Abacavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ziagen®
# Look-Alike Drug Names
There is limited information regarding Abacavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Abacavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Abacavir is a nucleoside analogue that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ZIAGEN Tablets and Oral Solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.
- Additional important information on the use of ZIAGEN for treatment of HIV-1 infection:
- ZIAGEN is one of multiple products containing abacavir. Before starting ZIAGEN, review medical history for prior exposure to any abacavir-containing product in order to avoid reintroduction in a patient with a history of hypersensitivity to abacavir
### Dosage
- A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.
- ZIAGEN may be taken with or without food.
- The recommended oral dose of ZIAGEN for adults is 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.
- The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child-Pugh score 5 to 6) is 200 mg twice daily. To enable dose reduction, ZIAGEN Oral Solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients.
### DOSAGE FORMS AND STRENGTHS
- ZIAGEN Tablets contain 300 mg of abacavir as abacavir sulfate. The tablets are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides.
- ZIAGEN Oral Solution contains 20 mg/mL of abacavir as abacavir sulfate. The solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abacavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abacavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The recommended oral dose of ZIAGEN Oral Solution in HIV-1-infected pediatric patients aged 3 months and older is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents.
- ZIAGEN is also available as a scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing ZIAGEN Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow ZIAGEN Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of ZIAGEN Tablets for HIV-1-infected pediatric patients is presented in Table 1.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abacavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abacavir in pediatric patients.
# Contraindications
- ZIAGEN is contraindicated in patients with:
- previously demonstrated hypersensitivity to abacavir or any other component of the products. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
- moderate or severe hepatic impairment
# Warnings
### Hypersensitivity Reaction
- Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.
- HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients.
- Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.
- Important information on signs and symptoms of hypersensitivity, as well as clinical management, is presented below. Signs and Symptoms of
- Hypersensitivity: Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups.
- Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported infrequently.
- Hypersensitivity to abacavir was reported in approximately 8% of 2,670 subjects (n = 206) in 9 clinical trials (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. The frequencies of symptoms are shown in Figure 1. Symptoms usually appeared within the first 6 weeks of treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset was 9 days; 89% appeared within the first 6 weeks; 95% of subjects reported symptoms from 2 or more of the 5 groups listed above.
- Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions. In one trial, 4 subjects (11%) receiving ZIAGEN 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 subjects receiving ZIAGEN 300 mg twice daily.
Physical findings associated with hypersensitivity to abacavir in some patients include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash.
- Laboratory abnormalities associated with hypersensitivity to abacavir in some patients include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia.
- Clinical Management of Hypersensitivity: Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. To minimize the risk of a life-threatening hypersensitivity reaction, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
- Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
- When therapy with ZIAGEN has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of ZIAGEN or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of ZIAGEN to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of ZIAGEN.
- If hypersensitivity cannot be ruled out, DO NOT reintroduce ZIAGEN or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of ZIAGEN or any other abacavir-containing product and that reintroduction of ZIAGEN or any other abacavir-containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.
- Risk Factor: HLA-B*5701 Allele: Trials have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.
- CNA106030 (PREDICT-1), a randomized, double-blind trial, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this trial, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this trial, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.
Screening for carriage of the HLA -B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.
- Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
### Lactic Acidosis/Severe Hepatomegaly With Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering ZIAGEN to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Treatment with ZIAGEN should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
### Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZIAGEN. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
### Fat Redistribution
- Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
### Myocardial Infarction
- In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI).1 In a sponsor-conducted pooled analysis of clinical trials, no excess risk of myocardial infarction was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Serious and sometimes fatal hypersensitivity reaction. In one trial, once-daily dosing of abacavir was associated with more severe hypersensitivity reactions .
- Lactic acidosis and severe hepatomegaly .
- Immune reconstitution syndrome .
- Fat redistribution.
- Myocardial infarction .
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adults:Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2.
- Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3.
- Five subjects receiving ZIAGEN in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.
- ZIAGEN Once Daily Versus ZIAGEN Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving ZIAGEN twice daily. However, subjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event.
- Laboratory Abnormalities: Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4.
- The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.
- Pediatric Trials: Therapy-Experienced Pediatric Subjects: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 8 mg/kg twice daily, lamivudine 4 mg/kg twice daily, and zidovudine 180 mg/m2 twice daily compared with lamivudine 4 mg/kg twice daily and zidovudine 180 mg/m2 twice daily from CNA3006 are listed in Table 6.
- Laboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving ZIAGEN (CNA3006) as compared with adult subjects (CNA30024).
- Other Adverse Events: In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT.
## Postmarketing Experience
- In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of ZIAGEN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ZIAGEN.
- Body as a Whole: Redistribution/accumulation of body fat.
- Cardiovascular: Myocardial infarction.
- Hepatic: Lactic acidosis and hepatic steatosis.
- Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.
- There have also been reports of erythema multiforme with abacavir use.
# Drug Interactions
- Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure .
- The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3)]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC.
- There are no adequate and well-controlled studies in pregnant women. ZIAGEN should be used during pregnancy only if the potential benefits outweigh the risk.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ZIAGEN, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 FREE
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abacavir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abacavir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
- Although it is not known if abacavir is excreted in human milk, abacavir is secreted into the milk of lactating rats. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving ZIAGEN.
### Pediatric Use
- The safety and effectiveness of ZIAGEN have been established in pediatric patients 3 months to 13 years of age. Use of ZIAGEN in these age-groups is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of ZIAGEN in adults and pediatric patients
### Geriatic Use
- Clinical studies of ZIAGEN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Abacavir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abacavir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Abacavir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Abacavir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
- oral
### Monitoring
There is limited information regarding Monitoring of Abacavir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Abacavir in the drug label.
# Overdosage
- There is no known antidote for ZIAGEN. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
# Pharmacology
## Mechanism of Action
- Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3′-OH group in the incorporated nucleotide analogue prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.
## Structure
- ZIAGEN is the brand name for abacavir sulfate, a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1. The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2•H2SO4 and a molecular weight of 670.76 daltons. It has the following structural formula:
- Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled water at 25°C. It has an octanol/water (pH 7.1 to 7.3) partition coefficient (log P) of approximately 1.20 at 25°C.
- ZIAGEN Tablets are for oral administration. Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir as active ingredient and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.
- ZIAGEN Oral Solution is for oral administration. Each milliliter (1 mL) of ZIAGEN Oral Solution contains abacavir sulfate equivalent to 20 mg of abacavir (i.e., 20 mg/mL) as active ingredient and the following inactive ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water.
- In vivo, abacavir sulfate dissociates to its free base, abacavir. All dosages for ZIAGEN are expressed in terms of abacavir.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Abacavir in the drug label.
## Pharmacokinetics
- The pharmacokinetic properties of abacavir have been studied in asymptomatic, HIV-1-infected adult subjects after administration of a single intravenous (IV) dose of 150 mg and after single and multiple oral doses. The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg/day.
- Abacavir was rapidly and extensively absorbed after oral administration. The geometric mean absolute bioavailability of the tablet was 83%. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (Cmax) was 3.0 ± 0.89 mcg/mL (mean ± SD) and AUC(0-12 hr) was 6.02 ± 1.73 mcg•hr/mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hr/mL.
- The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L/kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC(0-6 hr) to plasma abacavir AUC(0-6 hr) ratio ranged from 27% to 33%.
- Binding of abacavir to human plasma proteins is approximately 50%. Binding of abacavir to plasma proteins was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes.
- In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase (to form the 5′-carboxylic acid) and glucuronyl transferase (to form the 5′-glucuronide). The metabolites do not have antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.
- Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose.
- In single-dose trials, the observed elimination half-life (t1/2) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L/hr/kg (mean ± SD).
- Bioavailability of abacavir tablets was assessed in the fasting and fed states. There was no significant difference in systemic exposure (AUC∞) in the fed and fasting states; therefore, ZIAGEN Tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of ZIAGEN Oral Solution and ZIAGEN Tablets. Therefore, these products may be used interchangeably.
- The pharmacokinetic properties of ZIAGEN have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.
- The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh score 5 to 6). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased. A dose of 200 mg (provided by 10 mL of ZIAGEN Oral Solution) administered twice daily is recommended for patients with mild liver disease. The safety, efficacy, and pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients.
- The pharmacokinetics of abacavir have been studied after either single or repeat doses of ZIAGEN in 68 pediatric subjects. Following multiple-dose administration of ZIAGEN 8 mg/kg twice daily, steady-state AUC(0-12 hr) and Cmax were 9.8 ± 4.56 mcg•hr/mL and 3.71 ± 1.36 mcg/mL (mean ± SD), respectively [see Use in Specific Populations (8.4)]. In addition, to support dosing of ZIAGEN scored tablet (300 mg) for pediatric patients 14 kg to greater than 30 kg, analysis of actual and simulated pharmacokinetic data indicated comparable exposures are expected following administration of 300 mg scored tablet and the 8 mg/kg dosing regimen using oral solution.
- The pharmacokinetics of ZIAGEN have not been studied in patients over 65 years of age.
- A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.
- There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.
- In human liver microsomes, abacavir did not inhibit cytochrome P450 isoforms (2C9, 2D6, 3A4). Based on these data, it is unlikely that clinically significant drug interactions will occur between abacavir and drugs metabolized through these pathways.
- Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.
- Due to the common metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was studied in 24 HIV-1-infected male subjects. Each subject received the following treatments on separate occasions: a single 600-mg dose of abacavir, 0.7 g/kg ethanol (equivalent to 5 alcoholic drinks), and abacavir 600 mg plus 0.7 g/kg ethanol. Coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC∞ and a 26% increase in abacavir t1/2. In males, abacavir had no effect on the pharmacokinetic properties of ethanol, so no clinically significant interaction is expected in men. This interaction has not been studied in females.
- In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir.
### Microbiology
- Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3′-OH group in the incorporated nucleotide analogue prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.
- The antiviral activity of abacavir against HIV-1 was evaluated against a T-cell tropic laboratory strain HIV-1IIIB in lymphoblastic cell lines, a monocyte/macrophage tropic laboratory strain HIV-1BaL in primary monocytes/macrophages, and clinical isolates in peripheral blood mononuclear cells. The concentration of drug necessary to effect viral replication by 50 percent (EC50) ranged from 3.7 to 5.8 μM (1 μM = 0.28 mcg/mL) and 0.07 to 1.0 μM against HIV-1IIIB and HIV-1BaL, respectively, and was 0.26 ± 0.18 μM against 8 clinical isolates. The EC50 values of abacavir against different HIV-1 clades (A-G) ranged from 0.0015 to 1.05 μM, and against HIV-2 isolates, from 0.024 to 0.49 μM. The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. Ribavirin (50 μM) had no effect on the anti–HIV-1 activity of abacavir in cell culture.
- HIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture and were also obtained from subjects treated with abacavir. Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I in RT contributed to abacavir resistance. In a trial of therapy-naive adults receiving ZIAGEN 600 mg once daily (n = 384) or 300 mg twice daily (n = 386), in a background regimen of lamivudine 300 mg once daily and efavirenz 600 mg once daily (CNA30021), the incidence of virologic failure at 48 weeks was similar between the 2 groups (11% in both arms). Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this trial showed that the RT substitutions that emerged during abacavir once-daily and twice-daily therapy were K65R, L74V, Y115F, and M184V/I. The substitution M184V/I was the most commonly observed substitution in virologic failure isolates from subjects receiving abacavir once daily (56%, 10/18) and twice daily (40%, 8/20).
- Thirty-nine percent (7/18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a greater than 2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).
- Cross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in cell culture and in subjects. The K65R substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V substitution can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine. An increasing number of thymidine analogue mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.
## Nonclinical Toxicology
- Carcinogenicity: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose. It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
- Mutagenicity: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay.
- Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.
- Impairment of Fertility: Abacavir had no adverse effects on the mating performance or fertility of male and female rats at a dose approximately 8 times the human exposure at the recommended dose based on body surface area comparisons.
- Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.
# Clinical Studies
- Therapy-Naive Adults: CNA30024 was a multicenter, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Trial participants were male (81%), Caucasian (51%), black (21%), and Hispanic (26%). The median age was 35 years; the median pretreatment CD4+ cell count was 264 cells/mm3, and median plasma HIV-1 RNA was 4.79 log10 copies/mL. The outcomes of randomized treatment are provided in Table 7.
- After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells/mm3 in the group receiving ZIAGEN and 155 cells/mm3 in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving ZIAGEN (5 CDC classification C events and 3 deaths) and 5 subjects (2%) on the zidovudine arm (3 CDC classification C events and 2 deaths) experienced clinical disease progression.
- CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR® (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies/mL and plasma HIV-1 RNA greater than 100,000 copies/mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells/mm3, and median baseline plasma HIV-1 RNA was 4.8 log10 copies/mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies/mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8.
- In subjects with baseline viral load greater than 100,000 copies/mL, percentages of subjects with HIV-1 RNA levels less than 50 copies/mL were 31% in the group receiving abacavir versus 45% in the group receiving indinavir.
- Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells/mm3 was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir sulfate (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.
- CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), Caucasian (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells/mm3 (range 21 to 918 cells/mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies/mL (range: 2.60 to 6.99 log10 copies/mL).
- The outcomes of randomized treatment are provided in Table 10.
- After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm3 in the group receiving abacavir 600 mg once daily and 200 cells/mm3 in the group receiving abacavir 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.
- Therapy-Experienced Pediatric Subjects: CNA3006 was a randomized, double-blind trial comparing ZIAGEN 8 mg/kg twice daily plus lamivudine 4 mg/kg twice daily plus zidovudine 180 mg/m2 twice daily versus lamivudine 4 mg/kg twice daily plus zidovudine 180 mg/m2 twice daily. Two hundred and five therapy-experienced pediatric subjects were enrolled: female (56%), Caucasian (17%), black (50%), Hispanic (30%), median age of 5.4 years, baseline CD4+ cell percent greater than 15% (median = 27%), and median baseline plasma HIV-1 RNA of 4.6 log10 copies/mL. Eighty percent and 55% of subjects had prior therapy with zidovudine and lamivudine, respectively, most often in combination. The median duration of prior nucleoside analogue therapy was 2 years. At 16 weeks the proportion of subjects responding based on plasma HIV-1 RNA less than or equal to 400 copies/mL was significantly higher in subjects receiving ZIAGEN plus lamivudine plus zidovudine compared with subjects receiving lamivudine plus zidovudine, 13% versus 2%, respectively. Median plasma HIV-1 RNA changes from baseline were -0.53 log10 copies/mL in the group receiving ZIAGEN plus lamivudine plus zidovudine compared with -0.21 log10 copies/mL in the group receiving lamivudine plus zidovudine. Median CD4+ cell count increases from baseline were 69 cells/mm3 in the group receiving ZIAGEN plus lamivudine plus zidovudine and 9 cells/mm3 in the group receiving lamivudine plus zidovudine.
# How Supplied
- ZIAGEN Tablets, containing abacavir sulfate equivalent to 300 mg abacavir are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides. They are packaged as follows:
- Bottles of 60 tablets (NDC 49702-221-18).
- Unit dose blister packs of 60 tablets (NDC 49702-221-44). Each pack contains 6 blister cards of 10 tablets each.
- ZIAGEN Oral Solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows:
- Bottles of 240 mL (NDC 49702-222-48) with child-resistant closure. This product does not require reconstitution.
## Storage
- Store at controlled room temperature of 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 49702-221-18
ZIAGEN ®
(abacavir sulfate)
TABLETS
300 mg
Rx only
60 Tablets
Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir.
Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP).
See prescribing information for dosage information.
Notice to Authorized Dispenser:
Each time ZIAGEN is dispensed, give the patient a Medication Guide and Warning Card from the carton.
Manufactured for:
ViiV Healthcare
Research Triangle Park, NC 27709
by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in UK
10000000095110 Rev. 5/11
NDC 49702-222-48
ZIAGEN®
(abacavir sulfate)
ORAL SOLUTION
20 mg/mL
Rx only
240 mL
Each mL contains abacavir sulfate equivalent to 20 mg of abacavir.
Store at controlled room temperature of 20° to 25°C (68° to 77°F)
(see USP). DO NOT FREEZE.
See prescribing information for dosage information.
Notice to Authorized Dispenser:
Each time ZIAGEN is dispensed, give the patient a Medication Guide and Warning Card from the carton.
Manufactured for:
ViiV Healthcare
Research Triangle Park, NC 27709
by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in UK
©2011, ViiV Healthcare
Rev. 4/11 A094812
### Ingredients and Appearance
# Patient Counseling Information
- See FDA-approved patient labeling (Medication Guide)
- Hypersensitivity Reaction: Inform patients:
- that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of ZIAGEN, and encourage the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about ZIAGEN. (The complete text of the Medication Guide is reprinted at the end of this document.)
- to carry the Warning Card with them.
- how to identify a hypersensitivity reaction [see Medication Guide].
- that if they develop symptoms consistent with a hypersensitivity reaction they should call their doctor right away to determine if they should stop taking ZIAGEN.
- that a hypersensitivity reaction can worsen and lead to hospitalization or death if ZIAGEN is not immediately discontinued.
- that in one trial, more severe hypersensitivity reactions were seen when ZIAGEN was dosed 600 mg once daily.
- to not restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
- that a hypersensitivity reaction is usually reversible if it is detected promptly and ZIAGEN is stopped right away.
- that if they have interrupted ZIAGEN for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
- to not restart ZIAGEN or any other abacavir-containing product without medical consultation and that restarting abacavir needs to be undertaken only if medical care can be readily accessed by the patient or others.
- ZIAGEN should not be coadministered with EPZICOM ® (abacavir sulfate and lamivudine) Tablets or TRIZIVIR ® (abacavir sulfate, lamivudine, and zidovudine) Tablets.
- Lactic Acidosis/Hepatomegaly: Inform patients that some HIV medicines, including ZIAGEN, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).
- Redistribution/Accumulation of Body Fat: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
- Information About HIV-1 Infection: ZIAGEN is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using ZIAGEN.
- Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if ZIAGEN can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- Patients should be informed to take all HIV medications exactly as prescribed.
### MEDICATION GUIDE
(abacavir sulfate)
- Read this Medication Guide before you start taking ZIAGEN 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 your treatment. Be sure to carry your ZIAGEN Warning Card with you at all times.
1.Serious allergic reaction (hypersensitivity reaction). ZIAGEN contains abacavir (also contained in EPZICOM® and TRIZIVIR®). Patients taking ZIAGEN may have a serious allergic reaction (hypersensitivity reaction) that can cause death. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.
- If you get a symptom from 2 or more of the following groups while taking ZIAGEN, call your healthcare provider right away to find out if you should stop taking ZIAGEN.
- A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times.
- If you stop ZIAGEN because of an allergic reaction, never take ZIAGEN (abacavir sulfate) or any other abacavir-containing medicine (EPZICOM and TRIZIVIR) again. If you take ZIAGEN or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death. If you stop ZIAGEN, for any other reason, even for a few days, and you are not allergic to ZIAGEN, talk with your healthcare provider before taking it again. Taking ZIAGEN again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.
- If your healthcare provider tells you that you can take ZIAGEN again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.
2. Lactic Acidosis (buildup of acid in the blood). Some human immunodeficiency virus (HIV) medicines, including ZIAGEN, can cause a rare but serious condition called lactic acidosis. Lactic acidosis is a serious medical emergency that can cause death and must be treated in the hospital.
- Call your healthcare provider right away if you get any of the following signs or symptoms of lactic acidosis:
- you feel very weak or tired
- you have unusual (not normal) muscle pain
- you have trouble breathing
- you have stomach pain with nausea and vomiting
- you feel cold, especially in your arms and legs
- you feel dizzy or light-headed
- you have a fast or irregular heartbeat
3. Serious liver problems. Some people who have taken medicines like ZIAGEN have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Hepatomegaly with steatosis is a serious medical emergency that can cause death.Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:
- your skin or the white part of your eyes turns yellow (jaundice)
- your urine turns dark
- your bowel movements (stools) turn light in color
- you don’t feel like eating food for several days or longer
- you feel sick to your stomach (nausea)
- you have lower stomach area (abdominal) pain
- You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight, or have been taking nucleoside analogue medicines for a long time.
- ZIAGEN is a prescription medicine used to treat HIV infection. ZIAGEN is a medicine called a nucleoside analogue reverse transcriptase inhibitor (NRTI). ZIAGEN is always used with other anti-HIV medicines. When used in combination with these other medicines, ZIAGEN helps lower the amount of HIV in your blood.
- ZIAGEN does not cure HIV infection or AIDS.
- It is not known if ZIAGEN will help you live longer or have fewer of the medical problems that people get with HIV or AIDS.
- Do not take ZIAGEN if you:
- are allergic to abacavir or any of the ingredients in ZIAGEN. See the end of this Medication Guide for a complete list of ingredients in ZIAGEN.
- have certain liver problems.
- Before you take ZIAGEN, tell your healthcare provider if you:
- have been tested and know whether or not you have a particular gene variation called HLA-B*5701.
- have hepatitis B virus infection or have other liver problems.
- have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.
- are pregnant or plan to become pregnant. It is not known if ZIAGEN will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
- Pregnancy Registry. If you take ZIAGEN while you are pregnant, talk to your healthcare provider about how you can take part in the Pregnancy Registry for ZIAGEN. The purpose of the pregnancy registry is to collect information about the health of you and your baby.
- are breastfeeding or plan to breastfeed. Do not breastfeed. We do not know if ZIAGEN can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
- Especially tell your healthcare provider if you take:
- Ask your healthcare provider if you are not sure if you take one of the medicines listed above.
- ZIAGEN may affect the way other medicines work, and other medicines may affect how ZIAGEN works.
- Know the medicines you take. Keep a list of your medicines with you to show to your healthcare provider and pharmacist when you get a new medicine.
- Take ZIAGEN exactly as your healthcare provider tells you to take it.
- ZIAGEN is taken by mouth as a tablet or a strawberry- and banana-flavored liquid.
- ZIAGEN may be taken with or without food.
- Do not skip doses.
- Children aged 3 months and older can also take ZIAGEN. The child’s healthcare provider will decide the right dose and whether the child should take the tablet or liquid, based on the child’s weight. The dose should not be more than the recommended adult dose.
- Do not let your ZIAGEN run out.
- If you stop your anti-HIV medicines, even for a short time, the amount of virus in your blood may increase and the virus may become harder to treat. If you take too much ZIAGEN, call your healthcare provider or poison control center or go to the nearest hospital emergency room right away.
- ZIAGEN can cause serious side effects including allergic reactions, lactic acidosis, and liver problems. See “What is the most important information I should know about ZIAGEN?”
- Changes in immune system (Immune Reconstitution Syndrome). Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking ZIAGEN.
- Changes in body fat (fat redistribution). Changes in body fat (lipoatrophy or lipodystrophy) can happen in some people taking antiretroviral medicines including ZIAGEN.
- These changes may include:
- more fat in or around your trunk, upper back and neck (buffalo hump), breast, or chest
- loss of fat in your legs, arms, or face
- Heart attack (myocardial infarction). Some HIV medicines including ZIAGEN may increase your risk of heart attack.
- The most common side effects of ZIAGEN in adults include:
- bad dreams or sleep problems
- nausea
- headache
- tiredness
- vomiting
- The most common side effects of ZIAGEN in children include:
- fever and chills
- nausea
- vomiting
- rash
- ear, nose, or throat infections
- 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 ZIAGEN. 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 FREE.
- Store ZIAGEN at room temperature, between 68°F to 77°F (20°C to 25°C).
- Do not freeze ZIAGEN.
- Keep ZIAGEN and all medicines out of the reach of children.
- General information for safe and effective use of ZIAGEN
- Avoid doing things that can spread HIV infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZIAGEN for a condition for which it was not prescribed. Do not give ZIAGEN 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 ZIAGEN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information that is written for healthcare professionals.
- For more information go to www.ZIAGEN.com or call 1-877-844-8872 FREE.
- Tablets
- Active ingredient: abacavir sulfate
- Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate, and afilm‑coating made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.
- Oral Solution
- Active ingredient: abacavir sulfate
- Inactive ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water.
- This Medication Guide has been approved by the US Food and Drug Administration.
# Precautions with Alcohol
Alcohol-Abacavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ziagen®[1]
# Look-Alike Drug Names
There is limited information regarding Abacavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Abacavir | |
bef60e86d90411820486548b08a06faab0287716 | wikidoc | Thiamine | Thiamine
# Overview
Thiamine or thiamin, also known as vitamin B1 and aneurine hydrochloride, is one of the B vitamins. It is a colorless compound with chemical formula C12H17N4OS. It is soluble in water and insoluble in alcohol. Thiamine decomposes if heated. Its chemical structure contains a pyrimidine ring and a thiazole ring.
# History
Thiamine was first discovered in 1910 by Umetaro Suzuki in Japan when researching how rice bran cured patients of beriberi. He named it aberic acid (later orizanin). He did not determine its chemical composition, nor that it was an amine.
It was first crystallized by Jansen and Donath in 1926 (they named it aneurin, for antineuritic vitamin).
Its chemical composition and synthesis was finally reported by Robert R. Williams in 1935. He also coined the name for it, thiamine.
# Thiamine phosphate derivatives
There are four known natural thiamine phosphate derivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP) or thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and the recently discovered adenosine thiamine triphosphate (AThTP).
## Thiamine pyrophosphate
Thiamine pyrophosphate (TPP), also known as thiamine diphosphate (ThDP), is a coenzyme for several enzymes that catalyze the dehydrogenation (decarboxylation and subsequent conjugation to Coenzyme A) of alpha-keto acids. Examples include:
- In mammals:
pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (metabolism of carbohydrates)
branched-chain alpha-keto acid dehydrogenase
2-hydroxyphytanoyl-CoA lyase
transketolase (functions in the pentose phosphate pathway to synthesize NADPH and the pentose sugars deoxyribose and ribose)
- pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (metabolism of carbohydrates)
- branched-chain alpha-keto acid dehydrogenase
- 2-hydroxyphytanoyl-CoA lyase
- transketolase (functions in the pentose phosphate pathway to synthesize NADPH and the pentose sugars deoxyribose and ribose)
- In other species:
pyruvate decarboxylase (in yeast)
several additional bacterial enzymes
- pyruvate decarboxylase (in yeast)
- several additional bacterial enzymes
TPP is synthesized by the enzyme thiamine pyrophosphokinase, which requires free thiamine, magnesium, and adenosine triphosphate.
## Thiamine triphosphate
Thiamine triphosphate (ThTP) was long considered a specific neuroactive form of thiamine.
However, recently it was shown that ThTP exists in bacteria, fungi, plants and animals suggesting a much more general cellular role. In particular in E. coli it seems to play a role in response to amino acid starvation.
## Adenosine thiamine triphosphate
Adenosine thiamine triphosphate (AThTP) or thiaminylated adenosine triphosphate has recently been discovered in Escherichia coli where it accumulates as a result of carbon starvation. In E. coli, AThTP may account for up to 20 % of total thiamine.
It also exists in lesser amounts in yeast, roots of higher plants and animal tissues.
# Nutrition
Thiamine plays an important role in helping the body metabolize carbohydrates and fat to produce energy. It is essential for normal growth and development and helps to maintain proper functioning of the heart and the nervous and digestive systems. Thiamine is water-soluble and cannot be stored in the body; however, once absorbed, the vitamin is concentrated in muscle tissue.
## Good sources
Thiamine is found naturally in the following foods, each of which contains at least 0.1 mg of the vitamin per 28-100 g (1-3.5 oz):
Green peas,
Spinach,
Liver,
Beef,
Pork,
Navy beans,
Nuts,
Pinto beans,
Bananas,
Soybeans,
Goji berries,
Whole-grains,
Breads,
Yeast,the aleurone layer of unpolished rice, and Legumes.
## Deficiency
Systemic thiamine deficiency can lead to myriad problems including neurodegeneration, wasting and death. A lack of thiamine can be caused by malnutrition, alcoholism, a diet high in thiaminase-rich foods (raw freshwater fish, raw shellfish, ferns) and/or foods high in anti-thiamine factors (tea, coffee, betel nuts).
Well-known syndromes caused by thiamine deficiency include Wernicke-Korsakoff syndrome and beriberi, diseases also common with chronic alcoholism.
It is thought that many people with diabetes have a deficiency of thiamine and that this may be linked to some of the complications that can occur.
### Diagnostic testing for B1 deficiency
A positive diagnosis test for Thiamine deficiency can be ascertained by measuring the activity of transketolase in erythrocyte . Thiamine can also be seen directly in whole blood following the conversion of thiamine to a fluorescent thiochrome derivative.
August 10, 2007 article states deficiency of Vitamin B1 not revealed by above tests. See / for complete information regarding diabetic neuropathy and Vitamin B1 Deficiency.
# Genetic diseases
Genetic diseases of thiamine transport are rare but serious. Thiamine Responsive Megaloblastic Anemia with diabetes mellitus and sensorineural deafness (TRMA) is an autosomal recessive disorder caused by mutations in the gene SLC19A2, a high affinity thiamine transporter. TRMA patients do not show signs of systemic thiamine deficiency, suggesting redundancy in the thiamine transport system. This has led to the discovery of a second high affinity thiamine transporter, SLC19A3.
Online Mendelian Inheritance in Man (OMIM) 249270
# Research
## High doses
The RDA in most countries is set at about 1.4 mg. However, tests on volunteers at daily doses of about 50 mg have claimed an increase in mental acuity.
### Thiamine as an insect repellent
Some studies suggest that taking thiamine (vitamin B1) 25 mg to 50 mg three times per day is effective in reducing mosquito bites. A large intake of Thiamine produces a skin odor that is not detectable by humans, but is disagreeable to female mosquitoes. Thiamine takes more than 2 weeks before the odor fully saturates the skin. With the advances in topical preparations there is an increasing number of Thiamine based repellent products. Whilst there is considerable anecdotal evidence of Thiamine products being effective in the field (Australia, US and Canada), there have yet to be any clinical trials run to demonstrate the efficacy of these products.
## Autism
A 2002 pilot study administered thiamine tetrahydrofurfuryl disulfide (TTFD) rectally to ten autism spectrum children, and found beneficial clinical effect in eight. This study has not been replicated and a 2006 review of thiamine by the same author did not mention thiamine's possible effect on autism. | Thiamine
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Thiamine or thiamin, also known as vitamin B1 and aneurine hydrochloride, is one of the B vitamins. It is a colorless compound with chemical formula C12H17N4OS. It is soluble in water and insoluble in alcohol. Thiamine decomposes if heated. Its chemical structure contains a pyrimidine ring and a thiazole ring.
# History
Thiamine was first discovered in 1910 by Umetaro Suzuki in Japan when researching how rice bran cured patients of beriberi. He named it aberic acid (later orizanin). He did not determine its chemical composition, nor that it was an amine.
It was first crystallized by Jansen and Donath in 1926 (they named it aneurin, for antineuritic vitamin).
Its chemical composition and synthesis was finally reported by Robert R. Williams in 1935. He also coined the name for it, thiamine.
# Thiamine phosphate derivatives
There are four known natural thiamine phosphate derivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP) or thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and the recently discovered adenosine thiamine triphosphate (AThTP).
## Thiamine pyrophosphate
Thiamine pyrophosphate (TPP), also known as thiamine diphosphate (ThDP), is a coenzyme for several enzymes that catalyze the dehydrogenation (decarboxylation and subsequent conjugation to Coenzyme A) of alpha-keto acids. Examples include:
- In mammals:
pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (metabolism of carbohydrates)
branched-chain alpha-keto acid dehydrogenase
2-hydroxyphytanoyl-CoA lyase
transketolase (functions in the pentose phosphate pathway to synthesize NADPH and the pentose sugars deoxyribose and ribose)
- pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (metabolism of carbohydrates)
- branched-chain alpha-keto acid dehydrogenase
- 2-hydroxyphytanoyl-CoA lyase
- transketolase (functions in the pentose phosphate pathway to synthesize NADPH and the pentose sugars deoxyribose and ribose)
- In other species:
pyruvate decarboxylase (in yeast)
several additional bacterial enzymes
- pyruvate decarboxylase (in yeast)
- several additional bacterial enzymes
TPP is synthesized by the enzyme thiamine pyrophosphokinase, which requires free thiamine, magnesium, and adenosine triphosphate.
## Thiamine triphosphate
Thiamine triphosphate (ThTP) was long considered a specific neuroactive form of thiamine.
However, recently it was shown that ThTP exists in bacteria, fungi, plants and animals suggesting a much more general cellular role. In particular in E. coli it seems to play a role in response to amino acid starvation.
## Adenosine thiamine triphosphate
Adenosine thiamine triphosphate (AThTP) or thiaminylated adenosine triphosphate has recently been discovered in Escherichia coli where it accumulates as a result of carbon starvation. In E. coli, AThTP may account for up to 20 % of total thiamine.
It also exists in lesser amounts in yeast, roots of higher plants and animal tissues.
# Nutrition
Thiamine plays an important role in helping the body metabolize carbohydrates and fat to produce energy. It is essential for normal growth and development and helps to maintain proper functioning of the heart and the nervous and digestive systems. Thiamine is water-soluble and cannot be stored in the body; however, once absorbed, the vitamin is concentrated in muscle tissue.
## Good sources
Thiamine is found naturally in the following foods, each of which contains at least 0.1 mg of the vitamin per 28-100 g (1-3.5 oz):
Green peas,
Spinach,
Liver,
Beef,
Pork,
Navy beans,
Nuts,
Pinto beans,
Bananas,
Soybeans,
Goji berries,
Whole-grains,
Breads,
Yeast,the aleurone layer of unpolished rice, and Legumes.
## Deficiency
Systemic thiamine deficiency can lead to myriad problems including neurodegeneration, wasting and death. A lack of thiamine can be caused by malnutrition, alcoholism, a diet high in thiaminase-rich foods (raw freshwater fish, raw shellfish, ferns) and/or foods high in anti-thiamine factors (tea, coffee, betel nuts)[1].
Well-known syndromes caused by thiamine deficiency include Wernicke-Korsakoff syndrome and beriberi, diseases also common with chronic alcoholism.
It is thought that many people with diabetes have a deficiency of thiamine [2] and that this may be linked to some of the complications that can occur.
### Diagnostic testing for B1 deficiency
A positive diagnosis test for Thiamine deficiency can be ascertained by measuring the activity of transketolase in erythrocyte . Thiamine can also be seen directly in whole blood following the conversion of thiamine to a fluorescent thiochrome derivative.
August 10, 2007 article states deficiency of Vitamin B1 not revealed by above tests. See http://www2.warwick.ac.uk/newsandevents/pressreleases/researchers_find_vitamin/ for complete information regarding diabetic neuropathy and Vitamin B1 Deficiency.
# Genetic diseases
Genetic diseases of thiamine transport are rare but serious. Thiamine Responsive Megaloblastic Anemia with diabetes mellitus and sensorineural deafness (TRMA)[2] is an autosomal recessive disorder caused by mutations in the gene SLC19A2,[3] a high affinity thiamine transporter. TRMA patients do not show signs of systemic thiamine deficiency, suggesting redundancy in the thiamine transport system. This has led to the discovery of a second high affinity thiamine transporter, SLC19A3.[4]
Online Mendelian Inheritance in Man (OMIM) 249270
# Research
## High doses
The RDA in most countries is set at about 1.4 mg. However, tests on volunteers at daily doses of about 50 mg have claimed an increase in mental acuity. [5]
### Thiamine as an insect repellent
Some studies suggest that taking thiamine (vitamin B1) 25 mg to 50 mg three times per day is effective in reducing mosquito bites. A large intake of Thiamine produces a skin odor that is not detectable by humans, but is disagreeable to female mosquitoes.[6] Thiamine takes more than 2 weeks before the odor fully saturates the skin. With the advances in topical preparations there is an increasing number of Thiamine based repellent products. Whilst there is considerable anecdotal evidence of Thiamine products being effective in the field (Australia, US and Canada), there have yet to be any clinical trials run to demonstrate the efficacy of these products.
## Autism
A 2002 pilot study administered thiamine tetrahydrofurfuryl disulfide (TTFD) rectally to ten autism spectrum children, and found beneficial clinical effect in eight.[7] This study has not been replicated and a 2006 review of thiamine by the same author did not mention thiamine's possible effect on autism.[8] | https://www.wikidoc.org/index.php/Aberic_acid | |
daa029f555f5f817411378ff980dbb1c503ab872 | wikidoc | Ablation | Ablation
# Overview
Ablation is defined as the removal of material from the surface of an object by vaporization, chipping, or other erosive processes. The term occurs in space physicsassociated with atmospheric reentry, in glaciology, medicine and passive fire protection.
# Space physics
In space physics, ablation occurs to heat shields that are used to protect payloads from heat, such as the heat shields used by the Apollo Command Module on atmospheric reentry. In a basic sense, ablative material is designed to slowly burn away in a controlled manner, so that heat can be carried away from the spacecraft by the generated gases; while the remaining solid material insulates the craft from superheated gases. There is an entire branch of space physics research involving the search for new fireproofing materials to achieve the best ablative performance; this function is critical to protect the spacecraft occupants and payload from otherwise excessive heat loading. The same technology is used in some passive fire protection applications, in some cases by the same vendors, who offer different versions of these fireproofing products, some for aerospace and some for structural fire protection.
# Glaciology
In glaciology, ablation is used to define the removal of ice or snow from the surface of a mass of ice. Ablation may refer to melting and runoff or evaporation and sublimation of the ice, resulting in a thinning of the ice if it is not replenished by some other process. Ablation deposits are the masses of detritus left after surface melting of glacial ice.
# Medicine
In medicine, ablation is the same as removal of a part of biological tissue, usually by surgery, and more recently using other modalities such as radiofrequency ablation and cryoablation. The American Heritage Stedman's Medical Dictionary defines ablation as "Removal of a body part or the destruction of its function, as by a surgery, disease, or noxious substance."
Surface ablation in the skin (also called resurfacing, because it induces regeneration) can be carried out by chemicals (peeling) or by lasers. Its purpose is to remove skin spots, aged skin, wrinkles, thus rejuvenating it. Surface ablation is also employed in otolaryngology for several kinds of surgery, such as for snoring. Ablation therapy using radiofrequency waves on the heart is used to cure a variety of cardiac arrhythmias such as supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia and more recently atrial fibrillation. The term is often used in the context of laser ablation, a process by which the molecular bonds of a material are dissolved by a laser.
Rotoablation is a type of arterial cleansing that consists of inserting a tiny, diamond-tipped, drill-like device into the affected artery to remove fatty deposits or plaque. The procedure is used in the treatment of coronary heart disease to restore blood flow.
Bone marrow ablation is a process whereby the human bone marrow cells are eliminated in preparation for a bone marrow transplant. This is performed using high-intensity chemotherapy and total body irradiation. As such it has nothing to do with the vaporization techniques described in the rest of this article.
Recently, some researchers reported successful results with genetic ablation. In particular, genetic ablation is potentially a much more efficient method of removing unwanted cells, such as tumor cells, because large numbers of animals lacking specific cells could be generated. Genetically ablated lines can be maintained for a prolonged period of time and shared within the research community. Researchers at Columbia University report of reconstituted caspases combined from C. elegans and humans, which maintain a high degree of target specificity. The genetic ablation techniques described could prove useful in battling cancer.
# Biology
Ablation in biology can refer to genetic or cell ablation, for example. Genetic ablation describes a gene that has been silenced. It can be used on purpose in experiments where scientists can observe the effect of genetic silencing. Cell ablation is where individual cells are destroyed for experimental reasons.
# Laser ablation
Laser ablation is greatly affected by the nature of the material and its ability to absorb energy, therefore the wavelength of the ablation laser should have a minimum absorption depth. While these lasers can average a low power, they can offer peak intensity and fluence given by:
while the peak power is
Surface ablation of the cornea for several types of eye refractive surgery is now common, using an excimer laser system (LASIK and LASEK). Since the cornea does not grow back, laser is used to remodel the cornea refractive properties, in order to correct refraction errors, such as astigmatism, myopia and hyperopia.
# Passive fire protection
Firestopping and fireproofing products can be ablative in nature. This can mean endothermic materials, or merely materials that are sacrificial and become "spent" over time spent while exposed to fire. The latter version has also been used to describe silicone firestop products, which, by themselves, are sacrificial. In other words, given sufficient time under fire or heat conditions, these products actually char away, crumble and disappear. The idea is to put enough of this material in the way of the fire, so that a prescribed fire-resistance rating can be maintained, as proven in a fire test. Usually, ablative materials have a large concentration of organic matter, which is reduced by fire to ashes. In the case of silicone, organic rubber surrounds very finely divided silicadust (up to 380 m² of combined surface area of all the dust particles per gram of this dust). When the fire comes, it reduces the organic rubber to ash and leaves the silica dust, that the product started with, behind. If you burn some silicone caulking and then subsequently crush the remaining ashes, you will find that the interior of the black piece of ash is actually white. The silica was white to begin with. The black stuff is the carbonaceous remains of the organic rubber that surrounded each silica dust particle. | Ablation
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
# Overview
Ablation is defined as the removal of material from the surface of an object by vaporization, chipping, or other erosive processes. The term occurs in space physicsassociated with atmospheric reentry, in glaciology, medicine and passive fire protection.
# Space physics
In space physics, ablation occurs to heat shields that are used to protect payloads from heat, such as the heat shields used by the Apollo Command Module on atmospheric reentry. In a basic sense, ablative material is designed to slowly burn away in a controlled manner, so that heat can be carried away from the spacecraft by the generated gases; while the remaining solid material insulates the craft from superheated gases. There is an entire branch of space physics research involving the search for new fireproofing materials to achieve the best ablative performance; this function is critical to protect the spacecraft occupants and payload from otherwise excessive heat loading. The same technology is used in some passive fire protection applications, in some cases by the same vendors, who offer different versions of these fireproofing products, some for aerospace and some for structural fire protection.
# Glaciology
In glaciology, ablation is used to define the removal of ice or snow from the surface of a mass of ice. Ablation may refer to melting and runoff or evaporation and sublimation of the ice, resulting in a thinning of the ice if it is not replenished by some other process. Ablation deposits are the masses of detritus left after surface melting of glacial ice.
# Medicine
In medicine, ablation is the same as removal of a part of biological tissue, usually by surgery, and more recently using other modalities such as radiofrequency ablation and cryoablation. The American Heritage Stedman's Medical Dictionary defines ablation as "Removal of a body part or the destruction of its function, as by a surgery, disease, or noxious substance." [1]
Surface ablation in the skin (also called resurfacing, because it induces regeneration) can be carried out by chemicals (peeling) or by lasers. Its purpose is to remove skin spots, aged skin, wrinkles, thus rejuvenating it. Surface ablation is also employed in otolaryngology for several kinds of surgery, such as for snoring. Ablation therapy using radiofrequency waves on the heart is used to cure a variety of cardiac arrhythmias such as supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular tachycardia and more recently atrial fibrillation. The term is often used in the context of laser ablation, a process by which the molecular bonds of a material are dissolved by a laser.
Rotoablation is a type of arterial cleansing that consists of inserting a tiny, diamond-tipped, drill-like device into the affected artery to remove fatty deposits or plaque. The procedure is used in the treatment of coronary heart disease to restore blood flow.
Bone marrow ablation is a process whereby the human bone marrow cells are eliminated in preparation for a bone marrow transplant. This is performed using high-intensity chemotherapy and total body irradiation. As such it has nothing to do with the vaporization techniques described in the rest of this article.
Recently, some researchers reported successful results with genetic ablation. In particular, genetic ablation is potentially a much more efficient method of removing unwanted cells, such as tumor cells, because large numbers of animals lacking specific cells could be generated. Genetically ablated lines can be maintained for a prolonged period of time and shared within the research community. Researchers at Columbia University report of reconstituted caspases combined from C. elegans and humans, which maintain a high degree of target specificity. The genetic ablation techniques described could prove useful in battling cancer.[2]
# Biology
Ablation in biology can refer to genetic or cell ablation, for example. Genetic ablation describes a gene that has been silenced. It can be used on purpose in experiments where scientists can observe the effect of genetic silencing. Cell ablation is where individual cells are destroyed for experimental reasons.[3]
# Laser ablation
Laser ablation is greatly affected by the nature of the material and its ability to absorb energy, therefore the wavelength of the ablation laser should have a minimum absorption depth. While these lasers can average a low power, they can offer peak intensity and fluence given by:
while the peak power is
Surface ablation of the cornea for several types of eye refractive surgery is now common, using an excimer laser system (LASIK and LASEK). Since the cornea does not grow back, laser is used to remodel the cornea refractive properties, in order to correct refraction errors, such as astigmatism, myopia and hyperopia.
# Passive fire protection
Firestopping and fireproofing products can be ablative in nature. This can mean endothermic materials, or merely materials that are sacrificial and become "spent" over time spent while exposed to fire. The latter version has also been used to describe silicone firestop products, which, by themselves, are sacrificial. In other words, given sufficient time under fire or heat conditions, these products actually char away, crumble and disappear. The idea is to put enough of this material in the way of the fire, so that a prescribed fire-resistance rating can be maintained, as proven in a fire test. Usually, ablative materials have a large concentration of organic matter, which is reduced by fire to ashes. In the case of silicone, organic rubber surrounds very finely divided silicadust (up to 380 m² of combined surface area of all the dust particles per gram of this dust). When the fire comes, it reduces the organic rubber to ash and leaves the silica dust, that the product started with, behind. If you burn some silicone caulking and then subsequently crush the remaining ashes, you will find that the interior of the black piece of ash is actually white. The silica was white to begin with. The black stuff is the carbonaceous remains of the organic rubber that surrounded each silica dust particle.
# External links
- Physics of laser ablation
- Lasik Laser Eye Surgery. USA Food an Drugs Administration info.
- Physical Modalities, Including Laser. eMedicine index of articles on the subject.
- Chemical Peeling. American Society for Dermatological Surgery.
- Heart Arrhythmias Respond to Ablation UCLA Healthcare | https://www.wikidoc.org/index.php/Ablate | |
9d1e862d8910f1da6b8cae7f83b5f7dc45ec542d | wikidoc | Abortion | Abortion
Synonyms and keywords:Pregnancy loss, miscarriage, spontaneous abortion
# Overview
Abortion is the termination of pregnancy before 20 weeks of gestation, which was first described by an ancient Egyptian medical text as the Ebers Papyrus in 1550 BCE. Abortion is classified as threatened, complete, incomplete, inevitable, septic or missed. Chromosomal abnormalities is the most common cause of sporadic abortion that occur as early as 4-8 weeks gestation, or it could be due to either infectious, immunologic, and environmental factors. Fetal causes of abortion are genetic or chromosomal abnormalities while maternal causes include age, antiphospholipid syndrome, severe hypertension, or systemic lupus erythematosus (SLE). Risk factors for abortion include non-modifiable risk factors like advanced age >35 years and previous pregnancy loss. Modifiable risk factors include obesity, infections, acute and chronic stress, medication and substance use, cocaine, alcohol, tobacco and caffeine. Complications of abortion include infection, post abortion traid, uterine perforation, septic abortion, cervical shock, cervical laceration, and disseminated intravascular coagulation (DIC). The prognosis of abortion depends on the gestational age. The younger the gestational age, the lower the risk of complications.
# Historical Perspective
- Abortion means termination of a pregnancy and it has been known since ancient times.
- Abortion was first described by an ancient Egyptian medical text as the Ebers Papyrus in 1550 BCE, which suggested that an abortion can be induced with the use of a plant-fiber tampon coated with honey and crushed dates.
- During the ancient Egyptian, Persian, and Roman eras, abortion was practiced although it was never explicitly mentioned in any book of the Judeo-Christian Bible.
- In the fourth century BCE, Niddah 23a, a chapter of the Babylonian Talmud, reviews abortion as determining whether a woman is "unclean" and permitting abortion during early pregnancy.
" A woman can only abort something in the shape of a stone, and that can only be described as a lump."
- In 11th century BCE, the Code of Assura, '' a harsh set of laws restricting women in general'' was the earliest legal ban on abortion by forcing the death penalty on married women who obtain abortions without permission of their husbands.
- In the fifth century BCE, the Hippocratic Oath prohibited physicians from inducing elective abortions.
- In the 19th century, surgical abortions became common and Hegar dilator in 1879 invented dilation-and-curettage (D&C).
- On November 18, 1920, the Commissariats of Health and Justice legalized abortion in Soviet hospitals.
- In 1970, Hawaii, New York, Alaska and Washington declared their abortion laws. Hawaii was the first state to legalize abortions and New York allowed abortions up to the 24th week of pregnancy.
# Classification
Abortion can be classified into the following:
# Pathophysiology
- Chromosomal abnormalities is the most common cause of sporadic abortion that occurs as early as 4-8 weeks gestation, for instance aneuploidy, mosaicism, translocation, inversion, deletion, or fragile sites.
- First-trimester pregnancy loss could be due to either infectious, immunologic, and environmental factors.
- Immunologic factors is not well defined. Several theories suggest that early pregnancy loss could be due to:
Allogeneic factors.
Lack of the immunological protection of the embryos, such as complement regulatory proteins (eg, mannose-binding lectin, and HLA-DR, HLA-G or HLA-E)
Increased activity of uterine natural killer (uNK) cells.
Alloimmunization to blood group antigen P.
- Allogeneic factors.
- Lack of the immunological protection of the embryos, such as complement regulatory proteins (eg, mannose-binding lectin, and HLA-DR, HLA-G or HLA-E)
- Increased activity of uterine natural killer (uNK) cells.
- Alloimmunization to blood group antigen P.
- Anatomic distortion of uterus may be associated with early or second trimester pregnancy loss, eg: fibroids, polyps, adhesions, or septa depending on the size and position.
- The mechanism of pregnancy loss due to septate uterus is not clearly understood, one theory suggests that poor blood supply to the septum leads to poor implantation.
- FXIII and fibrinogen play an essential role in placental implantation and maintenance of pregnancy, that is why a deficiency of factor XIII (FXIII) and fibrinogen are associated with pregnancy loss.
- It is thought that miscarriage risk is associated with low plasma levels of the hormone kisspeptin.
- The mechanism of abortion in cases of PCOS is unknown, however it could be related to elevated serum luteinizing hormone (LH) levels, high testosterone and androstenedione concentrations or insulin resistance
# Causes
Early Pregnancy Loss
Fetal causes:
- Genetic or chromosomal abnormalities (45,X karyotype, Trisomies (Trisomy 16 is the most common), aneuploidy, mosaicism, translocation, inversion, deletion, fragile sites)
- Teratogenic and mutagenic factors.
Maternal causes:
- Genetic: Maternal age is directly related to the aneuploidy risk,
- Parental chromosomal anomaly balanced translocation
- Corpus luteum deficiency
- Active infection such as rubella virus, cytomegalovirus
- Antiphospholipid syndrome
- Severe hypertension
- Systemic lupus erythematosus (SLE)
- Renal disease
- Poorly controlled diabetes mellitus
- Polycystic ovary syndrome
# Differentiating abortion from other Diseases
Abortion should be differentiated from other causes of bleeding with cramping in early pregnancy:
- Related to Pregnancy
Ectopic pregnancy
Subchorionic hematoma
Hydatidiform mole
- Ectopic pregnancy
- Subchorionic hematoma
- Hydatidiform mole
- Unrelated to pregnancy
Infection (cervicitis)
Polyps
Fibroids
- Infection (cervicitis)
- Polyps
- Fibroids
# Epidemiology and Demographics
- The incidence of abortion worldwide was estimated to be 35 per 1,000 women ages 15 to 44 from 2010 to 2014.
- The rate in resource-rich countries was 27 per 1,000 and in resource-limited countries was 37 per 1,000. The incidence was highest in the Caribbean (65 per 1,000), and the lowest in North America (17 per 1,000).
- In the United States, one in four women will have an abortion during their reproductive life.
- The incidence of abortion is approximately 31%, the true incidence of abortion is difficult to ascertain, as many losses are not recognized
- The rate of abortion is influenced by maternal age and history of prior pregnancy loss. 15% of women experience sporadic abortion, 2% of pregnant women experience two consecutive abortion and only 0.4 to 1% have three consecutive abortion.
- The incidence of abortions in the United States were highest in women ages 20 to 24 (19.1 per 1,000 women) and 25 to 29 (18.5 per 1,000 women)
- Most abortions were done in women who were unmarried (85%) and had one or more children (59%).
- Abortion rates in individuals of non-Hispanic White were 38.7, 20.0 for Hispanic, and 7.7 for other races per 1,000 women.
- In the United States in 2018, 78% of abortions occur at 9 weeks or earlier, 92% at 13 weeks or earlier, and 8% at or after 14 weeks.
# Risk Factors
Non-modifiable risk factors include:
- Advanced age >35 years, the most significant risk factor because of the associated fetal chromosomal abnormalities.
- Extremes of age
- Advanced paternal age
- Previous pregnancy loss increases the risk of later pregnancy loss.
Modifiable risk factors include:
- Obesity
- Infection (eg: Parvovirus B19 infection,syphilis, cytomegalovirus (CMV) infection)
- Pre-gestational diabetes increases the risk of miscarriage two- to threefold.
- Hyper- and hypothyroidism
- Acute and chronic stress
- Medication and substance use, examples are NSAIDs (ibuprofen and diclofenac), cocaine, methamphetamines
- Alcohol, tobacco and caffeine
# Screening
There is insufficient evidence to recommend routine screening for abortion.
# Natural History, Complications, and Prognosis
- Complications of spontaneous abortion and therapeutic abortions include the following:
Complications of anesthesia
Post abortion triad (pain, bleeding, low-grade fever) caused by retained products of conception.
Retained products of conception
Uterine perforation
Septic abortion
Cervical shock
Cervical laceration
Disseminated intravascular coagulation (DIC)
- Complications of anesthesia
- Post abortion triad (pain, bleeding, low-grade fever) caused by retained products of conception.
- Retained products of conception
- Uterine perforation
- Septic abortion
- Cervical shock
- Cervical laceration
- Disseminated intravascular coagulation (DIC)
- Prognosis of abortion depends on the gestational age. The younger the gestational age, the lower the risk of complications. The highest risk of death is from a septic abortion; the majority of these cases are a result of illegal abortions in developing countries.
# Diagnosis
## Diagnostic Study of Choice
- Ultrasound shows no intrauterine pregnancy or loss of previously seen cardiac activity is diagnostic if the intrauterine pregnancy is confirmed by ultrasound in a previous visit.
- The diagnosis of early pregnancy loss (EPL) occurs if the initial transvaginal ultrasound shows intrauterine pregnancy without fetal cardiac activity and is based on the criteria made by the Society of Radiologists in Ultrasound Multi-specialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy, which include:
A gestational sac ≥25 mm in mean diameter that does not contain a yolk sac or embryo
An embryo with a crown-rump length (CRL) ≥7 mm that does not have cardiac activity
After a pelvic ultrasound shows a gestational sac without a yolk sac, absence of an embryo with a heartbeat in ≥2 weeks
After a pelvic ultrasound shows a gestational sac with a yolk sac, absence of an embryo with a heartbeat in ≥11 days
Findings that are suspicious for, but not diagnostic of, pregnancy loss include:
CRL <7 mm and no heartbeat.
Mean sac diameter of 16 to 24 mm and no embryo.
Absence of embryo with a heartbeat 7 to 13 days after a scan that showed a gestational sac without a yolk sac
Absence of embryo with a heartbeat 7 to 10 days after a scan that showed a gestational sac with a yolk sac
Absence of embryo ≥6 weeks after last menstrual period
Empty amnion (amnion seen adjacent to yolk sac with no visible embryo)
Enlarged yolk sac (>7 mm)
Small gestational sac in relation to the size of the embryo (<5 mm difference between mean sac diameter and CRL)
- A gestational sac ≥25 mm in mean diameter that does not contain a yolk sac or embryo
- An embryo with a crown-rump length (CRL) ≥7 mm that does not have cardiac activity
- After a pelvic ultrasound shows a gestational sac without a yolk sac, absence of an embryo with a heartbeat in ≥2 weeks
- After a pelvic ultrasound shows a gestational sac with a yolk sac, absence of an embryo with a heartbeat in ≥11 days
- Findings that are suspicious for, but not diagnostic of, pregnancy loss include:
CRL <7 mm and no heartbeat.
Mean sac diameter of 16 to 24 mm and no embryo.
Absence of embryo with a heartbeat 7 to 13 days after a scan that showed a gestational sac without a yolk sac
Absence of embryo with a heartbeat 7 to 10 days after a scan that showed a gestational sac with a yolk sac
Absence of embryo ≥6 weeks after last menstrual period
Empty amnion (amnion seen adjacent to yolk sac with no visible embryo)
Enlarged yolk sac (>7 mm)
Small gestational sac in relation to the size of the embryo (<5 mm difference between mean sac diameter and CRL)
- CRL <7 mm and no heartbeat.
- Mean sac diameter of 16 to 24 mm and no embryo.
- Absence of embryo with a heartbeat 7 to 13 days after a scan that showed a gestational sac without a yolk sac
- Absence of embryo with a heartbeat 7 to 10 days after a scan that showed a gestational sac with a yolk sac
- Absence of embryo ≥6 weeks after last menstrual period
- Empty amnion (amnion seen adjacent to yolk sac with no visible embryo)
- Enlarged yolk sac (>7 mm)
- Small gestational sac in relation to the size of the embryo (<5 mm difference between mean sac diameter and CRL)
## History and Symptoms
- Constitutional symptoms including fever or chills, suggesting septic abortion.
- The history should include when was the date of last menstrual period (LMP), estimated length of gestation, bleeding disorders, previous miscarriage.
- The symptoms that raise suspicion of abortion are:
Vaginal bleeding (the volume of bleeding varies) and suprapubic abdominal cramping (especially during passage of gestational tissue), passage of clot is an important sign.
Loss or reduction of pregnancy symptoms, such as decreased breast tenderness, nausea and vomiting.
- Vaginal bleeding (the volume of bleeding varies) and suprapubic abdominal cramping (especially during passage of gestational tissue), passage of clot is an important sign.
- Loss or reduction of pregnancy symptoms, such as decreased breast tenderness, nausea and vomiting.
- Asymptomatic discovered incidentally or on routine ultrasound in early pregnancy.
## Physical Examination
- Vital signs
Depends on the amount of bleeding, if severe, the patient will be hemodynamically unstable.
- Pelvic examination
Bimanual examination to determine the status of cervix and to estimate the gestational age, adnexal tenderness or masses or cervical motion tenderness to exclude ectopic pregnancy.
Speculum examination to see the source and quantity of bleeding and whether bleeding coming from the cervix and an open cervical os.
Common physical examination findings of threatened miscarriage include vital signs should be within reference ranges, soft and non-tender abdomen, and closed internal cervical os.
Common physical examination findings of incomplete miscarriage include enlarged and soft uterus, dilated and effaced cervix, and products of conception may be partially present in the uterus, at the external os, or may be present in the vagina.
Common physical examination findings of complete miscarriage include a closed cervix, and the uterus should be contracted.
Common physical examination findings of missed miscarriage include normal vital signs, the uterus is small for gestational age, absent fetal heart tones on sonogram and closed cervix.
- Bimanual examination to determine the status of cervix and to estimate the gestational age, adnexal tenderness or masses or cervical motion tenderness to exclude ectopic pregnancy.
- Speculum examination to see the source and quantity of bleeding and whether bleeding coming from the cervix and an open cervical os.
- Common physical examination findings of threatened miscarriage include vital signs should be within reference ranges, soft and non-tender abdomen, and closed internal cervical os.
- Common physical examination findings of incomplete miscarriage include enlarged and soft uterus, dilated and effaced cervix, and products of conception may be partially present in the uterus, at the external os, or may be present in the vagina.
- Common physical examination findings of complete miscarriage include a closed cervix, and the uterus should be contracted.
- Common physical examination findings of missed miscarriage include normal vital signs, the uterus is small for gestational age, absent fetal heart tones on sonogram and closed cervix.
## Laboratory Findings
- Laboratory studies may include the following:
Urine pregnancy test.
Complete blood count with differential, hemoglobin and hematocrit.
Blood type and Rh factor.
- Urine pregnancy test.
- Complete blood count with differential, hemoglobin and hematocrit.
- Blood type and Rh factor.
- Serum hCG and progesterone have limited utility in the diagnostic evaluation of abortion. In general, the diagnosis of pregnancy loss is made by an ultrasound (U/S) once the presence of intrauterine gestational sac is confirmed.
- An intrauterine pregnancy may be seen with (transvaginal ultrasound) (TVUS) at a ß-hCG level of 1500-2000 IU/L. However, indeterminate pregnancy on TVUS should undergo ß-hCG level testing and if ß-hCG levels 1500, do TVUS again.
- U/S is the most accurate diagnostic modality in the confirmation of a viable pregnancy during the first trimester.
- An empty uterus revealed by U/S in a pregnant woman with positive beta-hCG, suggests a very early pregnancy < 3 wk, a completed miscarriage, or an ectopic pregnancy.
## Electrocardiogram
There are no ECG findings associated with abortion.
## X-ray
There are no x-ray findings associated with abortion.
## Abdominal/ trans-vaginal Ultrasound
- Findings on an ultrasound suggestive of nonviable pregnancy include gestational sac >25-mm mean sac diameter on transabdominal sonogram; >16-mm MSD on endovaginal sonogram without a detectable embryo, embryo without a heartbeat, hyperechoic material within the uterine cavity.
- An incomplete miscarriage on ultrasound shows gestational sac misshaped or collapsed, an irregular complex mass within the endometrial or cervical canal may be present or echogenic material in the endometrial canal.
- A complete miscarriage may demonstrate an empty uterus noted on transvaginal ultrasound.
## CT scan
There are no CT scan findings associated with abortion. However, a CT scan may be helpful in the diagnosis of complications like uterine rupture.
## MRI
The use of a MRI in maternal emergency obstetric conditions is relatively limited, a MRI has a role where USG is indeterminate, particularly in ectopic pregnancy.
## Other Imaging Findings
There are no other imaging findings associated with abortion.
## Other Diagnostic Studies
There are no other diagnostic studies associated with abortion.
# Treatment
## Expectant management
- Waiting for pregnancy tissue to pass recommended only in the first trimester, after 13 weeks, medication management in a health facility or surgical management should be considered.
- Pain management in the first trimester is typically nonsteroidal anti-inflammatory drugs for pain.
- Follow-up to confirm complete passage of gestational tissue by ultrasound.
- Incomplete uterine emptying still require uterine aspiration.
- Administer RhoGAM to women with Rh-negative and is experiencing vaginal bleeding
## Medical Therapy
- Up to 13 weeks of gestation:
mifepristone followed by misoprostol 24 hours later.
Dose: mifepristone 200 mg orally followed in 24 hours by misoprostol 800 mcg per vagina (typically given as four 200 mcg tablets).
Antibiotics are not recommended for routine medication management of abortion.
Pain management with nonsteroidal anti-inflammatory drug (NSAID) prior to using misoprostol.
Misoprostol alone regemin 800 mcg per vagina (typically four 200 mcg tablets). For patients who do not have complete expulsion after a single dose, a second dose can be given. Between 9 and 12 weeks, the World Health Organization (WHO) recommends an initial 800 mcg dose of misoprostol followed by 400 mcg every three hours until expulsion.
- mifepristone followed by misoprostol 24 hours later.
- Dose: mifepristone 200 mg orally followed in 24 hours by misoprostol 800 mcg per vagina (typically given as four 200 mcg tablets).
- Antibiotics are not recommended for routine medication management of abortion.
- Pain management with nonsteroidal anti-inflammatory drug (NSAID) prior to using misoprostol.
- Misoprostol alone regemin 800 mcg per vagina (typically four 200 mcg tablets). For patients who do not have complete expulsion after a single dose, a second dose can be given. Between 9 and 12 weeks, the World Health Organization (WHO) recommends an initial 800 mcg dose of misoprostol followed by 400 mcg every three hours until expulsion.
- 13 to 20 weeks of gestation
Regardless of the gestational age, medication management of pregnancy loss includes mifepristone and misoprostol. The difference is that the misoprostol dose is often reduced and repeated, and should be done in a health facility.
- Regardless of the gestational age, medication management of pregnancy loss includes mifepristone and misoprostol. The difference is that the misoprostol dose is often reduced and repeated, and should be done in a health facility.
## Surgery
- Surgery evacuation with sharp curettage or suction curettage is not the first-line treatment option for patients with early pregnancy loss.
- Surgery is usually reserved for patients with either hemorrhage, hemodynamic instability, or signs of infection.
- This is also the preferred method of treatment for women with comorbid conditions such as cardiovascular disease, infection, severe anemia, or bleeding disorders.
- Antibiotic prophylaxis should be given before surgical evacuation
## Primary Prevention
Effective measures for the primary prevention of unsafe abortion include :
- Use of contraception has been shown an effective decrease in the abortion rate.
- Sexual education programs.
- Easy access to contraception.
- Social protection to reduce induced abortion among pregnant women who have been abandoned by their partners, rejected by their families.
## Secondary Prevention
The only way to prevent an unsafe abortion is to provide safe services for termination of pregnancy. | Abortion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2]
Synonyms and keywords:Pregnancy loss, miscarriage, spontaneous abortion
# Overview
Abortion is the termination of pregnancy before 20 weeks of gestation, which was first described by an ancient Egyptian medical text as the Ebers Papyrus in 1550 BCE. Abortion is classified as threatened, complete, incomplete, inevitable, septic or missed. Chromosomal abnormalities is the most common cause of sporadic abortion that occur as early as 4-8 weeks gestation, or it could be due to either infectious, immunologic, and environmental factors. Fetal causes of abortion are genetic or chromosomal abnormalities while maternal causes include age, antiphospholipid syndrome, severe hypertension, or systemic lupus erythematosus (SLE). Risk factors for abortion include non-modifiable risk factors like advanced age >35 years and previous pregnancy loss. Modifiable risk factors include obesity, infections, acute and chronic stress, medication and substance use, cocaine, alcohol, tobacco and caffeine. Complications of abortion include infection, post abortion traid, uterine perforation, septic abortion, cervical shock, cervical laceration, and disseminated intravascular coagulation (DIC). The prognosis of abortion depends on the gestational age. The younger the gestational age, the lower the risk of complications.
# Historical Perspective
- Abortion means termination of a pregnancy and it has been known since ancient times.
- Abortion was first described by an ancient Egyptian medical text as the Ebers Papyrus in 1550 BCE, which suggested that an abortion can be induced with the use of a plant-fiber tampon coated with honey and crushed dates.[1]
- During the ancient Egyptian, Persian, and Roman eras, abortion was practiced although it was never explicitly mentioned in any book of the Judeo-Christian Bible.[1]
- In the fourth century BCE, Niddah 23a, a chapter of the Babylonian Talmud, reviews abortion as determining whether a woman is "unclean" and permitting abortion during early pregnancy.[1]
" A woman can only abort something in the shape of a stone, and that can only be described as a lump."
- In 11th century BCE, the Code of Assura, '' a harsh set of laws restricting women in general'' was the earliest legal ban on abortion by forcing the death penalty on married women who obtain abortions without permission of their husbands.[2]
- In the fifth century BCE, the Hippocratic Oath prohibited physicians from inducing elective abortions.[3]
- In the 19th century, surgical abortions became common and Hegar dilator in 1879 invented dilation-and-curettage (D&C).[4]
- On November 18, 1920, the Commissariats of Health and Justice legalized abortion in Soviet hospitals.[5][6]
- In 1970, Hawaii, New York, Alaska and Washington declared their abortion laws. Hawaii was the first state to legalize abortions and New York allowed abortions up to the 24th week of pregnancy.[7]
# Classification
Abortion can be classified into the following:[8] [9][10]
# Pathophysiology
- Chromosomal abnormalities is the most common cause of sporadic abortion that occurs as early as 4-8 weeks gestation, for instance aneuploidy, mosaicism, translocation, inversion, deletion, or fragile sites.[11]
- First-trimester pregnancy loss could be due to either infectious, immunologic, and environmental factors.
- Immunologic factors is not well defined. Several theories suggest that early pregnancy loss could be due to: [12][13]
Allogeneic factors.
Lack of the immunological protection of the embryos, such as complement regulatory proteins (eg, mannose-binding lectin, and HLA-DR, HLA-G or HLA-E)
Increased activity of uterine natural killer (uNK) cells.
Alloimmunization to blood group antigen P.[14]
- Allogeneic factors.
- Lack of the immunological protection of the embryos, such as complement regulatory proteins (eg, mannose-binding lectin, and HLA-DR, HLA-G or HLA-E)
- Increased activity of uterine natural killer (uNK) cells.
- Alloimmunization to blood group antigen P.[14]
- Anatomic distortion of uterus may be associated with early or second trimester pregnancy loss, eg: fibroids, polyps, adhesions, or septa depending on the size and position.
- The mechanism of pregnancy loss due to septate uterus is not clearly understood, one theory suggests that poor blood supply to the septum leads to poor implantation.[15]
- FXIII and fibrinogen play an essential role in placental implantation and maintenance of pregnancy, that is why a deficiency of factor XIII (FXIII) and fibrinogen are associated with pregnancy loss.[16]
- It is thought that miscarriage risk is associated with low plasma levels of the hormone kisspeptin.[17]
- The mechanism of abortion in cases of PCOS is unknown, however it could be related to elevated serum luteinizing hormone (LH) levels, high testosterone and androstenedione concentrations or insulin resistance[18]
# Causes
Early Pregnancy Loss[19][20]
Fetal causes:
- Genetic or chromosomal abnormalities (45,X karyotype, Trisomies (Trisomy 16 is the most common), aneuploidy, mosaicism, translocation, inversion, deletion, fragile sites)
- Teratogenic and mutagenic factors.
-
Maternal causes:
- Genetic: Maternal age is directly related to the aneuploidy risk,
- Parental chromosomal anomaly balanced translocation
- Corpus luteum deficiency
- Active infection such as rubella virus, cytomegalovirus
- Antiphospholipid syndrome
- Severe hypertension
- Systemic lupus erythematosus (SLE)
- Renal disease
- Poorly controlled diabetes mellitus
- Polycystic ovary syndrome
# Differentiating abortion from other Diseases
Abortion should be differentiated from other causes of bleeding with cramping in early pregnancy:[21]
- Related to Pregnancy
Ectopic pregnancy
Subchorionic hematoma
Hydatidiform mole
- Ectopic pregnancy
- Subchorionic hematoma
- Hydatidiform mole
- Unrelated to pregnancy
Infection (cervicitis)
Polyps
Fibroids
- Infection (cervicitis)
- Polyps
- Fibroids
# Epidemiology and Demographics
- The incidence of abortion worldwide was estimated to be 35 per 1,000 women ages 15 to 44 from 2010 to 2014.[22]
- The rate in resource-rich countries was 27 per 1,000 and in resource-limited countries was 37 per 1,000. The incidence was highest in the Caribbean (65 per 1,000), and the lowest in North America (17 per 1,000). [23]
- In the United States, one in four women will have an abortion during their reproductive life.[23]
- The incidence of abortion is approximately 31%, the true incidence of abortion is difficult to ascertain, as many losses are not recognized[24][25]
- The rate of abortion is influenced by maternal age and history of prior pregnancy loss.[26] 15% of women experience sporadic abortion, 2% of pregnant women experience two consecutive abortion and only 0.4 to 1% have three consecutive abortion. [27]
- The incidence of abortions in the United States were highest in women ages 20 to 24 (19.1 per 1,000 women) and 25 to 29 (18.5 per 1,000 women)[28]
- Most abortions were done in women who were unmarried (85%) and had one or more children (59%).[28]
- Abortion rates in individuals of non-Hispanic White were 38.7, 20.0 for Hispanic, and 7.7 for other races per 1,000 women. [28]
- In the United States in 2018, 78% of abortions occur at 9 weeks or earlier, 92% at 13 weeks or earlier, and 8% at or after 14 weeks.[29]
# Risk Factors
Non-modifiable risk factors include: [30]
- Advanced age >35 years, the most significant risk factor because of the associated fetal chromosomal abnormalities.
- Extremes of age
- Advanced paternal age
- Previous pregnancy loss increases the risk of later pregnancy loss.[31]
Modifiable risk factors include:
- Obesity[32]
- Infection (eg: Parvovirus B19 infection,syphilis, cytomegalovirus (CMV) infection)[33][34][35]
- Pre-gestational diabetes increases the risk of miscarriage two- to threefold.[36]
- Hyper- and hypothyroidism [37]
- Acute and chronic stress[38]
- Medication and substance use, examples are NSAIDs (ibuprofen and diclofenac), cocaine, methamphetamines[39]
- Alcohol, tobacco and caffeine[40][41][42][43]
# Screening
There is insufficient evidence to recommend routine screening for abortion.
# Natural History, Complications, and Prognosis
- Complications of spontaneous abortion and therapeutic abortions include the following:[44]
Complications of anesthesia
Post abortion triad (pain, bleeding, low-grade fever) caused by retained products of conception.
Retained products of conception
Uterine perforation[45]
Septic abortion[46]
Cervical shock
Cervical laceration
Disseminated intravascular coagulation (DIC)
- Complications of anesthesia
- Post abortion triad (pain, bleeding, low-grade fever) caused by retained products of conception.
- Retained products of conception
- Uterine perforation[45]
- Septic abortion[46]
- Cervical shock
- Cervical laceration
- Disseminated intravascular coagulation (DIC)
- Prognosis of abortion depends on the gestational age. The younger the gestational age, the lower the risk of complications. The highest risk of death is from a septic abortion; the majority of these cases are a result of illegal abortions in developing countries.[47]
# Diagnosis
## Diagnostic Study of Choice
- Ultrasound shows no intrauterine pregnancy or loss of previously seen cardiac activity is diagnostic if the intrauterine pregnancy is confirmed by ultrasound in a previous visit.[48]
- The diagnosis of early pregnancy loss (EPL) occurs if the initial transvaginal ultrasound shows intrauterine pregnancy without fetal cardiac activity and is based on the criteria made by the Society of Radiologists in Ultrasound Multi-specialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy, which include:[49]
A gestational sac ≥25 mm in mean diameter that does not contain a yolk sac or embryo
An embryo with a crown-rump length (CRL) ≥7 mm that does not have cardiac activity
After a pelvic ultrasound shows a gestational sac without a yolk sac, absence of an embryo with a heartbeat in ≥2 weeks
After a pelvic ultrasound shows a gestational sac with a yolk sac, absence of an embryo with a heartbeat in ≥11 days
Findings that are suspicious for, but not diagnostic of, pregnancy loss include:
CRL <7 mm and no heartbeat.
Mean sac diameter of 16 to 24 mm and no embryo.
Absence of embryo with a heartbeat 7 to 13 days after a scan that showed a gestational sac without a yolk sac
Absence of embryo with a heartbeat 7 to 10 days after a scan that showed a gestational sac with a yolk sac
Absence of embryo ≥6 weeks after last menstrual period
Empty amnion (amnion seen adjacent to yolk sac with no visible embryo)
Enlarged yolk sac (>7 mm)
Small gestational sac in relation to the size of the embryo (<5 mm difference between mean sac diameter and CRL)
- A gestational sac ≥25 mm in mean diameter that does not contain a yolk sac or embryo
- An embryo with a crown-rump length (CRL) ≥7 mm that does not have cardiac activity
- After a pelvic ultrasound shows a gestational sac without a yolk sac, absence of an embryo with a heartbeat in ≥2 weeks
- After a pelvic ultrasound shows a gestational sac with a yolk sac, absence of an embryo with a heartbeat in ≥11 days
- Findings that are suspicious for, but not diagnostic of, pregnancy loss include:
CRL <7 mm and no heartbeat.
Mean sac diameter of 16 to 24 mm and no embryo.
Absence of embryo with a heartbeat 7 to 13 days after a scan that showed a gestational sac without a yolk sac
Absence of embryo with a heartbeat 7 to 10 days after a scan that showed a gestational sac with a yolk sac
Absence of embryo ≥6 weeks after last menstrual period
Empty amnion (amnion seen adjacent to yolk sac with no visible embryo)
Enlarged yolk sac (>7 mm)
Small gestational sac in relation to the size of the embryo (<5 mm difference between mean sac diameter and CRL)
- CRL <7 mm and no heartbeat.
- Mean sac diameter of 16 to 24 mm and no embryo.
- Absence of embryo with a heartbeat 7 to 13 days after a scan that showed a gestational sac without a yolk sac
- Absence of embryo with a heartbeat 7 to 10 days after a scan that showed a gestational sac with a yolk sac
- Absence of embryo ≥6 weeks after last menstrual period
- Empty amnion (amnion seen adjacent to yolk sac with no visible embryo)
- Enlarged yolk sac (>7 mm)
- Small gestational sac in relation to the size of the embryo (<5 mm difference between mean sac diameter and CRL)
## History and Symptoms
- Constitutional symptoms including fever or chills, suggesting septic abortion.
- The history should include when was the date of last menstrual period (LMP), estimated length of gestation, bleeding disorders, previous miscarriage.
- The symptoms that raise suspicion of abortion are:
Vaginal bleeding (the volume of bleeding varies) and suprapubic abdominal cramping (especially during passage of gestational tissue), passage of clot is an important sign.
Loss or reduction of pregnancy symptoms, such as decreased breast tenderness, nausea and vomiting.
- Vaginal bleeding (the volume of bleeding varies) and suprapubic abdominal cramping (especially during passage of gestational tissue), passage of clot is an important sign.
- Loss or reduction of pregnancy symptoms, such as decreased breast tenderness, nausea and vomiting.
- Asymptomatic discovered incidentally or on routine ultrasound in early pregnancy.
## Physical Examination
- Vital signs
Depends on the amount of bleeding, if severe, the patient will be hemodynamically unstable.
- Pelvic examination
Bimanual examination to determine the status of cervix and to estimate the gestational age, adnexal tenderness or masses or cervical motion tenderness to exclude ectopic pregnancy.
Speculum examination to see the source and quantity of bleeding and whether bleeding coming from the cervix and an open cervical os.
Common physical examination findings of threatened miscarriage include vital signs should be within reference ranges, soft and non-tender abdomen, and closed internal cervical os.
Common physical examination findings of incomplete miscarriage include enlarged and soft uterus, dilated and effaced cervix, and products of conception may be partially present in the uterus, at the external os, or may be present in the vagina.
Common physical examination findings of complete miscarriage include a closed cervix, and the uterus should be contracted.
Common physical examination findings of missed miscarriage include normal vital signs, the uterus is small for gestational age, absent fetal heart tones on sonogram and closed cervix.
- Bimanual examination to determine the status of cervix and to estimate the gestational age, adnexal tenderness or masses or cervical motion tenderness to exclude ectopic pregnancy.
- Speculum examination to see the source and quantity of bleeding and whether bleeding coming from the cervix and an open cervical os.
- Common physical examination findings of threatened miscarriage include vital signs should be within reference ranges, soft and non-tender abdomen, and closed internal cervical os.
- Common physical examination findings of incomplete miscarriage include enlarged and soft uterus, dilated and effaced cervix, and products of conception may be partially present in the uterus, at the external os, or may be present in the vagina.
- Common physical examination findings of complete miscarriage include a closed cervix, and the uterus should be contracted.
- Common physical examination findings of missed miscarriage include normal vital signs, the uterus is small for gestational age, absent fetal heart tones on sonogram and closed cervix.
## Laboratory Findings
- Laboratory studies may include the following:[50]
Urine pregnancy test.
Complete blood count with differential, hemoglobin and hematocrit.
Blood type and Rh factor.
- Urine pregnancy test.
- Complete blood count with differential, hemoglobin and hematocrit.
- Blood type and Rh factor.
- Serum hCG and progesterone have limited utility in the diagnostic evaluation of abortion. In general, the diagnosis of pregnancy loss is made by an ultrasound (U/S) once the presence of intrauterine gestational sac is confirmed.[50]
- An intrauterine pregnancy may be seen with (transvaginal ultrasound) (TVUS) at a ß-hCG level of 1500-2000 IU/L. However, indeterminate pregnancy on TVUS should undergo ß-hCG level testing and if ß-hCG levels <1500 repeat hCG in 2 days, if ß-hCG levels >1500, do TVUS again.[50]
- U/S is the most accurate diagnostic modality in the confirmation of a viable pregnancy during the first trimester.
- An empty uterus revealed by U/S in a pregnant woman with positive beta-hCG, suggests a very early pregnancy < 3 wk, a completed miscarriage, or an ectopic pregnancy.[50]
## Electrocardiogram
There are no ECG findings associated with abortion.
## X-ray
There are no x-ray findings associated with abortion.
## Abdominal/ trans-vaginal Ultrasound [51][52]
- Findings on an ultrasound suggestive of nonviable pregnancy include gestational sac >25-mm mean sac diameter on transabdominal sonogram; >16-mm MSD on endovaginal sonogram without a detectable embryo, embryo without a heartbeat, hyperechoic material within the uterine cavity.
- An incomplete miscarriage on ultrasound shows gestational sac misshaped or collapsed, an irregular complex mass within the endometrial or cervical canal may be present or echogenic material in the endometrial canal.
- A complete miscarriage may demonstrate an empty uterus noted on transvaginal ultrasound.
## CT scan
There are no CT scan findings associated with abortion. However, a CT scan may be helpful in the diagnosis of complications like uterine rupture.[53]
## MRI
The use of a MRI in maternal emergency obstetric conditions is relatively limited, a MRI has a role where USG is indeterminate, particularly in ectopic pregnancy.[54]
## Other Imaging Findings
There are no other imaging findings associated with abortion.
## Other Diagnostic Studies
There are no other diagnostic studies associated with abortion.
# Treatment
## Expectant management
- Waiting for pregnancy tissue to pass recommended only in the first trimester, after 13 weeks, medication management in a health facility or surgical management should be considered.
- Pain management in the first trimester is typically nonsteroidal anti-inflammatory drugs for pain.
- Follow-up to confirm complete passage of gestational tissue by ultrasound.
- Incomplete uterine emptying still require uterine aspiration.
- Administer RhoGAM to women with Rh-negative and is experiencing vaginal bleeding
## Medical Therapy
- Up to 13 weeks of gestation:[55][56]
mifepristone followed by misoprostol 24 hours later.
Dose: mifepristone 200 mg orally followed in 24 hours by misoprostol 800 mcg per vagina (typically given as four 200 mcg tablets).
Antibiotics are not recommended for routine medication management of abortion.[57]
Pain management with nonsteroidal anti-inflammatory drug (NSAID) prior to using misoprostol.[57]
Misoprostol alone regemin 800 mcg per vagina (typically four 200 mcg tablets). For patients who do not have complete expulsion after a single dose, a second dose can be given. Between 9 and 12 weeks, the World Health Organization (WHO) recommends an initial 800 mcg dose of misoprostol followed by 400 mcg every three hours until expulsion.[57]
- mifepristone followed by misoprostol 24 hours later.
- Dose: mifepristone 200 mg orally followed in 24 hours by misoprostol 800 mcg per vagina (typically given as four 200 mcg tablets).
- Antibiotics are not recommended for routine medication management of abortion.[57]
- Pain management with nonsteroidal anti-inflammatory drug (NSAID) prior to using misoprostol.[57]
- Misoprostol alone regemin 800 mcg per vagina (typically four 200 mcg tablets). For patients who do not have complete expulsion after a single dose, a second dose can be given. Between 9 and 12 weeks, the World Health Organization (WHO) recommends an initial 800 mcg dose of misoprostol followed by 400 mcg every three hours until expulsion.[57]
- 13 to 20 weeks of gestation
Regardless of the gestational age, medication management of pregnancy loss includes mifepristone and misoprostol. The difference is that the misoprostol dose is often reduced and repeated, and should be done in a health facility.
- Regardless of the gestational age, medication management of pregnancy loss includes mifepristone and misoprostol. The difference is that the misoprostol dose is often reduced and repeated, and should be done in a health facility.
## Surgery
- Surgery evacuation with sharp curettage or suction curettage is not the first-line treatment option for patients with early pregnancy loss.
- Surgery is usually reserved for patients with either hemorrhage, hemodynamic instability, or signs of infection.[58]
- This is also the preferred method of treatment for women with comorbid conditions such as cardiovascular disease, infection, severe anemia, or bleeding disorders.
- Antibiotic prophylaxis should be given before surgical evacuation
## Primary Prevention
Effective measures for the primary prevention of unsafe abortion include :[61]
- Use of contraception has been shown an effective decrease in the abortion rate.
- Sexual education programs.
- Easy access to contraception.
- Social protection to reduce induced abortion among pregnant women who have been abandoned by their partners, rejected by their families.
## Secondary Prevention
The only way to prevent an unsafe abortion is to provide safe services for termination of pregnancy.[61] | https://www.wikidoc.org/index.php/Aborted | |
1cbcb52f535afc7910ec41d88b186ecb4e75b6e2 | wikidoc | Abrasive | Abrasive
An abrasive is a material, often a mineral, that is used to shape or finish a workpiece through rubbing which leads to part of the workpiece being worn away. While finishing a material often means polishing it to gain a smooth, reflective surface it can also involve roughening as in satin, matte or beaded finishes.
Abrasives are extremely commonplace and are used very extensively in a wide variety of industrial, domestic, and technological applications. This gives rise to a large variation in the physical and chemical composition of abrasives as well as the shape of the abrasive. Common uses for abrasives include grinding, polishing, buffing, honing, cutting, drilling, sharpening, and sanding (see abrasive machining). (For simplicity, "mineral" in this article will be used loosely to refer to both minerals and mineral-like substances whether man-made or not.)
Files act by abrasion but are not classed as abrasives as they are a shaped bar of metal. However, diamond files are a form of coated abrasive (as they are metal rods coated with diamond powder).
Abrasives give rise to a form of wound called an abrasion or even an excoriation. Abrasions may arise following strong contract with surfaces made things such as concrete, stone, wood, carpet, and roads, though these surfaces are not intended for use as abrasives.
# Mechanics of abrasion
Abrasives generally rely upon a difference in hardness between the abrasive and the material being worked upon, the abrasive being the harder of the two substances. However, this is not necessary as any two solid materials that repeatedly rub against each other will tend to wear each other away (such as softer shoe soles wearing away wooden or stone steps over decades or centuries or glaciers abrading stone valleys).
Typically, materials used as abrasives are either hard minerals (rated at 7 or above on Mohs scale of mineral hardness) or are synthetic stones, some of which may be chemically and physically identical to naturally occurring minerals but which cannot be called minerals as they did not arise naturally. (While useful for comparative purposes, the Mohs scale is of limited value to materials engineers as it is an arbitrary, ordinal, irregular scale.) Diamond, a common abrasive, for instance occurs both naturally and is industrially produced , as is corundum which occurs naturally but which is nowadays more commonly manufactured from bauxite. However, even softer minerals like calcium carbonate are used as abrasives, such as "polishing agents" in toothpaste.
These minerals are either crushed or are already of a sufficiently small size (anywhere from macroscopic grains as large as about 2 mm to microscopic grains about 0.001 mm in diameter) to permit their use as an abrasive. These grains, commonly called grit, have rough edges, often terminating in points which will decrease the surface area in contact and increase the localised contact pressure. The abrasive and the material to be worked are brought into contact while in relative motion to each other. Force applied through the grains causes fragments of the worked material to break away while simultaneously smoothing the abrasive grain and/or causing the grain to work loose from the rest of the abrasive.
Some factors which will affect how quickly a substance is abraded include:
- Difference in hardness between the two substances: a much harder abrasive will cut faster and deeper
- Grain size (grit size): larger grains will cut faster as they also cut deeper
- Adhesion between grains, between grains and backing, between grains and matrix: determines how quickly grains are lost from the abrasive and how soon fresh grains, if present, are exposed
- Contact force: more force will cause faster abrasion
- Loading: worn abrasive and cast off work material tends to fill spaces between abrasive grains so reducing cutting efficiency while increasing friction
- Use of lubricant/coolant/metalworking fluid: Can carry away swarf (preventing loading), transport heat (which may affect the physical properties of the workpiece or the abrasive), decrease friction (with the substrate or matrix), suspend worn work material and abrasives allowing for a finer finish, conduct stress to the workpiece.
# Abrasive minerals
Abrasives may be classified as either natural or synthetic. When discussing sharpening stones, natural stones have long been considered superior but advances in material technology are seeing this distinction become less distinct. Many synthetic abrasives are effectively identical to a natural mineral, differing only in that the synthetic mineral has been manufactured rather than been mined. Impurities in the natural mineral may make it less effective.
Some naturally occurring abrasives are:
- Calcite (calcium carbonate)
- Emery (impure corundum)
- Diamond dust (synthetic diamonds are used extensively)
- Novaculite
- Pumice dust
- Rouge
- Sand
Some abrasive minerals (such as zirconia alumina) occur naturally but are sufficiently rare or sufficiently more difficult/costly to obtain such that a synthetic stone is used industrially. These and other artificial abrasives include:
- Borazon (cubic boron nitride or CBN)
- Ceramic
- Corundum (alumina or aluminium oxide)
- Dry ice
- Glass powder
- Silicon carbide (carborundum)
- Zirconia alumina
# Manufactured abrasives
Abrasives are shaped for various purposes. Natural abrasives are often sold as dressed stones, usually in the from of a rectangular block. Both natural and synthetic abrasives are commonly available in a wide variety of shapes, often coming as bonded or coated abrasives, including blocks, belts, discs, wheels, sheets, rods and loose grains.
## Bonded abrasives
A bonded abrasive is composed of an abrasive material contained within a matrix, although very fine aluminium oxide abrasive may comprise sintered material. This matrix is called a binder and is often a clay, a resin, a glass or a rubber. This mixture of binder and abrasive is typically shaped into blocks, sticks, or wheels. The most usual abrasive used is aluminium oxide. Also common are silicon carbide, tungsten carbide and garnet. Artificial sharpening stones are often a bonded abrasive and are readily available as a two sided block, each side being a different grade of grit.
Grinding wheels are cylinders that are rotated at high speed. While once worked with a foot pedal or hand crank, the introduction of electric motors has made it necessary to construct the wheel to withstand greater radial stress to prevent the wheel flying apart as it spins. Similar issues arise with cutting wheels which are often structurally reinforced with impregnated fibres. High relative speed between abrasive and workpiece often makes necessary the use of a lubricant of some kind. Traditionally they were called coolants as they were used to prevent frictional heat build up which could damage the workpiece (such as ruining the temper of a blade). Some research suggests that the heat transport property of a lubricant is less important when dealing with metals as the metal will quickly conduct heat from the work surface. More important are their effects upon lessening tensile stresses while increasing some compressive stresses and reducing "thermal and mechanical stresses during chip formation".
Various shapes are also used as heads on rotary tools used in precision work, such as scale modelling.
Bonded abrasives need to be trued and dressed after they are used. Dressing is cleaning the waste material (swarf and loose abrasive) from the surface and exposing fresh grit. Depending upon the abrasive and how it was used, dressing may involve the abrasive being simply placed under running water and brushed with a stiff brush for a soft stone or the abrasive being ground against another abrasive, such as aluminium oxide used to dress a grinding wheel.
Truing is restoring the abrasive to its original surface shape. Wheels and stones tend to wear unevenly, leaving the cutting surface no longer flat (said to be "dished out" if it is meant to be a flat stone) or no longer the same diameter across the cutting face. This will lead to uneven abrasion and other difficulties.
## Coated abrasives
A coated abrasive comprises an abrasive fixed to a backing material such as paper, cloth, rubber, resin, polyester or even metal, many of which are flexible. Sandpaper is a very common coated abrasive. Coated abrasives are commonly the same minerals as are used for bonded abrasives. A bonding agent (often some sort of adhesive or resin) is applied to the backing to provide a flat surface to which the grit is then subsequently adhered. A woven backing may also use a filler agent (again, often a resin) to provide additional resilience.
Coated abrasives may be shaped for use in rotary and orbital sanders, for wrapping around sanding blocks, as handpads, as closed loops for use on belt grinders, as striking surfaces on matchboxes, on diamond plates and diamond steels. Diamond tools, though for cutting, are often abrasive in nature.
## Other abrasives and their uses
Sand, glass beads, metal pellets and dry ice may all be used for a process called sandblasting (or similar, such as the use of glass beads which is "bead blasting"). Dry ice will sublimate meaning that there is no residual abrasive left afterwards.
Cutting compound used on automotive paint is an example of an abrasive suspended in a liquid, paste or wax, as are some polishing liquids for silverware and optical media. The liquid, paste or wax acts as a binding agent that keeps the abrasive attached to the cloth which is used to as a backing to move the abrasive across the workpiece. On cars in particular, wax may serve as both a protective agent by preventing exposure of the paint of metal to air and also act as an optical filler to make scratches less noticeable. Toothpaste contains calcium carbonate or silica as a "polishing agent" to remove plaque and other matter from teeth as the hardness of calcium carbonate is less than that of tooth enamel but more than that of the contaminating agent.
Very fine rouge powder was commonly used for grinding glass, being somewhat replaced by modern ceramics, and is still used in jewellery making for a highly reflective finish.
Cleaning products may also contain abrasives suspended in a paste or cream. They are chosen to be reasonably safe on some linoleum, tile, metal or stone surfaces. However, many laminate surfaces and ceramic topped stoves are easily damaged by these abrasive compounds. Even ceramic/pottery tableware or cookware can damage these surfaces, particularly the bottom of the tableware which is often unglazed in part or in whole and acts as simply another bonded abrasive.
Metal pots and stoves are often scoured with abrasive cleaners, typically in the form of the aforementioned cream or paste or of steel wool.
Human skin is also subjected to abrasion in the form of exfoliation. Abrasives for this can be much softer and more exotic than for other purposes and may include things like almond and oatmeal. Dermabrasion and microdermabrasion are now rather commonplace cosmetic procedures which use mineral abrasives.
Scratched compact discs and DVDs may sometimes be repaired through buffing with a very fine compound, the principle being that a multitude of small scratches will be more optically transparent than a single large scratch. However, this does take some skill and will eventually cause the protective coating of the disc to be entirely eroded (especially if the original scratch is deep), after which the data surface will be destroyed if abrasion continues.
# Choice of abrasive
The shape, size and nature of the workpiece and the desired finish will influence the choice of the abrasive used. A bonded abrasive grind wheel may be used to commercially sharpen a knife (producing a hollow grind), but an individual may then sharpen the same knife with a natural sharpening stone or an even flexible coated abrasive (like a sandpaper) stuck to a soft, non-slip surface to make achieving a convex grind easier. Similarly, a brass mirror may be cut with a bonded abrasive, have its surface flattened with a coated abrasive to achieve a basic shape, and then have finer grades of abrasive successively appied culminating in a wax paste impregnated with rouge to leave a sort of "grainless finish" called, in this case, a "mirror finish".
Also, different shapes of adhesive may make it harder to abrade certain areas of the workpiece. Health hazards can arise from any dust produced (which may be ameliorated through the use of a lubricant) which could lead to silicosis (when the abrasive or workpiece is a silicate) and the choice of any lubricant. Besides water, oils are the most common lubricants. These may present inhalation hazards, contact hazards and, as friction necessarily produces heat, flammable material hazards.
An abrasive which is too hard or too coarse can remove too much material or leave undesired scratch marks. Besides being unsightly, scratching can have other, more serious effects. Excessive abrasion or the presence of scratches may:
- diminish or destroy usefulness (as in the case of scratched optics and compact discs or a dull knife);
- trap dirt, water, or other material;
- increase surface area (permitting greater chemical reactivity such as increased rusting which is also affected by matter caught in scratches);
- erode or penetrate a coating (such as a paint or a chemical or wear resistant coating);
- overly quickly cause an object to wear away (such as a blade or a gemstone);
- increase friction (as in jeweled bearings and pistons).
A finer or softer abrasive will tend to leave much finer scratch marks which may even be invisible to the naked eye (a "grainless finish"); a softer abrasive may not even significantly abrade a certain object. A softer or finer abrasive will take longer to cut as tends to cut less deeply than a coarser, harder material. Also, the softer abrasive may become less effective more quickly as the abrasive is itself abraded. This allows fine abrasives to be used in the polishing of metal and lenses where the series of increasingly fine scratches tends to take on a much more shiny or reflective appearance or greater transparency. Very fine abrasives may be used to coat the strop for a cut-throat razors, however, the purpose of stropping is not to abrade material but to straighten the burr on an edge. The final stage of sharpening Japanese swords called polishing and may be a form of superfinishing.
Different chemical or structural modifications may be made to alter the cutting properties of the abrasive.
Other very important considerations are price and availability. Diamond, for a long time considered the hardest substance in existence, is actually softer than fullerite and even harder aggregated diamond nanorods, both of which have been synthesised in laboratories but no commercial process has yet been developed. Diamond itself is expensive due to scarcity in nature and the cost of synthesising it. Bauxite is a very common ore which, along with corundum's reasonably high hardness, contributes to corundum's status as a common, inexpensive abrasive.
Thought must be given to the desired task about using an appropriately hard abrasive. At one end, using an excessively hard abrasive wastes money by wearing it down when a cheaper, less hard abrasive would suffice. At the other end, if too soft, abrasion does not take place in a timely fashion, effectively wasting the abrasive as well as any accruing costs associated with loss of time.
# Other instances of abrasion
Aside from the aforementioned uses of shaping and finishing, abrasives may also be used to prepare surfaces for application of some sort of paint of adhesive. An excessively smooth surface may prevent paint and adhesives from adhering as strongly as an irregular surface could allow. Inflatable tyre repair kits (which, on bicycles particularly, are actually patches for the inner tube rather than the tyre) require use of an abrasive so that the self-vulcanising cement will stick strongly.
Inadvertently, people who use knives on glass or metal cutting boards are abrading their knife blades. The pressure at the knife edge can easily create microscopic (or even macroscopic) cuts in the board. This cut is a ready source of abrasive material as well as a channel full of this abrasive through which the edge slides. For this reason—without regard for the health benefits—wooden boards are much more desirable. A similar occurrence arises with glass-cutters. Glass-cutters are have circular blades that are designed to roll not slide. They should never retrace an already effected cut.
Undesired abrasion may result from the presence of carbon in internal combustion engines. While smaller particles are readily transported by the lubrication system, larger carbon particles may abrade components with close tolerances. The carbon arises from the excessive heating of engine oil or from incomplete combustion. This soot may contain fullerenes which are noted for their extreme hardness—and small size and limited quantity which would tend to limit their effect. | Abrasive
An abrasive is a material, often a mineral, that is used to shape or finish a workpiece through rubbing which leads to part of the workpiece being worn away. While finishing a material often means polishing it to gain a smooth, reflective surface it can also involve roughening as in satin, matte or beaded finishes.
Abrasives are extremely commonplace and are used very extensively in a wide variety of industrial, domestic, and technological applications. This gives rise to a large variation in the physical and chemical composition of abrasives as well as the shape of the abrasive. Common uses for abrasives include grinding, polishing, buffing, honing, cutting, drilling, sharpening, and sanding (see abrasive machining). (For simplicity, "mineral" in this article will be used loosely to refer to both minerals and mineral-like substances whether man-made or not.)
Files act by abrasion but are not classed as abrasives as they are a shaped bar of metal. However, diamond files are a form of coated abrasive (as they are metal rods coated with diamond powder).
Abrasives give rise to a form of wound called an abrasion or even an excoriation. Abrasions may arise following strong contract with surfaces made things such as concrete, stone, wood, carpet, and roads, though these surfaces are not intended for use as abrasives.
# Mechanics of abrasion
Abrasives generally rely upon a difference in hardness between the abrasive and the material being worked upon, the abrasive being the harder of the two substances. However, this is not necessary as any two solid materials that repeatedly rub against each other will tend to wear each other away (such as softer shoe soles wearing away wooden or stone steps over decades or centuries or glaciers abrading stone valleys).
Typically, materials used as abrasives are either hard minerals (rated at 7 or above on Mohs scale of mineral hardness) or are synthetic stones, some of which may be chemically and physically identical to naturally occurring minerals but which cannot be called minerals as they did not arise naturally. (While useful for comparative purposes, the Mohs scale is of limited value to materials engineers as it is an arbitrary, ordinal, irregular scale.) Diamond, a common abrasive, for instance occurs both naturally and is industrially produced , as is corundum which occurs naturally but which is nowadays more commonly manufactured from bauxite.[1] However, even softer minerals like calcium carbonate are used as abrasives, such as "polishing agents" in toothpaste.
These minerals are either crushed or are already of a sufficiently small size (anywhere from macroscopic grains as large as about 2 mm to microscopic grains about 0.001 mm in diameter) to permit their use as an abrasive. These grains, commonly called grit, have rough edges, often terminating in points which will decrease the surface area in contact and increase the localised contact pressure. The abrasive and the material to be worked are brought into contact while in relative motion to each other. Force applied through the grains causes fragments of the worked material to break away while simultaneously smoothing the abrasive grain and/or causing the grain to work loose from the rest of the abrasive.
Some factors which will affect how quickly a substance is abraded include:
- Difference in hardness between the two substances: a much harder abrasive will cut faster and deeper
- Grain size (grit size): larger grains will cut faster as they also cut deeper
- Adhesion between grains, between grains and backing, between grains and matrix: determines how quickly grains are lost from the abrasive and how soon fresh grains, if present, are exposed
- Contact force: more force will cause faster abrasion
- Loading: worn abrasive and cast off work material tends to fill spaces between abrasive grains so reducing cutting efficiency while increasing friction
- Use of lubricant/coolant/metalworking fluid: Can carry away swarf (preventing loading), transport heat (which may affect the physical properties of the workpiece or the abrasive), decrease friction (with the substrate or matrix), suspend worn work material and abrasives allowing for a finer finish, conduct stress to the workpiece.
# Abrasive minerals
Abrasives may be classified as either natural or synthetic. When discussing sharpening stones, natural stones have long been considered superior but advances in material technology are seeing this distinction become less distinct. Many synthetic abrasives are effectively identical to a natural mineral, differing only in that the synthetic mineral has been manufactured rather than been mined. Impurities in the natural mineral may make it less effective.
Some naturally occurring abrasives are:
- Calcite (calcium carbonate)
- Emery (impure corundum)
- Diamond dust (synthetic diamonds are used extensively)
- Novaculite
- Pumice dust
- Rouge
- Sand
Some abrasive minerals (such as zirconia alumina) occur naturally but are sufficiently rare or sufficiently more difficult/costly to obtain such that a synthetic stone is used industrially. These and other artificial abrasives include:
- Borazon (cubic boron nitride or CBN)
- Ceramic
- Corundum (alumina or aluminium oxide)
- Dry ice
- Glass powder
- Silicon carbide (carborundum)
- Zirconia alumina
# Manufactured abrasives
Abrasives are shaped for various purposes. Natural abrasives are often sold as dressed stones, usually in the from of a rectangular block. Both natural and synthetic abrasives are commonly available in a wide variety of shapes, often coming as bonded or coated abrasives, including blocks, belts, discs, wheels, sheets, rods and loose grains.
## Bonded abrasives
A bonded abrasive is composed of an abrasive material contained within a matrix, although very fine aluminium oxide abrasive may comprise sintered material. This matrix is called a binder and is often a clay, a resin, a glass or a rubber. This mixture of binder and abrasive is typically shaped into blocks, sticks, or wheels. The most usual abrasive used is aluminium oxide. Also common are silicon carbide, tungsten carbide and garnet. Artificial sharpening stones are often a bonded abrasive and are readily available as a two sided block, each side being a different grade of grit.
Grinding wheels are cylinders that are rotated at high speed. While once worked with a foot pedal or hand crank, the introduction of electric motors has made it necessary to construct the wheel to withstand greater radial stress to prevent the wheel flying apart as it spins. Similar issues arise with cutting wheels which are often structurally reinforced with impregnated fibres. High relative speed between abrasive and workpiece often makes necessary the use of a lubricant of some kind. Traditionally they were called coolants as they were used to prevent frictional heat build up which could damage the workpiece (such as ruining the temper of a blade). Some research suggests that the heat transport property of a lubricant is less important when dealing with metals as the metal will quickly conduct heat from the work surface. More important are their effects upon lessening tensile stresses while increasing some compressive stresses and reducing "thermal and mechanical stresses during chip formation". [2]
Various shapes are also used as heads on rotary tools used in precision work, such as scale modelling.
Bonded abrasives need to be trued and dressed after they are used. Dressing is cleaning the waste material (swarf and loose abrasive) from the surface and exposing fresh grit. Depending upon the abrasive and how it was used, dressing may involve the abrasive being simply placed under running water and brushed with a stiff brush for a soft stone or the abrasive being ground against another abrasive, such as aluminium oxide used to dress a grinding wheel.
Truing is restoring the abrasive to its original surface shape. Wheels and stones tend to wear unevenly, leaving the cutting surface no longer flat (said to be "dished out" if it is meant to be a flat stone) or no longer the same diameter across the cutting face. This will lead to uneven abrasion and other difficulties.
## Coated abrasives
A coated abrasive comprises an abrasive fixed to a backing material such as paper, cloth, rubber, resin, polyester or even metal, many of which are flexible. Sandpaper is a very common coated abrasive. Coated abrasives are commonly the same minerals as are used for bonded abrasives. A bonding agent (often some sort of adhesive or resin) is applied to the backing to provide a flat surface to which the grit is then subsequently adhered. A woven backing may also use a filler agent (again, often a resin) to provide additional resilience.
Coated abrasives may be shaped for use in rotary and orbital sanders, for wrapping around sanding blocks, as handpads, as closed loops for use on belt grinders, as striking surfaces on matchboxes, on diamond plates and diamond steels. Diamond tools, though for cutting, are often abrasive in nature.
## Other abrasives and their uses
Sand, glass beads, metal pellets and dry ice may all be used for a process called sandblasting (or similar, such as the use of glass beads which is "bead blasting"). Dry ice will sublimate meaning that there is no residual abrasive left afterwards.
Cutting compound used on automotive paint is an example of an abrasive suspended in a liquid, paste or wax, as are some polishing liquids for silverware and optical media. The liquid, paste or wax acts as a binding agent that keeps the abrasive attached to the cloth which is used to as a backing to move the abrasive across the workpiece. On cars in particular, wax may serve as both a protective agent by preventing exposure of the paint of metal to air and also act as an optical filler to make scratches less noticeable. Toothpaste contains calcium carbonate or silica as a "polishing agent" to remove plaque and other matter from teeth as the hardness of calcium carbonate is less than that of tooth enamel but more than that of the contaminating agent.
Very fine rouge powder was commonly used for grinding glass, being somewhat replaced by modern ceramics, and is still used in jewellery making for a highly reflective finish.
Cleaning products may also contain abrasives suspended in a paste or cream. They are chosen to be reasonably safe on some linoleum, tile, metal or stone surfaces. However, many laminate surfaces and ceramic topped stoves are easily damaged by these abrasive compounds. Even ceramic/pottery tableware or cookware can damage these surfaces, particularly the bottom of the tableware which is often unglazed in part or in whole and acts as simply another bonded abrasive.[3]
Metal pots and stoves are often scoured with abrasive cleaners, typically in the form of the aforementioned cream or paste or of steel wool.
Human skin is also subjected to abrasion in the form of exfoliation. Abrasives for this can be much softer and more exotic than for other purposes and may include things like almond and oatmeal.[4] Dermabrasion and microdermabrasion are now rather commonplace cosmetic procedures which use mineral abrasives.
Scratched compact discs and DVDs may sometimes be repaired through buffing with a very fine compound, the principle being that a multitude of small scratches will be more optically transparent than a single large scratch. However, this does take some skill and will eventually cause the protective coating of the disc to be entirely eroded (especially if the original scratch is deep), after which the data surface will be destroyed if abrasion continues.
# Choice of abrasive
The shape, size and nature of the workpiece and the desired finish will influence the choice of the abrasive used. A bonded abrasive grind wheel may be used to commercially sharpen a knife (producing a hollow grind), but an individual may then sharpen the same knife with a natural sharpening stone or an even flexible coated abrasive (like a sandpaper) stuck to a soft, non-slip surface to make achieving a convex grind easier. Similarly, a brass mirror may be cut with a bonded abrasive, have its surface flattened with a coated abrasive to achieve a basic shape, and then have finer grades of abrasive successively appied culminating in a wax paste impregnated with rouge to leave a sort of "grainless finish" called, in this case, a "mirror finish".
Also, different shapes of adhesive may make it harder to abrade certain areas of the workpiece. Health hazards can arise from any dust produced (which may be ameliorated through the use of a lubricant) which could lead to silicosis (when the abrasive or workpiece is a silicate) and the choice of any lubricant. Besides water, oils are the most common lubricants. These may present inhalation hazards, contact hazards and, as friction necessarily produces heat, flammable material hazards.[5]
An abrasive which is too hard or too coarse can remove too much material or leave undesired scratch marks. Besides being unsightly, scratching can have other, more serious effects. Excessive abrasion or the presence of scratches may:
- diminish or destroy usefulness (as in the case of scratched optics and compact discs or a dull knife);
- trap dirt, water, or other material;
- increase surface area (permitting greater chemical reactivity such as increased rusting which is also affected by matter caught in scratches);
- erode or penetrate a coating (such as a paint or a chemical or wear resistant coating);
- overly quickly cause an object to wear away (such as a blade or a gemstone);
- increase friction (as in jeweled bearings and pistons).
A finer or softer abrasive will tend to leave much finer scratch marks which may even be invisible to the naked eye (a "grainless finish"); a softer abrasive may not even significantly abrade a certain object. A softer or finer abrasive will take longer to cut as tends to cut less deeply than a coarser, harder material. Also, the softer abrasive may become less effective more quickly as the abrasive is itself abraded. This allows fine abrasives to be used in the polishing of metal and lenses where the series of increasingly fine scratches tends to take on a much more shiny or reflective appearance or greater transparency. Very fine abrasives may be used to coat the strop for a cut-throat razors, however, the purpose of stropping is not to abrade material but to straighten the burr on an edge. The final stage of sharpening Japanese swords called polishing and may be a form of superfinishing.
Different chemical or structural modifications may be made to alter the cutting properties of the abrasive.[6]
Other very important considerations are price and availability. Diamond, for a long time considered the hardest substance in existence, is actually softer than fullerite and even harder aggregated diamond nanorods, both of which have been synthesised in laboratories but no commercial process has yet been developed. Diamond itself is expensive due to scarcity in nature and the cost of synthesising it. Bauxite is a very common ore which, along with corundum's reasonably high hardness, contributes to corundum's status as a common, inexpensive abrasive.
Thought must be given to the desired task about using an appropriately hard abrasive. At one end, using an excessively hard abrasive wastes money by wearing it down when a cheaper, less hard abrasive would suffice. At the other end, if too soft, abrasion does not take place in a timely fashion, effectively wasting the abrasive as well as any accruing costs associated with loss of time.
# Other instances of abrasion
Aside from the aforementioned uses of shaping and finishing, abrasives may also be used to prepare surfaces for application of some sort of paint of adhesive. An excessively smooth surface may prevent paint and adhesives from adhering as strongly as an irregular surface could allow. Inflatable tyre repair kits (which, on bicycles particularly, are actually patches for the inner tube rather than the tyre) require use of an abrasive so that the self-vulcanising cement will stick strongly.
Inadvertently, people who use knives on glass or metal cutting boards are abrading their knife blades. The pressure at the knife edge can easily create microscopic (or even macroscopic) cuts in the board. This cut is a ready source of abrasive material as well as a channel full of this abrasive through which the edge slides. For this reason—without regard for the health benefits—wooden boards are much more desirable. A similar occurrence arises with glass-cutters. Glass-cutters are have circular blades that are designed to roll not slide. They should never retrace an already effected cut.
Undesired abrasion may result from the presence of carbon in internal combustion engines. While smaller particles are readily transported by the lubrication system, larger carbon particles may abrade components with close tolerances. The carbon arises from the excessive heating of engine oil or from incomplete combustion. This soot may contain fullerenes which are noted for their extreme hardness—and small size and limited quantity which would tend to limit their effect. | https://www.wikidoc.org/index.php/Abrasive | |
24e92f30424b18f0d770b7fcb9337bbf1d7f0dc3 | wikidoc | Aniridia | Aniridia
Synonyms and keywords: Absent iris
# Overview
Aniridia is a rare congenital condition characterized by the underdevelopment of the eye's iris. This usually occurs in both eyes. It is associated with poor development of the retina at the back of the eye preventing normal vision development.
# Classification
Aniridia may be broadly divided into hereditary and sporadic forms. Hereditary aniridia is usually transmitted in an autosomal dominant manner (each offspring has a 50% chance of being affected), although rarer autosomal recessive forms (such as Gillespie syndrome) have also been reported. Sporadic aniridia mutations may affect the WT1 region adjacent to the AN2 aniridia region, causing a kidney cancer called nephroblastoma (Wilms tumor). These patients often also have genitourinary abnormalities and mental retardation (WAGR syndrome).
The AN2 region of the short arm of chromosome 11 (11p13) includes the PAX6 gene (named for its PAired boX status), whose gene product helps regulate a cascade of other genetic processes involved in the development of the eye (as well as other nonocular structures). This PAX6 gene is around 95% similar to the pax gene found in zebrafish, a creature which diverged from the human ancestry around 400 million years ago. Thus, the PAX6 gene constitutes an important evolutionary link to mankind's distant ancestors.
Defects in the PAX6 gene cause aniridia-like ocular defects in mice (as well as Drosophilia = fruit flies). Aniridia is a heterozygotic disease, meaning that only one of the two chromosome 11 copies is affected. When both copies are altered (homozygous condition), the result is a uniformly fatal condition with near complete failure of entire eye formation. In 2001, two cases of homozygous Aniridia patients were reported; the foetuses died prior to birth and had severe brain damage. In mice, homozygous Small eye defect (mouse Pax-6) led to loss of eyes, nose and the foetuses suffered severe brain damage.
Several different mutations may affect the PAX6 gene. Some mutations appear to inhibit gene function more than others, with subsequent variability in the severity of the disease. Thus, some aniridic individuals are only missing a relatively small amount of iris, do not have foveal hypoplasia, and retain relatively normal vision. Presumably, the genetic defect in these individuals causes less "heterozygous insufficiency," meaning they retain enough gene function to yield a milder phenotype.
- Online Mendelian Inheritance in Man (OMIM) 106200 AN1
- Online Mendelian Inheritance in Man (OMIM) 106210 AN2
- Online Mendelian Inheritance in Man (OMIM) 106220 Aniridia and absent patella
- Online Mendelian Inheritance in Man (OMIM) 106230 Aniridia, microcornea, and spontaneously reabsorbed cataract
- Online Mendelian Inheritance in Man (OMIM) 206700 Aniridia, cerebellar ataxia, and mental deficiency (Gillespie syndrome)
# Clinical Presentation
## Ocular
- Stumps of iris usually apparent
- Some patients have partial aniridia with relatively preserved vision
- Corneal findings; Limbal stem cell deficiency = aniridic keratopathy
- Corneal pannus usually presents in early childhood with radial vessels at 6 and 12 o’clock, developing circumferential grayish haze which advances centrally
- Corneal epithelium may harbor ectopic conjunctival goblet cells, and inflammatory cells are usually present
- Microcornea is very common in aniridia
- Initial fine lens opacities in infants
- Visually significant cataract often acquired by 2nd-3rd decade
- Multiple cataract types described: anterior polar, pyramidal, nuclear, lamellar, and cortical
- Lens subluxation / ectopia lentis
- Nystagmus
- Sensory strabismus
- Glaucoma onset usually by 2nd decade
- Gradually increasing angle obstruction, though open angle also possible
- Possible glaucoma mechanism: Contractile membrane covering angle, with increase in iridocorneal processes; iris stump may become totally adherent to posterior corneal surface
- Foveal hypoplasia, which may be complete or very subtle; Fluorescein angiography may be needed to demonstrate lack of foveal avascular zone
- Optic nerve hypoplasia to some degree is present in up to 75% of aniridia patients
## Non-ocular
- Dysosmia / dysnomia = abnormal sense of smell due to hypoplastic olfactory bulbs
- Glucose intolerance / diabetes mellitus
- Reduced size of corpus callosum and anterior commissure
- Absent pineal gland: abnormal sleep due to melatonin abnormalities
- Unilateral polymicrogyria
- WAGR syndrome (Wilms tumor, aniridia, genitourinary abnormality, mental retardation)
- Wilms tumor occurs in 30–50% of cases
- External genital anomalies occur only in males, often delaying recognition of WAGR in females
- Late onset nephropathy is a well-recognized feature of this syndrome
# Treatment
Due to the high risk of glaucoma and cataract formation, aniridia patients should be under the care of an ophthalmologist familiar with the condition. The risk of progressive glaucoma persists from childhood into adulthood, necessitating long-term follow-up. Optometrists and low vision specialists are often valuable in maximizing visual and social functioning, prescribing glasses, and amelioriating light sensitivity (photophobia).
The iris functions to restrict the amount of light entering the eye, so if it is absent, most individuals with aniridia are sensitive to bright outdoor light and their eyes may need protecting. This can be done with tinted glasses, or with a contact lens which has an artificial iris painted onto it.
Aniridia is often associated with other health and developmental problems, as well as complicating eye conditions such as: foveal hypoplasia, nystagmus, glaucoma, corneal disease, cataract, lens subluxation and optic nerve disease. | Aniridia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Absent iris
# Overview
Aniridia is a rare congenital condition characterized by the underdevelopment of the eye's iris. This usually occurs in both eyes. It is associated with poor development of the retina at the back of the eye preventing normal vision development.
# Classification
Aniridia may be broadly divided into hereditary and sporadic forms. Hereditary aniridia is usually transmitted in an autosomal dominant manner (each offspring has a 50% chance of being affected), although rarer autosomal recessive forms (such as Gillespie syndrome) have also been reported. Sporadic aniridia mutations may affect the WT1 region adjacent to the AN2 aniridia region, causing a kidney cancer called nephroblastoma (Wilms tumor). These patients often also have genitourinary abnormalities and mental retardation (WAGR syndrome).
The AN2 region of the short arm of chromosome 11 (11p13) includes the PAX6 gene (named for its PAired boX status), whose gene product helps regulate a cascade of other genetic processes involved in the development of the eye (as well as other nonocular structures). This PAX6 gene is around 95% similar to the pax gene found in zebrafish, a creature which diverged from the human ancestry around 400 million years ago. Thus, the PAX6 gene constitutes an important evolutionary link to mankind's distant ancestors.
Defects in the PAX6 gene cause aniridia-like ocular defects in mice (as well as Drosophilia = fruit flies). Aniridia is a heterozygotic disease, meaning that only one of the two chromosome 11 copies is affected. When both copies are altered (homozygous condition), the result is a uniformly fatal condition with near complete failure of entire eye formation. In 2001, two cases of homozygous Aniridia patients were reported; the foetuses died prior to birth and had severe brain damage. In mice, homozygous Small eye defect (mouse Pax-6) led to loss of eyes, nose and the foetuses suffered severe brain damage.[1]
Several different mutations may affect the PAX6 gene. Some mutations appear to inhibit gene function more than others, with subsequent variability in the severity of the disease. Thus, some aniridic individuals are only missing a relatively small amount of iris, do not have foveal hypoplasia, and retain relatively normal vision. Presumably, the genetic defect in these individuals causes less "heterozygous insufficiency," meaning they retain enough gene function to yield a milder phenotype.
- Online Mendelian Inheritance in Man (OMIM) 106200 AN1
- Online Mendelian Inheritance in Man (OMIM) 106210 AN2
- Online Mendelian Inheritance in Man (OMIM) 106220 Aniridia and absent patella
- Online Mendelian Inheritance in Man (OMIM) 106230 Aniridia, microcornea, and spontaneously reabsorbed cataract
- Online Mendelian Inheritance in Man (OMIM) 206700 Aniridia, cerebellar ataxia, and mental deficiency (Gillespie syndrome)
# Clinical Presentation
## Ocular
- Stumps of iris usually apparent
- Some patients have partial aniridia with relatively preserved vision
- Corneal findings; Limbal stem cell deficiency = aniridic keratopathy
- Corneal pannus usually presents in early childhood with radial vessels at 6 and 12 o’clock, developing circumferential grayish haze which advances centrally
- Corneal epithelium may harbor ectopic conjunctival goblet cells, and inflammatory cells are usually present
- Microcornea is very common in aniridia
- Initial fine lens opacities in infants
- Visually significant cataract often acquired by 2nd-3rd decade
- Multiple cataract types described: anterior polar, pyramidal, nuclear, lamellar, and cortical
- Lens subluxation / ectopia lentis
- Nystagmus
- Sensory strabismus
- Glaucoma onset usually by 2nd decade
- Gradually increasing angle obstruction, though open angle also possible
- Possible glaucoma mechanism: Contractile membrane covering angle, with increase in iridocorneal processes; iris stump may become totally adherent to posterior corneal surface
- Foveal hypoplasia, which may be complete or very subtle; Fluorescein angiography may be needed to demonstrate lack of foveal avascular zone
- Optic nerve hypoplasia to some degree is present in up to 75% of aniridia patients
## Non-ocular
- Dysosmia / dysnomia = abnormal sense of smell due to hypoplastic olfactory bulbs
- Glucose intolerance / diabetes mellitus
- Reduced size of corpus callosum and anterior commissure
- Absent pineal gland: abnormal sleep due to melatonin abnormalities
- Unilateral polymicrogyria
- WAGR syndrome (Wilms tumor, aniridia, genitourinary abnormality, mental retardation)
- Wilms tumor occurs in 30–50% of cases
- External genital anomalies occur only in males, often delaying recognition of WAGR in females
- Late onset nephropathy is a well-recognized feature of this syndrome
# Treatment
Due to the high risk of glaucoma and cataract formation, aniridia patients should be under the care of an ophthalmologist familiar with the condition. The risk of progressive glaucoma persists from childhood into adulthood, necessitating long-term follow-up. Optometrists and low vision specialists are often valuable in maximizing visual and social functioning, prescribing glasses, and amelioriating light sensitivity (photophobia).
The iris functions to restrict the amount of light entering the eye, so if it is absent, most individuals with aniridia are sensitive to bright outdoor light and their eyes may need protecting. This can be done with tinted glasses, or with a contact lens which has an artificial iris painted onto it.
Aniridia is often associated with other health and developmental problems, as well as complicating eye conditions such as: foveal hypoplasia, nystagmus, glaucoma, corneal disease, cataract, lens subluxation and optic nerve disease. | https://www.wikidoc.org/index.php/Absent_iris | |
f91b7ea6a815f6aa4de4faacd5665e676b95f3b1 | wikidoc | Acarbose | Acarbose
# 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
Acarbose is an alpha-glucosidase inhibitor that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include abdominal pain, diarrhea, flatulence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- Dosage:
- Initial dosage: 25 mg given orally three times daily at the start (with the first bite) of each main meal.
- Maintenance dosage: Once a 25 mg t.i.d. dosage regimen is reached, dosage of acarbose should be adjusted at 4–8 week intervals based on one-hour postprandial glucose or glycosylated hemoglobin levels, and on tolerance.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acarbose in adult patients.
### Non–Guideline-Supported Use
- Prophylaxis of type 2 diabetes mellitus
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acarbose in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Acarbose in pediatric patients.
# Contraindications
- In patients with known hypersensitivity to the drug.
- In patients with diabetic ketoacidosis or cirrhosis.
- In patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction.
- In patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who have conditions that may deteriorate as a result of increased gas formation in the intestine.
# Warnings
### Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with acarbose or any other anti-diabetic drug.
### Hypoglycemia
Because of its mechanism of action, acarbose when administered alone should not cause hypoglycemia in the fasted or postprandial state. Sulfonylurea agents or insulin may cause hypoglycemia. Because acarbose given in combination with a sulfonylurea or insulin will cause a further lowering of blood glucose, it may increase the potential for hypoglycemia. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, and no increased incidence of hypoglycemia was observed in patients when acarbose was added to metformin therapy. Oral glucose (dextrose), whose absorption is not inhibited by acarbose, should be used instead of sucrose (cane sugar) in the treatment of mild to moderate hypoglycemia. Sucrose, whose hydrolysis to glucose and fructose is inhibited by acarbose, is unsuitable for the rapid correction of hypoglycemia. Severe hypoglycemia may require the use of either intravenous glucose infusion or glucagon injection.
### Elevated Serum Transaminase Levels
In long-term studies (up to 12 months, and including acarbose doses up to 300 mg t.i.d.) conducted in the United States, treatment-emergent elevations of serum transaminases (AST and/or ALT) above the upper limit of normal (ULN), greater than 1.8 times the ULN, and greater than 3 times the ULN occurred in 14%, 6%, and 3%, respectively, of acarbose-treated patients as compared to 7%, 2%, and 1%, respectively, of placebo-treated patients. Although these differences between treatments were statistically significant, these elevations were asymptomatic, reversible, more common in females, and, in general, were not associated with other evidence of liver dysfunction. In addition, these serum transaminase elevations appeared to be dose related. In US studies including acarbose doses up to the maximum approved dose of 100 mg t.i.d., treatment-emergent elevations of AST and/or ALT at any level of severity were similar between acarbose-treated patients and placebo-treated patients (p ≥ 0.496).
In approximately 3 million patient-years of international postmarketing experience with acarbose, 62 cases of serum transaminase elevations > 500 IU/L (29 of which were associated with jaundice) have been reported. Forty-one of these 62 patients received treatment with 100 mg t.i.d. or greater and 33 of 45 patients for whom weight was reported weighed < 60 kg. In the 59 cases where follow-up was recorded, hepatic abnormalities improved or resolved upon discontinuation of acarbose in 55 and were unchanged in two. Cases of fulminant hepatitis with fatal outcome have been reported; the relationship to acarbose is unclear.
### Loss of Control of Blood Glucose
When diabetic patients are exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of control of blood glucose may occur. At such times, temporary insulin therapy may be necessary.
# Adverse Reactions
## Clinical Trials Experience
### Digestive Tract
Gastrointestinal symptoms are the most common reactions to acarbose. In U.S. placebo-controlled trials, the incidences of abdominal pain, diarrhea, and flatulence were 19%, 31%, and 74% respectively in 1255 patients treated with acarbose 50–300 mg t.i.d., whereas the corresponding incidences were 9%, 12%, and 29% in 999 placebo-treated patients.
In a one-year safety study, during which patients kept diaries of gastrointestinal symptoms, abdominal pain and diarrhea tended to return to pretreatment levels over time, and the frequency and intensity of flatulence tended to abate with time. The increased gastrointestinal tract symptoms in patients treated with acarbose are a manifestation of the mechanism of action of acarbose and are related to the presence of undigested carbohydrate in the lower GI tract.
If the prescribed diet is not observed, the intestinal side effects may be intensified. If strongly distressing symptoms develop in spite of adherence to the diabetic diet prescribed, the doctor must be consulted and the dose temporarily or permanently reduced.
### Elevated Serum Transaminase Levels
Other Abnormal Laboratory Findings: Small reductions in hematocrit occurred more often in acarbose-treated patients than in placebo-treated patients but were not associated with reductions in hemoglobin. Low serum calcium and low plasma vitamin B6 levels were associated with acarbose therapy but are thought to be either spurious or of no clinical significance.
## Postmarketing Experience
Additional adverse events reported from worldwide postmarketing experience include fulminant hepatitis with fatal outcome, hypersensitive skin reactions (for example rash, erythema, exanthema and uticaria), edema, ileus/subileus, jaundice and/or hepatitis and associated liver damage, thrombocytopenia, and pneumatosis cystoides intestinalis.
There have been rare postmarketing reports of pneumatosis cystoides intestinalis associated with the use of alpha-glucosidase inhibitors, including acarbose. Pneumatosis cystoides intestinalis may present with symptoms of diarrhea, mucus discharge, rectal bleeding, and constipation. Complications may include pneumoperitoneum, volvulus, intestinal obstruction, intussusception, intestinal hemorrhage, and intestinal perforation. If pneumatosis cystoides intestinalis is suspected, discontinue acarbose and perform the appropriate diagnostic imaging.
# Drug Interactions
Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel-blocking drugs, and isoniazid. When such drugs are administered to a patient receiving acarbose, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from patients receiving acarbose in combination with sulfonylureas or insulin, patients should be observed closely for any evidence of hypoglycemia.
Patients Receiving Sulfonylureas or Insulin: Sulfonylurea agents or insulin may cause hypoglycemia. Acarbose given in combination with a sulfonylurea or insulin may cause a further lowering of blood glucose and may increase the potential for hypoglycemia. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made. Very rarely, individual cases of hypoglycemic shock have been reported in patients receiving acarbose therapy in combination with sulfonylureas and/or insulin.
Intestinal adsorbents (for example, charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (for example, amylase, pancreatin) may reduce the effect of acarbose and should not be taken concomitantly.
Acarbosehas been shown to change the bioavailability of digoxin when they are coadministered, which may require digoxin dose adjustment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
The safety of acarbose in pregnant women has not been established. Reproduction studies have been performed in rats at doses up to 480 mg/kg (corresponding to 9 times the exposure in humans, based on drug blood levels) and have revealed no evidence of impaired fertility or harm to the fetus due to acarbose. In rabbits, reduced maternal body weight gain, probably the result of the pharmacodynamic activity of high doses of acarbose in the intestines, may have been responsible for a slight increase in the number of embryonic losses. However, rabbits given 160 mg/kg acarbose (corresponding to 10 times the dose in man, based on body surface area) showed no evidence of embryotoxicity and there was no evidence of teratogenicity at a dose 32 times the dose in man (based on body surface area). There are, however, no adequate and well-controlled studies of acarbose in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Acarbose in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Acarbose during labor and delivery.
### Nursing Mothers
A small amount of radioactivity has been found in the milk of lactating rats after administration of radiolabeled acarbose. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, acarbose should not be administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Acarbose in pediatric settings.
### Geriatic Use
Of the total number of subjects in clinical studies of acarbose in the United States, 27% were 65 and over, while 4% were 75 and over. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. The mean steady-state area under the curve (AUC) and maximum concentrations of acarbose were approximately 1.5 times higher in elderly compared to young volunteers; however, these differences were not statistically significant.
### Gender
There is no FDA guidance on the use of Acarbose with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Acarbose with respect to specific racial populations.
### Renal Impairment
Plasma concentrations of acarbose in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine > 2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.
### Hepatic Impairment
There is no FDA guidance on the use of Acarbose in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Fertility studies conducted in rats after oral administration produced no untoward effect on fertility or on the overall capability to reproduce.
### Immunocompromised Patients
There is no FDA guidance one the use of Acarbose in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Therapeutic response to acarbose should be monitored by periodic blood glucose tests. Measurement of glycosylated hemoglobin levels is recommended for the monitoring of long-term glycemic control.
Acarbose, particularly at doses in excess of 50 mg t.i.d., may give rise to elevations of serum transaminases and, in rare instances, hyperbilirubinemia. It is recommended that serum transaminase levels be checked every 3 months during the first year of treatment with acarbose and periodically thereafter. If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist.
# IV Compatibility
There is limited information regarding the compatibility of Acarbose and IV administrations.
# Overdosage
Unlike sulfonylureas or insulin, an overdose of acarbose will not result in hypoglycemia. An overdose may result in transient increases in flatulence, diarrhea, and abdominal discomfort which shortly subside. In cases of overdosage the patient should not be given drinks or meals containing carbohydrates (polysaccharides, oligosaccharides and disaccharides) for the next 4–6 hours.
# Pharmacology
## Mechanism of Action
In contrast to sulfonylureas, acarbose does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.
Because its mechanism of action is different, the effect of acarbose to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, acarbose diminishes the insulinotropic and weight-increasing effects of sulfonylureas.
Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.
## Structure
## Pharmacodynamics
Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, acarbose reduces levels of glycosylated hemoglobin in patients with type 2 diabetes mellitus. Systemic non-enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.
## Pharmacokinetics
In a study of 6 healthy men, less than 2% of an oral dose of acarbose was absorbed as active drug, while approximately 35% of total radioactivity from a 14C-labeled oral dose was absorbed. An average of 51% of an oral dose was excreted in the feces as unabsorbed drug-related radioactivity within 96 hours of ingestion. Because acarbose acts locally within the gastrointestinal tract, this low systemic bioavailability of parent compound is therapeutically desired. Following oral dosing of healthy volunteers with 14C-labeled acarbose, peak plasma concentrations of radioactivity were attained 14–24 hours after dosing, while peak plasma concentrations of active drug were attained at approximately 1 hour. The delayed absorption of acarbose-related radioactivity reflects the absorption of metabolites that may be formed by either intestinal bacteria or intestinal enzymatic hydrolysis.
Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. A fraction of these metabolites (approximately 34% of the dose) was absorbed and subsequently excreted in the urine. At least 13 metabolites have been separated chromatographically from urine specimens. The major metabolites have been identified as 4-methylpyrogallol derivatives (that is, sulfate, methyl, and glucuronide conjugates). One metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-glucosidase inhibitory activity. This metabolite, together with the parent compound, recovered from the urine, accounts for less than 2% of the total administered dose.
The fraction of acarbose that is absorbed as intact drug is almost completely excreted by the kidneys. When acarbose was given intravenously, 89% of the dose was recovered in the urine as active drug within 48 hours. In contrast, less than 2% of an oral dose was recovered in the urine as active (that is, parent compound and active metabolite) drug. This is consistent with the low bioavailability of the parent drug. The plasma elimination half-life of acarbose activity is approximately 2 hours in healthy volunteers. Consequently, drug accumulation does not occur with three times a day (t.i.d.) oral dosing.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
Eight carcinogenicity studies were conducted with acarbose. Six studies were performed in rats (two strains, Sprague-Dawley and Wistar) and two studies were performed in hamsters.
In the first rat study, Sprague-Dawley rats received acarbose in feed at high doses (up to approximately 500 mg/kg body weight) for 104 weeks. Acarbose treatment resulted in a significant increase in the incidence of renal tumors (adenomas and adenocarcinomas) and benign Leydig cell tumors. This study was repeated with a similar outcome. Further studies were performed to separate direct carcinogenic effects of acarbose from indirect effects resulting from the carbohydrate malnutrition induced by the large doses of acarbose employed in the studies. In one study using Sprague-Dawley rats, acarbose was mixed with feed but carbohydrate deprivation was prevented by the addition of glucose to the diet. In a 26-month study of Sprague-Dawley rats, acarbose was administered by daily postprandial gavage so as to avoid the pharmacologic effects of the drug. In both of these studies, the increased incidence of renal tumors found in the original studies did not occur. Acarbose was also given in food and by postprandial gavage in two separate studies in Wistar rats. No increased incidence of renal tumors was found in either of these Wistar rat studies. In two feeding studies of hamsters, with and without glucose supplementation, there was also no evidence of carcinogenicity.
Acarbose did not induce any DNA damage in vitro in the CHO chromosomal aberration assay, bacterial mutagenesis (Ames) assay, or a DNA binding assay. In vivo, no DNA damage was detected in the dominant lethal test in male mice, or the mouse micronucleus test.
# Clinical Studies
### Clinical Experience from Dose Finding Studies in Type 2 Diabetes Mellitus Patients on Dietary Treatment Only
Results from six controlled, fixed-dose, monotherapy studies of acarbose in the treatment of type 2 diabetes mellitus, involving 769 acarbose-treated patients, were combined and a weighted average of the difference from placebo in the mean change from baseline in glycosylated hemoglobin (HbA1c) was calculated for each dose level as presented below:
Results from these six fixed-dose, monotherapy studies were also combined to derive a weighted average of the difference from placebo in mean change from baseline for one-hour postprandial plasma glucose levels as shown in the following figure:
### Clinical Experience in Type 2 Diabetes Mellitus Patients on Monotherapy, or in Combination with Sulfonylureas, Metformin or Insulin
Acarbose was studied as monotherapy and as combination therapy to sulfonylurea, metformin, or insulin treatment. The treatment effects on HbA1c levels and one-hour postprandial glucose levels are summarized for four placebo-controlled, double-blind, randomized studies conducted in the United States in Tables 2 and 3, respectively. The placebo-subtracted treatment differences, which are summarized below, were statistically significant for both variables in all of these studies.
Study 1 (n=109) involved patients on background treatment with diet only. The mean effect of the addition of acarbose to diet therapy was a change in HbA1c of -0.78%, and an improvement of one-hour postprandial glucose of -74.4 mg/dL.
In Study 2 (n=137), the mean effect of the addition of acarbose to maximum sulfonylurea therapy was a change in HbA1c of -0.54%, and an improvement of one-hour postprandial glucose of -33.5 mg/dL.
In Study 3 (n=147), the mean effect of the addition of acarbose to maximum metformin therapy was a change in HbA1c of -0.65%, and an improvement of one-hour postprandial glucose of -34.3 mg/dL.
Study 4 (n=145) demonstrated that acarbose added to patients on background treatment with insulin resulted in a mean change in HbA1c of -0.69%, and an improvement of one-hour postprandial glucose of -36.0 mg/dL.
A one year study of acarbose as monotherapy or in combination with sulfonylurea, metformin or insulin treatment was conducted in Canada in which 316 patients were included in the primary efficacy analysis (Figure 2). In the diet, sulfonylurea and metformin groups, the mean decrease in HbA1c produced by the addition of acarbose was statistically significant at six months, and this effect was persistent at one year. In the acarbose-treated patients on insulin, there was a statistically significant reduction in HbA1c at six months, and a trend for a reduction at one year.
# How Supplied
Acarbose is available as 25 mg, 50 mg or 100 mg round, unscored tablets.
## Storage
Do not store above 25°C (77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be told to take acarbose orally three times a day at the start (with the first bite) of each main meal. It is important that patients continue to adhere to dietary instructions, a regular exercise program, and regular testing of urine and/or blood glucose.
Acarbose itself does not cause hypoglycemia even when administered to patients in the fasted state. Sulfonylurea drugs and insulin, however, can lower blood sugar levels enough to cause symptoms or sometimes life-threatening hypoglycemia. Because acarbose given in combination with a sulfonylurea or insulin will cause a further lowering of blood sugar, it may increase the hypoglycemic potential of these agents. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, and no increased incidence of hypoglycemia was observed in patients when acarbose was added to metformin therapy. The risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be well understood by patients and responsible family members. Because acarbose prevents the breakdown of table sugar, patients should have a readily available source of glucose (dextrose, D-glucose) to treat symptoms of low blood sugar when taking acarbose in combination with a sulfonylurea or insulin.
If side effects occur with acarbose, they usually develop during the first few weeks of therapy. They are most commonly mild-to-moderate gastrointestinal effects, such as flatulence, diarrhea, or abdominal discomfort, and generally diminish in frequency and intensity with time.
# Precautions with Alcohol
Alcohol-Acarbose interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Precose
# Look-Alike Drug Names
There is limited information regarding Acarbose Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Acarbose
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
Acarbose is an alpha-glucosidase inhibitor that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include abdominal pain, diarrhea, flatulence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- Dosage:
- Initial dosage: 25 mg given orally three times daily at the start (with the first bite) of each main meal.
- Maintenance dosage: Once a 25 mg t.i.d. dosage regimen is reached, dosage of acarbose should be adjusted at 4–8 week intervals based on one-hour postprandial glucose or glycosylated hemoglobin levels, and on tolerance.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acarbose in adult patients.
### Non–Guideline-Supported Use
- Prophylaxis of type 2 diabetes mellitus
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acarbose in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Acarbose in pediatric patients.
# Contraindications
- In patients with known hypersensitivity to the drug.
- In patients with diabetic ketoacidosis or cirrhosis.
- In patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or in patients predisposed to intestinal obstruction.
- In patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption and in patients who have conditions that may deteriorate as a result of increased gas formation in the intestine.
# Warnings
### Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with acarbose or any other anti-diabetic drug.
### Hypoglycemia
Because of its mechanism of action, acarbose when administered alone should not cause hypoglycemia in the fasted or postprandial state. Sulfonylurea agents or insulin may cause hypoglycemia. Because acarbose given in combination with a sulfonylurea or insulin will cause a further lowering of blood glucose, it may increase the potential for hypoglycemia. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, and no increased incidence of hypoglycemia was observed in patients when acarbose was added to metformin therapy. Oral glucose (dextrose), whose absorption is not inhibited by acarbose, should be used instead of sucrose (cane sugar) in the treatment of mild to moderate hypoglycemia. Sucrose, whose hydrolysis to glucose and fructose is inhibited by acarbose, is unsuitable for the rapid correction of hypoglycemia. Severe hypoglycemia may require the use of either intravenous glucose infusion or glucagon injection.
### Elevated Serum Transaminase Levels
In long-term studies (up to 12 months, and including acarbose doses up to 300 mg t.i.d.) conducted in the United States, treatment-emergent elevations of serum transaminases (AST and/or ALT) above the upper limit of normal (ULN), greater than 1.8 times the ULN, and greater than 3 times the ULN occurred in 14%, 6%, and 3%, respectively, of acarbose-treated patients as compared to 7%, 2%, and 1%, respectively, of placebo-treated patients. Although these differences between treatments were statistically significant, these elevations were asymptomatic, reversible, more common in females, and, in general, were not associated with other evidence of liver dysfunction. In addition, these serum transaminase elevations appeared to be dose related. In US studies including acarbose doses up to the maximum approved dose of 100 mg t.i.d., treatment-emergent elevations of AST and/or ALT at any level of severity were similar between acarbose-treated patients and placebo-treated patients (p ≥ 0.496).
In approximately 3 million patient-years of international postmarketing experience with acarbose, 62 cases of serum transaminase elevations > 500 IU/L (29 of which were associated with jaundice) have been reported. Forty-one of these 62 patients received treatment with 100 mg t.i.d. or greater and 33 of 45 patients for whom weight was reported weighed < 60 kg. In the 59 cases where follow-up was recorded, hepatic abnormalities improved or resolved upon discontinuation of acarbose in 55 and were unchanged in two. Cases of fulminant hepatitis with fatal outcome have been reported; the relationship to acarbose is unclear.
### Loss of Control of Blood Glucose
When diabetic patients are exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of control of blood glucose may occur. At such times, temporary insulin therapy may be necessary.
# Adverse Reactions
## Clinical Trials Experience
### Digestive Tract
Gastrointestinal symptoms are the most common reactions to acarbose. In U.S. placebo-controlled trials, the incidences of abdominal pain, diarrhea, and flatulence were 19%, 31%, and 74% respectively in 1255 patients treated with acarbose 50–300 mg t.i.d., whereas the corresponding incidences were 9%, 12%, and 29% in 999 placebo-treated patients.
In a one-year safety study, during which patients kept diaries of gastrointestinal symptoms, abdominal pain and diarrhea tended to return to pretreatment levels over time, and the frequency and intensity of flatulence tended to abate with time. The increased gastrointestinal tract symptoms in patients treated with acarbose are a manifestation of the mechanism of action of acarbose and are related to the presence of undigested carbohydrate in the lower GI tract.
If the prescribed diet is not observed, the intestinal side effects may be intensified. If strongly distressing symptoms develop in spite of adherence to the diabetic diet prescribed, the doctor must be consulted and the dose temporarily or permanently reduced.
### Elevated Serum Transaminase Levels
Other Abnormal Laboratory Findings: Small reductions in hematocrit occurred more often in acarbose-treated patients than in placebo-treated patients but were not associated with reductions in hemoglobin. Low serum calcium and low plasma vitamin B6 levels were associated with acarbose therapy but are thought to be either spurious or of no clinical significance.
## Postmarketing Experience
Additional adverse events reported from worldwide postmarketing experience include fulminant hepatitis with fatal outcome, hypersensitive skin reactions (for example rash, erythema, exanthema and uticaria), edema, ileus/subileus, jaundice and/or hepatitis and associated liver damage, thrombocytopenia, and pneumatosis cystoides intestinalis.
There have been rare postmarketing reports of pneumatosis cystoides intestinalis associated with the use of alpha-glucosidase inhibitors, including acarbose. Pneumatosis cystoides intestinalis may present with symptoms of diarrhea, mucus discharge, rectal bleeding, and constipation. Complications may include pneumoperitoneum, volvulus, intestinal obstruction, intussusception, intestinal hemorrhage, and intestinal perforation. If pneumatosis cystoides intestinalis is suspected, discontinue acarbose and perform the appropriate diagnostic imaging.
# Drug Interactions
Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel-blocking drugs, and isoniazid. When such drugs are administered to a patient receiving acarbose, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from patients receiving acarbose in combination with sulfonylureas or insulin, patients should be observed closely for any evidence of hypoglycemia.
Patients Receiving Sulfonylureas or Insulin: Sulfonylurea agents or insulin may cause hypoglycemia. Acarbose given in combination with a sulfonylurea or insulin may cause a further lowering of blood glucose and may increase the potential for hypoglycemia. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made. Very rarely, individual cases of hypoglycemic shock have been reported in patients receiving acarbose therapy in combination with sulfonylureas and/or insulin.
Intestinal adsorbents (for example, charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (for example, amylase, pancreatin) may reduce the effect of acarbose and should not be taken concomitantly.
Acarbosehas been shown to change the bioavailability of digoxin when they are coadministered, which may require digoxin dose adjustment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
The safety of acarbose in pregnant women has not been established. Reproduction studies have been performed in rats at doses up to 480 mg/kg (corresponding to 9 times the exposure in humans, based on drug blood levels) and have revealed no evidence of impaired fertility or harm to the fetus due to acarbose. In rabbits, reduced maternal body weight gain, probably the result of the pharmacodynamic activity of high doses of acarbose in the intestines, may have been responsible for a slight increase in the number of embryonic losses. However, rabbits given 160 mg/kg acarbose (corresponding to 10 times the dose in man, based on body surface area) showed no evidence of embryotoxicity and there was no evidence of teratogenicity at a dose 32 times the dose in man (based on body surface area). There are, however, no adequate and well-controlled studies of acarbose in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Acarbose in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Acarbose during labor and delivery.
### Nursing Mothers
A small amount of radioactivity has been found in the milk of lactating rats after administration of radiolabeled acarbose. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, acarbose should not be administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Acarbose in pediatric settings.
### Geriatic Use
Of the total number of subjects in clinical studies of acarbose in the United States, 27% were 65 and over, while 4% were 75 and over. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. The mean steady-state area under the curve (AUC) and maximum concentrations of acarbose were approximately 1.5 times higher in elderly compared to young volunteers; however, these differences were not statistically significant.
### Gender
There is no FDA guidance on the use of Acarbose with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Acarbose with respect to specific racial populations.
### Renal Impairment
Plasma concentrations of acarbose in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine > 2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.
### Hepatic Impairment
There is no FDA guidance on the use of Acarbose in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Fertility studies conducted in rats after oral administration produced no untoward effect on fertility or on the overall capability to reproduce.
### Immunocompromised Patients
There is no FDA guidance one the use of Acarbose in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Therapeutic response to acarbose should be monitored by periodic blood glucose tests. Measurement of glycosylated hemoglobin levels is recommended for the monitoring of long-term glycemic control.
Acarbose, particularly at doses in excess of 50 mg t.i.d., may give rise to elevations of serum transaminases and, in rare instances, hyperbilirubinemia. It is recommended that serum transaminase levels be checked every 3 months during the first year of treatment with acarbose and periodically thereafter. If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist.
# IV Compatibility
There is limited information regarding the compatibility of Acarbose and IV administrations.
# Overdosage
Unlike sulfonylureas or insulin, an overdose of acarbose will not result in hypoglycemia. An overdose may result in transient increases in flatulence, diarrhea, and abdominal discomfort which shortly subside. In cases of overdosage the patient should not be given drinks or meals containing carbohydrates (polysaccharides, oligosaccharides and disaccharides) for the next 4–6 hours.
# Pharmacology
## Mechanism of Action
In contrast to sulfonylureas, acarbose does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.
Because its mechanism of action is different, the effect of acarbose to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, acarbose diminishes the insulinotropic and weight-increasing effects of sulfonylureas.
Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.
## Structure
## Pharmacodynamics
Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, acarbose reduces levels of glycosylated hemoglobin in patients with type 2 diabetes mellitus. Systemic non-enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.
## Pharmacokinetics
In a study of 6 healthy men, less than 2% of an oral dose of acarbose was absorbed as active drug, while approximately 35% of total radioactivity from a 14C-labeled oral dose was absorbed. An average of 51% of an oral dose was excreted in the feces as unabsorbed drug-related radioactivity within 96 hours of ingestion. Because acarbose acts locally within the gastrointestinal tract, this low systemic bioavailability of parent compound is therapeutically desired. Following oral dosing of healthy volunteers with 14C-labeled acarbose, peak plasma concentrations of radioactivity were attained 14–24 hours after dosing, while peak plasma concentrations of active drug were attained at approximately 1 hour. The delayed absorption of acarbose-related radioactivity reflects the absorption of metabolites that may be formed by either intestinal bacteria or intestinal enzymatic hydrolysis.
Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. A fraction of these metabolites (approximately 34% of the dose) was absorbed and subsequently excreted in the urine. At least 13 metabolites have been separated chromatographically from urine specimens. The major metabolites have been identified as 4-methylpyrogallol derivatives (that is, sulfate, methyl, and glucuronide conjugates). One metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-glucosidase inhibitory activity. This metabolite, together with the parent compound, recovered from the urine, accounts for less than 2% of the total administered dose.
The fraction of acarbose that is absorbed as intact drug is almost completely excreted by the kidneys. When acarbose was given intravenously, 89% of the dose was recovered in the urine as active drug within 48 hours. In contrast, less than 2% of an oral dose was recovered in the urine as active (that is, parent compound and active metabolite) drug. This is consistent with the low bioavailability of the parent drug. The plasma elimination half-life of acarbose activity is approximately 2 hours in healthy volunteers. Consequently, drug accumulation does not occur with three times a day (t.i.d.) oral dosing.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
Eight carcinogenicity studies were conducted with acarbose. Six studies were performed in rats (two strains, Sprague-Dawley and Wistar) and two studies were performed in hamsters.
In the first rat study, Sprague-Dawley rats received acarbose in feed at high doses (up to approximately 500 mg/kg body weight) for 104 weeks. Acarbose treatment resulted in a significant increase in the incidence of renal tumors (adenomas and adenocarcinomas) and benign Leydig cell tumors. This study was repeated with a similar outcome. Further studies were performed to separate direct carcinogenic effects of acarbose from indirect effects resulting from the carbohydrate malnutrition induced by the large doses of acarbose employed in the studies. In one study using Sprague-Dawley rats, acarbose was mixed with feed but carbohydrate deprivation was prevented by the addition of glucose to the diet. In a 26-month study of Sprague-Dawley rats, acarbose was administered by daily postprandial gavage so as to avoid the pharmacologic effects of the drug. In both of these studies, the increased incidence of renal tumors found in the original studies did not occur. Acarbose was also given in food and by postprandial gavage in two separate studies in Wistar rats. No increased incidence of renal tumors was found in either of these Wistar rat studies. In two feeding studies of hamsters, with and without glucose supplementation, there was also no evidence of carcinogenicity.
Acarbose did not induce any DNA damage in vitro in the CHO chromosomal aberration assay, bacterial mutagenesis (Ames) assay, or a DNA binding assay. In vivo, no DNA damage was detected in the dominant lethal test in male mice, or the mouse micronucleus test.
# Clinical Studies
### Clinical Experience from Dose Finding Studies in Type 2 Diabetes Mellitus Patients on Dietary Treatment Only
Results from six controlled, fixed-dose, monotherapy studies of acarbose in the treatment of type 2 diabetes mellitus, involving 769 acarbose-treated patients, were combined and a weighted average of the difference from placebo in the mean change from baseline in glycosylated hemoglobin (HbA1c) was calculated for each dose level as presented below:
Results from these six fixed-dose, monotherapy studies were also combined to derive a weighted average of the difference from placebo in mean change from baseline for one-hour postprandial plasma glucose levels as shown in the following figure:
### Clinical Experience in Type 2 Diabetes Mellitus Patients on Monotherapy, or in Combination with Sulfonylureas, Metformin or Insulin
Acarbose was studied as monotherapy and as combination therapy to sulfonylurea, metformin, or insulin treatment. The treatment effects on HbA1c levels and one-hour postprandial glucose levels are summarized for four placebo-controlled, double-blind, randomized studies conducted in the United States in Tables 2 and 3, respectively. The placebo-subtracted treatment differences, which are summarized below, were statistically significant for both variables in all of these studies.
Study 1 (n=109) involved patients on background treatment with diet only. The mean effect of the addition of acarbose to diet therapy was a change in HbA1c of -0.78%, and an improvement of one-hour postprandial glucose of -74.4 mg/dL.
In Study 2 (n=137), the mean effect of the addition of acarbose to maximum sulfonylurea therapy was a change in HbA1c of -0.54%, and an improvement of one-hour postprandial glucose of -33.5 mg/dL.
In Study 3 (n=147), the mean effect of the addition of acarbose to maximum metformin therapy was a change in HbA1c of -0.65%, and an improvement of one-hour postprandial glucose of -34.3 mg/dL.
Study 4 (n=145) demonstrated that acarbose added to patients on background treatment with insulin resulted in a mean change in HbA1c of -0.69%, and an improvement of one-hour postprandial glucose of -36.0 mg/dL.
A one year study of acarbose as monotherapy or in combination with sulfonylurea, metformin or insulin treatment was conducted in Canada in which 316 patients were included in the primary efficacy analysis (Figure 2). In the diet, sulfonylurea and metformin groups, the mean decrease in HbA1c produced by the addition of acarbose was statistically significant at six months, and this effect was persistent at one year. In the acarbose-treated patients on insulin, there was a statistically significant reduction in HbA1c at six months, and a trend for a reduction at one year.
# How Supplied
Acarbose is available as 25 mg, 50 mg or 100 mg round, unscored tablets.
## Storage
Do not store above 25°C (77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be told to take acarbose orally three times a day at the start (with the first bite) of each main meal. It is important that patients continue to adhere to dietary instructions, a regular exercise program, and regular testing of urine and/or blood glucose.
Acarbose itself does not cause hypoglycemia even when administered to patients in the fasted state. Sulfonylurea drugs and insulin, however, can lower blood sugar levels enough to cause symptoms or sometimes life-threatening hypoglycemia. Because acarbose given in combination with a sulfonylurea or insulin will cause a further lowering of blood sugar, it may increase the hypoglycemic potential of these agents. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, and no increased incidence of hypoglycemia was observed in patients when acarbose was added to metformin therapy. The risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be well understood by patients and responsible family members. Because acarbose prevents the breakdown of table sugar, patients should have a readily available source of glucose (dextrose, D-glucose) to treat symptoms of low blood sugar when taking acarbose in combination with a sulfonylurea or insulin.
If side effects occur with acarbose, they usually develop during the first few weeks of therapy. They are most commonly mild-to-moderate gastrointestinal effects, such as flatulence, diarrhea, or abdominal discomfort, and generally diminish in frequency and intensity with time.
# Precautions with Alcohol
Alcohol-Acarbose interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Precose [1]
# Look-Alike Drug Names
There is limited information regarding Acarbose Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Acarbose | |
92b7fdf9deaf2d4c1f820ccb8531954250a46153 | wikidoc | Overdose | Overdose
# Contact Poison Control at 1-800-222-1222
# Look up your local Poison Control Center in the United States
# Look up a poison control center anywhere in the world
# Report a side effect to the FDA at MedWatch Read more about MedWatch here
# Search for Drug-Drug Interactions
# Overview
There can be damaging physiologic effects of ingestion, inhalation, or other exposure to a broad range of chemicals, including pesticides, heavy metals, gases/vapors, drugs, and a variety of common household substances, such as bleach and ammonia. The term drug overdose (or simply overdose) describes the ingestion or application of a drug or other substance in quantities greater than are recommended, routinely prescribed, or have been researched. An overdose is generally considered harmful and dangerous as it can result in significant morbidity (permanent injury and/or disability) and mortality (death). Narcotic and stimulant use and misuse appear to be driving the increase in poisoning deaths. Alcohol and other drugs of abuse (methamphetamine, oxycodone, etc) are also important public health issues with enormous impacts on many types of injury and violence.
# Statistics
While they do not give separate figures for drug overdoses and other kinds of accidental poisoning, the National Center for Health Statistics report that 19,250 people died of accidental poisoning in the U.S. in the year 2004.
# Types
The word "overdose" implies that there is a safe dosage; therefore, the term is commonly only applied to drugs, not poison. Drug overdoses are sometimes caused intentionally to commit suicide or as self-harm, but many drug overdoses are accidental and are usually the result of either irresponsible behavior or the misreading of product labels. Other causes of overdose include use of multiple drugs with counter indications simultaneously (for instance, heroin/certain prescription pain medications and cocaine/amphetamines/alcohol) and use after a period of abstinence or unexpected purity of the drug consumed.
A common unintentional overdose in young children involves multi-vitamins containing iron. Iron is a component of the hemoglobin molecule in blood, used to transport oxygen to living cells. When taken in small amounts, iron allows the body to replenish hemoglobin, but in large amounts it causes severe pH imbalances in the body. If this overdose is not treated with chelation therapy, it can lead to death or permanent coma.
# Misconceptions
Deaths caused by adulterated drugs, most commonly heroin, are often incorrectly attributed to overdose.
# Symptoms
Symptoms of overdose occur in various forms:
- Exaggerated form of normal action (e.g., sleepiness on antiepileptics, hypoglycemia on insulin)
- Other effects due to chemical properties of the medication (e.g., metabolic acidosis in aspirin, liver failure due to paracetamol)
- Non-specific symptoms due to central nervous system irritation (e.g., confusion, vertigo, nausea, vomiting, delirium, seizures)
# Diagnosis
Diagnosis of an overdosed patient is generally straightforward if the drug is known. However, it can be very difficult if the patient cannot (or refuses to) state what drug they have overdosed on. At times, certain symptoms and signs exhibited by the patient, or blood tests, can reveal the drug in question. Even without knowing the drug, most patients can be treated with general supportive measures.
In some instances, antidotes may be administered if there is sufficient indication that the patient has overdosed on a particular type of medication. Naloxone in opioids and flumazenil in benzodiazepines, are specific receptor antagonists and they reverse completely the effect of the poisoning drug.
# First aid
The most important point to realize in care of the overdose patient is that initial treatment is largely supportive. Making sure that the patient has a patent (unobstructed) airway and adequate circulation are key. Assuring these can buy the patient valuable time until definitive treatment can be provided either by first-responders, such as Emergency Medicine Technicians / Paramedics (EMT / EMT-P) , or by a physician in the Emergency Department. While waiting for help to arrive, valuable information can also be obtained from the above listed numbers.
In the wake of this paradigm shift to supportive care, two previously recommended initial treatments have fallen out of favor. Induced vomiting and gastric lavage ("pumping one's stomach") have been proven not only to be of little benefit, but also to be detrimental in overdose care. Syrup of ipecac was once widely used as initial treatment in overdoses by both parents and healthcare providers especially if it could be administered shortly (less than 30 min) after toxic ingestion. Though it remains available at many pharmacies, it has fallen from favor in treatment algorithms. Several factors have lead to ipecac's contraindication in nearly all overdose situations. Firstly, many toxins involved in accidental and/or intentional overdoses are CNS depressants. This results in a severely decreased level of consciousness in the victim which places them at significant risk of aspiration. Aspiration, which is the entrance of stomach contents into the lungs, not only puts the patient at risk of suffocation, but also presents a significant risk of complications such as pneumonia and/or permanent lung damage. In addition certain toxins such as hydrocarbons (gasoline), lye, and bleach cause physical damage to the oropharynx and esophagus when ingested. Regurgitation of these substances exposes these tissues to a second exposure intensifying the damage done. Lastly, any toxin that results in CNS depression can also effectively lower the seizure threshold, and with the repetitive vomiting that frequently occurs with the use ipecac can lead to seizure activity.
An informative summary of the currently accepted Ipecac guidelines can be found here. NGC
The American Academy of Clinical Toxicology (AACT) has repeatedly recommended against the use of gastric lavage. In fact, in their 2004 "Position Paper: Gastric Lavage," they said, "Gastric lavage should not be employed routinely, if ever, in the management of poisoned patients."
## Depressants
First aid can prevent a death from overdose of depressants, as it may take several hours for someone to die in these cases. The common drugs in this category include opiates (ie. heroin, morphine and methadone), alcohol, and certain prescription drugs (such as Benzodiazepines). Signs of overdose are those of a depressed central nervous system — slow, infrequent or shallow breathing, blue lips or fingernails, cold or pale skin, slow or faint pulse, snoring or gurgling noises, and the inability to be aroused from nodding off (unresponsiveness).
- The first step is to stay calm and try to get a response from the person by pinching the back of their arm, calling their name, or rubbing your knuckles against their chest.
- If there is no response, check to make sure their airway is not blocked and see if they are breathing.
- If breathing or pulse are not detectable, commence cardiopulmonary resuscitation. If these signs are present, roll the person in question on his/her side into the recovery position.
- Call an ambulance. Ideally, someone should call an ambulance immediately while another person evaluates the patient and performs CPR if necessary.
## Stimulants
People can overdose on stimulants, such as amphetamines, and cocaine, with symptoms such as rapid heartbeat, muscle cramps, seizures, paranoia, psychosis, confusion, loss of control of movement, vomiting, lack of consciousness, and possibly cardiac arrest. It can result in an often fatal condition known as excited delirium.
First aid in these cases involves staying with the person and helping them to remain calm. Move them to a quiet area, and where possible, apply a wet cloth to their neck or forehead. If unconscious, place them in the recovery position and call an ambulance.
# Prevention
- Refrain from mixing depressant drugs like alcohol, barbiturates, benzodiazepines, and opiates together.
- Start with small amounts, in order to estimate the potency of a drug.
- Be careful when taking a drug after a period of abstinence, as your tolerance may be drastically lowered.
- If you have a pharmaceutical chemical, make sure it isn't expired. Toxicity can increase drastically.
# Common causes
Common types of drugs that are overdosed on:
- Barbiturates
Seconal
Nembutal
- Seconal
- Nembutal
- Benzodiazepines
Alprazolam
Clonazepam
- Alprazolam
- Clonazepam
- Narcotics
Oxycodone
Hydrocodone
Heroin
- Oxycodone
- Hydrocodone
- Heroin
- Stimulants
Methamphetamine
- Methamphetamine
- Ethyl Alcohol
Alcoholic beverages
- Alcoholic beverages
- Prescription drugs
Drug "cocktails", or a combination of numerous drugs
- Drug "cocktails", or a combination of numerous drugs
# Specific Drug Overdoses
Below is a listing of overdose information related to various drugs in alphabetical order:
# Causes of Unintentional Opiate-related Poisoning Deaths
## Legitimate medical treatment with opiates
Pain is very common. About 24% of U. S. adults reported moderate to extreme pain in the past month.7 In 2005, about 19% of the 50 million United States adults who used Express Scripts, a large commercial pharmacy benefit program, received a prescription for opiates.8
Chronic opiate use is linked to the development of tolerance to its analgesic or pain relieving effect.9 Tolerance is defined as a decrease in a drug’s effect over time so that larger doses are required to achieve the same effect. Chronic opiate use also may be associated with hyperalgesia, an increase in abnormal pain sensitivity.9 In an attempt to maintain pain relief, the combination of tolerance and hyperalgesia may lead to rampant dose escalation.9
Respiratory depression, a decrease in the rate or depth of a patient’s breathing, is one of the side effects or risks of opiate use. Opiate poisoning deaths are often due to respiratory failure from respiratory depression. As with pain relief, tolerance to respiratory depression develops with chronic opiate use. However, research suggests that tolerance to respiratory depression is incomplete and may develop more slowly than tolerance to the pain relieving effect.10
Other risk factors for unintentional opiate-related poisoning include:
- Concurrent use of other central nervous system depressants like benzodiazepines and sedative-hypnotics.
- The existence of other medical conditions associated with compromised respiratory function such as chronic obstructive pulmonary disease, congestive heart failure, and sleep apnea.
## Misuse of Prescription Opiates
In addition to legitimately prescribed opiates, prescription opiates can be obtained in various other ways:
- From a friend or relative with a prescription.
- Obtained from emergency rooms through fraudulent drug-seeking means.
- Purchased on the street or from the Internet.
- Stolen from pharmacies.
During treatment for chronic pain, prescription opiates can be misused by taking more than the prescribed dose or by combining opiates with illicit drugs or alcohol.
Nationally, the U. S. Substance Abuse and Mental Health Services Administration’s Drug Abuse Warning Network tracks drug-related emergency department visits. These visits relate to both misuse and abuse of drugs. For prescription drugs, the definition of ‘non-medical’ use includes:
- Taking more than the prescribed dose of a prescription drug.
- Taking a drug prescribed for another individual.
- Deliberate poisoning with a drug by another person.
- Documented misuse or abuse of a prescription drug.
Opiates accounted for about one-third of all non-medical prescription drug use visits, making them the most frequently reported drugs. In 2006 in King and Snohomish counties, there were 3,529 reports of prescription opiate emergency department visits. The visits were identified as:
- Drug abuse (54%).
- Adverse reaction (18%).
- Accidental overmedication (18%).
## Childhood Poisoning
While the highest death rates occur among adults, the majority of reports are for non-fatal poison exposures to children under six years.
- About 90% of the incidents occurred in a home.
- 52% of the incidents occurred to a child under six years.
- The majority of all exposure calls (83%) were handled without transfer to a health care facility.
- 94% percent of exposure calls to children ages six or under were handled without transfer to a health care facility.
The most common substances involved in possible exposures are medications. For example, the top three includes analgesics, topical preparations, and cold and cough preparations. Other common exposures include personal care products, and cosmetics. | Overdose
Editor-In-Chief: Scott Everett, M.D., Pharm. D. Assistant Professor of Emergency Medicine, Wake Forest University Baptist Medical Center, Winston Salem, NC Email Dr. Everett by clicking here
Editor in Chief: Jen Hannum M.D.
Associate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
# Contact Poison Control at 1-800-222-1222
# Look up your local Poison Control Center in the United States
# Look up a poison control center anywhere in the world
# Report a side effect to the FDA at MedWatch Read more about MedWatch here
# Search for Drug-Drug Interactions
# Overview
There can be damaging physiologic effects of ingestion, inhalation, or other exposure to a broad range of chemicals, including pesticides, heavy metals, gases/vapors, drugs, and a variety of common household substances, such as bleach and ammonia. The term drug overdose (or simply overdose) describes the ingestion or application of a drug or other substance in quantities greater than are recommended, routinely prescribed, or have been researched. An overdose is generally considered harmful and dangerous as it can result in significant morbidity (permanent injury and/or disability) and mortality (death). Narcotic and stimulant use and misuse appear to be driving the increase in poisoning deaths. Alcohol and other drugs of abuse (methamphetamine, oxycodone, etc) are also important public health issues with enormous impacts on many types of injury and violence.
# Statistics
While they do not give separate figures for drug overdoses and other kinds of accidental poisoning, the National Center for Health Statistics report that 19,250 people died of accidental poisoning in the U.S. in the year 2004.[1]
# Types
The word "overdose" implies that there is a safe dosage; therefore, the term is commonly only applied to drugs, not poison. Drug overdoses are sometimes caused intentionally to commit suicide or as self-harm, but many drug overdoses are accidental and are usually the result of either irresponsible behavior or the misreading of product labels. Other causes of overdose include use of multiple drugs with counter indications simultaneously (for instance, heroin/certain prescription pain medications and cocaine/amphetamines/alcohol) and use after a period of abstinence or unexpected purity of the drug consumed.
A common unintentional overdose in young children involves multi-vitamins containing iron. Iron is a component of the hemoglobin molecule in blood, used to transport oxygen to living cells. When taken in small amounts, iron allows the body to replenish hemoglobin, but in large amounts it causes severe pH imbalances in the body. If this overdose is not treated with chelation therapy, it can lead to death or permanent coma.
# Misconceptions
Deaths caused by adulterated drugs, most commonly heroin, are often incorrectly attributed to overdose.
# Symptoms
Symptoms of overdose occur in various forms:
- Exaggerated form of normal action (e.g., sleepiness on antiepileptics, hypoglycemia on insulin)
- Other effects due to chemical properties of the medication (e.g., metabolic acidosis in aspirin, liver failure due to paracetamol)
- Non-specific symptoms due to central nervous system irritation (e.g., confusion, vertigo, nausea, vomiting, delirium, seizures)
# Diagnosis
Diagnosis of an overdosed patient is generally straightforward if the drug is known. However, it can be very difficult if the patient cannot (or refuses to) state what drug they have overdosed on. At times, certain symptoms and signs exhibited by the patient, or blood tests, can reveal the drug in question. Even without knowing the drug, most patients can be treated with general supportive measures.
In some instances, antidotes may be administered if there is sufficient indication that the patient has overdosed on a particular type of medication. Naloxone in opioids and flumazenil in benzodiazepines, are specific receptor antagonists and they reverse completely the effect of the poisoning drug.
# First aid
The most important point to realize in care of the overdose patient is that initial treatment is largely supportive. Making sure that the patient has a patent (unobstructed) airway and adequate circulation are key. Assuring these can buy the patient valuable time until definitive treatment can be provided either by first-responders, such as Emergency Medicine Technicians / Paramedics (EMT / EMT-P) , or by a physician in the Emergency Department. While waiting for help to arrive, valuable information can also be obtained from the above listed numbers.
In the wake of this paradigm shift to supportive care, two previously recommended initial treatments have fallen out of favor. Induced vomiting and gastric lavage ("pumping one's stomach") have been proven not only to be of little benefit, but also to be detrimental in overdose care. Syrup of ipecac was once widely used as initial treatment in overdoses by both parents and healthcare providers especially if it could be administered shortly (less than 30 min) after toxic ingestion. Though it remains available at many pharmacies, it has fallen from favor in treatment algorithms. Several factors have lead to ipecac's contraindication in nearly all overdose situations. Firstly, many toxins involved in accidental and/or intentional overdoses are CNS depressants. This results in a severely decreased level of consciousness in the victim which places them at significant risk of aspiration. Aspiration, which is the entrance of stomach contents into the lungs, not only puts the patient at risk of suffocation, but also presents a significant risk of complications such as pneumonia and/or permanent lung damage. In addition certain toxins such as hydrocarbons (gasoline), lye, and bleach cause physical damage to the oropharynx and esophagus when ingested. Regurgitation of these substances exposes these tissues to a second exposure intensifying the damage done. Lastly, any toxin that results in CNS depression can also effectively lower the seizure threshold, and with the repetitive vomiting that frequently occurs with the use ipecac can lead to seizure activity.
An informative summary of the currently accepted Ipecac guidelines can be found here. NGC
The American Academy of Clinical Toxicology (AACT) has repeatedly recommended against the use of gastric lavage. In fact, in their 2004 "Position Paper: Gastric Lavage," they said, "Gastric lavage should not be employed routinely, if ever, in the management of poisoned patients."
## Depressants
First aid can prevent a death from overdose of depressants, as it may take several hours for someone to die in these cases. The common drugs in this category include opiates (ie. heroin, morphine and methadone), alcohol, and certain prescription drugs (such as Benzodiazepines). Signs of overdose are those of a depressed central nervous system — slow, infrequent or shallow breathing, blue lips or fingernails, cold or pale skin, slow or faint pulse, snoring or gurgling noises, and the inability to be aroused from nodding off (unresponsiveness).
- The first step is to stay calm and try to get a response from the person by pinching the back of their arm, calling their name, or rubbing your knuckles against their chest.
- If there is no response, check to make sure their airway is not blocked and see if they are breathing.
- If breathing or pulse are not detectable, commence cardiopulmonary resuscitation.[2] If these signs are present, roll the person in question on his/her side into the recovery position.
- Call an ambulance. Ideally, someone should call an ambulance immediately while another person evaluates the patient and performs CPR if necessary.
## Stimulants
People can overdose on stimulants, such as amphetamines, and cocaine, with symptoms such as rapid heartbeat, muscle cramps, seizures, paranoia, psychosis, confusion, loss of control of movement, vomiting, lack of consciousness, and possibly cardiac arrest. It can result in an often fatal condition known as excited delirium.
First aid in these cases involves staying with the person and helping them to remain calm. Move them to a quiet area, and where possible, apply a wet cloth to their neck or forehead. If unconscious, place them in the recovery position and call an ambulance.[2]
# Prevention
- Refrain from mixing depressant drugs like alcohol, barbiturates, benzodiazepines, and opiates together. [3]
- Start with small amounts, in order to estimate the potency of a drug.
- Be careful when taking a drug after a period of abstinence, as your tolerance may be drastically lowered.
- If you have a pharmaceutical chemical, make sure it isn't expired. Toxicity can increase drastically.
# Common causes
Common types of drugs that are overdosed on:
- Barbiturates
Seconal
Nembutal
- Seconal
- Nembutal
- Benzodiazepines
Alprazolam
Clonazepam
- Alprazolam
- Clonazepam
- Narcotics
Oxycodone
Hydrocodone
Heroin
- Oxycodone
- Hydrocodone
- Heroin
- Stimulants
Methamphetamine
- Methamphetamine
- Ethyl Alcohol
Alcoholic beverages
- Alcoholic beverages
- Prescription drugs
Drug "cocktails", or a combination of numerous drugs
- Drug "cocktails", or a combination of numerous drugs
# Specific Drug Overdoses
Below is a listing of overdose information related to various drugs in alphabetical order:
# Causes of Unintentional Opiate-related Poisoning Deaths
## Legitimate medical treatment with opiates
Pain is very common. About 24% of U. S. adults reported moderate to extreme pain in the past month.7 In 2005, about 19% of the 50 million United States adults who used Express Scripts, a large commercial pharmacy benefit program, received a prescription for opiates.8
Chronic opiate use is linked to the development of tolerance to its analgesic or pain relieving effect.9 Tolerance is defined as a decrease in a drug’s effect over time so that larger doses are required to achieve the same effect. Chronic opiate use also may be associated with hyperalgesia, an increase in abnormal pain sensitivity.9 In an attempt to maintain pain relief, the combination of tolerance and hyperalgesia may lead to rampant dose escalation.9
Respiratory depression, a decrease in the rate or depth of a patient’s breathing, is one of the side effects or risks of opiate use. Opiate poisoning deaths are often due to respiratory failure from respiratory depression. As with pain relief, tolerance to respiratory depression develops with chronic opiate use. However, research suggests that tolerance to respiratory depression is incomplete and may develop more slowly than tolerance to the pain relieving effect.10
Other risk factors for unintentional opiate-related poisoning include:
- Concurrent use of other central nervous system depressants like benzodiazepines and sedative-hypnotics.
- The existence of other medical conditions associated with compromised respiratory function such as chronic obstructive pulmonary disease, congestive heart failure, and sleep apnea.
## Misuse of Prescription Opiates
In addition to legitimately prescribed opiates, prescription opiates can be obtained in various other ways:
- From a friend or relative with a prescription.
- Obtained from emergency rooms through fraudulent drug-seeking means.
- Purchased on the street or from the Internet.
- Stolen from pharmacies.
During treatment for chronic pain, prescription opiates can be misused by taking more than the prescribed dose or by combining opiates with illicit drugs or alcohol.
Nationally, the U. S. Substance Abuse and Mental Health Services Administration’s Drug Abuse Warning Network tracks drug-related emergency department visits. These visits relate to both misuse and abuse of drugs. For prescription drugs, the definition of ‘non-medical’ use includes:
- Taking more than the prescribed dose of a prescription drug.
- Taking a drug prescribed for another individual.
- Deliberate poisoning with a drug by another person.
- Documented misuse or abuse of a prescription drug.
Opiates accounted for about one-third of all non-medical prescription drug use visits, making them the most frequently reported drugs. In 2006 in King and Snohomish counties, there were 3,529 reports of prescription opiate emergency department visits. The visits were identified as:
- Drug abuse (54%).
- Adverse reaction (18%).
- Accidental overmedication (18%).
## Childhood Poisoning
While the highest death rates occur among adults, the majority of reports are for non-fatal poison exposures to children under six years.
- About 90% of the incidents occurred in a home.
- 52% of the incidents occurred to a child under six years.
- The majority of all exposure calls (83%) were handled without transfer to a health care facility.
- 94% percent of exposure calls to children ages six or under were handled without transfer to a health care facility.
The most common substances involved in possible exposures are medications. For example, the top three includes analgesics, topical preparations, and cold and cough preparations. Other common exposures include personal care products, and cosmetics. | https://www.wikidoc.org/index.php/Accidental_overdose | |
c2f79a64f78f3a9f83752e351b2ecb8491b48d32 | wikidoc | Acidosis | Acidosis
# Overview
Acidosis is an acid-base imbalance that is an increased acidity (i.e. an increased hydrogen ion concentration). If not further qualified, it refers to acidity of the blood plasma.
Generally, acidosis is said to occur when arterial pH falls below 7.35, while its counterpart (alkalosis) occurs at a pH over 7.45. Arterial blood gas analysis and other tests are required to separate the main causes.
Strictly speaking, the term acidemia would be more appropriate to describe the state of low blood pH, reserving acidosis to describe the processes leading to these states. Nevertheless, most physicians use the terms interchangeably. The distinction may be relevant where a patient has factors causing both acidosis and alkalosis, where the relative severity of both determines whether the result is a high or a low pH.
The rate of cellular metabolic activity affects and, at the same time, is affected by the pH of the body fluids. In mammals, the normal pH of arterial blood lies between 7.35 and 7.50 depending on the species (e.g. healthy human-arterial blood pH varies between 7.35 and 7.45). Blood pH values compatible with life in mammals are limited to a pH range between 6.8 and 7.8. Changes in the pH of arterial blood (and therefore the extracellular fluid) outside this range result in irreversible cell damage (Needham, 2004).
# Classification
- Acidosis can either be metabolic or respiratory.
Both are caused by low arterial pH.
Metabolic acidosis is due to an increased accumulation of acid equivalents through impairment of the regulatory ability of the liver, kidneys, or metabolism.
Respiratory acidosis is caused by a retention of carbon dioxide due to inadequate hypoventilation or pulmonary ventilation.
- Both are caused by low arterial pH.
- Metabolic acidosis is due to an increased accumulation of acid equivalents through impairment of the regulatory ability of the liver, kidneys, or metabolism.
- Respiratory acidosis is caused by a retention of carbon dioxide due to inadequate hypoventilation or pulmonary ventilation.
# Pathophysiology
## Respiratory acidosis
Respiratory acidosis results from a build-up of carbon dioxide in the blood (hypercapnia) due to hypoventilation. It is most often caused by pulmonary problems, although head injuries, drugs (especially anaesthetics and sedatives), and brain tumors can also bring it on. Emphysema, chronic bronchitis, asthma, severe pneumonia, and aspiration are among the most frequent causes. It can also occur as a response to chronic metabolic alkalosis.
Blood gases show pH below 7.35 as above mentioned, and PaCO2 will be high (>45 mmHg / 6 kPa).
The key to distinguish between respiratory and metabolic acidosis is that in respiratory acidosis, the CO2 is increased while the bicarbonate is either normal (uncompensated) or increased (compensated). Compensation occurs if respiratory acidosis persists for days or longer and a chronic phase is entered with partial buffering of the acidosis through renal bicarbonate retention.
## Metabolic acidosis
Metabolic acidosis may result from disturbances in the ability to excrete acid via the kidneys. Renal acidosis is associated with an accumulation of urea and creatinine as well as metabolic acid residues of protein catabolism.
An increase in the production of metabolic acids may also produce metabolic acidosis. For example, lactic acidosis may occur from 1) severe (PaO2 <36mm Hg) hypoxemia causing a fall in the rate of oxygen diffusion from arterial blood to tissues, or 2) hypoperfusion (e.g. hypovolemic shock) causing an inadequate blood delivery of oxygen to tissues. A rise in lactate out of proportion to the level of pyruvate, e.g. in mixed venous blood, is termed "excess lactate" and is the best indicator of an inadequate flow of oxygen into the body's mitochondria from either cause. Oxygen debt (and muscle excess lactate) is also seen in strenuous exercise. Once oxygenation is restored, the acidosis clears quickly. Another example of increased production of acids occurs in starvation and diabetic acidosis. It is due to the accumulation of ketoacids (ketosis) and reflects a severe shift from glycolysis to lipolysis for fuel needs.
Acidic poisons, iron etc., and decreased production of bicarbonate may also produce metabolic acidosis.
Metabolic acidosis can result in stimulation of chemoreceptors and so increase alveolar ventilation, leading to respiratory compensation, otherwise known as Kussmaul breathing, which is a specific type of hyperventilation. Should this situation persist the patient is at risk for exhaustion leading to respiratory failure.
Mutations to the V-ATPase 'a4' or 'B1' isoforms result in distal renal tubular acidosis—a condition that leads to metabolic acidosis—in some cases with sensorineural deafness.
In blood gas tests, it is characterised by a low pH, low blood HCO3, and normal or low PaCO2.
In addition to arterial blood gas one can use the anion gap to differentiate between possible causes.
The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected.
# Causes
## Common causes of acidosis
- Traumatic shock
- Sepsis
- Severe hypoxemia
- Severe diarrhoea
- Renal failure
- Multiple organ dysfunction syndrome
- Nausea and Vomiting
- Mesenteric insufficiency
- Ketoacidosis
- Ischemic colitis
- Hypotension
- Ethanol ingestion
- Cardiogenic shock
- Alcohol
- Acetylsalicylic acid
## Causes by Organ System
## Causes in Alphabetical Order
- 3-alpha-hydroxyisobutyryl-CoA hydrolase deficiency
- 3-Hydroxyacyl-CoA dehydrogenase II Deficiency
- 3-methylglutaconic aciduria
- Acetazolamide
- Acetylsalicylic acid
- Acute disseminated encephalomyelitis
- acute glomerulonephritis
- Acute liver failure
- Acute renal failure
- Acute respiratory distress syndrome
- Adrenal cortex insufficiency
- Alcohol
- Apnea
- Aspirin
- Beriberi heart disease
- Biguanide
- Biliary fistula
- Biotinidase deficiency
- Carbon monoxide poisoning
- Carbonic anhydrase inhibitors
- Cardiac arrest
- Cardiogenic shock
- Cardiomyopathy
- Cataract and cardiomyopathy
- Cerebral edema
- Cerebral hypoxia
- Cerebral malaria
- Chronic interstitial nephritis
- Chronic kidney disease
- Chronic mesenteric insufficiency
- Chronic obstructive lung disease
- Clostridium difficile
- CNS depression
- Cocaine
- Coenzyme Q cytochrome c reductase deficiency
- Coma
- Complex 1 mitochondrial respiratory chain deficiency
- Congestive heart failure
- Copperhead snake poisoning
- Crotalidae snake poisoning
- Cyanide poisoning
- Cystinosis
- Decreased renal acid excretion
- Diabetes
- Diabetic ketoacidosis
- Diarrhea
- Didanosine
- Diethylene glycol
- Disseminated intravascular coagulation
- Distal renal tubular acidosis
- Drowning
- Endothall
- Epilepsy
- Ethanol
- Ethylene glycol
- Fanconi syndrome
- Fanconi-ichthyosis-dysmorphism
- Fever
- Fistula
- Fructose-16-bisphosphatase deficiency
- Germanium
- Glutaric acidemia type 2
- Glutaric aciduria type 1
- Glyburide
- Glycogen storage diseases
- GRACILE syndrome
- Grand mal seizure
- Hemorrhagic shock
- Hepatic failure
- Hepatopathy
- Hydroxyacyl-coa dehydrogenase deficiency type 2
- Hydroxysteroid dehydrogenase deficiency
- Hypercapnia
- Hyperchloremic acidosis
- Hyperkalemia
- Hyperosmolar non-ketotic diabetic coma
- Hypoaldosteronism
- Hypoglycemia
- Hypokalemic distal renal tubular acidosis
- Hypoperfusion
- Hypothermic shivering
- Ileus
- Inborn urea cycle disorder
- Infant respiratory distress syndrome
- Infection
- Ischemic colitis
- Isopropyl alcohol
- Ketoacidosis
- Kidney disorders
- Leukemia
- Lipoamide dehydrogenase deficiency
- Liver disease
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
- Lymphoma
- Malignant hypertension
- Medium-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
- MELAS
- Metabolic disorders
- Metformin
- Methanol
- Microvillus inclusion disease
- Mitochondrial DNA depletion syndrome
- Mitochondrial encephalomyopathy aminoacidopathy
- Mitochondrial myopathy
- Mitochondrial neurogastrointestinal encephalopathy syndrome
- Multiple carboxylase deficiency
- Myeloma
- Myocardial Infarction
- Myopathy
- NADH CoQ reductase deficiency
- Necrotizing enterocolitis
- Ondine's curse
- Pancreatic fistula
- Paracetamol
- Pergolide
- Permanent neonatal diabetes mellitus
- Phenformin
- Pheochromocytoma
- Propionic acidemia
- Propylene glycol
- Proximal renal tubular acidosis
- Pulmonary edema
- Pulmonary embolism
- Pulseless electrical activity
- Pyruvate carboxylase deficiency
- Pyruvate dehydrogenase phosphatase deficiency
- Renal circulatory insufficiency
- Renal failure
- Renal tubular acidosis
- Salicylate
- Salicylates
- SCHAD deficiency
- Sepsis
- Severe liver disease
- Shock
- Short bowel syndrome
- Sideroblastic anemia
- Small intestine fistula
- ST elevation myocardial infarction
- Starvation
- Status asthmaticus
- Strychnine
- Succinic acidemia
- Thyrotoxicosis
- Toluene
- Torsade de pointes
- Total parenteral nutrition
- Tumor
- Type I glycogen storage disease
- Ureterosigmoidostomy
- Urinary diversion
- Ventricular arrhythmias
- Ventricular fibrillation
- Volvulus
- Vomiting
- Von Gierke disease
- Wilson's Disease
- Zalcitabine
- Zidovudine
### Respiratory Acidosis
# Treatment
Treatment of any of the varieties of metabolic acidosis is focused upon correction of the underlying problem. However, neutralizing the acidosis with infusions of bases like sodium bicarbonate may be temporarily helpful in some critical emergencies. | Acidosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Carlos A Lopez, M.D. [2]
# Overview
Acidosis is an acid-base imbalance that is an increased acidity (i.e. an increased hydrogen ion concentration). If not further qualified, it refers to acidity of the blood plasma.
Generally, acidosis is said to occur when arterial pH falls below 7.35, while its counterpart (alkalosis) occurs at a pH over 7.45. Arterial blood gas analysis and other tests are required to separate the main causes.
Strictly speaking, the term acidemia would be more appropriate to describe the state of low blood pH, reserving acidosis to describe the processes leading to these states. Nevertheless, most physicians use the terms interchangeably. The distinction may be relevant where a patient has factors causing both acidosis and alkalosis, where the relative severity of both determines whether the result is a high or a low pH.
The rate of cellular metabolic activity affects and, at the same time, is affected by the pH of the body fluids. In mammals, the normal pH of arterial blood lies between 7.35 and 7.50 depending on the species (e.g. healthy human-arterial blood pH varies between 7.35 and 7.45). Blood pH values compatible with life in mammals are limited to a pH range between 6.8 and 7.8. Changes in the pH of arterial blood (and therefore the extracellular fluid) outside this range result in irreversible cell damage (Needham, 2004).
# Classification
- Acidosis can either be metabolic or respiratory.
Both are caused by low arterial pH.
Metabolic acidosis is due to an increased accumulation of acid equivalents through impairment of the regulatory ability of the liver, kidneys, or metabolism.
Respiratory acidosis is caused by a retention of carbon dioxide due to inadequate hypoventilation or pulmonary ventilation.
- Both are caused by low arterial pH.
- Metabolic acidosis is due to an increased accumulation of acid equivalents through impairment of the regulatory ability of the liver, kidneys, or metabolism.
- Respiratory acidosis is caused by a retention of carbon dioxide due to inadequate hypoventilation or pulmonary ventilation.
# Pathophysiology
## Respiratory acidosis
Respiratory acidosis results from a build-up of carbon dioxide in the blood (hypercapnia) due to hypoventilation. It is most often caused by pulmonary problems, although head injuries, drugs (especially anaesthetics and sedatives), and brain tumors can also bring it on. Emphysema, chronic bronchitis, asthma, severe pneumonia, and aspiration are among the most frequent causes. It can also occur as a response to chronic metabolic alkalosis.
Blood gases show pH below 7.35 as above mentioned, and PaCO2 will be high (>45 mmHg / 6 kPa).
The key to distinguish between respiratory and metabolic acidosis is that in respiratory acidosis, the CO2 is increased while the bicarbonate is either normal (uncompensated) or increased (compensated). Compensation occurs if respiratory acidosis persists for days or longer and a chronic phase is entered with partial buffering of the acidosis through renal bicarbonate retention.
## Metabolic acidosis
Metabolic acidosis may result from disturbances in the ability to excrete acid via the kidneys. Renal acidosis is associated with an accumulation of urea and creatinine as well as metabolic acid residues of protein catabolism.
An increase in the production of metabolic acids may also produce metabolic acidosis. For example, lactic acidosis may occur from 1) severe (PaO2 <36mm Hg) hypoxemia causing a fall in the rate of oxygen diffusion from arterial blood to tissues, or 2) hypoperfusion (e.g. hypovolemic shock) causing an inadequate blood delivery of oxygen to tissues. A rise in lactate out of proportion to the level of pyruvate, e.g. in mixed venous blood, is termed "excess lactate" and is the best indicator of an inadequate flow of oxygen into the body's mitochondria from either cause. Oxygen debt (and muscle excess lactate) is also seen in strenuous exercise. Once oxygenation is restored, the acidosis clears quickly. Another example of increased production of acids occurs in starvation and diabetic acidosis. It is due to the accumulation of ketoacids (ketosis) and reflects a severe shift from glycolysis to lipolysis for fuel needs.
Acidic poisons, iron etc., and decreased production of bicarbonate may also produce metabolic acidosis.
Metabolic acidosis can result in stimulation of chemoreceptors and so increase alveolar ventilation, leading to respiratory compensation, otherwise known as Kussmaul breathing, which is a specific type of hyperventilation. Should this situation persist the patient is at risk for exhaustion leading to respiratory failure.
Mutations to the V-ATPase 'a4' or 'B1' isoforms result in distal renal tubular acidosis—a condition that leads to metabolic acidosis—in some cases with sensorineural deafness.
In blood gas tests, it is characterised by a low pH, low blood HCO3, and normal or low PaCO2.
In addition to arterial blood gas one can use the anion gap to differentiate between possible causes.
The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected.
# Causes
## Common causes of acidosis
- Traumatic shock
- Sepsis
- Severe hypoxemia
- Severe diarrhoea
- Renal failure
- Multiple organ dysfunction syndrome
- Nausea and Vomiting
- Mesenteric insufficiency
- Ketoacidosis
- Ischemic colitis
- Hypotension
- Ethanol ingestion
- Cardiogenic shock
- Alcohol
- Acetylsalicylic acid
## Causes by Organ System
## Causes in Alphabetical Order [1] [2]
- 3-alpha-hydroxyisobutyryl-CoA hydrolase deficiency
- 3-Hydroxyacyl-CoA dehydrogenase II Deficiency
- 3-methylglutaconic aciduria
- Acetazolamide
- Acetylsalicylic acid
- Acute disseminated encephalomyelitis
- acute glomerulonephritis
- Acute liver failure
- Acute renal failure
- Acute respiratory distress syndrome
- Adrenal cortex insufficiency
- Alcohol
- Apnea
- Aspirin
- Beriberi heart disease
- Biguanide
- Biliary fistula
- Biotinidase deficiency
- Carbon monoxide poisoning
- Carbonic anhydrase inhibitors
- Cardiac arrest
- Cardiogenic shock
- Cardiomyopathy
- Cataract and cardiomyopathy
- Cerebral edema
- Cerebral hypoxia
- Cerebral malaria
- Chronic interstitial nephritis
- Chronic kidney disease
- Chronic mesenteric insufficiency
- Chronic obstructive lung disease
- Clostridium difficile
- CNS depression
- Cocaine
- Coenzyme Q cytochrome c reductase deficiency
- Coma
- Complex 1 mitochondrial respiratory chain deficiency
- Congestive heart failure
- Copperhead snake poisoning
- Crotalidae snake poisoning
- Cyanide poisoning
- Cystinosis
- Decreased renal acid excretion
- Diabetes
- Diabetic ketoacidosis
- Diarrhea
- Didanosine
- Diethylene glycol
- Disseminated intravascular coagulation
- Distal renal tubular acidosis
- Drowning
- Endothall
- Epilepsy
- Ethanol
- Ethylene glycol
- Fanconi syndrome
- Fanconi-ichthyosis-dysmorphism
- Fever
- Fistula
- Fructose-16-bisphosphatase deficiency
- Germanium
- Glutaric acidemia type 2
- Glutaric aciduria type 1
- Glyburide
- Glycogen storage diseases
- GRACILE syndrome
- Grand mal seizure
- Hemorrhagic shock
- Hepatic failure
- Hepatopathy
- Hydroxyacyl-coa dehydrogenase deficiency type 2
- Hydroxysteroid dehydrogenase deficiency
- Hypercapnia
- Hyperchloremic acidosis
- Hyperkalemia
- Hyperosmolar non-ketotic diabetic coma
- Hypoaldosteronism
- Hypoglycemia
- Hypokalemic distal renal tubular acidosis
- Hypoperfusion
- Hypothermic shivering
- Ileus
- Inborn urea cycle disorder
- Infant respiratory distress syndrome
- Infection
- Ischemic colitis
- Isopropyl alcohol
- Ketoacidosis
- Kidney disorders
- Leukemia
- Lipoamide dehydrogenase deficiency
- Liver disease
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
- Lymphoma
- Malignant hypertension
- Medium-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
- MELAS
- Metabolic disorders
- Metformin
- Methanol
- Microvillus inclusion disease
- Mitochondrial DNA depletion syndrome
- Mitochondrial encephalomyopathy aminoacidopathy
- Mitochondrial myopathy
- Mitochondrial neurogastrointestinal encephalopathy syndrome
- Multiple carboxylase deficiency
- Myeloma
- Myocardial Infarction
- Myopathy
- NADH CoQ reductase deficiency
- Necrotizing enterocolitis
- Ondine's curse
- Pancreatic fistula
- Paracetamol
- Pergolide
- Permanent neonatal diabetes mellitus
- Phenformin
- Pheochromocytoma
- Propionic acidemia
- Propylene glycol
- Proximal renal tubular acidosis
- Pulmonary edema
- Pulmonary embolism
- Pulseless electrical activity
- Pyruvate carboxylase deficiency
- Pyruvate dehydrogenase phosphatase deficiency
- Renal circulatory insufficiency
- Renal failure
- Renal tubular acidosis
- Salicylate
- Salicylates
- SCHAD deficiency
- Sepsis
- Severe liver disease
- Shock
- Short bowel syndrome
- Sideroblastic anemia
- Small intestine fistula
- ST elevation myocardial infarction
- Starvation
- Status asthmaticus
- Strychnine
- Succinic acidemia
- Thyrotoxicosis
- Toluene
- Torsade de pointes
- Total parenteral nutrition
- Tumor
- Type I glycogen storage disease
- Ureterosigmoidostomy
- Urinary diversion
- Ventricular arrhythmias
- Ventricular fibrillation
- Volvulus
- Vomiting
- Von Gierke disease
- Wilson's Disease
- Zalcitabine
- Zidovudine
### Respiratory Acidosis
# Treatment
Treatment of any of the varieties of metabolic acidosis is focused upon correction of the underlying problem. However, neutralizing the acidosis with infusions of bases like sodium bicarbonate may be temporarily helpful in some critical emergencies. | https://www.wikidoc.org/index.php/Acidemia | |
1ce879af81fb3c614fa254b783739d4bc9a78530 | wikidoc | Aconitum | Aconitum
Aconitum (A-co-ní-tum), known as aconite, monkshood, or wolfsbane, is a genus of flowering plant belonging to the buttercup family (Ranunculaceae). There are over 250 species of Aconitum.
# Overview
These herbaceous perennial plants are chiefly natives of the mountainous parts of the northern hemisphere, growing in moisture retentive but well draining soils on mountain meadows. Their dark green leaves lack stipules. They are palmate or deeply palmately lobed with 5–7 segments. Each segment again is 3-lobed with coarse sharp teeth. The leaves have a spiral or alternate arrangement. The lower leaves have long petioles.
These are handsome plants, the tall, erect stem being crowned by racemes of large and eye-catching blue, purple, white, yellow or pink zygomorphic flowers with numerous stamens. They are distinguishable by having one of the five petaloid sepals (the posterior one), called the galea, in the form of a cylindrical helmet; hence the English name monkshood. There are 2–10 petals, in the form of nectaries. The two upper petals are large. They are placed under the hood of the calyx and are supported on long stalks. They have a hollow spur at their apex, containing the nectar. The other petals are small and scale like or non forming. The 3–5 carpels are partially fused at the base.
The fruit is a follicle.
# Species
## Natural hybrids
- Aconitum × austriacum
- Aconitum × cammarum
- Aconitum × hebegynum
- Aconitum × oenipontanum (A. variegatum ssp. variegatum × ssp. paniculatum)
- Aconitum × pilosiusculum
- Aconitum × platanifolium (A. lycoctonum ssp. neapolitanum × ssp. vulparia)
- Aconitum × zahlbruckneri (A. napellus ssp. vulgare × A. variegatum ssp. variegatum)
# Uses
The most common plant in this genus, Aconitum napellus (the Common Monkshood) was considered to be of therapeutic and toxicological importance. Its roots have occasionally been mistaken for horseradish. It has a short underground stem, from which dark-colored tapering roots descend. The crown or upper portion of the root gives rise to new plants. When touched to one's lip, the juice of the aconite root produces a feeling of numbness and tingling. This plant is used as a food plant by some Lepidoptera species including Dot Moth, The Engrailed, Mouse Moth, Wormwood Pug, and Yellow-tail.
The roots of Aconitum ferox supply the Indian (Nepal) poison called bikh, bish, or nabee. It contains large quantities of the alkaloid pseudaconitine, which is a deadly poison. Aconitum palmatum yields another of the bikh poisons. The root of Aconitum luridum, of the Himalaya, is said to be as virulent as that of A. ferox or A. napellus.
Several species of Aconitum have been used as arrow poisons. The Minaro in Ladakh use A. napellus on their arrows to hunt ibex, while the Ainus in Japan used a species of Aconitum to hunt bear. The Chinese also used Aconitum poisons both for hunting, and for warfare.
Many species of Aconitum are cultivated in gardens, having either blue or yellow flowers. Aconitum lycoctonum (Alpine wolfsbane), is a yellow-flowered species common in the Alps of Switzerland. As garden plants the aconites are very ornamental, hardy perennial plants. They thrive well in any ordinary garden soil, and will grow beneath the shade of trees. They are easily propagated by divisions of the root or by seeds; care should be taken not to leave pieces of the root where livestock might eat them, owing to their poisonous character.
Aconite has been ascribed with supernatural powers relating to werewolves and other lycanthropes, either to repel them, relating to aconite's use in poisoning wolves and other animals, or in some way induce their lycanthropic condition, as aconite was often an important ingredient in witches' magic ointments. In folklore, Aconite was also said to make a person into a werewolf if it is worn, smelled, or eaten. They are also said to kill werewolves if they wear, smell, or eat aconite.
Canadian film actor Andre Noble died of aconitine poisoning on July 30, 2004, after accidentally ingesting it.
Aconite was reportedly found in toxicology samples from the former Pakistan cricket coach Bob Woolmer, but his death was later confirmed of natural causes.
Aconite have also been known under names such as wolfsbane, leopard's bane, women's bane, Devil's helmet or blue rocket.
# Pharmacology of Aconite and Aconitine
Aconite has long been used in the traditional medicine of India and China. In Ayurveda the herb is used to increase pitta and to enhance penetration in small doses. However more frequently the herb is detoxified according to the samskaras process and studies, cited in the detoxification section below show that it no longer possesses active toxicity. It is used in traditional Chinese medicine as a treatment for Yang deficiency, "coldness", general debilitation. The herb is considered hot and toxic. It is prepared in extremely small prepared doses. More frequently ginger processed aconite, of lower toxicity, "fu zi" is used. Aconite is one ingredient of Tribhuvankirti, an Ayurvedic preparation for treating a "cold in the head" and fever. Aconite was mixed with patrinia and coix, in a famous treatment for appendicitis described in a formula from the Jingui Yaolue (ca. 220 A.D.) Aconite was also described in Greek and Roman medicine by Theophrastus, Dioscorides, and Pliny the Elder, who most likely prescribed the Alpine species Aconitum lycoctonum. The herb was cultivated widely in Europe, probably reaching England before the tenth century, where it was farmed with some difficulty, but came to be widely valued as an anodyne, diuretic, and diaphoretic. In the nineteenth century much aconite was imported from China, Japan, Fiji, and Tonga, with a number of species used to manufacture alkaloids of varying potency but generally similar effect, most often used externally and rarely internally. Effects of different preparations were standardized by testing on guinea pigs.
In Western medicine preparations of aconite were used until just after the middle of the 20th century, but it is no longer employed as it has been replaced by safer and more effective drugs and treatments. The 1911 British Pharmaceutical Codex regarded the medical uses and toxicity of aconite root or leaves to be virtually identical to that of purified aconitine. Aconite first stimulates and later paralyses the nerves of pain, touch, and temperature if applied to the skin or to a mucous membrane; the initial tingling therefore gives place to a long-continued anaesthetic action. Great caution was required, as abraded skin could absorb a dangerous dose of the drug, and merely tasting some of the concentrated preparations available could be fatal. The local anaesthesia of peripheral nerves can be attributed to at least eleven alkaloids with varying potency and stability. External uses of aconite included treatment of ordinary facial or trigeminal neuralgia, rheumatism, and dental periostitis.
Internal uses were also pursued, to slow the pulse, as a sedative in pericarditis and heart palpitations, and well diluted as a mild diaphoretic, or to reduce feverishness in treatment of colds, pneumonia, quinsy, laryngitis, croup, and asthma due to exposure. Taken internally, aconite acts very notably on the circulation, the respiration, and the nervous system. The pulse is slowed, the number of beats per minute being actually reduced, under considerable doses, to forty, or even thirty, per minute. The blood-pressure synchronously falls, and the heart is arrested in diastole. Immediately before arrest, the heart may beat much faster than normally, though with extreme irregularity, and in the lower animals the auricles may be observed occasionally to miss a beat, as in poisoning by veratrine and colchicum. The action of aconitine on the circulation is due to an initial stimulation of the cardio-inhibitory centre in the medulla oblongata (at the root of the vagus nerves), and later to a directly toxic influence on the nerve-ganglia and muscular fibres of the heart itself. The fall in blood-pressure is not due to any direct influence on the vessels. The respiration becomes slower owing to a paralytic action on the respiratory centre and, in warm-blooded animals, death is due to this action, the respiration being arrested before the action of the heart. Aconite further depresses the activity of all nerve-terminals, the sensory being affected before the motor. In small doses, it therefore tends to relieve pain, if this be present. The activity of the spinal cord is similarly depressed. The pupil is at first contracted, and afterwards dilated. The cerebrum is totally unaffected by aconite, consciousness and the intelligence remaining normal to the last. The antipyretic action which considerable doses of aconite display is not specific but is the result of its influence on the circulation and respiration and of its slight diaphoretic action.
### Homeopathic therapeutics
Homeopathic preparations of aconite are used for complaints that begin after a fright or sudden shocking events and are used in subtoxic, succussed doses. .
## Toxicology
In a few minutes after the introduction of a poisonous dose of aconite, marked symptoms supervene. The initial signs of poisoning are referable to the alimentary canal. There is a sensation of burning, tingling, and numbness in the mouth, and of burning in the abdomen. Death usually supervenes before a numbing effect on the intestine can be observed. After about an hour, there is severe vomiting. Much motor weakness and cutaneous sensations similar to those above described soon follow. The pulse and respiration steadily fail, death occurring from asphyxia. As in strychnine poisoning, the patient is conscious and clear-minded to the last. The only post-mortem signs are those of asphyxia. The treatment is to empty the stomach by tube or by a non-depressant emetic. The physiological antidotes are atropine and digitalis or strophanthin, which should be injected subcutaneously in maximal doses. Alcohol, strychnine, and warmth must also be employed.
The above description of poisoning is characteristic of an oral administration. It should however be noted that aconitine may be easily absorbed through the skin, and poisoning may occur through this route simply by picking the leaves without the use of gloves; the toxin in the sap is absorbed through the skin. From practical experience, the sap oozing from eleven picked leaves will cause cardiac symptoms for a couple of hours. In this event, there will be no gastrointestinal effects. Tingling will however start at the point of absorption, and extend up the arm to the shoulder, after which the heart will start to be affected. The tingling will be followed by numbness—it is fairly unpleasant. As remarked above, atropine is an antidote. Atropine is a constituent of Belladonna.
Aconitine is a potent neurotoxin that blocks tetrodotoxin-sensitive sodium channels. Pretreatment with barakol—10 mg/kg IV the compound is isolated from the leaves of Cassia siamea Lam—reduces the incidence of aconitine-induced ventricular fibrillation and ventricular tachycardia, as well as mortality. 5 μg/kg IV of tetrodotoxin also had the same effect. The protective effects of barakol are probably due to the prevention of intracellular sodium ion accumulation.
Aconite was reported by the Sunday Mirror to have been used as poison in the murder of Pakistan cricket coach, Bob Woolmer during the 2007 Cricket World Cup. However there is now evidence that Bob Woolmer was not actually murdered.
## Detoxification
There are methods of processing aconite to reduce toxicity in both Chinese medicine and Ayurveda. In Chinese medicine, the traditional pao zhi or preparation of aconite is to steam with ginger in a fairly elaborate procedure. Due to the variable levels of toxicity in any given sample of the dried herb, there are still issues with using it. Most but not all cases of aconite toxicity in Taiwan were due to the consumption of unprocessed aconite.
According to an article by the Indian scientists Thorat and Dahanukar, "Crude aconite is an extremely lethal substance. However, the science of Ayurveda looks upon aconite as a therapeutic entity. Crude aconite is always processed i.e. it undergoes 'samskaras' before being utilized in the Ayurvedic formulations. This study was undertaken in mice, to ascertain whether 'processed' aconite is less toxic as compared to the crude or unprocessed one. It was seen that crude aconite was significantly toxic to mice (100% mortality at a dose of 2.6 mg/mouse) whereas the fully processed aconite was absolutely non-toxic (no mortality at a dose even 8 times as high as that of crude aconite). Further, all the steps in the processing were essential for complete detoxification"
# Aconitum in literature
Aconitum features in literature in a number of instances:
- In Greek mythology, Medea attempted to poison Theseus with a cup of wine poisoned with wolfsbane. However Aegeus his father interceded when he discerned his identity.
- John Keats, in his Ode on Melancholy, writes:
No, no, go not to Lethe, neither twist
Wolf's bane, tight-rooted, for its poisonous wine
Nor suffer thy pale forehead to be kissed
By nightshade, ruby grape of Proserpine…
- Wolfsbane has often been associated with the werewolf legend, although its uses vary from bringing on lycanthropy to banishing it.
- Aconitum plays a major role in the story "The cardinal Napellus" by Gustav Meyrink. It is identified with religious beliefs and connected to the idea of fate.
- Wolfsbane is mentioned in one of the verses of the Wiccan Rede:
Widdershins go when the Moon doth wane, An’ the Werewolf howls by the dread Wolfsbane.
- A gypsy poem was written for the Lon Chaney, Jr. series of werewolf movies; it has been quoted in other werewolf movies as well:
Even those who are pure of heart,
and say their prayers at night,
can become a wolf, when the wolfsbane blooms
and the autumn moon is bright.
- In the third book of the Brother Cadfael series, "Monk's Hood," the herbalist Cadfael uses aconite as an ingredient in a liniment, which is later stolen and used to poison a victim.
- Wolfsbane in the Harry Potter series is a toxic plant that can be used as an ingredient in the Wolfsbane Potion.
- An overdose of aconite was the method in which Rudolph Bloom, father of Leopold Bloom in James Joyce's Ulysses, committed suicide.
Rudolph Bloom died... in consequence of an overdose of monkshood (aconite) selfadministered in the form of a neuralgic liniment...
- Aconite poisoning is used as a means of disposal in the Alistair Maclean novel 'Bear Island'
- In Brian Jacques's Redwall book Outcast of Redwall, Veil the ferret uses wolfsbane to poison one of the residents of Redwall Abbey.
# Trivia
- In the 1931 film Dracula, Wolfsbane is used to keep Dracula out of households.
- It is mentioned in Chapter 8 of Harry Potter and the Sorcerer's Stone and the movie adaptation.
- It plays a big role in Ginger Snaps (film).
# Gallery
- Unidentified Aconitum (possibly Aconitum carmichaelii)
Unidentified Aconitum (possibly Aconitum carmichaelii)
- Trailing White Monkshood (Aconitum reclinatum)
Trailing White Monkshood (Aconitum reclinatum)
- Southern Blue Monkshood (Aconitum uncinatum)
Southern Blue Monkshood (Aconitum uncinatum)
# Notes
- ↑ Peissel, Michel. 1984. The Ants’ Gold. The Discovery of the Greek El Dorado in the Himalayas. London, Harvill Press, pp. 99-100.
- ↑ Sung, Ying-hsing. T’ien kung k’ai wu. Sung Ying-hsing. 1637. Published as Chinese Technology in the seventeenth century. Translated and annotated by E-tu Zen Sun and Shiou-chuan Sun. 1996. Mineola. New York. Dover Publications, p. 267.
- ↑ Chavannes, Édouard. “Trois Généraux Chinois de la dynastie des Han Orientaux. Pan Tch’ao (32-102 p.C.); – son fils Pan Yong; – Leang K’in (112 p.C.). Chapitre LXXVII du Heou Han chou.”. 1906. T’oung pao 7, pp. 226-227.
- ↑ Thatte UM, Rege NN, Phatak SD, Dahanukar SA (1993). "The flip side of Ayurveda". Journal of postgraduate medicine. 39 (4): 179–82.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}
- ↑ "VALERIAN AND NARDOSTACHYS".
- ↑ "A Modern Herbal".
- ↑ John M. Maisch, M.D. (1881). "Gleanings in Materia Medica". 53.
- ↑ "The British Pharmaceutical Codex". 1911.
- ↑ Bello-Ramírez AM, Nava-Ocampo AA (2004-04). "The local anesthetic activity of Aconitum alkaloids can be explained by their structural properties: a QSAR analysis". Fundam Clin Pharmacol. 18 (2): 157–61. PMID 15066129. Check date values in: |date= (help)
- ↑ Morrsion, MD, Roger (1993). Desktop guide to keynotes and comfirmatory symptoms. Grass Valley, CA: Hahnemann Clinic Publishing. pp. 3–6. ISBN 0-9635368-0-X.
- ↑ Tilotson, Alan,Safety and Regulation
- ↑ Chinese Herbal Medicine: Materia Medica, Third Edition by Dan Bensky, Steven Clavey, Erich Stoger, and Andrew Gamble (Hardcover - Sep 2004)
- ↑ Thorat S,Dahanukar S. Can We Dispense With Ayurvedic Samskaras? J Postgrad Med. 1991 Jul;37(3):157-9., 1991)
- ↑ Graves, R (1955). "Theseus and Medea". Greek Myths. London: Penguin. pp. 332–336. ISBN 0-14-001026-2.
# References and external links
- Template:1911
- James Grout: Aconite Poisoning, part of the Encyclopædia Romana
- Photographs of Aconite plants
de:Eisenhut
eo:Akonito
fa:تاجالملوک (گیاه)
lt:Kurpelė
nl:Monnikskap
sq:Aconitum
sv:Stormhattar
ur:ایکونائٹ | Aconitum
Template:Otheruses4
Aconitum (A-co-ní-tum), known as aconite, monkshood, or wolfsbane, is a genus of flowering plant belonging to the buttercup family (Ranunculaceae). There are over 250 species of Aconitum.
# Overview
These herbaceous perennial plants are chiefly natives of the mountainous parts of the northern hemisphere, growing in moisture retentive but well draining soils on mountain meadows. Their dark green leaves lack stipules. They are palmate or deeply palmately lobed with 5–7 segments. Each segment again is 3-lobed with coarse sharp teeth. The leaves have a spiral or alternate arrangement. The lower leaves have long petioles.
These are handsome plants, the tall, erect stem being crowned by racemes of large and eye-catching blue, purple, white, yellow or pink zygomorphic flowers with numerous stamens. They are distinguishable by having one of the five petaloid sepals (the posterior one), called the galea, in the form of a cylindrical helmet; hence the English name monkshood. There are 2–10 petals, in the form of nectaries. The two upper petals are large. They are placed under the hood of the calyx and are supported on long stalks. They have a hollow spur at their apex, containing the nectar. The other petals are small and scale like or non forming. The 3–5 carpels are partially fused at the base.
The fruit is a follicle.
# Species
## Natural hybrids
- Aconitum × austriacum
- Aconitum × cammarum
- Aconitum × hebegynum
- Aconitum × oenipontanum (A. variegatum ssp. variegatum × ssp. paniculatum)
- Aconitum × pilosiusculum
- Aconitum × platanifolium (A. lycoctonum ssp. neapolitanum × ssp. vulparia)
- Aconitum × zahlbruckneri (A. napellus ssp. vulgare × A. variegatum ssp. variegatum)
# Uses
The most common plant in this genus, Aconitum napellus (the Common Monkshood) was considered to be of therapeutic and toxicological importance. Its roots have occasionally been mistaken for horseradish. It has a short underground stem, from which dark-colored tapering roots descend. The crown or upper portion of the root gives rise to new plants. When touched to one's lip, the juice of the aconite root produces a feeling of numbness and tingling. This plant is used as a food plant by some Lepidoptera species including Dot Moth, The Engrailed, Mouse Moth, Wormwood Pug, and Yellow-tail.
The roots of Aconitum ferox supply the Indian (Nepal) poison called bikh, bish, or nabee. It contains large quantities of the alkaloid pseudaconitine, which is a deadly poison. Aconitum palmatum yields another of the bikh poisons. The root of Aconitum luridum, of the Himalaya, is said to be as virulent as that of A. ferox or A. napellus.
Several species of Aconitum have been used as arrow poisons. The Minaro in Ladakh use A. napellus on their arrows to hunt ibex, while the Ainus in Japan used a species of Aconitum to hunt bear.[1] The Chinese also used Aconitum poisons both for hunting,[2] and for warfare.[3]
Many species of Aconitum are cultivated in gardens, having either blue or yellow flowers. Aconitum lycoctonum (Alpine wolfsbane), is a yellow-flowered species common in the Alps of Switzerland. As garden plants the aconites are very ornamental, hardy perennial plants. They thrive well in any ordinary garden soil, and will grow beneath the shade of trees. They are easily propagated by divisions of the root or by seeds; care should be taken not to leave pieces of the root where livestock might eat them, owing to their poisonous character.
Aconite has been ascribed with supernatural powers relating to werewolves and other lycanthropes, either to repel them, relating to aconite's use in poisoning wolves and other animals, or in some way induce their lycanthropic condition, as aconite was often an important ingredient in witches' magic ointments. In folklore, Aconite was also said to make a person into a werewolf if it is worn, smelled, or eaten. They are also said to kill werewolves if they wear, smell, or eat aconite.
Canadian film actor Andre Noble died of aconitine poisoning on July 30, 2004, after accidentally ingesting it.
Aconite was reportedly found in toxicology samples from the former Pakistan cricket coach Bob Woolmer, but his death was later confirmed of natural causes[4].
Aconite have also been known under names such as wolfsbane, leopard's bane, women's bane, Devil's helmet or blue rocket.[5]
# Pharmacology of Aconite and Aconitine
Aconite has long been used in the traditional medicine of India and China. In Ayurveda the herb is used to increase pitta and to enhance penetration in small doses. However more frequently the herb is detoxified according to the samskaras process and studies, cited in the detoxification section below show that it no longer possesses active toxicity. It is used in traditional Chinese medicine as a treatment for Yang deficiency, "coldness", general debilitation. The herb is considered hot and toxic. It is prepared in extremely small prepared doses. More frequently ginger processed aconite, of lower toxicity, "fu zi" is used. Aconite is one ingredient of Tribhuvankirti, an Ayurvedic preparation for treating a "cold in the head" and fever.[6] Aconite was mixed with patrinia and coix, in a famous treatment for appendicitis described in a formula from the Jingui Yaolue (ca. 220 A.D.)[7] Aconite was also described in Greek and Roman medicine by Theophrastus, Dioscorides, and Pliny the Elder, who most likely prescribed the Alpine species Aconitum lycoctonum. The herb was cultivated widely in Europe, probably reaching England before the tenth century, where it was farmed with some difficulty, but came to be widely valued as an anodyne, diuretic, and diaphoretic.[8] In the nineteenth century much aconite was imported from China, Japan, Fiji, and Tonga, with a number of species used to manufacture alkaloids of varying potency but generally similar effect, most often used externally and rarely internally. Effects of different preparations were standardized by testing on guinea pigs.[9]
In Western medicine preparations of aconite were used until just after the middle of the 20th century, but it is no longer employed as it has been replaced by safer and more effective drugs and treatments. The 1911 British Pharmaceutical Codex regarded the medical uses and toxicity of aconite root or leaves to be virtually identical to that of purified aconitine.[10] Aconite first stimulates and later paralyses the nerves of pain, touch, and temperature if applied to the skin or to a mucous membrane; the initial tingling therefore gives place to a long-continued anaesthetic action. Great caution was required, as abraded skin could absorb a dangerous dose of the drug, and merely tasting some of the concentrated preparations available could be fatal. The local anaesthesia of peripheral nerves can be attributed to at least eleven alkaloids with varying potency and stability.[11] External uses of aconite included treatment of ordinary facial or trigeminal neuralgia, rheumatism, and dental periostitis.
Internal uses were also pursued, to slow the pulse, as a sedative in pericarditis and heart palpitations, and well diluted as a mild diaphoretic, or to reduce feverishness in treatment of colds, pneumonia, quinsy, laryngitis, croup, and asthma due to exposure. Taken internally, aconite acts very notably on the circulation, the respiration, and the nervous system. The pulse is slowed, the number of beats per minute being actually reduced, under considerable doses, to forty, or even thirty, per minute. The blood-pressure synchronously falls, and the heart is arrested in diastole. Immediately before arrest, the heart may beat much faster than normally, though with extreme irregularity, and in the lower animals the auricles may be observed occasionally to miss a beat, as in poisoning by veratrine and colchicum. The action of aconitine on the circulation is due to an initial stimulation of the cardio-inhibitory centre in the medulla oblongata (at the root of the vagus nerves), and later to a directly toxic influence on the nerve-ganglia and muscular fibres of the heart itself. The fall in blood-pressure is not due to any direct influence on the vessels. The respiration becomes slower owing to a paralytic action on the respiratory centre and, in warm-blooded animals, death is due to this action, the respiration being arrested before the action of the heart. Aconite further depresses the activity of all nerve-terminals, the sensory being affected before the motor. In small doses, it therefore tends to relieve pain, if this be present. The activity of the spinal cord is similarly depressed. The pupil is at first contracted, and afterwards dilated. The cerebrum is totally unaffected by aconite, consciousness and the intelligence remaining normal to the last. The antipyretic action which considerable doses of aconite display is not specific but is the result of its influence on the circulation and respiration and of its slight diaphoretic action.
### Homeopathic therapeutics
Homeopathic preparations of aconite are used for complaints that begin after a fright or sudden shocking events and are used in subtoxic, succussed doses. [12].
## Toxicology
In a few minutes after the introduction of a poisonous dose of aconite, marked symptoms supervene. The initial signs of poisoning are referable to the alimentary canal. There is a sensation of burning, tingling, and numbness in the mouth, and of burning in the abdomen. Death usually supervenes before a numbing effect on the intestine can be observed. After about an hour, there is severe vomiting. Much motor weakness and cutaneous sensations similar to those above described soon follow. The pulse and respiration steadily fail, death occurring from asphyxia. As in strychnine poisoning, the patient is conscious and clear-minded to the last. The only post-mortem signs are those of asphyxia. The treatment is to empty the stomach by tube or by a non-depressant emetic. The physiological antidotes are atropine and digitalis or strophanthin, which should be injected subcutaneously in maximal doses. Alcohol, strychnine, and warmth must also be employed.
The above description of poisoning is characteristic of an oral administration. It should however be noted that aconitine may be easily absorbed through the skin, and poisoning may occur through this route simply by picking the leaves without the use of gloves; the toxin in the sap is absorbed through the skin. From practical experience, the sap oozing from eleven picked leaves will cause cardiac symptoms for a couple of hours. In this event, there will be no gastrointestinal effects. Tingling will however start at the point of absorption, and extend up the arm to the shoulder, after which the heart will start to be affected. The tingling will be followed by numbness—it is fairly unpleasant. As remarked above, atropine is an antidote. Atropine is a constituent of Belladonna.
Aconitine is a potent neurotoxin that blocks tetrodotoxin-sensitive sodium channels. Pretreatment with barakol—10 mg/kg IV the compound is isolated from the leaves of Cassia siamea Lam—reduces the incidence of aconitine-induced ventricular fibrillation and ventricular tachycardia, as well as mortality. 5 μg/kg IV of tetrodotoxin also had the same effect. The protective effects of barakol are probably due to the prevention of intracellular sodium ion accumulation.
Aconite was reported by the Sunday Mirror to have been used as poison in the murder of Pakistan cricket coach, Bob Woolmer during the 2007 Cricket World Cup. However there is now evidence that Bob Woolmer was not actually murdered.[13]
## Detoxification
There are methods of processing aconite to reduce toxicity in both Chinese medicine and Ayurveda. In Chinese medicine, the traditional pao zhi or preparation of aconite is to steam with ginger in a fairly elaborate procedure. Due to the variable levels of toxicity in any given sample of the dried herb, there are still issues with using it. Most but not all cases of aconite toxicity in Taiwan were due to the consumption of unprocessed aconite.[14][15]
According to an article by the Indian scientists Thorat and Dahanukar, "Crude aconite is an extremely lethal substance. However, the science of Ayurveda looks upon aconite as a therapeutic entity. Crude aconite is always processed i.e. it undergoes 'samskaras' before being utilized in the Ayurvedic formulations. This study was undertaken in mice, to ascertain whether 'processed' aconite is less toxic as compared to the crude or unprocessed one. It was seen that crude aconite was significantly toxic to mice (100% mortality at a dose of 2.6 mg/mouse) whereas the fully processed aconite was absolutely non-toxic (no mortality at a dose even 8 times as high as that of crude aconite). Further, all the steps in the processing were essential for complete detoxification" [16]
# Aconitum in literature
Aconitum features in literature in a number of instances:
- In Greek mythology, Medea attempted to poison Theseus with a cup of wine poisoned with wolfsbane. However Aegeus his father interceded when he discerned his identity.[17]
- John Keats, in his Ode on Melancholy, writes:
No, no, go not to Lethe, neither twist
Wolf's bane, tight-rooted, for its poisonous wine
Nor suffer thy pale forehead to be kissed
By nightshade, ruby grape of Proserpine…
- Wolfsbane has often been associated with the werewolf legend, although its uses vary from bringing on lycanthropy to banishing it.
- Aconitum plays a major role in the story "The cardinal Napellus" by Gustav Meyrink. It is identified with religious beliefs and connected to the idea of fate.
- Wolfsbane is mentioned in one of the verses of the Wiccan Rede:
Widdershins go when the Moon doth wane, An’ the Werewolf howls by the dread Wolfsbane.
- A gypsy poem was written for the Lon Chaney, Jr. series of werewolf movies; it has been quoted in other werewolf movies as well:
Even those who are pure of heart,
and say their prayers at night,
can become a wolf, when the wolfsbane blooms
and the autumn moon is bright.
- In the third book of the Brother Cadfael series, "Monk's Hood," the herbalist Cadfael uses aconite as an ingredient in a liniment, which is later stolen and used to poison a victim.
- Wolfsbane in the Harry Potter series is a toxic plant that can be used as an ingredient in the Wolfsbane Potion.
- An overdose of aconite was the method in which Rudolph Bloom, father of Leopold Bloom in James Joyce's Ulysses, committed suicide.
Rudolph Bloom died... in consequence of an overdose of monkshood (aconite) selfadministered in the form of a neuralgic liniment...
- Aconite poisoning is used as a means of disposal in the Alistair Maclean novel 'Bear Island'
- In Brian Jacques's Redwall book Outcast of Redwall, Veil the ferret uses wolfsbane to poison one of the residents of Redwall Abbey.
# Trivia
Template:Trivia
- In the 1931 film Dracula, Wolfsbane is used to keep Dracula out of households.
- It is mentioned in Chapter 8 of Harry Potter and the Sorcerer's Stone and the movie adaptation.
- It plays a big role in Ginger Snaps (film).
# Gallery
- Unidentified Aconitum (possibly Aconitum carmichaelii)
Unidentified Aconitum (possibly Aconitum carmichaelii)
- Trailing White Monkshood (Aconitum reclinatum)
Trailing White Monkshood (Aconitum reclinatum)
- Southern Blue Monkshood (Aconitum uncinatum)
Southern Blue Monkshood (Aconitum uncinatum)
# Notes
- ↑ Peissel, Michel. 1984. The Ants’ Gold. The Discovery of the Greek El Dorado in the Himalayas. London, Harvill Press, pp. 99-100.
- ↑ Sung, Ying-hsing. T’ien kung k’ai wu. Sung Ying-hsing. 1637. Published as Chinese Technology in the seventeenth century. Translated and annotated by E-tu Zen Sun and Shiou-chuan Sun. 1996. Mineola. New York. Dover Publications, p. 267.
- ↑ Chavannes, Édouard. “Trois Généraux Chinois de la dynastie des Han Orientaux. Pan Tch’ao (32-102 p.C.); – son fils Pan Yong; – Leang K’in (112 p.C.). Chapitre LXXVII du Heou Han chou.”. 1906. T’oung pao 7, pp. 226-227.
- ↑ [1]
- ↑ [2]
- ↑ Thatte UM, Rege NN, Phatak SD, Dahanukar SA (1993). "The flip side of Ayurveda". Journal of postgraduate medicine. 39 (4): 179–82.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}
- ↑ "VALERIAN AND NARDOSTACHYS".
- ↑ "A Modern Herbal".
- ↑ John M. Maisch, M.D. (1881). "Gleanings in Materia Medica". 53.
- ↑ "The British Pharmaceutical Codex". 1911.
- ↑ Bello-Ramírez AM, Nava-Ocampo AA (2004-04). "The local anesthetic activity of Aconitum alkaloids can be explained by their structural properties: a QSAR analysis". Fundam Clin Pharmacol. 18 (2): 157–61. PMID 15066129. Check date values in: |date= (help)
- ↑ Morrsion, MD, Roger (1993). Desktop guide to keynotes and comfirmatory symptoms. Grass Valley, CA: Hahnemann Clinic Publishing. pp. 3–6. ISBN 0-9635368-0-X.
- ↑ [3]
- ↑ [4] Tilotson, Alan,Safety and Regulation
- ↑ Chinese Herbal Medicine: Materia Medica, Third Edition by Dan Bensky, Steven Clavey, Erich Stoger, and Andrew Gamble (Hardcover - Sep 2004)
- ↑ Thorat S,Dahanukar S. Can We Dispense With Ayurvedic Samskaras? J Postgrad Med. 1991 Jul;37(3):157-9., 1991)
- ↑ Graves, R (1955). "Theseus and Medea". Greek Myths. London: Penguin. pp. 332–336. ISBN 0-14-001026-2.
# References and external links
Template:Wikispecies
- Template:1911
- James Grout: Aconite Poisoning, part of the Encyclopædia Romana
- Photographs of Aconite plants
de:Eisenhut
eo:Akonito
fa:تاجالملوک (گیاه)
lt:Kurpelė
nl:Monnikskap
sq:Aconitum
sv:Stormhattar
ur:ایکونائٹ | https://www.wikidoc.org/index.php/Aconite | |
9438247a388d0fb28f18f9d88afe8cb21e8274ef | wikidoc | Acrolein | Acrolein
# Overview
In organic chemistry, the compound CH2=CH-CHO, more often called acrolein than the IUPAC name 2-propenal, is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity. It has a piercing, disagreeable, acrid smell similar to that of burning fat.
# Synthesis
Acrolein is prepared industrially by oxidation of propene. Efforts are underway to use propane as feedstock for the synthesis, however, this is more difficult.
Several million tonnes of acrolein are produced each year.
When glycerol is heated to 280 °C, it decomposes into acrolein.
Acrolein may also be produced on lab scale by the reaction of approximately 1 part sodium bisulfate on 3 parts glycerine by weight.
# Uses
Acrolein is used in the preparation of polyester resin, polyurethane, propylene glycol, acrylic acid, acrylonitrile, and glycerol.
Acrolein tends to polymerize when left at room temperature, leaving a gummy yellowish residue with a putrid odor. It is also thought to be an intermediate in the Skraup synthesis of quinolines, but is rarely used as such due to its instability.
# Health risks
Acrolein is a severe pulmonary irritant and lacrimating agent. It has been used as a chemical weapon during World War I. It is, however, not outlawed by the Chemical Weapons Convention.
Acrolein is also a metabolite of the chemotherapy drug cyclophosphamide, and is associated with hemorrhagic cystitis.
Skin exposure to acrolein causes serious damage. Acrolein concentrations of 2 ppm are immediately harmful.
Acrolein is a suspected human carcinogen.
In October 2006, researchers found connections between acrolein in the smoke from tobacco cigarettes and the risk of lung cancer.
# Acrolein test
Acrolein test is a test for the presence of glycerin or fats. A sample is heated with potassium bisulfate, and acrolein is released if the test is positive. When a fat is heated strongly in the presence of a dehydrating agent such as KHSO4, the glycerol portion of the molecule is dehydrated to form the unsaturated aldehyde, acrolein (CH2=CH-CHO), which has the peculiar odor of burnt grease. | Acrolein
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In organic chemistry, the compound CH2=CH-CHO, more often called acrolein than the IUPAC name 2-propenal, is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity. It has a piercing, disagreeable, acrid smell similar to that of burning fat.
# Synthesis
Acrolein is prepared industrially by oxidation of propene. Efforts are underway to use propane as feedstock for the synthesis, however, this is more difficult.[1]
Several million tonnes of acrolein are produced each year.
When glycerol is heated to 280 °C, it decomposes into acrolein.[2]
Acrolein may also be produced on lab scale by the reaction of approximately 1 part sodium bisulfate on 3 parts glycerine by weight.
# Uses
Acrolein is used in the preparation of polyester resin, polyurethane, propylene glycol, acrylic acid, acrylonitrile, and glycerol.
Acrolein tends to polymerize when left at room temperature, leaving a gummy yellowish residue with a putrid odor. It is also thought to be an intermediate in the Skraup synthesis of quinolines, but is rarely used as such due to its instability.
# Health risks
Acrolein is a severe pulmonary irritant and lacrimating agent. It has been used as a chemical weapon during World War I. It is, however, not outlawed by the Chemical Weapons Convention.
Acrolein is also a metabolite of the chemotherapy drug cyclophosphamide, and is associated with hemorrhagic cystitis.
Skin exposure to acrolein causes serious damage. Acrolein concentrations of 2 ppm are immediately harmful.
Acrolein is a suspected human carcinogen.[3]
[4] In October 2006, researchers found connections between acrolein in the smoke from tobacco cigarettes and the risk of lung cancer.[5]
# Acrolein test
Acrolein test is a test for the presence of glycerin or fats. A sample is heated with potassium bisulfate, and acrolein is released if the test is positive.[6] When a fat is heated strongly in the presence of a dehydrating agent such as KHSO4, the glycerol portion of the molecule is dehydrated to form the unsaturated aldehyde, acrolein (CH2=CH-CHO), which has the peculiar odor of burnt grease. | https://www.wikidoc.org/index.php/Acrolein | |
90a069dbf06f2068fdc2de6be8d99ea44c50ef14 | wikidoc | Charcoal | Charcoal
# Overview
Charcoal is the blackish residue consisting of impure carbon obtained by removing water and other volatile constituents from animal and vegetation substances. Charcoal is usually produced by heating wood, sugar, bone char, or others substances in the absence of oxygen (see char). The soft, brittle, lightweight, black, porous material resembles coal and is 85% to 98% carbon with the remainder consisting of volatile chemicals and ash.
The first part of the word is of obscure origin, but the first use of the term "coal" in English was as a reference to charcoal. In this compound term, the prefix "chare-" meant "turn," with the literal meaning being "to turn to coal." The independent use of "char," meaning to scorch, to reduce to carbon, is comparatively recent and must be a back-formation from the earlier charcoal. It may be a use of the word charren or churn, meaning to turn, i.e. wood changed or turned to coal, or it may be from the French charbon. A person who manufactured charcoal was formerly known as a collier (also as a wood collier). The word "collier" was also used for those who mined or dealt in coal, and for the ships that transported it.
# History
Historically, production of wood charcoal in districts where there is an abundance of wood dates back to a very remote period, and generally consists of piling billets of wood on their ends so as to form a conical pile, openings being left at the bottom to admit air, with a central shaft to serve as a flue. The whole pile is covered with turf or moistened clay. The firing is begun at the bottom of the flue, and gradually spreads outwards and upwards. The success of the operation depends upon the rate of the combustion. Under average conditions, 100 parts of wood yield about 60 parts by volume, or 25 parts by weight, of charcoal; small scale production on the spot often yields only about 50%, large scale was efficient to about 90% even by the 17th century. The operation is so delicate that it was generally left to professional charcoal burners. These often worked in solitary groups in the woods and had a rather bad social reputation, especially traveling ones who often sold a sack (priced at about a day's wage) with lots of rubbish mixed in to farmers and townsfolk.
The massive production of charcoal (at its height employing hundreds of thousands, mainly in Alpine and neighbouring forests) was a major cause of deforestation, especially in Central Europe. In England, many woods were managed as coppices, which were cut and regrew cyclically, so that a steady supply of charcoal would be available (in principle) forever; complaints (as early as in Stuart England) about shortages may relate to the results of temporary over-exploitation or the impossibility of increasing production. The increasing scarcity of easily harvested wood was a major factor for the switch to the fossil fuel equivalents, mainly coal and brown coal for industrial use.
The modern process of carbonizing wood, either in small pieces or as sawdust in cast iron retorts, is extensively practiced where wood is scarce, and also for the recovery of valuable byproducts (wood spirit, pyroligneous acid, wood tar), which the process permits. The question of the temperature of the carbonization is important; according to J. Percy, wood becomes brown at 220 °C, a deep brown-black after some time at 280°, and an easily powdered mass at 310°. Charcoal made at 300° is brown, soft and friable, and readily inflames at 380°; made at higher temperatures it is hard and brittle, and does not fire until heated to about 700°.
In Finland and Scandinavia, the charcoal was considered the by-product of wood tar production. The best tar came from pine, thus pinewoods were cut down for tar pyrolysis. The residual charcoal was widely used as substitute for metallurgical coke on blast furnaces for smelting. Tar production led to rapid deforestation: it has been estimated all Finnish forests are younger than 300 years by their age. The end of tar production in the end of the 19th century meant also rapid re-forestation.
The charcoal briquette, first invented by Henry Ford, was first made using wood and sawdust scraps from his automotive assembly plant.
# Types of charcoal
Commercial charcoal is found in either lump, briquette or extruded forms:
- Lump charcoal is made directly from hardwood material and usually produces far less ash than briquettes.
- Briquettes are made by compressing charcoal, typically made from sawdust and other wood by-products, with a binder and other additives. The binder is usually starch. Some briquettes may also include brown coal (heat source), mineral carbon (heat source), borax, sodium nitrate (ignition aid), limestone (ash-whitening agent), raw sawdust (ignition aid) and other additives like paraffin or petroleum solvents to aid in ignition.
- Extruded charcoal is made by extruding either raw ground wood or carbonized wood into logs without the use of a binder. The heat and pressure of the extruding process hold the charcoal together. If the extrusion is made from raw wood material, the extruded logs are then subsequently carbonized.
The characteristics of charcoal products (lump, briquette or extruded forms) vary widely from product to product. Thus it is a common misconception to stereotype any kind of charcoal, saying which burns hotter, etc.
Charcoal is sometimes used to power commercial road vehicles, usually buses - in countries where oil is scarce or completely unavailable. In the years immediately after the second world war, charcoal buses were in regular use in Japan and are still used today in North Korea.
# Uses
One of the most important historical applications of wood charcoal was as a constituent of gunpowder. It was also used in metallurgical operations as a reducing agent, but its application has been diminished by the introduction of coke, anthracite smalls, etc. A limited quantity is made up into the form of drawing crayons; but the greatest amount is used as a fuel, which burns hotter and cleaner than wood. Charcoal is often used by blacksmiths, for cooking, and for other industrial applications.
## Cooking fuel
Charcoal briquettes are widely used for outdoor grilling and barbeques in backyards and on camping trips. Charcoal cannot be burned indoors without an adequate ventilation system, because poisonous carbon monoxide (CO) is a combustion product.
## Industrial fuel
Historically, charcoal was used in great quantities for smelting iron in bloomeries and later blast furnaces and finery forges. This was replaced for this by coke during the Industrial Revolution. For this purpose, charcoal in England was measured in dozens (or loads) consisting of 12 sacks or shems or seams, each of 8 bushels.
## Automotive fuel
In times of scarce petroleum, automobiles and even buses have been converted to burn carbon monoxide released by burning charcoal. In occupied France during World War II, wood and wood charcoal production for such vehicles (called gazogènes) increased from pre-war figures of approximately fifty thousand tons a year to almost half a million tons in 1943.
## Purification/Filtration
The porosity of activated charcoal accounts for its ability to readily adsorb gases and liquids; charcoal is often used to filter water or adsorb odors. Its pharmacological action depends on the same property; it adsorbs the gases of the stomach and intestines, and also liquids and solids (hence its use in the treatment of certain poisonings). Charcoal filters are used in some types of gas mask to remove poisonous gases from inhaled air. Wood charcoal also to some extent removes coloring material from solutions, but animal charcoal is generally more effective.
Animal charcoal or bone black is the carbonaceous residue obtained by the dry distillation of bones; it contains only about 10% carbon, the remainder being calcium and magnesium phosphates (80%) and other inorganic material originally present in the bones. It is generally manufactured from the residues obtained in the glue and gelatin industries. Its decolorizing power was applied in 1812 by Derosne to the clarification of the syrups obtained in sugar refining; but its use in this direction has now greatly diminished, owing to the introduction of more active and easily managed reagents. It is still used to some extent in laboratory practice. The decolorizing power is not permanent, becoming lost after using for some time; it may be revived, however, by washing and reheating. Normal recommendation is to leave the charcoal under the sun for few hours every month.
## Art
Charcoal is used in art for drawing, making rough sketches in painting, and is one of the possible media for making a parsemage. It must usually be preserved by the application of a fixative. Artists generally utilize charcoal in three forms:
- Vine charcoal is created by burning sticks of wood (usually willow or linden/Tilia) into soft, medium, and hard consistencies. Bamboo charcoal is the principal tool in Japanese Sumi-e (炭絵 lit: charcoal drawing) art.
- Compressed charcoal charcoal powder mixed with gum binder compressed into round or square sticks. The amount of binder determines the hardness of the stick. Compressed charcoal is used in charcoal pencils.
- Powdered charcoal is often used to "tone" or cover large sections of a drawing surface. Drawing over the toned areas will darken it further, but the artist can also lighten (or completely erase) within the toned area to create lighter tones.
## Horticulture
One additional use of charcoal rediscovered recently is in horticulture. Although American gardeners have been using charcoal for a short while, research on Terra preta soils in the Amazon has found the widespread use of biochar by pre-Columbian natives to turn otherwise unproductive soil into very rich soil. The technique may find modern application, both to improve soils and as a means of carbon sequestration.
# Sources, references and external links
- Bamboo Charcoal - Bamboo Charcoal Home Air Purifiers and Water Purifiers
- Ignite Products - New generation charcoal products.
- Barbecue Charcoal - The available choices for the backyard barbecue
- Natural History of Europe - 2005 TV co-production including BBC and ZDF
- On Charcoal
- The Valley - BBC TV - one year of life on a 17th century farm reenacted by archaeologists and historians
- The Lump Charcoal Database - Information about lump charcoal.
- H E Z Organisation - Information about charcoal in Germany.
- - Information about charcoal.
- Photo of traditional charcoal production A forest kiln
- - Charcoal making community for livelihood
- - Traditional charcoal production method, India
- The River Wey and Wey Navigations Community Site — a non-commercial site of over 200,000 words all about the Wey Valley and includes a photo file on charcoal production and information relating to gunpowder manufacture at Chilworth.
- Catoctin Mountain Park, Maryland, USA, includes interpretive features ("Charcoal Trail", etc) on the history of charcoal making in the area.
- Bamboo Charcoal - Properties and Facts
- Coconut Charcoal - Facts
- Simple Home Charcoal Process
- Discovery of new charcoal production process and ARTI, Appropriate Rural Technologies Institute - Making powdered charcoal directly from sugar cane leaves and trash
- The "Adam-retort", or ICPS (Improved Charcoal Production System) | Charcoal
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Charcoal is the blackish residue consisting of impure carbon obtained by removing water and other volatile constituents from animal and vegetation substances. Charcoal is usually produced by heating wood, sugar, bone char, or others substances in the absence of oxygen (see char). The soft, brittle, lightweight, black, porous material resembles coal and is 85% to 98% carbon with the remainder consisting of volatile chemicals and ash.
The first part of the word is of obscure origin, but the first use of the term "coal" in English was as a reference to charcoal. In this compound term, the prefix "chare-" meant "turn," with the literal meaning being "to turn to coal." The independent use of "char," meaning to scorch, to reduce to carbon, is comparatively recent and must be a back-formation from the earlier charcoal. It may be a use of the word charren or churn, meaning to turn, i.e. wood changed or turned to coal, or it may be from the French charbon. A person who manufactured charcoal was formerly known as a collier (also as a wood collier). The word "collier" was also used for those who mined or dealt in coal, and for the ships that transported it.
# History
Historically, production of wood charcoal in districts where there is an abundance of wood dates back to a very remote period, and generally consists of piling billets of wood on their ends so as to form a conical pile, openings being left at the bottom to admit air, with a central shaft to serve as a flue. The whole pile is covered with turf or moistened clay. The firing is begun at the bottom of the flue, and gradually spreads outwards and upwards. The success of the operation depends upon the rate of the combustion. Under average conditions, 100 parts of wood yield about 60 parts by volume, or 25 parts by weight, of charcoal; small scale production on the spot often yields only about 50%, large scale was efficient to about 90% even by the 17th century. The operation is so delicate that it was generally left to professional charcoal burners. These often worked in solitary groups in the woods and had a rather bad social reputation, especially traveling ones who often sold a sack (priced at about a day's wage) with lots of rubbish mixed in to farmers and townsfolk.
The massive production of charcoal (at its height employing hundreds of thousands, mainly in Alpine and neighbouring forests) was a major cause of deforestation, especially in Central Europe. In England, many woods were managed as coppices, which were cut and regrew cyclically, so that a steady supply of charcoal would be available (in principle) forever; complaints (as early as in Stuart England) about shortages may relate to the results of temporary over-exploitation or the impossibility of increasing production. The increasing scarcity of easily harvested wood was a major factor for the switch to the fossil fuel equivalents, mainly coal and brown coal for industrial use.
The modern process of carbonizing wood, either in small pieces or as sawdust in cast iron retorts, is extensively practiced where wood is scarce, and also for the recovery of valuable byproducts (wood spirit, pyroligneous acid, wood tar), which the process permits. The question of the temperature of the carbonization is important; according to J. Percy, wood becomes brown at 220 °C, a deep brown-black after some time at 280°, and an easily powdered mass at 310°.[citation needed] Charcoal made at 300° is brown, soft and friable, and readily inflames at 380°; made at higher temperatures it is hard and brittle, and does not fire until heated to about 700°.
In Finland and Scandinavia, the charcoal was considered the by-product of wood tar production. The best tar came from pine, thus pinewoods were cut down for tar pyrolysis. The residual charcoal was widely used as substitute for metallurgical coke on blast furnaces for smelting. Tar production led to rapid deforestation: it has been estimated all Finnish forests are younger than 300 years by their age. The end of tar production in the end of the 19th century meant also rapid re-forestation.
The charcoal briquette, first invented by Henry Ford, was first made using wood and sawdust scraps from his automotive assembly plant.[1]
# Types of charcoal
Commercial charcoal is found in either lump, briquette or extruded forms:
- Lump charcoal is made directly from hardwood material and usually produces far less ash than briquettes.
- Briquettes are made by compressing charcoal, typically made from sawdust and other wood by-products, with a binder and other additives. The binder is usually starch. Some briquettes may also include brown coal (heat source), mineral carbon (heat source), borax, sodium nitrate (ignition aid), limestone (ash-whitening agent), raw sawdust (ignition aid) and other additives like paraffin or petroleum solvents to aid in ignition.[2]
- Extruded charcoal is made by extruding either raw ground wood or carbonized wood into logs without the use of a binder. The heat and pressure of the extruding process hold the charcoal together. If the extrusion is made from raw wood material, the extruded logs are then subsequently carbonized.
The characteristics of charcoal products (lump, briquette or extruded forms) vary widely from product to product. Thus it is a common misconception to stereotype any kind of charcoal, saying which burns hotter, etc.
Charcoal is sometimes used to power commercial road vehicles, usually buses - in countries where oil is scarce or completely unavailable. In the years immediately after the second world war, charcoal buses were in regular use in Japan and are still used today in North Korea.[3]
# Uses
One of the most important historical applications of wood charcoal was as a constituent of gunpowder. It was also used in metallurgical operations as a reducing agent, but its application has been diminished by the introduction of coke, anthracite smalls, etc. A limited quantity is made up into the form of drawing crayons; but the greatest amount is used as a fuel, which burns hotter and cleaner than wood. Charcoal is often used by blacksmiths, for cooking, and for other industrial applications.
## Cooking fuel
Charcoal briquettes are widely used for outdoor grilling and barbeques in backyards and on camping trips. Charcoal cannot be burned indoors without an adequate ventilation system, because poisonous carbon monoxide (CO) is a combustion product.[4]
## Industrial fuel
Historically, charcoal was used in great quantities for smelting iron in bloomeries and later blast furnaces and finery forges. This was replaced for this by coke during the Industrial Revolution. For this purpose, charcoal in England was measured in dozens (or loads) consisting of 12 sacks or shems or seams, each of 8 bushels.
## Automotive fuel
In times of scarce petroleum, automobiles and even buses have been converted to burn carbon monoxide released by burning charcoal. In occupied France during World War II, wood and wood charcoal production for such vehicles (called gazogènes) increased from pre-war figures of approximately fifty thousand tons a year to almost half a million tons in 1943.[5]
## Purification/Filtration
The porosity of activated charcoal accounts for its ability to readily adsorb gases and liquids; charcoal is often used to filter water or adsorb odors. Its pharmacological action depends on the same property; it adsorbs the gases of the stomach and intestines, and also liquids and solids (hence its use in the treatment of certain poisonings). Charcoal filters are used in some types of gas mask to remove poisonous gases from inhaled air. Wood charcoal also to some extent removes coloring material from solutions, but animal charcoal is generally more effective.
Animal charcoal or bone black is the carbonaceous residue obtained by the dry distillation of bones; it contains only about 10% carbon, the remainder being calcium and magnesium phosphates (80%) and other inorganic material originally present in the bones. It is generally manufactured from the residues obtained in the glue and gelatin industries. Its decolorizing power was applied in 1812 by Derosne to the clarification of the syrups obtained in sugar refining; but its use in this direction has now greatly diminished, owing to the introduction of more active and easily managed reagents. It is still used to some extent in laboratory practice. The decolorizing power is not permanent, becoming lost after using for some time; it may be revived, however, by washing and reheating. Normal recommendation is to leave the charcoal under the sun for few hours every month.
## Art
Charcoal is used in art for drawing, making rough sketches in painting, and is one of the possible media for making a parsemage. It must usually be preserved by the application of a fixative. Artists generally utilize charcoal in three forms:
- Vine charcoal is created by burning sticks of wood (usually willow or linden/Tilia) into soft, medium, and hard consistencies. Bamboo charcoal is the principal tool in Japanese Sumi-e (炭絵 lit: charcoal drawing) art.
- Compressed charcoal charcoal powder mixed with gum binder compressed into round or square sticks. The amount of binder determines the hardness of the stick. Compressed charcoal is used in charcoal pencils.
- Powdered charcoal is often used to "tone" or cover large sections of a drawing surface. Drawing over the toned areas will darken it further, but the artist can also lighten (or completely erase) within the toned area to create lighter tones.
## Horticulture
One additional use of charcoal rediscovered recently is in horticulture. Although American gardeners have been using charcoal for a short while, research on Terra preta soils in the Amazon has found the widespread use of biochar by pre-Columbian natives to turn otherwise unproductive soil into very rich soil. The technique may find modern application, both to improve soils and as a means of carbon sequestration.
# Sources, references and external links
- Bamboo Charcoal - Bamboo Charcoal Home Air Purifiers and Water Purifiers
- Ignite Products - New generation charcoal products.
- Barbecue Charcoal - The available choices for the backyard barbecue
- Natural History of Europe - 2005 TV co-production including BBC and ZDF
- On Charcoal
- The Valley - BBC TV - one year of life on a 17th century farm reenacted by archaeologists and historians
- The Lump Charcoal Database - Information about lump charcoal.
- H E Z Organisation - Information about charcoal in Germany.
- [2] - Information about charcoal.
- Photo of traditional charcoal production A forest kiln
- [3] - Charcoal making community for livelihood
- [4] - Traditional charcoal production method, India
- The River Wey and Wey Navigations Community Site — a non-commercial site of over 200,000 words all about the Wey Valley and includes a photo file on charcoal production and information relating to gunpowder manufacture at Chilworth.
- [5] Catoctin Mountain Park, Maryland, USA, includes interpretive features ("Charcoal Trail", etc) on the history of charcoal making in the area.
- Bamboo Charcoal - Properties and Facts
- Coconut Charcoal - Facts
- Simple Home Charcoal Process
- Discovery of new charcoal production process and ARTI, Appropriate Rural Technologies Institute - Making powdered charcoal directly from sugar cane leaves and trash
- The "Adam-retort", or ICPS (Improved Charcoal Production System) | https://www.wikidoc.org/index.php/Actidose-Aqua | |
8b83ab318b88ae9bfc97f52680b832727f7b48ba | wikidoc | Ursodiol | Ursodiol
# 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
Ursodiol is a bile acid and gastrointestinal agent that is FDA approved for the treatment of chemodissolution of gall bladder stone, prevention of gallstone formation in obese patients experiencing rapid weight loss and primary biliary cirrhosis. Common adverse reactions include rash, constipation, diarrhea, indigestion, nausea, vomiting, backache, dizziness, bronchitis, cough, pharyngitis and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ursodiol is indicated for patients with radiolucent, noncalcified gallbladder stones < 20 mm in greatest diameter in whom elective cholecystectomy would be undertaken except for the presence of increased surgical risk due to systemic disease, advanced age, idiosyncratic reaction to general anesthesia, or for those patients who refuse surgery. Safety of use of ursodiol beyond 24 months is not established.
- Ursodiol is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.
### Dosing Information
- The recommended dose for ursodiol treatment of radiolucent gallbladder stones is 8 - 10 mg/kg/day given in 2 or 3 divided doses. Ultrasound images of the gallbladder should be obtained at 6-month intervals for the first year of ursodiol therapy to monitor gallstone response. If gallstones appear to have dissolved, ursodiol therapy should be continued and dissolution confirmed on a repeat ultrasound examination within 1 to 3 months. Most patients who eventually achieve complete stone dissolution will show partial or complete dissolution at the first on-treatment reevaluation. If partial stone dissolution is not seen by 12 months of ursodiol therapy, the likelihood of success is greatly reduced.
- The recommended dosage of ursodiol for gallstone prevention in patients undergoing rapid weight loss is 400 mg/day (300 mg b.i.d.).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ursodiol in adult patients.
### Non–Guideline-Supported Use
- Biliary cirrhosis - Cystic fibrosis
- Cholestasis of parenteral nutrition
- Cholestatic jaundice syndrome
- Congenital dilatation of lobar intrahepatic bile duct
- Chronic hepatitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ursodiol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ursodiol in pediatric patients.
### Non–Guideline-Supported Use
- Biliary cirrhosis - Cystic fibrosis
- Cholestatic jaundice syndrome
# Contraindications
- Ursodiol will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Hence, patients with such stones are not candidates for ursodiol therapy.
- Patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-] are not candidates for ursodiol therapy.
- Allergy to bile acids.
# Warnings
### PRECAUTIONS
- Ursodiol therapy has not been associated with liver damage. Lithocholic acid, a naturally occurring bile acid, is known to be a liver-toxic metabolite. This bile acid is formed in the gut from ursodiol less efficiently and in smaller amounts than that seen from chenodiol. Lithocholic acid is detoxified in the liver by sulfation and, although man appears to be an efficient sulfater, it is possible that some patients may have a congenital or acquired deficiency in sulfation, thereby predisposing them to lithocholate-induced liver damage.
- Abnormalities in liver enzymes have not been associated with ursodiol therapy and, in fact, ursodiol has been shown to decrease liver enzyme levels in liver disease. However, patients given ursodiol should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances.
# Adverse Reactions
## Clinical Trials Experience
- The nature and frequency of adverse experiences were similar across all groups.
- The following tables provide comprehensive listings of the adverse experiences reported that occurred with a 5% incidence level:
- Gallstone Dissolution In Ursodiol and Placebo Patients
- Gallstone Prevention in Ursodiol and Placebo-Treated Patients
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ursodiol in the drug label.
# Drug Interactions
- Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum-based antacids have been shown to absorb bile acids in vitro and may be expected to interfere with ursodiol in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodiol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats and rabbits with ursodiol doses up to 200-fold the therapeutic dose and have revealed no evidence of impaired fertility or harm to the fetus at doses of 20- to 100-fold the human dose in rats and at 5-fold the human dose (highest dose tested) in rabbits. Studies employing 100- to 200-fold the human dose in rats have shown some reduction in fertility rate and litter size. There have been no adequate and well-controlled studies of the use of ursodiol in pregnant women, but inadvertent exposure of 4 women to therapeutic doses of the drug in the first trimester of pregnancy during the ursodiol trials led to no evidence of effects on the fetus or newborn baby. Although it seems unlikely, the possibility that ursodiol can cause fetal harm cannot be ruled out; hence, the drug is not recommended for use during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ursodiol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ursodiol during labor and delivery.
### Nursing Mothers
- It is not known whether ursodiol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ursodiol is administered to a nursing mother.
### Pediatric Use
There is no FDA guidance on the use of Ursodiol with respect to pediatric patients.
### Geriatic Use
- In worldwide clinical studies of ursodiol, approximately 14% of subjects were over 65 years of age (approximately 3% were over 75 years old). In a subgroup analysis of existing clinical trials, patients greater than 56 years of age did not exhibit statistically significantly different complete dissolution rates from the younger population. No age-related differences in safety and effectiveness were found. Other reported clinical experience has not identified differences in response in elderly and younger patients. However, small differences in efficacy and greater sensitivity of some elderly individuals taking ursodiol cannot be ruled out. Therefore, it is recommended that dosing proceed with caution in this population.
### Gender
There is no FDA guidance on the use of Ursodiol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ursodiol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ursodiol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ursodiol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ursodiol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ursodiol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ursodiol in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Ursodiol in the drug label.
# Overdosage
- Neither accidental nor intentional overdosing with Ursodiol has been reported. Doses of Ursodiol in the range of 16 - 20 mg/kg/day have been tolerated for 6 - 37 months without symptoms by 7 patients. The LD50 for ursodiol in rats is over 5000 mg/kg given over 7 - 10 days and over 7500 mg/kg for mice. The most likely manifestation of severe overdose with ursodiol would probably be diarrhea, which should be treated symptomatically.
# Pharmacology
## Mechanism of Action
- Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.
## Structure
- Ursodiol is a bile acid available as 300 mg capsules suitable for oral administration.
- Ursodeoxycholic acid,is a naturally occurring bile acid found in small quantities in normal human bile and in the biles of certain other mammals. It is a bitter-tasting, white powder freely soluble in ethanol, methanol, and glacial acetic acid; sparingly soluble in chloroform; slightly soluble in ether; and insoluble in water. The chemical name for ursodiol is 3α,7β-Dihydroxy-5β-cholan-24-oic acid (C24H40O4). Ursodiol, USP has a molecular weight of 392.57. Its structure is shown below:
## Pharmacodynamics
- Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.
- With repeated dosing, bile ursodeoxycholic acid concentrations reach a steady state in about 3 weeks. Although insoluble in aqueous media, cholesterol can be solubilized in at least two different ways in the presence of dihydroxy bile acids. In addition to solubilizing cholesterol in micelles, ursodiol acts by an apparently unique mechanism to cause dispersion of cholesterol as liquid crystals in aqueous media. Thus, even though administration of high doses (e.g., 15 - 18 mg/kg/day) does not result in a concentration of ursodiol higher than 60% of the total bile acid pool, ursodiol-rich bile effectively solubilizes cholesterol. The overall effect of ursodiol is to increase the concentration level at which saturation of cholesterol occurs.
- The various actions of ursodiol combine to change the bile of patients with gallstones from cholesterol-precipitating to cholesterolsolubilizing, thus resulting in bile conducive to cholesterol stone dissolution.
- After ursodiol dosing is stopped, the concentration of the bile acid in bile falls exponentially, declining to about 5% - 10% of its steady state level in about 1 week.
## Pharmacokinetics
- About 90% of a therapeutic dose of ursodiol is absorbed in the small bowel after oral administration. After absorption, ursodiol enters the portal vein and undergoes efficient extraction from portal blood by the liver (i.e., there is a large “first-pass” effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodiol in bile is concentrated in the gallbladder and expelled into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions provoked by physiologic responses to eating. Only small quantities of ursodiol appear in the systemic circulation and very small amounts are excreted into urine. The sites of the drug’s therapeutic actions are in the liver, bile, and gut lumen.
- Beyond conjugation, ursodiol is not altered or catabolized appreciably by the liver or intestinal mucosa. A small proportion of orally administered drug undergoes bacterial degradation with each cycle of enterohepatic circulation. Ursodiol can be both oxidized and reduced at the 7-carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, there is some bacterially catalyzed deconjugation of [[glyco-ursodeoxycholic acid
- The 7-dehydroxylation reaction appears to be alpha-specific, i.e., chenodiol is more efficiently 7-dehydroxylated than ursodiol and, for equimolar doses of ursodiol and chenodiol, levels of lithocholic acid appearing in bile are lower with the former. Man has the capacity to sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals, but such a deficiency has not yet been clearly demonstrated.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ursodiol in the drug label.
# Clinical Studies
- On the basis of clinical trial results in a total of 868 patients with radiolucent gallstones treated in 8 studies (three in the U.S. involving 282 patients, one in the U.K. involving 130 patients, and four in Italy involving 456 patients) for periods ranging from 6 - 78 months with ursodiol doses ranging from about 5 - 20 mg/kg/day, an ursodiol dose of about 8 - 10 mg/kg/day appeared to be the best dose.
- With an ursodiol dose of about 10 mg/kg/day, complete stone dissolution can be anticipated in about 30% of unselected patients with uncalcified gallstones 20 mm in maximal diameter rarely dissolve their stones. The chance of gallstone dissolution is increased up to 50% in patients with floating or floatable stones (i.e., those with high cholesterol content), and is inversely related to stone size for those < 20 mm in maximal diameter.
- Complete dissolution was observed in 81% of patients with stones up to 5 mm in diameter. Age, sex, weight, degree of obesity, and serum cholesterol level are not related to the chance of stone dissolution with ursodiol.
- A nonvisualizing gallbladder by oral cholecystogram prior to the initiation of therapy is not a contraindication to ursodiol therapy (the group of patients with nonvisualizing gallbladders in the ursodiol studies had complete stone dissolution rates similar to the group of patients with visualizing gallbladders). However, gallbladder nonvisualization developing during ursodiol treatment predicts failure of complete stone dissolution and in such cases therapy should be discontinued. Partial stone dissolution occurring within 6 months of beginning therapy with ursodiol appears to be associated with a > 70% chance of eventual complete stone dissolution with further treatment; partial dissolution observed within 1 year of starting therapy indicates a 40% probability of complete dissolution. Stone recurrence after dissolution with ursodiol therapy was seen within 2 years in 8/27 (30%) of patients in the U.K. studies. Of 16 patients in the U.K. study whose stones had previously dissolved on chenodiol but later recurred, 11 had complete dissolution on ursodiol. Stone recurrence has been observed in up to 50% of patients within 5 years of complete stone dissolution on ursodiol therapy. Serial ultrasonographic examinations should be obtained to monitor for recurrence of stones, bearing in mind that radiolucency of the stones should be established before another course of ursodiol is instituted. A prophylactic dose of ursodiol has not been established.
- Two placebo-controlled, multicenter, double-blind, randomized, parallel group trials in a total of 1,316 obese patients were undertaken to evaluate ursodiol in the prevention of gallstone formation in obese patients undergoing rapid weight loss. The first trial consisted of 1,004 obese patients with a body mass index (BMI) ≥ 38 who underwent weight loss induced by means of a very low calorie diet for a period of 16 weeks. An intent-to-treat analysis of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 400, or 1200 mg/day of ursodiol experienced a 6%, 3%, and 2% incidence of gallstone formation, respectively. The mean weight loss for this 16-week trial was 47 lb for the placebo group, and 47, 48, and 50 lb for the 300, 400, and 1200 mg/day ursodiol groups, respectively.
- The second trial consisted of 312 obese patients (BMI ≥ 40) who underwent rapid weight loss through gastric bypass surgery. The trial drug treatment period was for 6 months following this surgery. Results of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 400, or 1200 mg/day of Ursodiol experienced a 9%, 1%, and 5% incidence of gallstone formation, respectively. The mean weight loss for this 6-month trial was 64 lb for the placebo group, and 67, 74, and 72 lb for the 300, 400, and 1200 mg/day ursodiol groups, respectively.
- Ursodeoxycholic acid was tested in 2-year oral carcinogenicity studies in CD-1 mice and Sprague-Dawley rats at daily doses of 50, 250, and 1000 mg/kg/day. It was not tumorigenic in mice. In the rat study, it produced statistically significant dose-related increased incidences of pheochromocytomas of adrenal medulla in males (p=0.014, Peto trend test) and females (p=0.004, Peto trend test). A 78-week rat study employing intrarectal instillation of lithocholic acid and tauro-deoxycholic acid, metabolites of ursodiol and chenodiol, has been conducted. These bile acids alone did not produce any tumors. A tumor-promoting effect of both metabolites was observed when they were co-administered with a carcinogenic agent. Results of epidemiologic studies suggest that bile acids might be involved in the pathogenesis of human colon cancer in patients who had undergone a cholecystectomy, but direct evidence is lacking. Ursodiol is not mutagenic in the Ames test. Dietary administration of lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.
# How Supplied
Ursodiol Capsules USP, 300 mg are opaque white and pink capsules, filled with white powder. They are imprinted
“Є503” in black ink on cap and body and are supplied in bottles of 100 and 1000.
Keep out of reach of children.
Manufactured By:
Epic Pharma, LLC
Laurelton, NY 11413
Revised August 2014
MF503REV08/14
OE1105
## Storage
- Store at 20° - 25°C (68° - 77°F). Dispense contents in tight, light-resistant container as defined in the USP.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Ursodiol in the drug label.
# Precautions with Alcohol
- Alcohol-Ursodiol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Actigall®
- Urso®
- Urso 250®
- Urso Forte®
# Look-Alike Drug Names
There is limited information regarding Ursodiol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ursodiol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
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# Overview
Ursodiol is a bile acid and gastrointestinal agent that is FDA approved for the treatment of chemodissolution of gall bladder stone, prevention of gallstone formation in obese patients experiencing rapid weight loss and primary biliary cirrhosis. Common adverse reactions include rash, constipation, diarrhea, indigestion, nausea, vomiting, backache, dizziness, bronchitis, cough, pharyngitis and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ursodiol is indicated for patients with radiolucent, noncalcified gallbladder stones < 20 mm in greatest diameter in whom elective cholecystectomy would be undertaken except for the presence of increased surgical risk due to systemic disease, advanced age, idiosyncratic reaction to general anesthesia, or for those patients who refuse surgery. Safety of use of ursodiol beyond 24 months is not established.
- Ursodiol is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.
### Dosing Information
- The recommended dose for ursodiol treatment of radiolucent gallbladder stones is 8 - 10 mg/kg/day given in 2 or 3 divided doses. Ultrasound images of the gallbladder should be obtained at 6-month intervals for the first year of ursodiol therapy to monitor gallstone response. If gallstones appear to have dissolved, ursodiol therapy should be continued and dissolution confirmed on a repeat ultrasound examination within 1 to 3 months. Most patients who eventually achieve complete stone dissolution will show partial or complete dissolution at the first on-treatment reevaluation. If partial stone dissolution is not seen by 12 months of ursodiol therapy, the likelihood of success is greatly reduced.
- The recommended dosage of ursodiol for gallstone prevention in patients undergoing rapid weight loss is 400 mg/day (300 mg b.i.d.).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ursodiol in adult patients.
### Non–Guideline-Supported Use
- Biliary cirrhosis - Cystic fibrosis
- Cholestasis of parenteral nutrition
- Cholestatic jaundice syndrome
- Congenital dilatation of lobar intrahepatic bile duct
- Chronic hepatitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ursodiol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ursodiol in pediatric patients.
### Non–Guideline-Supported Use
- Biliary cirrhosis - Cystic fibrosis
- Cholestatic jaundice syndrome
# Contraindications
- Ursodiol will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones. Hence, patients with such stones are not candidates for ursodiol therapy.
- Patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-[[gastrointestinal fistula]] are not candidates for ursodiol therapy.
- Allergy to bile acids.
# Warnings
### PRECAUTIONS
- Ursodiol therapy has not been associated with liver damage. Lithocholic acid, a naturally occurring bile acid, is known to be a liver-toxic metabolite. This bile acid is formed in the gut from ursodiol less efficiently and in smaller amounts than that seen from chenodiol. Lithocholic acid is detoxified in the liver by sulfation and, although man appears to be an efficient sulfater, it is possible that some patients may have a congenital or acquired deficiency in sulfation, thereby predisposing them to lithocholate-induced liver damage.
- Abnormalities in liver enzymes have not been associated with ursodiol therapy and, in fact, ursodiol has been shown to decrease liver enzyme levels in liver disease. However, patients given ursodiol should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances.
# Adverse Reactions
## Clinical Trials Experience
- The nature and frequency of adverse experiences were similar across all groups.
- The following tables provide comprehensive listings of the adverse experiences reported that occurred with a 5% incidence level:
- Gallstone Dissolution In Ursodiol and Placebo Patients
- Gallstone Prevention in Ursodiol and Placebo-Treated Patients
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ursodiol in the drug label.
# Drug Interactions
- Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum-based antacids have been shown to absorb bile acids in vitro and may be expected to interfere with ursodiol in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodiol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats and rabbits with ursodiol doses up to 200-fold the therapeutic dose and have revealed no evidence of impaired fertility or harm to the fetus at doses of 20- to 100-fold the human dose in rats and at 5-fold the human dose (highest dose tested) in rabbits. Studies employing 100- to 200-fold the human dose in rats have shown some reduction in fertility rate and litter size. There have been no adequate and well-controlled studies of the use of ursodiol in pregnant women, but inadvertent exposure of 4 women to therapeutic doses of the drug in the first trimester of pregnancy during the ursodiol trials led to no evidence of effects on the fetus or newborn baby. Although it seems unlikely, the possibility that ursodiol can cause fetal harm cannot be ruled out; hence, the drug is not recommended for use during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ursodiol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ursodiol during labor and delivery.
### Nursing Mothers
- It is not known whether ursodiol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ursodiol is administered to a nursing mother.
### Pediatric Use
There is no FDA guidance on the use of Ursodiol with respect to pediatric patients.
### Geriatic Use
- In worldwide clinical studies of ursodiol, approximately 14% of subjects were over 65 years of age (approximately 3% were over 75 years old). In a subgroup analysis of existing clinical trials, patients greater than 56 years of age did not exhibit statistically significantly different complete dissolution rates from the younger population. No age-related differences in safety and effectiveness were found. Other reported clinical experience has not identified differences in response in elderly and younger patients. However, small differences in efficacy and greater sensitivity of some elderly individuals taking ursodiol cannot be ruled out. Therefore, it is recommended that dosing proceed with caution in this population.
### Gender
There is no FDA guidance on the use of Ursodiol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ursodiol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ursodiol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ursodiol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ursodiol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ursodiol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ursodiol in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Ursodiol in the drug label.
# Overdosage
- Neither accidental nor intentional overdosing with Ursodiol has been reported. Doses of Ursodiol in the range of 16 - 20 mg/kg/day have been tolerated for 6 - 37 months without symptoms by 7 patients. The LD50 for ursodiol in rats is over 5000 mg/kg given over 7 - 10 days and over 7500 mg/kg for mice. The most likely manifestation of severe overdose with ursodiol would probably be diarrhea, which should be treated symptomatically.
# Pharmacology
## Mechanism of Action
- Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.
## Structure
- Ursodiol is a bile acid available as 300 mg capsules suitable for oral administration.
- Ursodeoxycholic acid,is a naturally occurring bile acid found in small quantities in normal human bile and in the biles of certain other mammals. It is a bitter-tasting, white powder freely soluble in ethanol, methanol, and glacial acetic acid; sparingly soluble in chloroform; slightly soluble in ether; and insoluble in water. The chemical name for ursodiol is 3α,7β-Dihydroxy-5β-cholan-24-oic acid (C24H40O4). Ursodiol, USP has a molecular weight of 392.57. Its structure is shown below:
## Pharmacodynamics
- Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.
- With repeated dosing, bile ursodeoxycholic acid concentrations reach a steady state in about 3 weeks. Although insoluble in aqueous media, cholesterol can be solubilized in at least two different ways in the presence of dihydroxy bile acids. In addition to solubilizing cholesterol in micelles, ursodiol acts by an apparently unique mechanism to cause dispersion of cholesterol as liquid crystals in aqueous media. Thus, even though administration of high doses (e.g., 15 - 18 mg/kg/day) does not result in a concentration of ursodiol higher than 60% of the total bile acid pool, ursodiol-rich bile effectively solubilizes cholesterol. The overall effect of ursodiol is to increase the concentration level at which saturation of cholesterol occurs.
- The various actions of ursodiol combine to change the bile of patients with gallstones from cholesterol-precipitating to cholesterolsolubilizing, thus resulting in bile conducive to cholesterol stone dissolution.
- After ursodiol dosing is stopped, the concentration of the bile acid in bile falls exponentially, declining to about 5% - 10% of its steady state level in about 1 week.
## Pharmacokinetics
- About 90% of a therapeutic dose of ursodiol is absorbed in the small bowel after oral administration. After absorption, ursodiol enters the portal vein and undergoes efficient extraction from portal blood by the liver (i.e., there is a large “first-pass” effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodiol in bile is concentrated in the gallbladder and expelled into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions provoked by physiologic responses to eating. Only small quantities of ursodiol appear in the systemic circulation and very small amounts are excreted into urine. The sites of the drug’s therapeutic actions are in the liver, bile, and gut lumen.
- Beyond conjugation, ursodiol is not altered or catabolized appreciably by the liver or intestinal mucosa. A small proportion of orally administered drug undergoes bacterial degradation with each cycle of enterohepatic circulation. Ursodiol can be both oxidized and reduced at the 7-carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, there is some bacterially catalyzed deconjugation of [[glyco-ursodeoxycholic acid
- The 7-dehydroxylation reaction appears to be alpha-specific, i.e., chenodiol is more efficiently 7-dehydroxylated than ursodiol and, for equimolar doses of ursodiol and chenodiol, levels of lithocholic acid appearing in bile are lower with the former. Man has the capacity to sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals, but such a deficiency has not yet been clearly demonstrated.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ursodiol in the drug label.
# Clinical Studies
- On the basis of clinical trial results in a total of 868 patients with radiolucent gallstones treated in 8 studies (three in the U.S. involving 282 patients, one in the U.K. involving 130 patients, and four in Italy involving 456 patients) for periods ranging from 6 - 78 months with ursodiol doses ranging from about 5 - 20 mg/kg/day, an ursodiol dose of about 8 - 10 mg/kg/day appeared to be the best dose.
- With an ursodiol dose of about 10 mg/kg/day, complete stone dissolution can be anticipated in about 30% of unselected patients with uncalcified gallstones < 20 mm in maximal diameter treated for up to 2 years. Patients with calcified gallstones prior to treatment, or patients who develop stone calcification or gallbladder nonvisualization on treatment, and patients with stones > 20 mm in maximal diameter rarely dissolve their stones. The chance of gallstone dissolution is increased up to 50% in patients with floating or floatable stones (i.e., those with high cholesterol content), and is inversely related to stone size for those < 20 mm in maximal diameter.
- Complete dissolution was observed in 81% of patients with stones up to 5 mm in diameter. Age, sex, weight, degree of obesity, and serum cholesterol level are not related to the chance of stone dissolution with ursodiol.
- A nonvisualizing gallbladder by oral cholecystogram prior to the initiation of therapy is not a contraindication to ursodiol therapy (the group of patients with nonvisualizing gallbladders in the ursodiol studies had complete stone dissolution rates similar to the group of patients with visualizing gallbladders). However, gallbladder nonvisualization developing during ursodiol treatment predicts failure of complete stone dissolution and in such cases therapy should be discontinued. Partial stone dissolution occurring within 6 months of beginning therapy with ursodiol appears to be associated with a > 70% chance of eventual complete stone dissolution with further treatment; partial dissolution observed within 1 year of starting therapy indicates a 40% probability of complete dissolution. Stone recurrence after dissolution with ursodiol therapy was seen within 2 years in 8/27 (30%) of patients in the U.K. studies. Of 16 patients in the U.K. study whose stones had previously dissolved on chenodiol but later recurred, 11 had complete dissolution on ursodiol. Stone recurrence has been observed in up to 50% of patients within 5 years of complete stone dissolution on ursodiol therapy. Serial ultrasonographic examinations should be obtained to monitor for recurrence of stones, bearing in mind that radiolucency of the stones should be established before another course of ursodiol is instituted. A prophylactic dose of ursodiol has not been established.
- Two placebo-controlled, multicenter, double-blind, randomized, parallel group trials in a total of 1,316 obese patients were undertaken to evaluate ursodiol in the prevention of gallstone formation in obese patients undergoing rapid weight loss. The first trial consisted of 1,004 obese patients with a body mass index (BMI) ≥ 38 who underwent weight loss induced by means of a very low calorie diet for a period of 16 weeks. An intent-to-treat analysis of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 400, or 1200 mg/day of ursodiol experienced a 6%, 3%, and 2% incidence of gallstone formation, respectively. The mean weight loss for this 16-week trial was 47 lb for the placebo group, and 47, 48, and 50 lb for the 300, 400, and 1200 mg/day ursodiol groups, respectively.
- The second trial consisted of 312 obese patients (BMI ≥ 40) who underwent rapid weight loss through gastric bypass surgery. The trial drug treatment period was for 6 months following this surgery. Results of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 400, or 1200 mg/day of Ursodiol experienced a 9%, 1%, and 5% incidence of gallstone formation, respectively. The mean weight loss for this 6-month trial was 64 lb for the placebo group, and 67, 74, and 72 lb for the 300, 400, and 1200 mg/day ursodiol groups, respectively.
- Ursodeoxycholic acid was tested in 2-year oral carcinogenicity studies in CD-1 mice and Sprague-Dawley rats at daily doses of 50, 250, and 1000 mg/kg/day. It was not tumorigenic in mice. In the rat study, it produced statistically significant dose-related increased incidences of pheochromocytomas of adrenal medulla in males (p=0.014, Peto trend test) and females (p=0.004, Peto trend test). A 78-week rat study employing intrarectal instillation of lithocholic acid and tauro-deoxycholic acid, metabolites of ursodiol and chenodiol, has been conducted. These bile acids alone did not produce any tumors. A tumor-promoting effect of both metabolites was observed when they were co-administered with a carcinogenic agent. Results of epidemiologic studies suggest that bile acids might be involved in the pathogenesis of human colon cancer in patients who had undergone a cholecystectomy, but direct evidence is lacking. Ursodiol is not mutagenic in the Ames test. Dietary administration of lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.
# How Supplied
Ursodiol Capsules USP, 300 mg are opaque white and pink capsules, filled with white powder. They are imprinted
“Є503” in black ink on cap and body and are supplied in bottles of 100 and 1000.
Keep out of reach of children.
Manufactured By:
Epic Pharma, LLC
Laurelton, NY 11413
Revised August 2014
MF503REV08/14
OE1105
## Storage
- Store at 20° - 25°C (68° - 77°F). Dispense contents in tight, light-resistant container as defined in the USP.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Ursodiol in the drug label.
# Precautions with Alcohol
- Alcohol-Ursodiol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Actigall®
- Urso®
- Urso 250®
- Urso Forte®
# Look-Alike Drug Names
There is limited information regarding Ursodiol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Actigall | |
005083ea40a5c981e58abaf800ea6dd418cda295 | wikidoc | Actinide | Actinide
The actinoid (according to IUPAC terminology) (previously actinide) series encompasses the 15 chemical elements that lie between actinium and lawrencium included on the periodic table, with atomic numbers 89 - 103. The actinoid series derives its name from the first element in the series, actinium, and ultimately from the Greek ακτις (aktis), "ray," reflecting the elements' radioactivity.
The actinoid series (An) is included in some definitions of the rare earth elements. IUPAC is currently recommending the name actinoid rather than actinide, as the suffix "-ide" generally indicates ions (moreover, from Latin, the suffix -ide means "sons of actinium", while -oid means "similar to actinium"). There are alternative arrangements of the periodic table that exclude actinium or lawrencium from appearing together with the other actinoids.
The actinoids display less similarity in their chemical properties than the lanthanoid series (Ln), exhibiting a wider range of oxidation states, which initially led to confusion as to whether actinium, thorium, and uranium should be considered d-block elements. All actinoids are radioactive.
Only thorium and uranium occur naturally in the earth's crust in anything more than trace quantities. Neptunium and plutonium have been known to show up naturally in trace amounts in uranium ores as a result of decay or bombardment. The remaining actinides were discovered in nuclear fallout, or were synthesized in particle colliders. The latter half of the series possess exceedingly short half-lives.
The actinoids are typically placed below the main body of the periodic table (below the lanthanoid series), in the manner of a footnote. The full-width version of the periodic table shows the position of the actinoids more clearly.
An organometallic compound of an actinoid is known as an organoactinoid.
# History of the actinoid series
From the earlier known chemical properties of actinium (89) up to uranium (92), indicating a relation to the transition metals, it was generally assumed that the transuraniums would have similar qualities. During his Manhattan Project research in 1944, Glenn T. Seaborg experienced unexpected difficulty isolating americium (95) and curium (96). He began wondering if these elements more properly belonged to a different series than the transition metals, which would explain why the expected chemical properties of the new elements were different. In 1945, he went against the advice of colleagues and proposed the most significant change to Mendeleev's periodic table to have been accepted universally by the scientific community: the actinide series.
In 1945, Seaborg published his actinide concept of heavy element electronic structure, predicting that the actinides would form a transition series analogous to the rare earth series of lanthanoid elements.
In 1961, Antoni Przybylski discovered a star that contained unusually high amounts of actinides. | Actinide
The actinoid (according to IUPAC terminology) (previously actinide) series encompasses the 15 chemical elements that lie between actinium and lawrencium included on the periodic table, with atomic numbers 89 - 103.[1] [2] The actinoid series derives its name from the first element in the series, actinium, and ultimately from the Greek ακτις (aktis), "ray," reflecting the elements' radioactivity.
The actinoid series (An) is included in some definitions of the rare earth elements. IUPAC is currently recommending the name actinoid rather than actinide, as the suffix "-ide" generally indicates ions (moreover, from Latin, the suffix -ide means "sons of actinium", while -oid means "similar to actinium"). There are alternative arrangements of the periodic table that exclude actinium or lawrencium from appearing together with the other actinoids.
The actinoids display less similarity in their chemical properties than the lanthanoid series (Ln), exhibiting a wider range of oxidation states, which initially led to confusion as to whether actinium, thorium, and uranium should be considered d-block elements. All actinoids are radioactive.
Only thorium and uranium occur naturally in the earth's crust in anything more than trace quantities. Neptunium and plutonium have been known to show up naturally in trace amounts in uranium ores as a result of decay or bombardment. The remaining actinides were discovered in nuclear fallout, or were synthesized in particle colliders. The latter half of the series possess exceedingly short half-lives.
The actinoids are typically placed below the main body of the periodic table (below the lanthanoid series), in the manner of a footnote. The full-width version of the periodic table shows the position of the actinoids more clearly.
An organometallic compound of an actinoid is known as an organoactinoid.
# History of the actinoid series
From the earlier known chemical properties of actinium (89) up to uranium (92), indicating a relation to the transition metals, it was generally assumed that the transuraniums would have similar qualities. During his Manhattan Project research in 1944, Glenn T. Seaborg experienced unexpected difficulty isolating americium (95) and curium (96). He began wondering if these elements more properly belonged to a different series than the transition metals, which would explain why the expected chemical properties of the new elements were different. In 1945, he went against the advice of colleagues and proposed the most significant change to Mendeleev's periodic table to have been accepted universally by the scientific community: the actinide series.
In 1945, Seaborg published his actinide concept of heavy element electronic structure, predicting that the actinides would form a transition series analogous to the rare earth series of lanthanoid elements.
In 1961, Antoni Przybylski discovered a star that contained unusually high amounts of actinides. | https://www.wikidoc.org/index.php/Actinide | |
6cf676252b5cc038a833b6fe16b77deaa15c88aa | wikidoc | Diarrhea | Diarrhea
Synonyms and keywords: Loose stools
# Overview
Diarrhea is defined as the passage of unformed or abnormally liquid stools at an increased frequency. Diarrhea can be classified as acute or chronic. Acute diarrhea has a duration of less than 2 weeks and may be classified on the basis of etiology and presentation. On the basis of etiology, acute diarrhea may be classified into infectious and non-infectious subtypes. Subacute diarrhea is defined as a diarrhea lasting for two to four weeks. Although chronic diarrhea has multiple definitions, a current working definition is the production of loose stools for longer than 4 weeks. Frequent defecation with normal consistency is termed psuedo-diarrhea. There are 3 basic categories of chronic diarrhea: watery, fatty (malabsorption), and inflammatory (with blood and pus). The diagnosis is based on duration of symptoms, signs, microscopic stool examination and culture, stool osmolarity, and in some rare instances colonoscopy. The treatment is mainly based on severity of symptoms, etiology and availability of medications. Prevention is based on proper maintaining the filtration systems at water plants, hand wash, and effectively use of alcohol-based hand sanitizers. Vaccination for some viruses, such as Rotavirus is a part of preventive measures.
# Classification
Diarrhea can be classified as acute or chronic depending on the duration of onset of symptoms. Acute and chronic diarrhea can be further classified as follows:
## Classification of Acute Diarrhea
## Classification of Chronic Diarrhea
# Differential Diagnosis of Diarrhea of other diseases
To review the differential diagnosis of diarrhea, click here.
To review the differential diagnosis of acute diarrhea, click here.
To review the differential diagnosis of chronic diarrhea, click here.
To review the differential diagnosis of traveler's diarrhea, click here.
To review the differential diagnosis of acute watery diarrhea, click here.
To review the differential diagnosis of acute bloody diarrhea, click here.
To review the differential diagnosis of acute fatty diarrhea, click here.
To review the differential diagnosis of chronic watery diarrhea, click here.
To review the differential diagnosis of chronic bloody diarrhea, click here.
To review the differential diagnosis of chronic fatty diarrhea, click here.
To review the differential diagnosis of acute diarrhea and fever, click here.
To review the differential diagnosis of chronic diarrhea and fever, click here.
To review the differential diagnosis of acute diarrhea and abdominal pain, click here.
To review the differential diagnosis of chronic diarrhea and abdominal pain, click here.
To review the differential diagnosis of acute diarrhea and weight loss, click here.
To review the differential diagnosis of chronic diarrhea and weight loss, click here.
To review the differential diagnosis of acute diarrhea, fever, and abdominal pain, click here.
To review the differential diagnosis of chronic diarrhea, fever, and abdominal pain, click here.
To review the differential diagnosis of acute diarrhea, abdominal pain, and weight loss, click here.
To review the differential diagnosis of chronic diarrhea, abdominal pain, and weight loss, click here.
## Diarrhea
The following table outlines the major differential diagnoses of diarrhea.
Abbreviations: GI: Gastrointestinal, CBC: Complete blood count, WBC: White blood cell, RBC: Red blood cell, Plt: Platelet, Hgb: Hemoglobin, ESR: Erythrocyte sedimentation rate, CRP: C–reactive protein, IgE: Immunoglobulin E, IgA: Immunoglobulin A, ETEC: Escherichia coli enteritis, EPEC: Enteropathogenic Escherichia coli, EIEC: Enteroinvasive Escherichia coli, EHEC: Enterohemorrhagic Escherichia coli, EAEC: Enteroaggregative Escherichia coli, Nl: Normal, ASCA: Anti saccharomyces cerevisiae antibodies, ANCA: Anti–neutrophil cytoplasmic antibody, DNA: Deoxyribonucleic acid, CFTR: Cystic fibrosis transmembrane conductance regulator, SLC10A2: Solute carrier family 10 member 2, SeHCAT: Selenium homocholic acid taurine or tauroselcholic acid, IEL: Intraepithelial lymphocytes, MRCP: Magnetic resonance cholangiopancreatography, ANA: Antinuclear antibodies, AMA: Anti-mitochondrial antibody, LDH: Lactate dehydrogenase, CPK: Creatine phosphokinase, PCR: Polymerase chain reaction, ELISA: Enzyme–linked immunosorbent assay, LT: Heat–labile enterotoxin, ST: Heat–stable enterotoxin, RT-PCR: Reverse–transcriptase polymerase chain reaction, CD4: Cluster of differentiation 4, HIV: Human immunodeficiency virus, RUQ: Right-upper quadrant, VIP: Vasoactive intestinal peptide, GI: Gastrointestinal, FAP: Familial adenomatous polyposis, HNPCC: Hereditary nonpolyposis colorectal cancer, MTP: Microsomal triglyceride transfer protein, Scl‑70: Anti–topoisomerase I, TSH: Thyroid-stimulating hormone, T4: Thyroxine, T3: Triiodothyronine, DTR: Deep tendon reflex, RNA: Ribonucleic acid
# Related Chapters
- Constipation
- Gastroenteritis | Diarrhea
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2], Sadaf Sharfaei M.D.[3], Seyedmahdi Pahlavani, M.D. [4], Cafer Zorkun, M.D., Ph.D. [5], M.Umer Tariq [6]
Synonyms and keywords: Loose stools
# Overview
Diarrhea is defined as the passage of unformed or abnormally liquid stools at an increased frequency. Diarrhea can be classified as acute or chronic. Acute diarrhea has a duration of less than 2 weeks and may be classified on the basis of etiology and presentation. On the basis of etiology, acute diarrhea may be classified into infectious and non-infectious subtypes. Subacute diarrhea is defined as a diarrhea lasting for two to four weeks. Although chronic diarrhea has multiple definitions, a current working definition is the production of loose stools for longer than 4 weeks. Frequent defecation with normal consistency is termed psuedo-diarrhea. There are 3 basic categories of chronic diarrhea: watery, fatty (malabsorption), and inflammatory (with blood and pus). The diagnosis is based on duration of symptoms, signs, microscopic stool examination and culture, stool osmolarity, and in some rare instances colonoscopy. The treatment is mainly based on severity of symptoms, etiology and availability of medications. Prevention is based on proper maintaining the filtration systems at water plants, hand wash, and effectively use of alcohol-based hand sanitizers. Vaccination for some viruses, such as Rotavirus is a part of preventive measures.
# Classification
Diarrhea can be classified as acute or chronic depending on the duration of onset of symptoms. Acute and chronic diarrhea can be further classified as follows:
## Classification of Acute Diarrhea
## Classification of Chronic Diarrhea
# Differential Diagnosis of Diarrhea of other diseases
To review the differential diagnosis of diarrhea, click here.
To review the differential diagnosis of acute diarrhea, click here.
To review the differential diagnosis of chronic diarrhea, click here.
To review the differential diagnosis of traveler's diarrhea, click here.
To review the differential diagnosis of acute watery diarrhea, click here.
To review the differential diagnosis of acute bloody diarrhea, click here.
To review the differential diagnosis of acute fatty diarrhea, click here.
To review the differential diagnosis of chronic watery diarrhea, click here.
To review the differential diagnosis of chronic bloody diarrhea, click here.
To review the differential diagnosis of chronic fatty diarrhea, click here.
To review the differential diagnosis of acute diarrhea and fever, click here.
To review the differential diagnosis of chronic diarrhea and fever, click here.
To review the differential diagnosis of acute diarrhea and abdominal pain, click here.
To review the differential diagnosis of chronic diarrhea and abdominal pain, click here.
To review the differential diagnosis of acute diarrhea and weight loss, click here.
To review the differential diagnosis of chronic diarrhea and weight loss, click here.
To review the differential diagnosis of acute diarrhea, fever, and abdominal pain, click here.
To review the differential diagnosis of chronic diarrhea, fever, and abdominal pain, click here.
To review the differential diagnosis of acute diarrhea, abdominal pain, and weight loss, click here.
To review the differential diagnosis of chronic diarrhea, abdominal pain, and weight loss, click here.
## Diarrhea
The following table outlines the major differential diagnoses of diarrhea.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]
Abbreviations: GI: Gastrointestinal, CBC: Complete blood count, WBC: White blood cell, RBC: Red blood cell, Plt: Platelet, Hgb: Hemoglobin, ESR: Erythrocyte sedimentation rate, CRP: C–reactive protein, IgE: Immunoglobulin E, IgA: Immunoglobulin A, ETEC: Escherichia coli enteritis, EPEC: Enteropathogenic Escherichia coli, EIEC: Enteroinvasive Escherichia coli, EHEC: Enterohemorrhagic Escherichia coli, EAEC: Enteroaggregative Escherichia coli, Nl: Normal, ASCA: Anti saccharomyces cerevisiae antibodies, ANCA: Anti–neutrophil cytoplasmic antibody, DNA: Deoxyribonucleic acid, CFTR: Cystic fibrosis transmembrane conductance regulator, SLC10A2: Solute carrier family 10 member 2, SeHCAT: Selenium homocholic acid taurine or tauroselcholic acid, IEL: Intraepithelial lymphocytes, MRCP: Magnetic resonance cholangiopancreatography, ANA: Antinuclear antibodies, AMA: Anti-mitochondrial antibody, LDH: Lactate dehydrogenase, CPK: Creatine phosphokinase, PCR: Polymerase chain reaction, ELISA: Enzyme–linked immunosorbent assay, LT: Heat–labile enterotoxin, ST: Heat–stable enterotoxin, RT-PCR: Reverse–transcriptase polymerase chain reaction, CD4: Cluster of differentiation 4, HIV: Human immunodeficiency virus, RUQ: Right-upper quadrant, VIP: Vasoactive intestinal peptide, GI: Gastrointestinal, FAP: Familial adenomatous polyposis, HNPCC: Hereditary nonpolyposis colorectal cancer, MTP: Microsomal triglyceride transfer protein, Scl‑70: Anti–topoisomerase I, TSH: Thyroid-stimulating hormone, T4: Thyroxine, T3: Triiodothyronine, DTR: Deep tendon reflex, RNA: Ribonucleic acid
# Related Chapters
- Constipation
- Gastroenteritis | https://www.wikidoc.org/index.php/Acute_Infectious_Diarrheal_Diseases | |
5ce5f61e854865e90ba90db274058b2a0a3198b4 | wikidoc | Leukemia | Leukemia
Synonyms and keywords: Leukaemia
# Overview
Leukemia (Greek leukos, “white”; haima, “blood”) can be defined as a group of hematopoietic stem cell malignancies due to genetic abnormalities that may lead to clonal proliferation of these cells. These group of diseases are classified based on the type of hematopoietic stem cell involved and the duration of the disease. The leukemias are the most common malignancies among children younger than 15 years. Among them, Acute Lymphoblastic Leukemia (ALL) is the most common leukemia and accounts for 77% of childhood leukemia. However, Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia in adults, and it accounts for 30% of all leukemias in the United States. The increased rate of proliferation and decreased rate of apoptosis in this progeny of cells may compromise normal bone marrow function and ultimately result in marrow failure. Clinical manifestations, diagnosis, laboratory findings, and therapy are different according to the type of malignancy.
# Classification
Leukemia may be classified as follows:
# Differentiating Leukemia from other Diseases
Leukemia must be differentiated from various diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukemia, prolymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. Based on the expression of cell surface markers, the table below differentiates different types of leukemia from other diseases that cause similar clinical presentations:
# Epidemiology and Demographics
## Prevalence
- In the United States, the age-adjusted prevalence of leukemia is 75.3 per 100,000 in 2011.
## Incidence
- The delay-adjusted incidence of leukemia in 2011 was estimated as 15.48 per 100,000 individuals in the United States.
- In 2011, the age-adjusted incidence of leukemia was 13.66 per 100,000 individuals in the United States.
## Age
- The overall age-adjusted incidence of leukemia in the United States between 2007 and 2011 was 13 per 100,000 occurrences. The age-adjusted incidence of leukemia by age category is:
Under 65 years: 6.5 per 100,000
65 and over: 57.9 per 100,000
- Under 65 years: 6.5 per 100,000
- 65 and over: 57.9 per 100,000
- Shown below is a table depicting the overall age-adjusted incidence of leukemia per 100,000 individuals by age in the United States between 2007 and 2011 for the different types of leukemia.
## Gender
- In the United States, the age-adjusted prevalence of leukemia by gender in 2011 was:
In males: 92.7 per 100,000
In females: 60.7 per 100,000
- In males: 92.7 per 100,000
- In females: 60.7 per 100,000
- In the United States, the delay-adjusted incidence of leukemia by gender in 2011 was:
In males: 19.93 per 100,000 persons
In females: 11.89 per 100,000 persons
- In males: 19.93 per 100,000 persons
- In females: 11.89 per 100,000 persons
- In the United States, the age-adjusted incidence of leukemia by gender on 2011 was:
In males: 17.58 per 100,000 persons
In females: 10.49 per 100,000 persons
- In males: 17.58 per 100,000 persons
- In females: 10.49 per 100,000 persons
- Shown below is an image depicting the delay-adjusted incidence and observed incidence of leukemia by gender and race in the United States between 1975 and 2011. These graphs were gathered from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.
## Race
- Shown below is a table depicting the age-adjusted prevalence of leukemia by race in 2011 in the United States.
- Shown below is an image depicting the incidence of leukemia by race in the United States between 1975 and 2011.
API: Asian/Pacific Islander; AI/AN: American Indian/ Alaska Native
# Prognosis
## 5-Year Survival
- Between 2004 and 2010, the 5-year relative survival of patients with leukemia was 60.3%.
- When stratified by age, the 5-year relative survival of patients with leukemia was 68.5% (44.1% for patients <65 and ≥ 65 years of age respectively).
- Shown below is a table depicting the 5-year relative survival of patients by the type of leukemia in the United States between 2004 and 2010. | Leukemia
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2], Usama Talib, BSc, MD [3], Sadaf Sharfaei M.D.[4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]
Synonyms and keywords: Leukaemia
# Overview
Leukemia (Greek leukos, “white”; haima, “blood”) can be defined as a group of hematopoietic stem cell malignancies due to genetic abnormalities that may lead to clonal proliferation of these cells. These group of diseases are classified based on the type of hematopoietic stem cell involved and the duration of the disease. The leukemias are the most common malignancies among children younger than 15 years. Among them, Acute Lymphoblastic Leukemia (ALL) is the most common leukemia and accounts for 77% of childhood leukemia. However, Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia in adults, and it accounts for 30% of all leukemias in the United States. The increased rate of proliferation and decreased rate of apoptosis in this progeny of cells may compromise normal bone marrow function and ultimately result in marrow failure. Clinical manifestations, diagnosis, laboratory findings, and therapy are different according to the type of malignancy.
# Classification
Leukemia may be classified as follows:
# Differentiating Leukemia from other Diseases
Leukemia must be differentiated from various diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukemia, prolymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. Based on the expression of cell surface markers, the table below differentiates different types of leukemia from other diseases that cause similar clinical presentations:[1]
# Epidemiology and Demographics
## Prevalence
- In the United States, the age-adjusted prevalence of leukemia is 75.3 per 100,000 in 2011.[29]
## Incidence
- The delay-adjusted incidence of leukemia in 2011 was estimated as 15.48 per 100,000 individuals in the United States.
- In 2011, the age-adjusted incidence of leukemia was 13.66 per 100,000 individuals in the United States.
## Age
- The overall age-adjusted incidence of leukemia in the United States between 2007 and 2011 was 13 per 100,000 occurrences. The age-adjusted incidence of leukemia by age category is:
Under 65 years: 6.5 per 100,000
65 and over: 57.9 per 100,000
- Under 65 years: 6.5 per 100,000
- 65 and over: 57.9 per 100,000
- Shown below is a table depicting the overall age-adjusted incidence of leukemia per 100,000 individuals by age in the United States between 2007 and 2011 for the different types of leukemia.
## Gender
- In the United States, the age-adjusted prevalence of leukemia by gender in 2011 was:
In males: 92.7 per 100,000
In females: 60.7 per 100,000
- In males: 92.7 per 100,000
- In females: 60.7 per 100,000
- In the United States, the delay-adjusted incidence of leukemia by gender in 2011 was:
In males: 19.93 per 100,000 persons
In females: 11.89 per 100,000 persons
- In males: 19.93 per 100,000 persons
- In females: 11.89 per 100,000 persons
- In the United States, the age-adjusted incidence of leukemia by gender on 2011 was:
In males: 17.58 per 100,000 persons
In females: 10.49 per 100,000 persons
- In males: 17.58 per 100,000 persons
- In females: 10.49 per 100,000 persons
- Shown below is an image depicting the delay-adjusted incidence and observed incidence of leukemia by gender and race in the United States between 1975 and 2011. These graphs were gathered from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.
## Race
- Shown below is a table depicting the age-adjusted prevalence of leukemia by race in 2011 in the United States.
- Shown below is an image depicting the incidence of leukemia by race in the United States between 1975 and 2011.
API: Asian/Pacific Islander; AI/AN: American Indian/ Alaska Native
# Prognosis
## 5-Year Survival
- Between 2004 and 2010, the 5-year relative survival of patients with leukemia was 60.3%.
- When stratified by age, the 5-year relative survival of patients with leukemia was 68.5% (44.1% for patients <65 and ≥ 65 years of age respectively).
- Shown below is a table depicting the 5-year relative survival of patients by the type of leukemia in the United States between 2004 and 2010. | https://www.wikidoc.org/index.php/Acute_and_chronic_leukemias | |
394efb822e333c981889fd98212a2db5e7bf26d7 | wikidoc | AdaBoost | AdaBoost
AdaBoost, short for Adaptive Boosting, is a machine learning algorithm, formulated by Yoav Freund and Robert Schapire. It is a meta-algorithm, and can be used in conjunction with many other learning algorithms to improve their performance. AdaBoost is adaptive in the sense that subsequent classifiers built are tweaked in favor of those instances misclassified by previous classifiers. AdaBoost is sensitive to noisy data and outliers. Otherwise, it is less susceptible to the overfitting problem than most learning algorithms.
AdaBoost calls a weak classifier repeatedly in a series of rounds t = 1,\ldots,T. For each call a distribution of weights D_{t} is updated that indicates the importance of examples in the data set for the classification. On each round, the weights of each incorrectly classified example are increased (or alternative, the weights of each correctly classified example are decreased), so that the new classifier focuses more on those examples.
# The algorithm for the binary classification task
Given: (x_{1},y_{1}),\ldots,(x_{m},y_{m}) where x_{i} \in X,\, y_{i} \in Y = \{-1, +1\}
Initialise D_{1}(i) = \frac{1}{m}, i=1,\ldots,m.
For t = 1,\ldots,T:
- Find the classifier h_{t} : X \to \{-1,+1\} that minimizes the error with respect to the distribution D_{t}: h_{t} = \arg \min_{h_{j} \in \mathcal{H}} \epsilon_{j}, where \epsilon_{j} = \sum_{i=1}^{m} D_{t}(i)
- Prerequisite: \epsilon_{t} , otherwise stop.
- Choose \alpha_{t} \in \mathbf{R}, typically \alpha_{t}=\frac{1}{2}\textrm{ln}\frac{1-\epsilon_{t}}{\epsilon_{t}} where \epsilon_{t} is the weighted error rate of classifier h_{t}.
- Update:
D_{t+1}(i) = \frac{ D_{t}(i) \, e^{- \alpha_{t} y_{i} h_{t}(x_{i})} }{ Z_{t} }
where Z_{t} is a normalization factor (chosen so that D_{t+1} will be a probability distribution, i.e. sum one over all x).
Output the final classifier:
H(x) = \textrm{sign}\left( \sum_{t=1}^{T} \alpha_{t}h_{t}(x)\right)
The equation to update the distribution D_{t} is constructed so that:
e^{- \alpha_{t} y_{i} h_{t}(x_{i})} \begin{cases} 1, & y(i) \ne h_{t}(x_{i}) \end{cases}
Thus, after selecting an optimal classifier h_{t} \, for the distribution D_{t} \,, the examples x_{i} \, that the classifier h_{t} \, identified correctly are weighted less and those that it identified incorrectly are weighted more. Therefore, when the algorithm is testing the classifiers on the distribution D_{t+1} \,, it will select a classifier that better identifies those examples that the previous classifer missed.
# Statistical Understanding of Boosting
Boosting can be seen as minimization of a convex loss function over a convex set of functions. Specifically, the loss being minimized is the exponential loss
and we are seeking a function | AdaBoost
AdaBoost, short for Adaptive Boosting, is a machine learning algorithm, formulated by Yoav Freund and Robert Schapire. It is a meta-algorithm, and can be used in conjunction with many other learning algorithms to improve their performance. AdaBoost is adaptive in the sense that subsequent classifiers built are tweaked in favor of those instances misclassified by previous classifiers. AdaBoost is sensitive to noisy data and outliers. Otherwise, it is less susceptible to the overfitting problem than most learning algorithms.
AdaBoost calls a weak classifier repeatedly in a series of rounds <math> t = 1,\ldots,T</math>. For each call a distribution of weights <math>D_{t}</math> is updated that indicates the importance of examples in the data set for the classification. On each round, the weights of each incorrectly classified example are increased (or alternative, the weights of each correctly classified example are decreased), so that the new classifier focuses more on those examples.
# The algorithm for the binary classification task
Given: <math>(x_{1},y_{1}),\ldots,(x_{m},y_{m})</math> where <math>x_{i} \in X,\, y_{i} \in Y = \{-1, +1\}</math>
Initialise <math>D_{1}(i) = \frac{1}{m}, i=1,\ldots,m.</math>
For <math>t = 1,\ldots,T</math>:
- Find the classifier <math>h_{t} : X \to \{-1,+1\}</math> that minimizes the error with respect to the distribution <math>D_{t}</math>: <math>h_{t} = \arg \min_{h_{j} \in \mathcal{H}} \epsilon_{j}</math>, where <math> \epsilon_{j} = \sum_{i=1}^{m} D_{t}(i)[y_i \ne h_{j}(x_{i})]</math>
- Prerequisite: <math>\epsilon_{t} < 0.5</math>, otherwise stop.
- Choose <math>\alpha_{t} \in \mathbf{R}</math>, typically <math>\alpha_{t}=\frac{1}{2}\textrm{ln}\frac{1-\epsilon_{t}}{\epsilon_{t}}</math> where <math>\epsilon_{t}</math> is the weighted error rate of classifier <math>h_{t}</math>.
- Update:
<math>D_{t+1}(i) = \frac{ D_{t}(i) \, e^{- \alpha_{t} y_{i} h_{t}(x_{i})} }{ Z_{t} }</math>
where <math>Z_{t}</math> is a normalization factor (chosen so that <math>D_{t+1}</math> will be a probability distribution, i.e. sum one over all x).
Output the final classifier:
<math>H(x) = \textrm{sign}\left( \sum_{t=1}^{T} \alpha_{t}h_{t}(x)\right)</math>
The equation to update the distribution <math>D_{t}</math> is constructed so that:
<math>e^{- \alpha_{t} y_{i} h_{t}(x_{i})} \begin{cases} <1, & y(i)=h_{t}(x_{i}) \\ >1, & y(i) \ne h_{t}(x_{i}) \end{cases}</math>
Thus, after selecting an optimal classifier <math>h_{t} \,</math> for the distribution <math>D_{t} \,</math>, the examples <math>x_{i} \,</math> that the classifier <math>h_{t} \,</math> identified correctly are weighted less and those that it identified incorrectly are weighted more. Therefore, when the algorithm is testing the classifiers on the distribution <math>D_{t+1} \,</math>, it will select a classifier that better identifies those examples that the previous classifer missed.
# Statistical Understanding of Boosting
Boosting can be seen as minimization of a convex loss function over a convex set of functions. [1] Specifically, the loss being minimized is the exponential loss
and we are seeking a function | https://www.wikidoc.org/index.php/AdaBoost | |
e60e9c5fdf2788271c3404912d51a5f3ace46542 | wikidoc | Adderall | Adderall
Synonyms: (+/-)-beta-Phenylisopropylamine, (+/-)-Benzedrine, (+/-)-Desoxynorephedrine, 1-Methyl-2-phenylethylamine, 1-Phenyl-2-aminopropane, 3-Methoxy-a-methylbenzeneethanamine, 3-Methoxyamphetamine, 3-Methoxyphenylisopropylamine, alpha-Methylbenzeneethaneamine, Amphetamine Sulfate, beta-Aminopropylbenzene, dl-1-Phenyl-2-aminopropane, DL-alpha-Methylphenethylamine, dl-Amphetamine, dl-Benzedrine, Fenylo-izopropylaminyl, m-Methoxy-a-methylphenethylamine, m-Methoxyamphetamine, Methamphetamine HCL, amine, Phenylisopropylamine, Amfetamine, beta-phenyl-isopropylamine.
Brand Names: Actedron, Adipan, Allodene, Anorexide, Anorexine, Benzebar, Benzedrine, Benzolone, Desoxyn, Dexampex, Dexedrine, Dextrostat, Elastonon, Fenamin, Ferndex, Finam, Isoamycin, Isoamyne, Isomyn, Mecodrin, Methampex, Norephedrane, Novydrine, Oktedrin, Ortedrine, Paredrine, Percomon, Phenamine, Phenedrine, Profamina, Propisamine, Psychedrine, Raphetamine, Rhinalator, Simpatedrin, Simpatina, Sympamin, Sympamine, Sympatedrine, Weckamine.
# Dosing and Administration
Regardless of indication, amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted according to the therapeutic needs and response of the patient. Late evening doses should be avoided because of the resulting insomnia.
For the treatment of Attention Deficit Hyperactivity Disorder (ADHD):
Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained.
In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.
For Narcolepsy:
Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response.
Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6-12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
FDA Package Insert Resources
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en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Adderall
Return to top
# Publication Resources
Most Recent Articles on Adderall
Review Articles on Adderall
Articles on Adderall in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Adderall
Return to top
# Trial Resources
Ongoing Trials with Adderall at Clinical Trials.gov
Trial Results with Adderall
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# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Adderall
Cochrane Collaboration on Adderall
Cost Effectiveness of Adderall
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Adapted from the FDA Package Insert. | Adderall
Synonyms: (+/-)-beta-Phenylisopropylamine, (+/-)-Benzedrine, (+/-)-Desoxynorephedrine, 1-Methyl-2-phenylethylamine, 1-Phenyl-2-aminopropane, 3-Methoxy-a-methylbenzeneethanamine, 3-Methoxyamphetamine, 3-Methoxyphenylisopropylamine, alpha-Methylbenzeneethaneamine, Amphetamine Sulfate, beta-Aminopropylbenzene, dl-1-Phenyl-2-aminopropane, DL-alpha-Methylphenethylamine, dl-Amphetamine, dl-Benzedrine, Fenylo-izopropylaminyl, m-Methoxy-a-methylphenethylamine, m-Methoxyamphetamine, Methamphetamine HCL, [1-(3-Methoxyphenyl)-2-propyl]amine, Phenylisopropylamine, Amfetamine, beta-phenyl-isopropylamine.
Brand Names: Actedron, Adipan, Allodene, Anorexide, Anorexine, Benzebar, Benzedrine, Benzolone, Desoxyn, Dexampex, Dexedrine, Dextrostat, Elastonon, Fenamin, Ferndex, Finam, Isoamycin, Isoamyne, Isomyn, Mecodrin, Methampex, Norephedrane, Novydrine, Oktedrin, Ortedrine, Paredrine, Percomon, Phenamine, Phenedrine, Profamina, Propisamine, Psychedrine, Raphetamine, Rhinalator, Simpatedrin, Simpatina, Sympamin, Sympamine, Sympatedrine, Weckamine.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Dosing and Administration
Regardless of indication, amphetamines should be administered at the lowest effective dosage and dosage should be individually adjusted according to the therapeutic needs and response of the patient. Late evening doses should be avoided because of the resulting insomnia.
For the treatment of Attention Deficit Hyperactivity Disorder (ADHD):
Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained.
In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.
For Narcolepsy:
Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response.
Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6-12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
FDA Package Insert Resources
Indications, Contraindications, Side Effects, Drug Interactions, etc.
Calculate Creatine Clearance
On line calculator of your patients Cr Cl by a variety of formulas.
Convert pounds to Kilograms
On line calculator of your patients weight in pounds to Kg for dosing estimates.
Publication Resources
Recent articles, WikiDoc State of the Art Review, Textbook Information
Trial Resources
Ongoing Trials, Trial Results
Guidelines & Evidence Based Medicine Resources
US National Guidelines, Cochrane Collaboration, etc.
Media Resources
Slides, Video, Images, MP3, Podcasts, etc.
Patient Resources
Discussion Groups, Handouts, Blogs, News, etc.
International Resources
en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Adderall
Return to top
# Publication Resources
Most Recent Articles on Adderall
Review Articles on Adderall
Articles on Adderall in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Adderall
Return to top
# Trial Resources
Ongoing Trials with Adderall at Clinical Trials.gov
Trial Results with Adderall
Return to top
# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Adderall
Cochrane Collaboration on Adderall
Cost Effectiveness of Adderall
Return to top
# Media Resources
Powerpoint Slides on Adderall
Images of Adderall
Podcasts & MP3s on Adderall
Videos on Adderall
Return to top
# Patient Resources
Patient Resources on Adderall
Discussion Groups on Adderall
Patient Handouts on Adderall
Blogs on Adderall
Adderall in the News
Adderall in the Marketplace
Return to top
# International Resources
Adderall en Español
Return to top
Adapted from the FDA Package Insert. | https://www.wikidoc.org/index.php/Adderall | |
1fa7d7dc72b60b2544522221e27d9cdb5ec96902 | wikidoc | Adefovir | Adefovir
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# Black Box Warning
# Overview
Adefovir is a nucleotide analogue that is FDA approved for the treatment of chronic hepatitis B. There is a Black Box Warning for this drug as shown here. Common adverse reactions include asthenia, increased creatinine.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Adefovir Dipivoxil Tablets are indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
- This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.
- For patients 12 to less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function.
### Dosage
- The recommended dose of Adefovir Dipivoxil Tablets in chronic hepatitis B patients for patients 12 years of age and older with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.
- Adefovir Dipivoxil Tablets is not recommended for use in children less than 12 years of age.
- Significantly increased drug exposures were seen when Adefovir Dipivoxil Tablets were administered to adult patients with renal impairment. Therefore, the dosing interval of Adefovir Dipivoxil Tablets should be adjusted in adult patients with baseline creatinine clearance less than 50 mL per minute using the following suggested guidelines (see Table 1). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated.
- Additionally, it is important to note that these guidelines were derived from data in patients with pre-existing renal impairment at baseline. They may not be appropriate for patients in whom renal insufficiency evolves during treatment with Adefovir Dipivoxil Tablets . Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
- The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute; therefore, no dosing recommendation is available for these patients.
- No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency
### DOSAGE FORMS AND STRENGTHS
- Adefovir Dipivoxil is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white to off white, round, flat faced beveled edged tablets, debossed "Σ 3" on one side and plain on the other side.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adefovir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adefovir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Adefovir in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adefovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adefovir in pediatric patients.
# Contraindications
- Adefovir Dipivoxil Tablets are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
# Warnings
- Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Adefovir Dipivoxil Tablets. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least several months in patients who discontinue Adefovir Dipivoxil Tablets. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
- In clinical trials of Adefovir Dipivoxil Tablets, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of Adefovir Dipivoxil Tablets. These events were identified in studies GS-98-437 and GS-98-438 (N=492). Most of these events occurred within 12 weeks of drug discontinuation. These exacerbations generally occurred in the absence of HBeAg seroconversion, and presented as serum ALT elevations in addition to re-emergence of viral replication. In the HBeAg-positive and HBeAg-negative studies in patients with compensated liver function, the exacerbations were not generally accompanied by hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. Therefore, patients should be closely monitored after stopping treatment.
- Nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus was historically shown to be the treatment-limiting toxicity of adefovir dipivoxil therapy at substantially higher doses in HIV-infected patients (60 and 120 mg daily) and in chronic hepatitis B patients (30 mg daily). Chronic administration of Adefovir Dipivoxil Tablets (10 mg once daily) may result in delayed nephrotoxicity. The overall risk of nephrotoxicity in patients with adequate renal function is low. However, this is of special importance in patients at risk of or having underlying renal dysfunction and patients taking concomitant nephrotoxic agents such as cyclosporine, tacrolimus, aminoglycosides, vancomycin and non-steroidal anti-inflammatory drugs. It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Adefovir Dipivoxil Tablets.
- It is important to monitor renal function for all patients during treatment with Adefovir Dipivoxil Tablets, particularly for those with pre-existing or other risks for renal impairment. Patients with renal insufficiency at baseline or during treatment may require dose adjustment . The risks and benefits of Adefovir Dipivoxil Tablets treatment should be carefully evaluated prior to discontinuing Adefovir Dipivoxil Tablets in a patient with treatment-emergent nephrotoxicity.
- The efficacy and safety of Adefovir Dipivoxil Tablets have not been studied in patients less than 18 years of age with different degrees of renal impairment and no data are available to make dosage recommendations in these patients . Caution should be exercised when prescribing Adefovir Dipivoxil Tablets to adolescents with underlying renal dysfunction, and renal function in these patients should be closely monitored.
- Prior to initiating Adefovir Dipivoxil Tablets therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies, such as Adefovir Dipivoxil Tablets, that have activity against HIV in a chronic hepatitis B patient with unrecognized or untreated HIV infection may result in emergence of HIV resistance. Adefovir Dipivoxil Tablets has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of Adefovir Dipivoxil Tablets to treat patients with chronic hepatitis B co-infected with HIV.
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.
- A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Adefovir Dipivoxil Tablets therapy should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
- Adefovir Dipivoxil Tablets should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablet), COMPLERA® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate combination tablet), STRIBILD™ (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate combination tablet), and TRUVADA® (emtricitabine/tenofovir disoproxil fumarate combination tablet).
- Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome.
- In order to reduce the risk of resistance in patients with lamivudine resistant HBV, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy.
- In order to reduce the risk of resistance in all patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL with continued treatment.
- Long-term (144 week) data from Study 438 (N=124) show that patients with HBV DNA levels greater than 1000 copies/mL at Week 48 of treatment with Adefovir Dipivoxil Tablets were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in other sections of the labelling:
- Severe acute exacerbations of Hepatitis
- Nephrotoxicity
- 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.
- Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with Adefovir Dipivoxil Tablets.
- Adverse reactions to Adefovir Dipivoxil Tablets identified from placebo-controlled and open label studies include the following: asthenia, headache, abdominal pain, diarrhea, nausea, dyspepsia, flatulence, increased creatinine, and hypophosphatemia.
- The incidence of these adverse reactions in studies 437 and 438, where 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=294) or placebo (N=228) for 48 weeks is presented in Table 2. Patients who received open-label Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks.
- No patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or confirmed phosphorus decrease to 2 mg/dL or less by Week 48.
- By Week 96, 2% of Adefovir Dipivoxil Tablets-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine greater than or equal to 0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438, 4 of 125 patients (3%) had a confirmed increase of 0.5 mg/dL from baseline. The creatinine elevation resolved in 1 patient who permanently discontinued treatment and remained stable in 3 patients who continued treatment. For 65 patients who chose to continue Adefovir Dipivoxil Tablets for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration.
- In these studies, the overall incidence of adverse reactions with Adefovir Dipivoxil Tablets was similar to that reported with placebo. The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators.
- Pre- and Post-Liver Transplantation Patients
- Additional adverse reactions observed from an open-label study (Study 435) in pre- and post- liver transplantation patients with chronic hepatitis B and lamivudine-resistant hepatitis B administered Adefovir Dipivoxil Tablets once daily for up to 203 weeks include: abnormal renal function, renal failure, vomiting, rash, and pruritus.
- Changes in renal function occurred in pre-and post-liver transplantation patients with risk factors for renal dysfunction, including concomitant use of cyclosporine and tacrolimus, renal insufficiency at baseline, hypertension, diabetes, and on-study transplantation. Therefore, the contributory role of Adefovir Dipivoxil Tablets to these changes in renal function is difficult to assess.
- Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 37% and 53% of pre-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 32% and 51% of post-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Serum phosphorus values less than 2 mg/dL were observed in 3/226 (1.3%) of pre-liver transplantation patients and in 6/241 (2.5%) of post-liver transplantation patients by last study visit. Four percent (19 of 467) of patients discontinued treatment with Adefovir Dipivoxil Tablets due to renal adverse events.
- Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to less than 18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=115), or placebo (N=58) for 48 weeks.
- The safety profile of Adefovir Dipivoxil Tablets in patients 12 to less than 18 years of age (N=56) was similar to that observed in adults. No pediatric patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase to greater than or equal to 0.5 mg/dL or a confirmed phosphorus decrease to less than 2 mg/dL by Week 48.
## Postmarketing Experience
- In addition to adverse reaction reports from clinical trials, the following possible adverse reactions have also been identified during post-approval use of adefovir dipivoxil. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
- hypophosphatemia
- pancreatitis
- myopathy, osteomalacia (both associated with proximal renal tubulopathy)
(manifested as bone pain and may contribute to fractures), both associated with proximal renal tubulopathy.
- renal failure, Fanconi syndrome, proximal renal tubulopathy
# Drug Interactions
- Since adefovir is eliminated by the kidney, co-administration of Adefovir Dipivoxil Tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these co-administered drugs.
- Patients should be monitored closely for adverse events when Adefovir Dipivoxil Tablets is co-administered with drugs that are excreted renally or with other drugs known to affect renal function.
- Adefovir Dipivoxil Tablets should not be administered in combination with VIREAD
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of Adefovir Dipivoxil Tablets in pregnant women. Chronic hepatitis B is a serious condition that requires treatment. Adefovir Dipivoxil Tablets should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- Reproduction studies with oral administration of adefovir dipivoxil to pregnant rats and rabbits showed no evidence of embryotoxicity or teratogenicity at systemic exposures equivalent to 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose. However, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) occurred when adefovir was administered intravenously to pregnant rats at 38 times the human therapeutic exposure. These adverse reproductive effects did not occur following an intravenous dose where exposure was 12 times the human therapeutic exposure.
- Because animal reproduction studies are not always predictive of human response, Adefovir Dipivoxil Tablets should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits .
- To monitor fetal outcomes of pregnant women exposed to Adefovir Dipivoxil Tablets, a pregnancy registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adefovir in women who are pregnant.
### Labor and Delivery
- There are no studies in pregnant women and no data on the effect of Adefovir Dipivoxil Tablets on transmission of HBV from mother to infant. Therefore, appropriate infant immunizations should be used to prevent neonatal acquisition of hepatitis B virus.
### Nursing Mothers
- It is not known whether adefovir is excreted in human milk.
- Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Adefovir Dipivoxil Tablets, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Pediatric patients 12 to less than 18 years: The safety, efficacy, and pharmacokinetics of Adefovir Dipivoxil Tablets in pediatric patients (aged 12 to less than 18 years) were evaluated in a double-blind, randomized, placebo-controlled study (GS-US-103-518, Study 518) in 83 pediatric patients with chronic hepatitis B and compensated liver disease. The proportion of patients treated with Adefovir Dipivoxil Tablets who achieved the primary efficacy endpoint of serum HBV DNA less than 1,000 copies/mL and normal ALT levels at the end of 48 weeks blinded treatment was significantly greater (23%) when compared to placebo-treated patients (0%).
- Pediatric patients 2 to less than 12 years: Patients 2 to less than 12 years of age were also evaluated in Study 518. The efficacy of adefovir dipivoxil was not significantly different from placebo in patients less than 12 years of age.
- Adefovir Dipivoxil Tablets is not recommended for use in children below 12 years of age.
### Geriatic Use
- Clinical studies of Adefovir Dipivoxil Tablets did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised when prescribing to elderly patients since they have greater frequency of decreased renal or cardiac function due to concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Adefovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Adefovir with respect to specific racial populations.
### Renal Impairment
- It is recommended that the dosing interval for Adefovir Dipivoxil Tablets be modified in adult patients with baseline creatinine clearance less than 50 mL per minute. The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute or in adolescent patients with renal insufficiency; therefore, no dosing recommendations are available for these patients.
### Hepatic Impairment
There is no FDA guidance on the use of Adefovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Adefovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Adefovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months
- In patients at risk of or having underlying renal dysfunction, chronic administration of Adefovir Dipivoxil Tablets may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment
# IV Compatibility
There is limited information regarding IV Compatibility of Adefovir in the drug label.
# Overdosage
- Doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated with gastrointestinal side effects. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
- Following a 10 mg single dose of Adefovir Dipivoxil Tablets, a four-hour hemodialysis session removed approximately 35% of the adefovir dose.
# Pharmacology
## Mechanism of Action
- Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 µM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 µM and 0.97 µM, respectively.
## Structure
- Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV).
- The chemical name of adefovir dipivoxil is 9-2-bis(pivaloyloxy)methoxy-phosphinyl-methoxyethyladenine. It has a molecular formula of C20H32N5O8P, a molecular weight of 501.48 and the following structural formula:
- Adefovir dipivoxil is a white to off-white powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.
- Adefovir dipivoxil tablets are for oral administration. Each tablet contains 10 mg of adefovir dipivoxil and the following inactive ingredients: copovidone, anhydrous lactose, microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Adefovir in the drug label.
## Pharmacokinetics
- The pharmacokinetics of adefovir have been evaluated in healthy volunteers and patients with chronic hepatitis B. Adefovir pharmacokinetics are similar between these populations.
- Adefovir dipivoxil is a diester prodrug of the active moiety adefovir. Based on a cross study comparison, the approximate oral bioavailability of adefovir from Adefovir Dipivoxil Tablets is 59%.
- Following oral administration of a 10 mg single dose of Adefovir Dipivoxil Tablets to chronic hepatitis B patients (N=14), the peak adefovir plasma concentration (Cmax) was 18.4 ± 6.26 ng/mL (mean ± SD) and occurred between 0.58 and 4.00 hours (median=1.75 hours) post dose. The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng·h/mL. Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.
- The pharmacokinetics of adefovir in subjects with adequate renal function were not affected by once daily dosing of 10 mg Adefovir Dipivoxil Tablets over seven days. The impact of long-term once daily administration of 10 mg Adefovir Dipivoxil Tablets on adefovir pharmacokinetics has not been evaluated.
- Adefovir exposure was unaffected when a 10 mg single dose of Adefovir Dipivoxil Tablets was administered with food (an approximately 1000 kcal high-fat meal). Adefovir Dipivoxil Tablets may be taken without regard to food.
- In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% over the adefovir concentration range of 0.1 to 25 µg/mL. The volume of distribution at steady-state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 ± 75 and 352 ± 9 mL/kg, respectively.
- Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. Forty-five percent of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses of Adefovir Dipivoxil Tablets. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.
- Adefovir dipivoxil is rapidly converted to adefovir in vivo. At concentrations substantially higher (greater than 4000-fold) than those observed in vivo, adefovir did not inhibit any of the common human CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Adefovir is not a substrate for these enzymes. However, the potential for adefovir to induce CYP450 enzymes is unknown. Based on the results of these in vitro experiments and the renal elimination pathway of adefovir, the potential for CYP450 mediated interactions involving adefovir as an inhibitor or substrate with other medicinal products is low.
- The pharmacokinetics of adefovir have been evaluated in healthy adult volunteers following multiple dose administration of Adefovir Dipivoxil Tablets (10 mg once daily) in combination with lamivudine (100 mg once daily) (N=18), trimethoprim/sulfamethoxazole (160/800 mg twice daily) (N=18), acetaminophen (1000 mg four times daily) (N=20), ibuprofen (800 mg three times daily) (N=18), and enteric coated didanosine (400 mg) (N=21). The pharmacokinetics of adefovir have also been evaluated in post-liver transplantation patients following multiple dose administration of Adefovir Dipivoxil Tablets (10 mg once daily) in combination with tacrolimus (N=16). The pharmacokinetics of adefovir have been evaluated in healthy volunteers following single dose pegylated interferon α-2a (PEG-IFN) (180 mcg) (N=15).
- Adefovir did not alter the pharmacokinetics of lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, ibuprofen, enteric coated didanosine (didanosine EC), or tacrolimus. The evaluation of the effect of adefovir on the pharmacokinetics of pegylated interferon α-2a was inconclusive due to the high variability of pegylated interferon α-2a.
- The pharmacokinetics of adefovir were unchanged when Adefovir Dipivoxil Tablets was coadministered with lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, didanosine EC, tacrolimus (based on cross study comparison), and pegylated interferon α-2a. When Adefovir Dipivoxil Tablets was coadministered with ibuprofen (800 mg three times daily) increases in adefovir Cmax (33%), AUC (23%) and urinary recovery were observed. This increase appears to be due to higher oral bioavailability, not a reduction in renal clearance of adefovir.
- Apart from lamivudine, trimethoprim/sulfamethoxazole, and acetaminophen, the effects of co-administration of Adefovir Dipivoxil Tablets with drugs that are excreted renally, or other drugs known to affect renal function have not been evaluated.
- The effect of adefovir on cyclosporine concentrations is not known.
- No drug interaction studies have been performed in adolescent patients 12 to less than 18 years of age.
- Gender
- The pharmacokinetics of adefovir were similar in male and female patients.
- Race
- The pharmacokinetics of adefovir have been shown to be comparable in Caucasians and Asians. Pharmacokinetic data are not available for other racial groups.
- Geriatric Patients
- Pharmacokinetic studies have not been conducted in the elderly.
- Pediatric Patients
- The pharmacokinetics of adefovir were assessed from drug plasma concentrations in 53 HBeAg positive hepatitis B pediatric patients with compensated liver disease. The exposure of adefovir following a 48 week daily treatment with adefovir dipivoxil 10 mg tablet in pediatric patients aged 12 to less than 18 years of age(Cmax = 23.3 ng/ml and AUC0–24 = 248.8 ng·h/ml) was comparable to that observed in adult patients.
- Renal Impairment
- In adults with moderately or severely impaired renal function or with end-stage renal disease (ESRD) requiring hemodialysis, Cmax, AUC, and half-life (T1/2) were increased compared to adults with normal renal function. It is recommended that the dosing interval of adefovir dipivoxil tablets be modified in these patients.
- The pharmacokinetics of adefovir in non-chronic hepatitis B patients with varying degrees of renal impairment are described in Table 3. In this study, subjects received a 10 mg single dose of Adefovir Dipivoxil Tablets.
- A four-hour period of hemodialysis removed approximately 35% of the adefovir dose. The effect of peritoneal dialysis on adefovir removal has not been evaluated.
- The pharmacokinetics of adefovir have not been studied in adolescent patients with renal dysfunction .
- Hepatic Impairment
- The pharmacokinetics of adefovir following a 10 mg single dose of Adefovir Dipivoxil Tablets have been studied in non-chronic hepatitis B patients with hepatic impairment. There were no substantial alterations in adefovir pharmacokinetics in patients with moderate and severe hepatic impairment compared to unimpaired patients. No change in Adefovir Dipivoxil Tablets dosing is required in patients with hepatic impairment.
- The concentration of adefovir that inhibited 50% of viral DNA synthesis (EC50) in HBV transfected human hepatoma cell lines ranged from 0.2 to 2.5 µM. The combination of adefovir with lamivudine showed additive anti-HBV activity.
- Clinical isolates with genotypic changes conferring reduced susceptibility in cell culture to nucleoside analog reverse transcriptase inhibitors for the treatment of HBV infection have been observed. Long-term resistance analyses performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA demonstrated that amino acid substitutions rtN236T and rtA181T/V have been observed in association with adefovir resistance. In cell culture, the rtN236T substitution demonstrated 4- to 14-fold, the rtA181V substitution 2.5- to 4.2-fold, and the rtA181T substitution 1.3- to 1.9-fold reduced susceptibility to adefovir.
- In HBeAg-positive nucleoside-naïve patient isolates (Study GS-98-437, N=171), no adefovir resistance-associated substitutions were observed at Week 48. Sixty-five patients continued on long term treatment after a median duration on adefovir dipivoxil of 235 weeks (range 110–279 weeks). Isolates from 16 of 38 (42%) patients developed adefovir resistance-associated substitutions in the setting of virologic failure (confirmed increase of at least log10 HBV DNA copies/mL above nadir or never suppressed below 103 copies/mL). The substitutions included rtN236T (N=2), rtA181V (N=4), rtA181T (N=3), rtA181T+rtN236T (N=5), and rtA181V+rtN236T (N=2). In HBeAg-negative nucleoside-naïve patients (Study GS-98-438), isolates from 30 patients were identified with adefovir resistance-associated substitutions with a cumulative probability of 0%, 3%, 11%, 19%, and 30% at 48, 96, 144, 192, and 240 weeks, respectively. Of those 30 patients, 22 had a confirmed increase of at least log10 HBV DNA copies/mL above nadir or never achieved HBV DNA levels below 103 copies/mL; an additional 8 patients had adefovir resistance-associated substitutions without virologic failure. In addition, the long term (4 to 5 years) development of resistance to adefovir dipivoxil was significantly lower in patients who had serum HBV DNA below the limit of quantification (less than 1,000 copies/mL) at Week 48 as compared to patients who had serum HBV DNA above 1,000 copies/mL at Week 48.
- In an open-label study of pre- and post-liver transplantation patients (Study GS-98-435), isolates from 129 patients with clinical evidence of lamivudine-resistant hepatitis B virus at baseline were evaluated for adefovir resistance-associated substitutions. The incidence of adefovir resistance-associated (rtN236T or rtA181T/V) substitutions was 0% at 48 weeks. Isolates from four patients developed the rtN236T substitution after 72 weeks of adefovir dipivoxil therapy. Development of the rtN236T substitution was associated with serum HBV DNA rebound. All 4 patients who developed the rtN236T substitution in their HBV had discontinued lamivudine therapy before the development of genotypic resistance and all 4 lost the lamivudine resistance-associated substitutions present at baseline. In a study of 35 HIV/HBV co-infected patients with lamivudine-resistant HBV (Study 460i) who added adefovir dipivoxil to lamivudine, no adefovir resistance-associated substitutions were observed in HBV isolates from 15/35 patients tested up to 144 weeks of therapy.
- In a Phase 3 pediatric Study GS-US-103-518, HBV isolates from 49 of 56 pediatric subjects (aged 12 to 17 years) had serum HBV DNA greater than 169 copies/mL and were evaluated for adefovir resistance-associated substitutions. rtN236T and/or rtA181V adefovir resistance-associated substitutions were not observed at Week 48. However, the rtA181T substitution was present in baseline and Week 48 isolates from 2 pediatric patients.
- Recombinant HBV variants containing lamivudine-resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M + rtM204V, rtV173L + rtL180M + rtM204V) were susceptible to adefovir in cell culture. Adefovir dipivoxil has also demonstrated anti-HBV activity (median reduction in serum HBV DNA of 4.1 log10 copies/mL) in patients with HBV containing lamivudine-resistance-associated substitutions (Study 435). Adefovir also demonstrated in cell culture activity against HBV variants with entecavir resistance-associated substitutions (rtT184G, rtS202I, rtM250V). HBV variants with DNA polymerase substitutions rtT128N and rtR153Q or rtW153Q associated with resistance to hepatitis B virus immunoglobulin were susceptible to adefovir in cell culture.
- HBV variants expressing the adefovir resistance-associated substitution rtN236T showed no change in susceptibility to entecavir in cell culture, and a 2- to 3-fold decrease in lamivudine susceptibility. HBV mutants with the adefovir resistance-associated substitution rtA181V showed a range of decreased susceptibilities to lamivudine of 1- to 14-fold and a 12-fold decrease in susceptibility to entecavir. In patients whose HBV expressed the rtA181V substitution (N=2) or the rtN236T substitution (N=3), a reduction in serum HBV DNA of 2.4 to 3.1 and 2.0 to 5.1 log10 copies/mL, respectively, was observed when treatment with lamivudine was added to treatment with adefovir dipivoxil.
## Nonclinical Toxicology
- Long-term oral carcinogenicity studies of adefovir dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, adefovir dipivoxil was negative for carcinogenic findings. Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir dipivoxil was not clastogenic in the in vivo mouse micronucleus assay and adefovir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose.
- Animal reproduction studies were conducted in rats and rabbits with orally administered adefovir dipivoxil and intravenously administered adefovir.
- In rats and rabbits, no embryotoxicity or teratogenicity was shown from oral administration of adefovir dipivoxil at maternal doses producing systemic exposures approximately 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose of 10 mg/day.
- When pregnant rats were administered intravenous adefovir at maternally toxic doses associated with systemic exposure 38 times that in humans, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were observed. No adverse effects on development were seen with intravenous adefovir administered to pregnant rats at a systemic exposure 12 times that in humans.
- Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3 to 10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.
# Clinical Studies
- Study 437 was a randomized, double-blind, placebo-controlled, three-arm-study in patients with HBeAg-positive chronic hepatitis B that allowed for a comparison between placebo and Adefovir Dipivoxil Tablets. The median age of patients was 33 years. Seventy-four percent were male, 59% were Asian, 36% were Caucasian, and 24% had prior interferon-a treatment. At baseline, patients had a median total Knodell Histology Activity Index (HAI) score of 10, a median serum HBV DNA level as measured by the Roche Amplicor Monitor polymerase chain reaction (PCR) assay (LLOQ = 1000 copies/mL) of 8.36 log10 copies/mL and a median ALT level of 2.3 times the upper limit of normal.
- Study 438 was a randomized, double-blind, placebo-controlled study in patients who were HBeAg-negative at screening, and anti-HBe positive. The median age of patients was 46 years. Eighty-three percent were male, 66% were Caucasian, 30% were Asian and 41% had prior interferon-a treatment. At baseline, the median total Knodell HAI score was 10, the median serum HBV DNA level as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.08 log10 copies/mL, and the median ALT was 2.3 times the upper limit of normal.
- The primary efficacy endpoint in both studies was histological improvement at Week 48; results of which are shown in Table 4.
- In Study 437, continued treatment with Adefovir Dipivoxil Tablets to 72 weeks resulted in continued maintenance of mean reductions in serum HBV DNA observed at Week 48. An increase in the proportion of patients with ALT normalization was also observed in Study 437. The effect of continued treatment with Adefovir Dipivoxil Tablets on seroconversion is unknown.
- In Study 438, patients who received Adefovir Dipivoxil Tablets during the first 48 weeks were re-randomized in a blinded manner to continue on Adefovir Dipivoxil Tablets or receive placebo for an additional 48 weeks. At Week 96, 50 of 70 (71%) of patients who continued treatment with Adefovir Dipivoxil Tablets had undetectable HBV DNA levels (less than 1000 copies/mL), and 47 of 64 (73%) of patients had ALT normalization. HBV DNA and ALT levels returned towards baseline in most patients who stopped treatment with Adefovir Dipivoxil Tablets.
- From 141 eligible patients, there were 125 (89%) patients in Study 438 who chose to continue Adefovir Dipivoxil Tablets for up to 192 weeks or 240 weeks (4 years or 5 years). As these patients had already received Adefovir Dipivoxil Tablets for at least 48 weeks and appeared to be experiencing a benefit, they are not necessarily representative of patients initiating Adefovir Dipivoxil Tablets. Of these patients, 89/125 (71%) and 47/70 (67%) had an undetectable HBV DNA level (less than 1000 copies/mL) at Week 192 and Week 240, respectively. Of the patients who had an elevated ALT at baseline, 77/104 (74%) and 42/64 (66%) had a normal ALT at Week 192 and Week 240, respectively. Six (5%) patients experienced HBsAg loss.
- Intent-to-Treat population (patients with ≥1 dose of study drug) with assessable baseline biopsies.
- Adefovir Dipivoxil Tablets were also evaluated in an open-label, uncontrolled study of 467 chronic hepatitis B patients pre- (N=226) and post- (N=241) liver transplantation with clinical evidence of lamivudine- resistant hepatitis B virus (Study 435). At baseline, 60% of pre-liver transplantation patients were classified as Child-Pugh-Turcotte score of Class B or C. The median baseline HBV DNA as measured by the Roche Amplicor (LLOQ = 1000 copies/mL) was 7.4 and 8.2 log10 copies/mL, and the median baseline ALT was 1.8 and 2.0 times the upper limit of normal in pre- and post-liver transplantation patients, respectively. Results of this study are displayed in Table 7. Treatment with Adefovir Dipivoxil Tablets resulted in a similar reduction in serum HBV DNA regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. The significance of the efficacy results listed in Table 7 as they relate to clinical outcomes is not known.
- In Study 461, a double-blind, active controlled study in 59 chronic hepatitis B patients with clinical evidence of lamivudine-resistant hepatitis B virus, patients were randomized to receive either Adefovir Dipivoxil Tablets monotherapy or Adefovir Dipivoxil Tablets in combination with lamivudine 100 mg or lamivudine 100 mg alone. At Week 48, the mean ± SD decrease in serum HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 4.00 ± 1.41 log10 copies/mL for patients treated with Adefovir Dipivoxil Tablets and 3.46 ± 1.10 log10 copies/mL for patients treated with Adefovir Dipivoxil Tablets in combination with lamivudine. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log10 copies/mL in patients receiving lamivudine alone. ALT normalized in 47% of patients treated with Adefovir Dipivoxil Tablets, in 53% of patients treated with Adefovir Dipivoxil Tablets in combination with lamivudine, and 5% of patients treated with lamivudine alone. The significance of these findings as they relate to clinical outcomes is not known.
- Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to less than 18 years) with chronic hepatitis B (CHB) infection and elevated ALT were randomized 2:1 (115 receiving adefovir dipivoxil and 58 receiving placebo). Randomization was stratified by prior treatment and age 2 to less than 7 years old (cohort 1), 7 to less than 12 years old (cohort 2), and 12 to less than 18 years old (cohort 3). All patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts 1 and 2 received an investigational suspension formulation (0.3 mg/kg/day cohort 1, 0.25 mg/kg/day cohort 2) once daily. The primary efficacy endpoint was HBV DNA less than 1000 copies/mL plus normalization of ALT at the end of Week 48.
- In cohort 3 (N=83), significantly more patients treated with Adefovir Dipivoxil Tablets achieved the primary efficacy endpoint at the end of 48 weeks of blinded treatment (23%) when compared to placebo-treated patients (0%). The proportion of patients from cohorts 1 and 2 who responded to treatment with adefovir dipivoxil was not statistically significant when compared to the placebo arm, although the adefovir plasma concentrations in these patients were comparable to those observed in older patients. Overall, 22 of 115 (19%) of pediatric patients who received adefovir dipivoxil versus 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48
# How Supplied
- Adefovir Dipivoxil is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white are to off-white, round, flat faced beveled edged tablets, debossed "∑ 3" on one side and plain on the other side. They are packaged as follows: Bottles of 30 tablets (NDC 42794-003-08) containing polyester and desiccant and closed with a child-resistant closure.
## Storage
- Store in original container at 25 °C (77 °F), excursions permitted to 15° to 30 °C (59° to 86 °F) (see USP Controlled Room Temperature).
- Do not use if seal over bottle opening is broken or missing.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL- ADEFOVIR DIPIVOXIL 10 MG BOTTLE LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Instructions for Safe Use
- See FDA-APPROVED PATIENT LABELING (PATIENT INFORMATION)
- Physicians should inform patients of the potential risks and benefits of Adefovir Dipivoxil Tablets and of alternative modes of therapy.
- Physicians should instruct their patients to:
- Read the Patient Package Insert before starting Adefovir Dipivoxil Tablets therapy.
- Follow a regular dosing schedule to avoid missing doses.
- Immediately report any severe abdominal pain, muscle pain, yellowing of the eyes, dark urine, pale stools, and/or loss in appetite.
- Inform their doctor or pharmacist if they develop any unusual symptom(s), or if any known symptom persists or worsens.
- Patients should remain under the care of a physician when using Adefovir Dipivoxil Tablets.
- Patients should be advised that:
- The optimal duration of Adefovir Dipivoxil Tablets treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.
- Patients should not discontinue Adefovir Dipivoxil Tablets without first informing their physician.
- Routine laboratory monitoring and follow-up with a physician is important during Adefovir Dipivoxil Tablets therapy.
- Obtaining HIV antibody testing prior to starting Adefovir Dipivoxil Tablets is important
- Adefovir Dipivoxil Tablets should not be administered concurrently with ATRIPLA or COMPLERA or STRIBILD or TRUVADA or VIREA.
- Lamivudine-resistant patients should use Adefovir Dipivoxil Tablets in combination with lamivudine and not as Adefovir Dipivoxil Tablets monotherapy
- Physicians should inform women of childbearing age about the risks associated with exposure to Adefovir Dipivoxil Tablets during pregnancy.
- Patients should inform their physician if they become pregnant while using Adefovir Dipivoxil Tablets.
- Pregnant patients using Adefovir Dipivoxil Tablets should be informed about the Adefovir Dipivoxil Tablets pregnancy registry and offered the opportunity to enroll.
- Patients should be informed that it is not known whether Adefovir Dipivoxil Tablets is excreted into human milk or if it can harm a nursing infant. Therefore, a decision should be made whether to discontinue breastfeeding or drug.
# Precautions with Alcohol
- Alcohol-Adefovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Hepsera®
# Look-Alike Drug Names
There is limited information regarding Adefovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Adefovir
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
Adefovir is a nucleotide analogue that is FDA approved for the treatment of chronic hepatitis B. There is a Black Box Warning for this drug as shown here. Common adverse reactions include asthenia, increased creatinine.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Adefovir Dipivoxil Tablets are indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
- This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.
- For patients 12 to less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function.
### Dosage
- The recommended dose of Adefovir Dipivoxil Tablets in chronic hepatitis B patients for patients 12 years of age and older with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.
- Adefovir Dipivoxil Tablets is not recommended for use in children less than 12 years of age.
- Significantly increased drug exposures were seen when Adefovir Dipivoxil Tablets were administered to adult patients with renal impairment. Therefore, the dosing interval of Adefovir Dipivoxil Tablets should be adjusted in adult patients with baseline creatinine clearance less than 50 mL per minute using the following suggested guidelines (see Table 1). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated.
- Additionally, it is important to note that these guidelines were derived from data in patients with pre-existing renal impairment at baseline. They may not be appropriate for patients in whom renal insufficiency evolves during treatment with Adefovir Dipivoxil Tablets . Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
- The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute; therefore, no dosing recommendation is available for these patients.
- No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency
### DOSAGE FORMS AND STRENGTHS
- Adefovir Dipivoxil is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white to off white, round, flat faced beveled edged tablets, debossed "Σ 3" on one side and plain on the other side.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adefovir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adefovir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Adefovir in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Adefovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Adefovir in pediatric patients.
# Contraindications
- Adefovir Dipivoxil Tablets are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
# Warnings
- Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Adefovir Dipivoxil Tablets. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least several months in patients who discontinue Adefovir Dipivoxil Tablets. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
- In clinical trials of Adefovir Dipivoxil Tablets, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of Adefovir Dipivoxil Tablets. These events were identified in studies GS-98-437 and GS-98-438 (N=492). Most of these events occurred within 12 weeks of drug discontinuation. These exacerbations generally occurred in the absence of HBeAg seroconversion, and presented as serum ALT elevations in addition to re-emergence of viral replication. In the HBeAg-positive and HBeAg-negative studies in patients with compensated liver function, the exacerbations were not generally accompanied by hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. Therefore, patients should be closely monitored after stopping treatment.
- Nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus was historically shown to be the treatment-limiting toxicity of adefovir dipivoxil therapy at substantially higher doses in HIV-infected patients (60 and 120 mg daily) and in chronic hepatitis B patients (30 mg daily). Chronic administration of Adefovir Dipivoxil Tablets (10 mg once daily) may result in delayed nephrotoxicity. The overall risk of nephrotoxicity in patients with adequate renal function is low. However, this is of special importance in patients at risk of or having underlying renal dysfunction and patients taking concomitant nephrotoxic agents such as cyclosporine, tacrolimus, aminoglycosides, vancomycin and non-steroidal anti-inflammatory drugs. It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Adefovir Dipivoxil Tablets.
- It is important to monitor renal function for all patients during treatment with Adefovir Dipivoxil Tablets, particularly for those with pre-existing or other risks for renal impairment. Patients with renal insufficiency at baseline or during treatment may require dose adjustment [See DOSAGE AND ADMINISTRATION (2.2)]. The risks and benefits of Adefovir Dipivoxil Tablets treatment should be carefully evaluated prior to discontinuing Adefovir Dipivoxil Tablets in a patient with treatment-emergent nephrotoxicity.
- The efficacy and safety of Adefovir Dipivoxil Tablets have not been studied in patients less than 18 years of age with different degrees of renal impairment and no data are available to make dosage recommendations in these patients [See DOSAGE AND ADMINISTRATION (2.2)]. Caution should be exercised when prescribing Adefovir Dipivoxil Tablets to adolescents with underlying renal dysfunction, and renal function in these patients should be closely monitored.
- Prior to initiating Adefovir Dipivoxil Tablets therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies, such as Adefovir Dipivoxil Tablets, that have activity against HIV in a chronic hepatitis B patient with unrecognized or untreated HIV infection may result in emergence of HIV resistance. Adefovir Dipivoxil Tablets has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of Adefovir Dipivoxil Tablets to treat patients with chronic hepatitis B co-infected with HIV.
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.
- A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Adefovir Dipivoxil Tablets therapy should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
- Adefovir Dipivoxil Tablets should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablet), COMPLERA® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate combination tablet), STRIBILD™ (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate combination tablet), and TRUVADA® (emtricitabine/tenofovir disoproxil fumarate combination tablet).
- Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome.
- In order to reduce the risk of resistance in patients with lamivudine resistant HBV, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy.
- In order to reduce the risk of resistance in all patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL with continued treatment.
- Long-term (144 week) data from Study 438 (N=124) show that patients with HBV DNA levels greater than 1000 copies/mL at Week 48 of treatment with Adefovir Dipivoxil Tablets were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in other sections of the labelling:
- Severe acute exacerbations of Hepatitis
- Nephrotoxicity
- 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.
- Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with Adefovir Dipivoxil Tablets.
- Adverse reactions to Adefovir Dipivoxil Tablets identified from placebo-controlled and open label studies include the following: asthenia, headache, abdominal pain, diarrhea, nausea, dyspepsia, flatulence, increased creatinine, and hypophosphatemia.
- The incidence of these adverse reactions in studies 437 and 438, where 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=294) or placebo (N=228) for 48 weeks is presented in Table 2. Patients who received open-label Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks.
- No patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or confirmed phosphorus decrease to 2 mg/dL or less by Week 48.
- By Week 96, 2% of Adefovir Dipivoxil Tablets-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine greater than or equal to 0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438, 4 of 125 patients (3%) had a confirmed increase of 0.5 mg/dL from baseline. The creatinine elevation resolved in 1 patient who permanently discontinued treatment and remained stable in 3 patients who continued treatment. For 65 patients who chose to continue Adefovir Dipivoxil Tablets for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration.
- In these studies, the overall incidence of adverse reactions with Adefovir Dipivoxil Tablets was similar to that reported with placebo. The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators.
- Pre- and Post-Liver Transplantation Patients
- Additional adverse reactions observed from an open-label study (Study 435) in pre- and post- liver transplantation patients with chronic hepatitis B and lamivudine-resistant hepatitis B administered Adefovir Dipivoxil Tablets once daily for up to 203 weeks include: abnormal renal function, renal failure, vomiting, rash, and pruritus.
- Changes in renal function occurred in pre-and post-liver transplantation patients with risk factors for renal dysfunction, including concomitant use of cyclosporine and tacrolimus, renal insufficiency at baseline, hypertension, diabetes, and on-study transplantation. Therefore, the contributory role of Adefovir Dipivoxil Tablets to these changes in renal function is difficult to assess.
- Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 37% and 53% of pre-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 32% and 51% of post-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Serum phosphorus values less than 2 mg/dL were observed in 3/226 (1.3%) of pre-liver transplantation patients and in 6/241 (2.5%) of post-liver transplantation patients by last study visit. Four percent (19 of 467) of patients discontinued treatment with Adefovir Dipivoxil Tablets due to renal adverse events.
- Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to less than 18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=115), or placebo (N=58) for 48 weeks.
- The safety profile of Adefovir Dipivoxil Tablets in patients 12 to less than 18 years of age (N=56) was similar to that observed in adults. No pediatric patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase to greater than or equal to 0.5 mg/dL or a confirmed phosphorus decrease to less than 2 mg/dL by Week 48.
## Postmarketing Experience
- In addition to adverse reaction reports from clinical trials, the following possible adverse reactions have also been identified during post-approval use of adefovir dipivoxil. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
- hypophosphatemia
- pancreatitis
- myopathy, osteomalacia (both associated with proximal renal tubulopathy)
(manifested as bone pain and may contribute to fractures), both associated with proximal renal tubulopathy.
- renal failure, Fanconi syndrome, proximal renal tubulopathy
# Drug Interactions
- Since adefovir is eliminated by the kidney, co-administration of Adefovir Dipivoxil Tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these co-administered drugs.
- Patients should be monitored closely for adverse events when Adefovir Dipivoxil Tablets is co-administered with drugs that are excreted renally or with other drugs known to affect renal function.
- Adefovir Dipivoxil Tablets should not be administered in combination with VIREAD
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of Adefovir Dipivoxil Tablets in pregnant women. Chronic hepatitis B is a serious condition that requires treatment. Adefovir Dipivoxil Tablets should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- Reproduction studies with oral administration of adefovir dipivoxil to pregnant rats and rabbits showed no evidence of embryotoxicity or teratogenicity at systemic exposures equivalent to 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose. However, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) occurred when adefovir was administered intravenously to pregnant rats at 38 times the human therapeutic exposure. These adverse reproductive effects did not occur following an intravenous dose where exposure was 12 times the human therapeutic exposure.
- Because animal reproduction studies are not always predictive of human response, Adefovir Dipivoxil Tablets should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits [See NONCLINICAL TOXICOLOGY (13.2)].
- To monitor fetal outcomes of pregnant women exposed to Adefovir Dipivoxil Tablets, a pregnancy registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adefovir in women who are pregnant.
### Labor and Delivery
- There are no studies in pregnant women and no data on the effect of Adefovir Dipivoxil Tablets on transmission of HBV from mother to infant. Therefore, appropriate infant immunizations should be used to prevent neonatal acquisition of hepatitis B virus.
### Nursing Mothers
- It is not known whether adefovir is excreted in human milk.
- Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Adefovir Dipivoxil Tablets, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Pediatric patients 12 to less than 18 years: The safety, efficacy, and pharmacokinetics of Adefovir Dipivoxil Tablets in pediatric patients (aged 12 to less than 18 years) were evaluated in a double-blind, randomized, placebo-controlled study (GS-US-103-518, Study 518) in 83 pediatric patients with chronic hepatitis B and compensated liver disease. The proportion of patients treated with Adefovir Dipivoxil Tablets who achieved the primary efficacy endpoint of serum HBV DNA less than 1,000 copies/mL and normal ALT levels at the end of 48 weeks blinded treatment was significantly greater (23%) when compared to placebo-treated patients (0%).
- Pediatric patients 2 to less than 12 years: Patients 2 to less than 12 years of age were also evaluated in Study 518. The efficacy of adefovir dipivoxil was not significantly different from placebo in patients less than 12 years of age.
- Adefovir Dipivoxil Tablets is not recommended for use in children below 12 years of age.
### Geriatic Use
- Clinical studies of Adefovir Dipivoxil Tablets did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised when prescribing to elderly patients since they have greater frequency of decreased renal or cardiac function due to concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Adefovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Adefovir with respect to specific racial populations.
### Renal Impairment
- It is recommended that the dosing interval for Adefovir Dipivoxil Tablets be modified in adult patients with baseline creatinine clearance less than 50 mL per minute. The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute or in adolescent patients with renal insufficiency; therefore, no dosing recommendations are available for these patients.
### Hepatic Impairment
There is no FDA guidance on the use of Adefovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Adefovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Adefovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months
- In patients at risk of or having underlying renal dysfunction, chronic administration of Adefovir Dipivoxil Tablets may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment
# IV Compatibility
There is limited information regarding IV Compatibility of Adefovir in the drug label.
# Overdosage
- Doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated with gastrointestinal side effects. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
- Following a 10 mg single dose of Adefovir Dipivoxil Tablets, a four-hour hemodialysis session removed approximately 35% of the adefovir dose.
# Pharmacology
## Mechanism of Action
- Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 µM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 µM and 0.97 µM, respectively.
## Structure
- Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV).
- The chemical name of adefovir dipivoxil is 9-2-bis(pivaloyloxy)methoxy-phosphinyl-methoxyethyladenine. It has a molecular formula of C20H32N5O8P, a molecular weight of 501.48 and the following structural formula:
- Adefovir dipivoxil is a white to off-white powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.
- Adefovir dipivoxil tablets are for oral administration. Each tablet contains 10 mg of adefovir dipivoxil and the following inactive ingredients: copovidone, anhydrous lactose, microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Adefovir in the drug label.
## Pharmacokinetics
- The pharmacokinetics of adefovir have been evaluated in healthy volunteers and patients with chronic hepatitis B. Adefovir pharmacokinetics are similar between these populations.
- Adefovir dipivoxil is a diester prodrug of the active moiety adefovir. Based on a cross study comparison, the approximate oral bioavailability of adefovir from Adefovir Dipivoxil Tablets is 59%.
- Following oral administration of a 10 mg single dose of Adefovir Dipivoxil Tablets to chronic hepatitis B patients (N=14), the peak adefovir plasma concentration (Cmax) was 18.4 ± 6.26 ng/mL (mean ± SD) and occurred between 0.58 and 4.00 hours (median=1.75 hours) post dose. The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng·h/mL. Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.
- The pharmacokinetics of adefovir in subjects with adequate renal function were not affected by once daily dosing of 10 mg Adefovir Dipivoxil Tablets over seven days. The impact of long-term once daily administration of 10 mg Adefovir Dipivoxil Tablets on adefovir pharmacokinetics has not been evaluated.
- Adefovir exposure was unaffected when a 10 mg single dose of Adefovir Dipivoxil Tablets was administered with food (an approximately 1000 kcal high-fat meal). Adefovir Dipivoxil Tablets may be taken without regard to food.
- In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% over the adefovir concentration range of 0.1 to 25 µg/mL. The volume of distribution at steady-state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 ± 75 and 352 ± 9 mL/kg, respectively.
- Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. Forty-five percent of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses of Adefovir Dipivoxil Tablets. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.
- Adefovir dipivoxil is rapidly converted to adefovir in vivo. At concentrations substantially higher (greater than 4000-fold) than those observed in vivo, adefovir did not inhibit any of the common human CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Adefovir is not a substrate for these enzymes. However, the potential for adefovir to induce CYP450 enzymes is unknown. Based on the results of these in vitro experiments and the renal elimination pathway of adefovir, the potential for CYP450 mediated interactions involving adefovir as an inhibitor or substrate with other medicinal products is low.
- The pharmacokinetics of adefovir have been evaluated in healthy adult volunteers following multiple dose administration of Adefovir Dipivoxil Tablets (10 mg once daily) in combination with lamivudine (100 mg once daily) (N=18), trimethoprim/sulfamethoxazole (160/800 mg twice daily) (N=18), acetaminophen (1000 mg four times daily) (N=20), ibuprofen (800 mg three times daily) (N=18), and enteric coated didanosine (400 mg) (N=21). The pharmacokinetics of adefovir have also been evaluated in post-liver transplantation patients following multiple dose administration of Adefovir Dipivoxil Tablets (10 mg once daily) in combination with tacrolimus (N=16). The pharmacokinetics of adefovir have been evaluated in healthy volunteers following single dose pegylated interferon α-2a (PEG-IFN) (180 mcg) (N=15).
- Adefovir did not alter the pharmacokinetics of lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, ibuprofen, enteric coated didanosine (didanosine EC), or tacrolimus. The evaluation of the effect of adefovir on the pharmacokinetics of pegylated interferon α-2a was inconclusive due to the high variability of pegylated interferon α-2a.
- The pharmacokinetics of adefovir were unchanged when Adefovir Dipivoxil Tablets was coadministered with lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, didanosine EC, tacrolimus (based on cross study comparison), and pegylated interferon α-2a. When Adefovir Dipivoxil Tablets was coadministered with ibuprofen (800 mg three times daily) increases in adefovir Cmax (33%), AUC (23%) and urinary recovery were observed. This increase appears to be due to higher oral bioavailability, not a reduction in renal clearance of adefovir.
- Apart from lamivudine, trimethoprim/sulfamethoxazole, and acetaminophen, the effects of co-administration of Adefovir Dipivoxil Tablets with drugs that are excreted renally, or other drugs known to affect renal function have not been evaluated.
- The effect of adefovir on cyclosporine concentrations is not known.
- No drug interaction studies have been performed in adolescent patients 12 to less than 18 years of age.
- Gender
- The pharmacokinetics of adefovir were similar in male and female patients.
- Race
- The pharmacokinetics of adefovir have been shown to be comparable in Caucasians and Asians. Pharmacokinetic data are not available for other racial groups.
- Geriatric Patients
- Pharmacokinetic studies have not been conducted in the elderly.
- Pediatric Patients
- The pharmacokinetics of adefovir were assessed from drug plasma concentrations in 53 HBeAg positive hepatitis B pediatric patients with compensated liver disease. The exposure of adefovir following a 48 week daily treatment with adefovir dipivoxil 10 mg tablet in pediatric patients aged 12 to less than 18 years of age(Cmax = 23.3 ng/ml and AUC0–24 = 248.8 ng·h/ml) was comparable to that observed in adult patients.
- Renal Impairment
- In adults with moderately or severely impaired renal function or with end-stage renal disease (ESRD) requiring hemodialysis, Cmax, AUC, and half-life (T1/2) were increased compared to adults with normal renal function. It is recommended that the dosing interval of adefovir dipivoxil tablets be modified in these patients.
- The pharmacokinetics of adefovir in non-chronic hepatitis B patients with varying degrees of renal impairment are described in Table 3. In this study, subjects received a 10 mg single dose of Adefovir Dipivoxil Tablets.
- A four-hour period of hemodialysis removed approximately 35% of the adefovir dose. The effect of peritoneal dialysis on adefovir removal has not been evaluated.
- The pharmacokinetics of adefovir have not been studied in adolescent patients with renal dysfunction [See USE IN SPECIFIC POPULATIONS (8.4)].
- Hepatic Impairment
- The pharmacokinetics of adefovir following a 10 mg single dose of Adefovir Dipivoxil Tablets have been studied in non-chronic hepatitis B patients with hepatic impairment. There were no substantial alterations in adefovir pharmacokinetics in patients with moderate and severe hepatic impairment compared to unimpaired patients. No change in Adefovir Dipivoxil Tablets dosing is required in patients with hepatic impairment.
- The concentration of adefovir that inhibited 50% of viral DNA synthesis (EC50) in HBV transfected human hepatoma cell lines ranged from 0.2 to 2.5 µM. The combination of adefovir with lamivudine showed additive anti-HBV activity.
- Clinical isolates with genotypic changes conferring reduced susceptibility in cell culture to nucleoside analog reverse transcriptase inhibitors for the treatment of HBV infection have been observed. Long-term resistance analyses performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA demonstrated that amino acid substitutions rtN236T and rtA181T/V have been observed in association with adefovir resistance. In cell culture, the rtN236T substitution demonstrated 4- to 14-fold, the rtA181V substitution 2.5- to 4.2-fold, and the rtA181T substitution 1.3- to 1.9-fold reduced susceptibility to adefovir.
- In HBeAg-positive nucleoside-naïve patient isolates (Study GS-98-437, N=171), no adefovir resistance-associated substitutions were observed at Week 48. Sixty-five patients continued on long term treatment after a median duration on adefovir dipivoxil of 235 weeks (range 110–279 weeks). Isolates from 16 of 38 (42%) patients developed adefovir resistance-associated substitutions in the setting of virologic failure (confirmed increase of at least log10 HBV DNA copies/mL above nadir or never suppressed below 103 copies/mL). The substitutions included rtN236T (N=2), rtA181V (N=4), rtA181T (N=3), rtA181T+rtN236T (N=5), and rtA181V+rtN236T (N=2). In HBeAg-negative nucleoside-naïve patients (Study GS-98-438), isolates from 30 patients were identified with adefovir resistance-associated substitutions with a cumulative probability of 0%, 3%, 11%, 19%, and 30% at 48, 96, 144, 192, and 240 weeks, respectively. Of those 30 patients, 22 had a confirmed increase of at least log10 HBV DNA copies/mL above nadir or never achieved HBV DNA levels below 103 copies/mL; an additional 8 patients had adefovir resistance-associated substitutions without virologic failure. In addition, the long term (4 to 5 years) development of resistance to adefovir dipivoxil was significantly lower in patients who had serum HBV DNA below the limit of quantification (less than 1,000 copies/mL) at Week 48 as compared to patients who had serum HBV DNA above 1,000 copies/mL at Week 48.
- In an open-label study of pre- and post-liver transplantation patients (Study GS-98-435), isolates from 129 patients with clinical evidence of lamivudine-resistant hepatitis B virus at baseline were evaluated for adefovir resistance-associated substitutions. The incidence of adefovir resistance-associated (rtN236T or rtA181T/V) substitutions was 0% at 48 weeks. Isolates from four patients developed the rtN236T substitution after 72 weeks of adefovir dipivoxil therapy. Development of the rtN236T substitution was associated with serum HBV DNA rebound. All 4 patients who developed the rtN236T substitution in their HBV had discontinued lamivudine therapy before the development of genotypic resistance and all 4 lost the lamivudine resistance-associated substitutions present at baseline. In a study of 35 HIV/HBV co-infected patients with lamivudine-resistant HBV (Study 460i) who added adefovir dipivoxil to lamivudine, no adefovir resistance-associated substitutions were observed in HBV isolates from 15/35 patients tested up to 144 weeks of therapy.
- In a Phase 3 pediatric Study GS-US-103-518, HBV isolates from 49 of 56 pediatric subjects (aged 12 to 17 years) had serum HBV DNA greater than 169 copies/mL and were evaluated for adefovir resistance-associated substitutions. rtN236T and/or rtA181V adefovir resistance-associated substitutions were not observed at Week 48. However, the rtA181T substitution was present in baseline and Week 48 isolates from 2 pediatric patients.
- Recombinant HBV variants containing lamivudine-resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M + rtM204V, rtV173L + rtL180M + rtM204V) were susceptible to adefovir in cell culture. Adefovir dipivoxil has also demonstrated anti-HBV activity (median reduction in serum HBV DNA of 4.1 log10 copies/mL) in patients with HBV containing lamivudine-resistance-associated substitutions (Study 435). Adefovir also demonstrated in cell culture activity against HBV variants with entecavir resistance-associated substitutions (rtT184G, rtS202I, rtM250V). HBV variants with DNA polymerase substitutions rtT128N and rtR153Q or rtW153Q associated with resistance to hepatitis B virus immunoglobulin were susceptible to adefovir in cell culture.
- HBV variants expressing the adefovir resistance-associated substitution rtN236T showed no change in susceptibility to entecavir in cell culture, and a 2- to 3-fold decrease in lamivudine susceptibility. HBV mutants with the adefovir resistance-associated substitution rtA181V showed a range of decreased susceptibilities to lamivudine of 1- to 14-fold and a 12-fold decrease in susceptibility to entecavir. In patients whose HBV expressed the rtA181V substitution (N=2) or the rtN236T substitution (N=3), a reduction in serum HBV DNA of 2.4 to 3.1 and 2.0 to 5.1 log10 copies/mL, respectively, was observed when treatment with lamivudine was added to treatment with adefovir dipivoxil.
## Nonclinical Toxicology
- Long-term oral carcinogenicity studies of adefovir dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, adefovir dipivoxil was negative for carcinogenic findings. Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir dipivoxil was not clastogenic in the in vivo mouse micronucleus assay and adefovir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose.
- Animal reproduction studies were conducted in rats and rabbits with orally administered adefovir dipivoxil and intravenously administered adefovir.
- In rats and rabbits, no embryotoxicity or teratogenicity was shown from oral administration of adefovir dipivoxil at maternal doses producing systemic exposures approximately 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose of 10 mg/day.
- When pregnant rats were administered intravenous adefovir at maternally toxic doses associated with systemic exposure 38 times that in humans, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were observed. No adverse effects on development were seen with intravenous adefovir administered to pregnant rats at a systemic exposure 12 times that in humans.
- Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3 to 10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.
# Clinical Studies
- Study 437 was a randomized, double-blind, placebo-controlled, three-arm-study in patients with HBeAg-positive chronic hepatitis B that allowed for a comparison between placebo and Adefovir Dipivoxil Tablets. The median age of patients was 33 years. Seventy-four percent were male, 59% were Asian, 36% were Caucasian, and 24% had prior interferon-a treatment. At baseline, patients had a median total Knodell Histology Activity Index (HAI) score of 10, a median serum HBV DNA level as measured by the Roche Amplicor Monitor polymerase chain reaction (PCR) assay (LLOQ = 1000 copies/mL) of 8.36 log10 copies/mL and a median ALT level of 2.3 times the upper limit of normal.
- Study 438 was a randomized, double-blind, placebo-controlled study in patients who were HBeAg-negative at screening, and anti-HBe positive. The median age of patients was 46 years. Eighty-three percent were male, 66% were Caucasian, 30% were Asian and 41% had prior interferon-a treatment. At baseline, the median total Knodell HAI score was 10, the median serum HBV DNA level as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.08 log10 copies/mL, and the median ALT was 2.3 times the upper limit of normal.
- The primary efficacy endpoint in both studies was histological improvement at Week 48; results of which are shown in Table 4.
- In Study 437, continued treatment with Adefovir Dipivoxil Tablets to 72 weeks resulted in continued maintenance of mean reductions in serum HBV DNA observed at Week 48. An increase in the proportion of patients with ALT normalization was also observed in Study 437. The effect of continued treatment with Adefovir Dipivoxil Tablets on seroconversion is unknown.
- In Study 438, patients who received Adefovir Dipivoxil Tablets during the first 48 weeks were re-randomized in a blinded manner to continue on Adefovir Dipivoxil Tablets or receive placebo for an additional 48 weeks. At Week 96, 50 of 70 (71%) of patients who continued treatment with Adefovir Dipivoxil Tablets had undetectable HBV DNA levels (less than 1000 copies/mL), and 47 of 64 (73%) of patients had ALT normalization. HBV DNA and ALT levels returned towards baseline in most patients who stopped treatment with Adefovir Dipivoxil Tablets.
- From 141 eligible patients, there were 125 (89%) patients in Study 438 who chose to continue Adefovir Dipivoxil Tablets for up to 192 weeks or 240 weeks (4 years or 5 years). As these patients had already received Adefovir Dipivoxil Tablets for at least 48 weeks and appeared to be experiencing a benefit, they are not necessarily representative of patients initiating Adefovir Dipivoxil Tablets. Of these patients, 89/125 (71%) and 47/70 (67%) had an undetectable HBV DNA level (less than 1000 copies/mL) at Week 192 and Week 240, respectively. Of the patients who had an elevated ALT at baseline, 77/104 (74%) and 42/64 (66%) had a normal ALT at Week 192 and Week 240, respectively. Six (5%) patients experienced HBsAg loss.
- Intent-to-Treat population (patients with ≥1 dose of study drug) with assessable baseline biopsies.
- Adefovir Dipivoxil Tablets were also evaluated in an open-label, uncontrolled study of 467 chronic hepatitis B patients pre- (N=226) and post- (N=241) liver transplantation with clinical evidence of lamivudine- resistant hepatitis B virus (Study 435). At baseline, 60% of pre-liver transplantation patients were classified as Child-Pugh-Turcotte score of Class B or C. The median baseline HBV DNA as measured by the Roche Amplicor (LLOQ = 1000 copies/mL) was 7.4 and 8.2 log10 copies/mL, and the median baseline ALT was 1.8 and 2.0 times the upper limit of normal in pre- and post-liver transplantation patients, respectively. Results of this study are displayed in Table 7. Treatment with Adefovir Dipivoxil Tablets resulted in a similar reduction in serum HBV DNA regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. The significance of the efficacy results listed in Table 7 as they relate to clinical outcomes is not known.
- In Study 461, a double-blind, active controlled study in 59 chronic hepatitis B patients with clinical evidence of lamivudine-resistant hepatitis B virus, patients were randomized to receive either Adefovir Dipivoxil Tablets monotherapy or Adefovir Dipivoxil Tablets in combination with lamivudine 100 mg or lamivudine 100 mg alone. At Week 48, the mean ± SD decrease in serum HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 4.00 ± 1.41 log10 copies/mL for patients treated with Adefovir Dipivoxil Tablets and 3.46 ± 1.10 log10 copies/mL for patients treated with Adefovir Dipivoxil Tablets in combination with lamivudine. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log10 copies/mL in patients receiving lamivudine alone. ALT normalized in 47% of patients treated with Adefovir Dipivoxil Tablets, in 53% of patients treated with Adefovir Dipivoxil Tablets in combination with lamivudine, and 5% of patients treated with lamivudine alone. The significance of these findings as they relate to clinical outcomes is not known.
- Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to less than 18 years) with chronic hepatitis B (CHB) infection and elevated ALT were randomized 2:1 (115 receiving adefovir dipivoxil and 58 receiving placebo). Randomization was stratified by prior treatment and age 2 to less than 7 years old (cohort 1), 7 to less than 12 years old (cohort 2), and 12 to less than 18 years old (cohort 3). All patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts 1 and 2 received an investigational suspension formulation (0.3 mg/kg/day cohort 1, 0.25 mg/kg/day cohort 2) once daily. The primary efficacy endpoint was HBV DNA less than 1000 copies/mL plus normalization of ALT at the end of Week 48.
- In cohort 3 (N=83), significantly more patients treated with Adefovir Dipivoxil Tablets achieved the primary efficacy endpoint at the end of 48 weeks of blinded treatment (23%) when compared to placebo-treated patients (0%). The proportion of patients from cohorts 1 and 2 who responded to treatment with adefovir dipivoxil was not statistically significant when compared to the placebo arm, although the adefovir plasma concentrations in these patients were comparable to those observed in older patients. Overall, 22 of 115 (19%) of pediatric patients who received adefovir dipivoxil versus 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48
# How Supplied
- Adefovir Dipivoxil is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white are to off-white, round, flat faced beveled edged tablets, debossed "∑ 3" on one side and plain on the other side. They are packaged as follows: Bottles of 30 tablets (NDC 42794-003-08) containing polyester and desiccant and closed with a child-resistant closure.
## Storage
- Store in original container at 25 °C (77 °F), excursions permitted to 15° to 30 °C (59° to 86 °F) (see USP Controlled Room Temperature).
- Do not use if seal over bottle opening is broken or missing.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL- ADEFOVIR DIPIVOXIL 10 MG BOTTLE LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Instructions for Safe Use
- See FDA-APPROVED PATIENT LABELING (PATIENT INFORMATION)
- Physicians should inform patients of the potential risks and benefits of Adefovir Dipivoxil Tablets and of alternative modes of therapy.
- Physicians should instruct their patients to:
- Read the Patient Package Insert before starting Adefovir Dipivoxil Tablets therapy.
- Follow a regular dosing schedule to avoid missing doses.
- Immediately report any severe abdominal pain, muscle pain, yellowing of the eyes, dark urine, pale stools, and/or loss in appetite.
- Inform their doctor or pharmacist if they develop any unusual symptom(s), or if any known symptom persists or worsens.
- Patients should remain under the care of a physician when using Adefovir Dipivoxil Tablets.
- Patients should be advised that:
- The optimal duration of Adefovir Dipivoxil Tablets treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.
- Patients should not discontinue Adefovir Dipivoxil Tablets without first informing their physician.
- Routine laboratory monitoring and follow-up with a physician is important during Adefovir Dipivoxil Tablets therapy.
- Obtaining HIV antibody testing prior to starting Adefovir Dipivoxil Tablets is important
- Adefovir Dipivoxil Tablets should not be administered concurrently with ATRIPLA or COMPLERA or STRIBILD or TRUVADA or VIREA.
- Lamivudine-resistant patients should use Adefovir Dipivoxil Tablets in combination with lamivudine and not as Adefovir Dipivoxil Tablets monotherapy
- Physicians should inform women of childbearing age about the risks associated with exposure to Adefovir Dipivoxil Tablets during pregnancy.
- Patients should inform their physician if they become pregnant while using Adefovir Dipivoxil Tablets.
- Pregnant patients using Adefovir Dipivoxil Tablets should be informed about the Adefovir Dipivoxil Tablets pregnancy registry and offered the opportunity to enroll.
- Patients should be informed that it is not known whether Adefovir Dipivoxil Tablets is excreted into human milk or if it can harm a nursing infant. Therefore, a decision should be made whether to discontinue breastfeeding or drug.
# Precautions with Alcohol
- Alcohol-Adefovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Hepsera®[1]
# Look-Alike Drug Names
There is limited information regarding Adefovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Adefovir | |
be53da1c6dbb8e9255c5da529149fa606b8eb7b0 | wikidoc | Adhesive | Adhesive
# History
The first adhesives were natural gums and other plant resins or saps. It was believed that the Sumerian people were the first to use it until it was discovered that Neanderthals as far back as 50,000 years made adhesives from birch bark. The discovery of 6000-year-old ceramics brought evidence to archaeologists about the first practical uses and ingredients of the first adhesives. Most early adhesives were animal glues made by rendering animal products such as horse teeth. During the times of Babylonia, tar-like glue was used for gluing statues. The Egyptians made much use of animal glues to adhere furniture, ivory, and papyrus. The Mongols also used adhesives to make their short bows, and the Native Americans of the eastern United States used a mixture of spruce gum and fat as adhesives to add waterproof seams in their birchbark canoes.
In Medieval Europe/Eurasia, egg whites were used as glue to decorate parchments with gold leaf. Holland, in the early 1700s, founded the first ever glue factory. Later, in the 1750s, the British introduced fish glue. As the modern world evolved, several other patented materials, such as bones, starch, fish, and casein, were introduced as alternative materials for glue manufacture. Modern glues have improved beyond recognition. Such improvements are noticeable in its flexibility, toughness, curing rate, temperature, and chemical resistance. The bond between two items depends on the shape of the adhesive.
# Categories of adhesives
## Homemade casein adhesive
This is an adhesive prepared at home, or by one's own efforts with normal household products. There are many types of glue that can be made. Homemade glue may stick or hold better than commercial glue (for example, Elmer's glue), depending on the ingredients that are used. The glue is best kept in an airtight container in the refrigerator. See more at: Homemade glue
## Natural adhesives
Natural adhesives are made from inorganic mineral sources, or biological sources such as vegetable matter, starch (dextrin), natural resins, animal skin, and bioadhesives. A simple paste can be made by mixing flour and water.
## Synthetic adhesives
Elastomers, thermoplastic, and thermosetting adhesives are examples of synthetic adhesives.
## Drying adhesives
These adhesives are a mixture of ingredients (typically polymers) dissolved in a solvent. Glues such as white glue, and rubber cements are members of the drying adhesive family. As the solvent evaporates, the adhesive hardens. Depending on the chemical composition of the adhesive, they will adhere to different materials to greater or lesser degrees. These adhesives are typically weak and are used for household applications. Some intended for use by small children are now made non-toxic.
## Contact adhesives
Contact adhesive is one which must be applied to both surfaces and allowed some time to dry before the two surfaces are pushed together. Some contact adhesives require as long as 24 hours to dry before the surfaces are to be held together. Once the surfaces are pushed together, the bond forms very quickly, hence, it is usually not necessary to apply pressure for a long time. This means that there is no need to use clamps, which is convenient.
Natural rubber and polychloroprene (Neoprene) are commonly used contact adhesives. Both of these elastomers undergo strain crystallization.
Contact adhesives find use in laminates, such as bonding Formica to a wooden counter, and in footwear, for example attachment of an outsole to an upper.
## Hot adhesives (thermoplastic adhesives)
Also known as "hot melt" adhesives, these adhesives are thermoplastics; they are applied hot and simply allowed to harden as they cool. These adhesives have become popular for crafts because of their ease of use and the wide range of common materials to which they can adhere. A glue gun, pictured right, is one method of applying a hot adhesive. The glue gun melts the solid adhesive and then allows the liquid to pass through the "barrel" of the gun onto the material where it solidifies.
Paul E. Cope is reputed to have invented thermoplastic glue while working for Procter & Gamble as a chemical and packaging engineer. His invention solved a problem with water based adhesives that were commonly used in packaging at that time. Water based adhesives often released in humid climates which caused packages to open and become damaged. Mr. Cope was a graduate of the University of Cincinnati College of Engineering. He advanced at Procter & Gamble to become Associate Director, Head of Packaging Engineering. After spending 40 years with P&G, he retired in 1973. Patents issued to Paul Cope include the laminated toothpaste tube and this for In Package Sterilization
## Reactive adhesives
A reactive adhesive works either by chemical bonding with the surface material or by in-situ hardening as two reactant chemicals complete a polymerization reaction. They are usually applied in thin films.
Reactive adhesives are less effective when there is a secondary goal of filling gaps between the surfaces. These include two-part epoxy, peroxide, silane, metallic cross-links, or isocyanate.
Such adhesives are frequently used to prevent loosening of bolts and screws in rapidly moving assemblies, such as automobile engines. They are largely responsible for the quieter running modern car engines.
## UV and light curing adhesives
UV and light curing adhesives consist essentially of low or medium molecular weight resins.
## Pressure sensitive adhesives
Pressure sensitive adhesives (PSAs) form a bond by the application of light pressure to marry the adhesive with the adherend. They are designed with a balance between flow and resistance to flow. The bond forms because the adhesive is soft enough to flow (i.e. "wet") the adherend. The bond has strength because the adhesive is hard enough to resist flow when stress is applied to the bond. Once the adhesive and the adherend are in close proximity, molecular interactions, such as van der Waals' forces, become involved in the bond, contributing significantly to its ultimate strength.
Pressure sensitive adhesives (PSAs) are designed for either permanent or removable applications. Examples of permanent applications include safety labels for power equipment, foil tape for HVAC duct work, automotive interior trim assembly, and sound/vibration damping films. Some high performance permanent PSAs exhibit high adhesion values and can support kilograms of weight per square centimeter of contact area, even at elevated temperature. Permanent PSAs may be initially removable (for example to recover mislabeled goods) and build adhesion to a permanent bond after several hours or days.
Removable adhesives are designed to form a temporary bond, and ideally can be removed after months or years without leaving residue on the adherend. Removable adhesives are used in applications such as surface protection films, masking tapes, bookmark and note papers, price marking labels, promotional graphics materials, and for skin contact (wound care dressings, EKG electrodes, athletic tape, analgesic and transdermal drug patches, etc.). Some removable adhesives are designed to repeatedly stick and unstick. They have low adhesion and generally can not support much weight.
Pressure sensitive adhesives are manufactured with either a liquid carrier or in 100% solid form. Articles are made from liquid PSAs by coating the adhesive and drying off the solvent or water carrier. They may be further heated to initate a crosslinking reaction and increase molecular weight. 100% solid PSAs may be low viscosity polymers that are coated and then reacted with radiation to increase molecular weight and form the adhesive; or they may be high viscosity materials that are heated to reduce viscosity enough to allow coating, and then cooled to their final form.
Also see adhesive tape, blu-tack and gaffer tape.
Plastic wrap displays temporary adhesive properties as well.
# Mechanisms of adhesion
The strength of attachment, or adhesion, between an adhesive and its substrate depends on many factors, including the means by which this occurs. Adhesion may occur either by mechanical means, in which the adhesive works its way into small pores of the substrate, or by one of several chemical mechanisms.
In some cases an actual chemical bond occurs between adhesive and substrate. In others electrostatic forces, as in static electricity, hold the substances together. A third mechanism involves the van der Waals forces that develop between molecules. A fourth means involves the moisture-aided diffusion of the glue into the substrate, followed by hardening.
# Failure of the adhesive joint
When subjected to loading, debonding may occur at different locations in the adhesive joint. The major fracture types are the following:
## Cohesive fracture
“Cohesive” fracture" is obtained if a crack propagates in the bulk polymer which constitutes the adhesive. In this case the surfaces of both adherents after debonding will be covered by fractured adhesive. The crack may propagate in the centre of the layer or near an interface. For this last case, the “cohesive” fracture can be said to be “cohesive near the interface”. Most quality control standards consider that a “good” adhesive bonding must be “cohesive”.
## Interfacial fracture
The fracture is “adhesive” or “interfacial” when debonding occurs between the adhesive and the adherent. In most cases, the occurrence of “interfacial” fracture for a given adhesive goes along with a smaller fracture toughness. The “interfacial” character of a fracture surface is usually to identify the precise location of the crack path in the interphase.
## Other types of fracture
Beside these two cases, other types of fracture are
- The “mixed” fracture type which occurs if the crack propagates at some spots in a “cohesive” and in others in an “interfacial” manner. “Mixed” fracture surfaces can be characterised by a certain percentage of “adhesive” and “cohesive” areas.
- The “alternating crack path” fracture type which occurs if the cracks jumps from one interface to the other. This type of fracture appears in the presence of tensile pre-stresses in the adhesive layer.
- Fracture can also occur in the adherent if the adhesive is tougher than the adherent. In this case the adhesive remains intact and is still bonded to one substrate and the remnants of the other. For example, when one removes a price label, adhesive usually remains on the label and the surface. This is cohesive failure. If, however, a layer of paper remains stuck to the surface, the adhesive has not failed. Another example is when someone tries to pull apart Oreo cookies and all the filling remains on one side. The goal in this case is an adhesive failure, rather than a cohesive failure.
# Design of adhesive joints
A general design rule is a relation of the type: "Material Properties > Function (geometry, loads)"
The engineering work will consist in having a good model to evaluate the "Function". For most adhesive joints, this can be achieved using fracture mechanics. Concepts such as the stress concentration factor K and the energy release rate G can be used to predict failure. In such models, the behavior of the adhesive layer itself is neglected and only the adherents are considered.
Failure will also very much depend on the opening "mode" of the joint.
- Mode I is an opening or tensile mode where the loadings are normal to the crack.
- Mode II is a sliding or in-plane shear mode where the crack surfaces slide over one another in direction perpendicular to the leading edge of the crack. This is typically the mode for which the adhesive exhibits the higher resistance to fracture.
- Mode III is a tearing or antiplane shear mode.
As the loads are usually fixed, an acceptable design will result from combination of a material selection procedure and geometry modifications, if possible. In adhesively bonded structures, the global geometry and loads are fixed by structural considerations and the design procedure focuses on the “material properties” of the adhesive (i.e. select a "good" adhesive) and on local changes on the geometry.
Increasing the joint resistance is usually obtained by designing its geometry so that:
- The bonded zone is large
- It is mainly loaded in mode II
- Stable crack propagation will follow the appearance of a local failure.
# Testing the resistance of the adhesive
A wide range of testing devices have been imagined to evaluate the fracture resistance of bonded structures in pure mode I, pure mode II or in mixed mode. Most of these devices are beam type specimens. We will very shortly review the most popular:
- Double Cantilever Beam tests (DCB) measure the mode I fracture resistance of adhesives in a fracture mechanics framework. These tests consist in opening an assembly of two beams by applying a force at the ends of the two beams. The test in unstable (i.e. the crack propagates along the entire specimen once a critical load is attained) and a modified version of this test characterised by a non constant inertia was proposed called the Tapered double cantilever beam specimen (TDCB). File:Tests.jpgTesting devices
- Peel tests measure the fracture resistance of a thin layer bonded on a thick substrate or of two layers bonded together. They consist in measuring the force needed for tearing an adherent layer from a substrate or for tearing two adherent layers one from another. Whereas the structure is not symmetrical, various mode mixities can be introduced in these tests.
- Wedge tests measure the mode I dominated fracture resistance of adhesives used to bond thin plates. These tests consist in inserting a wedge in between two bonded plates. A critical energy release rate can be derived from the crack length during testing. This test is a mode I test but some mode II component can be introduced by bonding plates of different thicknesses.
- Mixed-Mode Delaminating Beam (MMDB) tests consist in a bonded bilayer with two starting cracks loaded on four points. The test presents roughly the same amount of mode I and mode II with a slight dependence on the ratio of the two layer thicknesses.
- End Notch Flexure tests consist in two bonded beams built-in on one side and loaded by a force on the other. As no normal opening is allowed, this device allows testing in essentially mode II condition.
- Crack Lap Shear (CLS) tests are application-oriented fracture resistance tests. They consist in two plates bonded on a limited length and loaded in tension on both ends. The test can be either symmetrical or dis-symmetrical. In the first case two cracks can be initiated and in the second only one crack can propagate. | Adhesive
# History
The first adhesives were natural gums and other plant resins or saps. It was believed that the Sumerian people were the first to use it until it was discovered that Neanderthals as far back as 50,000 years made adhesives from birch bark. The discovery of 6000-year-old ceramics brought evidence to archaeologists about the first practical uses and ingredients of the first adhesives. Most early adhesives were animal glues made by rendering animal products such as horse teeth. During the times of Babylonia, tar-like glue was used for gluing statues. The Egyptians made much use of animal glues to adhere furniture, ivory, and papyrus. The Mongols also used adhesives to make their short bows, and the Native Americans of the eastern United States used a mixture of spruce gum and fat as adhesives to add waterproof seams in their birchbark canoes.
In Medieval Europe/Eurasia, egg whites were used as glue to decorate parchments with gold leaf. Holland, in the early 1700s, founded the first ever glue factory. Later, in the 1750s, the British introduced fish glue. As the modern world evolved, several other patented materials, such as bones, starch, fish, and casein, were introduced as alternative materials for glue manufacture. Modern glues have improved beyond recognition. Such improvements are noticeable in its flexibility, toughness, curing rate, temperature, and chemical resistance. The bond between two items depends on the shape of the adhesive.
# Categories of adhesives
## Homemade casein adhesive
This is an adhesive prepared at home, or by one's own efforts with normal household products. There are many types of glue that can be made. Homemade glue may stick or hold better than commercial glue (for example, Elmer's glue), depending on the ingredients that are used. The glue is best kept in an airtight container in the refrigerator. See more at: Homemade glue
## Natural adhesives
Natural adhesives are made from inorganic mineral sources, or biological sources such as vegetable matter, starch (dextrin), natural resins, animal skin, and bioadhesives. A simple paste can be made by mixing flour and water.
## Synthetic adhesives
Elastomers, thermoplastic, and thermosetting adhesives are examples of synthetic adhesives.
## Drying adhesives
These adhesives are a mixture of ingredients (typically polymers) dissolved in a solvent. Glues such as white glue, and rubber cements are members of the drying adhesive family. As the solvent evaporates, the adhesive hardens. Depending on the chemical composition of the adhesive, they will adhere to different materials to greater or lesser degrees. These adhesives are typically weak and are used for household applications. Some intended for use by small children are now made non-toxic.
## Contact adhesives
Contact adhesive is one which must be applied to both surfaces and allowed some time to dry before the two surfaces are pushed together. Some contact adhesives require as long as 24 hours to dry before the surfaces are to be held together.[1] Once the surfaces are pushed together, the bond forms very quickly,[2] hence, it is usually not necessary to apply pressure for a long time. This means that there is no need to use clamps, which is convenient.
Natural rubber and polychloroprene (Neoprene) are commonly used contact adhesives. Both of these elastomers undergo strain crystallization.
Contact adhesives find use in laminates, such as bonding Formica to a wooden counter, and in footwear, for example attachment of an outsole to an upper.
## Hot adhesives (thermoplastic adhesives)
Also known as "hot melt" adhesives, these adhesives are thermoplastics; they are applied hot and simply allowed to harden as they cool. These adhesives have become popular for crafts because of their ease of use and the wide range of common materials to which they can adhere. A glue gun, pictured right, is one method of applying a hot adhesive. The glue gun melts the solid adhesive and then allows the liquid to pass through the "barrel" of the gun onto the material where it solidifies.
Paul E. Cope [deceased, 2003] is reputed to have invented thermoplastic glue [circa 1940] while working for Procter & Gamble as a chemical and packaging engineer. His invention solved a problem with water based adhesives that were commonly used in packaging at that time. Water based adhesives often released in humid climates which caused packages to open and become damaged. Mr. Cope was a graduate of the University of Cincinnati College of Engineering. He advanced at Procter & Gamble to become Associate Director, Head of Packaging Engineering. After spending 40 years with P&G, he retired in 1973. Patents issued to Paul Cope include the laminated toothpaste tube and this for In Package Sterilization
## Reactive adhesives
A reactive adhesive works either by chemical bonding with the surface material or by in-situ hardening as two reactant chemicals complete a polymerization reaction. They are usually applied in thin films.
Reactive adhesives are less effective when there is a secondary goal of filling gaps between the surfaces. These include two-part epoxy, peroxide, silane, metallic cross-links, or isocyanate.
Such adhesives are frequently used to prevent loosening of bolts and screws in rapidly moving assemblies, such as automobile engines. They are largely responsible for the quieter running modern car engines.
## UV and light curing adhesives
UV and light curing adhesives consist essentially of low or medium molecular weight resins.
## Pressure sensitive adhesives
Pressure sensitive adhesives (PSAs) form a bond by the application of light pressure to marry the adhesive with the adherend. They are designed with a balance between flow and resistance to flow. The bond forms because the adhesive is soft enough to flow (i.e. "wet") the adherend. The bond has strength because the adhesive is hard enough to resist flow when stress is applied to the bond. Once the adhesive and the adherend are in close proximity, molecular interactions, such as van der Waals' forces, become involved in the bond, contributing significantly to its ultimate strength.
Pressure sensitive adhesives (PSAs) are designed for either permanent or removable applications. Examples of permanent applications include safety labels for power equipment, foil tape for HVAC duct work, automotive interior trim assembly, and sound/vibration damping films. Some high performance permanent PSAs exhibit high adhesion values and can support kilograms of weight per square centimeter of contact area, even at elevated temperature. Permanent PSAs may be initially removable (for example to recover mislabeled goods) and build adhesion to a permanent bond after several hours or days.
Removable adhesives are designed to form a temporary bond, and ideally can be removed after months or years without leaving residue on the adherend. Removable adhesives are used in applications such as surface protection films, masking tapes, bookmark and note papers, price marking labels, promotional graphics materials, and for skin contact (wound care dressings, EKG electrodes, athletic tape, analgesic and transdermal drug patches, etc.). Some removable adhesives are designed to repeatedly stick and unstick. They have low adhesion and generally can not support much weight.
Pressure sensitive adhesives are manufactured with either a liquid carrier or in 100% solid form. Articles are made from liquid PSAs by coating the adhesive and drying off the solvent or water carrier. They may be further heated to initate a crosslinking reaction and increase molecular weight. 100% solid PSAs may be low viscosity polymers that are coated and then reacted with radiation to increase molecular weight and form the adhesive; or they may be high viscosity materials that are heated to reduce viscosity enough to allow coating, and then cooled to their final form.
Also see adhesive tape, blu-tack and gaffer tape.
Plastic wrap displays temporary adhesive properties as well.
# Mechanisms of adhesion
Template:Mainarticle
The strength of attachment, or adhesion, between an adhesive and its substrate depends on many factors, including the means by which this occurs. Adhesion may occur either by mechanical means, in which the adhesive works its way into small pores of the substrate, or by one of several chemical mechanisms.
In some cases an actual chemical bond occurs between adhesive and substrate. In others electrostatic forces, as in static electricity, hold the substances together. A third mechanism involves the van der Waals forces that develop between molecules. A fourth means involves the moisture-aided diffusion of the glue into the substrate, followed by hardening.
# Failure of the adhesive joint
When subjected to loading, debonding may occur at different locations in the adhesive joint. The major fracture types are the following:
## Cohesive fracture
“Cohesive” fracture" is obtained if a crack propagates in the bulk polymer which constitutes the adhesive. In this case the surfaces of both adherents after debonding will be covered by fractured adhesive. The crack may propagate in the centre of the layer or near an interface. For this last case, the “cohesive” fracture can be said to be “cohesive near the interface”. Most quality control standards consider that a “good” adhesive bonding must be “cohesive”.
## Interfacial fracture
The fracture is “adhesive” or “interfacial” when debonding occurs between the adhesive and the adherent. In most cases, the occurrence of “interfacial” fracture for a given adhesive goes along with a smaller fracture toughness. The “interfacial” character of a fracture surface is usually to identify the precise location of the crack path in the interphase.
## Other types of fracture
Beside these two cases, other types of fracture are
- The “mixed” fracture type which occurs if the crack propagates at some spots in a “cohesive” and in others in an “interfacial” manner. “Mixed” fracture surfaces can be characterised by a certain percentage of “adhesive” and “cohesive” areas.
- The “alternating crack path” fracture type which occurs if the cracks jumps from one interface to the other. This type of fracture appears in the presence of tensile pre-stresses in the adhesive layer.
- Fracture can also occur in the adherent if the adhesive is tougher than the adherent. In this case the adhesive remains intact and is still bonded to one substrate and the remnants of the other. For example, when one removes a price label, adhesive usually remains on the label and the surface. This is cohesive failure. If, however, a layer of paper remains stuck to the surface, the adhesive has not failed. Another example is when someone tries to pull apart Oreo cookies and all the filling remains on one side. The goal in this case is an adhesive failure, rather than a cohesive failure.
# Design of adhesive joints
A general design rule is a relation of the type: "Material Properties > Function (geometry, loads)"
The engineering work will consist in having a good model to evaluate the "Function". For most adhesive joints, this can be achieved using fracture mechanics. Concepts such as the stress concentration factor K and the energy release rate G can be used to predict failure. In such models, the behavior of the adhesive layer itself is neglected and only the adherents are considered.
Failure will also very much depend on the opening "mode" of the joint.
- Mode I is an opening or tensile mode where the loadings are normal to the crack.
- Mode II is a sliding or in-plane shear mode where the crack surfaces slide over one another in direction perpendicular to the leading edge of the crack. This is typically the mode for which the adhesive exhibits the higher resistance to fracture.
- Mode III is a tearing or antiplane shear mode.
As the loads are usually fixed, an acceptable design will result from combination of a material selection procedure and geometry modifications, if possible. In adhesively bonded structures, the global geometry and loads are fixed by structural considerations and the design procedure focuses on the “material properties” of the adhesive (i.e. select a "good" adhesive) and on local changes on the geometry.
Increasing the joint resistance is usually obtained by designing its geometry so that:
- The bonded zone is large
- It is mainly loaded in mode II
- Stable crack propagation will follow the appearance of a local failure.
# Testing the resistance of the adhesive
A wide range of testing devices have been imagined to evaluate the fracture resistance of bonded structures in pure mode I, pure mode II or in mixed mode. Most of these devices are beam type specimens. We will very shortly review the most popular:
- Double Cantilever Beam tests (DCB) measure the mode I fracture resistance of adhesives in a fracture mechanics framework. These tests consist in opening an assembly of two beams by applying a force at the ends of the two beams. The test in unstable (i.e. the crack propagates along the entire specimen once a critical load is attained) and a modified version of this test characterised by a non constant inertia was proposed called the Tapered double cantilever beam specimen (TDCB). File:Tests.jpgTesting devices
- Peel tests measure the fracture resistance of a thin layer bonded on a thick substrate or of two layers bonded together. They consist in measuring the force needed for tearing an adherent layer from a substrate or for tearing two adherent layers one from another. Whereas the structure is not symmetrical, various mode mixities can be introduced in these tests.
- Wedge tests measure the mode I dominated fracture resistance of adhesives used to bond thin plates. These tests consist in inserting a wedge in between two bonded plates. A critical energy release rate can be derived from the crack length during testing. This test is a mode I test but some mode II component can be introduced by bonding plates of different thicknesses.
- Mixed-Mode Delaminating Beam (MMDB) tests consist in a bonded bilayer with two starting cracks loaded on four points. The test presents roughly the same amount of mode I and mode II with a slight dependence on the ratio of the two layer thicknesses.
- End Notch Flexure tests consist in two bonded beams built-in on one side and loaded by a force on the other. As no normal opening is allowed, this device allows testing in essentially mode II condition.
- Crack Lap Shear (CLS) tests are application-oriented fracture resistance tests. They consist in two plates bonded on a limited length and loaded in tension on both ends. The test can be either symmetrical or dis-symmetrical. In the first case two cracks can be initiated and in the second only one crack can propagate. | https://www.wikidoc.org/index.php/Adhesive | |
1e349ca2f22c42b3fe04059be34868915794c560 | wikidoc | Aesculus | Aesculus
The genus Aesculus comprises 20–25 species of deciduous trees and shrubs native to the temperate northern hemisphere, with 7–10 species native to North America and 13–15 species native in Eurasia; there are also several natural hybrids. They have traditionally been treated in their own usually monogeneric family Hippocastanaceae, but genetic evidence has led to this family, along with the Aceraceae (Maples and Dipteronia), being included in the soapberry family (Sapindaceae).
The North American species are known as Buckeyes and the Eurasian species as Horse-chestnuts. Some are also called "White Chestnut" or "Red Chestnut" (as in some of the Bach flower remedies. In Britain, they are sometimes called "Conker trees" because of their link with the game of Conkers ).
# Etymology
The name Horse-chestnut, hyphenated here to avoid confusion with the true chestnuts (Castanea, Fagaceae), is also often given as "Horse Chestnut" or "Horsechestnut". One species very popular in cultivation, the Common Horse-chestnut Aesculus hippocastanum is also often known as just "Horse-chestnut". Linnaeus named the genus Aesculus after the Roman name for an edible acorn. The use of the term "horse" refers to their strength or inedibility, the word "horse" originally meant strong or powerful, and does not here refer to their fitness as fodder for horses, except in folk etymology. The name buckeye derives from the resemblance of the seed to the brown eye of a buck (male deer), and horse-chestnut from the external resemblance of the seed to a chestnut, but being inedible. The Buckeye blooms in summer and the Horse-chestnut in late spring.
# Description
Aesculus are woody plants from 4 to 35 m tall (depending on species), and have stout shoots with resinous, often sticky, buds; opposite, palmately divided leaves, often very large (to 65 cm across in the Japanese Horse-chestnut Aesculus turbinata); and showy insect-pollinated flowers, with a single four- or five-lobed petal (actually four or five petals fused at the base). Flowering starts after 80–110 growing degree days. The fruit is a rich glossy brown to blackish-brown nut 2–5 cm diameter, usually globose with one nut in a green or brown husk, but sometimes two nuts together in one husk, in which case the nuts are flat on one side; the point of attachment of the nut in the husk shows as a large circular whitish scar. The husk has scattered soft spines in some species, spineless in others, and splits into three sections to release the nut.
# Cultivation
The most familiar member of the genus worldwide is the Common Horse-chestnut Aesculus hippocastanum, native to a small area of the Balkans in southeast Europe, but widely cultivated throughout the temperate world. The Yellow Buckeye Aesculus flava (syn. A. octandra) is also a valuable ornamental tree with yellow flowers, but is less widely planted. Among the smaller species, the Bottlebrush Buckeye Aesculus parviflora also makes a very interesting and unusual flowering shrub. Several other members of the genus are used as ornamentals, and several horticultural hybrids have also been developed, most notably the Red Horse-chestnut A. x carnea, a hybrid between A. hippocastanum and A. pavia.
They are generally fairly problem-free, though a recently discovered leaf-mining moth Cameraria ohridella is currently causing major problems in much of Europe, causing premature leaf fall which looks very unattractive. The symptoms (brown blotches on the leaves) can be confused with damage caused by the leaf fungus Guignardia aesculi, which is also very common but usually less serious. Common Horse-chestnut is also used as a food plant by The Sycamore, another species of moth.
Another disease in parts of North West Europe and North America is Bleeding canker .
# Uses
The nuts contain high concentrations of a saponin-class toxin called Aesculin, which is toxic to many animals including humans because it causes hemolysis (destruction of red blood cells). The saponin can be eliminated by leaching the pulverized nuts in multiple changes of boiling water, to yield a wholesome starchy porridge once important to some Native American tribes. Some animals, notably deer and squirrels, are resistant to the toxins and can eat the nuts directly. An interesting side-note is that Aesculin is a natural pH indicator which, when extracted turns from colourless to fluorescent blue under UV light in an acidic pH range.
Crushed buckeye nuts have also been thrown into lakes by poachers, to kill fish for easy capture.
California Buckeyes Aesculus californica are known to cause poisoning of honeybees from toxic nectar (other locally native bee species not being affected). Other buckeye species are thought to have the same effect, but the toxins are diluted because the trees are not usually abundant enough in any one area.
The wood is very pale whitish-brown, fairly soft and little-used. Uses include cheap furniture, boxes and firewood.
In several European countries a new disease has been found in several species of Aesculus. For more information check (in Dutch).
In Britain and Ireland the game of conkers remains a common childhood pastime.
In some cultures, the buckeye tree is thought to bring good luck.
The Mexican Buckeye is related to Aesculus, but is in a separate genus, Ungnadia.
## Uses in homeopathic medicine
Aesculus is used in homeopathic medicine for pain in the sacroiliac region and rectal pain . | Aesculus
The genus Aesculus comprises 20–25 species of deciduous trees and shrubs native to the temperate northern hemisphere, with 7–10 species native to North America and 13–15 species native in Eurasia; there are also several natural hybrids. They have traditionally been treated in their own usually monogeneric family Hippocastanaceae, but genetic evidence has led to this family, along with the Aceraceae (Maples and Dipteronia), being included in the soapberry family (Sapindaceae).
The North American species are known as Buckeyes and the Eurasian species as Horse-chestnuts. Some are also called "White Chestnut" or "Red Chestnut" (as in some of the Bach flower remedies. In Britain, they are sometimes called "Conker trees" because of their link with the game of Conkers ).
# Etymology
The name Horse-chestnut, hyphenated here to avoid confusion with the true chestnuts (Castanea, Fagaceae), is also often given as "Horse Chestnut" or "Horsechestnut". One species very popular in cultivation, the Common Horse-chestnut Aesculus hippocastanum is also often known as just "Horse-chestnut". Linnaeus named the genus Aesculus after the Roman name for an edible acorn. The use of the term "horse" refers to their strength or inedibility, the word "horse" originally meant strong or powerful, and does not here refer to their fitness as fodder for horses, except in folk etymology. The name buckeye derives from the resemblance of the seed to the brown eye of a buck (male deer), and horse-chestnut from the external resemblance of the seed to a chestnut, but being inedible. The Buckeye blooms in summer and the Horse-chestnut in late spring.
# Description
Aesculus are woody plants from 4 to 35 m tall (depending on species), and have stout shoots with resinous, often sticky, buds; opposite, palmately divided leaves, often very large (to 65 cm across in the Japanese Horse-chestnut Aesculus turbinata); and showy insect-pollinated flowers, with a single four- or five-lobed petal (actually four or five petals fused at the base). Flowering starts after 80–110 growing degree days. The fruit is a rich glossy brown to blackish-brown nut 2–5 cm diameter, usually globose with one nut in a green or brown husk, but sometimes two nuts together in one husk, in which case the nuts are flat on one side; the point of attachment of the nut in the husk shows as a large circular whitish scar. The husk has scattered soft spines in some species, spineless in others, and splits into three sections to release the nut.
# Cultivation
The most familiar member of the genus worldwide is the Common Horse-chestnut Aesculus hippocastanum, native to a small area of the Balkans in southeast Europe, but widely cultivated throughout the temperate world. The Yellow Buckeye Aesculus flava (syn. A. octandra) is also a valuable ornamental tree with yellow flowers, but is less widely planted. Among the smaller species, the Bottlebrush Buckeye Aesculus parviflora also makes a very interesting and unusual flowering shrub. Several other members of the genus are used as ornamentals, and several horticultural hybrids have also been developed, most notably the Red Horse-chestnut A. x carnea, a hybrid between A. hippocastanum and A. pavia.
They are generally fairly problem-free, though a recently discovered leaf-mining moth Cameraria ohridella is currently causing major problems in much of Europe, causing premature leaf fall which looks very unattractive. The symptoms (brown blotches on the leaves) can be confused with damage caused by the leaf fungus Guignardia aesculi, which is also very common but usually less serious. Common Horse-chestnut is also used as a food plant by The Sycamore, another species of moth.
Another disease in parts of North West Europe and North America is Bleeding canker [1].
# Uses
The nuts contain high concentrations of a saponin-class toxin called Aesculin, which is toxic to many animals including humans because it causes hemolysis (destruction of red blood cells). The saponin can be eliminated by leaching the pulverized nuts in multiple changes of boiling water, to yield a wholesome starchy porridge once important to some Native American tribes. Some animals, notably deer and squirrels, are resistant to the toxins and can eat the nuts directly. An interesting side-note is that Aesculin is a natural pH indicator which, when extracted turns from colourless to fluorescent blue under UV light in an acidic pH range.
Crushed buckeye nuts have also been thrown into lakes by poachers, to kill fish for easy capture.
California Buckeyes Aesculus californica are known to cause poisoning of honeybees from toxic nectar (other locally native bee species not being affected). Other buckeye species are thought to have the same effect, but the toxins are diluted because the trees are not usually abundant enough in any one area.
The wood is very pale whitish-brown, fairly soft and little-used. Uses include cheap furniture, boxes and firewood.
In several European countries a new disease has been found in several species of Aesculus. For more information check http://www.kastanjeziekte.wur.nl (in Dutch).
In Britain and Ireland the game of conkers remains a common childhood pastime.
In some cultures, the buckeye tree is thought to bring good luck.[2][3]
The Mexican Buckeye is related to Aesculus, but is in a separate genus, Ungnadia.
## Uses in homeopathic medicine
Aesculus is used in homeopathic medicine for pain in the sacroiliac region and rectal pain [1]. | https://www.wikidoc.org/index.php/Aesculus | |
3f43118d07c7ce9ba9e64f346c34671a8a2f186c | wikidoc | Etiology | Etiology
# Overview
Etiology (alternately aetiology, aitiology) is the study of causation. Derived from the Greek αίτιολογία, "giving a reason for" (αἰτία "cause" + -logy).
The word is most commonly used in medical and philosophical theories, where it is used to refer to the study of why things occur, or even the reasons behind the way that things act, and is used in philosophy, physics, psychology, government, and medicine, and biology in reference to the causes of various phenomena. An etiological myth is a myth intended to explain a name or create a mythic history for a place or family.
# Medicine
In medicine in particular, the term refers to the causes of diseases or pathologies. Etiological discovery in medicine has a history in Robert Koch's demonstration that the tubercle bacillus (Mycobacterium tuberculosis complex) causes the disease tuberculosis, that Bacillus anthracis causes anthrax, and that cholera is caused by Vibrio cholerae. This line of thinking and evidence is summarized in Koch's postulates. Proof of causation in infectious diseases is limited, however, to individual cases that provide experimental evidence of etiology.
In epidemiology, several lines of evidence taken in aggregate are required to infer causation. Sir Adrian Bradford-Hill demonstrated a causal relationship between smoking and lung cancer, and summarized the line of reasoning in the epidemiological criteria for causation. Dr. Al Evans, a US epidemiologist, put forward the Unified Concept of Causation, a synthesis of the predecessors' ideas.
Etiological research in medicine has required further thinking in epidemiology - we may distinguish what seen to be associated or statistically correlated, as due to several possible relationships. Things may be associated in observation due to chance, or due to bias or confounding, as well as due to causation (or reverse causation). Careful sampling and measurement are more important in teasing out causation from chance, bias or confounding than sophisticated statistical analysis. Experimental evidence, involving interventions (providing or removing the supposed cause) gives the most compelling evidence of etiology.
Thus etiology may be one part of a chain of causation. An etiological agent (sine qua non) of disease may require an independent co-factor (necessary but not sufficient), and be subject to a promoter (increases expression) in producing a disease. An example of all the above would be the late recognition that peptic ulcer disease may be induced by stress, requires the presence of acid secretion in the stomach, and have primary etiology in Helicobacter pylori infection. Many chronic diseases of unknown cause may be studied in this framework to explain multiple epidemiological associations or risk factors which may or may not be causally related, and to seek the actual etiology.
Some diseases, such as diabetes, are syndromically defined by their signs and symptoms, but include more than one condition, and therefore can have more than one etiology. Alternatively, one etiology of disease such as Epstein-Barr virus may produce more than one disease, such as mononucleosis, or nasopharyngeal carcinoma, or Burkitt's lymphoma given different circumstances.
# Mythology
An etiological myth is a myth intended to explain the origins of cult practices, natural phenomena, proper names and the like. For example, the name Delphi and its associated deity, Apollon Delphinios, are explained in the Homeric Hymn which tells of how Apollo carried Cretans over the sea in the shape of a dolphin ("delphis") to make them his priests. While Delphi is actually related to the word delphys ("womb"), many etiological myths are similarly based on folk etymology (the term "Amazon", for example). In the Aeneid (published circa 17 BC), Vergil claims the descent of Augustus Caesar's Julian clan from the hero Aeneas through his son Ascanius, also called Julus. Other examples of etiological myth come from the Bible, such as the setting of the rainbow in the heavens as a sign of God's covenant with Noah (Genesis 9); or the story of Lot's wife in Genesis 19 (specifically 26), which explains why there are pillars of salt in the area of the Dead Sea. The story of Prometheus' sacrifice-trick in Hesiod's Theogony relates how Prometheus tricked Zeus into choosing the bones and fat of the first sacrificial animal rather than the meat to justify why, after a sacrifice, the Greeks offered the bones wrapped in fat to the gods while keeping the meat for themselves. | Etiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Etiology (alternately aetiology, aitiology) is the study of causation. Derived from the Greek αίτιολογία, "giving a reason for" (αἰτία "cause" + -logy).[1]
The word is most commonly used in medical and philosophical theories, where it is used to refer to the study of why things occur, or even the reasons behind the way that things act, and is used in philosophy, physics, psychology, government, and medicine, and biology in reference to the causes of various phenomena. An etiological myth is a myth intended to explain a name or create a mythic history for a place or family.
# Medicine
In medicine in particular, the term refers to the causes of diseases or pathologies.[2] Etiological discovery in medicine has a history in Robert Koch's demonstration that the tubercle bacillus (Mycobacterium tuberculosis complex) causes the disease tuberculosis, that Bacillus anthracis causes anthrax, and that cholera is caused by Vibrio cholerae. This line of thinking and evidence is summarized in Koch's postulates. Proof of causation in infectious diseases is limited, however, to individual cases that provide experimental evidence of etiology.
In epidemiology, several lines of evidence taken in aggregate are required to infer causation. Sir Adrian Bradford-Hill demonstrated a causal relationship between smoking and lung cancer, and summarized the line of reasoning in the epidemiological criteria for causation. Dr. Al Evans, a US epidemiologist, put forward the Unified Concept of Causation, a synthesis of the predecessors' ideas.
Etiological research in medicine has required further thinking in epidemiology - we may distinguish what seen to be associated or statistically correlated, as due to several possible relationships. Things may be associated in observation due to chance, or due to bias or confounding, as well as due to causation (or reverse causation). Careful sampling and measurement are more important in teasing out causation from chance, bias or confounding than sophisticated statistical analysis. Experimental evidence, involving interventions (providing or removing the supposed cause) gives the most compelling evidence of etiology.
Thus etiology may be one part of a chain of causation. An etiological agent (sine qua non) of disease may require an independent co-factor (necessary but not sufficient), and be subject to a promoter (increases expression) in producing a disease. An example of all the above would be the late recognition that peptic ulcer disease may be induced by stress, requires the presence of acid secretion in the stomach, and have primary etiology in Helicobacter pylori infection. Many chronic diseases of unknown cause may be studied in this framework to explain multiple epidemiological associations or risk factors which may or may not be causally related, and to seek the actual etiology.
Some diseases, such as diabetes, are syndromically defined by their signs and symptoms, but include more than one condition, and therefore can have more than one etiology. Alternatively, one etiology of disease such as Epstein-Barr virus may produce more than one disease, such as mononucleosis, or nasopharyngeal carcinoma, or Burkitt's lymphoma given different circumstances.
# Mythology
An etiological myth is a myth intended to explain the origins of cult practices, natural phenomena, proper names and the like. For example, the name Delphi and its associated deity, Apollon Delphinios, are explained in the Homeric Hymn which tells of how Apollo carried Cretans over the sea in the shape of a dolphin ("delphis") to make them his priests. While Delphi is actually related to the word delphys ("womb"), many etiological myths are similarly based on folk etymology (the term "Amazon", for example). In the Aeneid (published circa 17 BC), Vergil claims the descent of Augustus Caesar's Julian clan from the hero Aeneas through his son Ascanius, also called Julus. Other examples of etiological myth come from the Bible, such as the setting of the rainbow in the heavens as a sign of God's covenant with Noah (Genesis 9); or the story of Lot's wife in Genesis 19 (specifically 26), which explains why there are pillars of salt in the area of the Dead Sea.[3] The story of Prometheus' sacrifice-trick in Hesiod's Theogony relates how Prometheus tricked Zeus into choosing the bones and fat of the first sacrificial animal rather than the meat to justify why, after a sacrifice, the Greeks offered the bones wrapped in fat to the gods while keeping the meat for themselves. | https://www.wikidoc.org/index.php/Aetiologies | |
229bb359eb500fca44bba2d334513bddf2903fd9 | wikidoc | Afatinib | Afatinib
# 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
Afatinib is a kinase inhibitor that is FDA approved for the treatment of metastatic non-small cell lung cancer (NSCLC). Common adverse reactions include diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Afatinib is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take Afatinib at least 1 hour before or 2 hours after a meal.
- Do not take a missed dose within 12 hours of the next dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Afatinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Afatinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Afatinib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Afatinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Afatinib in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Diarrhea
- Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with Afatinib (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with Afatinib, out of which 3 (1.3%) were Grade 3.
- For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold Afatinib until diarrhea resolves to Grade 1 or less, and resume Afatinib with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.
- Bullous and Exfoliative Skin Disorders
- Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received Afatinib across clinical trials. In Study 1, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue Afatinib in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold Afatinib until the adverse reaction resolves to Grade 1 or less, and resume Afatinib with appropriate dose reduction.
- Interstitial Lung Disease (ILD)
- ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received Afatinib across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of Afatinib-treated patients.
- Withhold Afatinib during evaluation of patients with suspected ILD, and discontinue Afatinib in patients with confirmed ILD.
- Hepatic Toxicity
- In 3865 patients who received Afatinib across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with Afatinib.
- Obtain periodic liver testing in patients during treatment with Afatinib. Withhold Afatinib in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking Afatinib, treatment should be discontinued.
- Keratitis
- Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with Afatinib among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). Withhold Afatinib during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with Afatinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitisand ulceration.
- Embryofetal Toxicity
- Based on its mechanism of action, Afatinib can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. 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.
- Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of Afatinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Afatinib.
- Combination with Vinorelbine in HER2 Positive Metastatic Breast Cancer
- An early interim overall survival analysis of a randomized Phase 3 trial in HER2 positive metastatic breast cancer showed an increased mortality in patients receiving Afatinib in combination with vinorelbine compared to trastuzumab and vinorelbine. The combination of Afatinib and vinorelbine was also associated with a higher rate of adverse events (such as diarrhea, rash) and fatal events related to infections and cancer progression. Afatinib combined with vinorelbine should not be used in patients with HER2 positive metastatic breast cancer.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety evaluation of Afatinib is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving Afatinib monotherapy at or above the recommended dose.
- Controlled Study
- The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naïve Afatinib-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received Afatinib 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses.
- The median exposure was 11.0 months for patients treated with Afatinib and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the Afatinib arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on Afatinib and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (Afatinib 70%; pemetrexed/cisplatin 72%).
- Serious adverse reactions were reported in 29% of patients treated with Afatinib. The most frequent serious adverse reactions reported in patients treated with Afatinib were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in Afatinib-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
- Dose reductions due to adverse reactions were required in 57% of Afatinib-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with Afatinib were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%).
- Discontinuation of therapy in Afatinib-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in Afatinib-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).
- Clinical trials of Afatinib excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the Afatinib-treated group and as needed in the pemetrexed/cisplatin group. More Afatinib-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Afatinib in the drug label.
# Drug Interactions
- Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
- Oral administration of a P-gp inhibitor (ritonavir at 200 mg twice daily) 1 hour before administration of Afatinib increased systemic exposure to afatinib by 48%. There was no change in afatinib exposure when ritonavir was administered simultaneously with or 6 hours after Afatinib. Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with Afatinib can increase exposure to afatinib.
- Co-administration with oral dose of a P-gp inducer (rifampicin at 600 mg once daily for 7 days) decreased exposure to afatinib by 34%. Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s Wort) with Afatinib can decrease exposure to afatinib.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Risk Summary
- Based on its mechanism of action, Afatinib can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater. 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.
- Animal Data
- Administration of afatinib to pregnant rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater during the period of organogenesis caused increased post implantation loss and, in animals showing maternal toxicity, abortion at late gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times the exposure by AUC at the recommended human dose of 40 mg daily) there were reduced fetal weights, and increases in the incidence of runts, as well as visceral and dermal variations. In an embryofetal development study in rats, there were skeletal alterations consisting of incomplete or delayed ossifications and reduced fetal weight at a dose of 16 mg/kg (approximately twice the exposure at the recommended human dose of 40 mg daily).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Afatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Afatinib during labor and delivery.
### Nursing Mothers
- It is not known whether afatinib is present in human milk. Afatinib was present in the milk of lactating rats at concentrations 80-150 times higher than those found in plasma from 1 to 6 hours after administration. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Afatinib, 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
- Safety and effectiveness of Afatinib in pediatric patients have not been established.
### Geriatic Use
- Of the 3865 patients in the clinical studies of Afatinib, 32% of patients were 65 years and older, while 7% were 75 years and older. No overall differences in safety were observed between patients 65 years and over and younger patients. In Study 1, 39% of the 345 patients were 65 years of age or older and 4% were 75 years or older. No overall differences in effectiveness were observed between patients 65 years and older and younger patients.
### Gender
There is no FDA guidance on the use of Afatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Afatinib with respect to specific racial populations.
### Renal Impairment
- Afatinib has not been studied in patients with severely impaired renal function (creatinine clearance <30 mL/min). Adjustments to the starting dose of Afatinib are not considered necessary in patients with mild (CLcr 60-89 mL/min) renal impairment. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust Afatinib dose if not tolerated.
### Hepatic Impairment
- Afatinib has not been studied in patients with severe (Child Pugh C) hepatic impairment. Adjustments to the starting dose of Afatinib are not considered necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust Afatinib dose if not tolerated.
### Females of Reproductive Potential and Males
- Females
- Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with Afatinib, and for at least 2 weeks after the last dose of Afatinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Afatinib.
### Immunocompromised Patients
There is no FDA guidance one the use of Afatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Afatinib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Afatinib in the drug label.
# Overdosage
## Acute Overdose
- Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of Afatinib (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times upper limit of normal ). Both subjects recovered.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Afatinib in the drug label.
# Pharmacology
## Mechanism of Action
- Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling.
- Afatinib demonstrated inhibition of autophosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR or those expressing selected EGFR exon 19 deletion mutations or exon 21 L858R mutations, including some with a secondary T790M mutation, at afatinib concentrations achieved, at least transiently, in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.
- Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.
## Structure
- Afatinib tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N--7-oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:
- Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C32H33ClFN5O11, and a molecular weight of 718.1 g/mol.
- Afatinib tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of Afatinib are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).
## Pharmacodynamics
- Cardiac Electrophysiology
- The effect of multiple doses of Afatinib (50 mg once daily) on the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study.
## Pharmacokinetics
- Absorption and Distribution
- Following oral administration of Afatinib tablets, time to peak afatinib plasma concentrations (Tmax) is 2 to 5 hours. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) values increased slightly more than dose proportional in the range of 20 to 50 mg. The geometric mean relative bioavailability of 20 mg Afatinib tablets was 92% as compared to an oral solution. In vitro binding of afatinib to human plasma proteins is approximately 95%.
- A high-fat meal decreased Cmax by 50% and AUC0-∞ by 39% relative to the fasted condition.
- Metabolism and Elimination
- Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal.
- In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of -labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.
- The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. Steady-state plasma concentrations are achieved within 8 days of repeat dosing of Afatinib resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for Cmax.
- Specific Populations
- Renal Impairment: The median trough afatinib plasma concentrations in patients with mild (CLcr 60-89 mL/min) and moderate (CLcr 30-59 mL/min) renal impairment were 27% and 85% higher than those in patients with normal renal function (CLcr ≥90 mL/min). Afatinib has not been studied in patients with severely impaired renal function (CLcr <30 mL/min).
- Hepatic Impairment: Afatinib is eliminated mainly by biliary/fecal excretion. Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of Afatinib. Subjects with severe (Child Pugh C) hepatic dysfunction have not been studied.
- Body Weight, Gender, Age, and Race: Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.
- Drug Interactions
- Effect of P-gp Inhibitors and Inducers on Afatinib: The effect of ritonavir dosing time relative to a single oral dose of Afatinib was evaluated in healthy subjects taking 40 mg of Afatinib alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after Afatinib administration. The relative bioavailability for AUC0-∞ and Cmax of afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking Afatinib. In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of Afatinib, exposure to afatinib increased by 48% for AUC0-∞ and 39% for Cmax.
- Pre-treatment with a potent inducer of P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax).
- P-glycoprotein (P-gp): Based on in vitro data, afatinib is a substrate and an inhibitor of P-gp.
- Breast Cancer Resistance Protein (BCRP): Based on in vitro data, afatinib is a substrate and an inhibitor of the transporter BCRP.
- Effect of CYP450 Enzyme Inducers and Inhibitors on Afatinib: In vitro data indicated that drug-drug interactions with Afatinib due to inhibition or induction of CYP450 enzymes by concomitant medications are unlikely. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes. In humans, enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.
- Effect of Afatinib on CYP450 Enzymes: Afatinib is not an inhibitor or an inducer of CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4) in cultured primary human hepatocytes. Therefore, afatinib is unlikely to affect the metabolism of other drugs that are substrates of CYP450 enzymes.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with afatinib.
- A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. No mutagenic or genotoxic potential was identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as in the in vivo bone marrow micronucleus assay, the in vivo Comet assay, and an in vivo 4-week oral mutation study in the Muta™ Mouse.
- In a dedicated fertility study, male and female rats received afatinib daily by oral administration at doses of 4, 6, or 8 mg/kg. In males at doses of 6 mg/kg (approximately equal to the exposure by AUC in patients at the recommended human dose of 40 mg daily) or greater, there was an increase in the incidence of low or no sperm count, though overall fertility was not affected; decreases in sperm count were supported by findings of increased apoptosis in the testes and atrophy in the seminal vesicles and the prostate in general toxicology studies. In females at the high dose of 8 mg/kg (approximately 0.63 times the exposure by AUC in patients at the recommended human dose of 40 mg daily), there was a mild decrease in the number of corpora lutea along with a mild increase in post-implantation loss due to early resorptions. In a 4-week general toxicology study, female rats had decreases in ovarian weights at all dose levels; organ weight had not fully recovered by the end of a 2-week recovery period.
# Clinical Studies
- Study 1
- The efficacy and safety of Afatinib in the first-line treatment of 345 patients with EGFR mutation-positive, metastatic (Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer ) NSCLC were established in a randomized, multicenter, open-label trial (Study 1). Patients were randomized (2:1) to receive Afatinib 40 mg orally once daily (n=230) or up to 6 cycles of pemetrexed/cisplatin (n=115). Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included objective response rate (ORR) and overall survival (OS). EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to Afatinib and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen® EGFR RGQ PCR Kit, which is FDA-approved for selection of patients for Afatinib treatment.
- Among the patients randomized, 65% were female, the median age was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations.
- A statistically significant improvement in PFS as determined by the IRC was demonstrated for patients randomized to Afatinib compared with those randomized to chemotherapy. See Table 3 and Figure 1. There was no statistically significant difference for overall survival between the treatment arms at the interim analysis conducted at 84% of the planned events for the final analysis.
- There were 26 Afatinib-treated patients in the “other” (uncommon) EGFR mutations subgroup with nine unique mutation patterns. None of these 26 patients achieved a complete response, while four achieved a partial response (see Table 4 below). No responses were seen in Afatinib-treated patients with the following mutations: T790M alone (n=2), deletion 19 and T790M (n=3), G719X and T790M (n=1), exon 20 insertion (n=6), and L861Q alone (n=3). There were 11 chemotherapy-treated patients in the “other” uncommon EGFR mutation subgroup; of these, four (36%) achieved a partial response.
# How Supplied
- Afatinib tablets are available as follows:
- 40 mg: light blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T40” on one side and the Boehringer Ingelheim company symbol on the other side.
- Unit of use bottles of 30 NDC: 0597-0138-30
- 30 mg: dark blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T30” on one side and the Boehringer Ingelheim company symbol on the other side.
- Unit of use bottles of 30 NDC: 0597-0137-30
- 20 mg: white to slightly yellowish, film-coated, round, biconvex, bevel-edged tablets debossed with “T20” on one side and the Boehringer Ingelheim company symbol on the other side.
- Unit of use bottles of 30 NDC: 0597-0141-30
- Storage
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Dispense medication in the original container to protect from exposure to high humidity and light.
## Storage
There is limited information regarding Afatinib Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Diarrhea
- Advise patients that diarrhea occurs in nearly all patients who receive Afatinib. Inform patients that diarrhea may result in dehydration and renal impairment if not treated. Advise patients to notify their physician if diarrhea develops and to seek medical attention promptly for severe or persistent diarrhea.
- Bullous and Exfoliative Skin Disorders
- Advise patients to minimize sun exposure with protective clothing and use of sunscreen while taking Afatinib.
- Interstitial Lung Disease
- Advise patients to immediately report any new or worsening lung symptoms, or any combination of the following symptoms: trouble breathing or shortness of breath, cough, fever.
- Hepatic Toxicity
- Advise patients that they will need to undergo liver function monitoring periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy).
- Keratitis
- Advise patients to immediately report eye problems (e.g., eye pain, swelling, redness, blurred vision, or other vision changes).
- Left Ventricular Dysfunction
- Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening shortness of breath or exercise intolerance, cough, fatigue, swelling of the ankles/legs, palpitations, or sudden weight gain.
- Instructions for Taking Afatinib
- Advise patients to take Afatinib on an empty stomach at least 1 hour before or 2 hours after eating. Advise patients not to take a missed dose within 12 hours of the next dose.
- Embryofetal Toxicity
- Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after taking the last dose of Afatinib.
- Nursing Mothers
- Advise patients to discontinue nursing while taking Afatinib.
# Precautions with Alcohol
- Alcohol-Afatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GILOTRIF®
# Look-Alike Drug Names
There is limited information regarding Afatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Afatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]; Sree Teja Yelamanchili, MBBS [3]
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# Overview
Afatinib is a kinase inhibitor that is FDA approved for the treatment of metastatic non-small cell lung cancer (NSCLC). Common adverse reactions include diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Afatinib is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take Afatinib at least 1 hour before or 2 hours after a meal.
- Do not take a missed dose within 12 hours of the next dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Afatinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Afatinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Afatinib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Afatinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Afatinib in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Diarrhea
- Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with Afatinib (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with Afatinib, out of which 3 (1.3%) were Grade 3.
- For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold Afatinib until diarrhea resolves to Grade 1 or less, and resume Afatinib with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.
- Bullous and Exfoliative Skin Disorders
- Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received Afatinib across clinical trials. In Study 1, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue Afatinib in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold Afatinib until the adverse reaction resolves to Grade 1 or less, and resume Afatinib with appropriate dose reduction.
- Interstitial Lung Disease (ILD)
- ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received Afatinib across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of Afatinib-treated patients.
- Withhold Afatinib during evaluation of patients with suspected ILD, and discontinue Afatinib in patients with confirmed ILD.
- Hepatic Toxicity
- In 3865 patients who received Afatinib across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with Afatinib.
- Obtain periodic liver testing in patients during treatment with Afatinib. Withhold Afatinib in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking Afatinib, treatment should be discontinued.
- Keratitis
- Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with Afatinib among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). Withhold Afatinib during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with Afatinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitisand ulceration.
- Embryofetal Toxicity
- Based on its mechanism of action, Afatinib can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. 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.
- Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of Afatinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Afatinib.
- Combination with Vinorelbine in HER2 Positive Metastatic Breast Cancer
- An early interim overall survival analysis of a randomized Phase 3 trial in HER2 positive metastatic breast cancer showed an increased mortality in patients receiving Afatinib in combination with vinorelbine compared to trastuzumab and vinorelbine. The combination of Afatinib and vinorelbine was also associated with a higher rate of adverse events (such as diarrhea, rash) and fatal events related to infections and cancer progression. Afatinib combined with vinorelbine should not be used in patients with HER2 positive metastatic breast cancer.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety evaluation of Afatinib is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving Afatinib monotherapy at or above the recommended dose.
- Controlled Study
- The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naïve Afatinib-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received Afatinib 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses.
- The median exposure was 11.0 months for patients treated with Afatinib and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the Afatinib arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on Afatinib and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (Afatinib 70%; pemetrexed/cisplatin 72%).
- Serious adverse reactions were reported in 29% of patients treated with Afatinib. The most frequent serious adverse reactions reported in patients treated with Afatinib were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in Afatinib-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
- Dose reductions due to adverse reactions were required in 57% of Afatinib-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with Afatinib were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%).
- Discontinuation of therapy in Afatinib-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in Afatinib-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).
- Clinical trials of Afatinib excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the Afatinib-treated group and as needed in the pemetrexed/cisplatin group. More Afatinib-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Afatinib in the drug label.
# Drug Interactions
- Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
- Oral administration of a P-gp inhibitor (ritonavir at 200 mg twice daily) 1 hour before administration of Afatinib increased systemic exposure to afatinib by 48%. There was no change in afatinib exposure when ritonavir was administered simultaneously with or 6 hours after Afatinib. Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with Afatinib can increase exposure to afatinib.
- Co-administration with oral dose of a P-gp inducer (rifampicin at 600 mg once daily for 7 days) decreased exposure to afatinib by 34%. Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s Wort) with Afatinib can decrease exposure to afatinib.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Risk Summary
- Based on its mechanism of action, Afatinib can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater. 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.
- Animal Data
- Administration of afatinib to pregnant rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater during the period of organogenesis caused increased post implantation loss and, in animals showing maternal toxicity, abortion at late gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times the exposure by AUC at the recommended human dose of 40 mg daily) there were reduced fetal weights, and increases in the incidence of runts, as well as visceral and dermal variations. In an embryofetal development study in rats, there were skeletal alterations consisting of incomplete or delayed ossifications and reduced fetal weight at a dose of 16 mg/kg (approximately twice the exposure at the recommended human dose of 40 mg daily).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Afatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Afatinib during labor and delivery.
### Nursing Mothers
- It is not known whether afatinib is present in human milk. Afatinib was present in the milk of lactating rats at concentrations 80-150 times higher than those found in plasma from 1 to 6 hours after administration. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Afatinib, 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
- Safety and effectiveness of Afatinib in pediatric patients have not been established.
### Geriatic Use
- Of the 3865 patients in the clinical studies of Afatinib, 32% of patients were 65 years and older, while 7% were 75 years and older. No overall differences in safety were observed between patients 65 years and over and younger patients. In Study 1, 39% of the 345 patients were 65 years of age or older and 4% were 75 years or older. No overall differences in effectiveness were observed between patients 65 years and older and younger patients.
### Gender
There is no FDA guidance on the use of Afatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Afatinib with respect to specific racial populations.
### Renal Impairment
- Afatinib has not been studied in patients with severely impaired renal function (creatinine clearance [CLcr] <30 mL/min). Adjustments to the starting dose of Afatinib are not considered necessary in patients with mild (CLcr 60-89 mL/min) renal impairment. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust Afatinib dose if not tolerated.
### Hepatic Impairment
- Afatinib has not been studied in patients with severe (Child Pugh C) hepatic impairment. Adjustments to the starting dose of Afatinib are not considered necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust Afatinib dose if not tolerated.
### Females of Reproductive Potential and Males
- Females
- Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with Afatinib, and for at least 2 weeks after the last dose of Afatinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Afatinib.
### Immunocompromised Patients
There is no FDA guidance one the use of Afatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Afatinib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Afatinib in the drug label.
# Overdosage
## Acute Overdose
- Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of Afatinib (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times upper limit of normal [ULN]). Both subjects recovered.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Afatinib in the drug label.
# Pharmacology
## Mechanism of Action
- Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling.
- Afatinib demonstrated inhibition of autophosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR or those expressing selected EGFR exon 19 deletion mutations or exon 21 L858R mutations, including some with a secondary T790M mutation, at afatinib concentrations achieved, at least transiently, in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.
- Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.
## Structure
- Afatinib tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:
- Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C32H33ClFN5O11, and a molecular weight of 718.1 g/mol.
- Afatinib tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of Afatinib are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).
## Pharmacodynamics
- Cardiac Electrophysiology
- The effect of multiple doses of Afatinib (50 mg once daily) on the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study.
## Pharmacokinetics
- Absorption and Distribution
- Following oral administration of Afatinib tablets, time to peak afatinib plasma concentrations (Tmax) is 2 to 5 hours. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) values increased slightly more than dose proportional in the range of 20 to 50 mg. The geometric mean relative bioavailability of 20 mg Afatinib tablets was 92% as compared to an oral solution. In vitro binding of afatinib to human plasma proteins is approximately 95%.
- A high-fat meal decreased Cmax by 50% and AUC0-∞ by 39% relative to the fasted condition.
- Metabolism and Elimination
- Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal.
- In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [14C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.
- The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. Steady-state plasma concentrations are achieved within 8 days of repeat dosing of Afatinib resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for Cmax.
- Specific Populations
- Renal Impairment: The median trough afatinib plasma concentrations in patients with mild (CLcr 60-89 mL/min) and moderate (CLcr 30-59 mL/min) renal impairment were 27% and 85% higher than those in patients with normal renal function (CLcr ≥90 mL/min). Afatinib has not been studied in patients with severely impaired renal function (CLcr <30 mL/min).
- Hepatic Impairment: Afatinib is eliminated mainly by biliary/fecal excretion. Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of Afatinib. Subjects with severe (Child Pugh C) hepatic dysfunction have not been studied.
- Body Weight, Gender, Age, and Race: Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.
- Drug Interactions
- Effect of P-gp Inhibitors and Inducers on Afatinib: The effect of ritonavir dosing time relative to a single oral dose of Afatinib was evaluated in healthy subjects taking 40 mg of Afatinib alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after Afatinib administration. The relative bioavailability for AUC0-∞ and Cmax of afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking Afatinib. In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of Afatinib, exposure to afatinib increased by 48% for AUC0-∞ and 39% for Cmax.
- Pre-treatment with a potent inducer of P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax).
- P-glycoprotein (P-gp): Based on in vitro data, afatinib is a substrate and an inhibitor of P-gp.
- Breast Cancer Resistance Protein (BCRP): Based on in vitro data, afatinib is a substrate and an inhibitor of the transporter BCRP.
- Effect of CYP450 Enzyme Inducers and Inhibitors on Afatinib: In vitro data indicated that drug-drug interactions with Afatinib due to inhibition or induction of CYP450 enzymes by concomitant medications are unlikely. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes. In humans, enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.
- Effect of Afatinib on CYP450 Enzymes: Afatinib is not an inhibitor or an inducer of CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4) in cultured primary human hepatocytes. Therefore, afatinib is unlikely to affect the metabolism of other drugs that are substrates of CYP450 enzymes.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with afatinib.
- A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. No mutagenic or genotoxic potential was identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as in the in vivo bone marrow micronucleus assay, the in vivo Comet assay, and an in vivo 4-week oral mutation study in the Muta™ Mouse.
- In a dedicated fertility study, male and female rats received afatinib daily by oral administration at doses of 4, 6, or 8 mg/kg. In males at doses of 6 mg/kg (approximately equal to the exposure by AUC in patients at the recommended human dose of 40 mg daily) or greater, there was an increase in the incidence of low or no sperm count, though overall fertility was not affected; decreases in sperm count were supported by findings of increased apoptosis in the testes and atrophy in the seminal vesicles and the prostate in general toxicology studies. In females at the high dose of 8 mg/kg (approximately 0.63 times the exposure by AUC in patients at the recommended human dose of 40 mg daily), there was a mild decrease in the number of corpora lutea along with a mild increase in post-implantation loss due to early resorptions. In a 4-week general toxicology study, female rats had decreases in ovarian weights at all dose levels; organ weight had not fully recovered by the end of a 2-week recovery period.
# Clinical Studies
- Study 1
- The efficacy and safety of Afatinib in the first-line treatment of 345 patients with EGFR mutation-positive, metastatic (Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer [AJCC, 6th edition]) NSCLC were established in a randomized, multicenter, open-label trial (Study 1). Patients were randomized (2:1) to receive Afatinib 40 mg orally once daily (n=230) or up to 6 cycles of pemetrexed/cisplatin (n=115). Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included objective response rate (ORR) and overall survival (OS). EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to Afatinib and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen® EGFR RGQ PCR Kit, which is FDA-approved for selection of patients for Afatinib treatment.
- Among the patients randomized, 65% were female, the median age was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations.
- A statistically significant improvement in PFS as determined by the IRC was demonstrated for patients randomized to Afatinib compared with those randomized to chemotherapy. See Table 3 and Figure 1. There was no statistically significant difference for overall survival between the treatment arms at the interim analysis conducted at 84% of the planned events for the final analysis.
- There were 26 Afatinib-treated patients in the “other” (uncommon) EGFR mutations subgroup with nine unique mutation patterns. None of these 26 patients achieved a complete response, while four achieved a partial response (see Table 4 below). No responses were seen in Afatinib-treated patients with the following mutations: T790M alone (n=2), deletion 19 and T790M (n=3), G719X and T790M (n=1), exon 20 insertion (n=6), and L861Q alone (n=3). There were 11 chemotherapy-treated patients in the “other” uncommon EGFR mutation subgroup; of these, four (36%) achieved a partial response.
# How Supplied
- Afatinib tablets are available as follows:
- 40 mg: light blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T40” on one side and the Boehringer Ingelheim company symbol on the other side.
- Unit of use bottles of 30 NDC: 0597-0138-30
- 30 mg: dark blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T30” on one side and the Boehringer Ingelheim company symbol on the other side.
- Unit of use bottles of 30 NDC: 0597-0137-30
- 20 mg: white to slightly yellowish, film-coated, round, biconvex, bevel-edged tablets debossed with “T20” on one side and the Boehringer Ingelheim company symbol on the other side.
- Unit of use bottles of 30 NDC: 0597-0141-30
- Storage
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Dispense medication in the original container to protect from exposure to high humidity and light.
## Storage
There is limited information regarding Afatinib Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Diarrhea
- Advise patients that diarrhea occurs in nearly all patients who receive Afatinib. Inform patients that diarrhea may result in dehydration and renal impairment if not treated. Advise patients to notify their physician if diarrhea develops and to seek medical attention promptly for severe or persistent diarrhea.
- Bullous and Exfoliative Skin Disorders
- Advise patients to minimize sun exposure with protective clothing and use of sunscreen while taking Afatinib.
- Interstitial Lung Disease
- Advise patients to immediately report any new or worsening lung symptoms, or any combination of the following symptoms: trouble breathing or shortness of breath, cough, fever.
- Hepatic Toxicity
- Advise patients that they will need to undergo liver function monitoring periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy).
- Keratitis
- Advise patients to immediately report eye problems (e.g., eye pain, swelling, redness, blurred vision, or other vision changes).
- Left Ventricular Dysfunction
- Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening shortness of breath or exercise intolerance, cough, fatigue, swelling of the ankles/legs, palpitations, or sudden weight gain.
- Instructions for Taking Afatinib
- Advise patients to take Afatinib on an empty stomach at least 1 hour before or 2 hours after eating. Advise patients not to take a missed dose within 12 hours of the next dose.
- Embryofetal Toxicity
- Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after taking the last dose of Afatinib.
- Nursing Mothers
- Advise patients to discontinue nursing while taking Afatinib.
# Precautions with Alcohol
- Alcohol-Afatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GILOTRIF®[2]
# Look-Alike Drug Names
There is limited information regarding Afatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Afatinib | |
dcf8bab88c4b75889c6c7f8ddb1184f0b528746d | wikidoc | Agenesis | Agenesis
Agenesis is the medical term for the failure of an organ to develop during embryonic growth and development.
# Conditions
Many specific examples of agenesis are referred to by individual names, depending on the organ affected.
- Agenesis of the corpus callosum- failure of the Corpus callosum to develop.
- Renal agenesis- failure of one or both of the kidneys to develop.
- Phocomelia- failure of the arms or legs to develop, often caused by the drug thalidomide.
- Penile agenesis- failure of penis to develop.
# Alternate Definition
In theology and origins science, agenesis means to have no beginning or to have no creator. To come into existence without the influence of an outside intelligence.
da:Agenesi
de:Agenesie
nl:Agenesie | Agenesis
Agenesis is the medical term for the failure of an organ to develop during embryonic growth and development.
# Conditions
Many specific examples of agenesis are referred to by individual names, depending on the organ affected.
- Agenesis of the corpus callosum- failure of the Corpus callosum to develop.
- Renal agenesis- failure of one or both of the kidneys to develop.
- Phocomelia- failure of the arms or legs to develop, often caused by the drug thalidomide.
- Penile agenesis- failure of penis to develop.
# Alternate Definition
In theology and origins science, agenesis means to have no beginning or to have no creator. To come into existence without the influence of an outside intelligence.
Template:Disease-stub
da:Agenesi
de:Agenesie
nl:Agenesie | https://www.wikidoc.org/index.php/Agenesis | |
6cc647f1f7ddf70509f554e251a7e3029a40478f | wikidoc | Aggrecan | Aggrecan
Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ACAN gene. This gene is a member of the lectican (chondroitin sulfate proteoglycan) family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage.
Aggrecan is a proteoglycan, or a protein modified with large carbohydrates; the human form of the protein is 2316 amino acids long and can be expressed in multiple isoforms due to alternative splicing.
# Structure
Aggrecan is a high molecular weight (1x106 < M < 3x106) proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfate and keratan sulfate glycosaminoglycan (GAG) chains are attached to an extended protein core.
Aggrecan has a molecular mass >2,500 kDa. The core protein (~300 kDa) has around 100 GAG chains attached to it.
Aggrecan consists of two globular structural domains (G1 and G2) at the N-terminal end and one globular domain (G3) at the C-terminal end, separated by a large extended domain (CS) heavily modified with GAGs. (N-G1-G2-CS-G3-C)
The two main modifier moieties are themselves arranged into distinct regions, a chondroitin sulfate and a keratan sulfate region.
The three globular domains, G1, G2, and G3 are involved in aggregation, hyaluronan binding, cell adhesion, and chondrocyte apoptosis.
Along with type-II collagen, aggrecan forms a major structural component of cartilage, particularly articular cartilage.
The aggrecan family includes other important members such as versican, also named PG-M, neurocan, brevican and the cell surface HA receptor CD44. They are modular proteoglycans containing combinations of structural motifs, such as EGF-like domains, carbohydrate recognition domains (CRD), complement binding protein (CBP)-like domains, immunoglobulin folds and proteoglycan tandem repeats.
# Function
Aggrecan is a critical component for cartilage structure and the function of joints.
Functionally, the G1 domain interacts with hyaluronic acid and link protein, forming stable ternary complexes in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and of link protein and is involved in product processing. G3 makes up the carboxyl terminus of the core protein. It enhances glycosaminoglycan modification and product secretion. Aggrecan plays an important role in mediating chondrocyte-chondrocyte and chondrocyte-matrix interactions through its ability to bind hyaluronan.
Aggrecan provides intervertebral disc and cartilage with the ability to resist compressive loads. The localized high concentrations of aggrecan provide the osmotic properties necessary for normal tissue function with the GAGs producing the swelling pressure that counters compressive loads on the tissue. This functional ability is dependent on a high GAG/aggrecan concentration being present in the tissue extracellular matrix. In the disc, aggrecan concentrations peak in a person's twenties, and decline thereafter, with aggrecan degradation products slowly accumulating over the following decades. This causes discs to get stiffer and less resilient with age.
Aggrecan also plays an important role in the organization of the extracellular spaces between neurons in the brain. Through interactions with link protein and tenascins, aggrecan binds to hyaluronan, forming large aggregated complexes at the cell surface.
# Clinical significance
The synthesis and degradation of aggrecan are being investigated for their roles in cartilage deterioration during joint injury, disease, and aging.
The linker domain between the N-terminal globular domains, called the interglobular domain, is highly sensitive to proteolysis. Such degradation has been associated with the development of arthritis. Proteases capable of degrading aggrecans are called aggrecanases, and they are members of the ADAM (A Disintegrin And Metalloprotease) protein family.
Degenerative joint disease is a leading source of morbidity resulting in significant social and economic impact. Osteoarthritis is characterized by the slow progressive deterioration of articular cartilage and fibrosis of the synovium and joint capsule. Articular cartilage contains up to 10% proteoglycan by weight, most of which is aggrecan, and its loss is an early sign of the disease. | Aggrecan
Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ACAN gene.[1] This gene is a member of the lectican (chondroitin sulfate proteoglycan) family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage.
Aggrecan is a proteoglycan, or a protein modified with large carbohydrates; the human form of the protein is 2316 amino acids long and can be expressed in multiple isoforms due to alternative splicing.[1]
# Structure
Aggrecan is a high molecular weight (1x106 < M < 3x106) proteoglycan. It exhibits a bottlebrush structure, in which chondroitin sulfate and keratan sulfate glycosaminoglycan (GAG) chains are attached to an extended protein core.[2]
Aggrecan has a molecular mass >2,500 kDa.[3] The core protein (~300 kDa[4]) has around 100 GAG chains attached to it.[5]
Aggrecan consists of two globular structural domains (G1 and G2) at the N-terminal end and one globular domain (G3) at the C-terminal end, separated by a large extended domain (CS) heavily modified with GAGs. (N-G1-G2-CS-G3-C)
The two main modifier moieties are themselves arranged into distinct regions, a chondroitin sulfate and a keratan sulfate region.
The three globular domains, G1, G2, and G3 are involved in aggregation, hyaluronan binding, cell adhesion, and chondrocyte apoptosis.
Along with type-II collagen, aggrecan forms a major structural component of cartilage, particularly articular cartilage.
The aggrecan family includes other important members such as versican, also named PG-M, neurocan, brevican and the cell surface HA receptor CD44. They are modular proteoglycans containing combinations of structural motifs, such as EGF-like domains, carbohydrate recognition domains (CRD), complement binding protein (CBP)-like domains, immunoglobulin folds and proteoglycan tandem repeats.
# Function
Aggrecan is a critical component for cartilage structure and the function of joints.
Functionally, the G1 domain interacts with hyaluronic acid and link protein, forming stable ternary complexes in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and of link protein and is involved in product processing. G3 makes up the carboxyl terminus of the core protein. It enhances glycosaminoglycan modification and product secretion. Aggrecan plays an important role in mediating chondrocyte-chondrocyte and chondrocyte-matrix interactions through its ability to bind hyaluronan.[5]
Aggrecan provides intervertebral disc and cartilage with the ability to resist compressive loads. The localized high concentrations of aggrecan provide the osmotic properties necessary for normal tissue function with the GAGs producing the swelling pressure that counters compressive loads on the tissue. This functional ability is dependent on a high GAG/aggrecan concentration being present in the tissue extracellular matrix.[6] In the disc, aggrecan concentrations peak in a person's twenties, and decline thereafter, with aggrecan degradation products slowly accumulating over the following decades.[7] This causes discs to get stiffer and less resilient with age.
Aggrecan also plays an important role in the organization of the extracellular spaces between neurons in the brain.[8] Through interactions with link protein and tenascins, aggrecan binds to hyaluronan, forming large aggregated complexes at the cell surface.
# Clinical significance
The synthesis and degradation of aggrecan are being investigated for their roles in cartilage deterioration during joint injury, disease, and aging.
The linker domain between the N-terminal globular domains, called the interglobular domain, is highly sensitive to proteolysis. Such degradation has been associated with the development of arthritis. Proteases capable of degrading aggrecans are called aggrecanases, and they are members of the ADAM (A Disintegrin And Metalloprotease) protein family.[9]
Degenerative joint disease is a leading source of morbidity resulting in significant social and economic impact. Osteoarthritis is characterized by the slow progressive deterioration of articular cartilage and fibrosis of the synovium and joint capsule. Articular cartilage contains up to 10% proteoglycan by weight, most of which is aggrecan, and its loss is an early sign of the disease. | https://www.wikidoc.org/index.php/Aggrecan | |
4d6207e479f9cee58d9e914d2765ecd35f3c2856 | wikidoc | Agitoxin | Agitoxin
Agitoxin is a toxin found in the venom of the scorpion Leiurus quinquestriatus herbraeus (yellow scorpion).
Agitoxin binds to the Shaker K+ channel in Drosophila as well as to its mammalian homologue. It blocks this channel by binding with high affinity (Kd < 1 nmol/L) to its external vestibule.
Agitoxin can be purified using HPLC techniques. Its structure consists of a triple-stranded antiparallel beta-sheet and a single helix covering one face of the beta-sheet. The cysteine side chains connect the beta-sheet and the helix form to the core of the molecule. The fold of agitoxin is homologous to the previously determined folds of scorpion venom toxins.
Three types of agitoxin can be distinguished; all 3 agitoxins have been identified as 38 amino acid toxins (cystine bonds not shown):
- Agitoxin-1 Gly-Val-Pro-Ile-Asn-Val-Lys-Cys-Thr-Gly-Ser-Pro-Gln-Cys-Leu-Lys-Pro-Cys-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys-Ile-Asn-Gly-Lys-Cys-His-Cys-Thr-Pro-Lys (molecular weight = 4014.87 Da, molecular formula = C169H278N52O47S7)
- Agitoxin-2 Gly-Val-Pro-Ile-Asn-Val-Ser-Cys-Thr-Gly-Ser-Pro-Gln-Cys-Ile-Lys-Pro-Cys-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys-Met-Asn-Arg-Lys-Cys-His-Cys-Thr-Pro-Lys (molecular weight = 4090.95 Da, molecular formula = C169H278N54O48S8)
- Agitoxin-3 Gly-Val-Pro-Ile-Asn-Val-Pro-Cys-Thr-Gly-Ser-Pro-Gln-Cys-Ile-Lys-Pro-Cys-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys-Met-Asn-Arg-Lys-Cys-His-Cys-Thr-Pro-Lys (molecular weight = 4100.98 Da, molecular formula = C171H280N54O47S8, CAS Number 155646-23-4)
# References:
- Garcia ML; et al. (1994). "Purification and characterization of three inhibitors of voltage-dependent K+ channels from Leiurus quinquestriatus var. hebraeus venom". Biochemistry. 33 (22): 6834–6839.CS1 maint: Explicit use of et al. (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} doi: 10.1021/bi00188a012
- Gao YD; et al. (2003). "Interaction of agitoxin2, charybdotoxin, and iberiotoxin with potassium channels: selectivity between voltage-gated and Maxi-K channels". Proteins. 52 (2): 146–154.CS1 maint: Explicit use of et al. (link) doi: 10.1002/prot.10341 | Agitoxin
Agitoxin is a toxin found in the venom of the scorpion Leiurus quinquestriatus herbraeus (yellow scorpion).
Agitoxin binds to the Shaker K+ channel in Drosophila as well as to its mammalian homologue. It blocks this channel by binding with high affinity (Kd < 1 nmol/L) to its external vestibule.
Agitoxin can be purified using HPLC techniques. Its structure consists of a triple-stranded antiparallel beta-sheet and a single helix covering one face of the beta-sheet. The cysteine side chains connect the beta-sheet and the helix form to the core of the molecule. The fold of agitoxin is homologous to the previously determined folds of scorpion venom toxins.
Three types of agitoxin can be distinguished; all 3 agitoxins have been identified as 38 amino acid toxins (cystine bonds not shown):
- Agitoxin-1 Gly-Val-Pro-Ile-Asn-Val-Lys-Cys-Thr-Gly-Ser-Pro-Gln-Cys-Leu-Lys-Pro-Cys-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys-Ile-Asn-Gly-Lys-Cys-His-Cys-Thr-Pro-Lys (molecular weight = 4014.87 Da, molecular formula = C169H278N52O47S7)
- Agitoxin-2 Gly-Val-Pro-Ile-Asn-Val-Ser-Cys-Thr-Gly-Ser-Pro-Gln-Cys-Ile-Lys-Pro-Cys-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys-Met-Asn-Arg-Lys-Cys-His-Cys-Thr-Pro-Lys (molecular weight = 4090.95 Da, molecular formula = C169H278N54O48S8)
- Agitoxin-3 Gly-Val-Pro-Ile-Asn-Val-Pro-Cys-Thr-Gly-Ser-Pro-Gln-Cys-Ile-Lys-Pro-Cys-Lys-Asp-Ala-Gly-Met-Arg-Phe-Gly-Lys-Cys-Met-Asn-Arg-Lys-Cys-His-Cys-Thr-Pro-Lys (molecular weight = 4100.98 Da, molecular formula = C171H280N54O47S8, CAS Number 155646-23-4)
# References:
- Garcia ML; et al. (1994). "Purification and characterization of three inhibitors of voltage-dependent K+ channels from Leiurus quinquestriatus var. hebraeus venom". Biochemistry. 33 (22): 6834–6839.CS1 maint: Explicit use of et al. (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} doi: 10.1021/bi00188a012
- Gao YD; et al. (2003). "Interaction of agitoxin2, charybdotoxin, and iberiotoxin with potassium channels: selectivity between voltage-gated and Maxi-K channels". Proteins. 52 (2): 146–154.CS1 maint: Explicit use of et al. (link) doi: 10.1002/prot.10341
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Agitoxin | |
117b19550fbd449af0dd82080d009c169a3ea393 | wikidoc | Agronomy | Agronomy
Agronomy is a branch of agricultural science that deals with the study of crops and the soils in which they grow. Agronomists work to develop methods that will improve the use of soil and increase the production of food and fiber crops. They conduct research in crop rotation, irrigation and drainage, plant breeding, soil classification, soil fertility, weed control, and other areas.
Def. the "science of utilizing plants, animals and soils for food, fuel, feed, and fiber and more" is called agronomy.
# Agriculture
Agriculture is the science, art, or practice of farming, including cultivation of the soil for the growing of crops and the rearing of animals to provide food, wool, and other products.
# Soils
"In soil, estimates are that 80 to 99% of the microorganisms remain unidentified (1)."
"The soil at the Arlington site is a Plano silt-loam. The 20-cm-deep A horizon is a silt-loam and contains 4.4% organic matter. The loess mantel is >1.25 m deep. Four 2.5-cm-diameter soil cores were taken from the top 10 cm of a clover-grass pasture at the Arlington Agricultural Research Station. The soil samples were immediately placed on dry ice, mixed, and then stored at -70°C prior to DNA extraction. Soil analysis was done by the Soil Testing Laboratory of the University of Wisconsin—Madison as described by Schulte et al. (40). The soil sample contained 13% sand, 70% silt, 17% clay, 4.4% organic matter, 0.3% total N, 400 ppm of K+, and 98 ppm of P. The soil pH was 6.5. The site is well drained, with groundwater more than 25 m below the surface. Two-thirds of the 79-cm annual rainfall occurs from April to October. The site has an average of 165 frost-free days." | Agronomy
Agronomy is a branch of agricultural science that deals with the study of crops and the soils in which they grow. Agronomists work to develop methods that will improve the use of soil and increase the production of food and fiber crops. They conduct research in crop rotation, irrigation and drainage, plant breeding, soil classification, soil fertility, weed control, and other areas.
Def. the "science of utilizing plants, animals and soils for food, fuel, feed, and fiber and more"[1] is called agronomy.
# Agriculture
Agriculture is the science, art, or practice of farming, including cultivation of the soil for the growing of crops and the rearing of animals to provide food, wool, and other products.
# Soils
"In soil, estimates are that 80 to 99% of the microorganisms remain unidentified (1)."[2]
"The soil at the Arlington site is a Plano silt-loam. The 20-cm-deep A horizon is a silt-loam and contains 4.4% organic matter. The loess mantel is >1.25 m deep. Four 2.5-cm-diameter soil cores were taken from the top 10 cm of a clover-grass pasture at the Arlington Agricultural Research Station. The soil samples were immediately placed on dry ice, mixed, and then stored at -70°C prior to DNA extraction. Soil analysis was done by the Soil Testing Laboratory of the University of Wisconsin—Madison as described by Schulte et al. (40). The soil sample contained 13% sand, 70% silt, 17% clay, 4.4% organic matter, 0.3% total N, 400 ppm of K+, and 98 ppm of P. The soil pH was 6.5. The site is well drained, with groundwater more than 25 m below the surface. Two-thirds of the 79-cm annual rainfall occurs from April to October. The site has an average of 165 frost-free days."[2] | https://www.wikidoc.org/index.php/Agronomy | |
2cbb16b4058b2ca9dabca59b3ff6df76f5cc09ed | wikidoc | Aldehyde | Aldehyde
An aldehyde is an organic compound containing a terminal carbonyl group. This functional group, which consists of a carbon atom which is bonded to a hydrogen atom and double-bonded to an oxygen atom (chemical formula O=CH-), is called the aldehyde group. The aldehyde group is also called the formyl or methanoyl group.
The word aldehyde seems to have arisen from alcohol dehydrogenated. In the past, aldehydes were sometimes named after the corresponding alcohols, for example vinous aldehyde for acetaldehyde. (Vinous is from Latin vinum = wine, the traditional source of ethanol; compare vinyl.)
The aldehyde group is polar. Oxygen, more electronegative than carbon, pulls the electrons in the carbon-oxygen bond towards itself, creating an electron deficiency at the carbon atom.
Owing to resonance stabilization of the conjugate base, an α-hydrogen in an aldehyde is more acidic than a hydrogen atom in an alkane, with a typical pKa of 17.
# Nomenclature
## IUPAC names for aldehydes
IUPAC prescribes the following nomenclature for aldehydes:
- Acyclic aliphatic aldehydes are named as derivatives of the longest carbon chain containing the aldehyde group. Thus, HCHO is named as a derivative of methane, and CH3CH2CH2CHO is named as a derivative of butane. The name is formed by changing the suffix -e of the parent alkane to -al, so that HCHO is named methanal, and CH3CH2CH2CHO is named butanal.
- In other cases, such as when a -CHO group is attached to a ring, the suffix -carbaldehyde may be used. Thus, C6H11CHO is known as cyclohexanecarbaldehyde. If the presence of another functional group demands the use of a suffix, the aldehyde group is named with the prefix formyl-. This prefix is preferred to methanoyl-.
- If the compound is a natural product or a carboxylic acid, the prefix oxo- may be used to indicate which carbon atom is part of the aldehyde group; for example, CHOCH2COOH is named 3-oxopropanoic acid.
- If replacing the aldehyde group with a carboxyl (-COOH) group would yield a carboxylic acid with a trivial name, the aldehyde may be named by replacing the suffix -ic acid or -oic acid in this trivial name by -aldehyde. For example:
- HCHO may be called formaldehyde.
- CH3CHO may be called acetaldehyde.
- C6H5CHO may be called benzaldehyde.
## Other nomenclature
The carbon atom adjacent to a carbonyl group is called the α carbon. Carbon atoms further away from
the group may be named β for the carbon atom bonded to the α carbon, γ for the next, and so on.
Hydrogen atoms bonded to these carbon atoms are named likewise:
an α hydrogen is a hydrogen atom bonded to the α carbon and so on.
A reaction that introduces an aldehyde group is known as a formylation reaction.
# Chemistry
## Synthesis
There are several methods for preparing aldehydes:
- Reacting a primary alcohol with an oxidizing agent. In the laboratory this may be achieved by heating the alcohol with a chromium(VI) reagent an acidified solution of potassium dichromate, which is reduced to green Cr3+ during the reaction. Excess dichromate will further oxidise the aldehyde to form a carboxylic acid, so either the aldehyde is distilled out as it forms (if volatile), or milder methods and reagents such as PCC oxidation, IBX acid, Dess-Martin periodinane or Swern oxidation are used. The reaction is illustrated below with propan-1-ol being oxidised to form propionaldehyde, and again with pentan-1-ol being oxidized to form pentanal.
- Reacting an alkene (if there is a vinylic hydrogen) with ozone will form an ozonide (an unstable, explosive intermediate) which yields an aldehyde upon reduction with zinc and acid at reduced temperatures. This process is called ozonolysis.
- Reacting an ester with diisobutyl aluminium hydride (DIBAL-H) or sodium aluminium hydride can cause reduction, yielding an aldehyde.
- Reduction of an acid chloride using the Rosenmund reduction or using lithium tri-t-butoxyaluminium hydride (LiAlH(O-t-C4H9)3).
- Reaction of ketones with methoxymethylenetriphenylphosphine in a modified Wittig reaction.
- Various formylation reactions, such as the Vilsmeier-Haack reaction, can be used to introduce an aldehyde group.
- In the Nef reaction, aldehydes form by hydrolysis of salts of primary nitro compounds.
- Zincke aldehydes form by reaction of pyridinium salts with secondary amines followed by hydrolysis.
- In the Stephen aldehyde synthesis aldehydes form from nitriles, tin(II) chloride and hydrochloric acid.
## Keto-enol tautomerism
Aldehydes can exist in either the keto or enol tautomers. Keto-enol tautomerism is catalyzed by either acid or base.
## Common reactions
### Reduction and oxidation
- The aldehyde group can be reduced to the group -CH2OH, changing the aldehyde into a primary alcohol.
- The aldehyde group can be oxidized to the group -COOH, yielding a carboxylic acid. Suitable oxidizing agents include potassium permanganate, nitric acid, chromium(VI) oxide, and acidified potassium dichromate.
- Another oxidation reaction is the silver mirror test. In this test, an aldehyde is treated with Tollens' reagent, which is prepared by adding a drop of sodium hydroxide solution into silver nitrate solution to give a precipitate of silver(I) oxide, and then adding just enough dilute ammonia solution to redissolve the precipitate in aqueous ammonia to produce + complex. This reagent will convert aldehydes to carboxylic acids without attacking carbon-carbon double-bonds. The name silver mirror test arises because this reaction will produce a precipitate of silver whose presence can be used to test for the presence of an aldehyde.
### Nucleophilic addition reactions
In nucleophilic addition reactions a nucleophile can add to the carbon atom in the carbonyl group, yielding an addition compound where this carbon atom has tetrahedral molecular geometry. Together with protonation of the oxygen atom in the carbonyl group (which can take place either before or after addition), this yields a product where the carbon atom in the carbonyl group is bonded to the nucleophile, a hydrogen atom, and a hydroxyl group.
In many cases, a water molecule is removed after the addition
takes place; in this case, the reaction
is classed as an addition-elimination or addition-condensation reaction.
There are various examples of nucleophilic addition reactions.
- In the acetalisation reaction, under acidic or basic conditions, an alcohol adds to the carbonyl group and a proton is transferred to form a hemiacetal. Under acidic conditions, the hemiacetal and the alcohol can further react to form an acetal and water. Simple hemiacetals are usually unstable, although cyclic ones such as glucose can be stable. Acetals are stable, but revert to the aldehyde in the presence of acid.
- Aldehydes can react with water (under acidic or basic conditions) to form hydrates, R-C(H)(OH)(OH), although these are only stable when strong electron withdrawing groups are present, as in chloral hydrate. The mechanism is identical to hemiacetal formation.
- In alkylimino-de-oxo-bisubstitution, a primary or secondary amine adds to the carbonyl group and a proton is transferred from the nitrogen to the oxygen atom to create a carbinolamine. In the case of a primary amine, a water molecule can be eliminated from the carbinolamine to yield an imine. This reaction is catalyzed by acid.
- The cyano group in HCN can add to the carbonyl group to form cyanohydrins, R-C(H)(OH)(CN).
- In the Grignard reaction, a Grignard reagent adds to the group, eventually yielding an alcohol with a substituted group from the Grignard reagent.
- In the aldol reaction, the metal enolates of ketones, esters, amides and carboxylic acids will add to aldehydes to form β-hydroxycarbonyl compounds (aldols). Acid or base-catalyzed dehydration will then lead to α,β-unsaturated carbonyl compounds. The combination of these two steps is known as the aldol condensation.
- Hydroxylamine (NH2OH) can add to the carbonyl group. After the elimination of water, this will result in an oxime.
- An ammonia derivative of the form H2NNR2 such as hydrazine (H2NNH2) or 2,4-dinitrophenylhydrazine can add to the carbonyl group. After the elimination of water, this will result in the formation of a hydrazone. This forms the basis of a test for aldehydes and ketones.
### More complex reactions
- If an aldehyde is converted to a simple hydrazone (RCH=NHNH2) and this is heated with a base such as KOH, the terminal carbon is fully reduced via the Wolff-Kishner reaction to a methyl group. The Wolff-Kishner reaction may be performed as a one-pot reaction, giving the overall conversion RCH=O → RCH3.
- Reaction of aldehydes with reducing agents such as magnesium gives diols in a Pinacol coupling reaction.
- The Wittig reaction takes aldehydes to alkenes and the Corey-Fuchs reaction takes aldehydes to alkynes. Both use a triphenylphosphine reagent. The Corey-Chaykovsky reagent is a sulfonium ylide which converts aldehydes to epoxides.
# Examples of aldehydes
- Methanal (Formaldehyde)
- Ethanal (Acetaldehyde)
- Propanal (Propionaldehyde)
- Butanal (butyraldehyde)
- Glucose
- Benzaldehyde
- Cinnamaldehyde
# Related compounds
Other kinds of organic compounds containing carbonyl groups include
- Ketones
- Carboxylic acids | Aldehyde
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
An aldehyde is an organic compound containing a terminal carbonyl group. This functional group, which consists of a carbon atom which is bonded to a hydrogen atom and double-bonded to an oxygen atom (chemical formula O=CH-), is called the aldehyde group. The aldehyde group is also called the formyl or methanoyl group.
The word aldehyde seems to have arisen from alcohol dehydrogenated. In the past, aldehydes were sometimes named after the corresponding alcohols, for example vinous aldehyde for acetaldehyde. (Vinous is from Latin vinum = wine, the traditional source of ethanol; compare vinyl.)
The aldehyde group is polar. Oxygen, more electronegative than carbon, pulls the electrons in the carbon-oxygen bond towards itself, creating an electron deficiency at the carbon atom.
Owing to resonance stabilization of the conjugate base, an α-hydrogen in an aldehyde is more acidic than a hydrogen atom in an alkane, with a typical pKa of 17.
# Nomenclature
## IUPAC names for aldehydes
IUPAC prescribes the following nomenclature for aldehydes:[1][2][3]
- Acyclic aliphatic aldehydes are named as derivatives of the longest carbon chain containing the aldehyde group. Thus, HCHO is named as a derivative of methane, and CH3CH2CH2CHO is named as a derivative of butane. The name is formed by changing the suffix -e of the parent alkane to -al, so that HCHO is named methanal, and CH3CH2CH2CHO is named butanal.
- In other cases, such as when a -CHO group is attached to a ring, the suffix -carbaldehyde may be used. Thus, C6H11CHO is known as cyclohexanecarbaldehyde. If the presence of another functional group demands the use of a suffix, the aldehyde group is named with the prefix formyl-. This prefix is preferred to methanoyl-.
- If the compound is a natural product or a carboxylic acid, the prefix oxo- may be used to indicate which carbon atom is part of the aldehyde group; for example, CHOCH2COOH is named 3-oxopropanoic acid.
- If replacing the aldehyde group with a carboxyl (-COOH) group would yield a carboxylic acid with a trivial name, the aldehyde may be named by replacing the suffix -ic acid or -oic acid in this trivial name by -aldehyde. For example:
- HCHO may be called formaldehyde.
- CH3CHO may be called acetaldehyde.
- C6H5CHO may be called benzaldehyde.
## Other nomenclature
The carbon atom adjacent to a carbonyl group is called the α carbon. Carbon atoms further away from
the group may be named β for the carbon atom bonded to the α carbon, γ for the next, and so on.
Hydrogen atoms bonded to these carbon atoms are named likewise:
an α hydrogen is a hydrogen atom bonded to the α carbon and so on.
A reaction that introduces an aldehyde group is known as a formylation reaction.
# Chemistry
## Synthesis
There are several methods for preparing aldehydes:
- Reacting a primary alcohol with an oxidizing agent. In the laboratory this may be achieved by heating the alcohol with a chromium(VI) reagent an acidified solution of potassium dichromate, which is reduced to green Cr3+ during the reaction. Excess dichromate will further oxidise the aldehyde to form a carboxylic acid, so either the aldehyde is distilled out as it forms (if volatile), or milder methods and reagents such as PCC oxidation, IBX acid, Dess-Martin periodinane or Swern oxidation are used. The reaction is illustrated below with propan-1-ol being oxidised to form propionaldehyde, and again with pentan-1-ol being oxidized to form pentanal.
- Reacting an alkene (if there is a vinylic hydrogen) with ozone will form an ozonide (an unstable, explosive intermediate) which yields an aldehyde upon reduction with zinc and acid at reduced temperatures. This process is called ozonolysis.
- Reacting an ester with diisobutyl aluminium hydride (DIBAL-H) or sodium aluminium hydride can cause reduction, yielding an aldehyde.
- Reduction of an acid chloride using the Rosenmund reduction or using lithium tri-t-butoxyaluminium hydride (LiAlH(O-t-C4H9)3).
- Reaction of ketones with methoxymethylenetriphenylphosphine in a modified Wittig reaction.
- Various formylation reactions, such as the Vilsmeier-Haack reaction, can be used to introduce an aldehyde group.
- In the Nef reaction, aldehydes form by hydrolysis of salts of primary nitro compounds.
- Zincke aldehydes form by reaction of pyridinium salts with secondary amines followed by hydrolysis.
- In the Stephen aldehyde synthesis aldehydes form from nitriles, tin(II) chloride and hydrochloric acid.
## Keto-enol tautomerism
Aldehydes can exist in either the keto or enol tautomers. Keto-enol tautomerism is catalyzed by either acid or base.
## Common reactions
### Reduction and oxidation
- The aldehyde group can be reduced to the group -CH2OH, changing the aldehyde into a primary alcohol.
- The aldehyde group can be oxidized to the group -COOH, yielding a carboxylic acid. Suitable oxidizing agents include potassium permanganate, nitric acid, chromium(VI) oxide, and acidified potassium dichromate.
- Another oxidation reaction is the silver mirror test. In this test, an aldehyde is treated with Tollens' reagent, which is prepared by adding a drop of sodium hydroxide solution into silver nitrate solution to give a precipitate of silver(I) oxide, and then adding just enough dilute ammonia solution to redissolve the precipitate in aqueous ammonia to produce [Ag(NH3)2]+ complex. This reagent will convert aldehydes to carboxylic acids without attacking carbon-carbon double-bonds. The name silver mirror test arises because this reaction will produce a precipitate of silver whose presence can be used to test for the presence of an aldehyde.
### Nucleophilic addition reactions
In nucleophilic addition reactions a nucleophile can add to the carbon atom in the carbonyl group, yielding an addition compound where this carbon atom has tetrahedral molecular geometry. Together with protonation of the oxygen atom in the carbonyl group (which can take place either before or after addition), this yields a product where the carbon atom in the carbonyl group is bonded to the nucleophile, a hydrogen atom, and a hydroxyl group.
In many cases, a water molecule is removed after the addition
takes place; in this case, the reaction
is classed as an addition-elimination or addition-condensation reaction.
There are various examples of nucleophilic addition reactions.
- In the acetalisation reaction, under acidic or basic conditions, an alcohol adds to the carbonyl group and a proton is transferred to form a hemiacetal. Under acidic conditions, the hemiacetal and the alcohol can further react to form an acetal and water. Simple hemiacetals are usually unstable, although cyclic ones such as glucose can be stable. Acetals are stable, but revert to the aldehyde in the presence of acid.
- Aldehydes can react with water (under acidic or basic conditions) to form hydrates, R-C(H)(OH)(OH), although these are only stable when strong electron withdrawing groups are present, as in chloral hydrate. The mechanism is identical to hemiacetal formation.
- In alkylimino-de-oxo-bisubstitution, a primary or secondary amine adds to the carbonyl group and a proton is transferred from the nitrogen to the oxygen atom to create a carbinolamine. In the case of a primary amine, a water molecule can be eliminated from the carbinolamine to yield an imine. This reaction is catalyzed by acid.
- The cyano group in HCN can add to the carbonyl group to form cyanohydrins, R-C(H)(OH)(CN).
- In the Grignard reaction, a Grignard reagent adds to the group, eventually yielding an alcohol with a substituted group from the Grignard reagent.
- In the aldol reaction, the metal enolates of ketones, esters, amides and carboxylic acids will add to aldehydes to form β-hydroxycarbonyl compounds (aldols). Acid or base-catalyzed dehydration will then lead to α,β-unsaturated carbonyl compounds. The combination of these two steps is known as the aldol condensation.
- Hydroxylamine (NH2OH) can add to the carbonyl group. After the elimination of water, this will result in an oxime.
- An ammonia derivative of the form H2NNR2 such as hydrazine (H2NNH2) or 2,4-dinitrophenylhydrazine can add to the carbonyl group. After the elimination of water, this will result in the formation of a hydrazone. This forms the basis of a test for aldehydes and ketones.
### More complex reactions
- If an aldehyde is converted to a simple hydrazone (RCH=NHNH2) and this is heated with a base such as KOH, the terminal carbon is fully reduced via the Wolff-Kishner reaction to a methyl group. The Wolff-Kishner reaction may be performed as a one-pot reaction, giving the overall conversion RCH=O → RCH3.
- Reaction of aldehydes with reducing agents such as magnesium gives diols in a Pinacol coupling reaction.
- The Wittig reaction takes aldehydes to alkenes and the Corey-Fuchs reaction takes aldehydes to alkynes. Both use a triphenylphosphine reagent. The Corey-Chaykovsky reagent is a sulfonium ylide which converts aldehydes to epoxides.
# Examples of aldehydes
- Methanal (Formaldehyde)
- Ethanal (Acetaldehyde)
- Propanal (Propionaldehyde)
- Butanal (butyraldehyde)
- Glucose
- Benzaldehyde
- Cinnamaldehyde
# Related compounds
Other kinds of organic compounds containing carbonyl groups include
- Ketones
- Carboxylic acids | https://www.wikidoc.org/index.php/Aldehyde | |
690921d21b4930c40c638c1253ee9235ff22b02e | wikidoc | Aldicarb | Aldicarb
Aldicarb is a carbamate insecticide with structural formula: 2-methyl-2-(methylthio)propionaldehyde O-methylcarbamoyloxime. Aldicarb is the active substance in Temik pesticide, which is effective against thrips, aphids, spider mites, lygus, fleahoppers, and leafminers but is primarily used as a nematicide. In mammals it is a cholinesterase inhibitor (prevents neurotransmitter breakdown). In case of severe poisoning, the victim dies of respiratory failure. It is also highly toxic for birds.
# Regulatory Status
Aldicarb is approved by the USEPA for use by professional pesticide applicators on a variety of crops, including cotton, beans, and others. It is not approved for household use.
"Tres Pasitos", a mouse, rat, and roach killer that contains high concentrations of aldicarb, has been illegally imported into the United States from Mexico and other Latin American countries. The product is highly toxic to animals and people, and it should not be used. EPA
# Toxicity in mammals
Aldicarb is a fast-acting cholinesterase inhibitor, causing rapid accumulation of acetylcholine at the synaptic cleft.
It is widely used to study cholinergic neurotransmission in simple systems such as the nematode C. elegans.
Exposure to high amounts of aldicarb can cause weakness, blurred vision, headache, nausea, tearing, sweating, and tremors in people. Very high doses can kill people, because it can paralyze the respiratory system. EPA | Aldicarb
Template:Chembox new
Aldicarb is a carbamate insecticide with structural formula: 2-methyl-2-(methylthio)propionaldehyde O-methylcarbamoyloxime. Aldicarb is the active substance in Temik pesticide, which is effective against thrips, aphids, spider mites, lygus, fleahoppers, and leafminers but is primarily used as a nematicide.[1] In mammals it is a cholinesterase inhibitor (prevents neurotransmitter breakdown). In case of severe poisoning, the victim dies of respiratory failure. It is also highly toxic for birds.
# Regulatory Status
Aldicarb is approved by the USEPA for use by professional pesticide applicators on a variety of crops, including cotton, beans, and others. It is not approved for household use.[2]
"Tres Pasitos", a mouse, rat, and roach killer that contains high concentrations of aldicarb, has been illegally imported into the United States from Mexico and other Latin American countries. The product is highly toxic to animals and people, and it should not be used. EPA
# Toxicity in mammals
Aldicarb is a fast-acting cholinesterase inhibitor, causing rapid accumulation of acetylcholine at the synaptic cleft.
It is widely used to study cholinergic neurotransmission in simple systems such as the nematode C. elegans.
Exposure to high amounts of aldicarb can cause weakness, blurred vision, headache, nausea, tearing, sweating, and tremors in people. Very high doses can kill people, because it can paralyze the respiratory system. EPA | https://www.wikidoc.org/index.php/Aldicarb | |
001d389ac4f96694ed488f6df4936880db125efc | wikidoc | Aleatory | Aleatory
Aleatory means "pertaining to luck", and derives from the Latin word alea, the rolling of dice. Aleatoric, indeterminate, or chance art is that which exploits the principle of randomness.
# Law
In some legal systems, aleatory contracts are those where the effects (outcomes) for the parties to the contract are uncertain. This may apply to gambling contracts, insurance contracts and many modern forms of derivatives and options. For example, the French civil code contains a chapter on aleatory contracts, with specific provisions for gaming (gambling) and life annuities.
# Literature
An example of aleatory writing is the automatic writing of the French Surrealists involving dreams, et cetera. The French literary group Oulipo for example saw no merit in aleatory work and its members altogether eliminated chance and randomness from their writing, substituting potentiality as in Raymond Queneau's Cent Mille Milliards de Poèmes (Hundred Thousand Billion Poems).
Luke Rhinehart's novel The Dice Man tells the story of a psychiatrist named Luke Rhinehart who, feeling bored and unfulfilled in life, starts making decisions about what to do based on a roll of a die.
Charles Hartman's book
discusses several methods of automatic generation of poetry; see especially pp. 54-64.
# Music
Pierre Boulez applied the term aleatoric music to his own pieces to distinguish them from the indeterminate music of John Cage, though both are often described as aleatory. While Boulez purposefully composed his pieces to allow the performer certain liberties with regard to the sequencing and repetition of parts, Cage often composed through the application of chance operations without allowing the performer liberties. Another prolific aleatory music composer is Karlheinz Stockhausen. Qubais Reed Ghazala, founder of the circuit-bending chance-music movement, is an important contemporary chance artist also pioneering aleatoric work in visual media (original techniques in suminagashi, dye migration, aperture shift photography).
# Film
In film-making, there are several avant-garde examples; Andy Voda's "Chance Chants" (1979) was created completely using various chance operations (coin flip, choosing words out of a hat, a recorded "telephone game", the vagaries of tracing over drawings) in the decision-making for each creative choice. It was a three part film, the first part being a hand-made computer film, the second a visualization of Allison Knowles' computer poem "House of Dust", and the third a visualization of evolution through a children's telephone game. Fred Camper's SN (1984, first screening 2002) uses coin-flipping to determine which three of 18 possible reels to screen and what order they should go in (4896 permutations). Barry Salt, now better known as a film scholar, is known to have made a film, Permutations, six reels long which takes the word aleatory quite literally by including a customized die for the projectionist to roll to determine the reel order (720 permutations). | Aleatory
Aleatory means "pertaining to luck", and derives from the Latin word alea, the rolling of dice. Aleatoric, indeterminate, or chance art is that which exploits the principle of randomness.
# Law
In some legal systems, aleatory contracts are those where the effects (outcomes) for the parties to the contract are uncertain. This may apply to gambling contracts, insurance contracts and many modern forms of derivatives and options. For example, the French civil code contains a chapter on aleatory contracts, with specific provisions for gaming (gambling) and life annuities.[1]
# Literature
An example of aleatory writing is the automatic writing of the French Surrealists involving dreams, et cetera. The French literary group Oulipo for example saw no merit in aleatory work and its members altogether eliminated chance and randomness from their writing, substituting potentiality as in Raymond Queneau's Cent Mille Milliards de Poèmes (Hundred Thousand Billion Poems).
Luke Rhinehart's novel The Dice Man tells the story of a psychiatrist named Luke Rhinehart who, feeling bored and unfulfilled in life, starts making decisions about what to do based on a roll of a die.
Charles Hartman's book
[2]
discusses several methods of automatic generation of poetry; see especially pp. 54-64.
# Music
Pierre Boulez applied the term aleatoric music to his own pieces to distinguish them from the indeterminate music of John Cage, though both are often described as aleatory. While Boulez purposefully composed his pieces to allow the performer certain liberties with regard to the sequencing and repetition of parts, Cage often composed through the application of chance operations without allowing the performer liberties. Another prolific aleatory music composer is Karlheinz Stockhausen.[3] Qubais Reed Ghazala, founder of the circuit-bending chance-music movement, is an important contemporary chance artist also pioneering aleatoric work in visual media (original techniques in suminagashi, dye migration, aperture shift photography).
# Film
In film-making, there are several avant-garde examples; Andy Voda's[1] "Chance Chants" (1979) was created completely using various chance operations (coin flip, choosing words out of a hat, a recorded "telephone game", the vagaries of tracing over drawings) in the decision-making for each creative choice. It was a three part film, the first part being a hand-made computer film, the second a visualization of Allison Knowles'[2] computer poem "House of Dust", and the third a visualization of evolution through a children's telephone game. Fred Camper's SN (1984,[4] first screening 2002) uses coin-flipping to determine which three of 18 possible reels to screen and what order they should go in (4896 permutations). Barry Salt, now better known as a film scholar, is known to have made a film, Permutations, six reels long which takes the word aleatory quite literally by including a customized die for the projectionist to roll to determine the reel order (720 permutations).[5] | https://www.wikidoc.org/index.php/Aleatory | |
9e46e3967bb0063c786162807e0be30cabe7084b | wikidoc | Caffeine | Caffeine
# Overview
Caffeine is a bitter white crystalline xanthine alkaloid that acts as a psychoactive stimulant drug and a mild diuretic (speeds up urine production) in humans and other animals. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819. He coined the term "kaffein", a chemical compound in coffee, which in English became caffeine. Caffeine is also called guaranine when found in guarana, mateine when found in mate, and theine when found in tea; all of these names are synonyms for the same chemical compound.
Caffeine is found in varying quantities in the beans, leaves, and fruit of over 60 plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants. It is most commonly consumed by humans in infusions extracted from the beans of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut or from cacao. Other sources include yerba mate, guarana berries, and the Yaupon Holly.
In humans, caffeine is a central nervous system (CNS) stimulant, having the effect of temporarily warding off drowsiness and restoring alertness. Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity. Caffeine is the world's most widely consumed psychoactive substance, but unlike most others, it is legal and unregulated in nearly all jurisdictions. In North America, 90% of adults consume caffeine daily. The U.S. Food and Drug Administration lists caffeine as a "Multiple Purpose Generally Recognized as Safe Food Substance". One 2008 study suggested that women consuming 200 milligrams or more of caffeine per day had about twice the miscarriage risk as women who drank none, while another 2008 study found no link between miscarriage and caffeine consumption.
# Occurrence
Caffeine is a plant alkaloid, found in many plant species, where it acts as a natural pesticide, with high caffeine levels being reported in seedlings that are still developing foliages, but are lacking mechanical protection; caffeine paralyzes and kills certain insects feeding upon the plant. High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. It is therefore understood that caffeine has a natural function as both a natural pesticide and as an inhibitor of seed germination of other nearby coffee seedlings thus giving it a better chance of survival.
The most commonly used caffeine-containing plants are coffee, tea, and to a lesser extent cocoa. Other, less commonly used, sources of caffeine include the yerba mate and guarana plants, which are sometimes used in the preparation of teas and energy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of these plants. Some yerba mate enthusiasts assert that mateine is a stereoisomer of caffeine, which would make it a different substance altogether. This is not true because caffeine is an achiral molecule, and therefore has no enantiomers; nor does it have other stereoisomers. Many natural sources of caffeine also contain widely varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine and other substances such as polyphenols which can form insoluble complexes with caffeine.
The world's primary source of caffeine is the coffee bean (the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used; even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 40 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to about 100 milligrams for a cup (120 milliliters) of drip coffee. Generally, dark-roast coffee has less caffeine than lighter roasts because the roasting process reduces the bean's caffeine content. Arabica coffee normally contains less caffeine than the robusta variety. Coffee also contains trace amounts of theophylline, but no theobromine.
Tea is another common source of caffeine. Tea usually contains about half as much caffeine per serving as coffee, depending on the strength of the brew. Certain types of tea, such as black and oolong, contain somewhat more caffeine than most other teas. Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation has a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.
Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks such as Red Bull contain as much as 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.
Chocolate derived from cocoa contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline as well as caffeine. Chocolate contains too little of these compounds for a reasonable serving to create effects in humans that are on par with coffee. A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee.
In recent years various manufacturers have begun putting caffeine into shower products such as shampoo and soap, claiming that caffeine can be absorbed through the skin. However, the effectiveness of such products has not been proven, and they are likely to have little stimulatory effect on the central nervous system because caffeine is not readily absorbed through the skin.
In recent years various manufacturers have begun putting caffeine into tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness and is used by students that are studying for their exams. It is also used by people who work or drive for long hours.
# History
Humans have consumed caffeine since the Stone Age. Early peoples found that chewing the seeds, bark, or leaves of certain plants had the effects of easing fatigue, stimulating awareness, and elevating mood. Only much later was it found that the effect of caffeine was increased by steeping such plants in hot water. Many cultures have legends that attribute the discovery of such plants to people living many thousands of years ago.
According to one popular Chinese legend, the Emperor of China Shennong, reputed to have reigned in about 3000 BC, accidentally discovered that when some leaves fell into boiling water, a fragrant and restorative drink resulted. Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.
The history of coffee has been recorded as far back as the ninth century. During that time, coffee beans were available only in their native habitat, Ethiopia. A popular legend traces its discovery to a goatherder named Kaldi, who apparently observed goats that became elated and sleepless at night after browsing on coffee shrubs and, upon trying the berries that the goats had been eating, experienced the same vitality. The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th century Persian physician al-Razi. In 1587, Malaye Jaziri compiled a work tracing the history and legal controversies of coffee, entitled "Undat al safwa fi hill al-qahwa". In this work, Jaziri recorded that one Sheikh, Jamal-al-Din al-Dhabhani, mufti of Aden, was the first to adopt the use of coffee in 1454, and that in the 15th century the Sufis of Yemen routinely used coffee to stay awake during prayers.
Towards the close of the 16th century, the use of coffee was recorded by a European resident in Egypt, and about this time it came into general use in the Near East. The appreciation of coffee as a beverage in Europe, where it was first known as "Arabian wine," dates from the 17th century. During this time "coffee houses" were established, the first being opened in Constantinople and Venice. In Britain, the first coffee houses were opened in London in 1652, at St Michael's Alley, Cornhill. They soon became popular throughout Western Europe, and played a significant role in social relations in the 17th and 18th centuries.
The kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs. In 1911, kola became the focus of one of the earliest documented health scares when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging that the caffeine in its drink was "injurious to health". On March 13, 1911, the government initiated The United States v. Forty Barrels and Twenty Kegs of Coca-Cola, hoping to force Coca-Cola to remove caffeine from its formula by making claims, such as that the excessive use of Coca-Cola at one girls' school led to "wild nocturnal freaks, violations of college rules and female proprieties, and even immoralities." Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances which must be listed on a product's label.
The earliest evidence of cocoa use comes from residue found in an ancient Mayan pot dated to 600 BC. In the New World, chocolate was consumed in a bitter and spicy drink called xocoatl, often seasoned with vanilla, chile pepper, and achiote. Xocoatl was believed to fight fatigue, a belief that is probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.
Chocolate was introduced to Europe by the Spaniards and became a popular beverage by 1700. They also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as Black Bean.
In 1819, the German chemist Friedrich Ferdinand Runge isolated relatively pure caffeine for the first time. According to Runge, he did this at the behest of Johann Wolfgang von Goethe. In 1827, Oudry isolated "theine" from tea, but it was later proved by Mulder and Jobat that theine was the same as caffeine. The structure of caffeine was elucidated near the end of the 19th century by Hermann Emil Fischer, who was also the first to achieve its total synthesis. This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
Today, global consumption of caffeine has been estimated at 120,000 tonnes per annum, making it the world's most popular psychoactive substance. This number equates to one serving of a caffeine beverage for every person, per day. In North America, 90% of adults consume some amount of caffeine daily.
# Pharmacology
Caffeine is a central nervous system and metabolic stimulant, and is used both recreationally and medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses. Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.
## Metabolism
Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and is eliminated by first-order kinetics.
The half-life of caffeine—the time required for the body to eliminate one-half of the total amount of caffeine consumed at a given time—varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 3–4 hours. In women taking oral contraceptives this is increased to 5–10 hours, and in pregnant women the half-life is roughly 9–11 hours. Caffeine can accumulate in individuals with severe liver disease when its half-life can increase to 96 hours. In infants and young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30 hours. Other factors such as smoking can shorten caffeine's half-life.
Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2 isozyme) into three metabolic dimethylxanthines, which each have their own effects on the body:
- Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
- Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in cocoa, and therefore chocolate.
- Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.
Each of these metabolites is further metabolized and then excreted in the urine.
## Mechanism of action
Caffeine acts through multiple mechanisms involving both action on receptors and channels on the cell membrane, as well as intracellular action on calcium and cAMP pathways. By virtue of its purine structure it can act on some of the same targets as adenosine related nucleosides and nucleotides, like the cell surface P1 GPCRs for adenosine, as well as the intracellular Ryanodine receptor (RyR) which is the physiological target of cADPR (cyclic ADP-ribose), and cAMP-phosphodiesterase (cAMP-PDE). Although the action is agonistic in some cases, it is antagonistic in others. Physiologically, however, caffeine action is unlikely due to increased RyR opening, as it requires plasma concentration above lethal dosage. The action is most likely through adenosine receptors.
Like alcohol, nicotine, and antidepressants, caffeine readily crosses the blood brain barrier. Once in the brain, the principal mode of action of caffeine is as an antagonist of adenosine receptors found in the brain. The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (an "antagonist" mechanism of action). Therefore, caffeine acts as a competitive inhibitor.
Caffeine being a competitive inhibitor of adenosine, an understanding of adenosine’s role in the central nervous system is crucial. One of the roles of adenosine is as a signal that one neuron can use to tell another to stop releasing neurotransmitter because it can’t handle the stimulation. In doing this it is acting as a retrograde neurotransmitter (a neurotransmitter that is released by the post-synaptic cell and received by the pre-synaptic cell in the direction opposite to most neurotransmitters). Adenosine is the final breakdown product of adenosine triphosphate (ATP), which is the cellular currency of energy. When cells have used the energy of adenosine triphosphate it breaks into adenosine diphosphate, which is then used for energy and broken down into adenosine monophosphate. Finally, the last phosphate bond is broken for energy in the cell’s last attempt to squeeze molecular power from this molecule: adenosine monophosphate is broken down into simple adenosine. At this point, the neuron has very little energy left for the successful firing of an action potential. Adenosine from this process is then released from the postsynaptic cell and binds to receptors on the presynaptic cell. If the release of adenosine is great enough, this release has an inhibitory effect on the release of neurotransmitter from the presynaptic neuron’s axon terminal. This triggers a mechanism that inhibits the further secretion of excitatory neurotransmitters into the synapse. It is as if the postsynaptic neuron is telling the presynaptic neuron that its resources are scarce and it needs time to recover before further stimulation by neurotransmitters. Thus, adenosine works to inhibit activity of the central nervous system.
Caffeine being a competitive inhibitor of adenosine, it binds to the adenosine receptor, but does not trigger the chemical cascade that inhibits neurotransmitter release and blocks the site so adenosine cannot bind and get its message across the synapse. By inhibiting adenosine, caffeine excites the central nervous system and allows for continued stimulation of neurons that otherwise would not fire or would not release neurotransmitter into the synapse.
The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for its stimulatory effects. This inhibition of adenosine is the only known biochemical effect that caffeine has in humans at the concentrations achieved during normal human consumption of the drug. Further, coffee & tea drinkers on the whole do not consume enough caffeine to release dopamine in the nucleus accumbens shell, the key structure associated with motivation, reward & addiction. However, in high doses, caffeine induces dopamine release in nucleus accumbens, not unlike other psychostimulants, such as cocaine. In low and moderate doses, caffeine appears to increase dopamine and acetylcholine release in the prefrontal cortex (PFC) (providing a mechanism for reinforcment) and stimulates the caudate nucleus, increasing wakefulness & locomotor activity. Sustained caffeine usage causes tolerance to the (prefrontal cortical) dopamine-mediated effects and hence the locomotor stimulation, but not to its cholinergic effects in the PFC, which could account for its capability for sustained arousal even in the caffeine-tolerant. Caffeine also increases levels of epinephrine/adrenaline, possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood.
The inhibition of adenosine may be relevant in its diuretic properties. Because adenosine is known to constrict preferentially the afferent arterioles of the glomerulus, limiting blood flow and therefore urine production; its inhibition may cause vasodilation, with an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). This effect, called competitive inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of epinephrine and norepinephrine/noradrenaline released via the hypothalamic-pituitary-adrenal axis. Epinephrine, the natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin and inner organs. Biochemically, it stimulates glycogenolysis, inhibits glycolysis, and stimulates gluconeogenesis to produce more glucose in the muscles and release of glucose into the blood stream from the liver.
Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in activation of Protein Kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or methylphenidate. Increased concentrations of cAMP in parietal cells causes an increased activation of protein kinase A (PKA) which in turn increases activation of H+/K+ ATPase, resulting finally in increased gastric acid secretion by the cell.
Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the endoplasmic reticulum(ER). This release is only partially blocked by Ryanodine receptor blockade with ryanodine, dantrolene, ruthenium red, and procaine (thus may involve ryanodine receptor and probably some additional calcium channels), but completely abolished after calcium depletion of ER by SERCA inhibitors like Thapsigargin (TG) or cyclopiazonic acid (CPA). The action of caffeine on the ryanodine receptor may depend on both cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and dramatically increases the open time of the channel so that the calcium release is stronger than even an action potential can generate. This mode of action of caffeine is probably due to mimicking the action of the physiologic metabolite of NAD called cADPR (cyclic ADP ribose) which has a similar potentiating action on Ryanodine receptors.
Caffeine may also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal Ca2+ influx in certain vertebrate and invertebrate neurons.
The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles.
## Effects when taken in moderation
The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours. Consumption of caffeine does not eliminate the need for sleep: it only temporarily reduces the sensation of being tired.
With these effects, caffeine is an ergogenic: increasing the capacity for mental or physical labor. A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects who consumed caffeine compared to control tests. Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight. The extensive boost shown in the runners is not an isolated case; additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits.
Caffeine citrate has proven to be of short and long term benefit in treating the breathing disorders of apnea of prematurity and bronchopulmonary displasia in premature infants. Citrated caffeine, the only short term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy, and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.
While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more significant effect on spiders, for example, than most other drugs do.
Caffeine relaxes the internal anal sphincter muscles and thus should be avoided by those with fecal incontinence.
# Intoxication
An acute overdose of caffeine, usually in excess of about 300 milligrams, dependent on body weight and level of caffeine tolerance, can result in a state of central nervous system over-stimulation called caffeine intoxication, colloquially "caffeine jitters". The symptoms of caffeine intoxication are not unlike overdoses of other stimulants. It may include restlessness, nervousness, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation. In cases of much larger overdoses mania, depression, lapses in judgment, disorientation, loss of social inhibition, delusions, hallucinations, psychosis, rhabdomyolysis, and death may occur.
In cases of extreme overdose, death can result. The median lethal dose (LD50) given orally, is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adult taken within a limited time frame that is dependent on half-life. Though achieving lethal dose with caffeine would be exceptionally difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine. Death typically occurs due to ventricular fibrillation brought about by effects of caffeine on the cardiovascular system.
Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may be required.
## DSM-V Diagnostic Criteria for Caffeine Intoxication
## Risk Factors of Caffeine Intoxication
- Recent increase in caffeine intake
- Oral contraceptives
- Use of caffeine less frequently
## Differential Diagnosis of caffeine Intoxication
- Other mental disorders
- Amphetamine intoxication
- Generalized anxiety disorder
- Manic episodes
- Medication-induced side effects
- Panic disorder
- Sedative, hynotic, or anxiolytic withdrawal
- Sleep disorders
- Tobacco withdrawal
- Other caffeine-induced disorders
- Caffeine-induced anxiety disorder
- caffeine-induced sleep disorder
# Tolerance and Withdrawal
Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences. First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a tolerance adaptation. Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users.
Other research questions the idea that up-regulation of adenosine receptors is responsible for tolerance to the locomotor stimulant effects of caffeine, noting, among other things, that this tolerance is insurmountable by higher doses of caffeine (it should be surmountable if tolerance was due to an increase in receptors), and that the increase in adenosine receptor number is modest and does not explain the large tolerance which develops to caffeine.
Caffeine tolerance develops very quickly, especially among heavy coffee and energy drink consumers. Complete tolerance to sleep disruption effects of caffeine develops after consuming 400 mg of caffeine 3 times a day for 7 days. Complete tolerance to subjective effects of caffeine was observed to develop after consuming 300 mg 3 times per day for 18 days, and possibly even earlier. In another experiment, complete tolerance of caffeine was observed when the subject consumed 750–1200 mg per day while incomplete tolerance to caffeine has been observed in those that consume more average doses of caffeine.
Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild depression. Together, these effects have come to be known as a "crash".
Withdrawal symptoms—possibly including headache, irritability, an inability to concentrate, and stomach aches—may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from one to five days, representing the time required for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine. Most effective is a combination of both an analgesic and a small amount of caffeine.
This is not the only case where caffeine increases the effectiveness of a drug. Caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief. For this reason, many over-the-counter headache drugs include caffeine in their formula. It is also used with ergotamine in the treatment of migraine and cluster headaches as well as to overcome the drowsiness caused by antihistamines.
## DSM-V Diagnostic Criteria for Caffeine Withdrawl
## Epidemiology and Demographics of Caffeine Withdrawal
The prevalence of caffeine withdrawal is unclear in the overall population.
## Risk Factors of Caffeine Withdrawal
- Alcohol abuser
- Drug abuser
- Doses of caffeine significantly less than one's usual daily dose
- Eating disorders
- Genetic predisposition
- Mental disorders
- Prisoners
- Smokers
- Unavailability of caffeineo
## Differential Diagnosis of Caffeine Withdrawal
- Other medical disorders and medical side effects
- Drug withdrawal states
- Headache disorders
- Medication side effects
- Migraine
- Sinus conditions
- Viral illnesseso
# Other Notable Effects of Caffeine
### Anxiety and sleep disorders
Two infrequently diagnosed caffeine-induced disorders that are recognized by the American Psychiatric Association (APA) are caffeine-induced sleep disorder and caffeine-induced anxiety disorder, which can result from long-term excessive caffeine intake.
In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. A study in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of the population.
## Parkinson's disease
Several large studies have shown that caffeine intake is associated with a reduced risk of developing Parkinson's disease (PD) in men, but studies in women have been inconclusive. The mechanism by which caffeine affects PD remains a mystery. In animal models, researchers have shown that caffeine can prevent the loss of dopamine-producing nerve cells seen in Parkinson's Disease, but researchers still do not know how this occurs.
## Effects on memory and learning
An array of studies found that caffeine could have nootropic effects, inducing certain changes in memory and learning. However, it is still not definitely clear whether the effect is negative or positive.
Researchers have found that long-term consumption of low dose caffeine slowed hippocampus-dependent learning and impaired long-term memory. Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls during the experiment. The conclusion was that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.
In one study, caffeine was added to rat neurons in vitro. The dendritic spines (a part of the brain cell used in forming connections between neurons) taken from the hippocampus (a part of the brain associated with memory) grew by 33% and new spines formed. After an hour or two, however, these cells returned to their original shape.
Another study showed that subjects—after receiving 100 milligrams of caffeine—had increased activity in brain regions located in the frontal lobe, where a part of the working memory network is located, and the anterior cingulum, a part of the brain that controls attention. The caffeinated subjects also performed better on the memory tasks.
However, a different study showed that caffeine could impair short term memory and increase the likelihood of the tip of the tongue phenomenon. The study allowed the researchers to suggest that caffeine could aid short-term memory when the information to be recalled is related to the current train of thought, but also to hypothesize that caffeine hinders short-term memory when the train of thought is unrelated. In essence, focused thought coupled with caffeine consumption increases mental performance.
## Effects on the heart
Caffeine increases the levels of cAMP in the heart cells, mimicking the effects of epinephrine. cAMP diffuses through the cell and acts as a "secondary messenger," activating protein kinase A (PKA; cAMP-dependent protein kinase). According to one study, caffeine, in the form of coffee, significantly reduces the risk of heart disease in epidemiological studies. However, the protective effect was found only in participants who were not severely hypertensive (i.e. patients that are not suffering from a very high blood pressure). Furthermore, no significant protective effect was found in participants aged less than 65 years or in cerebrovascular disease mortality for those aged equal or more than 65 years.
## Effects on children
Scientific studies contradict the common belief that caffeine consumption causes stunted growth in children. However, as with adults, nausea, urinary urgency, nervousness, or other effects from an elevated caffeine intake via chocolate milk, sodas, cold medicines, iced tea, coffee and other products that are widely used, may be reasons to limit the amount of caffeine that is consumed each day.
## Caffeine intake during pregnancy
The Food Standards Agency has recommended that pregnant women should limit their caffeine intake to less than 300 mg of caffeine a day – the equivalent of four cups of coffee a day. A higher intake may be associated with miscarriage.
Dr De-Kun Li of Kaiser Permanente Division of Research, which appears in the American Journal of Obstetrics and Gynecology, concludes that an intake of 200 milligrams or more per day, representing two or more cups, "significantly increases the risk of miscarriage". However, Dr. David Savitz, a professor in community and preventive medicine at New York's Mount Sinai School of Medicine and lead author of the other new study on the subject published in the January issue of Epidemiology, found no link between miscarriage and caffeine consumption.
# Production
Caffeine extracted from coffee and tea during the decaffeination process is sold or used as an additive. Being readily available as a byproduct of decaffeination, caffeine is not usually synthesized. If desired, it may be synthesized from dimethyl urea and malonic acid.
# Decaffeination
Pure caffeine is a white powder, and can be extracted from a variety of natural sources. Caffeine extraction is an important industrial process and can be performed using a number of different solvents. Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the following main methods:
## Water extraction
Coffee beans are soaked in water. The water, which contains not only caffeine but also many other compounds which contribute to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.
## Supercritical carbon dioxide extraction
Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.
## Extraction by nonhazardous organic solvents
Organic solvents such as ethyl acetate present much less health and environmental hazard than previously used chlorinated and aromatic solvents. The hydrolysis products of ethyl acetate are ethanol and acetic acid, both nonhazardous in small quantities. Another method is to use triglyceride oils obtained from spent coffee grounds.
# Stereochemistry
The nitrogen atoms are all essentially planar (in sp2 orbital hybridisation). Even though some are often drawn with three single bonds, the lone pairs on these atoms are involved in resonance with adjacent double-bonded carbon atoms, resulting in the caffeine molecule having aromatic character.
# Religion
Some Mormons and Christian Scientists do not consume caffeine. Followers of both religions believe that God wishes them to be free of all addictions.
The Church of Jesus Christ of Latter-day Saints has said the following in regards to caffeinated beverages, “With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful habit-forming drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided.” (Priesthood Bulletin, Feb. 1972, p. 4.) See also Word of Wisdom.
Gaudiya Vaishnava Hindus generally also abstain from caffeine, as it clouds the mind and over-stimulates the senses. To be initiated under a guru, one must have had no caffeine (along with alcohol, nicotine and other drugs) for at least a year.
# Pill Images | Caffeine
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Caffeine is a bitter white crystalline xanthine alkaloid that acts as a psychoactive stimulant drug and a mild diuretic (speeds up urine production)[1] in humans and other animals. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819. He coined the term "kaffein", a chemical compound in coffee, which in English became caffeine.[2] Caffeine is also called guaranine when found in guarana, mateine when found in mate, and theine when found in tea; all of these names are synonyms for the same chemical compound.
Caffeine is found in varying quantities in the beans, leaves, and fruit of over 60 plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants. It is most commonly consumed by humans in infusions extracted from the beans of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut or from cacao. Other sources include yerba mate, guarana berries, and the Yaupon Holly.
In humans, caffeine is a central nervous system (CNS) stimulant, having the effect of temporarily warding off drowsiness and restoring alertness. Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity. Caffeine is the world's most widely consumed psychoactive substance, but unlike most others, it is legal and unregulated in nearly all jurisdictions. In North America, 90% of adults consume caffeine daily.[3] The U.S. Food and Drug Administration lists caffeine as a "Multiple Purpose Generally Recognized as Safe Food Substance".[4] One 2008 study suggested that women consuming 200 milligrams or more of caffeine per day had about twice the miscarriage risk as women who drank none, while another 2008 study found no link between miscarriage and caffeine consumption.[5]
# Occurrence
Caffeine is a plant alkaloid, found in many plant species, where it acts as a natural pesticide, with high caffeine levels being reported in seedlings that are still developing foliages, but are lacking mechanical protection;[6] caffeine paralyzes and kills certain insects feeding upon the plant.[7] High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. It is therefore understood that caffeine has a natural function as both a natural pesticide and as an inhibitor of seed germination of other nearby coffee seedlings[8] thus giving it a better chance of survival.
The most commonly used caffeine-containing plants are coffee, tea, and to a lesser extent[9] cocoa. Other, less commonly used, sources of caffeine include the yerba mate[10] and guarana plants, which are sometimes used in the preparation of teas and energy drinks. Two of caffeine's alternative names, mateine[11] and guaranine,[12] are derived from the names of these plants. Some yerba mate enthusiasts assert that mateine is a stereoisomer of caffeine, which would make it a different substance altogether.[10] This is not true because caffeine is an achiral molecule, and therefore has no enantiomers; nor does it have other stereoisomers. Many natural sources of caffeine also contain widely varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine and other substances such as polyphenols which can form insoluble complexes with caffeine.[13]
The world's primary source of caffeine is the coffee bean (the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used;[14] even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 40 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to about 100 milligrams for a cup (120 milliliters) of drip coffee. Generally, dark-roast coffee has less caffeine than lighter roasts because the roasting process reduces the bean's caffeine content.[15][16] Arabica coffee normally contains less caffeine than the robusta variety.[14] Coffee also contains trace amounts of theophylline, but no theobromine.
Tea is another common source of caffeine. Tea usually contains about half as much caffeine per serving as coffee, depending on the strength of the brew. Certain types of tea, such as black and oolong, contain somewhat more caffeine than most other teas. Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation has a significant impact on tea, and color is a very poor indicator of caffeine content.[17] Teas like the pale Japanese green tea gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.
Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks such as Red Bull contain as much as 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.[18]
Chocolate derived from cocoa contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline as well as caffeine.[19] Chocolate contains too little of these compounds for a reasonable serving to create effects in humans that are on par with coffee. A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee.
In recent years various manufacturers have begun putting caffeine into shower products such as shampoo and soap, claiming that caffeine can be absorbed through the skin.[20] However, the effectiveness of such products has not been proven, and they are likely to have little stimulatory effect on the central nervous system because caffeine is not readily absorbed through the skin.[21]
In recent years various manufacturers have begun putting caffeine into tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness and is used by students that are studying for their exams. It is also used by people who work or drive for long hours. [22]
# History
Humans have consumed caffeine since the Stone Age.[23] Early peoples found that chewing the seeds, bark, or leaves of certain plants had the effects of easing fatigue, stimulating awareness, and elevating mood. Only much later was it found that the effect of caffeine was increased by steeping such plants in hot water. Many cultures have legends that attribute the discovery of such plants to people living many thousands of years ago.
According to one popular Chinese legend, the Emperor of China Shennong, reputed to have reigned in about 3000 BC, accidentally discovered that when some leaves fell into boiling water, a fragrant and restorative drink resulted.[24] Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.[25]
The history of coffee has been recorded as far back as the ninth century. During that time, coffee beans were available only in their native habitat, Ethiopia. A popular legend traces its discovery to a goatherder named Kaldi, who apparently observed goats that became elated and sleepless at night after browsing on coffee shrubs and, upon trying the berries that the goats had been eating, experienced the same vitality. The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th century Persian physician al-Razi. In 1587, Malaye Jaziri compiled a work tracing the history and legal controversies of coffee, entitled "Undat al safwa fi hill al-qahwa". In this work, Jaziri recorded that one Sheikh, Jamal-al-Din al-Dhabhani, mufti of Aden, was the first to adopt the use of coffee in 1454, and that in the 15th century the Sufis of Yemen routinely used coffee to stay awake during prayers.
Towards the close of the 16th century, the use of coffee was recorded by a European resident in Egypt, and about this time it came into general use in the Near East. The appreciation of coffee as a beverage in Europe, where it was first known as "Arabian wine," dates from the 17th century. During this time "coffee houses" were established, the first being opened in Constantinople and Venice. In Britain, the first coffee houses were opened in London in 1652, at St Michael's Alley, Cornhill. They soon became popular throughout Western Europe, and played a significant role in social relations in the 17th and 18th centuries.[26]
The kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs. In 1911, kola became the focus of one of the earliest documented health scares when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging that the caffeine in its drink was "injurious to health".[27] On March 13, 1911, the government initiated The United States v. Forty Barrels and Twenty Kegs of Coca-Cola, hoping to force Coca-Cola to remove caffeine from its formula by making claims, such as that the excessive use of Coca-Cola at one girls' school led to "wild nocturnal freaks, violations of college rules and female proprieties, and even immoralities."[28] Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances which must be listed on a product's label.
The earliest evidence of cocoa use comes from residue found in an ancient Mayan pot dated to 600 BC. In the New World, chocolate was consumed in a bitter and spicy drink called xocoatl, often seasoned with vanilla, chile pepper, and achiote. Xocoatl was believed to fight fatigue, a belief that is probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.
Chocolate was introduced to Europe by the Spaniards and became a popular beverage by 1700. They also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as Black Bean.
In 1819, the German chemist Friedrich Ferdinand Runge isolated relatively pure caffeine for the first time. According to Runge, he did this at the behest of Johann Wolfgang von Goethe.[29] In 1827, Oudry isolated "theine" from tea, but it was later proved by Mulder and Jobat that theine was the same as caffeine.[29] The structure of caffeine was elucidated near the end of the 19th century by Hermann Emil Fischer, who was also the first to achieve its total synthesis.[30] This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
Today, global consumption of caffeine has been estimated at 120,000 tonnes per annum,[31] making it the world's most popular psychoactive substance. This number equates to one serving of a caffeine beverage for every person, per day. In North America, 90% of adults consume some amount of caffeine daily.[3]
# Pharmacology
Caffeine is a central nervous system and metabolic stimulant,[32] and is used both recreationally and medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses.[33] Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.
## Metabolism
Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and is eliminated by first-order kinetics.[34]
The half-life of caffeine—the time required for the body to eliminate one-half of the total amount of caffeine consumed at a given time—varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 3–4 hours. In women taking oral contraceptives this is increased to 5–10 hours,[35] and in pregnant women the half-life is roughly 9–11 hours.[36] Caffeine can accumulate in individuals with severe liver disease when its half-life can increase to 96 hours.[37] In infants and young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30 hours. Other factors such as smoking can shorten caffeine's half-life.[38]
Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2 isozyme) into three metabolic dimethylxanthines,[39] which each have their own effects on the body:
- Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
- Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in cocoa, and therefore chocolate.
- Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.
Each of these metabolites is further metabolized and then excreted in the urine.
## Mechanism of action
Caffeine acts through multiple mechanisms involving both action on receptors and channels on the cell membrane, as well as intracellular action on calcium and cAMP pathways. By virtue of its purine structure it can act on some of the same targets as adenosine related nucleosides and nucleotides, like the cell surface P1 GPCRs for adenosine, as well as the intracellular Ryanodine receptor (RyR) which is the physiological target of cADPR (cyclic ADP-ribose), and cAMP-phosphodiesterase (cAMP-PDE). Although the action is agonistic in some cases, it is antagonistic in others. Physiologically, however, caffeine action is unlikely due to increased RyR opening, as it requires plasma concentration above lethal dosage. The action is most likely through adenosine receptors.[citation needed]
Like alcohol, nicotine, and antidepressants, caffeine readily crosses the blood brain barrier. Once in the brain, the principal mode of action of caffeine is as an antagonist of adenosine receptors found in the brain.[40] The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (an "antagonist" mechanism of action). Therefore, caffeine acts as a competitive inhibitor.
Caffeine being a competitive inhibitor of adenosine, an understanding of adenosine’s role in the central nervous system is crucial. One of the roles of adenosine is as a signal that one neuron can use to tell another to stop releasing neurotransmitter because it can’t handle the stimulation. In doing this it is acting as a retrograde neurotransmitter (a neurotransmitter that is released by the post-synaptic cell and received by the pre-synaptic cell in the direction opposite to most neurotransmitters).[41] Adenosine is the final breakdown product of adenosine triphosphate (ATP), which is the cellular currency of energy. When cells have used the energy of adenosine triphosphate it breaks into adenosine diphosphate, which is then used for energy and broken down into adenosine monophosphate. Finally, the last phosphate bond is broken for energy in the cell’s last attempt to squeeze molecular power from this molecule: adenosine monophosphate is broken down into simple adenosine. At this point, the neuron has very little energy left for the successful firing of an action potential. Adenosine from this process is then released from the postsynaptic cell and binds to receptors on the presynaptic cell. If the release of adenosine is great enough, this release has an inhibitory effect on the release of neurotransmitter from the presynaptic neuron’s axon terminal. This triggers a mechanism that inhibits the further secretion of excitatory neurotransmitters into the synapse. It is as if the postsynaptic neuron is telling the presynaptic neuron that its resources are scarce and it needs time to recover before further stimulation by neurotransmitters. Thus, adenosine works to inhibit activity of the central nervous system.
Caffeine being a competitive inhibitor of adenosine, it binds to the adenosine receptor, but does not trigger the chemical cascade that inhibits neurotransmitter release and blocks the site so adenosine cannot bind and get its message across the synapse. By inhibiting adenosine, caffeine excites the central nervous system and allows for continued stimulation of neurons that otherwise would not fire or would not release neurotransmitter into the synapse.[41][42][43][44]
The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for its stimulatory effects. This inhibition of adenosine is the only known biochemical effect that caffeine has in humans at the concentrations achieved during normal human consumption of the drug.[41] Further, coffee & tea drinkers on the whole do not consume enough caffeine to release dopamine in the nucleus accumbens shell, the key structure associated with motivation, reward & addiction. However, in high doses, caffeine induces dopamine release in nucleus accumbens, not unlike other psychostimulants, such as cocaine.[45] In low and moderate doses, caffeine appears to increase dopamine and acetylcholine release in the prefrontal cortex (PFC) (providing a mechanism for reinforcment) and stimulates the caudate nucleus, increasing wakefulness & locomotor activity. Sustained caffeine usage causes tolerance to the (prefrontal cortical) dopamine-mediated effects and hence the locomotor stimulation, but not to its cholinergic effects in the PFC, which could account for its capability for sustained arousal even in the caffeine-tolerant.[46][47][48] Caffeine also increases levels of epinephrine/adrenaline,[49] possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood.[50]
The inhibition of adenosine may be relevant in its diuretic properties. Because adenosine is known to constrict preferentially the afferent arterioles of the glomerulus, limiting blood flow and therefore urine production; its inhibition may cause vasodilation, with an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). This effect, called competitive inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of epinephrine and norepinephrine/noradrenaline released via the hypothalamic-pituitary-adrenal axis.[50] Epinephrine, the natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin and inner organs. Biochemically, it stimulates glycogenolysis, inhibits glycolysis, and stimulates gluconeogenesis to produce more glucose in the muscles and release of glucose into the blood stream from the liver.
Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in activation of Protein Kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or methylphenidate. Increased concentrations of cAMP in parietal cells causes an increased activation of protein kinase A (PKA) which in turn increases activation of H+/K+ ATPase, resulting finally in increased gastric acid secretion by the cell.
Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the endoplasmic reticulum(ER). This release is only partially blocked by Ryanodine receptor blockade with ryanodine, dantrolene, ruthenium red, and procaine (thus may involve ryanodine receptor and probably some additional calcium channels), but completely abolished after calcium depletion of ER by SERCA inhibitors like Thapsigargin (TG) or cyclopiazonic acid (CPA).[51] The action of caffeine on the ryanodine receptor may depend on both cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and dramatically increases the open time of the channel so that the calcium release is stronger than even an action potential can generate. This mode of action of caffeine is probably due to mimicking the action of the physiologic metabolite of NAD called cADPR (cyclic ADP ribose) which has a similar potentiating action on Ryanodine receptors.
Caffeine may also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal Ca2+ influx in certain vertebrate and invertebrate neurons.
The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles.[52]
## Effects when taken in moderation
The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours.[33] Consumption of caffeine does not eliminate the need for sleep: it only temporarily reduces the sensation of being tired.
With these effects, caffeine is an ergogenic: increasing the capacity for mental or physical labor. A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects who consumed caffeine compared to control tests.[53] Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight.[54] The extensive boost shown in the runners is not an isolated case; additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits.[55]
Caffeine citrate has proven to be of short and long term benefit in treating the breathing disorders of apnea of prematurity and bronchopulmonary displasia in premature infants. Citrated caffeine,[56] the only short term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy,[57] and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.[58][59]
While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more significant effect on spiders, for example, than most other drugs do.[60]
Caffeine relaxes the internal anal sphincter muscles and thus should be avoided by those with fecal incontinence.[61]
# Intoxication
An acute overdose of caffeine, usually in excess of about 300 milligrams, dependent on body weight and level of caffeine tolerance, can result in a state of central nervous system over-stimulation called caffeine intoxication,[62] colloquially "caffeine jitters". The symptoms of caffeine intoxication are not unlike overdoses of other stimulants. It may include restlessness, nervousness, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation.[63] In cases of much larger overdoses mania, depression, lapses in judgment, disorientation, loss of social inhibition, delusions, hallucinations, psychosis, rhabdomyolysis, and death may occur.[64][65]
In cases of extreme overdose, death can result. The median lethal dose (LD50) given orally, is 192 milligrams per kilogram in rats.[66] The LD50 of caffeine in humans is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adult taken within a limited time frame that is dependent on half-life. Though achieving lethal dose with caffeine would be exceptionally difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine.[67][68][69][70] Death typically occurs due to ventricular fibrillation brought about by effects of caffeine on the cardiovascular system.
Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may be required.
## DSM-V Diagnostic Criteria for Caffeine Intoxication[71]
## Risk Factors of Caffeine Intoxication
- Recent increase in caffeine intake
- Oral contraceptives
- Use of caffeine less frequently
## Differential Diagnosis of caffeine Intoxication
- Other mental disorders
- Amphetamine intoxication
- Generalized anxiety disorder
- Manic episodes
- Medication-induced side effects
- Panic disorder
- Sedative, hynotic, or anxiolytic withdrawal
- Sleep disorders
- Tobacco withdrawal[71]
- Other caffeine-induced disorders
- Caffeine-induced anxiety disorder
- caffeine-induced sleep disorder[71]
# Tolerance and Withdrawal
Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences.[74] First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a tolerance adaptation. Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users.[74]
Other research questions the idea that up-regulation of adenosine receptors is responsible for tolerance to the locomotor stimulant effects of caffeine, noting, among other things, that this tolerance is insurmountable by higher doses of caffeine (it should be surmountable if tolerance was due to an increase in receptors), and that the increase in adenosine receptor number is modest and does not explain the large tolerance which develops to caffeine.[75]
Caffeine tolerance develops very quickly, especially among heavy coffee and energy drink consumers. Complete tolerance to sleep disruption effects of caffeine develops after consuming 400 mg of caffeine 3 times a day for 7 days. Complete tolerance to subjective effects of caffeine was observed to develop after consuming 300 mg 3 times per day for 18 days, and possibly even earlier.[76] In another experiment, complete tolerance of caffeine was observed when the subject consumed 750–1200 mg per day while incomplete tolerance to caffeine has been observed in those that consume more average doses of caffeine.[77]
Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild depression. Together, these effects have come to be known as a "crash".[78]
Withdrawal symptoms—possibly including headache, irritability, an inability to concentrate, and stomach aches[79]—may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from one to five days, representing the time required for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.[80] Most effective is a combination of both an analgesic and a small amount of caffeine.
This is not the only case where caffeine increases the effectiveness of a drug. Caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief.[81] For this reason, many over-the-counter headache drugs include caffeine in their formula. It is also used with ergotamine in the treatment of migraine and cluster headaches as well as to overcome the drowsiness caused by antihistamines.
## DSM-V Diagnostic Criteria for Caffeine Withdrawl[71]
## Epidemiology and Demographics of Caffeine Withdrawal
The prevalence of caffeine withdrawal is unclear in the overall population.[71]
## Risk Factors of Caffeine Withdrawal
- Alcohol abuser
- Drug abuser
- Doses of caffeine significantly less than one's usual daily dose
- Eating disorders
- Genetic predisposition
- Mental disorders
- Prisoners
- Smokers
- Unavailability of caffeineo[71]
## Differential Diagnosis of Caffeine Withdrawal
- Other medical disorders and medical side effects
- Drug withdrawal states
- Headache disorders
- Medication side effects
- Migraine
- Sinus conditions
- Viral illnesseso[71]
# Other Notable Effects of Caffeine
### Anxiety and sleep disorders
Two infrequently diagnosed caffeine-induced disorders that are recognized by the American Psychiatric Association (APA) are caffeine-induced sleep disorder and caffeine-induced anxiety disorder, which can result from long-term excessive caffeine intake.
In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. A study in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of the population.[82]
## Parkinson's disease
Several large studies have shown that caffeine intake is associated with a reduced risk of developing Parkinson's disease (PD) in men, but studies in women have been inconclusive.[83] The mechanism by which caffeine affects PD remains a mystery. In animal models, researchers have shown that caffeine can prevent the loss of dopamine-producing nerve cells seen in Parkinson's Disease, but researchers still do not know how this occurs.[84]
## Effects on memory and learning
An array of studies found that caffeine could have nootropic effects, inducing certain changes in memory and learning. However, it is still not definitely clear whether the effect is negative or positive.
Researchers have found that long-term consumption of low dose caffeine slowed hippocampus-dependent learning and impaired long-term memory. Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls during the experiment. The conclusion was that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.
[85]
In one study, caffeine was added to rat neurons in vitro. The dendritic spines (a part of the brain cell used in forming connections between neurons) taken from the hippocampus (a part of the brain associated with memory) grew by 33% and new spines formed. After an hour or two, however, these cells returned to their original shape.[86]
Another study showed that subjects—after receiving 100 milligrams of caffeine—had increased activity in brain regions located in the frontal lobe, where a part of the working memory network is located, and the anterior cingulum, a part of the brain that controls attention. The caffeinated subjects also performed better on the memory tasks.[87]
However, a different study showed that caffeine could impair short term memory and increase the likelihood of the tip of the tongue phenomenon. The study allowed the researchers to suggest that caffeine could aid short-term memory when the information to be recalled is related to the current train of thought, but also to hypothesize that caffeine hinders short-term memory when the train of thought is unrelated.[88] In essence, focused thought coupled with caffeine consumption increases mental performance.
## Effects on the heart
Caffeine increases the levels of cAMP in the heart cells, mimicking the effects of epinephrine. cAMP diffuses through the cell and acts as a "secondary messenger," activating protein kinase A (PKA; cAMP-dependent protein kinase). According to one study, caffeine, in the form of coffee, significantly reduces the risk of heart disease in epidemiological studies. However, the protective effect was found only in participants who were not severely hypertensive (i.e. patients that are not suffering from a very high blood pressure). Furthermore, no significant protective effect was found in participants aged less than 65 years or in cerebrovascular disease mortality for those aged equal or more than 65 years.[89]
## Effects on children
Scientific studies contradict the common belief that caffeine consumption causes stunted growth in children.[90] However, as with adults, nausea, urinary urgency, nervousness, or other effects from an elevated caffeine intake via chocolate milk, sodas, cold medicines, iced tea, coffee and other products that are widely used, may be reasons to limit the amount of caffeine that is consumed each day.[91]
## Caffeine intake during pregnancy
The Food Standards Agency has recommended that pregnant women should limit their caffeine intake to less than 300 mg of caffeine a day – the equivalent of four cups of coffee a day. A higher intake may be associated with miscarriage.[92][93]
Dr De-Kun Li of Kaiser Permanente Division of Research, which appears in the American Journal of Obstetrics and Gynecology, concludes that an intake of 200 milligrams or more per day, representing two or more cups, "significantly increases the risk of miscarriage".[94] However, Dr. David Savitz, a professor in community and preventive medicine at New York's Mount Sinai School of Medicine and lead author of the other new study on the subject published in the January issue of Epidemiology, found no link between miscarriage and caffeine consumption.[5]
# Production
Caffeine extracted from coffee and tea during the decaffeination process is sold or used as an additive. Being readily available as a byproduct of decaffeination, caffeine is not usually synthesized.[95] If desired, it may be synthesized from dimethyl urea and malonic acid.[96]
# Decaffeination
Pure caffeine is a white powder, and can be extracted from a variety of natural sources. Caffeine extraction is an important industrial process and can be performed using a number of different solvents. Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the following main methods:
## Water extraction
Coffee beans are soaked in water. The water, which contains not only caffeine but also many other compounds which contribute to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor.[97] Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.
## Supercritical carbon dioxide extraction
Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.[97]
## Extraction by nonhazardous organic solvents
Organic solvents such as ethyl acetate present much less health and environmental hazard than previously used chlorinated and aromatic solvents. The hydrolysis products of ethyl acetate are ethanol and acetic acid, both nonhazardous in small quantities. Another method is to use triglyceride oils obtained from spent coffee grounds.
# Stereochemistry
The nitrogen atoms are all essentially planar (in sp2 orbital hybridisation). Even though some are often drawn with three single bonds, the lone pairs on these atoms are involved in resonance with adjacent double-bonded carbon atoms, resulting in the caffeine molecule having aromatic character.
# Religion
Some Mormons and Christian Scientists[98] do not consume caffeine. Followers of both religions believe that God wishes them to be free of all addictions.
The Church of Jesus Christ of Latter-day Saints has said the following in regards to caffeinated beverages, “With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful habit-forming drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided.” (Priesthood Bulletin, Feb. 1972, p. 4.) See also Word of Wisdom.
Gaudiya Vaishnava Hindus generally also abstain from caffeine, as it clouds the mind and over-stimulates the senses. To be initiated under a guru, one must have had no caffeine (along with alcohol, nicotine and other drugs) for at least a year.
# Pill Images | https://www.wikidoc.org/index.php/Alert | |
550f11ad7b632afc7730405bbeb7c0ab69e07850 | wikidoc | Alhandal | Alhandal
Alhandal was a term used in Arabian pharmacy for the purgative extract of colocynth, or Bitter Cucumber (Citrullus colocynthis).
The Troches of Alhandal, or Trochisci Alhandalæ, were a kind of troche, or tablet, composed of colocynth, bdellium, and gum tragacanth. They were esteemed good purgatives, and used on diverse occasions.
The word alhandal is formed of the Arabic handel, or handhal, a name for colocynth. | Alhandal
Alhandal was a term used in Arabian pharmacy for the purgative extract of colocynth, or Bitter Cucumber (Citrullus colocynthis).
The Troches of Alhandal, or Trochisci Alhandalæ, were a kind of troche, or tablet, composed of colocynth, bdellium, and gum tragacanth. They were esteemed good purgatives, and used on diverse occasions.
The word alhandal is formed of the Arabic handel, or handhal, a name for colocynth. | https://www.wikidoc.org/index.php/Alhandal | |
14688ab0c41d6fc9f115290456766b2cc922fa4a | wikidoc | Alkaloid | Alkaloid
Alkaloid are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have have pharmacological effects and are used as medications and recreational drugs. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste.
# Alkaloid classifications
Alkaloids are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the molecule. When not much was known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those molecules' structures appear in the finished product; the opium alkaloids are sometimes called "phenanthrenes", for example), or by the plants or animals they were isolated from. When more is learned about a certain alkaloid, the grouping is changed to reflect the new knowledge, usually taking the name of a biologically-important amine that stands out in the synthesis process.
- Pyridine group: piperine, coniine, trigonelline, arecaidine, guvacine, pilocarpine, cytisine, nicotine, sparteine, pelletierine.
- Pyrrolidine group: hygrine, cuscohygrine, nicotine
- Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine
- Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine
- Isoquinoline group: The opium alkaloids (morphine, codeine, thebaine, Isopapa-dimethoxy-aniline, papaverine, narcotine, sanguinarine, narceine, hydrastine, berberine), emetine, berbamine, oxyacanthine
- Phenethylamine group: mescaline, ephedrine, dopamine, amphetamine
- Indole group:
Tryptamines: DMT, N-methyltryptamine, psilocybin, serotonin
Ergolines: the ergot alkaloids (ergine, ergotamine, lysergic acid, LSD etc.)
Beta-carbolines: harmine, harmaline, yohimbine, reserpine
Rauwolfia alkaloids: Reserpine
- Tryptamines: DMT, N-methyltryptamine, psilocybin, serotonin
- Ergolines: the ergot alkaloids (ergine, ergotamine, lysergic acid, LSD etc.)
- Beta-carbolines: harmine, harmaline, yohimbine, reserpine
- Rauwolfia alkaloids: Reserpine
- Purine group:
Xanthines: caffeine, theobromine, theophylline
- Xanthines: caffeine, theobromine, theophylline
- Terpenoid group:
Aconite alkaloids: aconitine
Steroids: solanine, samandaris (quaternary ammonium compounds): muscarine, choline, neurine
- Aconite alkaloids: aconitine
- Steroids: solanine, samandaris (quaternary ammonium compounds): muscarine, choline, neurine
- Vinca alkaloids: vinblastine, vincristine. They are antineoplastic and binds free tubulin dimers thereby disrupting balance between microtuble polymerization and delpolymerization resulting in arrest of cells in metaphase.
- Miscellaneous: capsaicin, cynarin, phytolaccine, phytolaccotoxin
# Physicochemical properties
Low-molecular weight alkaloids without hydrogen bond donors such as hydroxy groups are often liquid at room temperature, examples are nicotine, sparteine, coniine, and phenethylamine.
The basicity of alkaloids depends on the lone pairs of electrons on their nitrogen atoms. As organic bases, alkaloids form salts with mineral acids such as hydrochloric acid and sulfuric acid and organic acids such as tartaric acid or maleic acid. These salts are usually more water-soluble than their free base form. | Alkaloid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Alkaloid are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have have pharmacological effects and are used as medications and recreational drugs. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste.
# Alkaloid classifications
Alkaloids are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the molecule. When not much was known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those molecules' structures appear in the finished product; the opium alkaloids are sometimes called "phenanthrenes", for example), or by the plants or animals they were isolated from. When more is learned about a certain alkaloid, the grouping is changed to reflect the new knowledge, usually taking the name of a biologically-important amine that stands out in the synthesis process.
- Pyridine group: piperine, coniine, trigonelline, arecaidine, guvacine, pilocarpine, cytisine, nicotine, sparteine, pelletierine.
- Pyrrolidine group: hygrine, cuscohygrine, nicotine
- Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine
- Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine
- Isoquinoline group: The opium alkaloids (morphine, codeine, thebaine, Isopapa-dimethoxy-aniline, papaverine, narcotine, sanguinarine, narceine, hydrastine, berberine), emetine, berbamine, oxyacanthine
- Phenethylamine group: mescaline, ephedrine, dopamine, amphetamine
- Indole group:
Tryptamines: DMT, N-methyltryptamine, psilocybin, serotonin
Ergolines: the ergot alkaloids (ergine, ergotamine, lysergic acid, LSD etc.)
Beta-carbolines: harmine, harmaline, yohimbine, reserpine
Rauwolfia alkaloids: Reserpine
- Tryptamines: DMT, N-methyltryptamine, psilocybin, serotonin
- Ergolines: the ergot alkaloids (ergine, ergotamine, lysergic acid, LSD etc.)
- Beta-carbolines: harmine, harmaline, yohimbine, reserpine
- Rauwolfia alkaloids: Reserpine
- Purine group:
Xanthines: caffeine, theobromine, theophylline
- Xanthines: caffeine, theobromine, theophylline
- Terpenoid group:
Aconite alkaloids: aconitine
Steroids: solanine, samandaris (quaternary ammonium compounds): muscarine, choline, neurine
- Aconite alkaloids: aconitine
- Steroids: solanine, samandaris (quaternary ammonium compounds): muscarine, choline, neurine
- Vinca alkaloids: vinblastine, vincristine. They are antineoplastic and binds free tubulin dimers thereby disrupting balance between microtuble polymerization and delpolymerization resulting in arrest of cells in metaphase.
- Miscellaneous: capsaicin, cynarin, phytolaccine, phytolaccotoxin
# Physicochemical properties
Low-molecular weight alkaloids without hydrogen bond donors such as hydroxy groups are often liquid at room temperature, examples are nicotine, sparteine, coniine, and phenethylamine.
The basicity of alkaloids depends on the lone pairs of electrons on their nitrogen atoms. As organic bases, alkaloids form salts with mineral acids such as hydrochloric acid and sulfuric acid and organic acids such as tartaric acid or maleic acid. These salts are usually more water-soluble than their free base form. | https://www.wikidoc.org/index.php/Alkaloid | |
2fa4a6452b63d20bfe916ddb6f7a15a235d0852e | wikidoc | Alkoxide | Alkoxide
An alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They can be written as RO–, where R is the organic substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands. . Alkoxides, although generally not stable in protic solvents such as water, occur widely as intermediates in various reactions, including the Williamson ether synthesis. Transition metal alkoxides are widely used for coatings and as catalysts.
Enolates are unsaturated alkoxide derived by deprotonation of a C-H bond adjacent to a ketone or aldehyde. The nucleophilic center for simple alkoxides is located on the oxygen, whereas the nucleophilic site on enolates is delocalized onto both carbon and oxygen sites.
Phenoxides represent a special class of anions that are closely related to alkoxides, except the organic substitutent is a derivative of benzene. Phenol is significantly more acidic than a typical alcohol, thus phenoxides are correspondingly less basic and less nucleophilic. They are however often easier to handle and afford derivatives that are more crystalline than the alkoxides.
# Preparation
## From reducing metals
Alkoxides can be produced by several routes starting from an alcohol. Highly reducing metals react directly with alcohols to give the corresponding metal alkoxide. The alcohol serves as an acid, and hydrogen is produced as a by-product. A classic case is sodium methoxide produced by the addition of sodium metal to methanol:
Other alkali metals can be used in place of sodium, and most alcohols can be used in place of methanol.
## From electrophilic chlorides
The tetrachloride of titanium reacts with alcohols to give the corresponding tetraalkoxides, concomitant with the evolution of hydrogen chloride:
The reaction can be accelerated by the addition of a base, such as a tertiary amine. Many other metal and main group halides can be used instead of titanium, for example SiCl4, ZrCl4, and PCl3.
## By metathesis reactions
Many alkoxides are prepared by salt-forming reactions from a metal chloride and sodium alkoxide:
Such reactions are favored by the lattice energy of the NaCl, and purification of the product alkoxide is simplified by the fact that NaCl is insoluble in common organic solvents.
## By electrochemical processes
Many alkoxides can be prepared by anodic dissolution of the corresponding metals in water-free alcohols in the presence of electroconductive additive. The metals may be Sc, Ga, Y, La, Ln, Si, Ti, Ge, Zr, Hf, Nb, Ta, Mo, W, Fe, Co, Ni, Re, etc. The conductive additive may be lithium chloride, quaternary ammonium halogenide, or other. Some examples of metal alkoxides obtained by this technique: Ti(OC3H7-iso)4, Nb2(OCH3)10, Ta2(OCH3)10, 2, Re2O3(OCH3)6, Re4O6(OCH3)12, and Re4O6(OC3H7-iso)10.
# Properties
## Hydrolysis and transesterification
Metal alkoxides hydrolyse with water according to the following equation:
where R is an organic substituent and L is an unspecified ligand (often an alkoxide)
A well-studied case is the irreversible hydrolysis of titanium ethoxide:
By controlling the stoichiometry of steric properties of the alkoxide, such reactions can be arrested leading to metal-oxy-alkoxide clusters. Other alcohols can be employed in place of water. In this way one alkoxide can be converted to another, a process sometimes called transesterification. Sodium methoxide, for example, is commonly used for this purpose, a reaction that is relevant to the production of "bio-diesel." The position of the equilibrium can be controlled by the acidity of the alcohol; for example phenols typically react with alkoxides to release alcohols, giving the corresponding phenoxide. More simply, the trans-esterification can be controlled by selectively evaporating the more volatile component. In this way, ethoxides can be converted to butoxides, since ethanol (b.p. 78 °C) is more volatile than butanol (b.p. 118 °C).
## Formation of oxo-ligands
Many metal alkoxide compounds also feature oxo-ligands in their coordination sphere. Oxo-ligands typically arise via the hydrolysis, often accidentally, and via ether elimination:
Additionally, low valent metal alkoxides are susceptible to oxidation by air.
## Formation of polynuclear and heterometallic derivatives
Characteristically, transition metal alkoxides and oxides are polynuclear, that is they contain more than one metal. Oxides and alkoxides are sterically undemanding and highly basic ligands that tend to bridge metals.
Upon the isomorphic substitution of metal atoms close in properties crystalline complexes of variable composition are formed. The metal ratio in such compounds can vary over a broad range. For instance, the substitution of molybdenum and tungsten for rhenium in the complexes Re4O6-y(OCH3)12+y allowed one to obtain complexes Re4-xMoxO6-y(OCH3)12+y in the range of x= and Re4-xWxO6-y(OCH3)12+y in the range of x=.
## Thermal stability
Many metal alkoxides thermally decompose in the range ~100-300 °C. Depending on process conditions, this thermolysis can afford nanosized powders of oxide or metallic phases. This approach is a basis of processes of fabrication of functional materials intended for aircraft, space, electronic fields, and chemical industry: individual oxides, their solid solutions, complex oxides, powders of metals and alloys active towards sintering. Decomposition of mixtures of mono- and heterometallic alkoxide derivatives has also been examined. This method represents a prospective approach possessing an advantage of capability of obtaining functional materials with increased phase and chemical homogeneity and controllable grain size (including the preparation of nanosized materials) at relatively low temperature (less than 500-900°C) as compared with the conventional techniques.
# Illustrative alkoxides
- titanium isopropoxide, used as a catalyst in organic synthesis and a precursor to TiO2.
- aluminium isopropoxide, used as a reagent in organic synthesis.
- tetraethylorthosilicate, used as a precursor to SiO2.
- Potassium tert-butoxide, used as a base for organic elimination reactions.
- Rhenium oxomethoxide Re4O6(OCH3)12, a tetranuclear rhenium derivative. | Alkoxide
An alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They can be written as RO–, where R is the organic substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands. . Alkoxides, although generally not stable in protic solvents such as water, occur widely as intermediates in various reactions, including the Williamson ether synthesis. Transition metal alkoxides are widely used for coatings and as catalysts.[1]
Enolates are unsaturated alkoxide derived by deprotonation of a C-H bond adjacent to a ketone or aldehyde. The nucleophilic center for simple alkoxides is located on the oxygen, whereas the nucleophilic site on enolates is delocalized onto both carbon and oxygen sites.
Phenoxides represent a special class of anions that are closely related to alkoxides, except the organic substitutent is a derivative of benzene. Phenol is significantly more acidic than a typical alcohol, thus phenoxides are correspondingly less basic and less nucleophilic. They are however often easier to handle and afford derivatives that are more crystalline than the alkoxides.
# Preparation
## From reducing metals
Alkoxides can be produced by several routes starting from an alcohol. Highly reducing metals react directly with alcohols to give the corresponding metal alkoxide. The alcohol serves as an acid, and hydrogen is produced as a by-product. A classic case is sodium methoxide produced by the addition of sodium metal to methanol:
Other alkali metals can be used in place of sodium, and most alcohols can be used in place of methanol.
## From electrophilic chlorides
The tetrachloride of titanium reacts with alcohols to give the corresponding tetraalkoxides, concomitant with the evolution of hydrogen chloride:
The reaction can be accelerated by the addition of a base, such as a tertiary amine. Many other metal and main group halides can be used instead of titanium, for example SiCl4, ZrCl4, and PCl3.
## By metathesis reactions
Many alkoxides are prepared by salt-forming reactions from a metal chloride and sodium alkoxide:
Such reactions are favored by the lattice energy of the NaCl, and purification of the product alkoxide is simplified by the fact that NaCl is insoluble in common organic solvents.
## By electrochemical processes
Many alkoxides can be prepared by anodic dissolution of the corresponding metals in water-free alcohols in the presence of electroconductive additive. The metals may be Sc, Ga, Y, La, Ln, Si, Ti, Ge, Zr, Hf, Nb, Ta, Mo, W, Fe, Co, Ni, Re, etc. The conductive additive may be lithium chloride, quaternary ammonium halogenide, or other. Some examples of metal alkoxides obtained by this technique: Ti(OC3H7-iso)4, Nb2(OCH3)10, Ta2(OCH3)10, [MoO(OCH3)4]2, Re2O3(OCH3)6, Re4O6(OCH3)12, and Re4O6(OC3H7-iso)10.
# Properties
## Hydrolysis and transesterification
Metal alkoxides hydrolyse with water according to the following equation:
where R is an organic substituent and L is an unspecified ligand (often an alkoxide)
A well-studied case is the irreversible hydrolysis of titanium ethoxide:
By controlling the stoichiometry of steric properties of the alkoxide, such reactions can be arrested leading to metal-oxy-alkoxide clusters. Other alcohols can be employed in place of water. In this way one alkoxide can be converted to another, a process sometimes called transesterification. Sodium methoxide, for example, is commonly used for this purpose, a reaction that is relevant to the production of "bio-diesel." The position of the equilibrium can be controlled by the acidity of the alcohol; for example phenols typically react with alkoxides to release alcohols, giving the corresponding phenoxide. More simply, the trans-esterification can be controlled by selectively evaporating the more volatile component. In this way, ethoxides can be converted to butoxides, since ethanol (b.p. 78 °C) is more volatile than butanol (b.p. 118 °C).
## Formation of oxo-ligands
Many metal alkoxide compounds also feature oxo-ligands in their coordination sphere. Oxo-ligands typically arise via the hydrolysis, often accidentally, and via ether elimination:
Additionally, low valent metal alkoxides are susceptible to oxidation by air.
## Formation of polynuclear and heterometallic derivatives
Characteristically, transition metal alkoxides and oxides are polynuclear, that is they contain more than one metal. Oxides and alkoxides are sterically undemanding and highly basic ligands that tend to bridge metals.
Upon the isomorphic substitution of metal atoms close in properties crystalline complexes of variable composition are formed. The metal ratio in such compounds can vary over a broad range. For instance, the substitution of molybdenum and tungsten for rhenium in the complexes Re4O6-y(OCH3)12+y allowed one to obtain complexes Re4-xMoxO6-y(OCH3)12+y in the range of x=[0 to 2.82] and Re4-xWxO6-y(OCH3)12+y in the range of x=[0 to 2].
## Thermal stability
Many metal alkoxides thermally decompose in the range ~100-300 °C. Depending on process conditions, this thermolysis can afford nanosized powders of oxide or metallic phases. This approach is a basis of processes of fabrication of functional materials intended for aircraft, space, electronic fields, and chemical industry: individual oxides, their solid solutions, complex oxides, powders of metals and alloys active towards sintering. Decomposition of mixtures of mono- and heterometallic alkoxide derivatives has also been examined. This method represents a prospective approach possessing an advantage of capability of obtaining functional materials with increased phase and chemical homogeneity and controllable grain size (including the preparation of nanosized materials) at relatively low temperature (less than 500-900°C) as compared with the conventional techniques.
# Illustrative alkoxides
- titanium isopropoxide, used as a catalyst in organic synthesis and a precursor to TiO2.
- aluminium isopropoxide, used as a reagent in organic synthesis.
- tetraethylorthosilicate, used as a precursor to SiO2.
- Potassium tert-butoxide, used as a base for organic elimination reactions.
- Rhenium oxomethoxide Re4O6(OCH3)12, a tetranuclear rhenium derivative. | https://www.wikidoc.org/index.php/Alkoxide | |
7f87091591238ff2273f6e609bda7a293bcf0ed7 | wikidoc | Allergen | Allergen
# Overview
An allergen is a nonparasitic antigen capable of stimulating a type-I hypersensitivity reaction in atopic individuals.
Most humans mount significant IgE responses only as a defense against parasitic infections. However, some individuals mount an IgE response against common environmental antigens. This hereditory predisposition is called atopy. In atopic individuals, non-parasitic antigens stimulate inappropriate IgE production, leading to type I hypersensitivity.
Sensitivities vary from one person to another and it is possible to be allergic to an extraordinary range of substances.
# Types of allergies
Dust, pollen and pet dander are all common allergens, but it is possible to be allergic to anything from chlorine to perfume. Food allergies are not as common as food sensitivity, but some foods such as peanuts (really a legume), nuts, seafood and shellfish are the cause of serious allergies in many people.
Officially, the Food and Drug Administration does recognize 8 foods as being common for allergic reactions in a large segment of the sensitive population, which includes, peanuts, tree nuts, eggs, milk, shellfish, fish, wheat and their derivatives, soy and their derivatives, and sulphites (chemical based, often found in flavors and colors in foods) at 10ppm and over. See the FDA website for complete details. It should be noted that other countries, due to differences in genetic profiles of its citizens and different levels of exposure to different foods, the "official" allergen list will change. Canada recognizes all eight of the allergens recognized by the US, and also recognizes sesame seeds.
A few people have been recorded to be allergic to certain chemicals found in almost all water, and even water itself (see Aquagenic pruritus).
Poison ivy is a plant that will cause an allergic reaction in 70-85% of humans. But, given enough repeated contact—like any allergy, most human bodies will learn to fight the allergen.
An allergic reaction can be caused by any form of direct contact with the allergen—eating or drinking a food you are sensitive to (ingestion), breathing in pollen, perfume or pet dander (inhalation), or brushing your body against an allergy-causing plant (direct contact, generally resulting in hives). Other common causes of serious allergy are wasp, fire ant and bee stings, penicillin, and latex. An extremely serious form of an allergic reaction, which can kill in mere minutes, is called anaphylaxis. One form of treatment is the administration of sterile epinephrine (via "Epi-Pen") to the person experiencing anaphylaxis, which suppresses the body's overreaction to the food ingested, and allows for time to be transported to a medical facility (it does not "cure" the allergic reaction).
# Common allergens
In addition to foreign proteins found in foreign serum (from blood transfusions) and vaccines, common allergens include:
- Animal products
cat]s
fur and dander
cockroach calyx
dust mite excretion
- cat]s
- fur and dander
- cockroach calyx
- dust mite excretion
- Drugs
penicillin
sulfonamides
salicylates (also found naturally in numerous fruits)
local anaesthetics
- penicillin
- sulfonamides
- salicylates (also found naturally in numerous fruits)
- local anaesthetics
- Foods
celery and celeriac
corn or maize
eggs (typically albumin, the white)
fruit
pumpkin
legumes
beans
peas
peanuts
soybeans
milk
seafood
sesame
soy
tree nuts
pecans
almonds
wheat
- celery and celeriac
- corn or maize
- eggs (typically albumin, the white)
- fruit
pumpkin
- pumpkin
- legumes
beans
peas
peanuts
soybeans
- beans
- peas
- peanuts
- soybeans
- milk
- seafood
- sesame
- soy
- tree nuts
pecans
almonds
- pecans
- almonds
- wheat
- Insect stings
bee sting venom
wasp sting venom
mosquito stings
- bee sting venom
- wasp sting venom
- mosquito stings
- Mold spores
- Other
latex
metal
- latex
- metal
- Plant pollens (hay fever)
grass — ryegrass, timothy-grass
weeds — ragweed, plantago, nettle, artemisia vulgaris, chenopodium album, sorrel
trees — birch, alder, hazel, hornbeam, aesculus, willow, poplar, platanus, tilia, olea
- grass — ryegrass, timothy-grass
- weeds — ragweed, plantago, nettle, artemisia vulgaris, chenopodium album, sorrel
- trees — birch, alder, hazel, hornbeam, aesculus, willow, poplar, platanus, tilia, olea | Allergen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
An allergen is a nonparasitic antigen capable of stimulating a type-I hypersensitivity reaction in atopic individuals.[1]
Most humans mount significant IgE responses only as a defense against parasitic infections. However, some individuals mount an IgE response against common environmental antigens. This hereditory predisposition is called atopy. In atopic individuals, non-parasitic antigens stimulate inappropriate IgE production, leading to type I hypersensitivity.
Sensitivities vary from one person to another and it is possible to be allergic to an extraordinary range of substances.
# Types of allergies
Dust, pollen and pet dander are all common allergens, but it is possible to be allergic to anything from chlorine to perfume. Food allergies are not as common as food sensitivity, but some foods such as peanuts (really a legume), nuts, seafood and shellfish are the cause of serious allergies in many people.
Officially, the Food and Drug Administration does recognize 8 foods as being common for allergic reactions in a large segment of the sensitive population, which includes, peanuts, tree nuts, eggs, milk, shellfish, fish, wheat and their derivatives, soy and their derivatives, and sulphites (chemical based, often found in flavors and colors in foods) at 10ppm and over. See the FDA website for complete details. It should be noted that other countries, due to differences in genetic profiles of its citizens and different levels of exposure to different foods, the "official" allergen list will change. Canada recognizes all eight of the allergens recognized by the US, and also recognizes sesame seeds.[2]
A few people have been recorded to be allergic to certain chemicals found in almost all water, and even water itself (see Aquagenic pruritus).
Poison ivy is a plant that will cause an allergic reaction in 70-85% of humans. But, given enough repeated contact—like any allergy, most human bodies will learn to fight the allergen.
An allergic reaction can be caused by any form of direct contact with the allergen—eating or drinking a food you are sensitive to (ingestion), breathing in pollen, perfume or pet dander (inhalation), or brushing your body against an allergy-causing plant (direct contact, generally resulting in hives). Other common causes of serious allergy are wasp, fire ant and bee stings, penicillin, and latex. An extremely serious form of an allergic reaction, which can kill in mere minutes, is called anaphylaxis. One form of treatment is the administration of sterile epinephrine (via "Epi-Pen") to the person experiencing anaphylaxis, which suppresses the body's overreaction to the food ingested, and allows for time to be transported to a medical facility (it does not "cure" the allergic reaction).
# Common allergens
In addition to foreign proteins found in foreign serum (from blood transfusions) and vaccines, common allergens include:
- Animal products
cat]s
fur and dander
cockroach calyx
dust mite excretion
- cat]s
- fur and dander
- cockroach calyx
- dust mite excretion
- Drugs
penicillin
sulfonamides
salicylates (also found naturally in numerous fruits)
local anaesthetics
- penicillin
- sulfonamides
- salicylates (also found naturally in numerous fruits)
- local anaesthetics
- Foods
celery and celeriac [3]
corn or maize
eggs (typically albumin, the white)
fruit
pumpkin
legumes
beans
peas
peanuts
soybeans
milk
seafood
sesame
soy
tree nuts
pecans
almonds
wheat
- celery and celeriac [3]
- corn or maize
- eggs (typically albumin, the white)
- fruit
pumpkin
- pumpkin
- legumes
beans
peas
peanuts
soybeans
- beans
- peas
- peanuts
- soybeans
- milk
- seafood
- sesame
- soy
- tree nuts
pecans
almonds
- pecans
- almonds
- wheat
- Insect stings
bee sting venom
wasp sting venom
mosquito stings
- bee sting venom
- wasp sting venom
- mosquito stings
- Mold spores
- Other
latex
metal
- latex
- metal
- Plant pollens (hay fever)
grass — ryegrass, timothy-grass
weeds — ragweed, plantago, nettle, artemisia vulgaris, chenopodium album, sorrel
trees — birch, alder, hazel, hornbeam, aesculus, willow, poplar, platanus, tilia, olea
- grass — ryegrass, timothy-grass
- weeds — ragweed, plantago, nettle, artemisia vulgaris, chenopodium album, sorrel
- trees — birch, alder, hazel, hornbeam, aesculus, willow, poplar, platanus, tilia, olea | https://www.wikidoc.org/index.php/Allergen | |
ee2c199f33f80b21c537fae418a8eb2eb6401050 | wikidoc | Allspice | Allspice
Allspice, also called Jamaica pepper,"Kurundu" Myrtle pepper, pimento
, or newspice, is a spice which is the dried unripe fruit of the Pimenta dioica plant. The name "allspice" was coined by the English, who thought it combined the flavour of several aromatic spices, such as cinnamon, nutmeg, and cloves.
# Preparation/Form
Ground allspice is not, as some people believe, a mixture of spices. Rather, it is the dried fruit of the Pimenta dioica plant. The fruit is picked when it is green and unripe and traditionally dried in the sun. When dry, the fruits are brown and resemble large brown peppercorns. The whole fruits have a longer shelf life than the powdered product and produce a more aromatic product when freshly ground before use.
The leaves of the allspice plant are also used in cooking. For cooking, fresh leaves are used where available: they are similar in texture to bay leaves and are thus infused during cooking and then removed before serving. Unlike bay leaves, they lose much flavour when dried and stored. The leaves and wood are often used for smoking meats where allspice is a local crop. Allspice can also be found in essential oil form.
# Uses
Allspice is one of the most important ingredients of Caribbean cuisine. It is used in Caribbean jerk seasoning (the wood is used to smoke jerk in Jamaica, although the spice is a good substitute), in mole sauces, and in pickling; it is also an ingredient in commercial sausage preparations and curry powders. Allspice is also indispensable in Middle Eastern cuisine, particularly in the Levant where it is used to flavor a variety of stews and meat dishes. In Palestinian cuisine, for example, many main dishes call for allspice as the sole spice added for flavoring. In America, it is used mostly in desserts, but it is also responsible for giving Cincinnati-style chili its distinctive aroma and flavor as well. Allspice is commonly used in Great Britain and appears in many dishes, including in cakes. Even in many countries where allspice is not very popular in the household, such as Germany, it is used in large amounts by commercial sausage makers. Allspice is also a main flavor used in barbecue sauces. In the West Indies, an allspice liqueur called "pimento dram" is produced.
Allspice has also been used as a deodorant. Volatile oils found in the plant contain eugenol, a weak antimicrobial agent (Yaniv, Sohara et al. 2005). Allspice is also purported to provide relief for indigestion and gas.
# Cultivation
Allspice is a small scrubby tree, quite similar to the bay laurel in size and form. It can be grown outdoors in the tropics and subtropics with normal garden soil and watering. Smaller plants can be killed by frost, although larger plants are more tolerant. It adapts well to container culture and can be kept as a houseplant or in a greenhouse. The plant is dioecious, meaning plants are either male or female and hence male and female plants must be kept in proximity in order to allow fruits to develop.
To protect the pimento trade the plant was guarded against export from Jamaica. It is reported that many attempts were made at growing the pimento from seeds, all failed. At one time it was thought that the plant would grow nowhere else except in Jamaica where the plant was readily spread by birds. Experiments were then performed using the constituents of bird droppings, however these were also totally unsuccessful. Eventually it was realized that an elevated temperature, such as that found inside a bird's body, was essential for germinating the seeds.
## International naming
Пименто (Pimento) in Macedonian | Allspice
Allspice, also called Jamaica pepper,"Kurundu" Myrtle pepper, pimento[1]
, or newspice, is a spice which is the dried unripe fruit of the Pimenta dioica plant. The name "allspice" was coined by the English, who thought it combined the flavour of several aromatic spices, such as cinnamon, nutmeg, and cloves.
# Preparation/Form
Ground allspice is not, as some people believe, a mixture of spices. Rather, it is the dried fruit of the Pimenta dioica plant. The fruit is picked when it is green and unripe and traditionally dried in the sun. When dry, the fruits are brown and resemble large brown peppercorns. The whole fruits have a longer shelf life than the powdered product and produce a more aromatic product when freshly ground before use.
The leaves of the allspice plant are also used in cooking. For cooking, fresh leaves are used where available: they are similar in texture to bay leaves and are thus infused during cooking and then removed before serving. Unlike bay leaves, they lose much flavour when dried and stored. The leaves and wood are often used for smoking meats where allspice is a local crop. Allspice can also be found in essential oil form.
# Uses
Allspice is one of the most important ingredients of Caribbean cuisine. It is used in Caribbean jerk seasoning (the wood is used to smoke jerk in Jamaica, although the spice is a good substitute), in mole sauces, and in pickling; it is also an ingredient in commercial sausage preparations and curry powders. Allspice is also indispensable in Middle Eastern cuisine, particularly in the Levant where it is used to flavor a variety of stews and meat dishes. In Palestinian cuisine, for example, many main dishes call for allspice as the sole spice added for flavoring. In America, it is used mostly in desserts, but it is also responsible for giving Cincinnati-style chili its distinctive aroma and flavor as well. Allspice is commonly used in Great Britain and appears in many dishes, including in cakes. Even in many countries where allspice is not very popular in the household, such as Germany, it is used in large amounts by commercial sausage makers. Allspice is also a main flavor used in barbecue sauces. In the West Indies, an allspice liqueur called "pimento dram" is produced.
Allspice has also been used as a deodorant. Volatile oils found in the plant contain eugenol, a weak antimicrobial agent (Yaniv, Sohara et al. 2005). Allspice is also purported to provide relief for indigestion and gas[2].
# Cultivation
Allspice is a small scrubby tree, quite similar to the bay laurel in size and form. It can be grown outdoors in the tropics and subtropics with normal garden soil and watering. Smaller plants can be killed by frost, although larger plants are more tolerant. It adapts well to container culture and can be kept as a houseplant or in a greenhouse. The plant is dioecious, meaning plants are either male or female and hence male and female plants must be kept in proximity in order to allow fruits to develop.
To protect the pimento trade the plant was guarded against export from Jamaica. It is reported that many attempts were made at growing the pimento from seeds, all failed. At one time it was thought that the plant would grow nowhere else except in Jamaica where the plant was readily spread by birds. Experiments were then performed using the constituents of bird droppings, however these were also totally unsuccessful. Eventually it was realized that an elevated temperature, such as that found inside a bird's body, was essential for germinating the seeds.
## International naming
Пименто (Pimento) in Macedonian | https://www.wikidoc.org/index.php/Allspice | |
5c289d8ff4d35144c5f58ae8ccfd6d1b1a92d385 | wikidoc | Althesin | Althesin
Althesin is an intravenous anaesthetic agent now withdrawn from the market due to severe drug reactions. It was popular because of its short duration of action. It is composed of a mixture of alphaxolone and alphadolone, two steroids. It provides rapid onset of action and recovery.
Cremophor EL was the solubilizing agent (excipient / additive) of Althesin.
Some authors have said "It should be emphasized that there is no evidence of any toxic action from Cremophor in man. The toxic effects or reactions to Propanidid and Althesin are due to the drugs themselves" .
However, more recent literature state that Cremophor EL (aka Polyoxyl 35 Castor Oil, a surfactant and derivative of castor oil), when previously used as a solubilising agent in lipid emulsions (such as propofol, vitamin K, and Althesin), was responsible for severe anaphylactoid reactions. Propofol was reformulated as a Soya Bean Oil emulsion ("Diprivan"), and Vitamin K ("Konakion") is also free of Cremophor EL (see product descriptions).
Alphaxolone/Alphadolone has been re-branded as "Saffan" (Pitman-Moore Pharmaceuticals Ltd) and is available for use in veterinary anaesthesia. | Althesin
Althesin is an intravenous anaesthetic agent now withdrawn from the market due to severe drug reactions. It was popular because of its short duration of action. It is composed of a mixture of alphaxolone and alphadolone, two steroids. It provides rapid onset of action and recovery.
Cremophor EL was the solubilizing agent (excipient / additive) of Althesin.
Some authors have said "It should be emphasized that there is no evidence of any toxic action from Cremophor in man. The toxic effects or reactions to Propanidid and Althesin are due to the drugs themselves" [1].
However, more recent literature [2] state that Cremophor EL (aka Polyoxyl 35 Castor Oil, a surfactant and derivative of castor oil), when previously used as a solubilising agent in lipid emulsions (such as propofol, vitamin K, and Althesin), was responsible for severe anaphylactoid reactions. Propofol was reformulated as a Soya Bean Oil emulsion ("Diprivan"), and Vitamin K ("Konakion") is also free of Cremophor EL (see product descriptions).
Alphaxolone/Alphadolone has been re-branded as "Saffan" (Pitman-Moore Pharmaceuticals Ltd) and is available for use in veterinary anaesthesia. [3] | https://www.wikidoc.org/index.php/Althesin | |
e04e75950bc17f5539db5f298c076b27015c15f6 | wikidoc | Amaranth | Amaranth
Amaranthus, collectively known as amaranth or pigweed, is a cosmopolitan genus of herbs. Approximately 60 species are presently recognised, with inflorescences and foliage ranging from purple and red to gold. Members of this genus share many characteristics and uses with members of the closely related genus Celosia.
Although several species are often considered weeds, people around the world value amaranths as leaf vegetables, cereals and ornamentals.
The word comes from the Greek amarantos (Αμάρανθος or Αμάραντος) the "one that does not wither," or the never-fading (flower).
# Systematics
Amaranthus shows a wide variety of morphological diversity among and even within certain species. Although the family (Amaranthaceae) is distinctive, the genus has few distinguishing characters among the 70 species included. This complicates taxonomy and Amaranthus has generally been considered among systematists as a “difficult” genus.
Formerly, Sauer (1955) classified the genus into 2 sub-genera, differentiating only between monoecious and dioecious species: Acnida (L.) Aellen ex K.R. Robertson and Amaranthus. Although this classification was widely accepted, further infrageneric classification was (and still is) needed to differentiate this widely diverse group.
Currently, Amaranthus includes 3 recognized sub-genera and 70 species, although species numbers are questionable due to hybridization and species concepts. Infrageneric classification focuses on inflorescence, flower characters and whether a species is monoecious/dioecious, as in the Sauer (1955) suggested classification. A modified infrageneric classification of Amaranthus was published by Mosyakin & Robertson (1996) and includes 3 subgenera: Acnida, Amaranthus and Albersia. The taxonomy is further differentiated by sections within each of the sub-genera.
In some cultures it was known as a mythical flower that never fades.
# Uses
## Grain amaranth
Several species are raised for amaranth grain in Asia and the Americas. Ancient amaranth grains still used to this day include the 3 species, Amaranthus caudatus, Amaranthus cruentus, and Amaranthus hypochondriacus. Although amaranth was (and still is) cultivated on a small-scale in parts of Mexico, Guatemala, Peru, India, and Nepal, there is potential for further cultivation in the U.S and tropical countries and is often referred to as "the crop of the future." It has been proposed as an inexpensive native crop that could be cultivated by indigenous people in rural areas for several reasons: 1) easily harvested, 2) produces a lot of fruits (and thus seeds) which are used as grain, 3) highly tolerant of arid environments which are typical of most subtropical and some tropical regions, and 4) large amounts of protein and essential amino acids, such as lysine. Due to its weedy life history, amaranth grains grow very rapidly and their large seedheads can weigh up to 1 kilogram and contain a half-million seeds. Amaranthus species are reported to have a 30% higher protein value than other cereals, such as rice, wheat flour, oats and rye.
Amaranth grain is a crop of moderate importance in the Himalaya. It was one of the staple foodstuffs of the Incas, and it is known as kiwicha in the Andes today. It was also used by the ancient Aztecs, who called it huautli, and other Native America peoples in Mexico to prepare ritual drinks and foods. To this day, amaranth grains are toasted much like popcorn and mixed with honey or molasses to make a treat called alegría (literally "joy" in Spanish).
Amaranth was used in several Aztec ceremonies, where images of their gods (notably Huitzilopochtli) were made with amaranth mixed with honey. The images were cut to be eaten by the people. This looked like the Christian communion to the Roman Catholic priests, so the cultivation of the grain was forbidden for centuries.
Because of its importance as a symbol of indigenous culture, and because it is very palatable, easy to cook, and its protein particularly well suited to human nutritional needs, interest in grain amaranth (especially A. cruentus and A. hypochondriacus) was revived in the 1970s. It was recovered in Mexico from wild varieties and is now commercially cultivated. It is a popular snack sold in Mexico City and other parts of Mexico, sometimes mixed with chocolate or puffed rice, and its use has spread to Europe and other parts of North America. Amaranth and quinoa are called pseudograins because of their flavor and cooking similarities to grains. These are dicot plant seeds, and both contain exceptionally complete protein for plant sources. Besides protein, amaranth grain provides a good source of dietary fiber and dietary minerals such as iron, magnesium, phosphorus, copper, and especially manganese.
## Vegetables
Amaranth species are cultivated and consumed as a leaf vegetable in many parts of the world. There are 4 species of Amaranthus documented as cultivated vegetables in eastern Asia: Amaranthus cruentus, Amaranthus blitum, Amaranthus dubius, and Amaranthus tricolor.
In Indonesia and Malaysia, leaf amaranth is called bayam, while the Tagalogs in the Philippines call the plant kulitis. In Andhra Pradesh, India, this leaf is added in preparation of a popular dal called thotakura pappu. In China, the leaves and stems are used as a stir-fry vegetable and called yin choi (苋菜; pinyin: xiàncài; and variations on this transliteration in various dialects). In Congo it is known as lenga lenga or biteku teku.
In the Caribbean the leaves are called callaloo and are sometimes used in a soup called pepperpot soup.
In East Africa Amaranth leaf is known in Swahili as mchicha ("a vegetable for all"). It is sometimes recommended by some doctors for people having low red blood cell count.
In West Africa, Nigeria, it is known in Yoruba as efo tete or arowo jeja ("we have money left over for fish"). It is a common vegetable, and it goes with all Nigerian carbohydrate dishes.
## Dyes
The flowers of the 'Hopi Red Dye' amaranth were used by the Hopi Amerindians as the source of a deep red dye. There is also a synthetic dye that has been named "amaranth" for its similarity in color to the natural amaranth pigments known as betalains. This synthetic dye is also known as Red No. 2 in North America and E123 in the European Union.
## Ornamentals
The genus also contains several well-known ornamental plants, such as A. caudatus (love-lies-bleeding), a native of India and a vigorous, hardy annual with dark purplish flowers crowded in handsome drooping spikes. Another Indian annual, A. hypochondriacus (prince's feather), has deeply-veined lance-shaped leaves, purple on the under face, and deep crimson flowers densely packed on erect spikes.
Amaranths are recorded as food plants for some Lepidoptera (butterfly and moth) species including the Nutmeg and various case-bearers of the genus Coleophora: C. amaranthella, C. enchorda (feeds exclusively on Amaranthus), C. immortalis (feeds exclusively on Amaranthus), C. lineapulvella and C. versurella (recorded on A. spinosus).
# Nutritional value
Amaranth greens, also called Chinese spinach, hinn choy or yin tsoi (Template:Zh-stp), callaloo, thotakura (telugu) , tampala, or quelite, are a common leaf vegetable throughout the tropics and in many warm temperate regions. It is very popular in Andhra Pradesh. They are a very good source of vitamins including vitamin A, vitamin B6, vitamin C, riboflavin, and folate, and dietary minerals including calcium, iron, magnesium, phosphorus, potassium, zinc, copper, and manganese. Because of its valuable nutrition, some farmers grow amaranth today. However their moderately high content of oxalic acid inhibits the absorption of calcium and zinc, and also means that they should be avoided or eaten in moderation by people with kidney disorders, gout, or rheumatoid arthritis. Reheating cooked amaranth greens is often discouraged, particularly for consumption by small children, as the nitrates in the leaves can be converted to nitrites, similarly to spinach.
Amaranth seeds, like buckwheat and quinoa, contain protein that is unusually complete for plant sources. Most fruits and vegetables do not contain a complete set of amino acids, and thus different sources of protein must be used.
Several studies have shown that like oats, amaranth seed or oil may be of benefit for those with hypertension and cardiovascular disease; regular consumption reduces blood pressure and cholesterol levels, while improving antioxidant status and some immune parameters. While the active ingredient in oats appears to be water soluble fiber, amaranth appears to lower cholesterol via its content of plant stanols and squalene.
# Amaranth as a weed
Not all amaranth plants are cultivated. Most of the species from Amaranthus are summer annual weeds and are commonly referred to as pigweeds. These species have an extended period of germination, rapid growth, and high rates of seed production and have been causing farmers problems since the mid-1990’s. This is partially due to the reduction in tillage, reduction in herbicidal use and the evolution of herbicidal resistance in several species where herbicides have been applied more often. The following 9 species of Amaranthus are considered invasive and noxious weeds in the U.S and Canada: A. albus, A. blitoides, A. hybridus, A. palmeri, A. powellii, A. retroflexus, A. spinosus, A. tuberculatus, and A. viridis.
A new strain of the Palmer amaranth has appeared which is Glyphosate-resistant and as a result cannot be killed by the widely used Roundup herbicide. Also, this hardy plant can survive in tough conditions. This could be of particular concern to cotton farmers using Roundup Ready cotton. The species, Amaranthus palmeri (Palmer amaranth), causes the greatest reduction in soybean yields and has the potential to reduce yields by 17-68% in field experiments. Palmer amaranth is among the “top five most troublesome weeds” in the southeast and has already evolved resistances to dinitroanilines and acetolactate synthase inhibitors. This makes the proper identification of Amaranthus species at the seedling stage essential for agriculturalists. Proper herbicide treatment needs to be applied before the species successfully colonizes in the crop field and causes significant yield reductions.
Anecdotal reports indicate that some people are allergic to amaranth.
# Myth, legend and poetry
Amaranth, or Amarant (from the Greek amarantos, unwithering), a name chiefly used in poetry, and applied to Amaranth and other plants which, from not soon fading, typified immortality.
Aesop's Fables (6th century BC) compares the Rose to the Amaranth to illustrate the difference in fleeting and everlasting beauty.
Thus, in John Milton's Paradise Lost (1667), iii. 353:
Samuel Taylor Coleridge, in Work without Hope (1825), also references the herb, likely referencing Milton's earlier work. (ll 7-10 excerpted):
The original spelling is amarant; the more common spelling amaranth seems to have come from a folk etymology assuming that the final syllable derives from the Greek word anthos ("flower"), common in botanical names.
In ancient Greece the amaranth (also called chrysanthemum and helichrysum) was sacred to Ephesian Artemis. It was supposed to have special healing properties, and as a symbol of
immortality was used to decorate images of the gods and tombs. In legend, Amarynthus (a form of Amarantus) was a hunter of Artemis and king of Euboea; in a village of Amarynthus, of which he was the eponymous hero, there was a famous temple of Artemis Amarynthia or Amarysia (Strabo x. 448; Pausan. i. 31, p. 5). It was also widely used by the Chinese for its healing chemicals, curing illnesses such as infections, rashes, and migraines. The "Amarantos" is the name of a several-century-old popular Greek folk song:
Finnish symphonic metal band Nightwish featured a song titled Amaranth on their 2007 album Dark Passion Play.
The Swedish doom/gothic band Draconian have released a song called The Amaranth, where the plant is used as a symbol for the dark side of Venus.
Orson Scott Card's novel Speaker for the Dead features a plant called amaranth native to the planet Lusitania, where the majority of the story takes place.
In Vampire: The Masquerade lore, an amaranth placed on the bed of a vampire was the warning of Diablerie soon to come. The act of Diablerie was also referred to as "Amaranth".
Enya is referring to the everlasting amaranth in her song Amarantine. | Amaranth
Amaranthus, collectively known as amaranth or pigweed, is a cosmopolitan genus of herbs. Approximately 60 species are presently recognised, with inflorescences and foliage ranging from purple and red to gold. Members of this genus share many characteristics and uses with members of the closely related genus Celosia.
Although several species are often considered weeds, people around the world value amaranths as leaf vegetables, cereals and ornamentals.
The word comes from the Greek amarantos (Αμάρανθος or Αμάραντος) the "one that does not wither," or the never-fading (flower).
# Systematics
Amaranthus shows a wide variety of morphological diversity among and even within certain species. Although the family (Amaranthaceae) is distinctive, the genus has few distinguishing characters among the 70 species included.[1] This complicates taxonomy and Amaranthus has generally been considered among systematists as a “difficult” genus.[2]
Formerly, Sauer (1955) classified the genus into 2 sub-genera, differentiating only between monoecious and dioecious species: Acnida (L.) Aellen ex K.R. Robertson and Amaranthus. [2] Although this classification was widely accepted, further infrageneric classification was (and still is) needed to differentiate this widely diverse group.
Currently, Amaranthus includes 3 recognized sub-genera and 70 species, although species numbers are questionable due to hybridization and species concepts.[3] Infrageneric classification focuses on inflorescence, flower characters and whether a species is monoecious/dioecious, as in the Sauer (1955) suggested classification.[1] A modified infrageneric classification of Amaranthus was published by Mosyakin & Robertson (1996) and includes 3 subgenera: Acnida, Amaranthus and Albersia. The taxonomy is further differentiated by sections within each of the sub-genera.[4]
In some cultures it was known as a mythical flower that never fades.
# Uses
## Grain amaranth
Several species are raised for amaranth grain in Asia and the Americas. Ancient amaranth grains still used to this day include the 3 species, Amaranthus caudatus, Amaranthus cruentus, and Amaranthus hypochondriacus.[5] Although amaranth was (and still is) cultivated on a small-scale in parts of Mexico, Guatemala, Peru, India, and Nepal, there is potential for further cultivation in the U.S and tropical countries and is often referred to as "the crop of the future."[6] It has been proposed as an inexpensive native crop that could be cultivated by indigenous people in rural areas for several reasons: 1) easily harvested, 2) produces a lot of fruits (and thus seeds) which are used as grain, 3) highly tolerant of arid environments which are typical of most subtropical and some tropical regions, and 4) large amounts of protein and essential amino acids, such as lysine.[7] Due to its weedy life history, amaranth grains grow very rapidly and their large seedheads can weigh up to 1 kilogram and contain a half-million seeds.[8] Amaranthus species are reported to have a 30% higher protein value than other cereals, such as rice, wheat flour, oats and rye.[9]
Amaranth grain is a crop of moderate importance in the Himalaya. It was one of the staple foodstuffs of the Incas, and it is known as kiwicha in the Andes today. It was also used by the ancient Aztecs, who called it huautli, and other Native America peoples in Mexico to prepare ritual drinks and foods. To this day, amaranth grains are toasted much like popcorn and mixed with honey or molasses to make a treat called alegría (literally "joy" in Spanish).
Amaranth was used in several Aztec ceremonies, where images of their gods (notably Huitzilopochtli) were made with amaranth mixed with honey. The images were cut to be eaten by the people. This looked like the Christian communion to the Roman Catholic priests, so the cultivation of the grain was forbidden for centuries.
Because of its importance as a symbol of indigenous culture, and because it is very palatable, easy to cook, and its protein particularly well suited to human nutritional needs, interest in grain amaranth (especially A. cruentus and A. hypochondriacus) was revived in the 1970s. It was recovered in Mexico from wild varieties and is now commercially cultivated. It is a popular snack sold in Mexico City and other parts of Mexico, sometimes mixed with chocolate or puffed rice, and its use has spread to Europe and other parts of North America. Amaranth and quinoa are called pseudograins because of their flavor and cooking similarities to grains. These are dicot plant seeds, and both contain exceptionally complete protein for plant sources. Besides protein, amaranth grain provides a good source of dietary fiber and dietary minerals such as iron, magnesium, phosphorus, copper, and especially manganese.
## Vegetables
Amaranth species are cultivated and consumed as a leaf vegetable in many parts of the world. There are 4 species of Amaranthus documented as cultivated vegetables in eastern Asia: Amaranthus cruentus, Amaranthus blitum, Amaranthus dubius, and Amaranthus tricolor.[10]
In Indonesia and Malaysia, leaf amaranth is called bayam, while the Tagalogs in the Philippines call the plant kulitis. In Andhra Pradesh, India, this leaf is added in preparation of a popular dal called thotakura pappu. In China, the leaves and stems are used as a stir-fry vegetable and called yin choi (苋菜; pinyin: xiàncài; and variations on this transliteration in various dialects). In Congo it is known as lenga lenga or biteku teku.[11]
In the Caribbean the leaves are called callaloo and are sometimes used in a soup called pepperpot soup.
In East Africa Amaranth leaf is known in Swahili as mchicha ("a vegetable for all"). It is sometimes recommended by some doctors for people having low red blood cell count.
In West Africa, Nigeria, it is known in Yoruba as efo tete or arowo jeja ("we have money left over for fish"). It is a common vegetable, and it goes with all Nigerian carbohydrate dishes.
## Dyes
The flowers of the 'Hopi Red Dye' amaranth were used by the Hopi Amerindians as the source of a deep red dye. There is also a synthetic dye that has been named "amaranth" for its similarity in color to the natural amaranth pigments known as betalains. This synthetic dye is also known as Red No. 2 in North America and E123 in the European Union.[12]
## Ornamentals
The genus also contains several well-known ornamental plants, such as A. caudatus (love-lies-bleeding), a native of India and a vigorous, hardy annual with dark purplish flowers crowded in handsome drooping spikes. Another Indian annual, A. hypochondriacus (prince's feather), has deeply-veined lance-shaped leaves, purple on the under face, and deep crimson flowers densely packed on erect spikes.
Amaranths are recorded as food plants for some Lepidoptera (butterfly and moth) species including the Nutmeg and various case-bearers of the genus Coleophora: C. amaranthella, C. enchorda (feeds exclusively on Amaranthus), C. immortalis (feeds exclusively on Amaranthus), C. lineapulvella and C. versurella (recorded on A. spinosus).
# Nutritional value
Amaranth greens, also called Chinese spinach, hinn choy or yin tsoi (Template:Zh-stp), callaloo, thotakura (telugu) , tampala, or quelite, are a common leaf vegetable throughout the tropics and in many warm temperate regions. It is very popular in Andhra Pradesh. They are a very good source of vitamins including vitamin A, vitamin B6, vitamin C, riboflavin, and folate, and dietary minerals including calcium, iron, magnesium, phosphorus, potassium, zinc, copper, and manganese. Because of its valuable nutrition, some farmers grow amaranth today. However their moderately high content of oxalic acid inhibits the absorption of calcium and zinc, and also means that they should be avoided or eaten in moderation by people with kidney disorders, gout, or rheumatoid arthritis.[citation needed] Reheating cooked amaranth greens is often discouraged, particularly for consumption by small children, as the nitrates in the leaves can be converted to nitrites, similarly to spinach.[citation needed]
Amaranth seeds, like buckwheat and quinoa, contain protein that is unusually complete for plant sources.[13] Most fruits and vegetables do not contain a complete set of amino acids, and thus different sources of protein must be used.
Several studies have shown that like oats, amaranth seed or oil may be of benefit for those with hypertension and cardiovascular disease; regular consumption reduces blood pressure and cholesterol levels, while improving antioxidant status and some immune parameters.[14][15][16] While the active ingredient in oats appears to be water soluble fiber, amaranth appears to lower cholesterol via its content of plant stanols and squalene.
# Amaranth as a weed
Not all amaranth plants are cultivated. Most of the species from Amaranthus are summer annual weeds and are commonly referred to as pigweeds.[17] These species have an extended period of germination, rapid growth, and high rates of seed production[17] and have been causing farmers problems since the mid-1990’s. This is partially due to the reduction in tillage, reduction in herbicidal use and the evolution of herbicidal resistance in several species where herbicides have been applied more often.[18] The following 9 species of Amaranthus are considered invasive and noxious weeds in the U.S and Canada: A. albus, A. blitoides, A. hybridus, A. palmeri, A. powellii, A. retroflexus, A. spinosus, A. tuberculatus, and A. viridis.[19]
A new strain of the Palmer amaranth has appeared which is Glyphosate-resistant and as a result cannot be killed by the widely used Roundup herbicide. Also, this hardy plant can survive in tough conditions. This could be of particular concern to cotton farmers using Roundup Ready cotton.[3] The species, Amaranthus palmeri (Palmer amaranth), causes the greatest reduction in soybean yields and has the potential to reduce yields by 17-68% in field experiments.[17] Palmer amaranth is among the “top five most troublesome weeds” in the southeast and has already evolved resistances to dinitroanilines and acetolactate synthase inhibitors.[20] This makes the proper identification of Amaranthus species at the seedling stage essential for agriculturalists. Proper herbicide treatment needs to be applied before the species successfully colonizes in the crop field and causes significant yield reductions.
Anecdotal reports indicate that some people are allergic to amaranth.[citation needed]
# Myth, legend and poetry
Amaranth, or Amarant (from the Greek amarantos, unwithering), a name chiefly used in poetry, and applied to Amaranth and other plants which, from not soon fading, typified immortality.
Aesop's Fables (6th century BC) compares the Rose to the Amaranth to illustrate the difference in fleeting and everlasting beauty.
Thus, in John Milton's Paradise Lost (1667), iii. 353:
Samuel Taylor Coleridge, in Work without Hope (1825), also references the herb, likely referencing Milton's earlier work. (ll 7-10 excerpted):
The original spelling is amarant; the more common spelling amaranth seems to have come from a folk etymology assuming that the final syllable derives from the Greek word anthos ("flower"), common in botanical names.
In ancient Greece the amaranth (also called chrysanthemum and helichrysum) was sacred to Ephesian Artemis. It was supposed to have special healing properties, and as a symbol of
immortality was used to decorate images of the gods and tombs. In legend, Amarynthus (a form of Amarantus) was a hunter of Artemis and king of Euboea; in a village of Amarynthus, of which he was the eponymous hero, there was a famous temple of Artemis Amarynthia or Amarysia (Strabo x. 448; Pausan. i. 31, p. 5). It was also widely used by the Chinese for its healing chemicals, curing illnesses such as infections, rashes, and migraines. The "Amarantos" is the name of a several-century-old popular Greek folk song:
Finnish symphonic metal band Nightwish featured a song titled Amaranth on their 2007 album Dark Passion Play.
The Swedish doom/gothic band Draconian have released a song called The Amaranth, where the plant is used as a symbol for the dark side of Venus.
Orson Scott Card's novel Speaker for the Dead features a plant called amaranth native to the planet Lusitania, where the majority of the story takes place.
In Vampire: The Masquerade lore, an amaranth placed on the bed of a vampire was the warning of Diablerie soon to come. The act of Diablerie was also referred to as "Amaranth".
Enya is referring to the everlasting amaranth in her song Amarantine. | https://www.wikidoc.org/index.php/Amaranth | |
df63592bdd94792e1edbffa39ec4d02b7c7e9dd3 | wikidoc | Amatoxin | Amatoxin
Amatoxins are a subgroup of toxins found in Amanita phalloides and several other members of the genus Amanita, as well as some Conocybe, Galerina and Lepiota mushroom species.
Their swift intestinal absorption coupled with their thermostability explains why their toxic effects occur in a relative short period of time. The most severe effects are toxic hepatitis with centrolobular necrosis and hepatic steatosis, as well as acute tubulointerstitial nephropathy, which altogether induce a severe hepatorenal syndrome (with a potential fatal outcome).
The estimated minimum lethal dose is 0.1 mg/kg or 7 mg of toxin in adults. There are eight amatoxins:
- alpha-amanitin
- beta-amanitin
- gamma-amanitin
- epsilon-amanitin
- amanullin
- amanullinic acid
- proamanullin
da:Amatoxiner
it:Amatossine
fi:Amatoksiini | Amatoxin
Amatoxins are a subgroup of toxins found in Amanita phalloides and several other members of the genus Amanita, as well as some Conocybe, Galerina and Lepiota mushroom species.
Their swift intestinal absorption coupled with their thermostability explains why their toxic effects occur in a relative short period of time. The most severe effects are toxic hepatitis with centrolobular necrosis and hepatic steatosis, as well as acute tubulointerstitial nephropathy, which altogether induce a severe hepatorenal syndrome (with a potential fatal outcome).
The estimated minimum lethal dose is 0.1 mg/kg or 7 mg of toxin in adults. There are eight amatoxins:
- alpha-amanitin
- beta-amanitin
- gamma-amanitin
- epsilon-amanitin
- amanullin
- amanullinic acid
- proamanullin
da:Amatoxiner
it:Amatossine
fi:Amatoksiini
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Amatoxin | |
49661842b71b359e6428e4843889dc20a16fc250 | wikidoc | Ambazone | Ambazone
# Overview
Ambazone is an oral antiseptic.
Ambazon was patented in 1957 by Bayer under the trade name Iversal, and briefly used in Germany. It is still used in Russia, countries of the former Soviet Union and Romania. It has not been approved by the United States Food and Drug Administration (FDA).
# Synthesis
Ambazone can be obtained in a two step synthetic method, reacting 1,4-Benzochinone with Aminoguanidine and Thiosemicarbazide.,
Obtaining a pharmacetical grade material is difficult due to high amounts of byproducts, synthetic intermediates and decomposition products.
# Applications
Bacteriostatic action on hemolytic streptococcus, streptococcus pneumoniae and viridans streptococcus.
# Physical properties
Through experimental testing ambazone has shown antiseptic properties, along with anti-tumor properties. Ambazone has the following physical characteristics.
Ambazone is prepared by way of solid based crystallization or grinding.
# Mode of action
The mode of action for ambazone has been studied extensively and ambazone has been shown to react via different methods. Ambazone shows low mutagenic activity and no cardiovascular, CNS, metabolic, or gastrointestinal side-effects with I.V. doses up to 10-5 mol/kg and oral doses up to 10-3 mol/kg. As stated before ambazone can be administered via oral or I.V. administration, but the problem with oral administration is that one experimental study shows there is only a 35-50% absorption while another study shows 40% in the intestines; These results would tend to lead the reader to think that ambazone would not be the best choice for treatment, because with such a low absorbance, there is going to have to be a greater concentration ingested to gain a positive effect from the drug. The problem with a greater concentration is that ambazone has a half-life of 6–7 hours. It was stated above that ambazone possess no CNS side-effects and the reason we know this is, due to the fact, that it will not cross the blood brain barrier. Although this is the body’s way of protecting unwanted substances from attacking the brain, this also limits the treatment of brain tumors with ambazone.
# Therapeutic uses
The therapeutic properties of ambazone were studied in lab rats and the therapeutic dose was determined to be 60–125 mg/kg of body weight. As stated above, ambazone possesses anti-septic properties shown by its increased activity against gram-positive cocci. Along with anti-septic properties, ambazone has also shown its ability to fight forms of leukemia in lab rats. When administered orally the results showed prolongation of life expectancy and curing of L1210 and P388 leukemia in lab rats. Scientist used different methods to determine the results, such as; mean survival time (MST), percent increase of life span, survival rates, percent change in body weights and number of peritoneal cells. The results gathered show tremendous strides towards leukemia treatment. Although we can see positive results, one might wonder, “Are there side effects?” The results show different answers depending on the test performed. When testing ambazone via AMES with no metabolic activation we find there are no mutagenic or carcinogenic properties. When the same test is performed with metabolic activation or when the C-Test is performed we do see the potential for mutagenicity. The results show two different paths and until further testing has been performed we cannot determine if the good outweighs the bad when it comes to using ambazone for treatment. | Ambazone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ambazone is an oral antiseptic.
Ambazon was patented in 1957 by Bayer under the trade name Iversal, and briefly used in Germany. It is still used in Russia, countries of the former Soviet Union and Romania. It has not been approved by the United States Food and Drug Administration (FDA).
# Synthesis
Ambazone can be obtained in a two step synthetic method, reacting 1,4-Benzochinone with Aminoguanidine and Thiosemicarbazide.,[2][3]
Obtaining a pharmacetical grade material is difficult due to high amounts of byproducts, synthetic intermediates and decomposition products.[4]
# Applications
Bacteriostatic action on hemolytic streptococcus, streptococcus pneumoniae and viridans streptococcus.
# Physical properties
Through experimental testing ambazone has shown antiseptic properties, along with anti-tumor properties. Ambazone has the following physical characteristics.
Ambazone is prepared by way of solid based crystallization or grinding.
# Mode of action
The mode of action for ambazone has been studied extensively and ambazone has been shown to react via different methods. Ambazone shows low mutagenic activity and no cardiovascular, CNS, metabolic, or gastrointestinal side-effects with I.V. doses up to 10-5 mol/kg and oral doses up to 10-3 mol/kg. As stated before ambazone can be administered via oral or I.V. administration, but the problem with oral administration is that one experimental study shows there is only a 35-50% absorption while another study shows 40% in the intestines; These results would tend to lead the reader to think that ambazone would not be the best choice for treatment, because with such a low absorbance, there is going to have to be a greater concentration ingested to gain a positive effect from the drug. The problem with a greater concentration is that ambazone has a half-life of 6–7 hours. It was stated above that ambazone possess no CNS side-effects and the reason we know this is, due to the fact, that it will not cross the blood brain barrier. Although this is the body’s way of protecting unwanted substances from attacking the brain, this also limits the treatment of brain tumors with ambazone.
# Therapeutic uses
The therapeutic properties of ambazone were studied in lab rats and the therapeutic dose was determined to be 60–125 mg/kg of body weight. As stated above, ambazone possesses anti-septic properties shown by its increased activity against gram-positive cocci. Along with anti-septic properties, ambazone has also shown its ability to fight forms of leukemia in lab rats. When administered orally the results showed prolongation of life expectancy and curing of L1210 and P388 leukemia in lab rats. Scientist used different methods to determine the results, such as; mean survival time (MST), percent increase of life span, survival rates, percent change in body weights and number of peritoneal cells. The results gathered show tremendous strides towards leukemia treatment. Although we can see positive results, one might wonder, “Are there side effects?” The results show different answers depending on the test performed. When testing ambazone via AMES with no metabolic activation we find there are no mutagenic or carcinogenic properties. When the same test is performed with metabolic activation or when the C-Test is performed we do see the potential for mutagenicity. The results show two different paths and until further testing has been performed we cannot determine if the good outweighs the bad when it comes to using ambazone for treatment. | https://www.wikidoc.org/index.php/Ambazone | |
2007b98582d352d5f8b903e10924938d5091278d | wikidoc | Ambroxol | Ambroxol
# Overview
Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. It is the active ingredient of Mucosolvan, Mucobrox, Mucol, Lasolvan, Mucoangin, Surbronc, Ambolar, and Lysopain. The substance is a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract, which play an important role in the body’s natural defence mechanisms. It stimulates synthesis and release of surfactant by type II pneumocytes. Surfactant acts as an anti-glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport and in providing protection against infection and irritating agents. Ambroxol is often administered as an active ingredient in cough syrup.
Ambroxol is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply".
There are many different formulations developed since the first marketing authorisation in 1978. Ambroxol is available as syrup, tablets, pastilles, dry powder sachets, inhalation solution, drops and ampules as well as effervescent tablets.
Ambroxol also provides pain relief in acute sore throat. Pain in sore throat is the hallmark of acute pharyngitis. Sore throat is usually caused by a viral infection. The infection is self limited and the patient recovers normally after a few days. What is most bothering for the patient is the continuous pain in the throat maximized when the patient is swallowing. The main goal of treatment is thus to reduce pain. The main property of Ambroxol for treating sore throat is the local anaesthetic effect, described first in the late 1970s, but explained and confirmed in more recent work.
Ambroxol is a potent inhibitor of the neuronal Na+ channels. This property led to the development of a lozenge containing 20 mg of ambroxol. Many state-of-the-art clinical studies have demonstrated the efficacy of Ambroxol in relieving pain in acute sore throat, with a rapid onset of action, with its effect lasting at least three hours. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.
Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase. Because of this it may be a useful therapeutic agent for both Gaucher disease and Parkinson's disease.
# Side effects
Field tests to date have not uncovered specific contraindications of Ambroxol. However, caution is suggested for patients with gastric ulceration, and usage during the first trimester of pregnancy is not recommended.
# Synthesis | Ambroxol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. It is the active ingredient of Mucosolvan, Mucobrox, Mucol, Lasolvan, Mucoangin, Surbronc, Ambolar, and Lysopain. The substance is a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract, which play an important role in the body’s natural defence mechanisms. It stimulates synthesis and release of surfactant by type II pneumocytes. Surfactant acts as an anti-glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport and in providing protection against infection and irritating agents.[1][2] Ambroxol is often administered as an active ingredient in cough syrup.
Ambroxol is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply".[3]
There are many different formulations developed since the first marketing authorisation in 1978. Ambroxol is available as syrup, tablets, pastilles, dry powder sachets, inhalation solution, drops and ampules as well as effervescent tablets.
Ambroxol also provides pain relief in acute sore throat. Pain in sore throat is the hallmark of acute pharyngitis.[4] Sore throat is usually caused by a viral infection. The infection is self limited and the patient recovers normally after a few days. What is most bothering for the patient is the continuous pain in the throat maximized when the patient is swallowing. The main goal of treatment is thus to reduce pain. The main property of Ambroxol for treating sore throat is the local anaesthetic effect, described first in the late 1970s,[5][6] but explained and confirmed in more recent work.
Ambroxol is a potent inhibitor of the neuronal Na+ channels.[7] This property led to the development of a lozenge containing 20 mg of ambroxol. Many state-of-the-art clinical studies[4] have demonstrated the efficacy of Ambroxol in relieving pain in acute sore throat, with a rapid onset of action, with its effect lasting at least three hours. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.
Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase. Because of this it may be a useful therapeutic agent for both Gaucher disease and Parkinson's disease.[8]
# Side effects
Field tests to date have not uncovered specific contraindications of Ambroxol. However, caution is suggested for patients with gastric ulceration, and usage during the first trimester of pregnancy is not recommended.[9]
# Synthesis | https://www.wikidoc.org/index.php/Ambroxol | |
6159a37ca731591b4746abe0d0f2a817492fc226 | wikidoc | Hookworm | Hookworm
# Overview
The hookworm is a parasitic nematode worm that lives in the small intestine of its host, which may be a mammal such as a dog, cat, or human. Two species of hookworms commonly infect humans, Ancylostoma duodenale and Necator americanus. Necator americanus predominates in the Americas, Sub-Saharan Africa, Southeast Asia, China and Indonesia, while A. duodenale predominates in the Middle East, North Africa, India and (formerly) in southern Europe. Hookworms are thought to infect 800 million people worldwide. The A. braziliense and A. tubaeforme species infect cats, while A. caninum infects dogs. Uncinaria stenocephala infects both dogs and cats.
Hookworms are much smaller than the large roundworm, Ascaris lumbricoides, and the complications of tissue migration and mechanical obstruction so frequently observed with roundworm infestation are less frequent in hookworm infestation. The most significant risk of hookworm infection is anemia, secondary to loss of iron (and protein) in the gut. The worms suck blood voraciously and damage the mucosa. However, the blood loss in the stools is occult blood loss (not visibly apparent).
Ankylostomiasis, alternatively spelled anchylostomiasis and also called helminthiasis, "miners' anaemia", "tunnel disease", "brickmaker's anaemia", "Egyptian chlorosis" and in Germany Wurmkrankheit, is the disease caused by hookworms. It is caused when hookworms, present in large numbers, produce an iron deficiency anemia by voraciously sucking blood from the host's intestinal walls. The name is derived from Greek ancylo "crooked, bent" and stoma "mouth."
Hookworm is commonly called "larva migratoria" in Spanish and "bicho do pé" in Portuguese.
Hookworm is a leading cause of maternal and child morbidity in the developing countries of the tropics and subtropics. In susceptible children hookworms cause intellectual, cognitive and growth retardation, intrauterine growth retardation, prematurity, and low birth weight among newborns born to infected mothers. Hookworm infection is rarely fatal, but anemia can be significant in the heavily infected individual.
# History
The symptoms now attributed to hookworm appear in papyrus papers of ancient Egypt (c. 1600 B.C.), described as a derangement characterized by anemia. Avicenna, a Persian physician of the 11th century, discovered the worm in several of his patients and related it to their disease. In later times, the condition was noticeably prevalent in the mining industry in England, France, Germany, Belgium, North Queensland and elsewhere.
Italian physician Angelo Dubini was the modern-day discoverer of the worm in 1838 after an autopsy of a peasant woman. Dubini published details in 1843 and identified the species as A. duodenale. Working in the Egyptian medical system in 1852 German physician Theodor Bilharz, drawing upon the work of colleague Wilhelm Griesinger, found these worms during autopsies and went a step further in linking them to local endemic occurrences of chlorosis, which would probably be called iron deficiency anemia today.
A breakthrough came 25 years later following a diarrhea and anemia epidemic that took place among Italian workmen employed on the Gotthard Rail Tunnel. In an 1880 paper, physicians Camillo Bozzolo, Edoardo Perroncito, and Luigi Pagliani correctly hypothesized that hookworm was linked to the fact that workers had to defecate inside the 15 km tunnel, and that many wore worn-out shoes. In 1897, it was established that the skin was the principal avenue of infection and the biological life cycle of the hookworm was clarified. In 1899, American zoologist Charles Wardell Stiles brought this evidence to bear on health issues in the southeast United States, identifying "progressive pernicious anemia" seen in the southern United States was caused by A. duodenale and he also identified the other important hookworm species: U. Necator. Testing in the 1900s revealed very heavy infestations in schoolage children.
On October 26, 1909 the Rockefeller Sanitary Commission for the Eradication of Hookworm Disease was organized as a result of a gift of US$1 million from John D. Rockefeller, Sr. Though humanitarian reasons are cited, some speculateTemplate:Weasel-inline that the motive was to open markets in the Appalachian region by creating more disposable income. Nevertheless the five-year program was a remarkable success and a great contribution to United States public health, instilling public education, medication, field work and modern government health departments in eleven southern states. The hookworm exhibit was a prominent part of the 1910 Mississippi state fair. The program nearly eradicated hookworm. The program would flourish afterwards with new funding as the Rockefeller Foundation International Health Division.
In the 1920s, hookworm eradication reached the Caribbean and Latin America, where great mortality was reported among blacks in the West Indies towards the end of the 18th century, as well as through descriptions sent from Brazil and various other tropical and sub-tropical regions.
Early treatment was with thymol to kill the worms, followed by epsom salt to clear the body of the worms. Later on, tetrachloroethylene was the leading method. It was not until later in the mid-20th century when new organic drug compounds were developed.
# Pathology
Most individuals with hookworm infection are asymptomatic (without symptoms). Generally, very high loads of the parasite coupled with poor nutrition (inadequate intake of protein and iron) eventually lead to anemia.
The disease was linked to nematode worms (Ankylostoma duodenalis) from one-third to half an inch long in the intestine chiefly through the labours of Theodor Bilharz and Griesinger in Egypt (1854).
The symptoms can be linked to inflammation in the gut stimulated by feeding hookworms, such as nausea, abdominal pain and intermittent diarrhea, and to progressive anemia in prolonged disease: capricious appetite, pica (or dirt-eating), obstinate constipation followed by diarrhea, palpitations, thready pulse, coldness of the skin, pallor of the mucous membranes, fatigue and weakness, shortness of breath and in cases running a fatal course, dysentery, haemorrhages and oedema.
Blood tests in early infection often show a rise in numbers of eosinophils, a type of white blood cell that is preferentially stimulated by worm infections in tissues (large numbers of eosinophils are also present in the local inflammatory response). Falling blood hemoglobin levels will be seen in cases of prolonged infection with anemia.
In contrast to most intestinal helminthiases where the heaviest parasitic loads tend to occur in children, hookworm prevalence and intensity can be higher among adult males. The explanation for this is that hookworm infection tends to be occupational, so that plantation workers, coalminers and other groups maintain a high prevalence of infection among themselves by contaminating their work environment. However, in most endemic areas, adult women are the most severely affected by anemia, mainly because they have much higher physiological needs for iron (menstruation, repeated pregnancy), but also because customarily they have access to much poorer food than the men. In some communities, it is also these women who are most heavily exposed occupationally to hookworm, e.g. in rubber plantations, where women do the latex-tapping, working barefoot, and without latrines.
An interesting consequence of this in the case of Ancylostoma duodenale infection is translactational transmission of infection: the skin-invasive larvae of this species do not all immediately pass through the lungs and on into the gut, but spread around the body via the circulation, to become dormant inside muscle fibers. In a pregnant woman, after childbirth some or all of these larvae are stimulated to re-enter the circulation (presumably by sudden hormonal changes), then to pass into the mammary glands, so that the newborn baby can receive a large dose of infective larvae through its mother's milk. This accounts for otherwise inexplicable cases of very heavy, even fatal, hookworm infections in children a month or so of age, in places such as China, India and northern Australia.
(An identical phenomenon is much more commonly seen with Ancylostoma caninum infections in dogs, where the newborn pups can even die of hemorrhaging from their intestines caused by massive numbers of feeding hookworms. This also reflects the close evolutionary link between the human and canine parasites, which probably have a common ancestor dating back to when humans and dogs first started living closely together.)
# Hookworm in therapy
Moderate hookworm infections have been demonstrated to have beneficial effects on hosts suffering from diseases linked to overactive immune systems. This is possibly explained by the hygiene hypothesis. Research at the University of Nottingham conducted in Ethiopia has demonstrated that people with hookworm infections are half as likely to experience asthma or hay fever. It may also help sufferers of multiple sclerosis, Crohn's Disease and diabetes.
Hookworm therapy to treat a number of these diseases is currently in the trial stage at the University. Also, some Westerners have independently infected themselves with hookworms and reported positive results.
# Life cycle
See the image for the biological life cycle of the hookworms where it thrives in warm earth where temperatures are over 18°C. They exist primarily in sandy or loamy soil and cannot live in clay or muck. Rainfall averages must be more than 1000 mm (40 inches) a year. Only if these conditions exist can the eggs hatch.
Infective larvae of Necator americanus can survive at higher temperatures, whereas those of Ancylostoma duodenale are better adapted to cooler climates. Generally, they live for only a few weeks at most under natural conditions, and die almost immediately on exposure to direct sunlight or desiccation.
Once in the host gut, Necator tends to cause a prolonged infection, as some adult worms have been recorded to live for 15 years or more. On the other hand, Ancylostoma adults are shortlived, surviving on average for only about 6 months. However, infection can be prolonged because dormant larvae can be "recruited" sequentially from tissue "stores" (see Pathology, above) over many years, to replace expired adult worms. This can give rise to seasonal fluctuations in infection prevalence and intensity (apart from normal seasonal variations in transmission).
Because it takes 5-7 weeks for adult worms to mature, mate and produce eggs, in the early stages of very heavy infection, acute symptoms might occur without any eggs being detected in the patient's feces. This can make diagnosis very difficult.
# Prevention
The infective larvae develop and survive in an environment of damp dirt, particularly sandy and loamy soil. They cannot survive in clay or muck. The main lines of precaution are those dictated by sanitary science:
- Prevent skin/soil contact: do not walk barefoot
- Do not defecate outside latrines, toilets etc.
- Do not use human excrement or raw sewage as manure/fertilizer in agriculture
- Worm pet dogs — canine and feline hookworms rarely develop to adulthood in humans (Ancylostoma caninum, the common dog hookworm, occasionally develops into an adult to cause eosinophilic enteritis in people), but their invasive larvae can cause an itchy rash called cutaneous larva migrans.
Moxidectin has been released in the United States as part of Advantage Multi™ (imidacloprid + moxidectin) Topical Solution for dogs and cats. It utilizes moxidectin for control and prevention of roundworms, hookworms, heartworms, and whipworms.
In the late 1800s and early 1900s, many Mississippians were plagued by hookworms. They did not have indoor plumbing or proper sanitation facilities. As a result, hookworms, spread by fecal contamination of the environment, were very prevalent (as well as other diseases caused by lack of sanitation).
# Differentiating Hookworm infections from other diseases
The table below summarizes the findings that differentiate Hookworm infections from other nematode infections:
# Diagnosis
There are no specific symptoms or signs of hookworm infection. As mentioned above, they arise from a combination of intestinal inflammation and progressive iron/protein-deficiency anemia. Larval invasion of the skin might give rise to intense, local itching, usually on the foot or lower leg, which can be followed by lesions that look like insect bites, can blister ("ground itch"), and last for a week or more. Coughing, chest pain, wheezing, and fever will sometimes be experienced by people who have been exposed to very large numbers of larvae. Epigastric pains, indigestion, nausea vomiting, constipation, and diarrhea can occur early or in later stages as well, although gastrointestional symptoms tend to improve with time. Signs of advanced severe infection are those of anemia and protein deficiency, including emaciation, cardiac failure and abdominal distension with ascites.
Diagnosis depends on finding characteristic worm eggs on microscopic examination of the stools, although this is not possible in early infection. As the eggs of both Ancylostoma and Necator (and most other hookworm species) are indistinguishable, to identify the genus, they must be cultured in the lab to allow larvae to hatch out. If the fecal sample is left for a day or more under tropical conditions, the larvae will have hatched out, so eggs might no longer be evident. In such a case, it is essential to distinguish hookworms from Strongyloides larvae, as infection with the latter has more serious implications and requires different management. The larvae of the two hookworm species can also be distinguished microscopically, although this would not be done routinely, but usually for research purposes. Adult worms are rarely seen (except via endoscopy, surgery or autopsy), but if found, would allow definitive identification of the species.
# Treatment
The hookworm can be treated with local cryotherapy when it is still in the skin.
Albendazole is effective both in the intestinal stage and during the stage the parasite is still migrating under the skin.
In case of anemia, iron supplementation can cause relief symptoms of iron deficiency anemia. However, as red blood cell levels are restored, shortage of other essentials such as folic acid or vitamin B12 may develop, so this might also be supplemented.
# Quick Facts | Hookworm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The hookworm is a parasitic nematode worm that lives in the small intestine of its host, which may be a mammal such as a dog, cat, or human. Two species of hookworms commonly infect humans, Ancylostoma duodenale and Necator americanus. Necator americanus predominates in the Americas, Sub-Saharan Africa, Southeast Asia, China and Indonesia, while A. duodenale predominates in the Middle East, North Africa, India and (formerly) in southern Europe. Hookworms are thought to infect 800 million people worldwide. The A. braziliense and A. tubaeforme species infect cats, while A. caninum infects dogs. Uncinaria stenocephala infects both dogs and cats.
Hookworms are much smaller than the large roundworm, Ascaris lumbricoides, and the complications of tissue migration and mechanical obstruction so frequently observed with roundworm infestation are less frequent in hookworm infestation. The most significant risk of hookworm infection is anemia, secondary to loss of iron (and protein) in the gut. The worms suck blood voraciously and damage the mucosa. However, the blood loss in the stools is occult blood loss (not visibly apparent).
Ankylostomiasis, alternatively spelled anchylostomiasis and also called helminthiasis, "miners' anaemia", "tunnel disease", "brickmaker's anaemia", "Egyptian chlorosis" and in Germany Wurmkrankheit, is the disease caused by hookworms. It is caused when hookworms, present in large numbers, produce an iron deficiency anemia by voraciously sucking blood from the host's intestinal walls. The name is derived from Greek ancylo "crooked, bent" and stoma "mouth."
Hookworm is commonly called "larva migratoria" in Spanish and "bicho do pé" in Portuguese.
Hookworm is a leading cause of maternal and child morbidity in the developing countries of the tropics and subtropics. In susceptible children hookworms cause intellectual, cognitive and growth retardation, intrauterine growth retardation, prematurity, and low birth weight among newborns born to infected mothers. Hookworm infection is rarely fatal, but anemia can be significant in the heavily infected individual.
# History
The symptoms now attributed to hookworm appear in papyrus papers of ancient Egypt (c. 1600 B.C.), described as a derangement characterized by anemia. Avicenna, a Persian physician of the 11th century, discovered the worm in several of his patients and related it to their disease. In later times, the condition was noticeably prevalent in the mining industry in England, France, Germany, Belgium, North Queensland and elsewhere.
Italian physician Angelo Dubini was the modern-day discoverer of the worm in 1838 after an autopsy of a peasant woman. Dubini published details in 1843 and identified the species as A. duodenale. Working in the Egyptian medical system in 1852 German physician Theodor Bilharz, drawing upon the work of colleague Wilhelm Griesinger, found these worms during autopsies and went a step further in linking them to local endemic occurrences of chlorosis, which would probably be called iron deficiency anemia today.
A breakthrough came 25 years later following a diarrhea and anemia epidemic that took place among Italian workmen employed on the Gotthard Rail Tunnel. In an 1880 paper, physicians Camillo Bozzolo, Edoardo Perroncito, and Luigi Pagliani correctly hypothesized that hookworm was linked to the fact that workers had to defecate inside the 15 km tunnel, and that many wore worn-out shoes. In 1897, it was established that the skin was the principal avenue of infection and the biological life cycle of the hookworm was clarified. In 1899, American zoologist Charles Wardell Stiles brought this evidence to bear on health issues in the southeast United States, identifying "progressive pernicious anemia" seen in the southern United States was caused by A. duodenale and he also identified the other important hookworm species: U. Necator. Testing in the 1900s revealed very heavy infestations in schoolage children.
On October 26, 1909 the Rockefeller Sanitary Commission for the Eradication of Hookworm Disease was organized as a result of a gift of US$1 million from John D. Rockefeller, Sr. Though humanitarian reasons are cited, some speculateTemplate:Weasel-inline that the motive was to open markets in the Appalachian region by creating more disposable income.[citation needed] Nevertheless the five-year program was a remarkable success and a great contribution to United States public health, instilling public education, medication, field work and modern government health departments in eleven southern states. The hookworm exhibit was a prominent part of the 1910 Mississippi state fair. The program nearly eradicated hookworm. The program would flourish afterwards with new funding as the Rockefeller Foundation International Health Division.
In the 1920s, hookworm eradication reached the Caribbean and Latin America, where great mortality was reported among blacks in the West Indies towards the end of the 18th century, as well as through descriptions sent from Brazil and various other tropical and sub-tropical regions.
Early treatment was with thymol to kill the worms, followed by epsom salt to clear the body of the worms. Later on, tetrachloroethylene was the leading method. It was not until later in the mid-20th century when new organic drug compounds were developed.
# Pathology
Most individuals with hookworm infection are asymptomatic (without symptoms). Generally, very high loads of the parasite coupled with poor nutrition (inadequate intake of protein and iron) eventually lead to anemia.
The disease was linked to nematode worms (Ankylostoma duodenalis) from one-third to half an inch long in the intestine chiefly through the labours of Theodor Bilharz and Griesinger in Egypt (1854).
The symptoms can be linked to inflammation in the gut stimulated by feeding hookworms, such as nausea, abdominal pain and intermittent diarrhea, and to progressive anemia in prolonged disease: capricious appetite, pica (or dirt-eating), obstinate constipation followed by diarrhea, palpitations, thready pulse, coldness of the skin, pallor of the mucous membranes, fatigue and weakness, shortness of breath and in cases running a fatal course, dysentery, haemorrhages and oedema.
Blood tests in early infection often show a rise in numbers of eosinophils, a type of white blood cell that is preferentially stimulated by worm infections in tissues (large numbers of eosinophils are also present in the local inflammatory response). Falling blood hemoglobin levels will be seen in cases of prolonged infection with anemia.
In contrast to most intestinal helminthiases where the heaviest parasitic loads tend to occur in children, hookworm prevalence and intensity can be higher among adult males. The explanation for this is that hookworm infection tends to be occupational, so that plantation workers, coalminers and other groups maintain a high prevalence of infection among themselves by contaminating their work environment. However, in most endemic areas, adult women are the most severely affected by anemia, mainly because they have much higher physiological needs for iron (menstruation, repeated pregnancy), but also because customarily they have access to much poorer food than the men. In some communities, it is also these women who are most heavily exposed occupationally to hookworm, e.g. in rubber plantations, where women do the latex-tapping, working barefoot, and without latrines.
An interesting consequence of this in the case of Ancylostoma duodenale infection is translactational transmission of infection: the skin-invasive larvae of this species do not all immediately pass through the lungs and on into the gut, but spread around the body via the circulation, to become dormant inside muscle fibers. In a pregnant woman, after childbirth some or all of these larvae are stimulated to re-enter the circulation (presumably by sudden hormonal changes), then to pass into the mammary glands, so that the newborn baby can receive a large dose of infective larvae through its mother's milk. This accounts for otherwise inexplicable cases of very heavy, even fatal, hookworm infections in children a month or so of age, in places such as China, India and northern Australia.
(An identical phenomenon is much more commonly seen with Ancylostoma caninum infections in dogs, where the newborn pups can even die of hemorrhaging from their intestines caused by massive numbers of feeding hookworms. This also reflects the close evolutionary link between the human and canine parasites, which probably have a common ancestor dating back to when humans and dogs first started living closely together.)
# Hookworm in therapy
Moderate hookworm infections have been demonstrated to have beneficial effects on hosts suffering from diseases linked to overactive immune systems. This is possibly explained by the hygiene hypothesis[citation needed]. Research at the University of Nottingham conducted in Ethiopia has demonstrated that people with hookworm infections are half as likely to experience asthma[1] or hay fever.[2] It may also help sufferers of multiple sclerosis[3], Crohn's Disease[4] and diabetes.[5]
Hookworm therapy to treat a number of these diseases is currently in the trial stage at the University.[5] Also, some Westerners have independently infected themselves with hookworms and reported positive results.[6]
# Life cycle
See the image for the biological life cycle of the hookworms where it thrives in warm earth where temperatures are over 18°C. They exist primarily in sandy or loamy soil and cannot live in clay or muck. Rainfall averages must be more than 1000 mm (40 inches) a year. Only if these conditions exist can the eggs hatch.
Infective larvae of Necator americanus can survive at higher temperatures, whereas those of Ancylostoma duodenale are better adapted to cooler climates. Generally, they live for only a few weeks at most under natural conditions, and die almost immediately on exposure to direct sunlight or desiccation.
Once in the host gut, Necator tends to cause a prolonged infection, as some adult worms have been recorded to live for 15 years or more. On the other hand, Ancylostoma adults are shortlived, surviving on average for only about 6 months. However, infection can be prolonged because dormant larvae can be "recruited" sequentially from tissue "stores" (see Pathology, above) over many years, to replace expired adult worms. This can give rise to seasonal fluctuations in infection prevalence and intensity (apart from normal seasonal variations in transmission).
Because it takes 5-7 weeks for adult worms to mature, mate and produce eggs, in the early stages of very heavy infection, acute symptoms might occur without any eggs being detected in the patient's feces. This can make diagnosis very difficult.
# Prevention
The infective larvae develop and survive in an environment of damp dirt, particularly sandy and loamy soil. They cannot survive in clay or muck. The main lines of precaution are those dictated by sanitary science:
- Prevent skin/soil contact: do not walk barefoot
- Do not defecate outside latrines, toilets etc.
- Do not use human excrement or raw sewage as manure/fertilizer in agriculture
- Worm pet dogs — canine and feline hookworms rarely develop to adulthood in humans (Ancylostoma caninum, the common dog hookworm, occasionally develops into an adult to cause eosinophilic enteritis in people), but their invasive larvae can cause an itchy rash called cutaneous larva migrans.
Moxidectin has been released in the United States as part of Advantage Multi™ (imidacloprid + moxidectin) Topical Solution for dogs and cats. It utilizes moxidectin for control and prevention of roundworms, hookworms, heartworms, and whipworms.
In the late 1800s and early 1900s, many Mississippians were plagued by hookworms. They did not have indoor plumbing or proper sanitation facilities. As a result, hookworms, spread by fecal contamination of the environment, were very prevalent (as well as other diseases caused by lack of sanitation).
# Differentiating Hookworm infections from other diseases
The table below summarizes the findings that differentiate Hookworm infections from other nematode infections:
# Diagnosis
There are no specific symptoms or signs of hookworm infection. As mentioned above, they arise from a combination of intestinal inflammation and progressive iron/protein-deficiency anemia. Larval invasion of the skin might give rise to intense, local itching, usually on the foot or lower leg, which can be followed by lesions that look like insect bites, can blister ("ground itch"), and last for a week or more. Coughing, chest pain, wheezing, and fever will sometimes be experienced by people who have been exposed to very large numbers of larvae. Epigastric pains, indigestion, nausea vomiting, constipation, and diarrhea can occur early or in later stages as well, although gastrointestional symptoms tend to improve with time. Signs of advanced severe infection are those of anemia and protein deficiency, including emaciation, cardiac failure and abdominal distension with ascites.
Diagnosis depends on finding characteristic worm eggs on microscopic examination of the stools, although this is not possible in early infection. As the eggs of both Ancylostoma and Necator (and most other hookworm species) are indistinguishable, to identify the genus, they must be cultured in the lab to allow larvae to hatch out. If the fecal sample is left for a day or more under tropical conditions, the larvae will have hatched out, so eggs might no longer be evident. In such a case, it is essential to distinguish hookworms from Strongyloides larvae, as infection with the latter has more serious implications and requires different management. The larvae of the two hookworm species can also be distinguished microscopically, although this would not be done routinely, but usually for research purposes. Adult worms are rarely seen (except via endoscopy, surgery or autopsy), but if found, would allow definitive identification of the species.
# Treatment
The hookworm can be treated with local cryotherapy when it is still in the skin.
Albendazole is effective both in the intestinal stage and during the stage the parasite is still migrating under the skin.
In case of anemia, iron supplementation can cause relief symptoms of iron deficiency anemia. However, as red blood cell levels are restored, shortage of other essentials such as folic acid or vitamin B12 may develop, so this might also be supplemented.
# Quick Facts | https://www.wikidoc.org/index.php/American_hookworm | |
02888ab7532c2ffd6cc7a85fcae04137e4d18514 | wikidoc | Amidrine | Amidrine
Amidrine, Duradrin or Midrin, is a combination of Acetaminophen, Dichloralphenazone, and Isometheptene used mostly to treat headaches.
# Description
Acetaminophen (paracetamol) is a common over-the-counter pain reliever and fever reducer.
Dichloralphenazone is a mild sedative owing primarily to its hydrolysis product, chloral hydrate. Chloral hydrate, a schedule C-IV controlled substance, is a sedative/hypnotic drug that acts on the central nervous system to produce relaxation and decrease emotional stimuli that influence the perception of pain associated with headache.
Isometheptene is a vasoconstrictor, a drug that causes constriction (narrowing) of cerebral blood vessels.
The pathophysiology of vascular headaches, especially migraine, is thought to be related to dilation of these cerebral blood vessels, so drugs that act to constrict them are used in the treatment of these problems.
# Common Application
This drug is commonly used in the treatment of Migraine headaches and is currently available in the United States and United Kingdom by prescription only. | Amidrine
Amidrine, Duradrin or Midrin, is a combination of Acetaminophen, Dichloralphenazone, and Isometheptene used mostly to treat headaches.
# Description
Acetaminophen (paracetamol) is a common over-the-counter pain reliever and fever reducer.
Dichloralphenazone is a mild sedative owing primarily to its hydrolysis product, chloral hydrate. Chloral hydrate, a schedule C-IV controlled substance, is a sedative/hypnotic drug that acts on the central nervous system to produce relaxation and decrease emotional stimuli that influence the perception of pain associated with headache.
Isometheptene is a vasoconstrictor, a drug that causes constriction (narrowing) of cerebral blood vessels.
The pathophysiology of vascular headaches, especially migraine, is thought to be related to dilation of these cerebral blood vessels, so drugs that act to constrict them are used in the treatment of these problems.
# Common Application
This drug is commonly used in the treatment of Migraine headaches and is currently available in the United States and United Kingdom by prescription only.
Template:Pharma-stub | https://www.wikidoc.org/index.php/Amidrine | |
97ca74a3bb9f244fad3c01f790fbaff64c988019 | wikidoc | Aminorex | Aminorex
Aminorex is an anorectic stimulant drug of the 2-Amino-5-Aryloxazoline class. It is closely related to the popular drug 4-methyl-aminorex. It was disvered in 1960 by McNeil Laboratories, and was quickly found in 1962 to have an appetite suppressant effect in rats. It was introduced as a prescription anorectic in Germany, Switzerland and Austria in 1965 but was soon withdrawn when a number of occurrences of pulmonary hypertension including a number of fatalities were reported. The drug reappeared as a designer analog of 4-methyl-aminorex in the US during the 1990s. It is, in fact, 4 times stronger than 4-methyl-aminorex and the 4-fluoro analog is listed as four times as potent again as an anorectic (in rats), but is unknown outside the laboratory. Aminorex has been shown to have a locomotor stimulant properties lying midway between dextroamphetamine and methamphetamine.
The simple synthetic routes available mean that future outbreaks of abuse of this drug seem likely. The requirement for highly toxic precursors such as cyanogen bromide making the synthesis of aminorex and its derivatives potentially very dangerous for inexperienced clandestine chemists, has now been superseded with a newer route using cyanate salts which is easier, safer & cleaner. The route has been reported by the DEA in its monthly newsletter Microgram.
Ring-substituted aminorex derivatives have yet to be researched, but seem likely candidates for a new generation of designer drugs since the immediate precursors are legal and can easily be made from substituted benzaldehydes. The risk of pulmonary hypertension would be much lower if, for example, the DOM analogue were made, since the dosage level would be so much lower. However, the MDMA analogue would most likely be quite risky. | Aminorex
Aminorex is an anorectic stimulant drug of the 2-Amino-5-Aryloxazoline class. It is closely related to the popular drug 4-methyl-aminorex. It was disvered in 1960 by McNeil Laboratories, and was quickly found in 1962 to have an appetite suppressant effect in rats. It was introduced as a prescription anorectic in Germany, Switzerland and Austria in 1965 but was soon withdrawn when a number of occurrences of pulmonary hypertension including a number of fatalities were reported. The drug reappeared as a designer analog of 4-methyl-aminorex in the US during the 1990s. It is, in fact, 4 times stronger than 4-methyl-aminorex and the 4-fluoro analog is listed as four times as potent again as an anorectic (in rats), but is unknown outside the laboratory. Aminorex has been shown to have a locomotor stimulant properties lying midway between dextroamphetamine and methamphetamine.
The simple synthetic routes available mean that future outbreaks of abuse of this drug seem likely. The requirement for highly toxic precursors such as cyanogen bromide making the synthesis of aminorex and its derivatives potentially very dangerous for inexperienced clandestine chemists, has now been superseded with a newer route using cyanate salts which is easier, safer & cleaner. The route has been reported by the DEA in its monthly newsletter Microgram.
Ring-substituted aminorex derivatives have yet to be researched, but seem likely candidates for a new generation of designer drugs since the immediate precursors are legal and can easily be made from substituted benzaldehydes. The risk of pulmonary hypertension would be much lower if, for example, the DOM analogue were made, since the dosage level would be so much lower.[citation needed] However, the MDMA analogue would most likely be quite risky. | https://www.wikidoc.org/index.php/Aminorex | |
a3cee2d84831459990a5a0866ec5d870aafce9b4 | wikidoc | Ammonium | Ammonium
The ammonium cation is a positively charged polyatomic cation of the chemical formula NH4+. It has a molecular mass of 18.04 and is formed by protonation of ammonia (NH3). The resulting ion has a pKa of 9.25.
Ammonium and aminium are also general names for positively charged or protonated substituted amines and quaternary ammonium cations N+R4, where one or more hydrogen atoms are replaced by organic radical groups (which could be symbolized as R).
# Chemistry
In an ammonium ion, the positively charged nitrogen atom forms four covalent bonds, instead of three as in ammonia. This reaction is reversible. The ammonium ion can act as a very weak Brønsted-Lowry acid in the sense that it can protonate a stronger base using any one of its hydrogen ( H ) atoms and convert back to ammonia. This means that the ammonium ion is a conjugate acid of the base ammonia. In a solution, the degree to which ammonia forms the ammonium ion depends on the pH of the solution.
However, formation of ammonium compounds can also occur in the vapor phase; for example, when ammonia vapor comes in contact with hydrogen chloride vapor, a white cloud of ammonium chloride forms, which eventually settles out as a solid in a thin white layer on surfaces. Ammonium cations resemble alkali metal ions like Na+ or K+ and can be found in salts such as ammonium bicarbonate, ammonium chloride, and ammonium nitrate. Most simple ammonium salts are very water soluble.
The ammonium ion behaves somewhat like an alkali metal ion.
At attempt of reception of metal ammonium the ion, receiving electron, breaks up to ammonia and hydrogen:
Ammonium ions may dissolve in mercury to form an amalgam.
# Substituted ammonium ions
Any hydrogen in the ammonium ion can be substituted with an alkyl (or other organic radical) group to form a substituted ammonium ion, also called aminium ion; see amine for details. Depending on the number of organic radical groups, it is called a primary, a secondary, a tertiary, or a quaternary ammonium cation. They exist in an equilibrium with the respective substituted amine,depending on the pH.
Only quaternary ammonium cations are permanently charged.
An example of a reaction forming an ammonium ion is that between dimethylamine, (CH3)2NH, with an acid to give the dimethylaminium cation, (CH3)2NH2+:
NH4NO3
# In Biology
Ammonium ions are a toxic waste product of the metabolism in animals. In humans, it is converted in the urea cycle to urea, because it wastes less water to excrete. By water animals it is excreted unchanged in the urine. | Ammonium
The ammonium cation is a positively charged polyatomic cation of the chemical formula NH4+. It has a molecular mass of 18.04 and is formed by protonation of ammonia (NH3). The resulting ion has a pKa of 9.25.
Ammonium and aminium are also general names for positively charged or protonated substituted amines and quaternary ammonium cations N+R4, where one or more hydrogen atoms are replaced by organic radical groups (which could be symbolized as R).
# Chemistry
In an ammonium ion, the positively charged nitrogen atom forms four covalent bonds, instead of three as in ammonia. This reaction is reversible. The ammonium ion can act as a very weak Brønsted-Lowry acid in the sense that it can protonate a stronger base using any one of its hydrogen ( H ) atoms and convert back to ammonia. This means that the ammonium ion is a conjugate acid of the base ammonia. In a solution, the degree to which ammonia forms the ammonium ion depends on the pH of the solution.
However, formation of ammonium compounds can also occur in the vapor phase; for example, when ammonia vapor comes in contact with hydrogen chloride vapor, a white cloud of ammonium chloride forms, which eventually settles out as a solid in a thin white layer on surfaces. Ammonium cations resemble alkali metal ions like Na+ or K+ and can be found in salts such as ammonium bicarbonate, ammonium chloride, and ammonium nitrate. Most simple ammonium salts are very water soluble.
The ammonium ion behaves somewhat like an alkali metal ion.
At attempt of reception of metal ammonium the ion, receiving electron, breaks up to ammonia and hydrogen:
Ammonium ions may dissolve in mercury[1] to form an amalgam.
# Substituted ammonium ions
Any hydrogen in the ammonium ion can be substituted with an alkyl (or other organic radical) group to form a substituted ammonium ion, also called aminium ion; see amine for details. Depending on the number of organic radical groups, it is called a primary, a secondary, a tertiary, or a quaternary ammonium cation. They exist in an equilibrium with the respective substituted amine,depending on the pH.
Only quaternary ammonium cations are permanently charged.
An example of a reaction forming an ammonium ion is that between dimethylamine, (CH3)2NH, with an acid to give the dimethylaminium cation, (CH3)2NH2+:
NH4NO3
# In Biology
Ammonium ions are a toxic waste product of the metabolism in animals. In humans, it is converted in the urea cycle to urea, because it wastes less water to excrete. By water animals it is excreted unchanged in the urine. | https://www.wikidoc.org/index.php/Ammonium | |
22e13ad23af8d6f841e0f92547e43d166e58afc8 | wikidoc | Amrinone | Amrinone
# Overview
Amrinone (INN) or inamrinone (USAN, changed in 2000 to prevent confusion with amiodarone), trade name Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high gain CICR which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.
# Uses
It is used in the treatment of congestive heart failure.
It has been studied for use before coronary artery bypass surgery.
# Actions
Increases cardiac contractility, vasodilator. Acts by inhibiting the breakdown of both cAMP and cGMP by the phosphodiesterase (PDE3) enzyme. There is a long-standing controversy regarding whether the drug actually increases cardiac contractility in diseased myocardium (and therefore whether it is of any clinical use). The issue has been reviewed extensively by Dr Peter Wilmshurst, one of the first cardiologists and researchers to question the drug's efficacy.
# PDE- III inhibition and cardiac function
PDE III is present in cardiac muscle, vascular smooth muscle and platelets. PDE III degrades the phosphodiester bond in cAMP to break it down. When PDE III is inhibited, cAMP cannot be inactivated. An increase in cAMP with the administration of amrinone in vascular smooth muscle produces vasodilation by facilitating calcium uptake by the sarcoplasmic reticulum (a special type of smooth ER) and decreasing the calcium available for contraction. Since amrinone inhibits PDE III, it also inhibits the L type Ca2+ current in myocytes as well as facilitating an increase in Ca2+ uptake by the sarcoplasmic reticulum (SR). This may contribute to its positive inotropic effect on cardiac myocytes. Amrinone decreases the pulmonary capillary wedge pressure while increasing cardiac output because it functions as an arterial vasodilator and increases venous capacitance while decreasing venous return. There is a net decrease in myocardial wall tension, and O2 consumption when using amrinone. Amrinone also has beneficial effects during diastole in the left ventricle including relaxation, compliance and filling in patients with congestive heart failure.
# Indications
Short-term management of severe CHF (not used long term because of increased mortality, probably due to heart failure).
# How Inamrinone is used to correct Congestive Heart Failure
Congestive heart failure (CHF) is characterized by a reduction in ventricular performance and abnormalities in peripheral circulation and organs. A reduced release of endothelium derived relaxing factor (EDRF) causes a decrease in the stimulation of guanylate cyclase and cyclic GMP (cGMP) levels fall in vascular smooth muscle. This impairs relaxation in the vasculature and is a part of the vicious cycle of CHF. Patients with CHF have a down-regulation of their β-1 adrenergic receptors which alters their ability to activate intracellular adenylate cyclase which catalyzes cAMP formation. cAMP is the second messenger that controls the level of calcium available to allow the heart to contract. An IV administration of amrinone has been shown to increase cardiac output (CO) and stroke volume (SV) while concurrently reducing the filling pressure of the left ventricle and decreasing the resistance in the peripheral vasculature. This does not lead to an increase in heart rate or blood pressure. This improvement in performance of the ventricles is likely to result from a direct stimulation of the depressed myocardium as well as a decrease in peripheral vascular resistance.
# Contraindications
Patients with Aortic Stenosis, Hypertrophic Cardiomyopathy, or history of hypersensitivity to the drug.
# Precautions
May increase myocardial ischemia. Blood pressure, pulse, and EСG should be constantly monitored. Amrinone should only be diluted with normal saline or 1/2 normal saline; no dextrose solutions should be used. Furosemide should not be administered into an IV line delivering Amrinone.
# Side effects
Thrombocytopenia is the most prominent and dose-related side effect, but it is transient and asymptomatic. Nausea, diarrhoea, hepatotoxicity, arrhythmias and fever are other adverse effects.
# Routes
IV bolus and infusion as described earlier.
# Pediatric dosage
Safety in children has not been established.
# Amrinone discovery and progression
Early studies in patients with heart failure showed that amrinone produced short-term hemodynamic improvement, but had limited long-term clinical benefit. Some serious side effects of long term administration included sustained ventricular tachycardia resulting in circulatory collapse, worsening myocardial ischemia, acute myocardial infarction, and worsening congestive heart failure. Amrinone has good absorption from the gastrointestinal tract and may lead to some gastrointestinal upset when taken orally. The oral form of the drug is no longer in use. Currently, only acute intravenous administration takes place. The effects of amrinone vary widely with species and experimental condition; therefore inotropic effects are variable. A loss in sensitivity to PDE III inhibitors has been observed in end stage heart failure in humans and thus other treatment options may be necessary to improvement in these stages. | Amrinone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Amrinone (INN) or inamrinone (USAN, changed in 2000 to prevent confusion with amiodarone[1]), trade name Inocor, is a pyridine phosphodiesterase 3 inhibitor.[2] It is a drug that may improve the prognosis in patients with congestive heart failure.[3] Amrinone has been shown to increase the contractions initiated in the heart by high gain calcium induced calcium release (CICR).[4] The positive inotropic effect of amrinone is mediated by the selective enhancement of high gain CICR which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.[4]
# Uses
It is used in the treatment of congestive heart failure.
It has been studied for use before coronary artery bypass surgery.[5]
# Actions
Increases cardiac contractility, vasodilator. Acts by inhibiting the breakdown of both cAMP and cGMP by the phosphodiesterase (PDE3) enzyme. There is a long-standing controversy regarding whether the drug actually increases cardiac contractility in diseased myocardium (and therefore whether it is of any clinical use). The issue has been reviewed extensively by Dr Peter Wilmshurst, one of the first cardiologists and researchers to question the drug's efficacy.[6]
# PDE- III inhibition and cardiac function
PDE III is present in cardiac muscle, vascular smooth muscle and platelets. PDE III degrades the phosphodiester bond in cAMP to break it down.[7][8] When PDE III is inhibited, cAMP cannot be inactivated. An increase in cAMP with the administration of amrinone in vascular smooth muscle produces vasodilation by facilitating calcium uptake by the sarcoplasmic reticulum (a special type of smooth ER) and decreasing the calcium available for contraction.[7][9] Since amrinone inhibits PDE III, it also inhibits the L type Ca2+ current in myocytes as well as facilitating an increase in Ca2+ uptake by the sarcoplasmic reticulum (SR).[4] This may contribute to its positive inotropic effect on cardiac myocytes.[4] Amrinone decreases the pulmonary capillary wedge pressure while increasing cardiac output because it functions as an arterial vasodilator and increases venous capacitance while decreasing venous return.[7] There is a net decrease in myocardial wall tension, and O2 consumption when using amrinone. Amrinone also has beneficial effects during diastole in the left ventricle including relaxation, compliance and filling in patients with congestive heart failure.[7]
# Indications
Short-term management of severe CHF (not used long term because of increased mortality, probably due to heart failure).
# How Inamrinone is used to correct Congestive Heart Failure
Congestive heart failure (CHF) is characterized by a reduction in ventricular performance and abnormalities in peripheral circulation and organs.[8] A reduced release of endothelium derived relaxing factor (EDRF) causes a decrease in the stimulation of guanylate cyclase and cyclic GMP (cGMP) levels fall in vascular smooth muscle. This impairs relaxation in the vasculature and is a part of the vicious cycle of CHF.[8] Patients with CHF have a down-regulation of their β-1 adrenergic receptors which alters their ability to activate intracellular adenylate cyclase which catalyzes cAMP formation.[7] cAMP is the second messenger that controls the level of calcium available to allow the heart to contract. An IV administration of amrinone has been shown to increase cardiac output (CO) and stroke volume (SV) while concurrently reducing the filling pressure of the left ventricle and decreasing the resistance in the peripheral vasculature.[3][10][11] This does not lead to an increase in heart rate or blood pressure.[3][10][11] This improvement in performance of the ventricles is likely to result from a direct stimulation of the depressed myocardium as well as a decrease in peripheral vascular resistance.[12]
# Contraindications
Patients with Aortic Stenosis, Hypertrophic Cardiomyopathy, or history of hypersensitivity to the drug.
# Precautions
May increase myocardial ischemia. Blood pressure, pulse, and EСG should be constantly monitored. Amrinone should only be diluted with normal saline or 1/2 normal saline; no dextrose solutions should be used. Furosemide should not be administered into an IV line delivering Amrinone.
# Side effects
Thrombocytopenia is the most prominent and dose-related side effect, but it is transient and asymptomatic. Nausea, diarrhoea, hepatotoxicity, arrhythmias and fever are other adverse effects.
# Routes
IV bolus and infusion as described earlier.
# Pediatric dosage
Safety in children has not been established.
# Amrinone discovery and progression
Early studies in patients with heart failure showed that amrinone produced short-term hemodynamic improvement, but had limited long-term clinical benefit.[9] Some serious side effects of long term administration included sustained ventricular tachycardia resulting in circulatory collapse, worsening myocardial ischemia, acute myocardial infarction, and worsening congestive heart failure.[9][13] Amrinone has good absorption from the gastrointestinal tract [14] and may lead to some gastrointestinal upset when taken orally. The oral form of the drug is no longer in use.[13] Currently, only acute intravenous administration takes place.[13] The effects of amrinone vary widely with species and experimental condition; therefore inotropic effects are variable.[4] A loss in sensitivity to PDE III inhibitors has been observed in end stage heart failure in humans and thus other treatment options may be necessary to improvement in these stages.[4] | https://www.wikidoc.org/index.php/Amrinone | |
5b04a3f122d6905dcd3368edee9859bb43e5ff99 | wikidoc | Amygdala | Amygdala
The amygdalae (Latin, also corpus amygdaloideum, singular amygdala, from Greek αμυγδαλή, amygdalē, 'almond', 'tonsil') are almond-shaped groups of neurons located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.
# Anatomical subdivisions
The regions described as amygdalae encompass several nuclei with distinct functional traits. Among these nuclei are the basolateral complex, the centromedial nucleus and the cortical nucleus. The basolateral complex can be further subdivided into the lateral, the basal and the accessory basal nuclei.
## Connections
The amygdalae send impulses to the hypothalamus for important activation of the sympathetic nervous system, to the thalamic reticular nucleus for increased reflexes, to the nuclei of the trigeminal nerve and facial nerve for facial expressions of fear, and to the ventral tegmental area, locus coeruleus, and laterodorsal tegmental nucleus for activation of dopamine, norepinephrine and epinephrine.
The cortical nucleus is involved in the sense of smell and pheromone-processing. It receives input from the olfactory bulb and olfactory cortex. The lateral amygdalae, which send impulses to the rest of the basolateral complexes and to the centromedial nuclei, receive input from the sensory systems. The centromedial nuclei are the main outputs for the basolateral complexes, and are involved in emotional arousal in rats and cats.
# Emotional learning
In complex vertebrates, including humans, the amygdala perform primary roles in the formation and storage of memories associated with emotional events. Research indicates that during fear conditioning, sensory stimuli reach the basolateral complexes of the amygdalae, particularly the lateral nuclei, where they form associations with memories of the stimuli. The association between stimuli and the aversive events they predict may be mediated by long-term potentiation, a lingering potential for affected synapses to react more readily.
Memories of emotional experiences imprinted in reactions of synapses in the lateral nuclei elicit fear behavior through connections with the central nucleus of the amygdalae. The central nuclei are involved in the genesis of many fear responses, including freezing (immobility), tachycardia (rapid heartbeat), increased respiration, and stress-hormone release. Damage to the amygdalae impairs both the acquisition and expression of Pavlovian fear conditioning, a form of classical conditioning of emotional responses.
The amygdalae are also involved in appetitive (positive) conditioning. It seems that distinct neurons respond to positive and negative stimuli, but there is no clustering of these distinct neurons into clear anatomical nuclei.
Different nuclei within the amygdala have different functions in appetitive conditioning.
# Memory modulation
The amygdalae also are involved in the modulation of memory consolidation. Following any learning event, the long-term memory for the event is not instantaneously formed. Rather, information regarding the event is slowly assimilated into long-term storage over time (the duration of long-term memory storage can be infinite), a process referred to as memory consolidation, until it reaches a relatively permanent state.
During the consolidation period, the memory can be modulated. In particular, it appears that emotional arousal following the learning event influences the strength of the subsequent memory for that event. Greater emotional arousal following a learning event enhances a person's retention of that event. Experiments have shown that administration of stress hormones to mice immediately after they learn something enhances their retention when they are tested two days later.
The amygdalae, especially the basolateral nuclei, are involved in mediating the effects of emotional arousal on the strength of the memory for the event, as shown by many laboratories including that of James McGaugh. These laboratories have trained animals on a variety of learning tasks and found that drugs injected into the amygdala after training affect the animals' subsequent retention of the task. These tasks include basic classical conditioning tasks such as inhibitory avoidance, where a rat learns to associate a mild footshock with a particular compartment of an apparatus, and more complex tasks such as spatial or cued water maze, where a rat learns to swim to a platform to escape the water. If a drug that activates the amygdalae is injected into the amygdalae, the animals had better memory for the training in the task. If a drug that inactivates the amygdalae is injected, the animals had impaired memory for the task.
Despite the importance of the amygdalae in modulating memory consolidation, however, learning can occur without it, though such learning appears to be impaired, as in fear conditioning impairments following amygdalar damage.
Evidence from work with humans indicates that the amygdala plays a similar role. Amygdala activity at the time of encoding information correlates with retention for that information. However, this correlation depends on the relative "emotionalness" of the information. More emotionally-arousing information increases amygdalar activity, and that activity correlates with retention.
# Neuropsychological correlates of amygdala activity
Early research on primates provided explanations as to the functions of the amygdala, as well as a basis for further research. As early as 1888, rhesus monkeys with a lesioned temporal cortex (including the amygdala) were observed to have significant social and emotional deficits. Heinrich Klüver and Paul Bucy later expanded upon this same observation by showing that large lesions to the anterior temporal lobe produced noticeable changes, including overreaction to all objects, hypoemotionality, loss of fear, hypersexuality, and hyperorality, a condition in which inappropriate objects are placed in the mouth. Some monkeys also displayed an inability to recognize familiar objects and would approach animate and inanimate objects indiscriminately, exhibiting a loss of fear towards the experimenters. This behavioral disorder was later named Klüver-Bucy syndrome accordingly. Later studies served to focus on the amygdala specifically, as the temporal cortex encompasses a broad set of brain structures, making it difficult to find which ones specifically may have correlated with certain symptoms. Monkey mothers who had amygdala damage showed a reduction in maternal behaviors towards their infants, often physically abusing or neglecting them. In 1981, researchers found that selective radio frequency lesions of the whole amygdala caused Klüver-Bucy Syndrome.
With advances in neuroimaging technology such as MRI, neuroscientists have made significant findings concerning the amygdala in the human brain. Consensus of data shows the amygdala has a substantial role in mental states, and is related to many psychological disorders. In a 2003 study, subjects with Borderline Personality Disorder showed significantly greater left amygdala activity than normal control subjects. Some borderline patients even had difficulties classifying neutral faces or saw them as threatening. In 2006, researchers observed hyperactivity in the amygdala when patients were shown threatening faces or confronted with frightening situations. Patients with more severe social phobia showed a correlation with increased response in the amygdala. Similarly, depressed patients showed exaggerated left amygdala activity when interpreting emotions for all faces, and especially for fearful faces. Interestingly, this hyperactivity was normalized when patients went on antidepressants. By contrast, the amygdala has been observed to relate differently in people with Bipolar Disorder. A 2003 study found that adult and adolescent bipolar patients tended to have considerably smaller amygdala volumes and somewhat smaller hippocampal volumes. Many studies have focused on the connections between the amygdala and autism.
Recent research suggests that parasites, in particular toxoplasma, form cysts in the brain, often taking up residence in the amygdala. This may provide clues as to how specific parasites manipulate behavior and may contribute to the development of disorders, including paranoia.
# Additional images
- Coronal section of brain through intermediate mass of third ventricle.
- Brain | Amygdala
Template:Infobox Brain
The amygdalae (Latin, also corpus amygdaloideum, singular amygdala, from Greek αμυγδαλή, amygdalē, 'almond', 'tonsil')[1] are almond-shaped groups of neurons located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. [2] Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system. [3]
# Anatomical subdivisions
The regions described as amygdalae encompass several nuclei with distinct functional traits. Among these nuclei are the basolateral complex, the centromedial nucleus and the cortical nucleus. The basolateral complex can be further subdivided into the lateral, the basal and the accessory basal nuclei. [3][4]
## Connections
The amygdalae send impulses to the hypothalamus for important activation of the sympathetic nervous system, to the thalamic reticular nucleus for increased reflexes, to the nuclei of the trigeminal nerve and facial nerve for facial expressions of fear, and to the ventral tegmental area, locus coeruleus, and laterodorsal tegmental nucleus for activation of dopamine, norepinephrine and epinephrine.[4]
The cortical nucleus is involved in the sense of smell and pheromone-processing. It receives input from the olfactory bulb and olfactory cortex. The lateral amygdalae, which send impulses to the rest of the basolateral complexes and to the centromedial nuclei, receive input from the sensory systems. The centromedial nuclei are the main outputs for the basolateral complexes, and are involved in emotional arousal in rats and cats.[4][5]
# Emotional learning
In complex vertebrates, including humans, the amygdala perform primary roles in the formation and storage of memories associated with emotional events. Research indicates that during fear conditioning, sensory stimuli reach the basolateral complexes of the amygdalae, particularly the lateral nuclei, where they form associations with memories of the stimuli. The association between stimuli and the aversive events they predict may be mediated by long-term potentiation, a lingering potential for affected synapses to react more readily.[3]
Memories of emotional experiences imprinted in reactions of synapses in the lateral nuclei elicit fear behavior through connections with the central nucleus of the amygdalae. The central nuclei are involved in the genesis of many fear responses, including freezing (immobility), tachycardia (rapid heartbeat), increased respiration, and stress-hormone release. Damage to the amygdalae impairs both the acquisition and expression of Pavlovian fear conditioning, a form of classical conditioning of emotional responses.[3]
The amygdalae are also involved in appetitive (positive) conditioning. It seems that distinct neurons respond to positive and negative stimuli, but there is no clustering of these distinct neurons into clear anatomical nuclei.[6]
Different nuclei within the amygdala have different functions in appetitive conditioning.[7]
# Memory modulation
The amygdalae also are involved in the modulation of memory consolidation. Following any learning event, the long-term memory for the event is not instantaneously formed. Rather, information regarding the event is slowly assimilated into long-term storage over time (the duration of long-term memory storage can be infinite), a process referred to as memory consolidation, until it reaches a relatively permanent state.
During the consolidation period, the memory can be modulated. In particular, it appears that emotional arousal following the learning event influences the strength of the subsequent memory for that event. Greater emotional arousal following a learning event enhances a person's retention of that event. Experiments have shown [1] that administration of stress hormones to mice immediately after they learn something enhances their retention when they are tested two days later.
The amygdalae, especially the basolateral nuclei, are involved in mediating the effects of emotional arousal on the strength of the memory for the event, as shown by many laboratories including that of James McGaugh. These laboratories have trained animals on a variety of learning tasks and found that drugs injected into the amygdala after training affect the animals' subsequent retention of the task. These tasks include basic classical conditioning tasks such as inhibitory avoidance, where a rat learns to associate a mild footshock with a particular compartment of an apparatus, and more complex tasks such as spatial or cued water maze, where a rat learns to swim to a platform to escape the water. If a drug that activates the amygdalae is injected into the amygdalae, the animals had better memory for the training in the task.[8] If a drug that inactivates the amygdalae is injected, the animals had impaired memory for the task.
Despite the importance of the amygdalae in modulating memory consolidation, however, learning can occur without it, though such learning appears to be impaired, as in fear conditioning impairments following amygdalar damage.[9]
Evidence from work with humans indicates that the amygdala plays a similar role. Amygdala activity at the time of encoding information correlates with retention for that information. However, this correlation depends on the relative "emotionalness" of the information. More emotionally-arousing information increases amygdalar activity, and that activity correlates with retention.[citation needed]
# Neuropsychological correlates of amygdala activity
Early research on primates provided explanations as to the functions of the amygdala, as well as a basis for further research. As early as 1888, rhesus monkeys with a lesioned temporal cortex (including the amygdala) were observed to have significant social and emotional deficits.[10] Heinrich Klüver and Paul Bucy later expanded upon this same observation by showing that large lesions to the anterior temporal lobe produced noticeable changes, including overreaction to all objects, hypoemotionality, loss of fear, hypersexuality, and hyperorality, a condition in which inappropriate objects are placed in the mouth. Some monkeys also displayed an inability to recognize familiar objects and would approach animate and inanimate objects indiscriminately, exhibiting a loss of fear towards the experimenters. This behavioral disorder was later named Klüver-Bucy syndrome accordingly.[11] Later studies served to focus on the amygdala specifically, as the temporal cortex encompasses a broad set of brain structures, making it difficult to find which ones specifically may have correlated with certain symptoms. Monkey mothers who had amygdala damage showed a reduction in maternal behaviors towards their infants, often physically abusing or neglecting them.[12] In 1981, researchers found that selective radio frequency lesions of the whole amygdala caused Klüver-Bucy Syndrome.[13]
With advances in neuroimaging technology such as MRI, neuroscientists have made significant findings concerning the amygdala in the human brain. Consensus of data shows the amygdala has a substantial role in mental states, and is related to many psychological disorders. In a 2003 study, subjects with Borderline Personality Disorder showed significantly greater left amygdala activity than normal control subjects. Some borderline patients even had difficulties classifying neutral faces or saw them as threatening.[14] In 2006, researchers observed hyperactivity in the amygdala when patients were shown threatening faces or confronted with frightening situations. Patients with more severe social phobia showed a correlation with increased response in the amygdala.[15] Similarly, depressed patients showed exaggerated left amygdala activity when interpreting emotions for all faces, and especially for fearful faces. Interestingly, this hyperactivity was normalized when patients went on antidepressants.[16] By contrast, the amygdala has been observed to relate differently in people with Bipolar Disorder. A 2003 study found that adult and adolescent bipolar patients tended to have considerably smaller amygdala volumes and somewhat smaller hippocampal volumes.[17] Many studies have focused on the connections between the amygdala and autism.[18]
Recent research suggests that parasites, in particular toxoplasma, form cysts in the brain, often taking up residence in the amygdala. This may provide clues as to how specific parasites manipulate behavior and may contribute to the development of disorders, including paranoia.[19]
# Additional images
- Coronal section of brain through intermediate mass of third ventricle.
- Brain | https://www.wikidoc.org/index.php/Amygdala | |
c923b3180c08b9ad418a3e9577114f89752af941 | wikidoc | Anabaena | Anabaena
Anabaena is a genus of filamentous cyanobacteria, or blue-green algae, found as plankton. It is known for its nitrogen fixing abilities, and they form symbiotic relationships with certain plants, such as the mosquito fern. They are one of four genera of cyanobacteria that produce neurotoxins, which are harmful to local wildlife, as well as farm animals and pets.
A DNA sequencing project was undertaken in 1999, which mapped the complete genome of Anabaena, which is 7.2 million base pairs long. The study focussed on heterocysts, which convert nitrogen into ammonia. Certain species of Anabaena have been used on rice paddy fields, proving to be an effective natural fertilizer.
# Species
- Anabaena aequalis
- Anabaena affinis
- Anabaena angstumalis
Anabaena angstumalis angstumalis
Anabaena angstumalis marchica
- Anabaena angstumalis angstumalis
- Anabaena angstumalis marchica
- Anabaena aphanizomendoides
- Anabaena azollae
- Anabaena bornetiana
- Anabaena catenula
- Anabaena circinalis
- Anabaena confervoides
- Anabaena constricta
- Anabaena cycadeae
- Anabaena cylindrica
- Anabaena echinispora
- Anabaena felisii
- Anabaena flosaquae
Anabaena flosaquae flosaquae
Anabaena flosaquae minor
Anabaena flosaquae treleasei
- Anabaena flosaquae flosaquae
- Anabaena flosaquae minor
- Anabaena flosaquae treleasei
- Anabaena helicoidea
- Anabaena inaequalis
- Anabaena lapponica
- Anabaena laxa
- Anabaena lemmermannii
- Anabaena levanderi
- Anabaena limnetica
- Anabaena macrospora
Anabaena macrospora macrospora
Anabaena macrospora robusta
- Anabaena macrospora macrospora
- Anabaena macrospora robusta
- Anabaena monticulosa
- Anabaena oscillarioides
- Anabaena planctonica
- Anabaena raciborskii
- Anabaena scheremetievi
- Anabaena sphaerica
- Anabaena spiroides
Anabaena spiroides crassa
Anabaena spiroides spiroides
- Anabaena spiroides crassa
- Anabaena spiroides spiroides
- Anabaena subcylindrica
- Anabaena torulosa
- Anabaena unispora
- Anabaena variabilis
- Anabaena verrucosa
- Anabaena viguieri
- Anabaena wisconsinense
- Anabaena zierlingii
# Nitrogen Fixation by Anabaena
Under nitrogen-limiting conditions, vegetative cells differentiate into heterocysts at semi-regular intervals along the filaments. Heterocysts are cells that are terminally specialized for nitrogen fixation. The interior of these cells is microoxic as a result of increased respiration, inactivation of O2-producing photosystem (PS) II, and formation of a thickened envelope outside of the cell wall. Nitrogenase, sequestered within these cells, transforms dinitrogen into ammonium at the expense of ATP and reductant—both generated by carbohydrate metabolism, a process that is supplemented, in the light, by the activity of PS I. Carbohydrate, probably in the form of sucrose, is synthesized in vegetative cells and moves into heterocysts. In return, nitrogen fixed in heterocysts moves into the vegetative cells, at least in part in the form of amino acids. | Anabaena
Anabaena is a genus of filamentous cyanobacteria, or blue-green algae, found as plankton. It is known for its nitrogen fixing abilities, and they form symbiotic relationships with certain plants, such as the mosquito fern. They are one of four genera of cyanobacteria that produce neurotoxins, which are harmful to local wildlife, as well as farm animals and pets.
A DNA sequencing project was undertaken in 1999, which mapped the complete genome of Anabaena, which is 7.2 million base pairs long. The study focussed on heterocysts, which convert nitrogen into ammonia. Certain species of Anabaena have been used on rice paddy fields, proving to be an effective natural fertilizer.
# Species
- Anabaena aequalis
- Anabaena affinis
- Anabaena angstumalis
Anabaena angstumalis angstumalis
Anabaena angstumalis marchica
- Anabaena angstumalis angstumalis
- Anabaena angstumalis marchica
- Anabaena aphanizomendoides
- Anabaena azollae
- Anabaena bornetiana
- Anabaena catenula
- Anabaena circinalis
- Anabaena confervoides
- Anabaena constricta
- Anabaena cycadeae
- Anabaena cylindrica
- Anabaena echinispora
- Anabaena felisii
- Anabaena flosaquae
Anabaena flosaquae flosaquae
Anabaena flosaquae minor
Anabaena flosaquae treleasei
- Anabaena flosaquae flosaquae
- Anabaena flosaquae minor
- Anabaena flosaquae treleasei
- Anabaena helicoidea
- Anabaena inaequalis
- Anabaena lapponica
- Anabaena laxa
- Anabaena lemmermannii
- Anabaena levanderi
- Anabaena limnetica
- Anabaena macrospora
Anabaena macrospora macrospora
Anabaena macrospora robusta
- Anabaena macrospora macrospora
- Anabaena macrospora robusta
- Anabaena monticulosa
- Anabaena oscillarioides
- Anabaena planctonica
- Anabaena raciborskii
- Anabaena scheremetievi
- Anabaena sphaerica
- Anabaena spiroides
Anabaena spiroides crassa
Anabaena spiroides spiroides
- Anabaena spiroides crassa
- Anabaena spiroides spiroides
- Anabaena subcylindrica
- Anabaena torulosa
- Anabaena unispora
- Anabaena variabilis
- Anabaena verrucosa
- Anabaena viguieri
- Anabaena wisconsinense
- Anabaena zierlingii
# Nitrogen Fixation by Anabaena
Under nitrogen-limiting conditions, vegetative cells differentiate into heterocysts at semi-regular intervals along the filaments. Heterocysts are cells that are terminally specialized for nitrogen fixation. The interior of these cells is microoxic as a result of increased respiration, inactivation of O2-producing photosystem (PS) II, and formation of a thickened envelope outside of the cell wall. Nitrogenase, sequestered within these cells, transforms dinitrogen into ammonium at the expense of ATP and reductant—both generated by carbohydrate metabolism, a process that is supplemented, in the light, by the activity of PS I. Carbohydrate, probably in the form of sucrose, is synthesized in vegetative cells and moves into heterocysts. In return, nitrogen fixed in heterocysts moves into the vegetative cells, at least in part in the form of amino acids.[1] | https://www.wikidoc.org/index.php/Anabaena | |
2537f27dcc3d2d90762091ea005e6b9611db3983 | wikidoc | Anakinra | Anakinra
# Disclaimer
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# Overview
Anakinra is an interleukin-1 receptor antagonist that is FDA approved for the {{{indicationType}}} of rheumatoid arthritis (RA)and cryopyrin-associated periodic syndromes (CAPS). Common adverse reactions include upper respiratory tract infection, headache, nausea, diarrhea, sinusitis, arthralgia, flu like-symptoms, and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Kineret for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anakinra in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anakinra in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended starting dose of Kineret is 1-2 mg/kg for NOMID patients. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation.
- Adjust doses in 0.5 to 1.0 mg/kg increments. Once daily administration is generally recommended, but the dose may be split into twice daily administrations. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anakinra in pediatric patients.
### Non–Guideline-Supported Use
- Anakinra 2 mg/kilogram (kg) subcutaneously once daily.
# Contraindications
- Kineret is contraindicated in patients with known hypersensitivity to E coli-derived proteins, Kineret, or any components of the product.
# Warnings
### Precautions
- Serious Infections
- Kineret has been associated with an increased incidence of serious infections (2%) vs. Placebo (< 1%) in clinical trials in RA. Administration of Kineret in RA should be discontinued if a patient develops a serious infection. In Kineret treated NOMID patients the risk of a NOMID flare when discontinuing Kineret treatment should be weighed against the potential risk of continued treatment. Treatment with Kineret should not be initiated in patients with active infections. The safety and efficacy of Kineret in immunosuppressed patients or in patients with chronic infections have not been evaluated.
- Drugs that affect the immune system by blocking tumor necrosis factor (TNF) have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as Kineret that blocks IL-1 increases the risk of TB or other atypical or opportunistic infections. Health care providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with Kineret.
- Use With TNF Blocking Agents
- In a 24-week study of concurrent Kineret and etanercept therapy in RA patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). The combination of Kineret and etanercept did not result in higher ACR response rates compared to etanercept alone. Use of Kineret in combination with TNF blocking agents is not recommended.
- Hypersensitivity Reactions
- Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with Kineret. If a severe hypersensitivity reaction occurs, administration of Kineret should be discontinued and appropriate therapy initiated.
- The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
- Immunosuppression
- The impact of treatment with Kineret on active and/or chronic infections and the development of malignancies is not known.
- Immunizations
- In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret and placebo treatment groups when the tetanus/diphtheria toxoids vaccine was administered concurrently with Kineret. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be given concurrently with Kineret.
- Neutrophil Count
- Patients receiving Kineret may experience a decrease in neutrophil counts. Neutrophil counts should therefore be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly for 3 months, and thereafter quarterly for a period up to 1 year.
- In the placebo-controlled studies, 8% of RA patients receiving Kineret had decreases in neutrophil counts of at least one World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Nine Kineret-treated patients (0.4%) experienced neutropenia (ANC < 1 x 109/L).
- In 43 NOMID patients followed for up to 60 months 2 patients experienced neutropenia that resolved over time during continued Kineret treatment.
# 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 clinical practice.
- The most serious adverse reactions were:
- Serious Infections
- Neutropenia, particularly when used in combination with TNF blocking agents
- The most common adverse reaction with Kineret is injection-site reactions. These reactions were the most common reason for withdrawing from studies.
- The data described herein reflect exposure to Kineret in 3025 patients, including 2124 exposed for at least 6 months and 884 exposed for at least one year. Studies 1 and 4 used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis.
- Injection-site Reactions
- The most common and consistently reported treatment-related adverse event associated with Kineret is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain.
- Infections
- In Studies 1 and 4 combined, the incidence of infection was 39% in the Kineret-treated patients and 37% in placebo-treated patients during the first 6 months of blinded treatment. The incidence of serious infections in Studies 1 and 4 was 2% in Kineret-treated patients and 1% in patients receiving placebo over 6 months. The incidence of serious infection over 1 year was 3% in Kineret-treated patients and 2% in patients receiving placebo. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Majority of patients (73%) continued on study drug after the infection resolved. No serious opportunistic infections were reported. Patients with asthma appeared to be at higher risk of developing serious infections when treated with Kineret (8 of 177 patients, 4.5%) compared to placebo (0 of 50 patients, 0%).
- In open-label extension studies, the overall rate of serious infections was stable over time and comparable to that observed in controlled trials. In clinical studies and postmarketing experience, cases of opportunistic infections have been observed and included fungal, mycobacterial and bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret alone or in combination with immunosuppressive agents.
- In patients who received both Kineret and etanercept for up to 24 weeks, the incidence of serious infections was 7%. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure.
- Malignancies
- Among 5300 RA patients treated with Kineret in clinical trials for a mean of 15 months (approximately 6400 patient years of treatment), 8 lymphomas were observed for a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population, based on the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database.3 An increased rate of lymphoma, up to several fold, has been reported in the RA population, and may be further increased in patients with more severe disease activity. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common were breast, respiratory system, and digestive system. There were 3 melanomas observed in Study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known. While patients with RA, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of IL-1 blockers in the development of malignancy is not known.
- Hematologic Events
- In placebo-controlled studies with Kineret, 8% of patients receiving Kineret had decreases in total white blood counts of at least one WHO toxicity grade, compared with 2% of placebo patients. Nine Kineret-treated patients (0.4%) developed neutropenia (ANC < 1 x 109/L). 9 % of patients receiving Kineret had increases in eosinophil differential percentage of at least one WHO toxicity grade, compared with 3 % of placebo patients. Of patients treated concurrently with Kineret and etanercept 2% developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy. 2% of patients receiving Kineret had decreases in platelets, all of WHO toxicity grade one, compared to 0% of placebo patients.
- Hypersensitivity Reactions
- Hypersensitivity reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported with Kineret.
- Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. In Studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positive for anti-anakinra binding antibodies at one or more time points using a biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) tested positive for neutralizing antibodies in a cell-based bioassay. Of the 13 patients with available follow-up data, 5 patients remained positive for neutralizing antibodies at the end of the studies. No correlation between antibody development and adverse events was observed.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kineret with the incidence of antibodies to other products may be misleading.
- Other Adverse Events
- Table 1 reflects adverse events in Studies 1 and 4, that occurred with a frequency of ≥ 5% in Kineret-treated patients over a 6-month period.
- The data described herein reflect an open-label study in 43 NOMID patients exposed to Kineret for up to 60 months adding up to a total exposure of 159.8 patient years.
- Patients were treated with a starting dose of 1 to 2 mg/kg/day and an average maintenance dose of 3-4 mg/kg/day adjusted depending on the severity of disease. Among pediatric NOMID patients, doses up to 7.6 mg/kg/day have been maintained for up to 15 months.
- There were 24 serious adverse events (SAEs) reported in 14 of the 43 treated patients. The most common type of SAEs reported were infections. Five SAEs were related to lumbar puncture, which was part of the study procedure.
- There were no permanent discontinuations of study drug treatment due to AEs. Doses were adjusted in 5 patients because of AEs; all were dose increases in connection with disease flares.
- The reporting frequency of AEs was highest during the first 6 months of treatment. The incidence of AEs did not increase over time, and no new types of AEs emerged.
- The most commonly reported AEs during the first 6 months of treatment (incidence >10%) were injection site reaction (ISR), headache, vomiting, arthralgia, pyrexia, and nasopharyngitis (Table 2).
- The most commonly reported AEs during the 60-month study period, calculated as the number of events/patient years of exposure, were arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.
- The AE profiles for different age groups <2 years, 2-11 years, and 12-17 years corresponded to the AE profile for patients ≥18 years, with the exception of infections and related symptoms being more frequent in patients <2 years.
- Infections
- The reporting rate for infections was higher during the first 6 months of treatment (2.3 infections/patient-year) compared to after the first 6 months (1.7 infections/patient year). The most common infections were upper respiratory tract infection, sinusitis, ear infections, and nasopharyngitis.
- There were no deaths or permanent treatment discontinuations due to infections. In one patient Kineret administration was temporarily stopped during an infection and in 5 patients the dose of Kineret was increased due to disease flares in connection with infections. Thirteen infections in 7 patients were classified as serious, the most common being pneumonia and gastroenteritis occurring in 3 and 2 patients, respectively. No serious opportunistic infections were reported.
- The reporting frequency for infections was highest in patients <12 years of age.
- Hematologic Events
- After start of Kineret treatment neutropenia was reported in 2 patients. One of these patients experienced an upper respiratory tract infection and an otitis media infection. Both episodes of neutropenia resolved over time with continued Kineret treatment.
- Injection Site Reactions
- In total, 17 injection site reactions (ISRs) were reported in 10 patients during the 60-month study period. Out of the 17 ISRs, 11 (65%) occurred during the first month and 13 (76%) were reported during the first 6 months. No ISR was reported after Year 2 of treatment. The majority of ISRs were reported as mild (76% mild, 24% moderate). No patient permanently or temporarily discontinued Kineret treatment due to injection site reactions.
- Immunogenicity
- The immunogenicity of Kineret in NOMID patients was not evaluated.
- The most common adverse reactions occurring after the first 6-month period of treatment with Kineret (up to 60 months of treatment) included: arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Kineret. 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.
Elevations of transaminases, non-infectious hepatitis
# Drug Interactions
- TNF Blocking Agents
- A higher rate of serious infections has been observed in patients treated with concurrent Kineret and etanercept therapy than in patients treated with etanercept alone. Two percent of patients treated concurrently with Kineret and etanercept developed neutropenia (ANC < 1 x 109/L). Use of Kineret in combination with TNF blocking agents is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies of Kineret in pregnant women. Reproductive studies have been performed in rats and rabbits at doses up to 25 times the maximum recommended human dose (on a mg/kg basis at a maternal dose of 200 mg/kg/day) and have revealed no evidence of impaired fertility or harm to the fetus due to Kineret. Because animal reproduction studies are not always predictive of human response, Kineret should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anakinra in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Anakinra during labor and delivery.
### Nursing Mothers
- It is not known whether Kineret is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised if Kineret is administered to nursing women.
### Pediatric Use
- The NOMID study included 36 pediatric patients: 13 below 2 years, 18 between 2 and 11 years, and 5 between 12 and 17 years of age. A subcutaneous Kineret starting dose of 1–2 mg/kg/day was administered in all age groups. An average maintenance dose of 3–4 mg/kg/day was adequate to maintain clinical response throughout the study irrespective of age but a higher dose was, on occasion, required in severely affected patients. The prefilled syringe does not allow doses lower than 20 mg to be administered.
- Kineret was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA; ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Kineret for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Kineret is not recommended for pediatric use in Juvenile Rheumatoid Arthritis.
### Geriatic Use
- A total of 752 RA patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, were studied in clinical trials. No differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
### Gender
There is no FDA guidance on the use of Anakinra with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Anakinra with respect to specific racial populations.
### Renal Impairment
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
### Hepatic Impairment
- No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Anakinra in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Anakinra in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Anakinra in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Anakinra in the drug label.
# Overdosage
## Acute Overdose
- There have been no cases of overdose reported with Kineret in clinical trials of RA or NOMID. In sepsis trials no serious toxicities attributed to Kineret were seen when administered at mean calculated doses of up to 35 times those given patients with RA over a 72-hour treatment period.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Anakinra in the drug label.
# Pharmacology
## Mechanism of Action
- Kineret blocks the biologic activity of IL-1 alpha and beta by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs.
- IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from RA patients are not sufficient to compete with the elevated amount of locally produced IL-1.
- Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID.
## Structure
- Kineret (anakinra) is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus. Kineret consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA technology using an E coli bacterial expression system.
- Kineret is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, clear, colorless-to-white, preservative free solution for daily subcutaneous (SC) administration. The solution may contain trace amounts of small, translucent-to-white amorphous proteinaceous particles. Each prefilled glass syringe contains: 0.67 mL (100 mg) of anakinra in a solution (pH 6.5) containing disodium EDTA (0.12 mg), sodium chloride (5.48 mg), anhydrous citric acid (1.29 mg), and polysorbate 80 (0.70 mg) in Water for Injection, USP.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Anakinra in the drug label.
## Pharmacokinetics
- The absolute bioavailability of Kineret after a 70 mg subcutaneous bolus injection in healthy subjects (n = 11) is 95%. In subjects with RA, maximum plasma concentrations of Kineret occurred 3 to 7 hours after subcutaneous administration of Kineret at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of Kineret was observed after daily subcutaneous doses for up to 24 weeks.
- The influence of demographic covariates on the pharmacokinetics of Kineret was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous injection of Kineret at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated Kineret clearance increased with increasing creatinine clearance and body weight. After adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance.
- In NOMID patients, at a median SC dose of 3 mg/kg once daily and a median treatment time of 3.5 years, the median (range) steady-state serum exposure of anakinra was Cmax 3628 (655–8511) ng/mL (n=16) and C24h 203 (53–1979) ng/mL (n=16). The median (range) half-life of anakinra was 5.7 (3.1–28.2) hours (n=12). There was no obvious gender difference.
- Patients With Renal Impairment: The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance < 30 mL/min1), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of Kineret was removed by hemodialysis or continuous ambulatory peritoneal dialysis. Based on these observations, a dose schedule change should be considered for subjects with severe renal insufficiency or end stage renal disease .
- Patients with Hepatic Dysfunction: No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in patients with hepatic impairment.
## Nonclinical Toxicology
- Long-term animal studies to evaluate the carcinogenic potential of Kineret were not conducted. Using a standard in vivo and in vitro battery of mutagenesis assays, Kineret did not induce gene mutations in either bacteria or mammalian cells. Kineret had no effects on fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (approximately 25 times the maximum recommended dose).
# Clinical Studies
- The safety and efficacy of Kineret have been evaluated in three randomized, double-blind, placebo-controlled trials of 1790 patients ≥ 18 years of age with active rheumatoid arthritis (RA). An additional fourth study was conducted to assess safety. In the efficacy trials, Kineret was studied in combination with other disease-modifying antirheumatic drugs (DMARDs) other than Tumor Necrosis Factor (TNF) blocking agents (Studies 1 and 2) or as a monotherapy (Study 3).
- Study 1 involved 899 patients with active RA who had been on a stable dose of methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks. All patients had at least 6 swollen/painful and 9 tender joints and either a C-reactive protein (CRP) of ≥ 1.5 mg/dL or an erythrocyte sedimentation rate (ESR) of ≥ 28 mm/hr. Patients were randomized to Kineret or placebo in addition to their stable doses of MTX. The first 501 patients were evaluated for signs and symptoms of active RA. The total 899 patients were evaluated for progression of structural damage.
- Study 2 evaluated 419 patients with active RA who had received MTX for at least 6 months including a stable dose (15 to 25 mg/week) for at least 3 consecutive months prior to enrollment. Patients were randomized to receive placebo or one of five doses of Kineret subcutaneous daily for 12 to 24 weeks in addition to their stable doses of MTX.
- Study 3 evaluated 472 patients with active RA and had similar inclusion criteria to Study 1 except that these patients had received no DMARD for the previous 6 weeks or during the study. Patients were randomized to receive either Kineret or placebo. Patients were DMARD-naïve or had failed no more than 3 DMARDs.
- Study 4 was a placebo-controlled, randomized trial designed to assess the safety of Kineret in 1414 patients receiving a variety of concurrent medications for their RA including some DMARD therapies, as well as patients who were DMARD-free. The TNF blocking agents etanercept and infliximab were specifically excluded. Concurrent DMARDs included MTX, sulfasalazine, hydroxychloroquine, gold, penicillamine, leflunomide, and azathioprine. Unlike Studies 1, 2 and 3, patients predisposed to infection due to a history of underlying disease such as pneumonia, asthma, controlled diabetes, and chronic obstructive pulmonary disease (COPD) were also enrolled.
- In Studies 1, 2 and 3, the improvement in signs and symptoms of RA was assessed using the American College of Rheumatology (ACR) response criteria (ACR20, ACR50, ACR70). In these studies, patients treated with Kineret were more likely to achieve an ACR20 or higher magnitude of response (ACR50 and ACR70) than patients treated with placebo (Table 3). The treatment response rates did not differ based on gender or ethnic group. The results of the ACR component scores in Study 1 are shown in Table 4.
- Most clinical responses, both in patients receiving placebo and patients receiving Kineret, occurred within 12 weeks of enrollment.
- A 24-week study was conducted in 242 patients with active RA on background methotrexate who were randomized to receive either etanercept alone or the combination of Kineret and etanercept. The ACR50 response rate was 31% for patients treated with the combination of Kineret and etanercept and 41% for patients treated with etanercept alone, indicating no added clinical benefit of the combination over etanercept alone. Serious infections were increased with the combination compared to etanercept alone.
- In Study 1, the effect of Kineret on the progression of structural damage was assessed by measuring the change from baseline at month 12 in the Total Modified Sharp Score (TSS) and its subcomponents, erosion score, and joint space narrowing (JSN) score.2 Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months and 12 months and scored by readers who were unaware of treatment group. A difference between placebo and Kineret for change in TSS, erosion score (ES) and JSN score was observed at 12 months (Table 5).
- The disability index of the Health Assessment Questionnaire (HAQ) was administered monthly for the first six months and quarterly thereafter during Study 1. Health outcomes were assessed by the Short Form-36 (SF-36) questionnaire. The 1-year data on HAQ in Study 1 showed more improvement with Kineret than placebo. The physical component summary (PCS) score of the SF-36 also showed more improvement with Kineret than placebo but not the mental component summary (MCS).
- The efficacy of Kineret was evaluated in a prospective, long-term, open-label and uncontrolled study which incorporated a withdrawal period in a subset of 11 patients. This study included 43 NOMID patients 0.7 to 46 years of age treated for up to 60 months. Patients were given an initial Kineret dose of 1–2.4 mg/kg body weight. During the study, the dose was adjusted by 0.5 to 1 mg/kg increments to a protocol-specified maximum of 10 mg/kg daily, titrated to control signs and symptoms of disease. The maximum dose actually studied was 7.6 mg/kg/day. The average maintenance dose was 3 to 4 mg/kg daily. In general, the dose was given once daily, but for some patients, the dose was split into twice daily administrations for better control of disease activity.
- NOMID symptoms were assessed with a disease-specific Diary Symptom Sum Score (DSSS), which included the prominent disease symptoms fever, rash, joint pain, vomiting, and headache. In addition, serum amyloid A (SAA), hsCRP, and ESR levels were monitored. Changes in clinical and laboratory parameters from baseline to Months 3 to 6 and from Month 3 (before withdrawal) to the end of the withdrawal period were assessed in the subset of patients who underwent withdrawal. The estimated changes from baseline in DSSS are summarized through Month 60 in Table 6. Results were consistent across all subgroups, including age, gender, presence of CIAS1 mutation, and disease phenotype. Improvements occurred in all individual disease symptoms comprising the DSSS (Table 7), as well as in the serum markers of inflammation. For the 11 patients who went through a withdrawal phase, disease symptoms and serum markers of inflammation worsened after withdrawal and promptly responded to reinstitution of Kineret therapy. Upon withdrawal of treatment, the median time until disease flare criteria were met was 5 days.
- Kineret treatment also appeared to be associated with improvement of, or stability in, assessments of other NOMID disease manifestations, such as CNS, audiogram, and visual acuity data, up to Month 60.
# How Supplied
- Kineret is supplied in single-use preservative free, prefilled glass syringes with 27 gauge needles. Each prefilled glass syringe contains 100 mg of anakinra per 0.67 mL. The full syringe contains 100 mg anakinra. Kineret is dispensed in a 4 x 7 syringe dispensing pack containing 28 syringes (NDC 66658-234-28). Kineret is also dispensed in a 1 x 7 syringe dispensing pack containing 7 syringes (NDC 66658-234-07).
- Storage
- Kineret should be stored in the refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE OR SHAKE. Protect from light.
## Storage
There is limited information regarding Anakinra Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients and their caregivers on the proper dosage and administration of Kineret and provide all patients with the “Patient information and Instructions for Use” insert. While this Patient Information and Instructions for Use provides information about the product and its use, it is not intended to take the place of regular discussions between the patient and healthcare provider. The ability to inject subcutaneously should be assessed to ensure proper administration of Kineret. The prefilled syringe contains an outer rigid plastic needle shield attached to a grey inner needle cover. Inform patients and their caregivers that the inner needle cover contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex. Thoroughly instruct patients and their caregivers on the importance of proper disposal and caution against the reuse of needles, syringes, and drug product. A puncture-resistant container for the disposal of used syringes should be available to the patient. The full container should be disposed of according to the directions provided by the healthcare provider.
- Infections: Inform patients that Kineret may lower the ability of their immune system to fight infections. Advise patients of the importance of contacting their doctor if they develop any symptoms of infection.
- Injection-site reactions: Physicians should explain to patients that almost a quarter of patients in the clinical trial experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, purities, brusing, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Inform patients or their caregivers that the prefilled syringe should be removed from refrigeration and left at room temperature for 30 minutes before injecting. Patients should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician.
- Allergic or other drug reactions: Inform patients about the signs and symptoms of allergic and other adverse drug reactions and the appropriate actions they should take if they experience any of these signs and symptoms.
# Precautions with Alcohol
- Alcohol-Anakinra interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KINERET®
# Look-Alike Drug Names
- Kineret® — Amikin®
# Drug Shortage Status
# Price | Anakinra
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Anakinra is an interleukin-1 receptor antagonist that is FDA approved for the {{{indicationType}}} of rheumatoid arthritis (RA)and cryopyrin-associated periodic syndromes (CAPS). Common adverse reactions include upper respiratory tract infection, headache, nausea, diarrhea, sinusitis, arthralgia, flu like-symptoms, and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Kineret for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anakinra in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anakinra in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended starting dose of Kineret is 1-2 mg/kg for NOMID patients. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation.
- Adjust doses in 0.5 to 1.0 mg/kg increments. Once daily administration is generally recommended, but the dose may be split into twice daily administrations. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anakinra in pediatric patients.
### Non–Guideline-Supported Use
- Anakinra 2 mg/kilogram (kg) subcutaneously once daily.[1]
# Contraindications
- Kineret is contraindicated in patients with known hypersensitivity to E coli-derived proteins, Kineret, or any components of the product.
# Warnings
### Precautions
- Serious Infections
- Kineret has been associated with an increased incidence of serious infections (2%) vs. Placebo (< 1%) in clinical trials in RA. Administration of Kineret in RA should be discontinued if a patient develops a serious infection. In Kineret treated NOMID patients the risk of a NOMID flare when discontinuing Kineret treatment should be weighed against the potential risk of continued treatment. Treatment with Kineret should not be initiated in patients with active infections. The safety and efficacy of Kineret in immunosuppressed patients or in patients with chronic infections have not been evaluated.
- Drugs that affect the immune system by blocking tumor necrosis factor (TNF) have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as Kineret that blocks IL-1 increases the risk of TB or other atypical or opportunistic infections. Health care providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with Kineret.
- Use With TNF Blocking Agents
- In a 24-week study of concurrent Kineret and etanercept therapy in RA patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). The combination of Kineret and etanercept did not result in higher ACR response rates compared to etanercept alone. Use of Kineret in combination with TNF blocking agents is not recommended.
- Hypersensitivity Reactions
- Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported with Kineret. If a severe hypersensitivity reaction occurs, administration of Kineret should be discontinued and appropriate therapy initiated.
- The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
- Immunosuppression
- The impact of treatment with Kineret on active and/or chronic infections and the development of malignancies is not known.
- Immunizations
- In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret and placebo treatment groups when the tetanus/diphtheria toxoids vaccine was administered concurrently with Kineret. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be given concurrently with Kineret.
- Neutrophil Count
- Patients receiving Kineret may experience a decrease in neutrophil counts. Neutrophil counts should therefore be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly for 3 months, and thereafter quarterly for a period up to 1 year.
- In the placebo-controlled studies, 8% of RA patients receiving Kineret had decreases in neutrophil counts of at least one World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Nine Kineret-treated patients (0.4%) experienced neutropenia (ANC < 1 x 109/L).
- In 43 NOMID patients followed for up to 60 months 2 patients experienced neutropenia that resolved over time during continued Kineret treatment.
# 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 clinical practice.
- The most serious adverse reactions were:
- Serious Infections
- Neutropenia, particularly when used in combination with TNF blocking agents
- The most common adverse reaction with Kineret is injection-site reactions. These reactions were the most common reason for withdrawing from studies.
- The data described herein reflect exposure to Kineret in 3025 patients, including 2124 exposed for at least 6 months and 884 exposed for at least one year. Studies 1 and 4 used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis.
- Injection-site Reactions
- The most common and consistently reported treatment-related adverse event associated with Kineret is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain.
- Infections
- In Studies 1 and 4 combined, the incidence of infection was 39% in the Kineret-treated patients and 37% in placebo-treated patients during the first 6 months of blinded treatment. The incidence of serious infections in Studies 1 and 4 was 2% in Kineret-treated patients and 1% in patients receiving placebo over 6 months. The incidence of serious infection over 1 year was 3% in Kineret-treated patients and 2% in patients receiving placebo. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Majority of patients (73%) continued on study drug after the infection resolved. No serious opportunistic infections were reported. Patients with asthma appeared to be at higher risk of developing serious infections when treated with Kineret (8 of 177 patients, 4.5%) compared to placebo (0 of 50 patients, 0%).
- In open-label extension studies, the overall rate of serious infections was stable over time and comparable to that observed in controlled trials. In clinical studies and postmarketing experience, cases of opportunistic infections have been observed and included fungal, mycobacterial and bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret alone or in combination with immunosuppressive agents.
- In patients who received both Kineret and etanercept for up to 24 weeks, the incidence of serious infections was 7%. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure.
- Malignancies
- Among 5300 RA patients treated with Kineret in clinical trials for a mean of 15 months (approximately 6400 patient years of treatment), 8 lymphomas were observed for a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population, based on the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database.3 An increased rate of lymphoma, up to several fold, has been reported in the RA population, and may be further increased in patients with more severe disease activity. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common were breast, respiratory system, and digestive system. There were 3 melanomas observed in Study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known. While patients with RA, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of IL-1 blockers in the development of malignancy is not known.
- Hematologic Events
- In placebo-controlled studies with Kineret, 8% of patients receiving Kineret had decreases in total white blood counts of at least one WHO toxicity grade, compared with 2% of placebo patients. Nine Kineret-treated patients (0.4%) developed neutropenia (ANC < 1 x 109/L). 9 % of patients receiving Kineret had increases in eosinophil differential percentage of at least one WHO toxicity grade, compared with 3 % of placebo patients. Of patients treated concurrently with Kineret and etanercept 2% developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy. 2% of patients receiving Kineret had decreases in platelets, all of WHO toxicity grade one, compared to 0% of placebo patients.
- Hypersensitivity Reactions
- Hypersensitivity reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported with Kineret.
- Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. In Studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positive for anti-anakinra binding antibodies at one or more time points using a biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) tested positive for neutralizing antibodies in a cell-based bioassay. Of the 13 patients with available follow-up data, 5 patients remained positive for neutralizing antibodies at the end of the studies. No correlation between antibody development and adverse events was observed.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kineret with the incidence of antibodies to other products may be misleading.
- Other Adverse Events
- Table 1 reflects adverse events in Studies 1 and 4, that occurred with a frequency of ≥ 5% in Kineret-treated patients over a 6-month period.
- The data described herein reflect an open-label study in 43 NOMID patients exposed to Kineret for up to 60 months adding up to a total exposure of 159.8 patient years.
- Patients were treated with a starting dose of 1 to 2 mg/kg/day and an average maintenance dose of 3-4 mg/kg/day adjusted depending on the severity of disease. Among pediatric NOMID patients, doses up to 7.6 mg/kg/day have been maintained for up to 15 months.
- There were 24 serious adverse events (SAEs) reported in 14 of the 43 treated patients. The most common type of SAEs reported were infections. Five SAEs were related to lumbar puncture, which was part of the study procedure.
- There were no permanent discontinuations of study drug treatment due to AEs. Doses were adjusted in 5 patients because of AEs; all were dose increases in connection with disease flares.
- The reporting frequency of AEs was highest during the first 6 months of treatment. The incidence of AEs did not increase over time, and no new types of AEs emerged.
- The most commonly reported AEs during the first 6 months of treatment (incidence >10%) were injection site reaction (ISR), headache, vomiting, arthralgia, pyrexia, and nasopharyngitis (Table 2).
- The most commonly reported AEs during the 60-month study period, calculated as the number of events/patient years of exposure, were arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.
- The AE profiles for different age groups <2 years, 2-11 years, and 12-17 years corresponded to the AE profile for patients ≥18 years, with the exception of infections and related symptoms being more frequent in patients <2 years.
- Infections
- The reporting rate for infections was higher during the first 6 months of treatment (2.3 infections/patient-year) compared to after the first 6 months (1.7 infections/patient year). The most common infections were upper respiratory tract infection, sinusitis, ear infections, and nasopharyngitis.
- There were no deaths or permanent treatment discontinuations due to infections. In one patient Kineret administration was temporarily stopped during an infection and in 5 patients the dose of Kineret was increased due to disease flares in connection with infections. Thirteen infections in 7 patients were classified as serious, the most common being pneumonia and gastroenteritis occurring in 3 and 2 patients, respectively. No serious opportunistic infections were reported.
- The reporting frequency for infections was highest in patients <12 years of age.
- Hematologic Events
- After start of Kineret treatment neutropenia was reported in 2 patients. One of these patients experienced an upper respiratory tract infection and an otitis media infection. Both episodes of neutropenia resolved over time with continued Kineret treatment.
- Injection Site Reactions
- In total, 17 injection site reactions (ISRs) were reported in 10 patients during the 60-month study period. Out of the 17 ISRs, 11 (65%) occurred during the first month and 13 (76%) were reported during the first 6 months. No ISR was reported after Year 2 of treatment. The majority of ISRs were reported as mild (76% mild, 24% moderate). No patient permanently or temporarily discontinued Kineret treatment due to injection site reactions.
- Immunogenicity
- The immunogenicity of Kineret in NOMID patients was not evaluated.
- The most common adverse reactions occurring after the first 6-month period of treatment with Kineret (up to 60 months of treatment) included: arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Kineret. 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.
Elevations of transaminases, non-infectious hepatitis
# Drug Interactions
- TNF Blocking Agents
- A higher rate of serious infections has been observed in patients treated with concurrent Kineret and etanercept therapy than in patients treated with etanercept alone. Two percent of patients treated concurrently with Kineret and etanercept developed neutropenia (ANC < 1 x 109/L). Use of Kineret in combination with TNF blocking agents is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies of Kineret in pregnant women. Reproductive studies have been performed in rats and rabbits at doses up to 25 times the maximum recommended human dose (on a mg/kg basis at a maternal dose of 200 mg/kg/day) and have revealed no evidence of impaired fertility or harm to the fetus due to Kineret. Because animal reproduction studies are not always predictive of human response, Kineret should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anakinra in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Anakinra during labor and delivery.
### Nursing Mothers
- It is not known whether Kineret is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised if Kineret is administered to nursing women.
### Pediatric Use
- The NOMID study included 36 pediatric patients: 13 below 2 years, 18 between 2 and 11 years, and 5 between 12 and 17 years of age. A subcutaneous Kineret starting dose of 1–2 mg/kg/day was administered in all age groups. An average maintenance dose of 3–4 mg/kg/day was adequate to maintain clinical response throughout the study irrespective of age but a higher dose was, on occasion, required in severely affected patients. The prefilled syringe does not allow doses lower than 20 mg to be administered.
- Kineret was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA; ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Kineret for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Kineret is not recommended for pediatric use in Juvenile Rheumatoid Arthritis.
### Geriatic Use
- A total of 752 RA patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, were studied in clinical trials. No differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
### Gender
There is no FDA guidance on the use of Anakinra with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Anakinra with respect to specific racial populations.
### Renal Impairment
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
### Hepatic Impairment
- No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Anakinra in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Anakinra in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Anakinra in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Anakinra in the drug label.
# Overdosage
## Acute Overdose
- There have been no cases of overdose reported with Kineret in clinical trials of RA or NOMID. In sepsis trials no serious toxicities attributed to Kineret were seen when administered at mean calculated doses of up to 35 times those given patients with RA over a 72-hour treatment period.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Anakinra in the drug label.
# Pharmacology
## Mechanism of Action
- Kineret blocks the biologic activity of IL-1 alpha and beta by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs.
- IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from RA patients are not sufficient to compete with the elevated amount of locally produced IL-1.
- Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID.
## Structure
- Kineret (anakinra) is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus. Kineret consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA technology using an E coli bacterial expression system.
- Kineret is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, clear, colorless-to-white, preservative free solution for daily subcutaneous (SC) administration. The solution may contain trace amounts of small, translucent-to-white amorphous proteinaceous particles. Each prefilled glass syringe contains: 0.67 mL (100 mg) of anakinra in a solution (pH 6.5) containing disodium EDTA (0.12 mg), sodium chloride (5.48 mg), anhydrous citric acid (1.29 mg), and polysorbate 80 (0.70 mg) in Water for Injection, USP.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Anakinra in the drug label.
## Pharmacokinetics
- The absolute bioavailability of Kineret after a 70 mg subcutaneous bolus injection in healthy subjects (n = 11) is 95%. In subjects with RA, maximum plasma concentrations of Kineret occurred 3 to 7 hours after subcutaneous administration of Kineret at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of Kineret was observed after daily subcutaneous doses for up to 24 weeks.
- The influence of demographic covariates on the pharmacokinetics of Kineret was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous injection of Kineret at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated Kineret clearance increased with increasing creatinine clearance and body weight. After adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance.
- In NOMID patients, at a median SC dose of 3 mg/kg once daily and a median treatment time of 3.5 years, the median (range) steady-state serum exposure of anakinra was Cmax 3628 (655–8511) ng/mL (n=16) and C24h 203 (53–1979) ng/mL (n=16). The median (range) half-life of anakinra was 5.7 (3.1–28.2) hours (n=12). There was no obvious gender difference.
- Patients With Renal Impairment: The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance < 30 mL/min1), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of Kineret was removed by hemodialysis or continuous ambulatory peritoneal dialysis. Based on these observations, a dose schedule change should be considered for subjects with severe renal insufficiency or end stage renal disease [see Dosage and Administration (2.2)].
- Patients with Hepatic Dysfunction: No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in patients with hepatic impairment.
## Nonclinical Toxicology
- Long-term animal studies to evaluate the carcinogenic potential of Kineret were not conducted. Using a standard in vivo and in vitro battery of mutagenesis assays, Kineret did not induce gene mutations in either bacteria or mammalian cells. Kineret had no effects on fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (approximately 25 times the maximum recommended dose).
# Clinical Studies
- The safety and efficacy of Kineret have been evaluated in three randomized, double-blind, placebo-controlled trials of 1790 patients ≥ 18 years of age with active rheumatoid arthritis (RA). An additional fourth study was conducted to assess safety. In the efficacy trials, Kineret was studied in combination with other disease-modifying antirheumatic drugs (DMARDs) other than Tumor Necrosis Factor (TNF) blocking agents (Studies 1 and 2) or as a monotherapy (Study 3).
- Study 1 involved 899 patients with active RA who had been on a stable dose of methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks. All patients had at least 6 swollen/painful and 9 tender joints and either a C-reactive protein (CRP) of ≥ 1.5 mg/dL or an erythrocyte sedimentation rate (ESR) of ≥ 28 mm/hr. Patients were randomized to Kineret or placebo in addition to their stable doses of MTX. The first 501 patients were evaluated for signs and symptoms of active RA. The total 899 patients were evaluated for progression of structural damage.
- Study 2 evaluated 419 patients with active RA who had received MTX for at least 6 months including a stable dose (15 to 25 mg/week) for at least 3 consecutive months prior to enrollment. Patients were randomized to receive placebo or one of five doses of Kineret subcutaneous daily for 12 to 24 weeks in addition to their stable doses of MTX.
- Study 3 evaluated 472 patients with active RA and had similar inclusion criteria to Study 1 except that these patients had received no DMARD for the previous 6 weeks or during the study. Patients were randomized to receive either Kineret or placebo. Patients were DMARD-naïve or had failed no more than 3 DMARDs.
- Study 4 was a placebo-controlled, randomized trial designed to assess the safety of Kineret in 1414 patients receiving a variety of concurrent medications for their RA including some DMARD therapies, as well as patients who were DMARD-free. The TNF blocking agents etanercept and infliximab were specifically excluded. Concurrent DMARDs included MTX, sulfasalazine, hydroxychloroquine, gold, penicillamine, leflunomide, and azathioprine. Unlike Studies 1, 2 and 3, patients predisposed to infection due to a history of underlying disease such as pneumonia, asthma, controlled diabetes, and chronic obstructive pulmonary disease (COPD) were also enrolled.
- In Studies 1, 2 and 3, the improvement in signs and symptoms of RA was assessed using the American College of Rheumatology (ACR) response criteria (ACR20, ACR50, ACR70). In these studies, patients treated with Kineret were more likely to achieve an ACR20 or higher magnitude of response (ACR50 and ACR70) than patients treated with placebo (Table 3). The treatment response rates did not differ based on gender or ethnic group. The results of the ACR component scores in Study 1 are shown in Table 4.
- Most clinical responses, both in patients receiving placebo and patients receiving Kineret, occurred within 12 weeks of enrollment.
- A 24-week study was conducted in 242 patients with active RA on background methotrexate who were randomized to receive either etanercept alone or the combination of Kineret and etanercept. The ACR50 response rate was 31% for patients treated with the combination of Kineret and etanercept and 41% for patients treated with etanercept alone, indicating no added clinical benefit of the combination over etanercept alone. Serious infections were increased with the combination compared to etanercept alone.
- In Study 1, the effect of Kineret on the progression of structural damage was assessed by measuring the change from baseline at month 12 in the Total Modified Sharp Score (TSS) and its subcomponents, erosion score, and joint space narrowing (JSN) score.2 Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months and 12 months and scored by readers who were unaware of treatment group. A difference between placebo and Kineret for change in TSS, erosion score (ES) and JSN score was observed at 12 months (Table 5).
- The disability index of the Health Assessment Questionnaire (HAQ) was administered monthly for the first six months and quarterly thereafter during Study 1. Health outcomes were assessed by the Short Form-36 (SF-36) questionnaire. The 1-year data on HAQ in Study 1 showed more improvement with Kineret than placebo. The physical component summary (PCS) score of the SF-36 also showed more improvement with Kineret than placebo but not the mental component summary (MCS).
- The efficacy of Kineret was evaluated in a prospective, long-term, open-label and uncontrolled study which incorporated a withdrawal period in a subset of 11 patients. This study included 43 NOMID patients 0.7 to 46 years of age treated for up to 60 months. Patients were given an initial Kineret dose of 1–2.4 mg/kg body weight. During the study, the dose was adjusted by 0.5 to 1 mg/kg increments to a protocol-specified maximum of 10 mg/kg daily, titrated to control signs and symptoms of disease. The maximum dose actually studied was 7.6 mg/kg/day. The average maintenance dose was 3 to 4 mg/kg daily. In general, the dose was given once daily, but for some patients, the dose was split into twice daily administrations for better control of disease activity.
- NOMID symptoms were assessed with a disease-specific Diary Symptom Sum Score (DSSS), which included the prominent disease symptoms fever, rash, joint pain, vomiting, and headache. In addition, serum amyloid A (SAA), hsCRP, and ESR levels were monitored. Changes in clinical and laboratory parameters from baseline to Months 3 to 6 and from Month 3 (before withdrawal) to the end of the withdrawal period were assessed in the subset of patients who underwent withdrawal. The estimated changes from baseline in DSSS are summarized through Month 60 in Table 6. Results were consistent across all subgroups, including age, gender, presence of CIAS1 mutation, and disease phenotype. Improvements occurred in all individual disease symptoms comprising the DSSS (Table 7), as well as in the serum markers of inflammation. For the 11 patients who went through a withdrawal phase, disease symptoms and serum markers of inflammation worsened after withdrawal and promptly responded to reinstitution of Kineret therapy. Upon withdrawal of treatment, the median time until disease flare criteria were met was 5 days.
- Kineret treatment also appeared to be associated with improvement of, or stability in, assessments of other NOMID disease manifestations, such as CNS, audiogram, and visual acuity data, up to Month 60.
# How Supplied
- Kineret is supplied in single-use preservative free, prefilled glass syringes with 27 gauge needles. Each prefilled glass syringe contains 100 mg of anakinra per 0.67 mL. The full syringe contains 100 mg anakinra. Kineret is dispensed in a 4 x 7 syringe dispensing pack containing 28 syringes (NDC 66658-234-28). Kineret is also dispensed in a 1 x 7 syringe dispensing pack containing 7 syringes (NDC 66658-234-07).
- Storage
- Kineret should be stored in the refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE OR SHAKE. Protect from light.
## Storage
There is limited information regarding Anakinra Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients and their caregivers on the proper dosage and administration of Kineret and provide all patients with the “Patient information and Instructions for Use” insert. While this Patient Information and Instructions for Use provides information about the product and its use, it is not intended to take the place of regular discussions between the patient and healthcare provider. The ability to inject subcutaneously should be assessed to ensure proper administration of Kineret. The prefilled syringe contains an outer rigid plastic needle shield attached to a grey inner needle cover. Inform patients and their caregivers that the inner needle cover contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex. Thoroughly instruct patients and their caregivers on the importance of proper disposal and caution against the reuse of needles, syringes, and drug product. A puncture-resistant container for the disposal of used syringes should be available to the patient. The full container should be disposed of according to the directions provided by the healthcare provider.
- Infections: Inform patients that Kineret may lower the ability of their immune system to fight infections. Advise patients of the importance of contacting their doctor if they develop any symptoms of infection.
- Injection-site reactions: Physicians should explain to patients that almost a quarter of patients in the clinical trial experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, purities, brusing, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Inform patients or their caregivers that the prefilled syringe should be removed from refrigeration and left at room temperature for 30 minutes before injecting. Patients should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician.
- Allergic or other drug reactions: Inform patients about the signs and symptoms of allergic and other adverse drug reactions and the appropriate actions they should take if they experience any of these signs and symptoms.
# Precautions with Alcohol
- Alcohol-Anakinra interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KINERET®[2]
# Look-Alike Drug Names
- Kineret® — Amikin®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Anakinra | |
9313ac01a29513aa888860ee100f3bb39ca6461f | wikidoc | Analysis | Analysis
Analysis (from Greek ἀνάλυσις, "a breaking up") is the process of breaking a complex topic or substance into smaller parts to gain a better understanding of it. The technique has been applied in the study of mathematics and logic since before Aristotle, though analysis as a formal concept is a relatively recent development.
As a formal concept, the method has variously been ascribed to Ibn al-Haytham, Descartes (Discourse on the Method), Galileo, and Newton, as a practical method of physical discovery.
# Use in specific fields
## Chemistry
The field of chemistry uses analysis to break down chemical processes and examine chemical reactions between elements of matter. For example, analysis of the concentration of elements is important in managing a nuclear reactor, so nuclear scientists will analyze neutron activation to develop discrete measurements within vast samples. A matrix can have a considerable effect on the way a chemical analysis is conducted and the quality of its results. Analysis can be done manually or with a device. Chemical analysis is an important element of national security among the major world powers with Materials Measurement and Signature Intelligence (MASINT) capabilities.
### Isotopes
Chemists can use isotopes to assist analysts with issues in anthropology, archeology, food chemistry, forensics, geology, and a host of other questions of physical science. Analysts can discern the origins of natural and man-made isotopes in the study of environmental radioactivity.
## Computer science
- Analysis of algorithms
- Competitive analysis (online algorithm), shows how online algorithms perform and demonstrates the power of randomization in algorithms
- Worst-case execution time, determines the longest time that a piece of software can take to run
- Program analysis (computer science), the process of automatically analysing the behavior of computer programs
- Static code analysis, the analysis of computer software that is performed without actually executing programs built from that software
- Syntax analysis, a process in compilers that recognizes the structure of programming languages, also known as parsing
- Semantic analysis (computer science), a pass by a compiler that adds semantical information to the parse tree and performs certain checks
- Lexical analysis, the process of processing an input sequence of characters and producing as output a sequence of symbols
- Object-oriented analysis and design, à la Booch
- Structured Systems Analysis and Design Methodology, à la Yourdon
## Economics
- Business analysis, analysing which way improvement of IT systems increases business performance
- Agroecosystem analysis
- Financial analysis, the analysis of the accounts and the economic prospects of a firm
- Fundamental analysis, a stock valuation method that uses financial analysis
- Input-output model if applied to a region, is called Regional Impact Multiplier System
- Principal components analysis, a technique that can be used to simplify a dataset
- Technical analysis, the study of price action in securities markets in order to forecast future prices
- Price Analysis, involves the breakdown of a price to a unit figure
- Market analysis, consists of suppliers and customers, and price is determined by the interaction of supply and demand
## Engineering
Analysts in the field of engineering look at structures, mechanisms, systems and dimensions. Electrical engineers analyze systems in electronics. Life cycles and system failures are broken down and studied by engineers.
## Intelligence
The field of intelligence employs analysts to break down and understand a wide array of questions. intelligence agencies may use heuristics, inductive and deductive reasoning, social network analysis, dynamic network analysis, link analysis, and brainstorming to sort through problems they face. Military intelligence may explore issues through the use of game theory, Red Teaming, and wargaming. Signals intelligence applies cryptanalysis and frequency analysis to break codes and ciphers. Business intelligence applies theories of competitive intelligence analysis and competitor analysis to resolve questions in the marketplace. Law enforcement intelligence applies a number of theories in crime analysis.
## Linguistics
Linguistics began with the analysis of Sanskrit; today it looks at individual languages and language in general. It breaks language down and analyzes its component parts: theory, sounds and their meaning, utterance usage, word origins, the history of words, the meaning of words and word combinations, sentence construction, basic construction beyond the sentence level, stylistics, and conversation. It examines the above using statistics and modeling, and semantics. It analyzes language in context of anthropology, biology, evolution, geography, history, neurology, psychology, and sociology. It also takes the applied approach, looking at individual language development and clinical issues.
## Literary criticism
- Analysis (Homer), an influential school of thought in Homeric scholarship in the 19th-20th centuries
- Psychocriticism, Charles Mauron's method based on Freud's own initial interpretations of literary works such as Hamlet
## Mathematics
- Mathematical analysis, the generic name given to any branch of mathematics that depends upon the concepts of limits and convergence
- Complex analysis
- Fourier analysis
- Functional analysis
- Harmonic analysis
- Non-standard analysis
- Numerical analysis, the study of algorithms for the problems of continuous mathematics
- Real analysis
- Constructivist analysis
## Music
- Musical analysis, a process attempting to answer the question "How does this music work?"
- Schenkerian analysis
## Philosophy
- Philosophical analysis, a general term for the techniques used by philosophers
- Analysis is the name of a prominent journal in philosophy.
## Psychotherapy
- Psychoanalysis, seeks to elucidate connections among unconscious components of patients' mental processes
- Transactional analysis
## Signal processing
- Finite element analysis, a computer simulation technique used in engineering analysis
- Independent component analysis
- Link quality analysis, the analysis of signal quality
- Path quality analysis
## Statistics
- Analysis of variance (ANOVA), a collection of statistical models and their associated procedures which compare means by splitting the overall observed variance into different parts
- Meta-analysis, combines the results of several studies that address a set of related research hypotheses
- Time-series analysis, methods that attempt to understand a sequence of data points spaced apart at uniform time intervals
## Other
- Aura analysis, a technique in which supporters of the method claim that the body's aura, or energy field is analysed
- Bowling analysis, a notation summarizing a cricket bowler's performance
- Lithic analysis, the analysis of stone tools using basic scientific techniques
- Protocol analysis, a means for extracting persons' thoughts while they are performing a task | Analysis
Template:TOCRight
Analysis (from Greek ἀνάλυσις, "a breaking up") is the process of breaking a complex topic or substance into smaller parts to gain a better understanding of it. The technique has been applied in the study of mathematics and logic since before Aristotle, though analysis as a formal concept is a relatively recent development.
As a formal concept, the method has variously been ascribed to Ibn al-Haytham,[1] Descartes (Discourse on the Method), Galileo, and Newton, as a practical method of physical discovery.
# Use in specific fields
## Chemistry
Template:Seealso
The field of chemistry uses analysis to break down chemical processes and examine chemical reactions between elements of matter. For example, analysis of the concentration of elements is important in managing a nuclear reactor, so nuclear scientists will analyze neutron activation to develop discrete measurements within vast samples. A matrix can have a considerable effect on the way a chemical analysis is conducted and the quality of its results. Analysis can be done manually or with a device. Chemical analysis is an important element of national security among the major world powers with Materials Measurement and Signature Intelligence (MASINT) capabilities.
### Isotopes
Template:Seealso
Chemists can use isotopes to assist analysts with issues in anthropology, archeology, food chemistry, forensics, geology, and a host of other questions of physical science. Analysts can discern the origins of natural and man-made isotopes in the study of environmental radioactivity.
## Computer science
- Analysis of algorithms
- Competitive analysis (online algorithm), shows how online algorithms perform and demonstrates the power of randomization in algorithms
- Worst-case execution time, determines the longest time that a piece of software can take to run
- Program analysis (computer science), the process of automatically analysing the behavior of computer programs
- Static code analysis, the analysis of computer software that is performed without actually executing programs built from that software
- Syntax analysis, a process in compilers that recognizes the structure of programming languages, also known as parsing
- Semantic analysis (computer science), a pass by a compiler that adds semantical information to the parse tree and performs certain checks
- Lexical analysis, the process of processing an input sequence of characters and producing as output a sequence of symbols
- Object-oriented analysis and design, à la Booch
- Structured Systems Analysis and Design Methodology, à la Yourdon
## Economics
- Business analysis, analysing which way improvement of IT systems increases business performance
- Agroecosystem analysis
- Financial analysis, the analysis of the accounts and the economic prospects of a firm
- Fundamental analysis, a stock valuation method that uses financial analysis
- Input-output model if applied to a region, is called Regional Impact Multiplier System
- Principal components analysis, a technique that can be used to simplify a dataset
- Technical analysis, the study of price action in securities markets in order to forecast future prices
- Price Analysis, involves the breakdown of a price to a unit figure
- Market analysis, consists of suppliers and customers, and price is determined by the interaction of supply and demand
## Engineering
Template:Seealso
Analysts in the field of engineering look at structures, mechanisms, systems and dimensions. Electrical engineers analyze systems in electronics. Life cycles and system failures are broken down and studied by engineers.
## Intelligence
Template:Seealso
The field of intelligence employs analysts to break down and understand a wide array of questions. intelligence agencies may use heuristics, inductive and deductive reasoning, social network analysis, dynamic network analysis, link analysis, and brainstorming to sort through problems they face. Military intelligence may explore issues through the use of game theory, Red Teaming, and wargaming. Signals intelligence applies cryptanalysis and frequency analysis to break codes and ciphers. Business intelligence applies theories of competitive intelligence analysis and competitor analysis to resolve questions in the marketplace. Law enforcement intelligence applies a number of theories in crime analysis.
## Linguistics
Template:Seealso
Linguistics began with the analysis of Sanskrit; today it looks at individual languages and language in general. It breaks language down and analyzes its component parts: theory, sounds and their meaning, utterance usage, word origins, the history of words, the meaning of words and word combinations, sentence construction, basic construction beyond the sentence level, stylistics, and conversation. It examines the above using statistics and modeling, and semantics. It analyzes language in context of anthropology, biology, evolution, geography, history, neurology, psychology, and sociology. It also takes the applied approach, looking at individual language development and clinical issues.
## Literary criticism
- Analysis (Homer), an influential school of thought in Homeric scholarship in the 19th-20th centuries
- Psychocriticism, Charles Mauron's method based on Freud's own initial interpretations of literary works such as Hamlet
## Mathematics
- Mathematical analysis, the generic name given to any branch of mathematics that depends upon the concepts of limits and convergence
- Complex analysis
- Fourier analysis
- Functional analysis
- Harmonic analysis
- Non-standard analysis
- Numerical analysis, the study of algorithms for the problems of continuous mathematics
- Real analysis
- Constructivist analysis
## Music
- Musical analysis, a process attempting to answer the question "How does this music work?"
- Schenkerian analysis
## Philosophy
- Philosophical analysis, a general term for the techniques used by philosophers
- Analysis is the name of a prominent journal in philosophy.
## Psychotherapy
- Psychoanalysis, seeks to elucidate connections among unconscious components of patients' mental processes
- Transactional analysis
## Signal processing
- Finite element analysis, a computer simulation technique used in engineering analysis
- Independent component analysis
- Link quality analysis, the analysis of signal quality
- Path quality analysis
## Statistics
- Analysis of variance (ANOVA), a collection of statistical models and their associated procedures which compare means by splitting the overall observed variance into different parts
- Meta-analysis, combines the results of several studies that address a set of related research hypotheses
- Time-series analysis, methods that attempt to understand a sequence of data points spaced apart at uniform time intervals
## Other
- Aura analysis, a technique in which supporters of the method claim that the body's aura, or energy field is analysed
- Bowling analysis, a notation summarizing a cricket bowler's performance
- Lithic analysis, the analysis of stone tools using basic scientific techniques
- Protocol analysis, a means for extracting persons' thoughts while they are performing a task | https://www.wikidoc.org/index.php/Analysis | |
192aa0be85133f7cc152951eb39f8e884c47e5d0 | wikidoc | Androgen | Androgen
# Overview
Androgen is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of masculine characteristics in vertebrates by binding to androgen receptors. This includes the activity of the accessory male sex organs and development of male secondary sex characteristics. Androgens, which were first discovered in 1936, are also called androgenic hormones or testoids. Androgens are also the original anabolic steroids. They are also the precursor of all estrogens, the female sex hormones. The primary and most well-known androgen is testosterone.
# Types of androgens
A subset of androgens, adrenal androgens, includes any of the 19-carbon steroids synthesized by the adrenal cortex, the outer portion of the adrenal gland (zonula reticularis - innermost region of the adrenal cortex), that function as weak steroids or steroid precursors, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione.
Besides testosterone, other androgens include:
- Dehydroepiandrosterone (DHEA): a steroid hormone produced in the adrenal cortex from cholesterol. It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.
- Androstenedione (Andro): an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone. Use of androstenedione as an athletic or body building supplement has been banned by the International Olympic Committee as well as other sporting organizations.
- Androstenediol: the steroid metabolite that is thought to act as the main regulator of gonadotropin secretion.
- Androsterone: a chemical by-product created during the breakdown of androgens, or derived from progesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in the plasma and urine of both males and females.
- Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. It is produced in the adrenal cortex.
# Androgen functions
## Development of the male
### Testis formation
During mammalian development, the gonads are at first capable of becoming either ovaries or testes. In humans, starting at about week 4 the gonadal rudiments are present within the intermediate mesoderm adjacent to the developing kidneys. At about week 6, epithelial sex cords develop within the forming testes and incorporate the germ cells as they migrate into the gonads. In males, certain Y chromosome genes, particularly SRY, control development of the male phenotype, including conversion of the early bipotential gonad into testes. In males, the sex cords fully invade the developing gonads.
### Androgen production
The mesoderm-derived epithelial cells of the sex cords in developing testes become the Sertoli cells which will function to support sperm cell formation. A minor population of non-epithelial cells appear between the tubules by week 8 of human fetal development. These are Leydig cells. Soon after they differentiate, Leydig cells begin to produce androgens.
### Androgen effects
The androgens function as paracrine hormones required by the Sertoli cells in order to support sperm production. They are also required for masculinization of the developing male fetus (including penis and scrotum formation). Under the influence of androgens, remnants of the mesonephron, the Wolffian ducts, develop into the epididymis, vas deferens and seminal vesicles. This action of androgens is supported by a hormone from Sertoli cells, AMH, which prevents the embryonic Müllerian ducts from developing into fallopian tubes and other female reproductive tract tissues in male embryos. AMH and androgens cooperate to allow for the normal movement of testes into the scrotum.
### Early regulation
Before the production of the pituitary hormone LH by the embryo starting at about weeks 11-12, human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of androgens. Androgen action in target tissues often involves conversion of testosterone to 5α-dihydrotestosterone (DHT).
## Spermatogenesis
During puberty, androgen, LH and FSH production increase and the sex cords hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout adulthood, androgens and FSH cooperatively act on Sertoli cells in the testes to support sperm production. Exogenous androgen supplements can be used as a male contraceptive. Elevated androgen levels caused by use of androgen supplements can inhibit production of LH and block production of endogenous androgens by Leydig cells. Without the locally high levels of androgens in testes due to androgen production by Leydig cells, the seminiferous tubules can degenerate resulting in infertility. For this reason, many transdermal androgen patches are applied to the scrotum.
## Inhibition of fat deposition
Males typically have less adipose tissue than females. Recent results indicate that androgens inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function.
## Muscle mass
Males typically have more skeletal muscle mass than females. Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to enhance muscle function by acting on several cell types in skeletal muscle tissue.
## Brain
Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of human aggression and libido.
# Insensitivity to androgen in humans
Reduced ability of a XY karyotype fetus to respond to androgens can result in one of several problems, including infertility and several forms of intersex conditions. See androgen insensitivity syndrome (AIS).
# See Also
- List of steroid abbreviations | Androgen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Androgen is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of masculine characteristics in vertebrates by binding to androgen receptors. This includes the activity of the accessory male sex organs and development of male secondary sex characteristics. Androgens, which were first discovered in 1936, are also called androgenic hormones or testoids. Androgens are also the original anabolic steroids. They are also the precursor of all estrogens, the female sex hormones. The primary and most well-known androgen is testosterone.
# Types of androgens
A subset of androgens, adrenal androgens, includes any of the 19-carbon steroids synthesized by the adrenal cortex, the outer portion of the adrenal gland (zonula reticularis - innermost region of the adrenal cortex), that function as weak steroids or steroid precursors, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione.
Besides testosterone, other androgens include:
- Dehydroepiandrosterone (DHEA): a steroid hormone produced in the adrenal cortex from cholesterol. It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.
- Androstenedione (Andro): an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone. Use of androstenedione as an athletic or body building supplement has been banned by the International Olympic Committee as well as other sporting organizations.
- Androstenediol: the steroid metabolite that is thought to act as the main regulator of gonadotropin secretion.
- Androsterone: a chemical by-product created during the breakdown of androgens, or derived from progesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in the plasma and urine of both males and females.
- Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. It is produced in the adrenal cortex.
# Androgen functions
## Development of the male
### Testis formation
During mammalian development, the gonads are at first capable of becoming either ovaries or testes[1]. In humans, starting at about week 4 the gonadal rudiments are present within the intermediate mesoderm adjacent to the developing kidneys. At about week 6, epithelial sex cords develop within the forming testes and incorporate the germ cells as they migrate into the gonads. In males, certain Y chromosome genes, particularly SRY, control development of the male phenotype, including conversion of the early bipotential gonad into testes. In males, the sex cords fully invade the developing gonads.
### Androgen production
The mesoderm-derived epithelial cells of the sex cords in developing testes become the Sertoli cells which will function to support sperm cell formation. A minor population of non-epithelial cells appear between the tubules by week 8 of human fetal development. These are Leydig cells. Soon after they differentiate, Leydig cells begin to produce androgens.
### Androgen effects
The androgens function as paracrine hormones required by the Sertoli cells in order to support sperm production. They are also required for masculinization of the developing male fetus (including penis and scrotum formation). Under the influence of androgens, remnants of the mesonephron, the Wolffian ducts, develop into the epididymis, vas deferens and seminal vesicles. This action of androgens is supported by a hormone from Sertoli cells, AMH, which prevents the embryonic Müllerian ducts from developing into fallopian tubes and other female reproductive tract tissues in male embryos. AMH and androgens cooperate to allow for the normal movement of testes into the scrotum.
### Early regulation
Before the production of the pituitary hormone LH by the embryo starting at about weeks 11-12, human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of androgens. Androgen action in target tissues often involves conversion of testosterone to 5α-dihydrotestosterone (DHT).
## Spermatogenesis
During puberty, androgen, LH and FSH production increase and the sex cords hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout adulthood, androgens and FSH cooperatively act on Sertoli cells in the testes to support sperm production[2]. Exogenous androgen supplements can be used as a male contraceptive. Elevated androgen levels caused by use of androgen supplements can inhibit production of LH and block production of endogenous androgens by Leydig cells. Without the locally high levels of androgens in testes due to androgen production by Leydig cells, the seminiferous tubules can degenerate resulting in infertility. For this reason, many transdermal androgen patches are applied to the scrotum.
## Inhibition of fat deposition
Males typically have less adipose tissue than females. Recent results indicate that androgens inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function[3].
## Muscle mass
Males typically have more skeletal muscle mass than females. Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to enhance muscle function by acting on several cell types in skeletal muscle tissue[4].
## Brain
Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of human aggression[5] and libido.
# Insensitivity to androgen in humans
Reduced ability of a XY karyotype fetus to respond to androgens can result in one of several problems, including infertility and several forms of intersex conditions. See androgen insensitivity syndrome (AIS).
# See Also
- List of steroid abbreviations | https://www.wikidoc.org/index.php/Androgen | |
6331e1341d09b63bf3c08fabc58ee5c552d00c0b | wikidoc | Anethole | Anethole
# Overview
Anethole (or trans-anethole) is an aromatic compound that accounts for the distinctive "licorice" flavor of anise, fennel, star anise, and anise myrtle. It may also be referred to as p-propenylanisole, anise camphor, isoestragole, or oil of aniseed. It is unrelated to glycyrrhizic acid, the compound which makes licorice taste sweet. The full chemical name is trans-1-methoxy-4-(prop-1-enyl)benzene. The chemical structure is shown at right. Chemically, an aromatic, unsaturated ether.
Anethole appears as white crystals at room temperature. Its melting point is 21 °C, and its boiling point is 234 °C. It has a chemical formula of C10H12O, and is closely related to estragole, an aromatic compound found in tarragon and basil.
Anethole is distinctly sweet as well as having its flavoring properties and is measured to be 13 times sweeter than sugar. It is perceived as being pleasant to the taste even at higher concentrations.
It is slightly toxic and may act as an irritant in large quantities. It can stimulate hepatic regeneration in rats, and can also produce spasmolytic activity in high doses. It is a chemical precursor for paramethoxyamphetamine (PMA), which has been sold as ecstasy resulting in several deaths. | Anethole
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Anethole (or trans-anethole) is an aromatic compound that accounts for the distinctive "licorice" flavor of anise, fennel, star anise, and anise myrtle. It may also be referred to as p-propenylanisole, anise camphor, isoestragole, or oil of aniseed. It is unrelated to glycyrrhizic acid, the compound which makes licorice taste sweet. The full chemical name is trans-1-methoxy-4-(prop-1-enyl)benzene. The chemical structure is shown at right. Chemically, an aromatic, unsaturated ether.
Anethole appears as white crystals at room temperature. Its melting point is 21 °C, and its boiling point is 234 °C. It has a chemical formula of C10H12O, and is closely related to estragole, an aromatic compound found in tarragon and basil.
Anethole is distinctly sweet as well as having its flavoring properties and is measured to be 13 times sweeter than sugar. It is perceived as being pleasant to the taste even at higher concentrations.
It is slightly toxic and may act as an irritant in large quantities. It can stimulate hepatic regeneration in rats, and can also produce spasmolytic activity in high doses. It is a chemical precursor for paramethoxyamphetamine (PMA), which has been sold as ecstasy resulting in several deaths. | https://www.wikidoc.org/index.php/Anethole | |
3ae8a52cfd006c005b91d4c2f348dabfda2884ad | wikidoc | Ångström | Ångström
An ångström or angstrom (symbol Å) (Template:PronEng; Swedish: Template:IPA2) is a non-SI unit of length that is internationally recognized, equal to 0.1 nanometre or 1Template:E metres. It is sometimes used in expressing the sizes of atoms, lengths of chemical bonds and visible-light spectra, and dimensions of parts of integrated circuits. It is commonly applied in structural biology. It is named after Anders Jonas Ångström.
Unicode includes the "angstrom sign" at U+212B (Å). However, the "angstrom sign" is normalized into U+00C5 (Å), and is thereby seen as a (pre-existing) encoding mistake, and it is better to use U+00C5 (Å) directly.
# History
The ångström is named after the Swedish physicist Anders Jonas Ångström (1814–1874), one of the founders of spectroscopy who is known also for studies of astrophysics, heat transfer, terrestrial magnetism, and the aurora borealis.
In 1868, Ångström created a spectrum chart of solar radiation that expresses the wavelength of electromagnetic radiation in the electromagnetic spectrum in multiples of one ten-millionth of a millimetre, or 1Template:E metres. This unit of length later became known as the ångström, Å.
The visual sensitivity of a human being is from about 4,000 ångströms (violet) to 7,000 ångströms (deep red) so the use of the ångström as a unit provided a fair amount of discrimination without resort to fractional units. Because of its closeness to the scale of atomic and molecular structures it also became popular in chemistry and crystallography.
Although intended to correspond to 1Template:E metres, for precise spectral analysis the ångström needed to be defined more accurately than the metre which until 1960 was still defined based on the length of a bar of metal held in Paris. In 1907 the International Astronomical Union defined the international ångström by making the wavelength of the red line of cadmium in air equal to 6438.4696 international ångströms, and this definition was endorsed by the International Bureau of Weights and Measures in 1927. From 1927 to 1960, the ångström remained a secondary unit of length for use in spectroscopy, defined separately from the metre, but in 1960, the metre itself was redefined in spectroscopic terms, thus aligning the ångström as a submultiple of the metre.
Since the ångström is now defined as exactly 1Template:E metres, there are therefore 10,000 ångströms in a micrometre (commonly called a 'micron', abbreviated μm, of which there are 1 million to a metre), and 10 in a nanometre (1 nm = 1Template:E metres).
Today, the use of the ångström as a unit is less popular than it used to be and the nanometre (nm) is often used instead (with the ångström being officially discouraged by both the International Committee for Weights and Measures and the American National Standard for Metric Practice). | Ångström
Template:Unit of length
An ångström or angstrom (symbol Å) (Template:PronEng; Swedish: Template:IPA2) is a non-SI unit of length that is internationally recognized, equal to 0.1 nanometre or 1Template:E metres. It is sometimes used in expressing the sizes of atoms, lengths of chemical bonds and visible-light spectra, and dimensions of parts of integrated circuits. It is commonly applied in structural biology. It is named after Anders Jonas Ångström.
Unicode includes the "angstrom sign" at U+212B (Å). However, the "angstrom sign" is normalized into U+00C5 (Å), and is thereby seen as a (pre-existing) encoding mistake, and it is better to use U+00C5 (Å) directly.[1]
# History
The ångström is named after the Swedish physicist Anders Jonas Ångström (1814–1874), one of the founders of spectroscopy who is known also for studies of astrophysics, heat transfer, terrestrial magnetism, and the aurora borealis.
In 1868, Ångström created a spectrum chart of solar radiation that expresses the wavelength of electromagnetic radiation in the electromagnetic spectrum in multiples of one ten-millionth of a millimetre, or 1Template:E metres. This unit of length later became known as the ångström, Å.
The visual sensitivity of a human being is from about 4,000 ångströms (violet) to 7,000 ångströms (deep red) so the use of the ångström as a unit provided a fair amount of discrimination without resort to fractional units. Because of its closeness to the scale of atomic and molecular structures it also became popular in chemistry and crystallography.
Although intended to correspond to 1Template:E metres, for precise spectral analysis the ångström needed to be defined more accurately than the metre which until 1960 was still defined based on the length of a bar of metal held in Paris. In 1907 the International Astronomical Union defined the international ångström by making the wavelength of the red line of cadmium in air equal to 6438.4696 international ångströms, and this definition was endorsed by the International Bureau of Weights and Measures in 1927. From 1927 to 1960, the ångström remained a secondary unit of length for use in spectroscopy, defined separately from the metre, but in 1960, the metre itself was redefined in spectroscopic terms, thus aligning the ångström as a submultiple of the metre.
Since the ångström is now defined as exactly 1Template:E metres, there are therefore 10,000 ångströms in a micrometre (commonly called a 'micron', abbreviated μm, of which there are 1 million to a metre), and 10 in a nanometre (1 nm = 1Template:E metres).
Today, the use of the ångström as a unit is less popular than it used to be and the nanometre (nm) is often used instead (with the ångström being officially discouraged by both the International Committee for Weights and Measures and the American National Standard for Metric Practice). | https://www.wikidoc.org/index.php/Angstrom | |
0671ede61526c8d58a635334a63a07495f49802d | wikidoc | Anisodus | Anisodus
Anisodus is a genus of flowering plant in the family Solanaceae. It is native to China, Tibet, India, Bhutan, and Nepal.
One species, A. tanguticus (Chinese: 山莨菪; pinyin: shān làngdàng), is one of the 50 fundamental herbs used in traditional Chinese medicine.
# Species
- Anisodus acutangulus C. Y. Wu & C. Chen
Anisodus acutangulus var. acutangulus
Anisodus acutangulus var. breviflorus C. Y. Wu & C. Chen
- Anisodus acutangulus var. acutangulus
- Anisodus acutangulus var. breviflorus C. Y. Wu & C. Chen
- Anisodus carniolicoides (C. Y. Wu & C. Chen) D'Arcy & Z. Y. Zhang
- Anisodus luridus Link
- Anisodus mariae Pascher
- Anisodus tanguticus (Maximowicz) Pascher | Anisodus
Anisodus is a genus of flowering plant in the family Solanaceae. It is native to China, Tibet, India, Bhutan, and Nepal.
One species, A. tanguticus (Chinese: 山莨菪; pinyin: shān làngdàng), is one of the 50 fundamental herbs used in traditional Chinese medicine.
# Species
- Anisodus acutangulus C. Y. Wu & C. Chen
Anisodus acutangulus var. acutangulus
Anisodus acutangulus var. breviflorus C. Y. Wu & C. Chen
- Anisodus acutangulus var. acutangulus
- Anisodus acutangulus var. breviflorus C. Y. Wu & C. Chen
- Anisodus carniolicoides (C. Y. Wu & C. Chen) D'Arcy & Z. Y. Zhang
- Anisodus luridus Link
- Anisodus mariae Pascher
- Anisodus tanguticus (Maximowicz) Pascher
# External links
- Anisodus page
Template:Solanales-stub
Template:Alt-med-stub | https://www.wikidoc.org/index.php/Anisodus | |
fde012840b37e26726f87b295866653d0d61c7c3 | wikidoc | Ankyrins | Ankyrins
# Overview
Ankyrins are a family of proteins that mediates the attachment of integral membrane proteins to the cytoskeleton.
Ankyrin 1, was first discovered in the erythrocytes but also later found to be expressed in the brain and muscles. In erythrocytes, Ankyrin 1 links membrane receptor CD44 to inositol triphosphate and the cytoskeleton.
Ankyrin contains three functional domains: a conserved N-terminal ankyrin repeat domain (ARD) consisting of 22–24 tandem repeats of 33 amino acids, a spectrin binding domain and a variably sized C-terminal regulatory domain.
Ankyrin was discovered by Dr. G. Vann Bennett (M.D., PhD.) in 1976. | Ankyrins
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Ankyrins are a family of proteins that mediates the attachment of integral membrane proteins to the cytoskeleton.[1]
Ankyrin 1, was first discovered in the erythrocytes but also later found to be expressed in the brain and muscles. In erythrocytes, Ankyrin 1 links membrane receptor CD44 to inositol triphosphate and the cytoskeleton.[2]
Ankyrin contains three functional domains: a conserved N-terminal ankyrin repeat domain (ARD) consisting of 22–24 tandem repeats of 33 amino acids, a spectrin binding domain and a variably sized C-terminal regulatory domain.
Ankyrin was discovered by Dr. G. Vann Bennett (M.D., PhD.) in 1976. | https://www.wikidoc.org/index.php/Ankyrin_B | |
2906955a0cbd14962097729cf9528b19cef373e7 | wikidoc | Perineum | Perineum
# Overview
In human anatomy, the perineum, also called the "taint", "grundel" or "gooch", is generally defined as the surface region in both males and females between the pubic symphysis and the coccyx.
A diamond-shaped area on the inferior surface of the trunk which includes the anus and, in females, the vagina. Its definition varies: it can refer to only the superficial structures in this region, or it can be used to include both superficial and deep structures.
The perineum corresponds to the outlet of the pelvis.
The anogenital distance is a measure of male feminisation measuring the distance between the anus and the base of the penis. Studies show that the perineum is twice as long in males as in females. The AGD in males may be shortened through exposure to phthalates found in some plastics.
# Boundaries
Its deep boundaries are as follows:
- in front: the pubic arch and the arcuate ligament of the pubis
- behind: the tip of the coccyx
- on either side: the inferior rami of the pubis and Ischium, and the sacrotuberous ligament
In Alfred Kinsey's 1967 report, he concluded that the perineum was one of the 6 key errogenous zones for males.
# Triangles
A line drawn transversely across in front of the ischial tuberosities divides the space into two triangles:
## Perineal fascia
The terminology of the perineal fascia can be confusing, and there is some controversy over the nomenclature. This stems from the fact that there are two parts to the fascia, the superficial and deep parts, and each of these can be subdivided into superficial and deep parts.
The layers and contents are as follows, from superficial to deep:
- 1) Skin
- 2) superficial perineal fascia: Subcutaneous tissue divided into two layers: (a) A superficial fatty layer, and (b) Colles' fascia, a deeper, membranous layer.
- 3) deep perineal fascia and muscles:
- 4) fascia and muscles of pelvic floor (levator ani, coccygeus)
## Areas of the perineum
The region of the perineum can be considered a distinct area from pelvic cavity, with the two regions separated by the pelvic diaphragm. The following areas are thus classified as parts of the perineal region:
- perineal pouches: superficial and deep (see above for details)
- Ischioanal fossa - a fat filled space
Anal canal
Pudendal canal - contains internal pudendal artery and the pudendal nerve.
- Anal canal
- Pudendal canal - contains internal pudendal artery and the pudendal nerve.
# Riding
This area can become extremely sore among inexperienced bicyclists, horseback riders, motocross riders, and even ATV'ers.
# Additional images
- Diameters of inferior aperture of lesser pelvis (female).
- The perineum. The integument and superficial layer of superficial fascia reflected.
- Muscles of the female perineum.
- The superficial branches of the internal pudendal artery.
- The posterior aspect of the rectum exposed by removing the lower part of the sacrum and the coccyx.
- Stages in the development of the external sexual organs in the male and female. | Perineum
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In human anatomy, the perineum, also called the "taint", "grundel" or "gooch", is generally defined as the surface region in both males and females between the pubic symphysis and the coccyx.
A diamond-shaped area on the inferior surface of the trunk which includes the anus and, in females, the vagina[1]. Its definition varies: it can refer to only the superficial structures in this region, or it can be used to include both superficial and deep structures.
The perineum corresponds to the outlet of the pelvis.
The anogenital distance is a measure of male feminisation measuring the distance between the anus and the base of the penis. Studies show that the perineum is twice as long in males as in females. The AGD in males may be shortened through exposure to phthalates found in some plastics.
# Boundaries
Its deep boundaries are as follows:[2]
- in front: the pubic arch and the arcuate ligament of the pubis
- behind: the tip of the coccyx
- on either side: the inferior rami of the pubis and Ischium, and the sacrotuberous ligament
In Alfred Kinsey's 1967 report, he concluded that the perineum was one of the 6 key errogenous zones for males.
# Triangles
A line drawn transversely across in front of the ischial tuberosities divides the space into two triangles:
## Perineal fascia
The terminology of the perineal fascia can be confusing, and there is some controversy over the nomenclature. This stems from the fact that there are two parts to the fascia, the superficial and deep parts, and each of these can be subdivided into superficial and deep parts.
The layers and contents are as follows, from superficial to deep:
- 1) Skin
- 2) superficial perineal fascia: Subcutaneous tissue divided into two layers: (a) A superficial fatty layer, and (b) Colles' fascia, a deeper, membranous layer.
- 3) deep perineal fascia and muscles:
- 4) fascia and muscles of pelvic floor (levator ani, coccygeus)
## Areas of the perineum
The region of the perineum can be considered a distinct area from pelvic cavity, with the two regions separated by the pelvic diaphragm. The following areas are thus classified as parts of the perineal region:
- perineal pouches: superficial and deep (see above for details)
- Ischioanal fossa - a fat filled space
Anal canal
Pudendal canal - contains internal pudendal artery and the pudendal nerve.
- Anal canal
- Pudendal canal - contains internal pudendal artery and the pudendal nerve.
# Riding
This area can become extremely sore among inexperienced bicyclists, horseback riders, motocross riders, and even ATV'ers.
# Additional images
- Diameters of inferior aperture of lesser pelvis (female).
- The perineum. The integument and superficial layer of superficial fascia reflected.
- Muscles of the female perineum.
- The superficial branches of the internal pudendal artery.
- The posterior aspect of the rectum exposed by removing the lower part of the sacrum and the coccyx.
- Stages in the development of the external sexual organs in the male and female. | https://www.wikidoc.org/index.php/Anogenital_distance | |
4743aaaf6dd1ebcff3f2372a3c6979577a0a904b | wikidoc | Glucagon | Glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers the extracellular glucose.
The pancreas releases glucagon when the concentration of insulin (and indirectly glucose) in the bloodstream falls too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. High blood-glucose levels, on the other hand, stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress. Glucagon belongs to the secretin family of hormones.
# Function
Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis. Glucagon also decreases fatty acid synthesis in adipose tissue and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised to generate energy in tissues such as skeletal muscle when required.
Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.
Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression (such as diabetes mellitus type 1).
Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.
# Mechanism of action
Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.
Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.
Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose-2,6-bisphosphate. The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose-2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose-2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis) by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).
Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes.
# Physiology
## Production
The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. Production, which is otherwise freerunning, is suppressed/regulated by insulin from the adjacent beta cells. (Actually, GABA is the interlock signal chemical that prevents simultaneous insulin and glucagon production in the pancreas. It is produced by the pancreatic ß cells at the same time insulin is being produced. It prevents the α cells from being switched on.)
When blood sugar drops, insulin production drops and more glucagon is produced In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.
Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.
## Regulation
Secretion of glucagon is stimulated by:
- Hypoglycemia
- Epinephrine (via β2, α2, and α1 adrenergic receptors)
- Arginine
- Alanine (often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase reaction).
- Acetylcholine
- Cholecystokinin
- Gastric inhibitory polypeptide
Secretion of glucagon is inhibited by:
- Somatostatin
- Insulin (via GABA)
- PPARγ/retinoid X receptor heterodimer.
- Increased free fatty acids and keto acids into the blood.
- Increased urea production
- Glucagon-like peptide-1
# Structure
Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-COOH.
The polypeptide has a molecular weight of 3485 daltons. Glucagon is a peptide (nonsteroid) hormone.
Glucagon is generated from the cleavage of proglucagon by proprotein convertase 2 in pancreatic islet α cells. In intestinal L cells, proglucagon is cleaved to the alternate products glicentin, GLP-1 (an incretin), IP-2, and GLP-2 (promotes intestinal growth).
# Pathology
Abnormally elevated levels of glucagon may be caused by pancreatic tumors, such as glucagonoma, symptoms of which include necrolytic migratory erythema, reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1
Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes. As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon. As a result, glucagon is released from the alpha cells at a maximum, causing rapid breakdown of glycogen to glucose and fast ketogenesis. It was found that a subset of adults with type 1 diabetes took 4 times longer on average to approach ketoacidosis when given somatostatin (inhibits glucagon production) with no insulin. Inhibiting glucagon has been a popular idea of diabetes treatment, however some have warned that doing so will give rise to brittle diabetes in patients with adequately stable blood glucose.
The absence of alpha cells (and hence glucagon) is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy.
# History
In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923. The amino acid sequence of glucagon was described in the late 1950s. A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.
## Etymology
Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the glucose agonist. | Glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body.[1] It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers the extracellular glucose.[2]
The pancreas releases glucagon when the concentration of insulin (and indirectly glucose) in the bloodstream falls too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream.[3] High blood-glucose levels, on the other hand, stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress.[4] Glucagon belongs to the secretin family of hormones.
# Function
Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis.[5] Glucagon also decreases fatty acid synthesis in adipose tissue and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised to generate energy in tissues such as skeletal muscle when required.[6]
Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.
Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression (such as diabetes mellitus type 1).[7]
Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.[8]
# Mechanism of action
Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.
Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.
Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose-2,6-bisphosphate.[9] The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose-2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose-2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis)[10] by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).
Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes.[11]
# Physiology
## Production
The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. Production, which is otherwise freerunning, is suppressed/regulated by insulin from the adjacent beta cells. (Actually, GABA is the interlock signal chemical that prevents simultaneous insulin and glucagon production in the pancreas. It is produced by the pancreatic ß cells at the same time insulin is being produced. It prevents the α cells from being switched on.)
When blood sugar drops, insulin production drops and more glucagon is produced[12] In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.[12]
Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.[13]
## Regulation
Secretion of glucagon is stimulated by:
- Hypoglycemia
- Epinephrine (via β2, α2,[14] and α1[15] adrenergic receptors)
- Arginine
- Alanine (often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase reaction).
- Acetylcholine[16]
- Cholecystokinin
- Gastric inhibitory polypeptide
Secretion of glucagon is inhibited by:
- Somatostatin
- Insulin (via GABA)[17]
- PPARγ/retinoid X receptor heterodimer.[18]
- Increased free fatty acids and keto acids into the blood.[19]
- Increased urea production
- Glucagon-like peptide-1
# Structure
Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-COOH.
The polypeptide has a molecular weight of 3485 daltons.[20] Glucagon is a peptide (nonsteroid) hormone.
Glucagon is generated from the cleavage of proglucagon by proprotein convertase 2 in pancreatic islet α cells. In intestinal L cells, proglucagon is cleaved to the alternate products glicentin, GLP-1 (an incretin), IP-2, and GLP-2 (promotes intestinal growth).[21]
# Pathology
Abnormally elevated levels of glucagon may be caused by pancreatic tumors, such as glucagonoma, symptoms of which include necrolytic migratory erythema,[22] reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1[23]
Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes. As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon. As a result, glucagon is released from the alpha cells at a maximum, causing rapid breakdown of glycogen to glucose and fast ketogenesis.[24] It was found that a subset of adults with type 1 diabetes took 4 times longer on average to approach ketoacidosis when given somatostatin (inhibits glucagon production) with no insulin.[citation needed] Inhibiting glucagon has been a popular idea of diabetes treatment, however some have warned that doing so will give rise to brittle diabetes in patients with adequately stable blood glucose.[citation needed]
The absence of alpha cells (and hence glucagon) is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy.
# History
In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[25] The amino acid sequence of glucagon was described in the late 1950s.[26] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.[citation needed]
## Etymology
Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the glucose agonist.[27] | https://www.wikidoc.org/index.php/Antagonistic_hormone | |
a3a5117552d755bb0b697745c3c52bca548f39ce | wikidoc | Myelitis | Myelitis
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Myelitis is a disease involving swelling of the spinal cord, which disrupts central nervous system functions linking the brain and limbs.
# Symptoms and signs
Symptoms vary by region of the CNS affected.
- fever
- headaches
- tingling
- Bladder dysfunction (loss of bladder control)
- pain
- Meningeal signs may develop
- (central or peripheral paresis
- Numbness; Altered sensation, Sensorimotor paralysis below the level of the inflammation (Absent tendon reflexes below the level of the inflammation), loss of feeling
- Leg weakness
- Arm weakness
- Paresthesia
- Back pain
- Leg pain
- Arm pain
- Bowel dysfunction
- Muscle spasms
- Malaise
- Anorexia
- Leg paresthesia
- Urinary retention
- Sexual dysfunction
- Fecal incontinence
- Abdominal muscle paralysis
# Diagnosis
- Spinal MRI
- Myelography
# Differential Diagnosis of Causes of Myelitis
## Infections
- Certain viruses - causing viral myelitis:
- Herpesvirus
- Polio virus
- HIV
- Syphilis
## Myelitis as a complication
Other conditions that might have Myelitis as a complication might be potential underlying conditions. The list of conditions listing Myelitis as a complication includes:
- Gnathostoma Infection
- Poxviridae disease
## Myelitis as a symptom
- Bing-Neel syndrome
# Prognosis
Untreated myelitis may rapidly lead to a permanently damaged spinal cord. | Myelitis
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Myelitis is a disease involving swelling of the spinal cord, which disrupts central nervous system functions linking the brain and limbs.
# Symptoms and signs
Symptoms vary by region of the CNS affected.
- fever
- headaches
- tingling
- Bladder dysfunction (loss of bladder control)
- pain
- Meningeal signs may develop
- (central or peripheral paresis
- Numbness; Altered sensation, Sensorimotor paralysis below the level of the inflammation (Absent tendon reflexes below the level of the inflammation), loss of feeling
- Leg weakness
- Arm weakness
- Paresthesia
- Back pain
- Leg pain
- Arm pain
- Bowel dysfunction
- Muscle spasms
- Malaise
- Anorexia
- Leg paresthesia
- Urinary retention
- Sexual dysfunction
- Fecal incontinence
- Abdominal muscle paralysis
# Diagnosis
- Spinal MRI
- Myelography
# Differential Diagnosis of Causes of Myelitis
## Infections
- Certain viruses - causing viral myelitis:
- Herpesvirus
- Polio virus
- HIV
- Syphilis
## Myelitis as a complication
Other conditions that might have Myelitis as a complication might be potential underlying conditions. The list of conditions listing Myelitis as a complication includes:
- Gnathostoma Infection
- Poxviridae disease
## Myelitis as a symptom
- Bing-Neel syndrome
# Prognosis
Untreated myelitis may rapidly lead to a permanently damaged spinal cord. | https://www.wikidoc.org/index.php/Anterior_myelitis | |
91b3da32b197b259517341ee963959d469a037c2 | wikidoc | Antibody | Antibody
Antibodies (also known as immunoglobulins) are proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. They are made of a few basic structural units called chains; each antibody has two large heavy chains H and two small light chains L. Antibodies are produced by a kind of white blood cell called a B cell. There are several different types of antibody heavy chain, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter.
Although the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures to exist. This region is known as the hypervariable region. Each of these variants can bind to a different target, known as an antigen. This huge diversity of antibodies allows the immune system to recognize an equally wide diversity of antigens. The unique part of the antigen recognized by an antibody is called an epitope. These epitopes bind with their antibody in a highly specific interaction, called induced fit, that allows antibodies to identify and bind only their unique antigen in the midst of the millions of different molecules that make up an organism. Recognition of an antigen by an antibody tags it for attack by other parts of the immune system. Antibodies can also neutralize targets directly by, for example, binding to a part of a pathogen that it needs to cause an infection.
The large and diverse population of antibodies is generated by random combinations of a set of gene segments that encode different antigen binding sites (or paratopes), followed by random mutations in this area of the antibody gene, which create further diversity. Antibody genes also re-organize in a process called class switching that changes the base of the heavy chain to another, creating a different isotype of the antibody that retains the antigen specific variable region. This allows a single antibody to be used by several different parts of the immune system. Production of antibodies is the main function of the humoral immune system.
# Antibody forms
Antibodies occur in two forms: a soluble form secreted into the blood and tissue fluids, and a membrane-bound form attached to the surface of a B cell that is called the B cell receptor (BCR). The BCR allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation. Activated B cells differentiate into either antibody generating factories called plasma cells that secrete soluble antibody, or into memory cells that survive in the body for years afterwards to allow the immune system to remember an antigen and respond faster upon future exposures. Antibodies are, therefore, an essential component of the adaptive immune system that learns, adapts and remembers responses to invading pathogens.
# Isotypes
Antibodies can come in different varieties known as isotypes or classes. In mammals there are five antibody isotypes known as IgA, IgD, IgE,IgG and IgM. They are each named with an "Ig" prefix that stands for immunoglobulin, another name for antibody, and differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table.
The antibody isotype of a B cell changes during the cell's development and activation. Immature B cells, which have never been exposed to antigen, are known as naïve B cells and express only the IgM isotype in a cell surface bound form. B cells begin to express both IgM and IgD when they reach maturity - the co-expression of both these immunoglobulin isotypes renders the B cell 'mature' and ready to respond to antigen. B cell activation follows engagement of the cell bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody producing cell called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antibodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA or IgG, that have defined roles in the immune system.
# Structure
Antibodies are heavy (~150kDa) globular plasma proteins that are also known as immunoglobulins. They have sugar chains added to some of their amino acid residues. In other words, antibodies are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
## Immunoglobulin domains
The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds.
Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function. They possess a characteristic immunoglobulin fold in which two beta sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
## Heavy chain
There are five types of mammalian Ig heavy chain denoted by the Greek letters: α, δ, ε, γ, and μ. The type of heavy chain present defines the class of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids, while μ and ε have approximately 550 amino acids.
Each heavy chain has two regions, the constant region and the variable region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem (in a line) Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
## Light chain
In mammals there are two types of light chain, which are called lambda (λ) and kappa (κ). A light chain has two successive domains: one constant domain and one variable domain. The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. Other types of light chains, such as the iota (ι) chain, are found in lower vertebrates like Chondrichthyes and Teleostei.
## Fab and Fc Regions
Some parts of an antibody have unique functions. The tip of the Y, for example, contains the site that binds antigen and, therefore, recognizes specific foreign objects. This region of the antibody is called the Fab (fragment, antigen binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody. The paratope is shaped at the amino terminal end of the antibody monomer by the variable domains from the heavy and light chains.
The base of the Y plays a role in modulating immune cell activity. This region is called the Fc (Fragment, crystallizable) region, and is composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. By binding to specific proteins the Fc region ensures that each antibody generates an appropriate immune response for a given antigen. The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins. By doing this, it mediates different physiological effects including opsonization, cell lysis, and degranulation of mast cells, basophils and eosinophils.
# Function
Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen, a virus hull protein fragment, for example. Antibodies contribute to immunity in three main ways: they can prevent pathogens from entering or damaging cells by binding to them; they can stimulate removal of a pathogen by macrophages and other cells by coating the pathogen; and they can trigger direct pathogen destruction by stimulating other immune responses such as the complement pathway.
## Activation of complement
Antibodies that bind to surface antigens on, for example a bacterium, attract the first component of the complement cascade with their Fc region and initiate activation of the "classical" complement system. This results in the killing of bacteria in two ways. First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly.
## Activation of effector cells
To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody possesses at least two paratopes it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region.
Those cells which recognize coated pathogens have Fc receptors which, as the name suggests, interacts with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of the invading microbe. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens.
# Immunoglobulin diversity
Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens. It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes.
## V(D)J recombination
Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces - known as gene segments. These segments are called variable (V), diversity (D) and joining (J) segments. V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities.
After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion) thus each B cell can produce antibodies containing only one kind of variable chain.
## Somatic hypermutation and affinity maturation
Another mechanism that generates antibody diversity occurs in the mature B cell. Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division. As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains.
Somatic hypermutation serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding affinity. Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity). B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis. Thus, B cells expressing higher affinity antibodies for will outcompete those with weaker affinities for function and survival. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells.
## Class switching
Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG). The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naïve B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function, therefore, after activation, an antibody with a IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from the same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment.
Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions, found in DNA upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of enzymes at two selected S-regions. The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype.
# Medical applications
## Disease diagnosis
Detection of particular antibodies is a very common form of medical diagnostics, and applications such as serology depend on these methods. For example, in biochemical assays for disease diagnosis, a titer of antibodies directed against Epstein-Barr virus or Lyme disease is estimated from the blood. If those antibodies are not present, either the person is not infected, or the infection occurred a very long time ago, and the B cells generating these specific antibodies have naturally decayed. In clinical immunology, levels of individual classes of immunoglobulins are measured by nephelometry (or turbidimetry) to characterize the antibody profile of patient. Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of liver damage in patients whom the diagnosis is unclear. For example, elevated IgA indicates alcoholic cirrhosis, elevated IgM indicates viral hepatitis and primary biliary cirrhosis, while IgG is elevated in viral hepatitis, autoimmune hepatitis and cirrhosis. Autoimmune disorders can often be traced to antibodies that bind the body's own epitopes; many can be detected through blood tests. Antibodies directed against red blood cell surface antigens in immune mediated hemolytic anemia are detected with the Coombs test. The Coombs test is also used for antibody screening in blood transfusion preparation and also for antibody screening in antenatal women.
Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA, immunofluorescence, Western blot, immunodiffusion, and immunoelectrophoresis.
## Disease therapy
"Targeted" monoclonal antibody therapy is employed to treat diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, and many forms of cancer including non-Hodgkin's lymphoma, colorectal cancer, head and neck cancer and breast cancer.
Some immune deficiencies, such as X-linked agammaglobulinemia and hypogammaglobulinemia, result in partial or complete lack of antibodies. These diseases are often treated by inducing a short term form of immunity called passive immunity. Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal serum, pooled immunoglobulin or monoclonal antibodies, into the affected individual.
## Prenatal therapy
Rho(D) Immune Globulin antibodies are specific for human Rhesus D (RhD) antigen, also known as Rhesus factor. These anti-RhD antibodies are known under several brand names, including RhoGAM, BayRHo-D, Gamulin Rh, HypRho-D, and WinRho SDF. Rhesus factor is an antigen found on red blood cells; individuals that are Rhesus-positive (Rh+) have this antigen on their red blood cells and individuals that are Rhesus-negative (Rh-) do not.
During normal childbirth, delivery trauma or complications during pregnancy, blood from a fetus can enter the mother's system. In the case of an Rh-incompatible mother and child, consequential blood mixing may sensitize an Rh- mother to the Rh antigen on the blood cells of the Rh+ child, putting the remainder of the pregnancy, and any subsequent pregnancies, at risk for hemolytic disease of the newborn. Anti-RhD antibodies are administered as part of a prenatal treatment regimen to prevent sensitization that may occur when a Rhesus-negative mother has a Rhesus-positive
fetus.
Treatment of a mother with Anti-RhD antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. Importantly, this occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rhesus antigens of the current or subsequent baby. Rho(D) Immune Globulin treatment prevents sensitization that can lead to Rh disease, but does not prevent or treat the underlying disease itself.
# Research applications
Specific antibodies are produced by injecting an antigen into a mammal, such as a mouse, rat or rabbit for small quantities of antibody, or goat, sheep, or horse for large quantities of antibody. Blood isolated from these animals contains polyclonal antibodies — multiple antibodies that bind to the same antigen — in the serum, which can now be called antiserum. Antigens are also injected into chickens for generation of polyclonal antibodies in egg yolk. To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting lymphocytes are isolated from the animal and immortalized by fusing them with a cancer cell line. The fused cells are called hybridomas, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by dilution cloning to generate cell clones that all produce the same antibody; these antibodies are called monoclonal antibodies.
Generated polyclonal and monoclonal antibodies are often purified using Protein A/G or antigen-affinity chromatography.
## Use
In research, purified antibodies are used in many applications. They are most commonly used to identify and locate intracellular and extracellular proteins. Antibodies are used in flow cytometry to differentiate cell types by the proteins they express; different types of cell express different combinations of cluster of differentiation molecules on their surface, and produce different intracellular and secretable proteins. They are also used in immunoprecipitation to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a cell lysate, in Western blot analyses to identify proteins separated by electrophoresis, and in immunohistochemistry or immunofluorescence to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a microscope. Proteins can also be detected and quantified with antibodies, using ELISA and ELISPOT techniques.
# History
The study of antibodies began in 1890 when Emil von Behring and Shibasaburo Kitasato described antibody activity against diphtheria and tetanus toxins. Behring and Kitasato put forward the theory of humoral immunity, proposing that a mediator in serum could react with a foreign antigen. Their idea prompted Paul Ehrlich to propose the side chain theory for antibody and antigen interaction in 1897, when he hypothesized that receptors (described as “side chains”) on the surface of cells could bind specifically to toxins – in a "lock-and-key" interaction – and that this binding reaction was the trigger for the production of antibodies. Other researchers believed that antibodies existed freely in the blood and, in 1904, Almroth Wright suggested that soluble antibodies coated bacteria to label them for phagocytosis and killing; a process that he named opsoninization.
In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies were made of protein. The biochemical properties of antigen-antibody binding interactions were examined in more detail in the late 1930s by John Marrack. The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depended more on their shape than their chemical composition. In 1948, Astrid Fagreaus discovered that B cells, in the form of plasma cells, were responsible for generating antibodies.
Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by Gerald Edelman and Joseph Gally of the antibody light chain, and their realization that this protein was the same as the Bence-Jones protein described in 1845 by Henry Bence Jones. Edelman went on to discover that antibodies are composed of disulphide bond-linked heavy and light chains. Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by Rodney Porter. Together, these scientists deduced the structure and complete amino acid sequence of IgG, a feat for which they were jointly awarded the 1972 Nobel prize in Physiology or Medicine. While most of these early studies focused on IgM and IgG, other immunoglobulin isotypes were identified in the 1960s: Thomas Tomasi discovered secretory antibody (IgA) and David Rowe and John Fahey identified IgD, and IgE was identified by Kikishige Ishizaka and Teruki Ishizaka as a class of antibodies involved in allergic reactions.
Genetic studies revealed the basis of the vast diversity of these antibody proteins when somatic recombination of immunoglobulin genes was identified by Susumu Tonegawa in 1976. | Antibody
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
Antibodies (also known as immunoglobulins[1]) are proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. They are made of a few basic structural units called chains; each antibody has two large heavy chains H and two small light chains L. Antibodies are produced by a kind of white blood cell called a B cell. There are several different types of antibody heavy chain, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter.[2]
Although the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures to exist. This region is known as the hypervariable region. Each of these variants can bind to a different target, known as an antigen.[3] This huge diversity of antibodies allows the immune system to recognize an equally wide diversity of antigens. The unique part of the antigen recognized by an antibody is called an epitope. These epitopes bind with their antibody in a highly specific interaction, called induced fit, that allows antibodies to identify and bind only their unique antigen in the midst of the millions of different molecules that make up an organism. Recognition of an antigen by an antibody tags it for attack by other parts of the immune system. Antibodies can also neutralize targets directly by, for example, binding to a part of a pathogen that it needs to cause an infection.[4]
The large and diverse population of antibodies is generated by random combinations of a set of gene segments that encode different antigen binding sites (or paratopes), followed by random mutations in this area of the antibody gene, which create further diversity.[2][5] Antibody genes also re-organize in a process called class switching that changes the base of the heavy chain to another, creating a different isotype of the antibody that retains the antigen specific variable region. This allows a single antibody to be used by several different parts of the immune system. Production of antibodies is the main function of the humoral immune system.[6]
# Antibody forms
Antibodies occur in two forms: a soluble form secreted into the blood and tissue fluids, and a membrane-bound form attached to the surface of a B cell that is called the B cell receptor (BCR). The BCR allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation.[7] Activated B cells differentiate into either antibody generating factories called plasma cells that secrete soluble antibody, or into memory cells that survive in the body for years afterwards to allow the immune system to remember an antigen and respond faster upon future exposures.[8] Antibodies are, therefore, an essential component of the adaptive immune system that learns, adapts and remembers responses to invading pathogens.
# Isotypes
Antibodies can come in different varieties known as isotypes or classes. In mammals there are five antibody isotypes known as IgA, IgD, IgE,IgG and IgM. They are each named with an "Ig" prefix that stands for immunoglobulin, another name for antibody, and differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table.[11]
The antibody isotype of a B cell changes during the cell's development and activation. Immature B cells, which have never been exposed to antigen, are known as naïve B cells and express only the IgM isotype in a cell surface bound form. B cells begin to express both IgM and IgD when they reach maturity - the co-expression of both these immunoglobulin isotypes renders the B cell 'mature' and ready to respond to antigen.[12] B cell activation follows engagement of the cell bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody producing cell called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antibodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA or IgG, that have defined roles in the immune system.
# Structure
Antibodies are heavy (~150kDa) globular plasma proteins that are also known as immunoglobulins. They have sugar chains added to some of their amino acid residues.[13] In other words, antibodies are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.[14]
## Immunoglobulin domains
The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds.[11]
Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function.[15] They possess a characteristic immunoglobulin fold in which two beta sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
## Heavy chain
There are five types of mammalian Ig heavy chain denoted by the Greek letters: α, δ, ε, γ, and μ.[3] The type of heavy chain present defines the class of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.[4] Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids, while μ and ε have approximately 550 amino acids.[3]
Each heavy chain has two regions, the constant region and the variable region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem (in a line) Ig domains, and a hinge region for added flexibility;[11] heavy chains μ and ε have a constant region composed of four immunoglobulin domains.[3] The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
## Light chain
In mammals there are two types of light chain, which are called lambda (λ) and kappa (κ).[3] A light chain has two successive domains: one constant domain and one variable domain. The approximate length of a light chain is 211 to 217 amino acids.[3] Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. Other types of light chains, such as the iota (ι) chain, are found in lower vertebrates like Chondrichthyes and Teleostei.
## Fab and Fc Regions
Some parts of an antibody have unique functions. The tip of the Y, for example, contains the site that binds antigen and, therefore, recognizes specific foreign objects. This region of the antibody is called the Fab (fragment, antigen binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody.[16] The paratope is shaped at the amino terminal end of the antibody monomer by the variable domains from the heavy and light chains.
The base of the Y plays a role in modulating immune cell activity. This region is called the Fc (Fragment, crystallizable) region, and is composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody.[3] By binding to specific proteins the Fc region ensures that each antibody generates an appropriate immune response for a given antigen.[17] The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins. By doing this, it mediates different physiological effects including opsonization, cell lysis, and degranulation of mast cells, basophils and eosinophils.[11][18]
# Function
Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen, a virus hull protein fragment, for example. Antibodies contribute to immunity in three main ways: they can prevent pathogens from entering or damaging cells by binding to them; they can stimulate removal of a pathogen by macrophages and other cells by coating the pathogen; and they can trigger direct pathogen destruction by stimulating other immune responses such as the complement pathway.[19]
## Activation of complement
Antibodies that bind to surface antigens on, for example a bacterium, attract the first component of the complement cascade with their Fc region and initiate activation of the "classical" complement system.[19] This results in the killing of bacteria in two ways.[6] First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly.[20]
## Activation of effector cells
To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody possesses at least two paratopes it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region.[6]
Those cells which recognize coated pathogens have Fc receptors which, as the name suggests, interacts with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of the invading microbe. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens.[3]
# Immunoglobulin diversity
Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens.[21] It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen.[22] Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes.[23]
## V(D)J recombination
Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces - known as gene segments. These segments are called variable (V), diversity (D) and joining (J) segments.[23] V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities.[2]
After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion) thus each B cell can produce antibodies containing only one kind of variable chain.[24][3]
## Somatic hypermutation and affinity maturation
Another mechanism that generates antibody diversity occurs in the mature B cell. Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division.[5] As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains.
Somatic hypermutation serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding affinity.[25] Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity).[26] B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis.[26] Thus, B cells expressing higher affinity antibodies for will outcompete those with weaker affinities for function and survival. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells.[27]
## Class switching
Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG).[2] The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naïve B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function, therefore, after activation, an antibody with a IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from the same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment.[28]
Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions, found in DNA upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of enzymes at two selected S-regions.[29][30] The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype.[31]
# Medical applications
## Disease diagnosis
Detection of particular antibodies is a very common form of medical diagnostics, and applications such as serology depend on these methods.[32] For example, in biochemical assays for disease diagnosis,[33] a titer of antibodies directed against Epstein-Barr virus or Lyme disease is estimated from the blood. If those antibodies are not present, either the person is not infected, or the infection occurred a very long time ago, and the B cells generating these specific antibodies have naturally decayed. In clinical immunology, levels of individual classes of immunoglobulins are measured by nephelometry (or turbidimetry) to characterize the antibody profile of patient.[34] Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of liver damage in patients whom the diagnosis is unclear.[4] For example, elevated IgA indicates alcoholic cirrhosis, elevated IgM indicates viral hepatitis and primary biliary cirrhosis, while IgG is elevated in viral hepatitis, autoimmune hepatitis and cirrhosis. Autoimmune disorders can often be traced to antibodies that bind the body's own epitopes; many can be detected through blood tests. Antibodies directed against red blood cell surface antigens in immune mediated hemolytic anemia are detected with the Coombs test.[35] The Coombs test is also used for antibody screening in blood transfusion preparation and also for antibody screening in antenatal women.[35]
Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA, immunofluorescence, Western blot, immunodiffusion, and immunoelectrophoresis.
## Disease therapy
"Targeted" monoclonal antibody therapy is employed to treat diseases such as rheumatoid arthritis,[36] multiple sclerosis,[37] psoriasis,[38] and many forms of cancer including non-Hodgkin's lymphoma,[39] colorectal cancer, head and neck cancer and breast cancer.[40]
Some immune deficiencies, such as X-linked agammaglobulinemia and hypogammaglobulinemia, result in partial or complete lack of antibodies.[41] These diseases are often treated by inducing a short term form of immunity called passive immunity. Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal serum, pooled immunoglobulin or monoclonal antibodies, into the affected individual.[42]
## Prenatal therapy
Rho(D) Immune Globulin antibodies are specific for human Rhesus D (RhD) antigen, also known as Rhesus factor.[43] These anti-RhD antibodies are known under several brand names, including RhoGAM, BayRHo-D, Gamulin Rh, HypRho-D, and WinRho SDF. Rhesus factor is an antigen found on red blood cells; individuals that are Rhesus-positive (Rh+) have this antigen on their red blood cells and individuals that are Rhesus-negative (Rh-) do not.
During normal childbirth, delivery trauma or complications during pregnancy, blood from a fetus can enter the mother's system. In the case of an Rh-incompatible mother and child, consequential blood mixing may sensitize an Rh- mother to the Rh antigen on the blood cells of the Rh+ child, putting the remainder of the pregnancy, and any subsequent pregnancies, at risk for hemolytic disease of the newborn.[44] Anti-RhD antibodies are administered as part of a prenatal treatment regimen to prevent sensitization that may occur when a Rhesus-negative mother has a Rhesus-positive
fetus.
Treatment of a mother with Anti-RhD antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. Importantly, this occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rhesus antigens of the current or subsequent baby. Rho(D) Immune Globulin treatment prevents sensitization that can lead to Rh disease, but does not prevent or treat the underlying disease itself.[43]
# Research applications
Specific antibodies are produced by injecting an antigen into a mammal, such as a mouse, rat or rabbit for small quantities of antibody, or goat, sheep, or horse for large quantities of antibody. Blood isolated from these animals contains polyclonal antibodies — multiple antibodies that bind to the same antigen — in the serum, which can now be called antiserum. Antigens are also injected into chickens for generation of polyclonal antibodies in egg yolk.[45] To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting lymphocytes are isolated from the animal and immortalized by fusing them with a cancer cell line. The fused cells are called hybridomas, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by dilution cloning to generate cell clones that all produce the same antibody; these antibodies are called monoclonal antibodies.[46]
Generated polyclonal and monoclonal antibodies are often purified using Protein A/G or antigen-affinity chromatography.[47]
## Use
In research, purified antibodies are used in many applications. They are most commonly used to identify and locate intracellular and extracellular proteins. Antibodies are used in flow cytometry to differentiate cell types by the proteins they express; different types of cell express different combinations of cluster of differentiation molecules on their surface, and produce different intracellular and secretable proteins.[48] They are also used in immunoprecipitation to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a cell lysate,[49] in Western blot analyses to identify proteins separated by electrophoresis,[50] and in immunohistochemistry or immunofluorescence to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a microscope.[51][48] Proteins can also be detected and quantified with antibodies, using ELISA and ELISPOT techniques.[52][53]
# History
The study of antibodies began in 1890 when Emil von Behring and Shibasaburo Kitasato described antibody activity against diphtheria and tetanus toxins. Behring and Kitasato put forward the theory of humoral immunity, proposing that a mediator in serum could react with a foreign antigen.[54][55] Their idea prompted Paul Ehrlich to propose the side chain theory for antibody and antigen interaction in 1897, when he hypothesized that receptors (described as “side chains”) on the surface of cells could bind specifically to toxins – in a "lock-and-key" interaction – and that this binding reaction was the trigger for the production of antibodies.[56] Other researchers believed that antibodies existed freely in the blood and, in 1904, Almroth Wright suggested that soluble antibodies coated bacteria to label them for phagocytosis and killing; a process that he named opsoninization.[57]
In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies were made of protein.[58] The biochemical properties of antigen-antibody binding interactions were examined in more detail in the late 1930s by John Marrack.[59] The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depended more on their shape than their chemical composition.[60] In 1948, Astrid Fagreaus discovered that B cells, in the form of plasma cells, were responsible for generating antibodies.[61]
Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by Gerald Edelman and Joseph Gally of the antibody light chain,[62] and their realization that this protein was the same as the Bence-Jones protein described in 1845 by Henry Bence Jones.[63] Edelman went on to discover that antibodies are composed of disulphide bond-linked heavy and light chains. Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by Rodney Porter.[64] Together, these scientists deduced the structure and complete amino acid sequence of IgG, a feat for which they were jointly awarded the 1972 Nobel prize in Physiology or Medicine.[64] While most of these early studies focused on IgM and IgG, other immunoglobulin isotypes were identified in the 1960s: Thomas Tomasi discovered secretory antibody (IgA) [65] and David Rowe and John Fahey identified IgD,[66] and IgE was identified by Kikishige Ishizaka and Teruki Ishizaka as a class of antibodies involved in allergic reactions.[67]
Genetic studies revealed the basis of the vast diversity of these antibody proteins when somatic recombination of immunoglobulin genes was identified by Susumu Tonegawa in 1976.[68] | https://www.wikidoc.org/index.php/Antibody | |
8aaeb1aadcc886dcbd701d3e3e8dc10197ca0e3f | wikidoc | Nematode | Nematode
# Overview
The nematodes or roundworms (Phylum Nematoda from Greek Template:Polytonic (nema): "thread" + Template:Polytonic -ode "like") are one of the most common phyla of animals, with over 80,000 different described species (over 15,000 are parasitic). They are ubiquitous in freshwater, marine, and terrestrial environments, where they often outnumber other animals in both individual and species counts, and are found in locations as diverse as Antarctica and oceanic trenches. Further, there are a great many parasitic forms, including pathogens in most plants, animals, and also in humans.
The nematodes were originally named nematoidea by Rudolphi (1808). They were renamed nematodes by Burmeister 1837 (as a family; Leuckart 1848 and von Siebold 1848 both promoted them to the rank of order), then nematoda (Diesing 1861), though Nathan Cobb (1919) argued that they should be called nemata or nemates (and in English 'nemas' rather than 'nematodes'). After some confusion which saw the nematodes placed (often together with the horsehair worms, nematomorpha) as a class or order in various groups such as Aschelminthes, Lankester (1877) definitively promoted them to the level of phylum.
# Morphology
Nematodes are unsegmented, bilaterally symmetric and triploblastic protostomes with a complete digestive system. Roundworms have no circulatory or respiratory systems so they use diffusion to breathe. Although they lack a circulatory system, nutrients are transported throughout the body via fluid in the pseudocoelom. They are thin and are round in cross section. Nematodes are one of the simplest animal groups to have a complete digestive system, with a separate orifice for food intake and waste excretion, a pattern followed by all subsequent, more complex animals. The body cavity is a pseudocoelom (persistent blastula), which lacks the muscles of coelomate animals used to force food down the digestive tract. Nematodes thus depend on internal/external pressures and body movement to move food through their digestive tracts. The mouth is often surrounded by various flaps or projections used in feeding and sensation. The portion of the body past the anus or cloaca is called the "tail." As they grow, their cells get larger, but the total number is constant, called eutely. The epidermis secretes a layered cuticle made of three layers of collagen that protects the body from drying out, from digestive juices, or from other harsh environments. Although this cuticle allows movement and shape changes via a hydrostatic skeletal system, it is very inelastic so does not allow the volume of the worm to increase. Therefore, as the worm grows, it has to molt and form new cuticles. The cuticles don't allow volume to increase so as to keep hydrostatic pressure inside the organism very high. For this reason, the roundworms do not possess circular muscles (just longitudinal ones) as they're not required. This hydrostatic pressure is the reason the roundworms are round.
Nematodes have a simple nervous system, with a main ventral nerve cord and a smaller dorsal nerve cord. Sensory structures at the anterior end are called amphids, while sensory structures at the posterior end are called phasmids.
Most free-living nematodes are microscopic, though a few parasitic forms can grow to over a meter in length (typically as parasites of very large animals such as whales). There are no circular muscles, so the body can only undulate from side to side. Contact with solid objects is necessary for locomotion; its thrashing motions vary from mostly to completely ineffective at swimming.
Nematodes generally eat bacteria, fungi and protozoans, although some are filter feeders. Excretion is through a separate excretory pore. Nematodes also contract bacterial infections within excretion pores.
# Reproduction
Reproduction is usually sexual. Males are usually smaller than females (often much smaller) and often have a characteristically bent tail for holding the female for copulation. During copulation, one or more chitinized spicules move out of the cloaca and are inserted into genital pore of the female. Amoeboid sperm crawl along the spicule into the female worm. Nematode sperm is thought to be the only eukaryotic cell without the globular protein G-actin.
Eggs may be embryonated or unembryonated when passed by the female, meaning that their fertilized eggs may not yet be developed. In free-living roundworms, the eggs hatch into larva, which eventually grow into adults; in parasitic roundworms, the life cycle is often much more complicated.
Some nematodes, specifically Heterorhabditis spp., undergo a process called endotokia matricida; intra-uterine birth causing maternal death. The hermaphroditic nematode keeps its self-fertilized eggs inside its uterus until they hatch. The juvenile nematodes will then ingest the parent nematode. This process is significantly promoted in environments with a low or reducing food supply.
# Free-living species
In free-living species, development usually consists of four molts of the cuticle during growth. Different species feed on materials as varied as algae, fungi, small animals, fecal matter, dead organisms and living tissues. Free-living marine nematodes are important and abundant members of the meiobenthos. They play an important role in the decomposition process, aid in recycling of nutrients in marine environments and are sensitive to changes in the environment caused by pollution. One roundworm of note is Caenorhabditis elegans, which lives in the soil and has found much use as a model organism. C. elegans has had its entire genome sequenced, as well as the developmental fate of every cell determined, and every neuron mapped.
Some Nematodes can undergo cryptobiosis.
# Parasitic species
Parasitic forms often have quite complicated life cycles, moving between several different hosts or locations in the host's body. Infection occurs variously by eating uncooked meat with larvae in it, by entrance into unprotected cuts or directly through the skin, by transfer via blood-sucking insects, and so forth.
Nematodes commonly parasitic on humans include whipworms, hookworms, pinworms, ascarids, and filarids. The species Trichinella spiralis, commonly known as the trichina worm, occurs in rats, pigs, and humans, and is responsible for the disease trichinosis. Baylisascaris usually infests wild animals but can be deadly to humans as well. Haemonchus contortus is one of the most abundant infectious agents in sheep around the world, causing great economic damage to sheep farms.
In contrast, entomopathogenic nematodes parasitize insects and are considered by humans to be beneficial.
One form of nematode is entirely dependent upon the wasps which are the sole source of fig fertilization. They prey upon the wasps, riding them from the ripe fig of the wasp's birth to the fig flower of its death, where they kill the wasp, and their offspring await the birth of the next generation of wasps as the fig ripens.
Plant parasitic nematodes include several groups causing severe crop losses. The most common genera are: Aphelenchoides (foliar nematodes), Meloidogyne (root-knot nematodes), Heterodera, Globodera (cyst nematodes) such as the potato cyst nematode, Nacobbus, Pratylenchus (lesion nematodes), Ditylenchus, Xiphinema, Longidorus, Trichodorus. Several phytoparasitic nematode species cause histological damages to roots, including the formation of visible galls (Meloidogyne) which are useful characters for their diagnostic in the field. Some nematode species transmit plant viruses through their feeding activity on roots. One of them is Xiphinema index, vector of GFLV (Grapevine Fanleaf Virus), an important disease of grapes.
Other nematodes attack bark and forest trees. The most important representative of this group is Bursaphelenchus xylophilus, the pine wood nematode, present in Asia and America and recently discovered in Europe.
The largest nematode ever recorded, Placentonema gigantissima, was discovered parasitizing the placenta of a sperm whale, measuring 8.5 m in length with a diameter of 0.3 mm, and containing 32 ovaries.
Other large nematodes include: Dioctophyma renale, the giant kidney worm, a parasite most commonly found in mink but also in dogs and humans, that can reach up to 103 cm in length.
# Abundance
The nematode species are very difficult to distinguish. Of the pseudocoelomates, the nematodes are the most common. Nematodes have successfully adapted to nearly every niche from marine to fresh water, from the polar regions to the tropics, as well as the highest to the lowest of elevations. They represent, for example, 90% of all life on the seafloor of the Earth. Though 20,000 species have been classified it is estimated that this number might be upwards of 500,000 if all were known.. In certain fertile areas the topsoil is estimated to contain in the billions of nematodes per acre. In the 1914 edition of the Yearbook of the United States Department of Agriculture N.A.Cobb wrote on the abundance of nematodes: Template:Cquote2
# Gardening
Depending on the species, a nematode may be beneficial or detrimental to a gardener's cause.
From a gardening perspective, there are two categories of nematode: predatory ones, which will kill garden pests like cutworms, and pest nematodes, like the root-knot nematode, which attack garden plants.
Predatory nematodes can be bred by soaking a specific recipe of leaves and other detritus in water, in a dark, cool place, and can even be purchased as an organic form of pest control.
# Phylogeny
While it has recently been suggested that nematodes are related to the arthropods and priapulids and should be grouped with them in the Ecdysozoa (molting animals), there is substantial resistance within the nematology community. Grouping organisms based on behaviors is not generally accepted. While there seems to be some evolutionary connection between these phyla, the exact nature of their relationship is still being debated.
That the roundworms have a large number of peculiar apomorphies and in many cases a parasitic lifestyle confounds analyses; the DNA sequence data hitherto analyzed is equivocal on ecdysozoan monophyly. Genetic analyses of roundworms suggest that - as is also indicated by their unique morphological features - the group has been under intense selective pressure during its early radiation, resulting apparently in accelerated rates of both morphological and molecular evolution. Until a strong phylogenetic tree based on combined evidence is produced, most agree that the Nematoda should simply be referred to as part of the Metazoa.
# Cultural references
- The first episode of the children's television show Doug involves a nematode, though it is posited that the animal is purely fictional. See List of Doug episodes, #1.
- In the SpongeBob SquarePants episode Home Sweet Pineapple, nematodes eat Spongebob's pineapple house, and he is forced to find a new home. In Best Day Ever, SpongeBob leads hungry nematodes away from the Krusty Krab by playing the song "Best Day Ever" with his hands and proboscis. In the episode Sailor Mouth SpongeBob reads graffiti that says "Nematoads are people too."
# Robustness
- Hundreds of nematode worms (C. elegans), featured in a research project on mission STS-107, survived the Space Shuttle Columbia Disaster. | Nematode
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
# Overview
The nematodes or roundworms (Phylum Nematoda from Greek Template:Polytonic (nema): "thread" + Template:Polytonic -ode "like") are one of the most common phyla of animals, with over 80,000 different described species (over 15,000 are parasitic). They are ubiquitous in freshwater, marine, and terrestrial environments, where they often outnumber other animals in both individual and species counts, and are found in locations as diverse as Antarctica and oceanic trenches. Further, there are a great many parasitic forms, including pathogens in most plants, animals, and also in humans.
The nematodes were originally named nematoidea by Rudolphi (1808). They were renamed nematodes by Burmeister 1837 (as a family; Leuckart 1848 and von Siebold 1848 both promoted them to the rank of order), then nematoda (Diesing 1861), though Nathan Cobb (1919) argued that they should be called nemata or nemates (and in English 'nemas' rather than 'nematodes'). After some confusion which saw the nematodes placed (often together with the horsehair worms, nematomorpha) as a class or order in various groups such as Aschelminthes, Lankester (1877) definitively promoted them to the level of phylum.
# Morphology
Nematodes are unsegmented, bilaterally symmetric and triploblastic protostomes with a complete digestive system. Roundworms have no circulatory or respiratory systems so they use diffusion to breathe.[1] Although they lack a circulatory system, nutrients are transported throughout the body via fluid in the pseudocoelom. They are thin and are round in cross section. Nematodes are one of the simplest animal groups to have a complete digestive system, with a separate orifice for food intake and waste excretion, a pattern followed by all subsequent, more complex animals. The body cavity is a pseudocoelom (persistent blastula), which lacks the muscles of coelomate animals used to force food down the digestive tract. Nematodes thus depend on internal/external pressures and body movement to move food through their digestive tracts. The mouth is often surrounded by various flaps or projections used in feeding and sensation. The portion of the body past the anus or cloaca is called the "tail." As they grow, their cells get larger, but the total number is constant, called eutely. The epidermis secretes a layered cuticle made of three layers of collagen[2] that protects the body from drying out, from digestive juices, or from other harsh environments. Although this cuticle allows movement and shape changes via a hydrostatic skeletal system, it is very inelastic so does not allow the volume of the worm to increase. Therefore, as the worm grows, it has to molt and form new cuticles. The cuticles don't allow volume to increase so as to keep hydrostatic pressure inside the organism very high. For this reason, the roundworms do not possess circular muscles (just longitudinal ones) as they're not required. This hydrostatic pressure is the reason the roundworms are round.
Nematodes have a simple nervous system, with a main ventral nerve cord and a smaller dorsal nerve cord[3]. Sensory structures at the anterior end are called amphids, while sensory structures at the posterior end are called phasmids.
Most free-living nematodes are microscopic, though a few parasitic forms can grow to over a meter in length (typically as parasites of very large animals such as whales). There are no circular muscles, so the body can only undulate from side to side. Contact with solid objects is necessary for locomotion; its thrashing motions vary from mostly to completely ineffective at swimming.
Nematodes generally eat bacteria, fungi and protozoans, although some are filter feeders. Excretion is through a separate excretory pore. Nematodes also contract bacterial infections within excretion pores.
# Reproduction
Reproduction is usually sexual. Males are usually smaller than females (often much smaller) and often have a characteristically bent tail for holding the female for copulation. During copulation, one or more chitinized spicules move out of the cloaca and are inserted into genital pore of the female. Amoeboid sperm crawl along the spicule into the female worm. Nematode sperm is thought to be the only eukaryotic cell without the globular protein G-actin.
Eggs may be embryonated or unembryonated when passed by the female, meaning that their fertilized eggs may not yet be developed. In free-living roundworms, the eggs hatch into larva, which eventually grow into adults; in parasitic roundworms, the life cycle is often much more complicated.
Some nematodes, specifically Heterorhabditis spp., undergo a process called endotokia matricida; intra-uterine birth causing maternal death.[4] The hermaphroditic nematode keeps its self-fertilized eggs inside its uterus until they hatch. The juvenile nematodes will then ingest the parent nematode. This process is significantly promoted in environments with a low or reducing food supply.[4]
# Free-living species
In free-living species, development usually consists of four molts of the cuticle during growth. Different species feed on materials as varied as algae, fungi, small animals, fecal matter, dead organisms and living tissues. Free-living marine nematodes are important and abundant members of the meiobenthos. They play an important role in the decomposition process, aid in recycling of nutrients in marine environments and are sensitive to changes in the environment caused by pollution. One roundworm of note is Caenorhabditis elegans, which lives in the soil and has found much use as a model organism. C. elegans has had its entire genome sequenced, as well as the developmental fate of every cell determined, and every neuron mapped.
Some Nematodes can undergo cryptobiosis.
# Parasitic species
Parasitic forms often have quite complicated life cycles, moving between several different hosts or locations in the host's body. Infection occurs variously by eating uncooked meat with larvae in it, by entrance into unprotected cuts or directly through the skin, by transfer via blood-sucking insects, and so forth.
Nematodes commonly parasitic on humans include whipworms, hookworms, pinworms, ascarids, and filarids. The species Trichinella spiralis, commonly known as the trichina worm, occurs in rats, pigs, and humans, and is responsible for the disease trichinosis. Baylisascaris usually infests wild animals but can be deadly to humans as well. Haemonchus contortus is one of the most abundant infectious agents in sheep around the world, causing great economic damage to sheep farms.
In contrast, entomopathogenic nematodes parasitize insects and are considered by humans to be beneficial.
One form of nematode is entirely dependent upon the wasps which are the sole source of fig fertilization. They prey upon the wasps, riding them from the ripe fig of the wasp's birth to the fig flower of its death, where they kill the wasp, and their offspring await the birth of the next generation of wasps as the fig ripens.
Plant parasitic nematodes include several groups causing severe crop losses. The most common genera are: Aphelenchoides (foliar nematodes), Meloidogyne (root-knot nematodes), Heterodera, Globodera (cyst nematodes) such as the potato cyst nematode, Nacobbus, Pratylenchus (lesion nematodes), Ditylenchus, Xiphinema, Longidorus, Trichodorus. Several phytoparasitic nematode species cause histological damages to roots, including the formation of visible galls (Meloidogyne) which are useful characters for their diagnostic in the field. Some nematode species transmit plant viruses through their feeding activity on roots. One of them is Xiphinema index, vector of GFLV (Grapevine Fanleaf Virus), an important disease of grapes.
Other nematodes attack bark and forest trees. The most important representative of this group is Bursaphelenchus xylophilus, the pine wood nematode, present in Asia and America and recently discovered in Europe.
The largest nematode ever recorded, Placentonema gigantissima, was discovered parasitizing the placenta of a sperm whale, measuring 8.5 m in length with a diameter of 0.3 mm, and containing 32 ovaries.[5]
Other large nematodes include: Dioctophyma renale, the giant kidney worm, a parasite most commonly found in mink but also in dogs and humans, that can reach up to 103 cm in length.[6][5]
# Abundance
The nematode species are very difficult to distinguish. Of the pseudocoelomates, the nematodes are the most common. Nematodes have successfully adapted to nearly every niche from marine to fresh water, from the polar regions to the tropics, as well as the highest to the lowest of elevations. They represent, for example, 90% of all life on the seafloor of the Earth. [4] Though 20,000 species have been classified it is estimated that this number might be upwards of 500,000 if all were known.[7]. In certain fertile areas the topsoil is estimated to contain in the billions of nematodes per acre.[2] In the 1914 edition of the Yearbook of the United States Department of Agriculture N.A.Cobb wrote on the abundance of nematodes[2]: Template:Cquote2
# Gardening
Depending on the species, a nematode may be beneficial or detrimental to a gardener's cause.
From a gardening perspective, there are two categories of nematode: predatory ones, which will kill garden pests like cutworms, and pest nematodes, like the root-knot nematode, which attack garden plants.
Predatory nematodes can be bred by soaking a specific recipe of leaves and other detritus in water, in a dark, cool place, and can even be purchased as an organic form of pest control.
# Phylogeny
Template:Refimprove-section
While it has recently been suggested that nematodes are related to the arthropods and priapulids and should be grouped with them in the Ecdysozoa (molting animals), there is substantial resistance within the nematology community. Grouping organisms based on behaviors is not generally accepted. While there seems to be some evolutionary connection between these phyla, the exact nature of their relationship is still being debated.[8]
That the roundworms have a large number of peculiar apomorphies and in many cases a parasitic lifestyle confounds analyses; the DNA sequence data hitherto analyzed is equivocal on ecdysozoan monophyly. Genetic analyses of roundworms suggest that - as is also indicated by their unique morphological features - the group has been under intense selective pressure during its early radiation, resulting apparently in accelerated rates of both morphological and molecular evolution. Until a strong phylogenetic tree based on combined evidence is produced, most agree that the Nematoda should simply be referred to as part of the Metazoa.
# Cultural references
- The first episode of the children's television show Doug involves a nematode, though it is posited that the animal is purely fictional. See List of Doug episodes, #1.
- In the SpongeBob SquarePants episode Home Sweet Pineapple, nematodes eat Spongebob's pineapple house, and he is forced to find a new home. In Best Day Ever, SpongeBob leads hungry nematodes away from the Krusty Krab by playing the song "Best Day Ever" with his hands and proboscis. In the episode Sailor Mouth SpongeBob reads graffiti that says "Nematoads are people too."
# Robustness
- Hundreds of nematode worms (C. elegans), featured in a research project on mission STS-107, survived the Space Shuttle Columbia Disaster.[9] | https://www.wikidoc.org/index.php/Antinematodals | |
ea5f3f5c9afa1969a83bc02105af307ac4c189b4 | wikidoc | Aphorism | Aphorism
The word aphorism (literally distinction or definition, from Template:Lang-el) denotes an original thought, spoken or written in a laconic and easily memorable form.
The name was first used in the Aphorisms of Hippocrates. The term came to be applied later to other sententious statements of physical science and later still to statements of all kinds of philosophical, moral or literary principles.
The Aphorisms of Hippocrates were the earliest collection of the kind. They include such notable and often invoked phrases as:"Life is short, art is long, opportunity fugitive, experimenting dangerous, reasoning difficult: it is necessary not only to do oneself what is right, but also to be seconded by the patient, by those who attend him, by external circumstances."
The aphoristic genre developed together with literacy, and after the invention of printing aphorisms were collected and published in book form. The first noted published collection of aphorisms is "Adagia" by Erasmus of Rotterdam. Other important early aphorists were François de La Rochefoucauld and Blaise Pascal.
Two influential collections of aphorisms published in the 20th century were "The Uncombed Thoughts" by Stanislaw Jerzy Lec (in Polish), and "Itch of Wisdom" by Mikhail Turovsky (in Russian).
# Examples
Usually an aphorism is a concise statement containing a personal truth or observation cleverly and pithily written. Aphorisms can be both prosaic or poetic, sometimes they have repeated words or phrases, and sometimes they have two parts that are of the same grammatical structure. Some examples include:
- Lost time is never found again. — Benjamin Franklin
- Greed is a permanent slavery. — Ali
- Render unto Caesar what is Caesar. Render unto God what is God's. — Jesus Christ
- Mediocrity is forgiven more easily than talent.' Emil Krotky
- Nothing great was ever achieved without enthusiasm. — Ralph Waldo Emerson
- Death with dignity is better than life with humiliation. — Husayn ibn Ali
- That which does not destroy us makes us stronger. — Friedrich Nietzsche
- If you see the teeth of the lion, do not think that the lion is smiling at you. — Al-Mutanabbi
- When your legs get weaker time starts running faster. — Mikhail Turovsky
- Many of those who tried to enlighten were hanged from the lampposts. — Stanislaw Jerzy Lec
- A mystic hangs a fig leaf on a eunuch.' Stanislaw Jerzy Lec
- The psychology of committees is a special case of the psychology of mobs. — Celia Green
- It is not uncommon to commiserate with a stranger's misfortune, but it takes a really fine nature to appreciate a friend's success. — Oscar Wilde
- Hypocrisy is the tribute that vice pays to virtue. — Unknown, possibly French proverb, or authored by François de La Rochefoucauld
- One death is a tragedy; a million is a statistic. — Joseph Stalin
- Believe nothing you hear, and only half of what you see. — Mark Twain
- It is better to be hated for what one is, than loved for what one is not. — André Gide
- A lie told often enough becomes the truth. — Vladimir Lenin
- Like a road in Autumn: Hardly is it swept clean before it is covered again with dead leaves. — Franz Kafka
- Love the sinner and hate the sin. (Cum dilectione hominum et odio vitiorum.) - St. Augustine of Hippo
# Aphorism and literature
Aphoristic collections, sometimes known as wisdom literature, have a prominent place in the canons of several ancient societies: E.g. the Biblical Book of Proverbs, Islamic Hadith, Hesiod's Works and Days, or Epictetus' Handbook. Aphoristic collections also make up an important part of the work of some modern authors, such as Georg Christoph Lichtenberg, Friedrich Nietzsche, Franz Kafka, Karl Kraus, La Rouchefoucauld, Thomas Szasz, Stanislaw Jerzy Lec, Mikhail Turovsky, Celia Green, Robert A. Heinlein, Blaise Pascal, E. M. Cioran, and Oscar Wilde. A 1559 oil-on-oak-panel painting, Netherlandish Proverbs (also called The Blue Cloak or The Topsy Turvy World) by Pieter Brueghel the Elder, artfully depicts a land populated with literal renditions of Flemish aphorisms (proverbs) of the day.
# Poetics of the aphorism
The aphorism is considered a compressed poetic genre in itself. Aphorisms typically make extensive use of such devices as alliteration (penny wise, pound foolish), anaphora (a penny saved is a penny earned) and rhyme (a stitch in time saves nine).
Consider, for example, the aphorism "Children should be seen and not heard", which has persisted in common usage despite many compelling objections to its wisdom. Whatever the value of its message, the phrase could, in fact, be considered a masterpiece of oral-poetic art.
"Children should be seen and not heard" contains emphatic repetition of the consonants n and d (Children should be seen and not heard). Metrically, it consists of four syllables without strong rhythmical marking (Children should be) followed by a pronounced choriamb (seen and not heard). It is thus remarkably similar to octosyllabic verse-forms found in many ancient literatures, including Sappho's lyrics and the hymns of the Rig-Veda.
# Aphorism and society
In a number of cultures, such as Samuel Johnson's England and tribal societies throughout the world, the ability to spontaneously produce aphoristic sayings at exactly the right moment is a key determinant of social status.
Many societies have traditional sages or culture heroes to whom aphorisms are commonly attributed, such as the Seven Sages of Greece, Confucius or King Solomon.
Misquoted or misadvised aphorisms are frequently used as a source of humour; for instance, wordplays around aphorisms appear in the works of P. G. Wodehouse, Terry Pratchett and Douglas Adams (e.g. Zaphod Beeblebrox saying "Right now I need aphorisms like I need holes in my heads"). Aphorisms being misquoted by sports players, coaches and commentators forms the basis of Private Eye's Colemanballs section.
# Aphorists
An aphorist is someone who produces or collects aphorisms. Famous aphorists include: | Aphorism
The word aphorism (literally distinction or definition, from Template:Lang-el) denotes an original thought, spoken or written in a laconic and easily memorable form. [1]
The name was first used in the Aphorisms of Hippocrates. The term came to be applied later to other sententious statements of physical science and later still to statements of all kinds of philosophical, moral or literary principles.
The Aphorisms of Hippocrates were the earliest collection of the kind. They include such notable and often invoked phrases as:"Life is short, art is long, opportunity fugitive, experimenting dangerous, reasoning difficult: it is necessary not only to do oneself what is right, but also to be seconded by the patient, by those who attend him, by external circumstances."
The aphoristic genre developed together with literacy, and after the invention of printing aphorisms were collected and published in book form. The first noted published collection of aphorisms is "Adagia" by Erasmus of Rotterdam. Other important early aphorists were François de La Rochefoucauld and Blaise Pascal.
Two influential collections of aphorisms published in the 20th century were "The Uncombed Thoughts" by Stanislaw Jerzy Lec (in Polish), and "Itch of Wisdom" by Mikhail Turovsky (in Russian).
# Examples
Usually an aphorism is a concise statement containing a personal truth or observation cleverly and pithily written. Aphorisms can be both prosaic or poetic, sometimes they have repeated words or phrases, and sometimes they have two parts that are of the same grammatical structure. Some examples include:
- Lost time is never found again. — Benjamin Franklin
- Greed is a permanent slavery. — Ali
- Render unto Caesar what is Caesar. Render unto God what is God's. — Jesus Christ
- Mediocrity is forgiven more easily than talent.' Emil Krotky
- Nothing great was ever achieved without enthusiasm. — Ralph Waldo Emerson
- Death with dignity is better than life with humiliation. — Husayn ibn Ali
- That which does not destroy us makes us stronger. — Friedrich Nietzsche
- If you see the teeth of the lion, do not think that the lion is smiling at you. — Al-Mutanabbi
- When your legs get weaker time starts running faster. — Mikhail Turovsky
- Many of those who tried to enlighten were hanged from the lampposts. — Stanislaw Jerzy Lec
- A mystic hangs a fig leaf on a eunuch.' Stanislaw Jerzy Lec
- The psychology of committees is a special case of the psychology of mobs. — Celia Green
- It is not uncommon to commiserate with a stranger's misfortune, but it takes a really fine nature to appreciate a friend's success. — Oscar Wilde
- Hypocrisy is the tribute that vice pays to virtue. — Unknown, possibly French proverb, or authored by François de La Rochefoucauld
- One death is a tragedy; a million is a statistic. — Joseph Stalin
- Believe nothing you hear, and only half of what you see. — Mark Twain
- It is better to be hated for what one is, than loved for what one is not. — André Gide
- A lie told often enough becomes the truth. — Vladimir Lenin
- Like a road in Autumn: Hardly is it swept clean before it is covered again with dead leaves. — Franz Kafka
- Love the sinner and hate the sin. (Cum dilectione hominum et odio vitiorum.) - St. Augustine of Hippo[2]
# Aphorism and literature
Aphoristic collections, sometimes known as wisdom literature, have a prominent place in the canons of several ancient societies: E.g. the Biblical Book of Proverbs, Islamic Hadith, Hesiod's Works and Days, or Epictetus' Handbook. Aphoristic collections also make up an important part of the work of some modern authors, such as Georg Christoph Lichtenberg, Friedrich Nietzsche, Franz Kafka, Karl Kraus, La Rouchefoucauld, Thomas Szasz, Stanislaw Jerzy Lec, Mikhail Turovsky, Celia Green, Robert A. Heinlein, Blaise Pascal, E. M. Cioran, and Oscar Wilde. A 1559 oil-on-oak-panel painting, Netherlandish Proverbs (also called The Blue Cloak or The Topsy Turvy World) by Pieter Brueghel the Elder, artfully depicts a land populated with literal renditions of Flemish aphorisms (proverbs) of the day.
# Poetics of the aphorism
The aphorism is considered a compressed poetic genre in itself. Aphorisms typically make extensive use of such devices as alliteration (penny wise, pound foolish), anaphora (a penny saved is a penny earned) and rhyme (a stitch in time saves nine).
Consider, for example, the aphorism "Children should be seen and not heard", which has persisted in common usage despite many compelling objections to its wisdom. Whatever the value of its message, the phrase could, in fact, be considered a masterpiece of oral-poetic art.
"Children should be seen and not heard" contains emphatic repetition of the consonants n and d (Children should be seen and not heard). Metrically, it consists of four syllables without strong rhythmical marking (Children should be) followed by a pronounced choriamb (seen and not heard). It is thus remarkably similar to octosyllabic verse-forms found in many ancient literatures, including Sappho's lyrics and the hymns of the Rig-Veda.
# Aphorism and society
In a number of cultures, such as Samuel Johnson's England and tribal societies throughout the world, the ability to spontaneously produce aphoristic sayings at exactly the right moment is a key determinant of social status.[dubious – discuss]
Many societies have traditional sages or culture heroes to whom aphorisms are commonly attributed, such as the Seven Sages of Greece, Confucius or King Solomon.
Misquoted or misadvised aphorisms are frequently used as a source of humour; for instance, wordplays around aphorisms appear in the works of P. G. Wodehouse, Terry Pratchett and Douglas Adams (e.g. Zaphod Beeblebrox saying "Right now I need aphorisms like I need holes in my heads"). Aphorisms being misquoted by sports players, coaches and commentators forms the basis of Private Eye's Colemanballs section.
# Aphorists
An aphorist is someone who produces or collects aphorisms. Famous aphorists include: | https://www.wikidoc.org/index.php/Aphorism | |
99d77cb3e013d6ebafe9d5504ab63dcd3d057a3d | wikidoc | Apitoxin | Apitoxin
Apitoxin, or honey bee venom, is a bitter colorless liquid. The active portion of the venom is a complex mixture of proteins, which causes local inflammation and acts as an anticoagulant. The venom is produced in the abdomen of worker bees from a mixture of acidic and basic secretions. Apitoxin is acidic (pH 4.5 to 5.5). A honeybee can inject 0.1 mg of venom via its stinger. Apitoxin is similar to snake venom and nettle toxin. It is estimated that 1% of the population is allergic to bee stings. Apitoxin can be deactivated with ethanol.
Bee venom therapy is used by some as a treatment for rheumatism and joint diseases due to its anticoagulant and anti-inflammatory properties. It is also used to desensitize people allergic to insect stings. Bee venom therapy can also be delivered in the form of Bee Venom Balm although this may be less potent than using live bee stings.
# Components of Apitoxin
The main component is melittin comprising 52% of venom peptides. Melittin is a strong anti-inflammatory agent and induces the production of cortisol in the body. It also prevents cell destruction in cases of strong inflammation.
- Apamin increases cortisol production in the adrenal gland. Apamin also acts as a nerve toxin.
- Adolapin, comprising 2-5% of the peptides, acts as an anti-inflammatory and analgesic because it blocks cyclooxygenase.
- Phospholipase A2 comprises 10-12% of peptides and it is the most destructive component of apitoxin. It is an enzyme which degrades the phospholipids which cellular membranes are made of. It also causes decreased blood pressure and inhibits blood coagulation. Phospholipase A2 activates arachidonic acid which is metabolized in the cyclooxygenase-cycle to form prostaglandins. Prostaglandins regulate the body's inflammatory response. The toxin from wasps contains phospholipase A1.
- Hyaluronidase comprising 1-3% of peptides dilates the capillaries causing the spread of inflammation.
- Histamine comprising 0.5-2% and is involved in the allergic response.
- Dopamine and noradrenaline which comprise 1-2% increase pulse rate.
- Protease-inhibitors comprise 2% and act as anti-inflammatory agents and stop bleeding.
# Footnotes
- ↑ "Treatment with Bee Venom"..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}
- ↑ Meier J, White J. (1995). Clinical toxicology of animal venoms and poisons. CRC Press, Inc. ISBN 0-8493-4489-1. | Apitoxin
Apitoxin, or honey bee venom, is a bitter colorless liquid. The active portion of the venom is a complex mixture of proteins, which causes local inflammation and acts as an anticoagulant. The venom is produced in the abdomen of worker bees from a mixture of acidic and basic secretions. Apitoxin is acidic (pH 4.5 to 5.5). A honeybee can inject 0.1 mg of venom via its stinger. Apitoxin is similar to snake venom and nettle toxin. It is estimated that 1% of the population is allergic to bee stings. Apitoxin can be deactivated with ethanol.
Bee venom therapy is used by some as a treatment for rheumatism and joint diseases due to its anticoagulant and anti-inflammatory properties. It is also used to desensitize people allergic to insect stings. Bee venom therapy can also be delivered in the form of Bee Venom Balm although this may be less potent than using live bee stings. [1]
# Components of Apitoxin
The main component is melittin comprising 52% of venom peptides.[2] Melittin is a strong anti-inflammatory agent and induces the production of cortisol in the body. It also prevents cell destruction in cases of strong inflammation.
- Apamin increases cortisol production in the adrenal gland. Apamin also acts as a nerve toxin.
- Adolapin, comprising 2-5% of the peptides, acts as an anti-inflammatory and analgesic because it blocks cyclooxygenase.
- Phospholipase A2 comprises 10-12% of peptides and it is the most destructive component of apitoxin. It is an enzyme which degrades the phospholipids which cellular membranes are made of. It also causes decreased blood pressure and inhibits blood coagulation. Phospholipase A2 activates arachidonic acid which is metabolized in the cyclooxygenase-cycle to form prostaglandins. Prostaglandins regulate the body's inflammatory response. The toxin from wasps contains phospholipase A1.
- Hyaluronidase comprising 1-3% of peptides dilates the capillaries causing the spread of inflammation.
- Histamine comprising 0.5-2% and is involved in the allergic response.
- Dopamine and noradrenaline which comprise 1-2% increase pulse rate.
- Protease-inhibitors comprise 2% and act as anti-inflammatory agents and stop bleeding.
# Footnotes
- ↑ "Treatment with Bee Venom"..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}
- ↑ Meier J, White J. (1995). Clinical toxicology of animal venoms and poisons. CRC Press, Inc. ISBN 0-8493-4489-1. | https://www.wikidoc.org/index.php/Apitoxin | |
7ede8df51762237e4b4ce67821dccd2c4965a194 | wikidoc | Apixaban | Apixaban
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# Black Box Warning
# Overview
Apixaban is an anticoagulant that is FDA approved for the {{{indicationType}}} of stroke and systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis following hip or knee replacement surgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Eliquis is 5 mg taken orally twice daily.
- Dosing Information
- The recommended dose of Eliquis is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
- In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days.
- In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.
- In patients with nonvalvular atrial fibrillation: The recommended dose of Eliquis is 2.5 mg twice daily in patients with any 2 of the following characteristics:
- Age ≥80 years
- Body weight ≤60 kg
- Serum creatinine ≥1.5 mg/dL
- Coadministration with CYP3A4 and P-gp inhibitors
- For patients receiving Eliquis 5 mg twice daily when Eliquis is coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin), the recommended dose is 2.5 mg twice daily.
- In patients already taking 2.5 mg twice daily, coadministration of Eliquis with strong dual inhibitors of CYP3A4 and P-gp should be avoided.
- If a dose of Eliquis is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose.
- Eliquis should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. Eliquis should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping Eliquis and prior to the intervention is not generally required. Eliquis should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
- Switching from warfarin to Eliquis
- Warfarin should be discontinued and Eliquis started when the international normalized ratio (INR) is below 2.0.
- Switching from Eliquis to warfarin: Eliquis affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin. If continuous anticoagulation is necessary, discontinue Eliquis and begin both a parenteral anticoagulant and warfarin at the time the next dose of Eliquis would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
- Switching between Eliquis and anticoagulants other than warfarin: Discontinue one being taken and begin the other at the next scheduled dose.
- No dose adjustment is required in patients with mild hepatic impairment.
- Because patients with moderate hepatic impairment may have intrinsic coagulation abnormalities and there is limited clinical experience with Eliquis in these patients, dosing recommendations cannot be provided.
- Eliquis is not recommended in patients with severe hepatic impairment.
- The dosing adjustment for moderate renal impairment is described above. The recommended dose for nonvalvular atrial fibrillation patients with end-stage renal disease (ESRD) maintained on hemodialysis is 5 mg twice daily. Reduce dose to 2.5 mg twice daily if one of the following patient characteristics (age ≥80 years or body weight ≤60 kg) is present.
- For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg Eliquis tablets may be crushed and suspended in 60 mL D5W and immediately delivered through a nasogastric tube (NGT). Information regarding the administration of crushed and suspended Eliquis tablets swallowed by mouth is not available.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Apixaban in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 2.5 mg or 5 mg PO twice daily
# 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 Apixaban in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Apixaban in pediatric patients.
# Contraindications
- Active pathological bleeding
- Severe hypersensitivity reaction to Eliquis (e.g., anaphylactic reactions)
# Warnings
- Increased Risk of Stroke with Discontinuation of Eliquis in Patients with Nonvalvular Atrial Fibrillation
- Discontinuing Eliquis in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from Eliquis to warfarin in clinical trials in patients with nonvalvular atrial fibrillation. If Eliquis must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.
- Bleeding
- Eliquis increases the risk of bleeding and can cause serious, potentially fatal, bleeding.
- Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs).
- Patients should be made aware of signs and symptoms of blood loss and instructed to report them immediately or go to an emergency room. Eliquis should be discontinued in patients with active pathological hemorrhage.
- There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for at least 24 hours after the last dose, i.e., for about two half-lives. A specific antidote for Eliquis is not available. Hemodialysis does not appear to have a substantial impact on apixaban exposure. Protamine sulfate and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration.
- Spinal/Epidural Anesthesia or Puncture
- When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
- The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of Eliquis. The next dose of Eliquis should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of Eliquis for 48 hours.
- Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
- Patients with Prosthetic Heart Valves
- The safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves. Therefore, use of Eliquis is not recommended in these patients.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of Eliquis was evaluated in the ARISTOTLE and AVERROES studies, including 11,284 patients exposed to Eliquis 5 mg twice daily and 602 patients exposed to Eliquis 2.5 mg twice daily. The duration of Eliquis exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patients-years).
- The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with Eliquis and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on Eliquis and aspirin, respectively.
- Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per year) in ARISTOTLE and AVERROES.
- Major bleeding was defined as clinically overt bleeding that was accompanied by one or more of the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; or bleeding that was fatal. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
- In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, Eliquis dose, type of atrial fibrillation (AF), and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0% per year) than did subjects without diabetes (1.9% per year).
- Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of patients receiving Eliquis.
- The safety of Eliquis has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to Eliquis 2.5 mg twice daily undergoing major orthopedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days.
- In total, 11% of the patients treated with Eliquis 2.5 mg twice daily experienced adverse reactions.
- bleeding results during the treatment period in the Phase III studies are shown in Table 3. bleeding was assessed in each study beginning with the first dose of double-blind study drug.
- Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4.
- Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥0.1% to <1%:
- Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)
- Vascular disorders: hypotension (including procedural hypotension)
- Respiratory, thoracic, and mediastinal disorders: epistaxis
- Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia
- Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased
- Renal and urinary disorders: hematuria (including respective laboratory parameters)
- Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage
- Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of <0.1%:
- Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Apixaban in the drug label.
# Drug Interactions
- Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke.
- For patients receiving 5 mg twice daily, the dose of Eliquis should be decreased to 2.5 mg twice daily when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin).
- In patients already taking Eliquis at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp.
- Avoid concomitant use of Eliquis with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban.
- Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.
- APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2.77% per year with apixaban versus 0.62% per year with placebo in patients receiving single antiplatelet therapy and was 5.91% per year with apixaban versus 2.50% per year with placebo in those receiving dual antiplatelet therapy.
- In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on Eliquis from 1.8% per year to 3.4% per year and the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with Eliquis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies of Eliquis in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Eliquis should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.
- Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted in fetal exposure to apixaban, but was not associated with increased risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and rabbits at maternal exposures that were 19, 4, and 1 times, respectively, the human exposure of unbound drug, based on area under plasma-concentration time curve (AUC) comparisons at the maximum recommended human dose (MRHD) of 10 mg (5 mg twice daily).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apixaban in women who are pregnant.
### Labor and Delivery
- Safety and effectiveness of Eliquis during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using Eliquis in this setting.
- Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure based on unbound apixaban) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding. However, increased incidence of maternal bleeding, primarily during gestation, occurred at apixaban doses of ≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure.
### Nursing Mothers
- It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose).
- Women should be instructed either to discontinue breastfeeding or to discontinue Eliquis therapy, 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 subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16% were 75 and older. No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups.
### Gender
There is no FDA guidance on the use of Apixaban with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Apixaban with respect to specific racial populations.
### Renal Impairment
- Patients with ESRD with or without hemodialysis were not studied in clinical efficacy and safety studies with Eliquis; therefore, the dosing recommendation for patients with nonvalvular atrial fibrillation is based on pharmacokinetic and pharmacodynamic (anti-Factor Xa activity) data in subjects with ESRD maintained on dialysis. The recommended dose for ESRD patients maintained with hemodialysis is 5 mg orally twice daily. For ESRD patients maintained with hemodialysis with one of the following patient characteristics, age ≥80 years or body weight ≤60 kg, reduce dose to 2.5 mg twice daily.
### Hepatic Impairment
There is no FDA guidance on the use of Apixaban in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Apixaban in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Apixaban in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
- Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
# IV Compatibility
There is limited information regarding IV Compatibility of Apixaban in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is no antidote to Eliquis. Overdose of Eliquis increases the risk of bleeding.
- In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no clinically relevant adverse effects.
### Management
- In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Apixaban in the drug label.
# Pharmacology
## Mechanism of Action
- Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.
## Structure
- Eliquis (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6--4,5,6,7-tetrahydro-1H-pyrazolopyridine-3-carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula:
- Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.
- Eliquis tablets are available for oral administration in strengths of 2.5 mg and 5 mg of apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).
## Pharmacodynamics
- As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.
- The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans during the apixaban development program. A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF.
- This test is not recommended for assessing the anticoagulant effect of apixaban.
- Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel. A 50% to 60% increase in anti-FXa activity was observed when apixaban was coadministered with enoxaparin or naproxen.
- Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.
- Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-to-moderate hepatic impairment and healthy subjects. However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied.
- Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.
## Pharmacokinetics
- Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg.
- The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of Eliquis. Food does not affect the bioavailability of apixaban. Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of Eliquis. At doses ≥25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability. Following administration of a crushed 5 mg Eliquis tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube (NGT), exposure was similar to that seen in other clinical trials involving healthy volunteers receiving a single oral 5 mg tablet dose.
- Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
- Approximately 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation.
- Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites.
- Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces.
- Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life of approximately 12 hours following oral administration.
- Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.
- In vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.
- The effects of coadministered drugs on the pharmacokinetics of apixaban and associated dose recommendations are summarized in Figure 2.
- In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.
- In studies conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid.
- The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of apixaban are summarized in Figure 3.
- A study in healthy subjects comparing the pharmacokinetics in males and females showed no meaningful difference.
- The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity.
- In subjects with ESRD, a 4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min started 2 hours after administration of a single 5 mg dose of apixaban, the AUC of apixaban was 17% greater compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min resulting in a 14% decrease in exposure due to hemodialysis compared to off-dialysis period.
- Protein binding was similar (92%-94%) between healthy controls and the on-dialysis and off-dialysis periods.
## Nonclinical Toxicology
- Carcinogenesis
- Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure.
- Mutagenesis
- Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in vivo.
- Impairment of Fertility
- Apixaban had no effect on fertility in male or female rats when given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 4 times, respectively, the human exposure.
- Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring (F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5 times the human exposure. Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day.
# Clinical Studies
- Evidence for the efficacy and safety of Eliquis was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of Eliquis and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0–3.0). Patients had to have one or more of the following additional risk factors for stroke:
- Prior stroke or transient ischemic attack (TIA)
- Prior systemic embolism
- Age ≥75 years
- Arterial hypertension requiring treatment
- Diabetes mellitus
- Heart failure ≥New York Heart Association Class 2
- Left ventricular ejection fraction ≤40%
- The primary objective of ARISTOTLE was to determine whether Eliquis 5 mg twice daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of Eliquis to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause.
- A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA) “naive,” defined as having received ≤30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤40%) 35%, and prior myocardial infarction 14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0–3.0) of 62%.
- Eliquis was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 5 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs.
- Eliquis also showed significantly fewer major bleeds than warfarin.
- All-cause death was assessed using a sequential testing strategy that allowed testing for superiority if effects on earlier endpoints (stroke plus systemic embolus and major bleeding) were demonstrated. Eliquis treatment resulted in a significantly lower rate of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms.
- In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent across most major subgroups including weight, CHADS2 score (a scale from 0 to 6 used to predict risk of stroke in patients with AF, with higher scores predicting greater risk), prior warfarin use, level of renal impairment, geographic region, Eliquis dose, type of AF, and aspirin use at randomization (Figure 5).
- At the end of the ARISTOTLE study, warfarin patients who completed the study were generally maintained on a VKA with no interruption of anticoagulation. Eliquis patients who completed the study were generally switched to a VKA with a 2-day period of coadministration of Eliquis and VKA, so that some patients may not have been adequately anticoagulated after stopping Eliquis until attaining a stable and therapeutic INR. During the 30 days following the end of the study, there were 21 stroke or systemic embolism events in the 6791 patients (0.3%) in the Eliquis arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm.
- In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. The primary objective of the study was to determine if Eliquis was superior to aspirin for preventing the composite outcome of stroke or systemic embolism. AVERROES was stopped early on the basis of a prespecified interim analysis showing a significant reduction in stroke and systemic embolism for Eliquis compared to aspirin that was associated with a modest increase in major bleeding (Table 6).
- The clinical evidence for the effectiveness of Eliquis is derived from the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip (ADVANCE-3) or knee (ADVANCE-2 and ADVANCE-1) replacement surgery. A total of 11,659 patients were randomized in 3 double-blind, multi-national studies. Included in this total were 1866 patients age 75 or older, 1161 patients with low body weight (≤60 kg), 2528 patients with Body Mass Index ≥33 kg/m2, and 625 patients with severe or moderate renal impairment.
- In the ADVANCE-3 study, 5407 patients undergoing elective hip replacement surgery were randomized to receive either Eliquis 2.5 mg orally twice daily or enoxaparin 40 mg subcutaneously once daily. The first dose of Eliquis was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment duration was 32 to 38 days.
- In patients undergoing elective knee replacement surgery, Eliquis 2.5 mg orally twice daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, N=3057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3195). In the ADVANCE-2 study, the first dose of Eliquis was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. In the ADVANCE-1 study, both Eliquis and enoxaparin were initiated 12 to 24 hours post surgery. Treatment duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days.
- In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was tested for noninferiority, then superiority, of Eliquis to enoxaparin. In ADVANCE-1, the primary endpoint was tested for noninferiority of Eliquis to enoxaparin.
- The efficacy data are provided in Tables 7 and 8.
- The efficacy profile of Eliquis was generally consistent across subgroups of interest for this indication (e.g., age, gender, race, body weight, renal impairment).
# How Supplied
## Storage
There is limited information regarding Apixaban Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Apixaban interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Eliquis®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Apixaban
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
Apixaban is an anticoagulant that is FDA approved for the {{{indicationType}}} of stroke and systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis following hip or knee replacement surgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Eliquis is 5 mg taken orally twice daily.
- Dosing Information
- The recommended dose of Eliquis is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
- In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days.
- In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.
- In patients with nonvalvular atrial fibrillation: The recommended dose of Eliquis is 2.5 mg twice daily in patients with any 2 of the following characteristics:
- Age ≥80 years
- Body weight ≤60 kg
- Serum creatinine ≥1.5 mg/dL
- Coadministration with CYP3A4 and P-gp inhibitors
- For patients receiving Eliquis 5 mg twice daily when Eliquis is coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin), the recommended dose is 2.5 mg twice daily.
- In patients already taking 2.5 mg twice daily, coadministration of Eliquis with strong dual inhibitors of CYP3A4 and P-gp should be avoided.
- If a dose of Eliquis is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose.
- Eliquis should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. Eliquis should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping Eliquis and prior to the intervention is not generally required. Eliquis should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
- Switching from warfarin to Eliquis
- Warfarin should be discontinued and Eliquis started when the international normalized ratio (INR) is below 2.0.
- Switching from Eliquis to warfarin: Eliquis affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin. If continuous anticoagulation is necessary, discontinue Eliquis and begin both a parenteral anticoagulant and warfarin at the time the next dose of Eliquis would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
- Switching between Eliquis and anticoagulants other than warfarin: Discontinue one being taken and begin the other at the next scheduled dose.
- No dose adjustment is required in patients with mild hepatic impairment.
- Because patients with moderate hepatic impairment may have intrinsic coagulation abnormalities and there is limited clinical experience with Eliquis in these patients, dosing recommendations cannot be provided.
- Eliquis is not recommended in patients with severe hepatic impairment.
- The dosing adjustment for moderate renal impairment is described above. The recommended dose for nonvalvular atrial fibrillation patients with end-stage renal disease (ESRD) maintained on hemodialysis is 5 mg twice daily. Reduce dose to 2.5 mg twice daily if one of the following patient characteristics (age ≥80 years or body weight ≤60 kg) is present.
- For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg Eliquis tablets may be crushed and suspended in 60 mL D5W and immediately delivered through a nasogastric tube (NGT). Information regarding the administration of crushed and suspended Eliquis tablets swallowed by mouth is not available.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Apixaban in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 2.5 mg or 5 mg PO twice daily[1]
# 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 Apixaban in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Apixaban in pediatric patients.
# Contraindications
- Active pathological bleeding
- Severe hypersensitivity reaction to Eliquis (e.g., anaphylactic reactions)
# Warnings
- Increased Risk of Stroke with Discontinuation of Eliquis in Patients with Nonvalvular Atrial Fibrillation
- Discontinuing Eliquis in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from Eliquis to warfarin in clinical trials in patients with nonvalvular atrial fibrillation. If Eliquis must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.
- Bleeding
- Eliquis increases the risk of bleeding and can cause serious, potentially fatal, bleeding.
- Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs).
- Patients should be made aware of signs and symptoms of blood loss and instructed to report them immediately or go to an emergency room. Eliquis should be discontinued in patients with active pathological hemorrhage.
- There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for at least 24 hours after the last dose, i.e., for about two half-lives. A specific antidote for Eliquis is not available. Hemodialysis does not appear to have a substantial impact on apixaban exposure. Protamine sulfate and vitamin K would not be expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration.
- Spinal/Epidural Anesthesia or Puncture
- When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
- The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of Eliquis. The next dose of Eliquis should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of Eliquis for 48 hours.
- Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
- Patients with Prosthetic Heart Valves
- The safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves. Therefore, use of Eliquis is not recommended in these patients.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of Eliquis was evaluated in the ARISTOTLE and AVERROES studies, including 11,284 patients exposed to Eliquis 5 mg twice daily and 602 patients exposed to Eliquis 2.5 mg twice daily. The duration of Eliquis exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patients-years).
- The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with Eliquis and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on Eliquis and aspirin, respectively.
- Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per year) in ARISTOTLE and AVERROES.
- Major bleeding was defined as clinically overt bleeding that was accompanied by one or more of the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; or bleeding that was fatal. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
- In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, Eliquis dose, type of atrial fibrillation (AF), and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0% per year) than did subjects without diabetes (1.9% per year).
- Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of patients receiving Eliquis.
- The safety of Eliquis has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to Eliquis 2.5 mg twice daily undergoing major orthopedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days.
- In total, 11% of the patients treated with Eliquis 2.5 mg twice daily experienced adverse reactions.
- bleeding results during the treatment period in the Phase III studies are shown in Table 3. bleeding was assessed in each study beginning with the first dose of double-blind study drug.
- Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4.
- Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥0.1% to <1%:
- Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)
- Vascular disorders: hypotension (including procedural hypotension)
- Respiratory, thoracic, and mediastinal disorders: epistaxis
- Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia
- Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased
- Renal and urinary disorders: hematuria (including respective laboratory parameters)
- Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage
- Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of <0.1%:
- Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Apixaban in the drug label.
# Drug Interactions
- Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke.
- For patients receiving 5 mg twice daily, the dose of Eliquis should be decreased to 2.5 mg twice daily when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin).
- In patients already taking Eliquis at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp.
- Avoid concomitant use of Eliquis with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to apixaban.
- Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.
- APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2.77% per year with apixaban versus 0.62% per year with placebo in patients receiving single antiplatelet therapy and was 5.91% per year with apixaban versus 2.50% per year with placebo in those receiving dual antiplatelet therapy.
- In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on Eliquis from 1.8% per year to 3.4% per year and the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with Eliquis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies of Eliquis in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Eliquis should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.
- Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted in fetal exposure to apixaban, but was not associated with increased risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and rabbits at maternal exposures that were 19, 4, and 1 times, respectively, the human exposure of unbound drug, based on area under plasma-concentration time curve (AUC) comparisons at the maximum recommended human dose (MRHD) of 10 mg (5 mg twice daily).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apixaban in women who are pregnant.
### Labor and Delivery
- Safety and effectiveness of Eliquis during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using Eliquis in this setting.
- Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure based on unbound apixaban) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding. However, increased incidence of maternal bleeding, primarily during gestation, occurred at apixaban doses of ≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure.
### Nursing Mothers
- It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose).
- Women should be instructed either to discontinue breastfeeding or to discontinue Eliquis therapy, 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 subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16% were 75 and older. No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups.
### Gender
There is no FDA guidance on the use of Apixaban with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Apixaban with respect to specific racial populations.
### Renal Impairment
- Patients with ESRD with or without hemodialysis were not studied in clinical efficacy and safety studies with Eliquis; therefore, the dosing recommendation for patients with nonvalvular atrial fibrillation is based on pharmacokinetic and pharmacodynamic (anti-Factor Xa activity) data in subjects with ESRD maintained on dialysis. The recommended dose for ESRD patients maintained with hemodialysis is 5 mg orally twice daily. For ESRD patients maintained with hemodialysis with one of the following patient characteristics, age ≥80 years or body weight ≤60 kg, reduce dose to 2.5 mg twice daily.
### Hepatic Impairment
There is no FDA guidance on the use of Apixaban in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Apixaban in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Apixaban in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
- Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
# IV Compatibility
There is limited information regarding IV Compatibility of Apixaban in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is no antidote to Eliquis. Overdose of Eliquis increases the risk of bleeding.
- In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no clinically relevant adverse effects.
### Management
- In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Apixaban in the drug label.
# Pharmacology
## Mechanism of Action
- Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.
## Structure
- Eliquis (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula:
- Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.
- Eliquis tablets are available for oral administration in strengths of 2.5 mg and 5 mg of apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).
## Pharmacodynamics
- As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.
- The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans during the apixaban development program. A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF.
- This test is not recommended for assessing the anticoagulant effect of apixaban.
- Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel. A 50% to 60% increase in anti-FXa activity was observed when apixaban was coadministered with enoxaparin or naproxen.
- Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.
- Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-to-moderate hepatic impairment and healthy subjects. However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied.
- Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.
## Pharmacokinetics
- Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg.
- The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of Eliquis. Food does not affect the bioavailability of apixaban. Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of Eliquis. At doses ≥25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability. Following administration of a crushed 5 mg Eliquis tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube (NGT), exposure was similar to that seen in other clinical trials involving healthy volunteers receiving a single oral 5 mg tablet dose.
- Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
- Approximately 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation.
- Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites.
- Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces.
- Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life of approximately 12 hours following oral administration.
- Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.
- In vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.
- The effects of coadministered drugs on the pharmacokinetics of apixaban and associated dose recommendations are summarized in Figure 2.
- In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.
- In studies conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid.
- The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of apixaban are summarized in Figure 3.
- A study in healthy subjects comparing the pharmacokinetics in males and females showed no meaningful difference.
- The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity.
- In subjects with ESRD, a 4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min started 2 hours after administration of a single 5 mg dose of apixaban, the AUC of apixaban was 17% greater compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min resulting in a 14% decrease in exposure due to hemodialysis compared to off-dialysis period.
- Protein binding was similar (92%-94%) between healthy controls and the on-dialysis and off-dialysis periods.
## Nonclinical Toxicology
- Carcinogenesis
- Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure.
- Mutagenesis
- Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in vivo.
- Impairment of Fertility
- Apixaban had no effect on fertility in male or female rats when given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 4 times, respectively, the human exposure.
- Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring (F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5 times the human exposure. Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day.
# Clinical Studies
- Evidence for the efficacy and safety of Eliquis was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of Eliquis and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0–3.0). Patients had to have one or more of the following additional risk factors for stroke:
- Prior stroke or transient ischemic attack (TIA)
- Prior systemic embolism
- Age ≥75 years
- Arterial hypertension requiring treatment
- Diabetes mellitus
- Heart failure ≥New York Heart Association Class 2
- Left ventricular ejection fraction ≤40%
- The primary objective of ARISTOTLE was to determine whether Eliquis 5 mg twice daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of Eliquis to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause.
- A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA) “naive,” defined as having received ≤30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤40%) 35%, and prior myocardial infarction 14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0–3.0) of 62%.
- Eliquis was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 5 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs.
- Eliquis also showed significantly fewer major bleeds than warfarin.
- All-cause death was assessed using a sequential testing strategy that allowed testing for superiority if effects on earlier endpoints (stroke plus systemic embolus and major bleeding) were demonstrated. Eliquis treatment resulted in a significantly lower rate of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms.
- In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent across most major subgroups including weight, CHADS2 score (a scale from 0 to 6 used to predict risk of stroke in patients with AF, with higher scores predicting greater risk), prior warfarin use, level of renal impairment, geographic region, Eliquis dose, type of AF, and aspirin use at randomization (Figure 5).
- At the end of the ARISTOTLE study, warfarin patients who completed the study were generally maintained on a VKA with no interruption of anticoagulation. Eliquis patients who completed the study were generally switched to a VKA with a 2-day period of coadministration of Eliquis and VKA, so that some patients may not have been adequately anticoagulated after stopping Eliquis until attaining a stable and therapeutic INR. During the 30 days following the end of the study, there were 21 stroke or systemic embolism events in the 6791 patients (0.3%) in the Eliquis arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm.
- In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. The primary objective of the study was to determine if Eliquis was superior to aspirin for preventing the composite outcome of stroke or systemic embolism. AVERROES was stopped early on the basis of a prespecified interim analysis showing a significant reduction in stroke and systemic embolism for Eliquis compared to aspirin that was associated with a modest increase in major bleeding (Table 6).
- The clinical evidence for the effectiveness of Eliquis is derived from the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip (ADVANCE-3) or knee (ADVANCE-2 and ADVANCE-1) replacement surgery. A total of 11,659 patients were randomized in 3 double-blind, multi-national studies. Included in this total were 1866 patients age 75 or older, 1161 patients with low body weight (≤60 kg), 2528 patients with Body Mass Index ≥33 kg/m2, and 625 patients with severe or moderate renal impairment.
- In the ADVANCE-3 study, 5407 patients undergoing elective hip replacement surgery were randomized to receive either Eliquis 2.5 mg orally twice daily or enoxaparin 40 mg subcutaneously once daily. The first dose of Eliquis was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment duration was 32 to 38 days.
- In patients undergoing elective knee replacement surgery, Eliquis 2.5 mg orally twice daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, N=3057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3195). In the ADVANCE-2 study, the first dose of Eliquis was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. In the ADVANCE-1 study, both Eliquis and enoxaparin were initiated 12 to 24 hours post surgery. Treatment duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days.
- In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was tested for noninferiority, then superiority, of Eliquis to enoxaparin. In ADVANCE-1, the primary endpoint was tested for noninferiority of Eliquis to enoxaparin.
- The efficacy data are provided in Tables 7 and 8.
- The efficacy profile of Eliquis was generally consistent across subgroups of interest for this indication (e.g., age, gender, race, body weight, renal impairment).
# How Supplied
## Storage
There is limited information regarding Apixaban Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Apixaban interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Eliquis®[2]
# Look-Alike Drug Names
- N/A[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Apixaban | |
83918562b4c12751804b35ebc21a5c6bc6703ef2 | wikidoc | Apoplast | Apoplast
Within a plant, the apoplast is the free diffusional space outside the plasma membrane. It is interrupted by the Casparian strip in roots, air spaces between plant cells and the cuticula of the plant.
Structurally, the apoplast is formed by the continuum of cell walls of adjacent cells as well as the extracellular spaces, forming a tissue level compartment comparable to the symplast. The apoplastic route facilitates the transport of water and solutes across a tissue or organ. This process is known as apoplastic transport.
The apoplast is important for all the plant's communication to its environment. The main carbon source (carbon dioxide) needs to be solubilized in the apoplast before it is to be taken up by chloroplasts and consumed during photosynthesis. In the roots, ions diffuse into the apoplast of the epidermis before being taken up into the symplast by specific ion channels and being pulled by the plant's transpiration stream, which also occurs completely within the boundaries of the apoplast. Similarly, all gaseous molecules emitted and received by plants such as plant hormones and other pheromones must pass the apoplast. The apoplast is also a site for cell-to-cell communication. During local oxidative stress, hydrogen peroxide and superoxide anion can diffuse through the apoplast and transport a warning signal to neighbouring cells. In addition, a local alkalinization of the apoplast due to such a stress can travel within minutes to the rest of the plant body via the xylem and trigger systemic acquired resistance.
# Notes
- Apoplast was previously defined as "everything but the symplast, consisting of cell walls and spaces between cells in which water and solutes can move freely". However, since solutes can neither freely move through the air spaces between plant cells nor through the cuticula, this definition has been changed. When referring to "everything outside the plasma membrane", the term "extracellular space" is in use.
- The word apoplasm is also in use with similar meaning as apoplast, although less common. | Apoplast
Within a plant, the apoplast is the free diffusional space outside the plasma membrane. It is interrupted by the Casparian strip in roots, air spaces between plant cells and the cuticula of the plant.
Structurally, the apoplast is formed by the continuum of cell walls of adjacent cells as well as the extracellular spaces, forming a tissue level compartment comparable to the symplast. The apoplastic route facilitates the transport of water and solutes across a tissue or organ[1]. This process is known as apoplastic transport.
The apoplast is important for all the plant's communication to its environment. The main carbon source (carbon dioxide) needs to be solubilized in the apoplast before it is to be taken up by chloroplasts and consumed during photosynthesis. In the roots, ions diffuse into the apoplast of the epidermis before being taken up into the symplast by specific ion channels and being pulled by the plant's transpiration stream, which also occurs completely within the boundaries of the apoplast. Similarly, all gaseous molecules emitted and received by plants such as plant hormones and other pheromones must pass the apoplast. The apoplast is also a site for cell-to-cell communication. During local oxidative stress, hydrogen peroxide and superoxide anion can diffuse through the apoplast and transport a warning signal to neighbouring cells. In addition, a local alkalinization of the apoplast due to such a stress can travel within minutes to the rest of the plant body via the xylem and trigger systemic acquired resistance[2].
# Notes
- Apoplast was previously defined as "everything but the symplast, consisting of cell walls and spaces between cells in which water and solutes can move freely". However, since solutes can neither freely move through the air spaces between plant cells nor through the cuticula, this definition has been changed. When referring to "everything outside the plasma membrane", the term "extracellular space" is in use.
- The word apoplasm is also in use with similar meaning as apoplast, although less common. | https://www.wikidoc.org/index.php/Apoplast | |
60f8fd6481b666c3f03ef2fb5d7f52b07a310e58 | wikidoc | Apoplexy | Apoplexy
# Overview
Apoplexy is an old-fashioned medical term, which can be used to mean 'neurological impairment' or 'hemorrhage'. It can be used non-medically to mean a state of extreme rage. The word derives from the Greek word for 'seizure', apoplexia (Template:Polytonic), in the sense of being struck down.
# Neurological Impairment
Apoplexy has been used as a synonym for "stroke" because many stroke patients lose consciousness during the acute stage of the vascular compromise (either through bleeding or ischemia).
# Historical Meaning of the Word
Historically, the word "apoplexy" was also used to describe any sudden death that began with a sudden loss of consciousness, especially one where the victim died within a matter of seconds after losing consciousness. Those reading historical documents should take into consideration the possibility that the word "apoplexy" may be used to describe the symptom of sudden loss of consciousness immediately preceding death and not an actual verified disease process. Sudden cardiac deaths, ruptured cerebral aneurysms, certain ruptured aortic aneurysms, and even heart attacks may have been misdiagnosed as apoplexy in the distant past.
# Hemorrhage
The term 'apoplexy' is used to describe bleeding within internal organs. In such usage it is coupled with an adjective describing the site of the bleeding. For example, bleeding within the pituitary gland is called pituitary apoplexy, and bleeding within the adrenal glands can be called adrenal apoplexy.
In both pituitary and adrenal apoplexy, the word apoplexy refers to both hemorrhage with the gland and to accompanying neurological problems such as confusion, headache, and impairment of consciousness.
# Non-medical Usage
Colloquially, particularly in the adjective form apoplectic, apoplexy means furious, enraged, or upset to the point of being unable to deal with a situation rationally or diplomatically.
# Related Chapters
- Transient ischemic attack
- Stroke
da:Apopleksi
ko:뇌졸중
it:Apoplessia
CME Category::Cardiology | Apoplexy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Apoplexy is an old-fashioned medical term, which can be used to mean 'neurological impairment' or 'hemorrhage'. It can be used non-medically to mean a state of extreme rage. The word derives from the Greek word for 'seizure', apoplexia (Template:Polytonic), in the sense of being struck down.
# Neurological Impairment
Apoplexy has been used as a synonym for "stroke" because many stroke patients lose consciousness during the acute stage of the vascular compromise (either through bleeding or ischemia).
# Historical Meaning of the Word
Historically, the word "apoplexy" was also used to describe any sudden death that began with a sudden loss of consciousness, especially one where the victim died within a matter of seconds after losing consciousness. Those reading historical documents should take into consideration the possibility that the word "apoplexy" may be used to describe the symptom of sudden loss of consciousness immediately preceding death and not an actual verified disease process. Sudden cardiac deaths, ruptured cerebral aneurysms, certain ruptured aortic aneurysms, and even heart attacks may have been misdiagnosed as apoplexy in the distant past.
# Hemorrhage
The term 'apoplexy' is used to describe bleeding within internal organs. In such usage it is coupled with an adjective describing the site of the bleeding. For example, bleeding within the pituitary gland is called pituitary apoplexy, and bleeding within the adrenal glands can be called adrenal apoplexy.
In both pituitary and adrenal apoplexy, the word apoplexy refers to both hemorrhage with the gland and to accompanying neurological problems such as confusion, headache, and impairment of consciousness.
# Non-medical Usage
Colloquially, particularly in the adjective form apoplectic, apoplexy means furious, enraged, or upset to the point of being unable to deal with a situation rationally or diplomatically.
# Related Chapters
- Transient ischemic attack
- Stroke
da:Apopleksi
ko:뇌졸중
it:Apoplessia
Template:WikiDoc Sources
CME Category::Cardiology | https://www.wikidoc.org/index.php/Apoplexy |
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