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Information about Sibutramine

Sibutramine (trade name Meridia in the USA, Reductil in Europe and other countries), usually as sibutramide hydrochloride monohydrate, is an orally administered agent for the treatment of obesity. It is a centrally acting stimulant chemically related to amphetamines.[1] Sibutramine is classified as a Schedule IV controlled substance in the United States.

Sibutramine's manufacturer is Abbott Laboratories.

Pharmacokinetics

Sibutramine is well absorbed from the GI tract (77%), but undergoes considerable first-pass metabolism reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a half-life of 1 hour. Sibutramine is metabolized by cytochrome P450 isozyme CYP3A4 resulting in 2 active primary and secondary amines (called active metabolites 1 and 2) with half-lives of 14 and 16 hours, respectively. Peak plasma concentrations of active metabolites 1 and 2 are reached after 3 to 4 hours. The following metabolic pathway mainly results in two inactive conjugated and hydroxylated metabolites (called metabolites 5 and 6). Metabolites 5 and 6 are mainly excreted in the urine.

Pharmacological aspects

Sibutramine is a neurotransmitter reuptake inhibitor that helps enhance satiety by inhibiting the reuptake of serotonin (by 53%), norepinephrine (by 54%), and dopamine (by 16%). Despite its actions upon the aforementioned neurotransmitters, sibutramine failed to demonstrate antidepressant properties in animal studies. It was approved by the U.S. Food and Drug Administration (FDA) in November 1997[2] for the treatment of obesity.

Sibutramine acts by increasing serotonin and norepinephrine levels in the brain. The serotonergic action, in particular, is thought to influence appetite.

Contraindications

Sibutramine is contraindicated in:

Side effects

Frequently encountered side effects are: dry mouth, paradoxically increased appetite, nausea, strange taste in the mouth, anorgasmia and delayed ejaculation, upset stomach, constipation, trouble sleeping, dizziness, drowsiness, menstrual cramps/pain, headache, flushing, or joint/muscle pain.

Sibutramine can substantially increase blood pressure and pulse in some patients. Therefore all patients treated with sibutramine should have regular monitoring of blood pressure and pulse.

The following side effects are infrequent but serious and require immediate medical attention: cardiac arrhythmias, paresthesia, mental/mood changes (e.g., excitement, restlessness, confusion, depression, rare thoughts of suicide).

Symptoms that require urgent medical attention are seizures, problems urinating, abnormal bruising or bleeding, melena, hematemesis, jaundice, fever and rigors, chest pain, hemiplegia, abnormal vision, dyspnea and edema.

Currently, no case of pulmonary hypertension has been noted, although related compounds (such as Fen-Phen) have shown this rare but clinically significant problem.

Interactions

Sibutramine has a number of clinically significant interactions. The concomitant use of sibutramine and monoamine oxidase inhibitors (MAOIs, such as selegiline) is not indicated, as it may increase the risk of serotonin syndrome, a somewhat rare but serious adverse drug reaction.[3] Sibutramine should not be taken less than two weeks after stopping or before starting use of an MAOI. Taking both sibutramine and certain medications used in the treatment of migraines—such as ergolines and triptans—, as well as opioids, may also increase the risk for serotonin syndrome, as may the use of more than one serotonin reuptake inhibitor at the same time.[3]

The concomitant use of sibutramine and drugs which inhibit CYP3A4, such as ketoconazole and erythromycin, may increase plasma levels of sibutramine.[4] Sibutramine has no effect on the efficacy of hormonal contraception.[3]

Dosage

10 mg once daily (usually in the morning), if this proves insufficient the dose may be increased to 15 mg daily after 4 weeks.

Safety concerns

Studies are ongoing into reports of sudden death, heart failure, renal failure and gastrointestinal problems. Despite a petition by Ralph Nader-founded NGO Public Citizen,[5] the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005.[6] Similarly, Dr. David Graham, FDA "whistleblower", testified before a Senate Finance Committee hearing that sibutramine may be more dangerous than the conditions it is used for.[7]

A large randomized-controlled study with over 9000 patients (SCOUT) is currently ongoing to examine whether or not sibutramine reduces the risk for cardiovascular complications in people at high risk for heart disease.[8]

References

1. ^ (2002) "New Drugs". Australian Prescriber 25 (1): 22.  PDF
2. ^ U.S. Food and Drug Administration (November 24 1997). FDA APPROVES SIBUTRAMINE TO TREAT OBESITY. Press release. Retrieved on 2007-04-29.
3. ^ Meridia Side Effects, and Drug Interactions. RxList.com (2007). Retrieved on 2007-04-29.
4. ^ (Portuguese) Cloridrato de sibutramina monoidratado. Bula. [Sibutramine hydrochloride monohydrate—label information]. Medley (2007).
5. ^ Wolfe, Sidney M.; Larry D. Sasich, Elizabeth Barbehenn (March 19 2002). Petition to FDA to ban the diet drug sibutramine (MERIDIA) (HRG Publication #1613). Public Citizen. Retrieved on 2007-04-29.
6. ^ Bruce Japsen. "FDA weighs decision on Meridia ; Health advisory likely for Abbott obesity drug". Chicago Tribune. Chicago, Ill.: Mar 13, 2005. pg. 1.
7. ^ Hearing of 17 November 2004. Related CBS news item 19 November 2004.
8. ^ James WPT. The SCOUT study: risk-benefit profile of sibutramine in overweight high-risk cardiovascular patients. Eur Heart J 2005;7 Suppl;L44-48. Abstract.

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Stimulants
EugeroicsAdrafinil • Carphedon • Modafinil/Armodafinil
Phenethylamines
PiperazinesBZP • MeOPP • MBZP
XanthinesCaffeine • Aminophylline • Paraxanthine • Theobromine • Theophylline
Others
See also
 •  • [ e]
Antiobesity preparations (A08)
Centrally actingPhentermine - Fenfluramine - Amfepramone - Dexfenfluramine - Mazindol - Cathine - Clobenzorex - Sibutramine - Rimonabant
Peripherally actingOrlistat
Obesity
Classification & external resources

Silhouettes representing healthy, overweight, and obese.
ICD-10 E 66.
ICD-9 278

DiseasesDB 9099
MedlinePlus 003101
eMedicine med/1653  

MeSH C23.888.144.699.
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Stimulants are drugs that temporarily increase alertness and awareness. They usually have increased side-effects with increased effectiveness, and the more powerful variants are therefore often prescription medicines or illegal drugs.
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Amphetamine or Amfetamine(Alpha-Methyl-PHenEThylAMINE), also known as beta-phenyl-isopropylamine and benzedrine, is a prescription stimulant commonly used to treat Attention-deficit hyperactivity disorder (ADHD) in adults and children.
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Schedule IV or Schedule 4 is a legal category assigned to substances in certain jurisdictions:
  • In Australia: Schedule 4
  • In Canada: Schedule IV (Canada)
  • In Estonia: Narcotic Drugs and Psychotropic Substances Act (Estonia)

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A controlled substance is generally a drug or chemical whose manufacture, possession and use are regulated by a government. This may include Illegal drugs and Prescription medications (designated Controlled Drug in the United Kingdom).
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Motto
"In God We Trust"   (since 1956)
"E Pluribus Unum"   ("From Many, One"; Latin, traditional)
Anthem
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Abbott Laboratories

Public (NYSE:  ABT )
Founded 1888
Headquarters Abbott Park, North Chicago, Illinois, USA

Key people Miles D. White, Chairman and CEO
Richard A.
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gastrointestinal tract (GI tract), also called the digestive tract, or the alimentary canal, is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste.
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Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of hemoproteins found in bacteria, archaea and eukaryotes.[1] They are so named because of their properties i.e.
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Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters (i.e. different KM values), or different regulatory properties.
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Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97 ), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body.
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Amines are organic compounds and a type of functional group that contain nitrogen as the key atom. Structurally amines resemble ammonia, wherein one or more hydrogen atoms are replaced by organic substituents such as alkyl and aryl groups.
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Blood plasma is the liquid component of blood, in which the blood cells are suspended. It makes up about 55% of total blood volume. Blood plasma is prepared simply by spinning a tube of fresh blood in a centrifuge until the blood cells fall to the bottom of the tube.
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Serotonin (pronounced IPA: /ˌsɛrəˈtoʊnən/) (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and
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Norepinephrine (INN)(abbr. norepi or NE) or noradrenaline (BAN) is a catecholamine and a phenethylamine with chemical formula C8H11NO3. The natural stereoisomer is L -(−)-(R)-norepinephrine.
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Dopamine is a hormone and neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In chemical structure, it is a phenethylamine.
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Neurotransmitters are chemicals that are used to relay, amplify and modulate signals between a neuron and another cell. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:

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antidepressant, is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia ('milder' depression). Drug groups known as MAOIs, tricyclics and SSRIs are particularly associated with the term.
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Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible the safety regulation of most types of foods, dietary supplements, drugs, vaccines, biological medical products, blood products, medical devices,
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Serotonin (pronounced IPA: /ˌsɛrəˈtoʊnən/) (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and
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Norepinephrine (INN)(abbr. norepi or NE) or noradrenaline (BAN) is a catecholamine and a phenethylamine with chemical formula C8H11NO3. The natural stereoisomer is L -(−)-(R)-norepinephrine.
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In animals, the brain or encephalon (Greek for "in the skull"), is the control center of the central nervous system, responsible for behavior. The brain is located in the head, protected by the skull and close to the primary sensory apparatus of vision, hearing,
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Bulimia nervosa
Classification & external resources

ICD-10 F50.2
ICD-9 307.51

Bulimia nervosa, commonly known as bulimia , is an eating disorder and psychological condition in which the subject engages in recurrent binge eating followed by
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Anorexia Nervosa
Classification & external resources

ICD-10 F 50.0 -F 50.1
ICD-9 307.1

OMIM 606788
DiseasesDB 749

eMedicine emerg/34   med/144

For the symphonic black metal band, see Anorexia Nervosa (band)''

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Depression
Classification & external resources

ICD-10 F 32. , F 33.
ICD-9 296

OMIM 608516
DiseasesDB 3589
MedlinePlus 003213
eMedicine med/532  

Clinical depression (also called major-depressive disorder, or
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Bipolar disorder''. For the classical mythological figures named Mania, see Mania (mythology).
For other uses, see Manic (disambiguation).
Manic episode
Classification & external resources

ICD-10 F30
ICD-9 296.
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MeSH D006967 Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. Hypersensitivity reactions require a pre-sensitized (immune) state of the host.
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Monoamine oxidase inhibitors (MAOIs) are a class of powerful antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression, and have also shown efficacy in helping smokers to quit.
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antidepressant, is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia ('milder' depression). Drug groups known as MAOIs, tricyclics and SSRIs are particularly associated with the term.
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The central nervous system (CNS) represents the largest part of the nervous system, including the brain and the spinal cord. Together with the peripheral nervous system, it has a fundamental role in the control of behavior.
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