Anti-obesity drug
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2008-07-10T01:46:02Z
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'''Anti-obesity drugs''' refer to all [[Pharmacology|pharmacological]] treatments intended to reduce or control weight. Because these [[medication|drugs]] are intended to alter one of the fundamental processes of the [[human anatomy|human body]], anti-[[obesity]] drugs are [[medical prescription|medically prescribed]] only in cases of [[morbid obesity]], where weight loss is life-saving.<ref name="pmid15809464">{{cite journal |author=Snow V, Barry P, Fitterman N, Qaseem A, Weiss K |title=Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians |journal=Ann. Intern. Med. |volume=142 |issue=7 |pages=525–31 |year=2005 |pmid=15809464 |doi=|url=http://www.annals.org/cgi/content/full/142/7/525}}</ref><ref name="pmid17080028">{{cite journal |author=Cooke D, Bloom S |title=The obesity pipeline: current strategies in the development of anti-obesity drugs |journal=Nature reviews. Drug discovery |volume=5 |issue=11 |pages=919–31 |year=2006 |pmid=17080028 |doi=10.1038/nrd2136|url=http://www.nature.com/nrd/journal/v5/n11/abs/nrd2136.html}}</ref>
A [[meta-analysis]] of [[randomized controlled trials]] by the international [[Cochrane Collaboration]] concluded that in ''diabetic'' patients found:<ref name="pmid15674929">{{cite journal |author=Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Lau J |title=Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus |journal=Cochrane database of systematic reviews (Online) |volume= |issue=1 |pages=CD004096 |year=2005 |pmid=15674929 |doi=10.1002/14651858.CD004096.pub2}}</ref>
: "Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 12 to 57 weeks. The magnitude of weight loss is modest, however, and the long-term health benefits remain unclear. The safety of sibutramine is uncertain. There is a paucity of data on other drugs for weight loss or control in persons with type 2 diabetes."
==Mechanisms of action==
Anti-obesity drugs operate through one or more of the following mechanisms:
* Suppression of the [[appetite]]. [[Anticonvulsant|Epilepsy medications]] and [[catecholamines]] and their derivatives (such as [[amphetamine]]-based drugs) are the main tools used for this. Drugs blocking the [[cannabinoid receptor]]s may be a future strategy for appetite suppression.{{Fact|date=July 2007}}
* Increase of the body's [[metabolism]]. {{Fact|date=February 2007}}
* Interference with the body's ability to absorb specific nutrients in food. For example, [[Orlistat]] (also known as Xenical and Allī) blocks fat breakdown and thereby prevents fat absorption. The OTC fiber supplements [[glucomannan]] and [[guar gum]] have been used for the purpose of inhibiting digestion and lowering caloric absorption
[[Anorectic]]s (also known as anorexigenics) are primarily intended to suppress the appetite, but most of the drugs in this class also act as [[stimulant]]s ([[dexedrine]], e.g.), and patients have abused drugs "off label" to suppress appetite (e.g. [[digoxin]]).
==Available anti-obesity drugs==
If diet and exercise are ineffective alone, [[anti-obesity drug]]s are a choice for some patients. Some prescription weight loss drugs are stimulants, which are recommended only for short-term use, and thus are of limited usefulness for extremely obese patients, who may need to reduce weight over months or years.{{Fact|date=August 2007}}
===Orlistat===
[[Orlistat]] (Xenical) reduces intestinal fat absorption by inhibiting pancreatic lipase. Originally available only by prescription, it was approved by the FDA for over-the-counter sale in February 2007. [http://www.fda.gov/bbs/topics/NEWS/2007/NEW01557.html] Orlistat may cause frequent, oily bowel movements ([[steatorrhea]]), but if fat in the diet is reduced, symptoms often improve.
===Sibutramine===
[[Sibutramine]] ([[Reductil]] or [[Meridia]]) is an [[anorectic]] or appetite suppressant, reducing the desire to eat. Both drugs have side effects. Sibutramine may increase blood pressure and may cause dry mouth, constipation, headache, and insomnia.
===Metformin===
In people with [[Diabetes mellitus type 2]], the drug [[metformin]] (Glucophage) can reduce weight.<ref>{{cite journal | author = George A. Bray and Frank L. Greenway | year = 1999 | title = Current and Potential Drugs for Treatment of Obesity: Table 19: Clinical trials with metformin for the treatment of obese diabetics | journal = Endocrine Reviews | volume = 20 | pages = 805–87 | url = http://edrv.endojournals.org/cgi/content/full/20/6/805/T19 | accessdate = 2006-08-07 | doi = 10.1210/er.20.6.805 | pmid = 10605627 }}</ref>
===Byetta===
Byetta ([[Exenatide]]) is a long-acting analogue of the hormone GLP-1, which the intestines secrete in response to the presence of food. Among other effects, GLP-1 delays gastric emptying and promotes a feeling of satiety. Some obese people are deficient in GLP-1, and dieting reduces GLP-1 further.<ref name="PMID: 17536190">{{cite journal |author=de Luis DA, Gonzalez Sagrado M, Conde R, Aller R, Izaola O|title=Decreased basal levels of glucagon-like peptide-1 after weight loss in obese subjects|journal=Annals of Nutrition and Metabolism |year=2007 |pmid=17536190}}</ref> Byetta is currently available as a treatment for [[Diabetes mellitus type 2]]. Some, but not all, patients find that they lose substantial weight when taking Byetta. Drawbacks of Byetta include that it must be injected twice daily, and that it causes severe nausea in some patients, especially when therapy is initiated. Byetta is recommended only for patients with Type 2 Diabetes. A somewhat similar drug, Symlin, is currently available for treating diabetes and is in testing for treating obesity in non-diabetics.
===Symlin===
Symlin ([[Pramlintide]]) is a synthetic analogue of the hormone Amylin, which in normal people is secreted by the pancreas in response to eating. Among other effects, Amylin delays gastric emptying and promotes a feeling of satiety. Many diabetics are deficient in Amylin. Currently, Symlin is only approved to be used along with insulin by Type 1 and Type 2 diabetics. However, Symlin is currently being tested in non-diabetics as a treatment for obesity. A drawback is that Symlin must be injected at mealtimes.
===Rimonabant===
Recent pharmaceutical research has produced potential obesity combating drugs. The discovery of [[cannabinoid receptor]]s in the [[brain]], [[liver]] and [[muscle]] has stimulated research in a new class of drugs, namely cannabinoid (CB1) receptor antagonists. These drugs not only causes weight loss, but prevent or reverse the metabolic effects of obesity, such as [[insulin resistance]] and [[hyperlipidemia]], and may also decrease the tendency to abuse substances such as [[alcohol]] and [[tobacco]].
[[Sanofi-Aventis]] has received approval to market [[Rimonabant]] as a prescription anti-obesity drug in the European Union, subject to some restrictions. Due to safety concerns, the drug has not received approval in the United States, either as an anti-obesity treatment or as a smoking-cessation drug. Merck has a CB1 inverse agonist, codenamed MK-0364, in Phase IIb/III [[clinical trials|development]] for which it hopes to file a [[New Drug Application]] in 2008
===Other drugs===
Other weight loss drugs have also been associated with medical complications, such as fatal pulmonary hypertension and heart valve damage due to [[Dexfenfluramine|Redux]] and [[Fen-phen]], and hemorrhagic stroke due [[phenylpropanolamine]].<ref>{{cite journal | author = Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. | year = 1996 | title = Appetite-suppressant drugs and the risk of primary pulmonary hypertension | journal = The New England Journal of Medicine | volume = 29;335(9) | pages = 609–616 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8692238 | format = Abstract | accessdate = 2006-07-24 | doi = 10.1056/NEJM199608293350901 | pmid = 8692238 }}</ref><ref>{{cite journal | author = Alfred P. Fishman, MD | year = 1999 | title = Aminorex to Fen/Phen: An Epidemic Foretold | journal = Circulation | volume = 99 | pages = 156–161 | url = http://circ.ahajournals.org/cgi/content/full/99/1/156|accessdate = 2006-07-24 | pmid = 9884392 }}</ref> Many of these substances are related to [[amphetamine]].
Unresearched nonprescription products or programs for weight loss are heavily promoted by mail and print advertising and on the internet. The US [[Food and Drug Administration]] recommends caution with use of these products,<ref>U. S. Food and Drug Administration: [http://vm.cfsan.fda.gov/~dms/wgtloss.html The Facts About Weight Loss Products and Programs]</ref> since many of the claims of safety and effectiveness are unsubstantiated.<ref>{{cite press release | title = Prepared Statement of the Federal Trade Commission on the Marketing of Dietary Supplements | publisher = Committee on Governmental Affairs, United States Senate | date = [[2002-10-08]] | url = http://www.ftc.gov/os/2002/10/dietary_testimony.htm | accessdate = 2006-08-07}}</ref> Individuals with [[anorexia nervosa]] and some athletes try to control body weight with [[laxatives]], [[diet pill]]s or [[diuretic]] drugs, although these generally have no impact on body fat.<ref>{{cite journal | last = Malissa Martin, EdD, ATC, Gretchen Schlabach, PhD, ATC, and Kim Shibinski, MS | title = The Use of Nonprescription Weight Loss Products Among Female Basketball, Softball, and Volleyball Athletes from NCAA Division I Institutions: Issues and Concerns | journal = Journal of Athletic Training | volume = 33 | issue = 1 | pages = 41–44 | date = 1998 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1320374|accessdate = 2006-08-07 | pmid = 16558483 }}</ref> Products that work as a laxative can cause the blood's potassium level to drop, which may cause heart and/or muscle problems. [[Pyruvate]] is a popular product that may result in a small amount of weight loss. However, pyruvate, which is found in red apples, cheese, and red wine, has not been thoroughly studied and its weight loss potential has not been scientifically established.<ref>{{cite journal | author = George A. Bray and Frank L. Greenway | year = 1999 | title = Current and Potential Drugs for Treatment of Obesity: Postabsorptive modifiers of nutrient metabolism | journal = Endocrine Reviews | volume = 20 | pages = 805–87 | url = http://edrv.endojournals.org/cgi/content/full/20/6/805#SEC4 | accessdate = 2006-08-07 | doi = 10.1210/er.20.6.805 | pmid = 10605627 }}</ref>
==Side effects==
Some anti-obesity drugs have severe and often life-threatening side effects. (See, for example, [[Fen-phen]].) These side effects are often associated with their mechanism of action. In general, stimulants carry a risk of [[high blood pressure]], faster [[heart rate]], [[palpitation]]s, closed-angle [[glaucoma]], [[drug addiction]], restlessness, agitation, and [[insomnia]].
Another drug, [[Orlistat]], blocks absorption of dietary fats, and as a result may cause oily spotting bowel movements ([[steatorrhea]]), oily stools, stomach pain, and [[flatulence]]. A similar medication, designed for patients with Type 2 diabetes, is [[Acarbose]] which partially blocks absorption of carbohydrates in the small intestine, and produces similar side effects including stomach pain, and [[flatulence]].
==Limitations of current knowledge==
The limitation of drugs for obesity is that we do not fully understand the neural basis of appetite and how to modulate it. Appetite is clearly a very important instinct to promote survival. Arguably any drug that would abolish appetite may carry a high mortality risk and may be unsuitable for clinical use.{{Fact|date=April 2008}}
Because the human body uses various chemicals and [[hormone]]s to protect its stores of [[fat]] (a reaction probably useful to our ancestors when food was scarce in the past,) there has not yet been found a 'silver bullet', or a way to completely circumvent this natural habit of protecting excess food stores. Because of this, anti-obesity drugs are not a practical long-term solution for people who are overweight.{{Fact|date=April 2008}}
In order to circumvent the number of feedback mechanisms that prevent most monotherapies from producing sustained large amounts of weight loss, it has been hypothesized that combinations of drugs may be more effective by targeting multiple pathways and possibly inhibiting feedback pathways that work to cause a plateau in weight loss. This was evidenced by the success of the combination of [[phentermine]] and [[fenfluramine]] or [[dexfenfluramine]], popularly referred to phen-fen, in producing significant weight loss but fenfluramine and dexfenfluramine were pulled from the market due to safety fears regarding a potential link to heart valve damage. The damage was found to be a result of activity of [[fenfluramine]] and [[dexfenfluramine]] at the 5-HT2B serotonin receptor in heart valves. Newer combinations of SSRIs and phentermine, known as phenpro, have been used with equal efficiency as fenphen with no known heart valve damage due to lack of activity at this particular serotonin receptor due to SSRIs. There has been a recent resurgence in combination therapy clinical development with the development of 3 combinations: Qnexa ([[topiramate]] + phentermine), Excalia ([[bupropion]] + [[zonisamide]]) and Contrave (bupropion + [[naltrexone]]).{{Fact|date=April 2008}}
==Future developments==
Other classes of drugs in development include lipase inhibitors, similar to Xenical ([[Orlistat]]). Another lipase inhibitor, called GT 389-255, is being developed by Peptimmune<ref>[http://www.peptimmune.com Peptimmune homepage]</ref> (licensed from [[Genzyme]]). This is a novel combination of an inhibitor and a polymer designed to bind the undigested triglycerides therefore allowing increased fat excretion without side effects such as oily stools that occur with Xenical. The development seems to be stalled as Phase 1 trials were conducted in 2004 and there has been no further human clinical development since then.
Another potential long-term approach to anti-obesity medication is through the development of ribonucleic acid interference ([[RNAi]]). Animal studies have illustrated that the deletion of the RIP140 gene in mice by genetic knockout results in the lack of fat accumulation, even when mice are fed a high fat diet<ref>{{cite journal | author= Leonardsson G, Steel JH, Christian M, Pocock V, ''et al.'' | title= Nuclear receptor corepressor RIP140 regulates fat accumulation | journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 22 |pages= 8437–8442|year= 2004|pmid= 15155905 |doi= 10.1073/pnas.0401013101 }}</ref>. Experiments conducted by Professor Malcolm Parker of Imperial College show that by silencing RIP 140, a nuclear hormone co-repressor which regulates fat accumulation, animal models exhibit a lean profile throughout their life, are resistant to diet-induced obesity, and show an enhanced metabolic rate{{Fact|date=March 2008}}. [[CytRx]] Corporation is developing RNAi therapeutics against this drug target for the treatment of obesity and type 2 diabetes{{Fact|date=March 2008}}.
Luigi Ambrosio, a lead researcher at the National Research Council's Institute for Composite and Biomedical Materials in Naples is testing a new hydrogel diet pill{{Fact|date=March 2008}}. The pill, which is undergoing clinical trials at Rome's Policlinico Gemelli hospital, is made from biodegradable polycellulose that soaks up to 1,000 times its weight in water, which the body flushes out in a few hours while giving dieters a sense of satiety. Because there are no active ingredients, successful safety trials could put this hydrogel pill on the market in 2008.
==References==
{{reflist|2}}
==See also==
* [[:Category:Antiobesity drugs]] for a listing of anti-obesity drugs with Wikipedia articles
==External links==
*[http://win.niddk.nih.gov/publications/prescription.htm Prescription Medications for the Treatment of Obesity]
{{Major drug groups}}
[[Category:Antiobesity drugs|*]]
[[Category:Obesity]]
[[it:Dimagrante]]