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Anti-obesity drugs include all pharmacological treatments intended to reduce or control weight. Because these drugs are intended to alter one of the fundamental processes of the human body, anti-obesity drugs are medically prescribed only in cases of morbid obesity, where weight loss is life-saving. Mechanisms of action

Anti-obesity drugs operate through one or more of the following mechanisms:

• Suppression of the appetite.
• Increase of the body's metabolism.
• Interference with the body's ability to absorb specific nutrients in food. For example, orlistat blocks fat breakdown and thereby prevents fat absorption.

Anorectics (also known as anorexigenics) are primarily intended to suppress the appetite, but most of the drugs in this class also act as stimulants (dexedrine, e.g.), and patients have abused drugs "off label" to suppress appetite (e.g. digoxin).

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, palpitations, 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, 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 still do not know fully 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.

Because the human body uses various chemicals and hormones 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.

In order to circumvent the number of feedback mechanisms that prevent most monotherapies from producing sustained large amounts of weight loss, it has been hypothesised that combinations of drugs may be more effective by targeting multiple pathways and possibly inhibiting feedback pathways that work to cause a plateau in weightloss. 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 dex-fenfluramine were pulled from the market due to safety fears regarding a potential link to heart valve damage. 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).

Future developments

More recent developments may be promising in development of drugs that can combat obesity. The discovery of cannabinoid receptors in the brain, liver and muscle has stimulated research in a new class of drugs, namely cannabinoid (CB1) receptor antagonists. One such drug in development is Rimonabant from Sanofi-Aventis, it is designed to block the effects of endogenous cannabinoids. This type of drug is particularly interesting since it not only causes weight loss but reverses the metabolic effects of obesity such as insulin resistance and hyperlipidemia. It is also interesting to note that this class of drugs may decrease the tendency to abuse substances such as alcohol and tobacco. The weight loss reported with Rimonabant is modest (approximately 20 lbs.). Although it is unlikely that this drug will successfully treat morbid obesity, it promises to be very useful in treating modest obesity and reversing some of the metabolic complications of this condition. Merck has a CB1 inverse agonist, codenamed MK-0364, in Phase IIb/III development that it hopes to file an NDA for in 2008. Pfizer has a CB1 antagonist, codenamed CP-945,598, that it has started Phase III trials for.

There are a number of other drugs in development in addition to the many CB1 antagonists or inverse agonists. These include lipase inhibitors, similar to Xenical (Orlistat). One is called Cetilistat (or ATL-962) being developed by Alizyme. The drug has shown a better tolerability profile than Xenical in terms of less GI-related adverse events and similar efficacy. The drug has compelted Phase II trials and is set to enter Phase III trials in 2007. Another lipase inhibitor, called GT 389-255, is being developed by Peptimmune (licensed from Genzyme). This is a novel combination of an inhbitor and a polymer designed to bind the undigested triglycerides therefore allowing increased fat exrection 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.

Source: http://en.wikipedia.org/wiki/Anti-obesity_drug

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