Today most nations reached a point where obesity has changed from an individual health problem to a major public health issue reaching epidemic proportions.In the United States, 65% of Americans are overweight and of these, 31% are obese. Obesity is a complex health condition associated with increased risk of numerous diseases, including type 2 diabetes, hypertension, stroke, cardiovascular disease, respiratory problems, gallbladder disease, osteoarthritis, sleep apnea and certain cancers (including endometrial, colon, gall bladder, prostate, kidney and postmenopausal breast cancer); obesity also has serious social and psychological consequences, such as low self-esteem and clinical depression, and affects all ages and socioeconomic groups [1]. There is no definite single contributing factor to this epidemic but some of them can be credited largely to the lifestyle changes with the promotion of a highly technological urban existence with the ability of successful functioning when eating more and moving less.

The research on fat metabolism has made large progress over the last decade and has challenged several established views. One of the most important findings in recent obesity research was revealing that fat is an endocrine tissue (gland that secrets hormones in the body). Also, very important was the discovery of a number of peptides (short protein chains) that function as central regulators of food intake and energy metabolism. Such findings revealed that the neural and hormonal body systems are involved in complex interactions where the central nervous system (brain and the spinal cord) and fat communicate through hormones and neurotransmitters, and affect other organs.

The anti-obesity effect might be achieved by any of three basic approaches: a reduction in energy intake, a decrease in energy storage or an increase in energy expenditure. Each of them can be addressed by various specific mechanisms. With such perspectives one would expect the drug marked to be blooming. In reality, disregarding the advertising scams and marketing schemes, there is not much it the store today. And what is available is disappointingly far from perfect. In fact, all today available drugs and most of those in clinical development belong to the reduction in energy intake category and act either by appetite suppression or inhibition of intestinal absorption.

One class of drugs used to treat obesity today belongs to amphetamines (dextroamphetamine - Dexedrine), which are potent stimulants and can cause unacceptable tachycardia and hypertension. Other sympathomimetic adrenergic agents include: phentermine (Fastin), benzphetamine (Didrex), phendimetrazine (Bontril), mazindol (Sanorex), and diethylpropion (Tenuate). They have less abuse potential than amphetamines but these agents may have adverse cardiovascular side effects, and their indicated use is only short term (few weeks) [2].

Only two drugs are currently approved in the US for the long-term treatment of obesity: orlistat (Xenical) and sibutramine (Meridia). Sibutramine has an indication for treatment of obesity by primarily increasing satiety. Sibutramine-associated weight loss occurs within the first 6 months of treatment, may be maintained for at least 2 years, and may have favorable effects on coronary heart disease risk factors. Unfortunately, sibutramine's use is contraindicated in patients with uncontrolled hypertension, coronary heart disease, cardiac dysrhythmias, congestive heart failure, or stroke [3].

Orlistat is a gastrointestinal lipase inhibitor that impairs the absorption of dietary fat. Orlistat may improve lipid blood levels, improve glucose metabolism in obese patients and reduce high blood pressure [4]. Orlistat use frequently results in adverse events including flatus, oily stools, fecal urgency or fecal incontinence, and abdominal pain, particularly among patients who do not follow the recommended low-fat diet.

As the three major obesity drugs on the US market today: orlistat, sibutramine and phentermine have not satisfied the society requirements there are more compounds in the pharma cooking today. The most prominent include some new and promising approaches and are already in clinical trials. One developed by Sandofi-Aventis is already approved in the European Union - Rimonabant (Acomplia), and in clinical trials it was shown that 33% of people on Rimonabant lost 10% of body weight and kept their weight down for two years. This is a record, no other diet drug has managed to keep a person's weight down for so long. The drug also helps quit the smoking habit. Rimonabant blocks nerve receptors called CB1 cannabiniod receptors which tell the body to overeat (and also to intake nicotine) [5].

Among other anti-obesity drugs in clinical trials the Contrave from Orexigen is a combination of bupropion, a dopamine and norepinephrine reuptake inhibitor, with naltrexone, an opioid antagonist used to treat various addictive disorders [6]. It is believed that combining these two drugs may improve the ability to initiate weight loss, and importantly, to continue weight loss by blocking the body's attempts to compensate for weight loss during the treatment [7].

Alizyme company of UK works on compound named ALT-962 (Cetilistat). It is a Lipase inhibitor that inhibits gastric and pancreatic lipases in the the gastrointestinal tract to decrease absorption of dietary fat. It belongs to the same class of drugs as above described Orlistat, but it has less potency of inducing side effects [7].

The AOD9604 is a compound studied by Metabolic Pharmaceuticals of Australia. It is a peptide fragment of human growth hormone available orally and promoting lipid-metabolism, resulting in fat burning [7].

Vivus of Mountain View, CA is testing a combination of low doses of the active ingredients phentermine and topiramate (an anticonvulsant) under the name Qnexa. It is believed to affect both excessive hunger and the inability to feel satisfied [10].

Arena Pharmaceuticals of San Diego, CA developed APD-356 (Lorcaserin), which selectively stimulates the 5-HT2C serotonin receptor, located in the hypothalamus (an appetite control center of the brain) [7].

A new CB1 receptor antagonist (the same class as rimonabant) in trials is CP-945,598 developed by Pfizer. According to Pfizer it was well tolerated in Phase I trials and is one of their four CB-1 candidate medicines in development [7].

Amylin Pharmaceuticals of San Diego, CA runs clinical trials of Pramilitide a stable analog of Amylin, a peptide hormone that is co-secreted with insulin from the pancreatic ß-cell and is thus deficient in diabetic people. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent [8].

PYY(3-36) from Nastech of Bothell, WA is a naturally occurring human hormone released by cells in the intestine after meals. The amount secreted increases with the number of calories ingested and research has demonstrated the PYY has appetite suppressing function [7].

7TM Pharma of Denmark is developing TM30338, a synthetic analogue of both PYY(3-36) and PP (Pancreatic Polypeptide), which normally are released during a meal. Both these hormones are known to play a role in the regulation of food intake and appetite in man as satiety signals carried from the gastro-intestinal-tract to the brain [7].

These are just some of the most prominent candidates, however none of them brings the promise to effectively manage the worldwide epidemic of obesity. Nevertheless, the current medical research potential, with small and big research breakthroughs reported weekly, gives us rather strong feelings that the true medical help for obesity in near. By that time however we need to feel encouraged to change our lifestyle to move more and eat less. If you plan on loosing weight and beating your obesity problem you should first talk to your physician to get evaluation and professional guidance to do it safely and successfully. For some there might be quite a bit to loose in this game, but who would regret such loss in the end?

References:

1. Kopelman, P. G. (2000). Obesity as a medical problem. Nature, vol. 404, 635-643.

2. Ioannides-Demos, L. L., Proietto, J., Tonkin, A. M. & McNeil, J. J. (2006). Safety of drug therapies used for weight loss and treatment of obesity. Drug Safety, vol. 29, 277-302.

3. Kim, SH, Lee, YM, Jee, SH, Nam, CM. (2003). Effect of sibutramine on weight loss and blood pressure: a meta-analysis of controlled trials. Obes. Res., vol. 11, 1116-1123.

4. Rossner, S, Sjöström, L, Noack, R, Meinders, AE, Noseda, G. (2000). Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes. Res., vol. 8, 49-61.

5. Ravinet Trillou, C., Arnone, M., Delgorge, C., Gonalons, N., Keane, P., Maffrand, J-P. and Soubrié, P. (2003). Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am. J. Physiol. Regul. Integr. Comp. Physiol., vol. 284, 345-353.

6. Appolinario, J. C., Bueno, J. R. & Coutinho, W. (2004). Psychotropic drugs in the treatment of obesity: what promise? CNS Drugs, vol. 18, 629-651.

7. Dunstan Cooke and Steve Bloom. (2006). The obesity pipeline: current strategies in the development of anti-obesity drugs. Nature Reviews | Drug Discovery, vol. 5, 921-931.

8. Schmitz, O., Brock, B. and Rungby, J. (2004). Amylin Agonists: A Novel Approach in the Treatment of Diabetes. Diabetes, vol. 53, 233-238.