Obesity drugs as adjuncts

Innovative drugs will be most effective when they are used as adjuncts to, rather than substituted for life style changes to improve the metabolic fitness of obese individuals, say Kole P L, A Kaushik, G Agarwal and A N Nagappa

THE World Health Organisation (Geneva) and its International Obesity Task Force, recently declared that obesity is a global epidemic, posing one of the greatest threat to human health and well being. Studies have established that obesity is a major risk factor for several chronic disease conditions, including coronary heart disease (CHD), type II diabetes mellitus (DM), hypertensions, stroke and cancers of the breast, endometrium, prostate and colon.

Present options

The route cause of obesity can simply be defined in terms of thermodynamics. If calorific intake is in excess of output then the surplus amount of the calories are accumulated in the body. This accumulation is in terms of fats and adipose tissues. The old ‘‘Exercise and diet’’ concept is not able to work very well in today’s life which is more fast and need the results fast.

At present context, therapeutic drugs designed for the treatment of the same acts through four mechanism viz.,

• Reducing the amount of fat absorbed
• Increasing fat metabolism
• Curbing appetite
• Resetting the central controls of body weight.

New breakthroughs

1) Energy based approach: Alternative target to combat the obesity include Uncoupling Proteins (UCPs), which were fist discovered in brown fats and also metabolise fats, creating heat. Increasing the expression of UCPs could be one approach to treat obesity. Agonists of adrengeric receptor are also under investigation as targets for increasing energy expenditure and Sanofi-Synthelabo, France based pharmaceutical company (Le Plessis, France) has one such product in process of drug development.

2) Feeding based approach: An alternative means of controlling consumption of food materials is by harnessing peripheral control of feeding. Peptides produced by the gastrointestinal system and pancreas naturally regulate feeling of satiety (fullness of stomach) and the amount of food consumed during meal, but would likely not be effective at large term control of body weight.

The peptides like cholecystokinin, neuromedin B, gastrin releasing hormone, and enterostatin, are physiologically found to be responsible for the feeling of fullfillness. With the due physiologically found to be responsible for the feeling of fullfillness. With the due physiological role, these peptides can be thought as new targets for better control of the over feeling and thus an approach for combating the obesity. But, these targets have been observed non useful in long term control of the obesity. To date, centrally acting appetite suppressants have proved the most commercially viable therapeutic approach.

3) Hormonal based approach: A new sense of optimism has been created within the industry following genetic studies. In, 1994, the discovery of ‘‘Leptin’’, a fat regulating hormone was the beginning of molecular medicine for treatment of obesity.

Shortly, after the discovery of leptin, researchers have identified a receptor for leptin, named as ‘‘OBR’’. A truncated shortens form of the receptor, so called OBR-A, shuttles leptin across the blood-brain barrier. Researchers now suspect that obese people appear to be resistant to leptin because the hormone is not retransported to the brain. Instead studies, suggest that the level of leptin in the cerebrospinal fluid of these obese individual is much lower than the anticipated considering their blood concentration.

OBR-A is therefore yet an unexplored target for treatment. An important element in the leptin signaling pathway is melanocyte stimulating hormone (MSH), which was actually found to be a fragment of precursor protein POMC. Mutation in the POMC gene causes a rare hereditary form of obesity. MSH acts primarily through the MCR-4 receptor to reduce appetite. According to Barsh’s data, mutation in MCR-4 accounts for 2-3 per cent of cases of severe obesity and agonist of the MCR-4 receptor make obvious choices for the development of treatment for obesity and one that millennium is currently pursuing.

In addition to its effect on alpha-MSH, leptin increases the production of the SOCS-3 (suppressor of cytokine signalling-3 protein, which terminates its activity at the leptin receptor. The SOCS-3 protein is probably a regulator of the leptin signalling pathways in healthy individuals. If this pathway is overactive in obese patient, drugs that target SOCS-3 might have considerable potential.

New target has been located in June 2000, when researchers at Johns Hopkins University (Baltimore, MD) discovered that the molecule malonyl coenzyme a inhibits NPY1 independently of leptin, decreasing appetite in mice. The team also developed an inhibitor that prevents malonyl-CoA from being broken in the body, resulting in its accumulation leading to weight loss.

Although a number of other neuropeptides are known to be involved in the central control of appetite, many of these are not suitable targets for drug development because they play role in wider range of physiological processes. Further research into neuropeptide such as Corticotropin Releasing Hormone (CRH), Orexin, Gelanin, Cocaine and Amphetamine regulated Transcript (CART) may, however, help clarify the working of the weight control system. Drugs targeting any of these pathways would act primarily as appetite suppressants and strike at the heart of disease problem. Drug that reduces fat absorption of increase fat metabolism may help to shift body fat, but in turn they will modulate leptin levels triggering the contemporary changes in feeding and metabolism.

Serendipity has also played role, Axokine (Ciliary Neutropic Factor, CNTF) as a treatment for amytropic lateral sclerosis. Although Axokine did not alleviate ALS, it causes the patient to loose weight. Subsequent studies revealed that Axokine used the same signalling pathway to leptin and it was doing overlapping part of the brain. So far, CNTF is under clinical trial and giving better result. The prospect of long term administration raises another problem with many of the potential biotechnology based obesity treatment as protein, they will need to be injected and may have short half-life although dose of this drug is very small so severe injectibles is not going to be much of a problem.

Perspectives and future prospects

Investigations at the pharmacologic, physiologic and behavioural level will be critical for evaluation of all new anti-obesity drugs. The most effective pharmacologic treatments are likely to be those that involve the use of a combination of drugs. Obesity is a chronic disease and the possibility of the long term treatment - either continuous or intermittent treatment through adult life - is a concept that is receiving more attention. In this context, risk benefit and quality of life analysis of pharmacologic treatment becomes increasingly important. Innovative drugs will be most effective when they are used as adjuncts to, rather than substituted for life style changes to improve the metabolic fitness, health and quality of life for obese individuals.

The writers are with BITS, Pilani