Treatment of obesity

Two recently introduced antidepressants are notable m that they are selective serotonin uptake inhibitors Citalopram (19) is reported to be as effective as amitriptyline m the treatment of endogenous depression [75, 16] Fluoxetine (20) as the hydrochlonde is approved for major depressive disorders mcludmg those with concomitant anxiety Interestmgly, it also appears useful m the treatment of obesity [17]... 

Sanofi-Synthelabo researchers discovered pyrazole 53 and analogs to have potent Cannabinoid receptor-1 (CB-1) antagonist/inverse agonist activity and have progressed 53 into development for treatment of obesity and alcohol dependence. The synthesis of 53 was accomplished by heating the diketone sodium salt 51 with the aryl hydrazine hydrochloride in acetic acid to provide the intermediate 52, which was further derivatized... 

Heterocycles as drugs in pharmacological treatment of obesity 99JMC181. 

Little attempt has been made to develop drugs targeted specifically to white adipose tissue and the production of adipokines. It is likely, however, that there will be an increasing emphasis on this approach to the pharmacological treatment of obesity-related diseases, given the current views on the centrality of the adipokines to these disorders. It is, of course, the diseases that obesity leads to, rather than obesity itself, that constitute the main medical challenge. 

Anti-obesity Drugs. Table 1 Profile of drugs approved for long-term treatment of obesity... 

ANOREXIANTS When an anorexiant or amphetamine is used as part of the treatment of obesity, the drug is usually prescribed for outpatient use The nurse obtains and records the blood pressure, pulse, respiratory rate, and weight before therapy is started. 

PhentEimine (11),used in the treatment of obesity, is a t-alkyl amine. The Ritter reaction, using HCN as the nitrile (p T63), is ideal for this,... 

Investigation of the differences in crystal packing between (431) and (426) from comparison of their respective X-ray structures, revealed that (431) was more tightly packed than (442), reflected in their respective melting points of 235 and 170 °C. It was postulated that the absence of in vivo activity for (431) may be explained by the resultant reduction in water solubility and dissolution rate compared with (426). The comparatively high calculated polar surface area of (431) (122.5A ) compared with (426) (89.3 A ) was also proposed as a factor influencing the marked difference in bioavailability between the two related compounds. Compound (426) (SLV-319) is currently being developed with Bristol-Myers Squibb for the potential treatment of obesity and other metabolic disorders. Phase I trials for obesity were started in April 2004. Earlier Phase I clinical trials for the treatment of schizophrenia and psychosis, which commenced in April 2002, appear to have been abandoned. 

Stated to be particularly useful in the treatment of obesity, a series of 1,5-diaryl-pyrrole-based compounds from AstraZeneca was claimed in a recent patent application [313], including compound (509). Although no specific biological data were presented, the CBi receptor affinities are claimed to be less than 1 pM and preferably less than 200 nM. 

A number of azetidine-based compounds have been disclosed in patent applications from Aventis Pharma for CBi-modulated treatment of diseases such as obesity, Parkinson s disease, schizophrenia, respiratory and neurological diseases [330-334]. Compound (556) was specifically claimed for use in two formulation patent applications [330, 331] for a stable semi-solid composition and oral emulsion composition, respectively. The optional coadministration of an agent that activates norepinephrinergic and se-rotoninergic neurotransmission (for example, sibutramine) or dopaminergic neurotransmission was also claimed for the treatment of obesity. The optional use of a dopamine agonist (for example, levodopa) was claimed... 

Our current understanding of the potential therapeutic applications of CBi antagonists owes a great deal to the discovery of rimonabant (382). Indeed, clinical data demonstrating the efficacy of (382) in the treatment of obesity and nicotine addiction has provided a substantial driving force for the expanding research effort into this approach. 

Treatment of obesity includes lifestyle changes (e.g., dietary modification, enhanced physical activity, and behavioral therapy),... 

Orzano AJ, Scott JG. Diagnosis and treatment of obesity in adults An applied evidence-based review. J Am Board Fam Pract 2004 17(5) 359-369. 

Anorectic A drug that reduces appetite and, thus, is sometimes used in the treatment of obesity. Many are amphetamines or amphetamine-like drugs (e.g., fenfluramine). 

Drugs that act on the H3 receptor are being developed for the treatment of obesity, sleep disturbances, epilepsy and cognitive disorders. The ability of histamine to promote arousal, suppress appetite, elevate seizure threshold and stimulate cognitive processes implies that compounds able to enhance the release of neuronal histamine should mimic these effects. Several H3 antagonists currently in development demonstrate such activity and show promise as effective and novel therapeutic agents [40, 84-86]. Because H3 agonists suppress the release of... 

The National Task Force on the Prevention and Treatment of Obesity concluded that short-term use of anorectic agents is difficult to justify because of the predictable weight regain that occurs upon discontinuation. Long-term use may have a role for patients who have no contraindications, but further study is needed before widespread, routine use is implemented. 

Lipase Inhibitor Orlistat (Xenical, Roche) is prescribed for the treatment of obesity. It inhibits the gastrointestinal lipase enzymes by binding to the lipase through the serine site and inactivates the enzyme. Fat in the form of triglycerides cannot be hydrolyzed by the lipase and converted to free fatty acids and monoglycerides. Thus, there is no uptake of fat molecules into the cell tissue. 

Leptin is a homeostatic hormone. It inhibits food intake and promotes energy expenditnre. Therefore, in the face of a loss in body fat, the levels of leptin decrease and food intake is stimnlated. In contrast, if body fat stores increase, the levels of leptin increase as well and food intake is decreased and energy expenditure increased. Therefore, leptin tends to maintain body weight within fairly close limits. Since ob/ob mice are genetically deficient in leptin, it follows that administration of leptin shonld tend to restore normal body weight. That is exactly what happens. Injection of leptin into ob/ob mice reduces their food intake dramatically and they tend toward the body weights of their normal littermates. In these mice at least, leptin is a powerful force for treatment of obesity. 

Although details of the biochemistry of energy transformation have been established for over 50 years, it is only recently that this knowledge has been applied to key life processes in health and disease. This has been driven by several factors appreciation of the importance of provision of chemical energy (i.e. food) for patients, in hospital, provision of chemical energy for physical activity of all kinds and the need to balance energy intake and expenditure for prevention and treatment of obesity. In discussions of the last point, even the mass media refer to the first law of thermodynamics. 

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