Emerging drugs for obesity therapy

Abstract

Central obesity have an important impact on the development of risk factors for coronary heart disease, including dislipidemia, glucose intolerance, insulin resistance and hypertension. These factors contribute to building cardiovascular (CV) disease as a major cause of death. The approach to obesity therapy should be designed to reduce CV risk and mortality. Diet and lifestyle changes remain the cornerstones of therapy for obesity, but the resultant weight loss is often small and long-term success is uncommon and disappointing. Drug therapy is considered for individuals with a body mass index greater than 30 kg/m 2 or ranging from 25 to 30 kg/m 2 if they have comorbid conditions. Antiobesity agents can be helpful to some patients in achieving and maintaining meaningful weight loss, but yet our pharmaceutical tools are of limited effectiveness considering the magnitude of the problem. At the present, only two drugs, orlistat and sibutramine, are approved for long-term treatment of obesity and promote no more than 5 to 10% of weight loss. Rimonabant, a cannabinoid-1 receptor antagonist, was withdrawn from the market because of concerns about its safety, including risk of suicidal and seizures, although very effective in promoting clinically meaningful weight loss, reduction in waist circumference, and improvements in several metabolic risk factors, rimonabant, a cannabinoid-1 receptor antagonist was withdrawn from the market because it concerns about its safety, including risk of suicidal and seizures. Fortunately, recent fundamental insights into the neuroendocrine mechanisms regulating body weight provide an expanding list of molecular targets for novel, rationally designed antiobesity drugs. In this review, the therapeutic potential of some antiobesity molecules in the development will be analyzed based on an understanding of energy homeostasis. Arq Bras Endocrinol Metab. 2009;53(2):271-280. KeywordsObesity therapy; antiobesity drugs; antiobesity molecules, weight loss resumo Obesidade e, particularmente, a obesidade central têm influência importante na predisposição a fatores de risco para doença coronariana, incluindo dislipidemia, intolerância à glicose, resistência à insulina e hipertensão. Tais fatores contribuem para tornar as doenças cardiovasculares (DC) causas frequentes de morte. Os métodos de tratamento da obesidade deveriam ser voltados à redução do risco e da mortalidade devido às doenças cardiovasculares. Dietas e mudanças no estilo de vida continuam sendo fatores-chave no tratamento à obesidade, mas a perda de peso resultante é geralmente pequena e o sucesso em longo prazo costuma ser incomum e frustrante. O tratamento com medicamentos é indicado para indivíduos com índice de massa corpórea superior a 30 kg/m 2 ou entre 25 e 30 kg/m 2 , se apresentarem comorbidades. Agentes antiobesidade podem ajudar alguns pacientes a alcançar e manter uma perda de peso significativa, mas, ainda assim, os agentes farmacológicos são pouco efetivos considerando-se a magnitude do problema. Atualmente, apen...

Exploratory Literature Meta‐Analysis to Characterize the Relationship Between Early and Longer Term Body Weight Loss for Antiobesity Compounds

“…More and more is being discovered about the specific counterregulatory mechanisms associated with various drug therapies that produce weight loss. For example, reduction in sibutramine efficacy over time (a phenomenon known as sibutramine tachyphylaxis) has been shown to be a result of the brain opposing weight loss by stimulating appetite, increased food reward/food intake, decrease in basal energy expenditure, and decreased circulating levels of leptin in blood (associated with body fat reduction). This may trigger counterregulatory mechanisms that block further weight loss effects of sibutramine.…”

Sibutramine Effects on Central Mechanisms Regulating Energy Homeostasis

“…Indeed, in energy-restricted rats, sibutramine treatment increased the transport of the anorexigenic hormone leptin into the ARC, which in turn activated proopiomelanocorticotropin (POMC)/cocaine amphetamine regulating transcript (CART) neurons and inhibited neuropeptide Y (NPY)/agouti related peptide (AgRP) neurons [8,[16][17][18]. Consequently, this stimulated the secretion of the anorexigenic neuropeptides POMC and its derived melanocortin -melanocyte-stimulating hormone ( -MSH), and of corticotrophin-releasing hormone (CRH) and CART [8,16,18]. Released -MSH may bind to and activate melanocortin receptors (MCR), particularly MCR-4, in the PVN [7].…”

“…Released -MSH may bind to and activate melanocortin receptors (MCR), particularly MCR-4, in the PVN [7]. On the contrary, the secretion of the orexigenic neuropeptides NPY, AgRP, orexin A and B and melanocortin-concentrating hormone (MCH) is inhibited [8,18]. The ability of sibutramine to decrease body weight can also be attributed to the fact that it increases energy expenditure.…”

Progressos recentes e novas perspectivas em farmacoterapia da obesidade

“…Logo, estabelecer como alvo uma determinada via molecular pode levar à perda de peso, mas respostas homeostáticas compensatórias serão ativadas, minimizando a eficácia da droga (20). Em analogia com o tratamento da HAS (por exemplo, associação de inibidor da ECA/ tiazídico) e do DM2 (por exemplo, associação de metformina/sulfonilureia), seriam utilizadas duas substân-cias com mecanismos de ação e propostas diferentes, na tentativa de maximizar o efeito desejado e, simultaneamente, diminuir a chance de efeitos colaterais (19)(20)(21). No presente momento, as combinações propostas em estágio mais avançado de desenvolvimento são: bupropiona/naltrexona, bupropiona/zonisamida, fentermina/topiramato e pramlintide/metreleptina.…”