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Expert Opin Investig Drugs. 2005 Mar;14(3):243-50.

Advances in anti-obesity therapeutics.

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Department of Metabolic Disorders, Merck Research Laboratories, R80M-213, PO Box 2000, Rahway, NJ 07065, USA.


Obesity is rapidly becoming an epidemic in developed countries. Currently available anti-obesity therapeutics are only modestly effective and are accompanied by significant adverse effects. In recent years, substantial advances have been made in the basic understanding of brain control of feeding behaviour and metabolism. As a result, several compounds have progressed to Phase III development, with additional compounds at various stages of Phase II development. Most of the late-stage development candidates are CNS agents, which reflects the consensus that the brain exerts a dominant control on feeding behaviour and peripheral metabolism through the autonomic nervous system. Homeostatic mechanisms encompassing hypothalamic/brainstem pathways have long been recognised in obesity research. In addition, non-homeostatic mechanisms encompassing the reward circuit and volitional control need to be targeted to control feeding behaviour and physical activity, especially in humans. While recognising the importance of CNS control, certain peripherally acting agents can affect mitochondrial metabolism, lipolysis, nutrient absorption or the vagal feedback pathway, such that these peripherally acting agents can potentially be combined with CNS agents to achieve maximal efficacy. It is expected that newer generations of anti-obesity therapeutics will be superior to existing agents and will facilitate lifestyle modification.

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