title: Appetite suppressants, cardiac valve disease and combination pharmacotherapy.
abstract: The prevalence of obesity in the United States is a major health problem associated with significant morbidity, mortality, and economic burden. Although obesity and drug addiction are typically considered distinct clinical entities, both diseases involve dysregulation of biogenic amine neuron systems in the brain. Thus, research efforts to develop medications for treating drug addiction can contribute insights into the pharmacotherapy for obesity. Here, we review the neurochemical mechanisms of selected stimulant medications used in the treatment of obesity and issues related to fenfluramine-associated cardiac valvulopathy. In particular, we discuss the evidence that cardiac valve disease involves activation of mitogenic serotonin 2B (5-HT2B) receptors by norfenfluramine, the major metabolite of fenfluramine. Advances in medication discovery suggest that novel molecular entities that target 2 different neurochemical mechanisms, that is, "combination pharmacotherapy," will yield efficacious antiobesity medications with reduced adverse side effects.
authors.affiliation: Clinical Psychopharmacology Section, Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse, Department of Health and Human Services, Baltimore, MD 21224, USA. rrothman@mail.nih.gov
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
mesh_terms: D001067:Appetite Depressants / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005277:Fenfluramine / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D006349:Heart Valve Diseases / Q000139:chemically induced*; D006801:Humans; D009642:Norfenfluramine / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D010645:Phentermine / Q000009:adverse effects / Q000627:therapeutic use; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism
chemical_list: D001067:Appetite Depressants; D044403:Receptor, Serotonin, 5-HT2B; D058826:Serotonin 5-HT2 Receptor Agonists; D009642:Norfenfluramine; D005277:Fenfluramine; D010645:Phentermine