Review paper: Current strategies in the development of anti-obesity drugs and their safety concerns.

Obesity is a well-established risk factor for hypertension, hyperlipidemia, type II diabetes, coronary heart disease, stroke, obstructive sleep apnea, asthma, orthopedic disorders, and certain cancers. Despite this risk, the prevalence of obesity continues to increase worldwide, and there is a growing demand for safe and effective antiobesity drugs. Previous antiobesity drugs or anorexigens, particularly centrally acting agents, have poor safety records. Life-threatening safety issues led to the withdrawal of aminorex in 1968, fenfluramine and dexfenfluramine in 1997, and phenylpropanolamine in 2000. Many of the safety issues, such as valvulopathy with fenfluramine and pulmonary arterial hypertension with aminorex, were initially not predicted by routine preclinical toxicology studies. To date, there are no validated animal models or preclinical and/or toxicologic screens to accurately predict anorexigen-induced valvulopathy and pulmonary arterial hypertension in humans. This review covers the current state of antiobesity drugs and their safety concerns, and highlights new therapeutic targets and scientific advances toward the development of appropriate animal models by using novel techniques that will aid in understanding pathogenesis and pathophysiology of anorexigen-related safety issues.