Elangbam C S
Department of Pathology, Safety Assessment, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Vet Pathol. 2009 Jan;46(1):10-24. doi: 10.1354/vp.46-1-10.
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.
肥胖是高血压、高脂血症、II型糖尿病、冠心病、中风、阻塞性睡眠呼吸暂停、哮喘、骨科疾病和某些癌症公认的危险因素。尽管存在这种风险，但肥胖在全球的患病率仍在持续上升，对安全有效的抗肥胖药物的需求也日益增长。以往的抗肥胖药物或食欲抑制剂，尤其是中枢作用药物，安全性记录不佳。危及生命的安全问题导致1968年氨基雷克斯、1997年芬氟拉明和右芬氟拉明以及2000年苯丙醇胺退市。许多安全问题，如芬氟拉明导致的瓣膜病和氨基雷克斯导致的肺动脉高压，最初并未被常规临床前毒理学研究预测到。迄今为止，尚无经过验证的动物模型或临床前和/或毒理学筛查方法来准确预测食欲抑制剂在人类中引起的瓣膜病和肺动脉高压。本综述涵盖了抗肥胖药物的现状及其安全性问题，并强调了新的治疗靶点以及利用新技术开发合适动物模型的科学进展，这些新技术将有助于理解食欲抑制剂相关安全问题的发病机制和病理生理学。
