Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications
Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications
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DOI：
10.1161/01.cir.102.23.2836
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发表时间：
2000-12
期刊：
影响因子：
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通讯作者：
R. Rothman;M. Baumann;J. Savage;Laura Rauser;A. McBride;S. Hufeisen;B. Roth
中科院分区：
文献类型：
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作者：
R. Rothman;M. Baumann;J. Savage;Laura Rauser;A. McBride;S. Hufeisen;B. Roth
背景-具有不同作用机制的5-羟色胺能药物被用于治疗精神疾病，并正在被研究作为药物依赖的治疗方法。芬氟拉明相关性瓣膜心脏病(VHD)的发生引起了人们的担忧，即其他5-羟色胺能药物也可能增加发生VHD的风险。我们假设芬氟拉明或其代谢物去甲氟拉明和其他已知的产生VHD的药物对能够刺激有丝分裂发生的特定5-羟色胺受体亚型有较高的亲和力。方法和结果：通过配基结合方法和功能分析筛选已知或怀疑引起VHD的药物(阳性对照)和与VHD无关的药物(阴性对照)在11个克隆的5-羟色胺受体亚型上的活性。阳性对照药物为(±)-芬氟拉明、(+)-芬氟拉明、(−)-芬氟拉明及其代谢物(±)-氟苯丙胺、(+)-氟苯丙胺、(−)-氟苯丙胺、麦角胺、甲基色胺及其代谢物甲基麦角新碱。阴性对照药物为芬太尼、氟西汀及其代谢物诺氟西汀、曲唑酮及其活性代谢物间氯苯哌嗪。(±)-、(+)-和(−)-去甲苯丙胺、麦角胺和甲基麦角新碱对克隆的人5-HT2B受体均有较高的亲和力，并对5-HT2B受体的完全激动剂有部分亲和力。结论：我们的数据表明，5-HT2B受体的激活是产生VHD所必需的，而不激活5-HT2B受体的5-羟色胺能药物不太可能产生VHD。我们建议所有临床上可用的具有5-HT2B受体活性的药物及其活性代谢物都应进行5-HT2B受体激动剂活性的筛选，临床医生应考虑暂停使用5-HT2B受体活性显著的药物。
Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (−)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (−)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (±)-, (+)-, and (−)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT2B receptor and were partial to full agonists at the 5-HT2B receptor. Conclusions—Our data imply that activation of 5-HT2B receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT2B receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT2B receptors.