期刊
EXPERT OPINION ON DRUG SAFETY
卷 8, 期 3, 页码 317-329出版社
TAYLOR & FRANCIS LTD
DOI: 10.1517/14740330902931524
关键词
5-HT transporter; 5-HT2B receptor; blood 5-HT; fenfluramine; norfenfluramine; plasma 5-HT
资金
- National Institutes of Health
- NATIONAL INSTITUTE ON DRUG ABUSE [ZIADA000523, Z01DA000119, ZIADA000522] Funding Source: NIH RePORTER
Background: The serotonin (5-HT) releasers (+/-)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use owing to increased risk of valvular heart disease. One prevailing hypothesis (i.e., the '5-HT hypothesis') suggests that fenfluramine-induced increases in plasma 5-HT underlie the disease. Objective: Here, we critically evaluate the possible mechanisms responsible for fenfluramine-associated valve disease. Methods: Findings from in vitro and in vivo experiments performed in our laboratory are reviewed. The data are integrated with existing literature to address the validity of the 5-HT hypothesis and suggest alternative explanations. Conclusions: The overwhelming majority of evidence refutes the 5-HT hypothesis. A more likely cause of fenfluramine-induced valvulopathy is activation of 5-HT2B receptors on heart valves by the metabolite norfenfluramine. Future serotonergic medications should be designed to lack 5-HT2B agonist activity.
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