Ritchie Helen Elizabeth, Polson Jaimie W, Xia Andrea, Webster William
School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW, Australia.
Curr Res Toxicol. 2023 Sep 17;5:100125. doi: 10.1016/j.crtox.2023.100125. eCollection 2023.
Vinpocetine is a readily available nutritional supplement claimed to improve memory and weight loss. However, it blocks the kr current essential for cardiac action potential repolarisation and Ikr inhibition can cause "torsade de pointes" arrhythmias and sudden death. Moreover, Ikr blockers have exhibited teratogenic effects in reproductive toxicology studies, leading to increased birth defects and embryonic mortality. The FDA advises against vinpocetine use in pregnant and prospective mothers based on animal studies showing dose-dependent fetal mortality in rats and rabbits, and cardiovascular malformations in surviving fetuses. However, the mechanisms responsible for vinpocetine's fetal toxicity remain unclear. The present study used rat embryo culture to evaluate vinpocetine and its major metabolite, apovincaminic acid, on embryonic heart rate, a possible causative factor behind its adverse effects. Both compounds induced embryonic bradycardia in a concentration-dependent manner, with vinpocetine proving more potent. The minimum vinpocentine concentration to induce bradycardia was 100 nM, a level unlikely to be reached in humans following typical doses. Embryonic arrhythmias were also observed at the highest concentrations. These results suggest that the FDA's cautionary statement may generate undue anxiety, although re-evaluation of teratogenicity risk associated with vinpocetine should be revisited if a link to cardiac arrhythmias in adults is established.
长春西汀是一种容易获得的营养补充剂，据称具有改善记忆力和减肥的功效。然而，它会阻断心脏动作电位复极化所必需的钾离子流（Ikr），抑制Ikr会导致“尖端扭转型”心律失常和猝死。此外，在生殖毒理学研究中，Ikr阻滞剂已显示出致畸作用，导致出生缺陷增加和胚胎死亡。基于动物研究显示大鼠和兔子中存在剂量依赖性胎儿死亡率以及存活胎儿出现心血管畸形，美国食品药品监督管理局（FDA）建议孕妇和准母亲不要使用长春西汀。然而，长春西汀胎儿毒性的作用机制仍不清楚。本研究使用大鼠胚胎培养来评估长春西汀及其主要代谢产物阿朴长春胺酸对胚胎心率的影响，胚胎心率可能是其不良反应背后的一个致病因素。两种化合物均以浓度依赖性方式诱导胚胎心动过缓，长春西汀的作用更强。诱导心动过缓的长春西汀最低浓度为100 nM，在人类服用典型剂量后不太可能达到这一水平。在最高浓度下也观察到了胚胎心律失常。这些结果表明，FDA的警示声明可能会引起不必要的焦虑，不过，如果确定长春西汀与成人心律失常之间存在联系，则应重新评估与长春西汀相关的致畸风险。
