D.L. Higgins Consulting, 115 Crestview Court, San Carlos, CA 94070, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2012 Jan;385(1):103-9. doi: 10.1007/s00210-011-0687-x. Epub 2011 Sep 8.
In 2007, the results from a meta analysis of 29 clinical studies indicated that tegaserod (Zelnorm®), a 5-hydroxytryptamine(4) (5-HT(4)) receptor agonist with gastrointestinal prokinetic activity, was associated with an increased incidence of cardiovascular ischemic events, resulting in its withdrawal from many markets around the world. Stimulation of platelet aggregation has been proposed to explain the phenomenon. However, data from recent epidemiological studies have suggested that there is no correlation between tegaserod use and the incidence of cardiovascular ischemia. In this study, the influence of tegaserod, at concentrations up to tenfold higher than the total plasma C (max) for the 6 mg clinical dose, has been investigated on platelet aggregation under standard conditions with platelet-rich plasma (PRP) obtained from healthy human subjects. Additionally, the influence of tegaserod on coronary artery tone was evaluated as an alternative pro-ischemic mechanism. The positive control, thrombopoietin, but not tegaserod, demonstrated a statistically significant increase in platelet aggregation using the same PRP samples with either adenosine diphosphate (ADP) or ADP plus 5-HT as an aggregation agonist. Tegaserod had no contractile activity in either porcine or human isolated coronary artery preparations, and only a small and variable response in canine coronary arteries at concentrations higher than those achieved clinically. Taken together, these studies do not identify a mechanism for the ischemic events that have been attributed to tegaserod in humans.
2007 年，29 项临床研究的荟萃分析结果表明，具有胃肠道促动力作用的 5-羟色胺（4）（5-HT（4））受体激动剂替扎司特（Zelnorm®）与心血管缺血性事件的发生率增加有关，导致其在世界许多市场被撤出。血小板聚集的刺激被认为可以解释这种现象。然而，最近的流行病学研究数据表明，替扎司特的使用与心血管缺血的发生率之间没有相关性。在这项研究中，研究了替扎司特在高达比 6mg 临床剂量的总血浆 C（max）高十倍的浓度下对血小板聚集的影响，使用从健康人类受试者获得的富含血小板的血浆（PRP）在标准条件下进行血小板聚集。此外，还评估了替扎司特对冠状动脉张力的影响，作为一种替代的缺血性机制。阳性对照物，血小板生成素，但不是替扎司特，在使用相同的 PRP 样本时，用二磷酸腺苷（ADP）或 ADP 加 5-HT 作为聚集激动剂，显示出统计学上显著增加的血小板聚集。替扎司特在猪或人分离的冠状动脉制剂中没有收缩活性，仅在高于临床浓度的犬冠状动脉中显示出较小且可变的反应。综上所述，这些研究并未确定与替扎司特在人类中归因于缺血性事件相关的机制。
