Sinai Center for Thrombosis Research, 23303Sinai Hospital of Baltimore, LifeBridge Health, Baltimore, MD, USA.
Inova Center for Thrombosis Research and Drug Development, 237248Inova Heart and Vascular Institute, Fairfax, VA, USA.
J Cardiovasc Pharmacol Ther. 2021 Jan;26(1):40-50. doi: 10.1177/1074248420942004. Epub 2020 Jul 16.
Tegaserod, an orally active, potent 5-hydroxytryptamine-4 serotonin receptor agonist, was previously indicated for irritable bowel syndrome but was voluntarily withdrawn due to potential cardiovascular side effects. In vitro studies suggested that tegaserod increased platelet aggregation, but these results were not reproduced or were inconclusive. We sought to assess ex vivo effects of tegaserod on platelet aggregation.
In this double-blind, placebo-controlled, crossover study, we randomized a majority of healthy patients with no history of cardiovascular risk factors (n = 21) to receive tegaserod or matching placebo for 7 + 2 days followed by a 7- to 10-day washout period, and then patients were crossed over to the other study drug for the next 7 + 2 days. Unstimulated and agonist-stimulated platelet aggregation; P-selectin expression; serum thromboxane (Tx)B and urinary 11-dehydro (11-dh) TxB; and tegaserod and M29.0 concentrations were serially assessed.
There was no significant difference in percentage change in unstimulated or adenosine diphosphate (ADP)- and ADP + serotonin-, collagen- and thrombin receptor activating peptide-induced maximum platelet aggregation and in platelet P-selectin expression in the presence of tegaserod at any time point when compared to placebo. Similarly, there was no significant difference in percentage change in serum TxB or urinary 11-dhTxB levels between placebo and tegaserod. No new or unexpected findings were observed in evaluations of safety or pharmacokinetic parameters.
This comprehensive pharmacodynamic study, by employing established markers used in prior investigations, which have been considered by the Food and Drug Administration to indicate drug-related platelet effects, does not demonstrate any influence of tegaserod treatment on platelet function.
替加色罗是一种口服有效的、强效的 5-羟色胺-4 （5-HT4）受体激动剂，先前被批准用于治疗肠易激综合征，但由于潜在的心血管副作用而被自愿撤回。体外研究表明替加色罗可增加血小板聚集，但这些结果未被复制或结果不确定。我们试图评估替加色罗对血小板聚集的体外作用。
在这项双盲、安慰剂对照、交叉研究中，我们将大多数无心血管危险因素史的健康患者（n=21）随机分为替加色罗组或匹配的安慰剂组，分别接受替加色罗或安慰剂治疗 7+2 天，然后进行 7 至 10 天的洗脱期，然后患者交叉接受下一组药物治疗 7+2 天。连续评估未刺激和激动剂刺激的血小板聚集；P 选择素表达；血清血栓素（Tx）B 和尿 11-脱氢（11-dh）TxB；以及替加色罗和 M29.0 浓度。
与安慰剂相比，在任何时间点，替加色罗对未刺激或二磷酸腺苷（ADP）和 ADP+5-羟色胺、胶原和血栓素受体激活肽诱导的最大血小板聚集以及血小板 P 选择素表达的无刺激变化百分比均无显著差异。同样，替加色罗与安慰剂相比，血清 TxB 或尿 11-dhTxB 水平的变化百分比也无显著差异。在安全性或药代动力学参数的评估中，未观察到新的或意外的发现。
这项综合的药效学研究通过使用先前研究中考虑的已建立的标志物，这些标志物被食品和药物管理局认为表明药物相关的血小板作用，未显示替加色罗治疗对血小板功能有任何影响。
