临床前模型中COX-2选择性抑制与心血管风险之间的脱节

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Yevgeniya E. Koshman, Aimee L. Bielinski, Brandan M. Bird, Jonathon R. Green, Kenneth L. Kowalkowski, Jie Lai-Zhang, Prathap Kumar Mahalingaiah, James W. Sawicki, Nari N. Talaty, Amanda S. Wilsey, Mark T. Zafiratos, Terry R. Van Vleet
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引用次数: 0

摘要

二级药理学分析通常应用于药物发现,以研究药物在不同于预期治疗分子靶标(靶标上)的分子靶标上的药理作用。来自一项随机、安慰剂对照临床试验的数据,批准(腺瘤性息肉预防VIOXX, rofecoxib)试验,引起了对COX-2抑制作为主要或次要靶点的重大关注,影响了一些制药公司的筛选和决策过程。COX-2经常被列入脱靶筛选,这是由于与该靶标的二次相互作用对心血管(CV)安全性的担忧。cox -2介导的心肌梗死的几种潜在机制被认为包括对血小板黏性/聚集、血管张力和血压以及内皮细胞活化的影响。在本研究中,我们将重点关注这些机制作为COX-2抑制剂的潜在作用,并通过各种体外和体内临床前模型寻找其机制的证据。方法在研究中测试的化合物,具有一定范围的COX-2选择性,包括罗非昔布、塞来昔布、依托度酸和美洛昔康。筛选化合物对COX-2和COX-1酶活性的抑制、体外血小板聚集(使用多种动物的全血)、体外犬股血管环模型、体外人内皮细胞激活(有和没有COX-2诱导)以及体内心血管评估(麻醉犬)。结果COX-2结合评价基本证实了先前报道的COX-2选择性。COX-2抑制剂对血小板功能(自发聚集或抑制聚集)、心血管参数(平均动脉压、心率和左心室收缩力)或内皮细胞活化没有影响。然而,罗非昔布在犬股动脉中产生内皮介导的收缩反应。结论:我们的数据表明,人类与罗非昔布相关的心血管事件不能通过COX-2效价或选择性来预测。此外,血管环模型提示COX-2抑制剂可能对心血管产生不良影响,尽管这些影响未在体内研究中发现。这些结果也可能表明,COX-2抑制本身并不是罗非昔布介导的不良心血管结局的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disconnect between COX-2 selective inhibition and cardiovascular risk in preclinical models

Introduction

Secondary pharmacology profiling is routinely applied in pharmaceutical drug discovery to investigate the pharmaceutical effects of a drug at molecular targets distinct from (off-target) the intended therapeutic molecular target (on-target). Data from a randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX, rofecoxib) trial, raised significant concerns about COX-2 inhibition as a primary or secondary target, shaping the screening and decision-making processes of some pharmaceutical companies. COX-2 is often included in off-target screens due to cardiovascular (CV) safety concerns about secondary interactions with this target. Several potential mechanisms of COX-2-mediated myocardial infarctions have been considered including, effects on platelet stickiness/aggregation, vasal tone and blood pressure, and endothelial cell activation. In the present study, we focused on each of these mechanisms as potential effects of COX-2 inhibitors, to find evidence of mechanism using various in vitro and in vivo preclinical models.

Methods

Compounds tested in the study, with a range of COX-2 selectivity, included rofecoxib, celecoxib, etodolac, and meloxicam. Compounds were screened for inhibition of COX-2 vs COX-1 enzymatic activity, ex vivo platelet aggregation (using whole blood from multiple species), ex vivo canine femoral vascular ring model, in vitro human endothelial cell activation (with and without COX-2 induction), and in vivo cardiovascular assessment (anesthetized dog).

Results

The COX-2 binding assessment generally confirmed the COX-2 selectivity previously reported. COX-2 inhibitors did not have effects on platelet function (spontaneous aggregation or inhibition of aggregation), cardiovascular parameters (mean arterial pressure, heart rate, and left ventricular contractility), or endothelial cell activation. However, rofecoxib uniquely produced an endothelial mediated constriction response in canine femoral arteries.

Conclusion

Our data suggest that rofecoxib-related cardiovascular events in humans are not predicted by COX-2 potency or selectivity. In addition, the vascular ring model suggested possible adverse cardiovascular effects by COX-2 inhibitors, although these effects were not seen in vivo studies. These results may also suggest that COX-2 inhibition alone is not responsible for rofecoxib-mediated adverse cardiovascular outcomes.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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