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
{"title":"临床前模型中COX-2选择性抑制与心血管风险之间的脱节","authors":"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","doi":"10.1016/j.vascn.2023.107251","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>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 <em>in vitro</em> and <em>in vivo</em> preclinical models.</p></div><div><h3>Methods</h3><p>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 <em>vs</em> COX-1 enzymatic activity, <em>ex vivo</em> platelet aggregation (using whole blood from multiple species), <em>ex vivo</em> canine femoral vascular ring model, <em>in vitro</em> human endothelial cell activation (with and without COX-2 induction), and <em>in vivo</em> cardiovascular assessment (anesthetized dog).</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusion</h3><p>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 <em>in vivo studies</em>. These results may also suggest that COX-2 inhibition alone is not responsible for rofecoxib-mediated adverse cardiovascular outcomes.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Disconnect between COX-2 selective inhibition and cardiovascular risk in preclinical models\",\"authors\":\"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\",\"doi\":\"10.1016/j.vascn.2023.107251\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p>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 <em>in vitro</em> and <em>in vivo</em> preclinical models.</p></div><div><h3>Methods</h3><p>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 <em>vs</em> COX-1 enzymatic activity, <em>ex vivo</em> platelet aggregation (using whole blood from multiple species), <em>ex vivo</em> canine femoral vascular ring model, <em>in vitro</em> human endothelial cell activation (with and without COX-2 induction), and <em>in vivo</em> cardiovascular assessment (anesthetized dog).</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusion</h3><p>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 <em>in vivo studies</em>. 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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.
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.