Evaluation of the translation of multiple cardiovascular regulatory mechanisms in the anesthetized dog

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Olivera Antic, Yevgeniya E. Koshman, Brandan M. Bird, Geena Jasiek, Amanda S. Wilsey, Scott W. Mittelstadt, C. Michael Foley
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Abstract

The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low threshold to initiate, and have quick delivery of decision quality data. We have aimed to profile compounds with diverse mechanism of actions (MoAs) of “non-QT” cardiovascular drug effects and evaluate the ability of nonclinical in vivo cardiovascular models to detect clinically reported effects. The hemodynamic effects of 11 drugs (atropine, itraconazole, atenolol, ivabradine, milrinone, enalaprilat, fasudil, amlodipine, prazosin, amiloride, and hydrochlorothiazide) were profiled in an anesthetized dog cardiovascular model. Derived parameters included: heart rate, an index of left ventricular contractility, mean arterial pressure, systemic vascular resistance, and cardiac output. Species specific plasma protein data was generated (human, dog) and utilized to calculate free drug concentrations. Using the anesthetized dog cardiovascular model, 10 of the 11 drugs displayed the predicted changes in CV parameters based on their primary MoAs and corresponding clinically described effects. Interestingly but not unexpected, 1 of 11 failed to display their predicted CV pattern which is likely due to a delay in pharmacodynamic effect that is beyond the duration of the experimental model (hydrochlorothiazide). The analysis from the current study supports the strategic use of the anesthetized dog model early in the drug discovery process for a comprehensive cardiovascular evaluation with good translation to human.

评估麻醉狗体内多种心血管调节机制的转化。
在药物发现的早期阶段,战略性地、有针对性地使用麻醉犬心血管模型,可以对潜在的安全性责任进行全面的心血管和电生理学评估,并在启动慢性毒理学研究之前指导化合物的选择。理想的模型应能建立暴露-反应关系以指导安全系数计算,启动门槛低,并能快速提供决策质量数据。我们的目标是剖析具有不同作用机制(MoAs)的 "非 QT "心血管药物效应化合物,并评估非临床体内心血管模型检测临床报告效应的能力。在麻醉狗心血管模型中分析了 11 种药物(阿托品、伊曲康唑、阿替洛尔、伊伐布雷定、米力农、依那普利拉、法舒地尔、氨氯地平、哌唑嗪、阿米洛利和氢氯噻嗪)的血液动力学效应。得出的参数包括:心率、左心室收缩力指数、平均动脉压、全身血管阻力和心输出量。生成的特定物种血浆蛋白数据(人、狗)用于计算游离药物浓度。通过使用麻醉狗心血管模型,11 种药物中有 10 种根据其主要作用剂量和相应的临床描述效应显示出了预测的心血管参数变化。有趣但并非意料之外的是,11 种药物中有 1 种未能显示其预测的 CV 模式,这可能是由于药效学效应的延迟超出了实验模型的持续时间(氢氯噻嗪)。本研究的分析结果支持在药物发现过程的早期战略性地使用麻醉狗模型来进行全面的心血管评估,以便很好地转化到人体。
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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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