Koshman Yevgeniya E, Herzberg Brett R, Seifert Terese R, Polakowski James S, Mittelstadt Scott W
AbbVie, North Chicago, IL 60064, United States.
AbbVie, North Chicago, IL 60064, United States.
J Pharmacol Toxicol Methods. 2018 May-Jun;91:27-35. doi: 10.1016/j.vascn.2018.01.002. Epub 2018 Jan 9.
The goal of this study was to determine whether assessment of myocardial contractility and hemodynamics in an anesthetized dog model, could consistently detect drug-induced changes in the inotropic state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility.
Derived parameters included: diastolic, systolic and mean arterial BP, peak systolic LVP, HR, end-diastolic LVP, and LVdP/dt as the primary contractility index.
These results demonstrate that statistically significant increases (amrinone and pimobendan) and decreases (atenolol and itraconazole) in left ventricular dP/dt were observed at clinically relevant exposures.
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 that can include left ventricular dP/dt with good translation to human.
本研究的目的是确定在麻醉犬模型中评估心肌收缩力和血流动力学，是否能够使用已知对心肌收缩力具有临床相关正性和负性作用的药物，一致地检测出药物引起的心脏变力状态变化。
导出参数包括：舒张压、收缩压和平均动脉压、收缩期峰值左心室压、心率、舒张末期左心室压，以及作为主要收缩力指标的左心室dp/dt。
这些结果表明，在临床相关暴露水平下，观察到左心室dp/dt有统计学显著升高（氨力农和匹莫苯丹）和降低（阿替洛尔和伊曲康唑）。
本研究的分析支持在药物发现过程早期战略性地使用麻醉犬模型进行全面的心血管评估，其中可包括左心室dp/dt，且与人类情况有良好的相关性。
