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首页> 外文期刊>British Journal of Clinical Pharmacology >Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system.
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Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system.

机译：评估血管紧张素激发方法，以评估作用于肾素-血管紧张素系统的降压药的药效学特征。

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AIMS: The performance of the experimental paradigm of angiotensin challenges with continuous non-invasive blood pressure measurement was evaluated. Angiotensin dose-response relationships were characterized, along with the influence of clinical covariates. The stability of angiotensin-induced peaks and the variability of the angiotensin doses were assessed. Finally, the predictive value of studies based on angiotensin challenges to determine drug doses effective in therapeutics was evaluated. METHODS: The data were gathered from 13 clinical studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one dual ACE-NEP inhibitor, using Finapres for measuring the response to exogenous angiotensin challenges. Modelling of angiotensin dose-response curves and determination of the inter and intrasubject variability were performed by nonlinear regression (NONMEM). The different sources of variations in angiotensin I and II doses and angiotensin-induced peaks were evaluated by analyses of variance. The dose of ACE inhibitors and angiotensin II receptor antagonists inhibiting blood pressure increase by at least 75%, as measured by this method, was chosen for comparison with the labelled starting dose. RESULTS: Angiotensin challenges exhibited a clear dose-response relationship which can be characterized both by an Emax or a log linear model. The log linear model gave an average systolic/diastolic response of 24+/-6/20+/-5 mmHg for a unit dose of 1 microgram of angiotensin II equivalents, and an increase of 6/6 mmHg for each doubling of the dose. The angiotensin ED50 calculated values were 0.67 microgram for systolic and 0.84 microgram for diastolic blood pressure. The angiotensin doses for eliciting a given response and the angiotensin induced peaks were fairly constant between period and subject, but vary significantly between studies. Based on an inhibition of blood pressure by 75%, the agreement was good between the doses of ACE inhibitors and angiotensin receptor antagonists predicted from studies using the methodology of angiotensin challenges and the doses shown to be clinically efficacious, in spite of high intersubject and intrasubject variabilities. CONCLUSIONS: This experimental method represents a valid surrogate for the therapeutic target and a useful tool for the pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin-angiotensin system.
机译：目的：评估了连续无创血压测量的血管紧张素挑战实验范式的性能。表征血管紧张素的剂量反应关系，以及临床协变量的影响。评估了血管紧张素诱导的峰的稳定性和血管紧张素剂量的变异性。最后，评估了基于血管紧张素激发试验确定治疗中有效药物剂量的研究的预测价值。方法：数据收集自13种临床研究，涉及9种血管紧张素II受体拮抗剂，1种ACE抑制剂和1种双重ACE-NEP抑制剂，使用Finapres来测量对外源性血管紧张素激发的反应。通过非线性回归（NONMEM）进行血管紧张素剂量反应曲线的建模以及受试者之间和受试者内部的变异性的确定。通过方差分析评估了血管紧张素I和II剂量变化的不同来源以及血管紧张素诱导的峰。选择通过该方法测得的抑制血压升高至少75％的ACE抑制剂和血管紧张素II受体拮抗剂的剂量与标记的起始剂量进行比较。结果：血管紧张素激发表现出明显的剂量反应关系，可以通过Emax或对数线性模型来表征。对数线性模型对单位剂量1微克血管紧张素II当量的平均收缩压/舒张压响应为24 +/- 6/20 +/- 5 mmHg，每增加一倍剂量，平均收缩/舒张反应增加6/6 mmHg 。血管紧张素ED50的计算值对于收缩压为0.67微克，对于舒张压为0.84微克。在期间和受试者之间，用于引起给定反应的血管紧张素剂量和血管紧张素诱导的峰是相当恒定的，但是在研究之间差异很大。基于75％的血压抑制作用，尽管受试者之间和受试者之间的高度参与，但使用血管紧张素激发方法进行的研究预测的ACE抑制剂和血管紧张素受体拮抗剂的剂量之间的一致性很好，并且显示出临床上有效的剂量变异性。结论：该实验方法代表了治疗靶点的有效替代物，并且是作用于肾素-血管紧张素系统的药物的药代动力学和药效动力学分析的有用工具。

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