当前位置： SCI文献检索 > JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS期刊下所有文献 > The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model.

The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model.

Abstract：

INTRODUCTION:In recent years, the anesthetized guinea pig has been used increasingly to evaluate the cardiovascular effects of drug-candidate molecules during lead optimization prior to conducting longer, more resource intensive safety pharmacology and toxicology studies. The aim of these studies was to evaluate the correlations between pharmacologically-induced ECG changes in the anesthetized cardiovascular guinea pig (CVGP) with ECG changes in conscious non-rodent telemetry models, human clinical studies and effects on key cardiac ion channels. METHODS:We compared the effects of 38 agents on ion channel inhibition to their ECG effects in the CVGP. 26 of these agents were also evaluated in non-rodent telemetry and compared to the results in the CVGP. RESULTS:The CVGP was highly sensitive for detecting QTc, PR and QRS interval prolongation mediated by inhibition of hERG, hCav1.2 and hNav1.5, respectively. There were robust correlations between ion channel inhibitory potencies and the free plasma concentrations (Cu) producing prolongation of the QTc, PR or QRS interval. Further evaluation showed that ECG changes in the CVGP were predictive of their effects on the QTc, PR and QRS intervals in non-rodent telemetry models with 92%, 92% and 100% accuracy, respectively. The CVGP proved to be 100% specific and 88%, 75% and 100% sensitive for QTc, PR and QRS interval prolongation, respectively. Similarly, the Cu that prolonged the QTc, PR and QRS in CVGP and humans correlated well. DISCUSSION:The CVGP is a sensitive model for assessing QTc, PR and QRS prolongation elicited by effects on hERG, hCav1.2 and hNav1.5, respectively. ECG changes in the CVGP are predictive of changes in non-rodent telemetry models and in humans (QTc). ECG parameters can be reliably evaluated with the CVGP model which increases the efficiency of CV derisking. Importantly, the design and implementation of this model is consistent with the "3Rs" for animal research.

journal_name

J Pharmacol Toxicol Methods

journal_title

Journal of pharmacological and toxicological methods

authors

Morissette P,Nishida M,Trepakova E,Imredy J,Lagrutta A,Chaves A,Hoagland K,Hoe CM,Zrada MM,Travis JJ,Zingaro GJ,Gerenser P,Friedrichs G,Salata JJ

doi

10.1016/j.vascn.2013.04.010

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

137-49

issue

eissn

1056-8719

issn

1873-488X

pii

S1056-8719(13)00250-5

journal_volume

pub_type

杂志文章

在线工具

The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model.