Article ID Journal Published Year Pages File Type
2549118 Journal of Pharmacological and Toxicological Methods 2014 8 Pages PDF
Abstract

IntroductionThe absence of drug-induced changes in heart rate (HR), aortic pressure (AOP) and ECG, the minimum endpoints suggested in ICH S7A, does not necessarily indicate the absence of cardiovascular (CV) pharmacodynamic activity. This potential pitfall can be avoided by prospectively incorporating “follow-up” endpoints in initial evaluations made possible by the advent of new telemetry implants capable of also measuring changes in cardiac output (CO) and left ventricular pressure (LVP). The purpose of this study was (1) to evaluate the sensitivity of a new, fully implantable telemetry device, and (2) to highlight the importance of the device to simultaneously measure cardiac output and left ventricular pressure in order to adequately evaluate the full potential for a drug to impact global cardiovascular function.Methods4 dogs were instrumented with Konigsberg Instruments, Inc. (KI) TU7/T27H series fully implantable telemetry device and recovered for > 8 weeks. Sotalol (8 mg/kg), milrinone (0.2 mg/kg), hydralazine (0.2 mg/kg) and control were administered 1 week apart. Data were collected for 1 h pre- and 24 h post-treatment and time-averaged to fully characterize the a priori pharmacodynamic effects of interest for each drug. This included PR and QTci (sotalol); HR, AOP and LVP (milrinone); HR, AOP, CO and systemic vascular resistance (SVR) (hydralazine).ResultsExpected changes in CV parameters were observed following all drugs with the following detection sensitivities: PR and QTci of 4 ms and 3 ms, respectively (sotalol); AOP and LVP dP/dt +max of 5 mm Hg and 232 mm Hg/s, respectively (milrinone); HR, CO and SVR of 11 bpm, 0.302 l/min and 5 mm Hg ∗ min/l, respectively (hydralazine).DiscussionKI TU7/T27H implant detects drug-induced CV changes with statistical significance using a standard, four-subject design. The ability of the TU7/T27H to also measure CO and LVP allowed for full characterization of the CV impact of hydralazine and milrinone, which could have been misinterpreted/missed altogether if these drugs were novel and the endpoints evaluated were prospectively limited to the minimum suggested in ICH S7A.

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