Left ventricular pressure, contractility and dP/dt(max) in nonclinical drug safety assessment studies.

Increasing or decreasing cardiac contractility is an undesirable property of drugs being developed for noncardiovascular indications. The International Conference on Harmonization (ICH) Topic S7A and S7B guidelines only require the assessment of heart rate, blood pressure and the electrocardiogram in nonclinical in vivo safety pharmacology studies. Assessment of drug effects on contractility is only suggested as an optional follow-up study.

A comparison of mortality and cardiac biomarker response between three outbred stocks of Sprague Dawley rats treated with isoproterenol.

The authors compared the mortality and cardiac biomarker responses in three outbred stocks of Sprague Dawley rats (CD/IGS, Sasco, Harlan) treated with isoproterenol hydrochloride. Cardiac injury was confirmed by histologic evaluation, and increases in cardiac troponin I concentration in serum were measured by two methods. CD/IGS rats had a higher incidence and earlier mortality compared with Sasco or Harlan rats.

Heartbeat dynamics in adrenergic blocker treated conscious beagle dogs.

Introduction: Adrenergic blockade as a treatment for chronic heart failure (CHF) has proved effective, but its pharmacological mechanism on CHF remains unclear. In the past two decades, studies on heart rate variability (HRV) have reported that CHF patients generally have a reduced temporal complexity in heart rate variability. On the other hand, adrenergic blockers have been shown to restore such complexity.

Statistical power analysis for hemodynamic cardiovascular safety pharmacology studies in beagle dogs.

Introduction: We studied the statistical power of a replicated Latin square design where eight animals each receive a vehicle control and three dose levels of a drug on four separate dosing days. Cardiovascular parameters evaluated in the study were systolic arterial pressure, diastolic arterial pressure, left ventricular heart rate, and dP/dt(max).

Methods: Observations were simulated based on historical data and drug response profiles from cardiovascular safety pharmacology studies conducted at Lilly Research Laboratories.