Karen Philp

Greater antiarrhythmic activity of acute 17β-estradiol in female than male anaesthetized rats: correlation with Ca2+ channel blockade

Female sex hormones may protect pre‐menopausal women from sudden cardiac death. We therefore investigated the effects of the main female sex hormone, 17β‐estradiol, on ischaemia‐induced cardiac arrhythmias and on the L‐type Ca2+ current (ICaL).

The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt(max) and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration-effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal.

Optimising conditions for studying the acute effects of drugs on indices of cardiac contractility and on haemodynamics in anaesthetized guinea pigs.

INTRODUCTION Detecting adverse effects of drugs on cardiac contractility is becoming a priority in pre-clinical safety pharmacology. The aim of this work was to optimise conditions and explore the potential of using the anaesthetized guinea pig as an in vivo model. METHODS Guinea pigs were anaesthetized with Hypnorm/Hypnovel, isoflurane, pentobarbital or fentanyl/pentobarbital. The electrocardiogram (ECG), heart rate, arterial blood pressure and indices of cardiac contractility were recorded. In further experiments in fentanyl/pentobarbital anaesthetized guinea pigs the influence of bilateral versus unilateral carotid artery occlusion on haemodynamic responses was investigated and the effects of inotropic drugs on left ventricular (LV) dP/dt(max) and the QA interval were determined. RESULTS Pentobarbital, given alone or after fentanyl, provided suitable anaesthesia for these experiments. Bilateral carotid artery occlusion did not alter heart rate or arterial blood pressure responses to isoprenaline or angiotensin II. Isoprenaline and ouabain increased LVdP/dt(max) and decreased the QA interval whereas verapamil had opposite effects and strong inverse correlations between LVdP/dt(max) and the QA interval were found. DISCUSSION Conditions can be optimised to allow the pentobarbital-anaesthetized guinea pig to be used for simultaneous measurement of the effects of drugs on the ECG, haemodynamics and indices of cardiac contractility. The use of this small animal model in early pre-clinical safety pharmacology should contribute to improvements in detecting unwanted actions on the heart during the drug development process.

Biomarkers for safety and toxicology: Drug induced cardiac injury and dysfunction

Abstract Cancer chemotherapeutic drugs, by their very nature of targeting robust and often rapidly dividing cells, inherently carry more toxicological burden and risk than drugs aimed at treating more benign disease. However, clinical oncologists have a continual need to utilise every therapeutic tool in their armoury in their attempts to treat this debilitating and often fatal disease. It is important that the physician has suitable biomarkers not only for efficacy, but also for drug related toxicity, in order to exploit maximally what is often a narrow therapeutic margin between benefit and unacceptable toxicity. Here we present data on a novel anticancer agent intended for combination therapy. The drug caused impaired cardiac functionality in pre- clinical studies at high doses, potentially leading to restrictive exclusion criteria in early clinical trials. To assist in clinical development, we generated biomarker data to be used in a weight of evidence approach to increase confidence in safe clinical progression.