All Souls College, Oxford
 

 

 


 

 

 




 


Aim

The primary aim of the company is identification of potential toxic actions of drugs on the heart. In addition the company is happy to assist in any aspect of drug development that requires experiments on cardiac tissue or on cell lines expressing cardiac proteins.

Regulatory considerations

It is now recommended that all new drugs should be subjected to pre-clinical tests (both in vitro and in vivo) to screen for potential harmful effects on cardiac repolarisation.

Background

Any Drug that prolongs cardiac repolarisation (associated with prolongation of the QT interval on the electrocardiogram) is potentially harmful, as this prolongation may induce a potentially fatal arrhythmia, known as torsades de pointes (TdP).  Although effects on cardiac repolarisation were first detected in drugs designed to act on the heart, it is becoming increasingly apparent that a wide range of compounds designed to act elsewhere in the body (such as antimicrobials, antihistamines, CNS drugs and drugs designed to act on the gastrointestinal system) may nevertheless adversely affect electrical activity in the heart. A particular concern for the pharmaceutical industry is that over the past few years a number of compounds have either been withdrawn from the market (e.g. prenylamine, terodiline, sertindole, astemizole and in some countries terfenadine and cisapride) or have had their sale restricted (e.g. cisapride, terfenadine and halofantrine).

Detecting drug-induced effects on cardiac repolarisation

Drug effects on the action potential configuration

Prolongation of the QT interval and subsequent increased risk of arrhythmia is caused by the prolongation of the action potential duration (APD).  OCP acurately determines the effect of your compound on the profile of the action potential recorded in single ventricular myocytes or in isolated Purkinje fibres.  Recordings will be made using conventional electrophysiological techniques using the most up-to-date hardware and software.  Measurements that are made include resting potential, up-stroke velocity, action potential amplitude, action potential duration at 50% (APD50) and 90% (APD90) repolarisation levels.  The effect of the compound on any of these parameters provides further information about the mechanism of action of the compound.

Repolarisation Assays

Drug effects on the delayed rectifier IKr

The delayed rectifier potassium currents (particularly IKr) are the primary determinants of ventricular repolarisation in ventricular myocytes and almost all drugs that have been shown to prolong QT interval include inhibition of IKr as one of their properties. OCP will determine the effects of your compound on delayed rectifier potassium currents  IKr and IKs or total current).  These currents will be recorded from native cells (ventricular myocytes) with conventional high resistance microelectrodes using the discontinuous-single-electrode voltage clamp technique or with the whole-cell patch-clamp technique.

Ion Channel Assays

 

Drug effects on hERG channel currents

In addition to the above experiments on native cardiac myocytes, OCP will also investigate actions of your compound on cell lines expressing cloned cardiac ion channels. In particular, potential drug action will be investigated on currents recorded under voltage-clamp conditions in HEK cells expressing hERG channels.

An individual service

All protocols have been carefully designed and validated by the Study Director and scientists at OCP.  However, we encourage a personalised approach to each study and in close consultation with all clients we at OCP will design the best experimental approach tailored to the client's individual needs.

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