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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years a number of compounds have either been withdrawn from the market (e.g. prenylamine,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.
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Repolarisation Assays
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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.
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Ion Channel Assays
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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.
To download the OCP Ltd advert click on
OCP advert.pdf
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