QT
Prolongation
During the last 10 years there
have been several drug limitations or withdrawals secondary
to putative concerns over their proven or suspected
effects on QT prolongation . A manufacturer of a drug
with a known or suspected QT prolongation potential
will have an uphill battle convincing the regulators
that these would not or had not resulted in clinical
manifestations, in particular torsade de pointes or
sudden unexpected deaths.
Delayed ventricular repolarisation
is normally measured by a prolongation of the electrocardiographic
QT interval. Excessive QT prolongation has been associated
with an increased risk of ventricular arrhythmia, including
torsade de pointes, which may result in fatal arrhythmias.
Although there has been considerable interest recently
concerning the potential of certain drugs, in isolation
or as part of a class effect, to promote QT prolongation,
other risk factors prolonging the QT interval include
hypocalcaemia, hypokalaemia, myocardial ischaemia, diabetes,
hypothyroidism, structural heart disease, bradycardia
and congenital long QT interval syndrome.
In the guidelines ICH (INTERNATIONAL CONFERENCE ON
HARMONISATION) S7 A and B, issued by a joint committee
of experts representing the regulatory authorities of
the USA (FDA), the European Union, and Japan, screening
for the potential risk of QT interval prolongation is
necessary to protect patient populations from these
potentially fatal complications which can be induced
by novel pharmaceutical compounds.
It Is now recommended that all novel pharmaceuticals
should be screened for activity against hERG before
first administration to human volunteers.
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hERG
potassium channel
The hERG potassium channel is a
major molecular component of the delayed rectifier K+
current underlying cardiac repolarization. Decreased hERG
function prolongs the QT interval and can lead to the
potentially lethal ventricular arrhythmia Torsades de
pointes (TdP).More than 40 marketed drugs have been associated
with K+ channel block, QT prolongation and TdP. During
the 1990's, products removed from the market due to these
effects resulted in over $1.5 billion lost in annual sales.
If done early, non-clinical safety testing can:
Identify
compounds with potentially lethal toxicity
Save
investment time & cut development costs
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Patch-clamp:
the gold standard
Undoubtedly, the definitive method for studying ion channel
function is that of patch-clamping. The method can detect
signals in the pA range and even measures the current
passing through a single ion channel protein in real time.
The time-resolution is in the tens of microseconds range
and, crucially, patch-clamps allow the experimenter to
fix the membrane potential of the cell (voltage-clamp).
Gold
standard
The
only method for kinetic measurement (activation, inactivation,
gating)
High
sensitivity
Superior
accuracy
Screening methods utilizing fluorescence,
ion efflux and compound binding can underestimate the
potency of blockers, reveal significant numbers of false
positives due to compound-dye interactions, and/or fail
to identify blockers. These assays only measure end point,
no kinetics available. Significant IC50 shifts compared
to patch-clamp recordings.
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