The Characterization and Development of Electrophysiological Pharmacology Assays Testing for Potential QT Prolongation
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Authors
Boyle-Holmes, Yvonne
Issue Date
2005
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
A number of drugs with cardiac and non-cardiac targets have been implicated in
cases of "torsades de pointes" (T dP), a potentially fatal arrhythmia. One of the factors in
the development of this anomaly is a disruption of the heart's action potential, referred to
as QT prolongation. Assays have been developed to anticipate whether a novel
compound will pose a risk for T dP, but all contain drawbacks. These shortcomings lead
a drive for new, improved assays. This study examined the temperature-dependent
properties of an existing assay, the hERG assay, which tests a compound's inhibition on a particular type of potassium channel that is prone to drug block. A three-fold increase in the inhibition level between room and physiological temperature was found, indicating a more efficacious inhibition at higher temperatures. Other possible avenues for ion channel safety assays were also examined, including the use of primary isolated
myocytes to measure effects of multi-channel block and a smooth muscle cell line (A 10)
to examine a compound's potential for calcium channel block. The A I0 cells'
measurable calcium currents and response to known calcium channel blockers do indicate potential for the development of a calcium channel assay. These results indicate that a vast area of expansion exists within the field of ion channel inhibition testing that could serve to improve the pharmacological analysis of novel compounds
Description
vi, 39 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.