Abstract：
BACKGROUND AND PURPOSE:QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A negative electro-mechanical (E-M) window has recently been proposed as an alternative risk marker for TdP in a canine LQT1 model. Here, we evaluated the E-M window in anaesthetized guinea pigs as a screening marker for TdP in humans. EXPERIMENTAL APPROACH:The effects of various reference drugs and changes in body temperature on the E-M window were assessed in instrumented guinea pigs. The E-M window was defined as the delay between the duration of the electrical (QT interval) and mechanical (QLVP(end) ) systole. KEY RESULTS:Drugs with known TdP liability (quinidine, haloperidol, domperidone, terfenadine, thioridazine and dofetilide), but not those with no TdP risk in humans (salbutamol and diltiazem) consistently decreased the E-M window. Interestingly, drugs with known clinical QT prolongation, but with low risk for TdP (amiodarone, moxifloxacin and ciprofloxacin) did not decrease the E-M window. Furthermore, the E-M window was minimally affected by changes in heart rate or body temperature. CONCLUSIONS AND IMPLICATIONS:A decreased E-M window was consistently observed with drugs already known to have high TdP risk, but not with drugs with low or no TdP risk. These results suggest that the E-M window in anaesthetized guinea pigs is a risk marker for TdP in humans.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Guns PJ,Johnson DM,Van Op den Bosch J,Weltens E,Lissens Jdoi
10.1111/j.1476-5381.2011.01795.xsubject
Has Abstractpub_date
2012-05-01 00:00:00pages
689-701issue
2eissn
0007-1188issn
1476-5381journal_volume
166pub_type
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journal_title：British journal of pharmacology
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doi：
更新日期：1979-05-01 00:00:00
