The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk

Guns, P-J.; Johnson, D.M.; Van Op den bosch, J.; Weltens, E. and Lissens, J. (2012). The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk. British Journal of Pharmacology, 166(2) pp. 689–701.

DOI: https://doi.org/10.1111/j.1476-5381.2011.01795.x

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.

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About

• Item ORO ID
• 68857
• Item Type
• Journal Item
• ISSN
• 0007-1188
• Keywords
• guinea pig; electro‐mechanical window; E‐M window; QT interval; Torsade de Pointes; TdP proarrhythmia; drug induced QT prolongation; ICH S7B; anaesthetized safety pharmacology
• Academic Unit or School
• Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
  Faculty of Science, Technology, Engineering and Mathematics (STEM)
• Copyright Holders
• © 2011 The British Pharmacological Society, © 2011 Bio‐Plus Services. British Journal of Pharmacology
• Depositing User
• Daniel Johnson