title: The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors: Bio-Plus Safety Pharmacology, Bio-Plus Services, Mol, Belgium. pg@bio-plus.org
authors: P-J
authors: PJ
authors: Guns
authors: D M
authors: DM
authors: Johnson
authors: J
authors: J
authors: Van Op den Bosch
authors: E
authors: E
authors: Weltens
authors: J
authors: J
authors: Lissens
mesh_terms: D000758:Anesthesia; D000818:Animals; D001831:Body Temperature; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D012306:Risk; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology*