title: Effects of tedisamil, atenolol and their combination on heart and rate-dependent QT interval in healthy volunteers.
abstract: OBJECTIVE
  Tedisamil is a new blocker of K+ currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a beta-adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests.
  
  
  METHODS
  The effects of tedisamil (100 mg twice daily) and atenolol (50 mg twice daily) on heart rate and QT interval duration were analysed in a three-period crossover study in healthy male volunteers.
  
  
  RESULTS
  This study showed that tedisamil exerted a significant (P<0.05) bradycardic action at rest (-10 beats min(-1); 95% CI: -6 to -15 beats min(-1)) similar to atenolol (-14 beats min(-1); -11 to -17) and drug combination (-9 beats min(-1); -6 to -12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (-42 beats min(-1); -37 to -47) and combination (-47 beats min(-1); -41 to 52). Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000 ms, but not at RR<700 ms (combination). Tedisamil alone and in combination induced a reverse rate-dependent QT interval prolongation.
  
  
  CONCLUSIONS
  These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.
authors.affiliation: Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Démolis
authors.forename: C
authors.initials: C
authors.lastname: Martel
authors.forename: C
authors.initials: C
authors.lastname: Funck-Brentano
authors.forename: A
authors.initials: A
authors.lastname: Sachse
authors.forename: H J
authors.initials: HJ
authors.lastname: Weimann
authors.forename: P
authors.initials: P
authors.lastname: Jaillon
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001262:Atenolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003521:Cyclopropanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003967:Diarrhea / Q000139:chemically induced; D004338:Drug Combinations; D004562:Electrocardiography / Q000187:drug effects*; D005080:Exercise Test; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate
chemical_list: D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D004338:Drug Combinations; D001262:Atenolol; C059921:tedisamil