Comparison of the effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine in canine models of arrhythmia.
The effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine sulfate were evaluated and compared in 24-h infarction, programmed electrical stimulation (PES), and ventricular fibrillation threshold (VFT) canine models of cardiac arrhythmias. In the 24-h infarction model (24 h after myocardial infarction), animals averaged 85% arrhythmic beats before treatment. LNC-834 gave greater suppression of these spontaneous arrhythmias (97%) and had a longer duration of action (150 min) than did quinidine (70% and 85 min, respectively) at 10 mg of base/kg, although plasma levels were comparable (1.82 +/- 0.19 and 1.50 +/- 0.27 micrograms/ml of plasma for LNC-834 and quinidine, respectively). At 10 mg of base/kg, LNC-834 and quinidine increased effective refractory periods by 9 and 7%, respectively. In the PES model, LNC-834 (3 mg of base/kg) suppressed ventricular tachycardia (VT) in 33% (2/6) of the dogs tested: none of the six quinidine-treated animals displayed suppression of VT at cumulative doses of 0.3 to 30 mg of base/kg. In PES dogs, inducible and noninducible, mortality was less with LNC-834 treatment than with quinidine [9% (1/11) and 36% (4/11), respectively]. Neither LNC-834 nor quinidine elevated VFT in naive, anesthetized dogs. Although no treatment significantly affected the intrinsic heart rate in VFT dogs, both LNC-834 and quinidine produced significant hypotension; however, LNC-834 caused less hypotension than did quinidine at equal doses. This study demonstrates that LNC-834 may be a useful antiarrhythmic agent with efficacy comparable to and hemodynamic advantages over quinidine.
D'Alonzo
A J
AJ
Cardiac Department, Norwich Eaton Pharmaceuticals, Inc., Procter and Gamble Company, Norwich, New York 13815.
Butterfield
J L
JL
Drexler
A P
AP
Sergio
S L
SL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced; D008297:Male; D011802:Quinidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; C066172:3-hydroxy-10,11-dihydroquinidine; D011802:Quinidine