Effects of the antihypoxic and neuroprotective drug, lubeluzole, on repolarization phase of canine heart assessed by monophasic action potential recording.
The cardiovascular effects of the antihypoxic and neuroprotective drug, lubeluzole, were investigated using beagle dogs anesthetized with halothane. Endocardial-contact electrode catheter was used for continuous monitoring of monophasic action potential (MAP), which could provide a precise information of repolarization phase. Intravenous administration of an efficacious dose of lubeluzole (0.63 mg/kg, n = 6) slightly decreased both the heart rate and the blood pressure. It did not change PQ interval and QRS width, while it significantly prolonged QT interval, corrected QT (QTc) and the duration of the MAP during the observation period over 60 min. The effects of drug on repolarization phase were late-onset and long-lasting compared with the time course of plasma drug concentrations, which changed as predicted by the two-compartment theory of pharmacokinetics. Additional injection of lubeluzole (2.5 mg/kg, n = 6) showed qualitatively similar changes to those of lower dose, and did not induce the cardiovascular collapse in any dog. Neither afterdepolarization nor ventricular escaped beat was detected during the observation period. The drug concentration in cardiac tissue was correlated linearly with the plasma drug concentration at 60 min after the second drug administration. These results indicate that lubeluzole exerts only minor cardiovascular effects except the prolongation of the repolarization period. The monitoring of plasma drug concentration may be helpful to estimate the steady-state distribution of drug to the heart, but less helpful to predict the QT prolongation. In future clinical trials, care must be taken with patients, especially those at risk to have prolonged repolarization.
Sugiyama
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A
Department of Pharmacology, Yamanashi Medical University Tamaho-cho, Japan.
Ni
C
C
Arita
J
J
Eto
K
K
Xue
Y X
YX
Hashimoto
K
K
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006328:Cardiac Catheterization; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008839:Microelectrodes; D009206:Myocardium / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D002317:Cardiovascular Agents; D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; C097722:lubeluzole