Does the sedative agent, JM-1232(-) cause QT prolongation with subsequent torsades de pointes?
OBJECTIVE
JM-1232(-) ((-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f] isoindole-1(2H)-one) is a novel isoindoline compound that acts on benzodiazepine receptors. Clinical trials are being conducted to assess its potential clinical use as an intravenous anesthetic or sedative agent. In the present study, we investigated the possibility of QT prolongation caused by JM-1232(-).


METHODS
We examined telemetry electrocardiogram (ECG) recordings from unrestrained guinea pigs after intravenous administration of 1, 10, 25 or 50mg/kg of JM-1232(-). We also examined in situ measurements of monophasic action potential duration at 30 and 90% of repolarization (MAP(30) and MAP(90), respectively) and MAP triangulation (MAP(90-30)) from guinea pig hearts that were perfused on a Langendorff apparatus with 0, 0.1, 1, 5, 10 and 20 microg/ml of JM-1232(-). The telemetry ECG recordings showed QTc prolongation 20 min after administration of JM-1232(-) at 50mg/kg.


RESULTS
In Langendorff-perfused hearts, MAP(30), which indicates Ca(2+) current, was significantly shortened after perfusion with JM-1232(-) at 10 and 20 microg/ml. MAP(90), which indicates K(+) current, was significantly prolonged after perfusion with JM-1232(-) at 20 microg/ml; therefore, this prolongation was attributed to a decreased heart rate. MAP triangulation (MAP(90-30)) was significantly prolonged after perfusion with JM-1232(-) at 5, 10 and 20 microg/ml; however, this prolongation was attributed to the shortened MAP(30), suggesting a possible inhibition of Ca(2+) influx.


CONCLUSIONS
High-dose (more than 50 times the hypnotic dose) JM-1232(-) treatment associated with a high plasma concentration of the drug is unlikely to cause QT prolongation with subsequent torsades de pointes.
Kato
Ryuji
R
Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takastuki, Osaka 569-1094, Japan.
Watanabe
Rei
R
Miki
Haruna
H
Ijiri
Yoshio
Y
Hayashi
Tetsuya
T
Tanaka
Kazuhiko
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000494:pharmacology*; D054833:Isoindoles / Q000009:adverse effects / Q000494:pharmacology*; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced*
C534223:3-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta(f)isoindol-1(2H)-one; D006993:Hypnotics and Sedatives; D054833:Isoindoles; D010879:Piperazines