Abstract：
AIMS: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(-). MAIN 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. KEY FINDINGS: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. SIGNIFICANCE: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.
journal_name
Life Scijournal_title
Life sciencesauthors
Kato R,Watanabe R,Miki H,Ijiri Y,Hayashi T,Tanaka Kdoi
10.1016/j.lfs.2009.10.002subject
Has Abstractpub_date
2009-11-18 00:00:00pages
737-41issue
21-22eissn
0024-3205issn
1879-0631pii
S0024-3205(09)00418-4journal_volume
85pub_type
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