title: α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs.
abstract: Clinical use of arsenic trioxide (As₂O₃), which can induce the remission of relapsed or refractory acute promyelocytic leukemia, is often limited because of its cardiotoxicity. Symptoms of cardiotoxicity include acute cardiac conduction disturbances, such as QT prolongation. The present study was undertaken to evaluate the effects of α-lipoic acid (LA) on acute As₂O₃-induced ECG abnormalities (QTc interval prolongation) in anesthetized guinea pigs. Intravenous injection of As₂O₃ in guinea pigs caused QTc interval prolongation, which was significantly attenuated by co-treatment with LA (0.35, 3.5 and 35 mg/kg) in a dose-dependent manner. In isolated guinea pig cardiomyocytes, the decrease in IKs current induced by As₂O3 (1 μM) was rapidly restored to the basal level by the addition of LA (10 μM). Consistent with this finding, the As₂O₃-induced QTc interval prolongation was also improved rapidly by post-treatment with LA in guinea pigs. Electrospray ionization time-of-flight mass spectrometry analysis detected an expected peak of arsenic-LA complex in vitro, indicating that LA and As₂O3 form a new compound in vivo. In addition, pre-treatment with a chelating agent, British anti-Lewisite (BAL, 3.5 or 35 mg/kg), also attenuated the As₂O₃-induced QTc interval prolongation. In this study, co- and post-treatments with LA and pre-treatment with BAL ameliorated As₂O₃-induced acute QT prolongation in anesthetized guinea pigs. Because LA and probably BAL may bind to As₂O₃, these agents may exert protective effects through their chelating activity. Further studies are needed to determine whether LA is beneficial as a prophylactic or rescue agent for acute promyelocytic leukemia patients treated with As₂O₃.
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kumazaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Kentarou
authors.initials: K
authors.lastname: Ushijima
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.forename: Shiho
authors.initials: S
authors.lastname: Yamato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Washino
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Koshimizu
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
mesh_terms: D000758:Anesthesia; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology; D006168:Guinea Pigs; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010087:Oxides; D008063:Thioctic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001152:Arsenicals; D002316:Cardiotonic Agents; D051668:Delayed Rectifier Potassium Channels; D010087:Oxides; D008063:Thioctic Acid; D000077237:Arsenic Trioxide