title: Direct cardiac effects of As2O3 in rabbits: evidence of reversible chronic toxicity and tissue accumulation of arsenicals after parenteral administration.
abstract: Although parenteral administration of As(2)O(3) is highly effective in the treatment of acute promyelocytic leukemia, cardiac toxicity has been reported. This study employed Langendorff perfusion to determine the direct effects of As(2)O(3) in the electrophysiological properties of rabbit hearts after acute or chronic As(2)O(3) treatment (0.2 mg/kg/day iv for 30 days). Tissue accumulations of arsenicals and pathological changes as well as the reversibility of chronic As(2)O(3) effects were assessed. We found that cardiac conduction and repolarization were not altered whatsoever after acute As(2)O(3) treatment at clinically relevant (1, 3, and 10 microM) and higher (30 microM) doses. Nevertheless, an extremely high concentration of As(2)O(3) (300 microM) prolonged the corrected QT interval. Subsequent to chronic As(2)O(3) administration and with 30 microM As(2)O(3) via Langendorff perfusion, polymorphic ventricular tachycardia was observed (1/7, 14%). Corrected QT interval was prolonged, while basic cycle length was shortened. Significant accumulation of arsenicals in the cardiac tissue was found, but without any pathological changes. After As(2)O(3) was discontinued for 30 days, the chronic As(2)O(3) -induced electrophysiological changes improved, no ventricular arrhythmia was noted, and the tissue concentration of arsenicals decreased considerably. We therefore conclude that, although no immediate cardiac effects were discemable at clinically relevant doses, an extremely high concentration of As(2)O(3) could prolong ventricular repolarization. Chronic As(2)O(3) treatment resulted in a prolonged ventricular repolarization, in association with arsenicals accumulation and with risk of ventricular tachycardia. These chronic cardiac toxicities and the tissue accumulation of arsenicals were, however, partially reversible after cessation of As(2)O(3).
authors.affiliation: Department of Pediatrics, National Waiwan University Hospital and National Taiwan University, College of Medicine, National Taiwan University, Taipei, Taiwan. mhwu@ha.mc.ntu.edu.tw
authors.forename: Mei-Hwan
authors.initials: MH
authors.lastname: Wu
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Lin
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Ming-Jai
authors.initials: MJ
authors.lastname: Su
authors.forename: Selma Siu-Man
authors.initials: SS
authors.lastname: Sun
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000493:pharmacokinetics; D002319:Cardiovascular System / Q000187:drug effects*; D004334:Drug Administration Schedule; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D010087:Oxides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011817:Rabbits; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide