title: Famotidine does not induce long QT syndrome: experimental evidence from in vitro and in vivo test systems.
abstract: The effects of famotidine on the cardiac repolarization process were assessed using four different levels of test systems described in the draft stage guideline ICH S7B. A supratherapeutic concentration of famotidine (10(-5) M), which is >8 times higher than C(max) obtained after its therapeutic dose, neither inhibited human ether-a-go-go-related gene (HERG) K(+) current expressed in human embryonic kidney 293 (HEK293) cells nor affected any of the action potential parameters of guinea pig papillary muscles. Therapeutic (0.3 mg/kg, i.v.) to supratherapeutic doses (3-10 mg/kg, i.v.) of famotidine did not affect the repolarization process of the halothane-anesthetized canine model, while only supratherapeutic doses exerted the positive chronotropic, inotropic and dromotropic effects without affecting the mean blood pressure. Moreover, supratherapeutic doses of famotidine (1-10 mg/kg, i.v.) neither induced torsades de pointes nor prolonged QT interval in the canine chronic atrioventricular conduction block model. These results suggest that famotidine possesses no cardiovascular effects at a therapeutic dose, while it may exert cardiostimulatory actions after drug overdoses that might potentiate the proarrhythmic potential of co-administered cardiotonic agents by increasing the intracellular Ca(2+) concentration.
authors.affiliation: Department of Pharmacology, University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan. atsushis@res.yamanashi-med.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Yoshioki
authors.initials: Y
authors.lastname: Satoh
authors.forename: Akira
authors.initials: A
authors.lastname: Takahara
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Masao
authors.initials: M
authors.lastname: Shimizu-Sasamata
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyata
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D015738:Famotidine / Q000009:adverse effects*; D006168:Guinea Pigs; D006327:Heart Block / Q000139:chemically induced / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000009:adverse effects*; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D015738:Famotidine; D016593:Terfenadine; C063533:dofetilide