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Titolo:
Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine
Autore:
Khalifa, M; Drolet, B; Daleau, P; Lefez, C; Gilbert, M; Plante, S; OHara, GE; Gleeton, O; Hamelin, BA; Turgeon, J;
Indirizzi:
Univanadal, Fac Pharm, Laval Hosp, Quebec Heart Inst, St Foy, PQ G1K 7P4, C Univ Laval St Foy PQ Canada G1K 7P4 bec Heart Inst, St Foy, PQ G1K 7P4, C Univ Laval, Fac Med, St Foy, PQ G1K 7P4, Canada Univ Laval St Foy PQ Canada G1K 7P4 , Fac Med, St Foy, PQ G1K 7P4, Canada
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 2, volume: 288, anno: 1999,
pagine: 858 - 865
SICI:
0022-3565(199902)288:2<858:BOPCIG>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
TORSADE-DE-POINTES; RECTIFIER K+-CURRENT; LONG QT SYNDROME; DELAYED RECTIFIER; TERFENADINE; ANTIHISTAMINES; ASTEMIZOLE; COMPONENT; INTERVAL; CHANNEL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Turgeon, J Hop Laval, Ctr Rech, 2725 Chemin St Foy, St Foy, PQ G1V 4G5, Canada Hop Laval 2725 Chemin St Foy St Foy PQ Canada G1V 4G5 5, Canada
Citazione:
M. Khalifa et al., "Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine", J PHARM EXP, 288(2), 1999, pp. 858-865

Abstract

Treatment with second generation histamine H1 receptor antagonists has been associated with lengthening of the Q-T interval and proarrhythmia. Similarly, lengthening of the Q-T interval has been reported in patients after overdosing with diphenhydramine (DPH), a first generation agent. Therefore, our study was designed 1) to assess effects of DPH on cardiac repolarizationand 2) to characterize effects of the drug on major voltage-dependent cardiac K+ currents. First, we noticed that oral administration of DPH at usualdosages to healthy volunteers or to patients (prior to angioplasty) was associated with prolongation of the Q-T-c interval. Although this effect was modest in most individuals, Q-T-c was increased more than 20 ms in 7 of 20 patients. Second, we noticed that exposure of isolated guinea pig hearts toDPH 10(-5) M caused a lengthening of monophasic action potential duration. This effect was potentiated by the combined perfusion of other K+ channel blockers such as indapamide. Finally, experiments performed with the patch-clamp technique demonstrated unequivocal block of the rapid component of the delayed rectifier (I-Kr) by DPH; however, IC50 determined for block of I-Kr (3 . 10(-5) M) is similar to 40-fold greater than plasma concentrations of the drug measured at usual dosages (7 . 10(-7) M). Consequently, in agreement with the long-term clinical use of the drug, prolongation of cardiac repolarization should be minimal in most patients at usual dosages but may be observed with overdosing. Nevertheless, caution remains since excessive lengthening of cardiac repolarization may occur after administration of DPHwith other drugs due to 1) concomitant block of other ionic currents or 2)pharmacokinetic interactions leading to toxic concentrations of DPH.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/09/18 alle ore 08:04:32