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Titolo:
The antitussive effect of dextromethorphan in relation to CYP2D6 activity
Autore:
Manap, RA; Wright, CE; Gregory, A; Rostami-Hodjegan, A; Meller, ST; Kelm, GR; Lennard, MS; Tucker, GT; Morice, AH;
Indirizzi:
Univ Sheffield, No Gen Hosp, Div Clin Sci, Sheffield S5 7AU, S Yorkshire, England Univ Sheffield Sheffield S Yorkshire England S5 7AU S Yorkshire, England Univ Sheffield, Royal Hallamshire Hosp, Div Clin Sci, Sect Mol Pharmacol &Pharmacogenet, Sheffield S10 2JF, S Yorkshire, England Univ Sheffield Sheffield S Yorkshire England S10 2JF S Yorkshire, England Procter & Gamble Co, OTC HCTD, Mason, OH 45040 USA Procter & Gamble Co Mason OH USA 45040 Co, OTC HCTD, Mason, OH 45040 USA
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 3, volume: 48, anno: 1999,
pagine: 382 - 387
SICI:
0306-5251(199909)48:3<382:TAEODI>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
SPARTEINE OXIDATION; 3 METABOLITES; INDUCED COUGH; QUINIDINE; CHROMATOGRAPHY; CODEINE; PLASMA; HUMANS;
Keywords:
antitussive effect; CYP2D6; dextromethorphan; genetic polymorphism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
25
Recensione:
Indirizzi per estratti:
Indirizzo: Morice, AH Univ Hull, Castle Hill Hosp, Dept Med, Castle Rd, Cottingham HU16 5JQ, E Yorks, England Univ Hull Castle Rd Cottingham E Yorks England HU16 5JQ England
Citazione:
R.A. Manap et al., "The antitussive effect of dextromethorphan in relation to CYP2D6 activity", BR J CL PH, 48(3), 1999, pp. 382-387

Abstract

Aims To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and atintervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results Inhibition of CYP2D6 by quinidine caused a significant increase inthe mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P<0.001). The mean (+/-s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) forplace bo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P<0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P<0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX30 (P=0.071, -7, +241; P=0.254, -37, +211; P=0.187, -29, +219, respectively). Conclusions A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 06:34:49