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Titolo:
Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients
Autore:
Graff, DW; Williamson, KM; Pieper, JA; Carson, SW; Adams, KF; Cascio, WE; Patterson, JH;
Indirizzi:
Univ N Carolina, Sch Pharm, Div Pharmacotherapy, Chapel Hill, NC 27599 USAUniv N Carolina Chapel Hill NC USA 27599 erapy, Chapel Hill, NC 27599 USA Univ N Carolina, Sch Med, Div Cardiol, Chapel Hill, NC 27599 USA Univ N Carolina Chapel Hill NC USA 27599 rdiol, Chapel Hill, NC 27599 USA
Titolo Testata:
JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 1, volume: 41, anno: 2001,
pagine: 97 - 106
SICI:
0091-2700(200101)41:1<97:EOFOCP>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE MYOCARDIAL-INFARCTION; RATE-VARIABILITY; DEPRESSED-PATIENTS; BETA-BLOCKADE; MORTALITY; NORFLUOXETINE; METAANALYSIS; ENANTIOMERS; DISPOSITION; METABOLITES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Patterson, JH Univ N Carolina, Sch Pharm, Div Pharmacotherapy, CB 7360 Beard Hall, Chapel Hill, NC 27599 USA Univ N Carolina CB 7360 Beard Hall Chapel Hill NC USA 27599
Citazione:
D.W. Graff et al., "Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients", J CLIN PHAR, 41(1), 2001, pp. 97-106

Abstract

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo wasadministered in a randomized, double-blind, two-period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid andgiven fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12-hour carvedilol dosing interval, and the concentrations of the R() and S(-) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes inautonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resultedin a 77% increase in mean (+/-SD) R(+) enantiomer AUC(0-12) (522 +/- 413 vs. 927 +/- 506 ng.h/mL, p = 0.01) and a nonsignificant increase in S(-) enantiomer AUC (244 +/- 185 vs. 330 +/- 179 ng.h/ml, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetineadministration (R(+): 10.3 +/- 7.2 vs. 4.5 +/- 2.2 mL/min/kg; S(-): 22.5 +/- 12.3 vs. 12.6 +/- 7.4 mL/min/kg; p 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in astereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(-) enantiomer. However, this interaction was of little clinical significance in our sample population. Journal of Clinical Pharmacology, 2001;41:97-106 (C) 2001 the American College of Clinical Pharmacology.

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Documento generato il 25/01/20 alle ore 19:12:06