RESUMEN
AIMS: To test the influence of frequent concentration peaking, as occurs in multiple-dosing of non-steroidal anti-inflammatory drugs (NSAIDs) with short t (1/2), and duration of therapy of NSAIDs on gastrointestinal permeability. METHODOLOGY: 2.5 mg/(kg 12 h) flurbiprofen was administered as repeated oral and interperitoneal (i.p) doses or as i.p. osmotic pump (once implanted to mimic long t(1/2)) for 7 days to healthy rats. Urinary excretion of (51)Cr-EDTA (days 0, 1, 4 and 7 during all regimens) and sucrose (days 0, 1 and 7 for i.p. doses) were measured as markers of gastroduodenal and intestinal permeability, respectively. RESULTS: Both i.p. regimens elevated (51)Cr-EDTA permeability suggestive of a systemic effect. There was no significant difference between the i.p regimens in (51)Cr-EDTA permeability. The first day (51)Cr-EDTA permeability was significantly higher for the oral than for the i.p. doses suggestive of a topcal effect. The effect became less potent with time despite continuous dosing indicating adaptation for both topical and systemic effects. None of the i.p. regimen altered sucrose permeability. CONCLUSION: NSAID's potency to increase permeability reduces with time despite continuous dosing. Topical effect following oral dosing, and not the frequent peaking differentiates regimens from each other in elevating (51)Cr-EDTA permeability. The repeated dosing rather than the magnitude of t(1/2) may influence the gut safety profile of NSAIDs.
Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Flurbiprofeno/toxicidad , Absorción Intestinal/efectos de los fármacos , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Radioisótopos de Cromo , Esquema de Medicación , Ácido Edético/metabolismo , Flurbiprofeno/administración & dosificación , Flurbiprofeno/farmacocinética , Semivida , Bombas de Infusión Implantables , Infusiones Parenterales , Inyecciones Intraperitoneales , Masculino , Permeabilidad , Ratas , Ratas Sprague-Dawley , Sacarosa/metabolismoRESUMEN
The purpose of this study was to determine whether the pharmacokinetics of warfarin and ciprofloxacin PR (a prolonged-release formulation of ciprofloxacin) were altered after coadministration. Eighteen healthy male volunteers were given a single oral 7.5-mg dose of warfarin, a single oral 500-mg dose of ciprofloxacin PR, or both drugs administered together in a randomized, open-label, 3-way crossover study. Ciprofloxacin concentrations, warfarin (R)- and (S)-enantiomer concentrations, prothrombin time, and activated partial thromboplastin time were measured over 120 hours following study drug administration. There were no significant differences in pharmacokinetic or pharmacodynamic parameters among treatments. A slightly greater value of half-life for (R)-warfarin was observed when coadministered with ciprofloxacin PR compared with warfarin administered alone (52.6 vs 50.1 hours, P = .029). This difference is not considered clinically relevant, because the values remain similar. These results show that warfarin pharmacokinetics and pharmacodynamics are not altered with concomitant administration of ciprofloxacin PR.
Asunto(s)
Antiinfecciosos , Anticoagulantes , Ciprofloxacina , Warfarina , Adolescente , Adulto , Análisis de Varianza , Antiinfecciosos/administración & dosificación , Antiinfecciosos/farmacocinética , Antiinfecciosos/farmacología , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Ciprofloxacina/administración & dosificación , Ciprofloxacina/farmacocinética , Ciprofloxacina/farmacología , Estudios Cruzados , Preparaciones de Acción Retardada , Interacciones Farmacológicas , Semivida , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Estereoisomerismo , Comprimidos , Warfarina/farmacocinética , Warfarina/farmacologíaRESUMEN
Two open-label, randomized, 2-way crossover studies (1 single-dose and 1 steady-state) were conducted in healthy volunteers to compare the pharmacokinetics and pharmacodynamics of a novel extended-release ciprofloxacin (ciprofloxacin ER; 500 mg once daily) and immediate-release ciprofloxacin (ciprofloxacin IR; 250 mg twice daily). For both studies, mean ciprofloxacin maximum concentration (Cmax) values after once-daily ciprofloxacin ER were significantly greater than those after the first daily dose of ciprofloxacin IR (P < .0001) but were lower than those after the second daily dose of ciprofloxacin IR (P < .05). The relative bioavailability of ciprofloxacin ER compared to ciprofloxacin IR was 93.8% in the single-dose study and 97.7% in the steady-state study. Mean urinary ciprofloxacin concentrations and excretion rates after either treatment were substantially greater than the minimum inhibitory concentrations (MICs) for susceptible uropathogens in both studies. The area under the concentration-time curve (AUC)/MIC, Cmax/MIC, amount excreted (Ae)/MIC, and Ae24/MIC ratios with ciprofloxacin ER were similar to or slightly greater than with ciprofloxacin IR for all susceptible organisms.
Asunto(s)
Antiinfecciosos/administración & dosificación , Antiinfecciosos/farmacocinética , Ciprofloxacina/administración & dosificación , Ciprofloxacina/farmacocinética , Adulto , Bacterias/efectos de los fármacos , Estudios Cruzados , Preparaciones de Acción Retardada , Esquema de Medicación , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana EdadRESUMEN
The 5-HT3 receptor antagonist alosetron (Lotronex) is indicated for use in women with severe, chronic, diarrhea-predominant irritable bowel syndrome (IBS) who have failed conventional therapy. Oral contraceptives (OCs) and alosetron are potential co-medications in women of childbearing age. This study assessed the effect of alosetron co-administration on pharmacodynamic markers of contraceptive efficacy, on the pharmacokinetics of estrogen and progesterone OC components, and on the activity of biochemical markers for the risk of thrombosis. This was an open label, nonrandomized two-way crossover study in 18 healthy women stabilized for 3 months on a low-dose OC containing ethinyl estradiol (EE) and levonorgestrel (LN). Alosetron had no effect on serum concentrations of luteinizing hormone (LH) or follicle-stimulating hormone. Ovarian activity grades (assessing follicle size, progesterone, and 17beta-estradiol concentrations) were similar during OC use with and without alosetron. Steady-state (Day 21) AUC24, Cmax, and tmax of both LN and EE were similar during coadministration of alosetron with an OC. Concentrations and activity of biochemical markers of thrombosis risk were not different in the presence of alosetron. These results indicate that alosetron does not alter the pharmacokinetics or pharmacodynamic markers of efficacy for a low-dose combination OC. The results also suggest that thromboembolic risk is not increased when alosetron is co-administered with an OC.