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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans (2000)
    Springer
    European journal of clinical pharmacology 56 (2000), S. 167-174 
    Details
    ISSN: 1432-1041
    Keywords: Key words Rofecoxib ; Pharmacokinetics ; COX-2 specificity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (VioxxTM), characterized in vitro as a COX-2 inhibitor. Methods: Four panels of healthy men (n=8 per panel) were administered rofecoxib (n=6) (25, 100, 250, 375 mg) or placebo (n=2) once daily on day 1 and days 3–14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose. Results: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient. Conclusion: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050736
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  • 2
    Electronic Resource
    Electronic Resource
    Plasma drug profiles and tolerability of MK-571 (L-660,711), a leukotriene D4 receptor antagonist, in man (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 427-430 
    Details
    ISSN: 1432-1041
    Keywords: MK-571 ; LTD4 receptor antagonist ; tolerability ; plasma profiles ; enantiomer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the tolerability and plasma drug profiles of a leukotriene D4 receptor antagonist, MK-571, given intravenously and as an oral solution in two separate trials. Study I (i.v.) involved 2 panels of 6 healthy men in a double-blind, alternating, incrementally increasing dose study with single doses up to 1500 mg. There was good tolerability at all doses. Plasma was assayed stereospecifically by HPLC for the S(+) and R(−) enantiomers of MK-571. For each enantiomer AUC values increased more than proportionately with increasing dose, suggesting nonlinear kinetics. The S(+) enantiomer was cleared more rapidly than the R(−) enantiomer. The apparent initial volume of distribution was less than 101 for both enantiomers. Study II (oral) involved 18 healthy subjects in 3 parallel groups who took multiple oral doses of 100, 300, and 600 mg t. i. d. for 31 doses. MK-571 administration was well tolerated, with only mild to moderate gastrointestinal discomfort at the highest dose. Total MK-571 (plasma samples assayed nonstereoselectively) was rapidly absorbed after oral administration, reaching peak concentrations at 1–2 h. Mean 8 h AUC increased from dose 1 to dose 31 in all subjects at all doses, suggesting a modest extent of accumulation (about 50 %) of total MK-571 in plasma with a t. i. d. dosage regimen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02220621
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Moexipril does not alter the pharmacokinetics or pharmacodynamics of warfarin (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 291-293 
    Details
    ISSN: 1432-1041
    Keywords: Moexipril ; Warfarin ; pharmacokinetics ; pharmacodynamics ; drug-interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The potential effect of moexipril, a new converting enzyme inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of warfarin has been investigated. Ten healthy male volunteers received in a randomised crossover fashion a single oral dose of 50 mg warfarin sodium alone and together with the first dose of 6 days of oral treatment with moexipril 15 mg o.d. Mean oral plasma clearance of (R)-warfarin was 175 ml·h−1 in the absence and 181 ml·h−1 in the presence of moexipril, and the corresponding values for (S)-warfarin were 248 ml·h−1 and 249 ml·h−1. Apparent volume of distribution, peak plasma concentration, time to reach peak concentration and area under the plasma concentration-time curve both of (R)- and (S)-warfarin were not significantly affected. Moexipril did not alter the maximum prothrombin time (20.3 versus 20.1 s, respectively in the absence and presence of moexipril), time to maximum response (48.0 versus 50 h) and area under the prothrombin time versus time curve. The results suggest that a clinically important interaction between moexipril and warfarin is unlikely to occur in patients treated with both drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315400
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    Paper (German National Licenses)
    Fulltext
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