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  • 1
    ISSN: 1432-1041
    Keywords: indomethacin ; diflunisal ; pharmacokinetics ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose pharmacokinetics of indomethacin following 100 mg rectally was measured in two groups of 8 healthy subjects before and after diflunisal 500 mg p.o. once daily, or 500 mg in the morning and 1000 mg in the evening, until steady state conditions were reached. A further group of 8 healthy subjects was given 50 mg indomethacin rectally before and after diflunisal 500 mg p.o. twice daily. High dose diflunisal (1500 mg/day) decreased the renal clearance of indomethacin from 21.9 to 1.8 ml/min (92%) and reduced the renal excretion of both unchanged (63%) and conjugated (82%) indomethacin. The apparent total body clearance (0.12 l/h/kg), apparent volume of distribution (0.98 l/kg), and volume of distribution at steady state (0.80 l/kg) were decreased by 47%, 35% and 30%. The maximum plasma concentration (2.4 µg/ml) and total area under the curve (13.0 µg × h/ml) were increased by 40% and 119%, respectively. The terminal elimination half-life (5.7 h) and mean residence time (6.7 h) were slightly prolonged (7.0 h and 8.8 h) in the presence of diflunisal. The contribution of metabolism to the overall elimination of indomethacin was increased by only 2%. Similar results were obtained when the subjects were challenged with the low dose of diflunisal (500 mg/day), although the magnitude of the changes were smaller. The interaction between indomethacin and diflunisal may be due to competition both at the metabolic (conjugation) and the excretory (tubular secretion) levels. When the subjects were given 50 mg indomethacin and diflunisal 1000 mg/day simultaneously, the achieved maximum plasma concentration of indomethacin (2.53 µg/ml) was comparable to that seen after 100 mg in the absence of diflunisal (3.1 µg/ml), but the AUC was greater (21.7 µg × h/ml vs 13.0 µg × h/ml). Adverse central nervous reactions were more frequent and more pronounced at higher plasma indomethacin concentrations.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1041
    Keywords: diflunisal ; pharmacokinetics ; healthy volunteers ; kidney failure ; rheumatoid arthritis ; aged subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose plasma kinetics of diflunisal was studied in healthy young and old subjects, in patients with rheumatoid arthritis, and in patients with renal failure. The plasma and urine kinetics of the glucuronidated metabolites of diflunisal were studied in the healthy elderly subjects and in the patients with renal failure. In addition, the multiple-dose plasma kinetics of diflunisal was assessed in healthy volunteers and in patients with rheumatoid arthritis. After a single dose of diflunisal the terminal plasma half-life, mean residence time and apparent volume of distribution were higher in elderly subjects than in young adults. No difference was observed in any pharmacokinetic parameter between age-matched healthy subjects and patients with rheumatoid arthritis. The elimination half-life of unchanged diflunisal was correlated with the creatinine clearance (r=+0.89) and its apparent total body clearance exhibited linear dependence on creatinine clearance (r=+0.78). In patients with renal failure, the terminal plasma half-life and mean residence time of diflunisal were prolonged. The renal and apparent total body clearances were lower, the mean apparent volume of distribution was higher and the mean area under the concentration-time curve extrapolated to infinity (AUC) was greater in the renal failure patients than in controls. The plasma concentration of the glucuronidated metabolites rapidly rose to levels above those of unchanged drug in renal patients, whereas they were lower than those of unchanged diflunisal in controls. The AUC (0–96 h) of diflunisal glucuronides in the patients was four-times that in controls, and the terminal elimination half-life of the glucuronides was prolonged in them. The renal excretion and clearance of diflunisal glucuronides were reduced when renal function was impaired. After multiple dosing, the pre-dose steady-state plasma-concentration increased with decreasing creatinine clearance (r=-0.79). When the plasma concentration exceeded 200 µmol·1−1, the elimination half-life was doubled, due to partial saturation of diflunisal conjugation. This finding suggests that lower doses could be used in long-term treatment. Thus, old age and arthritic disease appear to have little influence on the kinetics of diflunisal in the absence of renal functional impairment. Ordinary doses can be given for short term treatment of elderly patients with or without RA. In patients with renal failure, however, reduced doses of diflunisal are recommended.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 42 (1992), S. 301-305 
    ISSN: 1432-1041
    Keywords: Indomethacin ; Osteoarthritis ; pharmakokinetics ; intraarticular administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intraarticular indomethacin was evaluated in 10 patients with osteoarthritis in an open labelled, randomized, cross-over study. Each patient received a single dose of 10 mg indomethacin by the intraarticular and the intravenous routes with a seven-day interval between the injections. Blood was repeatedly collected and urine was collected for 24 h after dosing. Indomethacin was rapidly absorbed from the joint, giving a maximum serum concentration (Cmax) of 0.60 μg · ml−1 approximately 1 h after dosing. The systemic bioavailability (f) was 80% and the mean absorption time (MAT) was about 2 h. The apparent terminal half-life and mean residence time (MRT) were 2.8 h and 4 h, respectively. The urinary recovery of total indomethacin (unchanged + glucuronides) was 24% of the dose and renal clearance (CLR) was estimated to be about 21 ml · min−1. The disposition of indomethacin after intravenous and intraarticular administration appeared to be similar. The results suggest that the intraarticular administration of indomethacin would not exclude the risk of developing untoward, systemic, concentration-dependent effects.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 629 (1991), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Fisheries Research 18 (1993), S. 147-159 
    ISSN: 0165-7836
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0044-8486
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0044-8486
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Aquaculture 28 (1982), S. 113-121 
    ISSN: 0044-8486
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We examined the ability of the inhaled leukotriene D4 antagonist (L-648, 051) to inhibit antigen-induced asthmatic responses. Twelve patients with stable exogenous asthma participated in two separate double-blind, placebo-controlled, cross-over trials. The ability of the antagonist to reverse or inhibit antigen-induced bronchoconstrictor response was examined; both the immediate and the late phases were studied. In the reversal study, patients inhaled 800 μ of L-648, 051 during the immediate phase (15 min after antigen challenge) and again during in the late phase (7 h after antigen challenge). In the prevention study, the same dose (800 μ) of L-648, 051 was inhaled before the expected immediate reaction (5 min before antigen challenge) as well as before the expected late reaction (2.5 h after antigen challenge). The LTD4 antagonist was not effective in reversing the airway response to inhaled antigen, as measured by airway resistance (Rt), forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC). When the antagonist was given prior to antigen challenge, a slight reduction in R1 was observed during the immediate phase, but not during the late phase. Some improvement in FEV1 and FVC during the immediate phase was also observed, but these changes did not reach statistical significance. These results suggest that LTD4 plays a role in the immediate phase of antigen-induced asthma.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We studied the effect of the inhaled leukotriene D4 antagonist, L-648,051, on antigen-induced bronchoconstriction and nonspecific bronchial reactivity. Ten males with mild atopic asthma completed a double-blind, randomized, two-period, placebo-controlled cross-over study. For a 7-day period patients inhaled either placebo or 6 mg of L-648,051 four times daily. Bronchial reactivity to methacholine was measured at base line (day 1) and after 6 days, treatment (day 7). On day 8, after inhaling 6 mg of the antagonist (or placebo), the patients were challenged by inhaled antigen; they received an additional 6 mg of the antagonist (or placebo) 3 h later. Pulmonary function (forced expiratory volume in 1 s, FEV1) was measured serially through an 8-h post-antigen challenge. Nonspecific airway reactivity was again measured on day 9. Compared to placebo, L-648,051 treatment diminished the methacholine reactivity, on both day 7 (NS) and on day 9 (P〈0.05). In addition, the immediate and late bronchial responses to antigen challenge on day 8 were attenuated in the patients when treated with L-648,051. In the immediate phase (0–3 h postchallenge), the airway response was significantly reduced at all recordings between 20 min and 1 h postchallenge. In the late phase (3–8 h postchallenge), the pulmonary response was also reduced. However, the reduction was statistically significant only at the 5–h recording. The results suggest that sulfidopeptide leukotrienes are of importance for nonspecific airway reactivity, and that leukotriene D4 is a significant mediator in the immediate asthmatic reaction.
    Type of Medium: Electronic Resource
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