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Biomedical subjects

P De Schepper

Publications and source records attributed to P De Schepper.

14 recordsLinked to original sources
PubMed1999

Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase. The induction of COX-2 after inflammatory stimuli has led to the hypothesis that COX-2 inhibition primarily accounts for the therapeutic properties of NSAIDs. METHODS: Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX-isoform specific assays (serum thromboxane B2 [TXB2] and lipopolysaccharide [LPS]-stimulated whole blood prostaglandin E2 and assays of COX-1 and COX-2 activity, respectively). A double-blind, parallel-group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain. RESULTS: Rofecoxib showed a >800-fold COX-2 selectivity with use of CHO cells that express human COX-1 and COX-2. In subjects, dose- and concentration-dependent inhibition of LPS-stimulated prostaglandin E2 was observed with both rofecoxib (IC50 [the concentration estimated to produce 50% inhibition], 0.77 micromol/L) and indomethacin (IC50, 0.33 micromol/L). Whereas indomethacin inhibited TXB2, (IC50, 0.14 micromol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen (P > .20). All active treatments showed greater improvement than placebo (P < .001) CONCLUSIONS: Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2.

Adult↗
PubMed1991

Hormonal effects of a 5 alpha-reductase inhibitor (finasteride) on hormonal levels in normal men and in patients with benign prostatic hyperplasia.

Finasteride is a potent competitive 5 alpha-reductase inhibitor, active at a dose as low as 1 mg/day. After a single dose, the effects on 5 alpha-reductase last as long as 7 days. Both hepatic and target tissue 5 alpha-reductase are inhibited. Plasma testosterone and estradiol are unaffected and luteinizing hormone levels do not change. During chronic treatment with finasteride 5 mg/day, the effects on 5 alpha-reductase are maintained. Since the only significant effect of chronic finasteride therapy appears to be 5 alpha-reductase inhibition, and testosterone or estradiol levels are not affected, neither libido nor potency is lost. Testosterone is the active androgen at the muscular level; therefore, muscular catabolism is not expected.

5-alpha Reductase Inhibitors↗
PubMed1989

Hormonal effects of an orally active 4-azasteroid inhibitor of 5 alpha-reductase in humans.

The objective of this study was to estimate the minimum in vivo effective oral dose and duration of action of the competitive 5 alpha-reductase inhibitor MK-906, a 4-azasteroid, in humans. Plasma dihydrotesterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (AD), and its glucuronide (ADG), as well as urinary androsterone (A) and 5 alpha-pregnane-3 alpha,11 beta, 17 alpha,21-tetrol-20-one (aH4F) were determined in 54 healthy young men before and up to 7 days after a single morning dose of the compound. Twenty-four hours after a single 5- to 40-mg dose (n = 24), plasma DHT levels decreased by a mean of +/- 65%, with slow recovery of DHT levels. Seven days later, DHT remained decreased by +/- 15%. Plasma AD levels decreased to a similar degree, whereas ADG levels decreased by about 75%, indicating inhibition of target tissue 5 alpha-reductase. Testosterone levels did not show any significant variations. The A as well as aH4F excretion in the 24-hour urine test following drug administration decreased by 65%, indicating inhibition of the hepatic 5 alpha-reductase. After a single dose of 1.5 or 0.5 mg, DHT levels decreased by 50% 24 hours after administration, returning to normal within 5-7 days; at this dose, urinary A and aH4F excretion decreased by 50%. A single dose of 0.2 mg appeared to be slightly active as a 5 alpha-reductase inhibitor, but no statistically significant effect on DHT levels was observed after administration of a single 0.04-mg dose. It is concluded that MK-906 is a highly effective 5 alpha-reductase inhibitor in vivo. The effect on plasma DHT lasts for several days after administration of a single oral dose. The data suggest that both hepatic and extrasplanchnic 5 alpha-reductases are inhibited.

5-alpha Reductase Inhibitors↗
PubMed1988

Effectiveness and tolerability of CV-3988, a selective PAF antagonist, after intravenous administration to man.

1. The efficacy and tolerability of CV-3988, a selective PAF antagonist with structural analogies with PAF, were studied after intravenous infusion in man. 2. The compound, in doses from 750 to 2,000 micrograms kg-1, significantly reduced platelet sensitivity for PAF. The threshold aggregating concentration (TAC) of PAF, expressed in % of the mean predosing value, increased in a dose dependent manner reaching 356 +/- 162% of the basal TAC at the end and 266 +/- 123% of the basal TAC 4 h after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 h after the end of the infusion. 3. CV-3988 did not cause major side effects nor changes in blood pressure, pulse and respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and 4 h after the end of the infusion, indicating a slight haemolysis. 4. Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can safely be administered to man and should be useful in elucidating the role of PAF in disease.

Adult↗
PubMed1985

Determination of cotinine in biological fluids by capillary gas chromatography-mass spectrometry-selected-ion monitoring.

A sensitive and selective method for the determination of cotinine in plasma and urine is presented. Quantitation is effected by capillary gas chromatography-mass spectrometry after liquid--liquid extraction of 0.25-1 ml of biological specimens with a trideuterated cotinine internal standard. The procedure is linear and has acceptable precision over the range of concentrations encountered in pharmacokinetic studies of nicotine or cotinine. The suitability of the assay is shown by a number of plasma concentration--time curves after a single oral or intravenous administration of cotinine to a human volunteer and after multiple-dose intravenous administration of nicotine.

Body Fluids↗