J Biol Chem. 1995 Jun 9;270(23):13948-55.
Tepoxalin, a novel dual inhibitor of the prostaglandin-H synthase cyclooxygenase and peroxidase activities.

Tam SS, Lee DH, Wang EY, Munroe DG, Lau CY.

R. W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.

Prostaglandin-H synthase-1, the rate-limiting enzyme in prostaglandin synthesis, has both cyclooxygenase (CO) and peroxidase (PO) activities. While most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit only the CO activity, we describe an inhibitor, tepoxalin, that inhibits both the CO (IC50 = 0.1 microM) and the PO (IC50 = 4 microM) activities. Unlike many NSAIDs which are competitive inhibitors of CO, tepoxalin is a noncompetitive inhibitor of CO and its inhibitory effect on PO but not CO is reversed by excess heme. Moreover, inhibition of the PO activity by tepoxalin is not dependent on the enzymatic turnover of the CO activity. The hydroxamic acid of tepoxalin is responsible for the PO inhibition since a carboxylic acid derivative of tepoxalin retains full CO but not PO inhibition. We postulated that the hydroxamic group might confer the ability to inhibit PO on conventional CO inhibitors. This idea was supported by the observation that naproxen hydroxamic acid, but not naproxen showed PO inhibition. Furthermore, tepoxalin's carboxylic acid analogue and naproxen each competitively relieved PO inhibition by their respective hydroxamic acids. The intracellular activity of PO as monitored by the release of reactive oxygen species was also inhibited by both tepoxalin and naproxen hydroxamic acid. These observations suggest a strategy for design of novel compounds to inhibit prostaglandin synthase PO. The therapeutic implications of these novel PO inhibitors are discussed.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7775455&dopt=Abstract Naproxen Naprosyn





Eur J Clin Pharmacol. 1989;37(6):563-5.
Effects of naproxen on the in vivo synthesis of thromboxane and prostacyclin in man.

Vesterqvist O, Green K.

Department of Clinical Chemistry and Blood Coagulation, Karolinska Hospital, Stockholm, Sweden.

The effect of a single oral dose of 500 mg naproxen on the synthesis in vivo of thromboxane A2 and prostacyclin was studied in healthy volunteers. The synthesis of the prostanoids was assessed by measuring the urinary excretion of the metabolites 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha, respectively, using stable isotope dilution assays based on gas chromatography - mass spectrometry. Naproxen caused significant inhibition of the excretion of both metabolites for about two days. The reduction of the thromboxane metabolite was more pronounced (75% inhibition) than that of the prostacyclin metabolite (about 50% inhibition). The data support the idea that naproxen causes reversible inhibition of cyclooxygenase.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2515064&dopt=Abstract Naproxen Naprosyn





J Clin Pharmacol. 1993 Feb;33(2):109-14.
The effect of naproxen and interleukin-1 on proteoglycan catabolism and on neutral metalloproteinase activity in normal articular cartilage in vitro.

Glazer PA, Rosenwasser MP, Ratcliffe A.

Department of Orthopaedic Surgery, Columbia University, New York, NY.

The events in inflammatory and degenerative joint diseases involve major changes in the metabolic events in the articular cartilage. The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on articular cartilage metabolism remain unclear, however. The objective of this catabolism of proteoglycans in articular cartilage explants maintained in culture. Release of proteoglycan from the cartilage was compared with release of neutral metalloproteinase activity. The effect of the drug also was determined on the IL-1-stimulated release of proteoglycan and neutral metalloproteinase activity from the explants. At concentrations that included those present in synovial fluids of patients treated with the drug, naproxen sodium was found to suppress the release of proteoglycan and neutral metalloproteinase activity from the articular cartilage extracts. This is in contrast to the well-documented effect of interleukin-1 (IL-1), which was shown to stimulate release of proteoglycan and neutral metalloproteinase activity from articular cartilage. The effect of naproxen sodium on the IL-1-stimulated release was to suppress, but not totally overcome, the increased release of proteoglycan and neutral metalloproteinase activity. In summary, these in vitro studies of cartilage metabolism indicate that naproxen sodium has the potential to suppress catabolic activities in articular cartilage, including those that are motivated by IL-1.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8440758&dopt=Abstract Naproxen Naprosyn





Analyst. 1989 Mar;114(3):387-91.
Construction of a naproxen ion-selective electrode and its application to pharmaceutical analysis.

Valsami GN, Macheras PE, Koupparis MA.

A naproxenate-selective electrode with a liquid membrane consisting of a tetraheptylammonium-naproxenate ion pair dissolved in p-nitrocumene is described. The electrode exhibits a rapid and near-Nernstian response to naproxenate activity from 10(-1) to 10(-4) M at pH 9.0 (borate buffer). No serious interference from common ions and tablet excipients was found and the electrode was used for the direct assay of naproxen tablets by means of the calibration graph technique and of suppositories using the standard additions technique. A dissolution study of naproxen tablets was also carried out and the results compared favourably with those given by the USP XXI methods.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2719282&dopt=Abstract Naproxen Naprosyn





Clin Pharmacol Ther. 1981 Feb;29(2):168-73.
Relation of naproxen kinetics to effect on platelet prostaglandin release in men and dysmenorrheic women.

Tomson G, Lunell NO, Oliw E, Rane A.

The purpose of our investigation was to determine kinetics of naproxen [(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid] relative to its inhibition of PGF 2 alpha release during thrombin-induced platelet aggregation in man after a single oral dose of 250 or 500 mg. Naproxen and its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid were measured by high-performance, reversed-phase liquid chromatography with fluorimetric detection. PGF 2 alpha was measured by radioimmunoassay in platelet-rich plasma (PRP). Our subjects were four healthy adult men and five dysmenorrheic women. Peak concentrations of naproxen varied between 26 and 69 microgram/ml and half-lifes varied between 9.5 and 21.9 hr, mean = 16.4 hr +/- 4.4 (SD). Naproxen plasma protein binding exceeded 99.9%. The concentration of the metabolite was less than 1% of naproxen and followed the same plasma concentration profile as the parent compound. The based concentration of PGF 2 alpha varied between 0.13 and 6.3 ng/ml, mean = 1.5 +/- 1.9 ng/ml. With no exception, there was a marked decrease in the PGF 2 alpha concentration in thrombin-stimulated PRP during therapy, and concentration was inversely correlated to the total plasma naproxen concentration.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7460481&dopt=Abstract Naproxen Naprosyn





Clin Pharmacol Ther. 1979 Jan;25(1):51-60.
Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose or warfarin.

Slattery JT, Levy G, Jain A, McMahon FG.

The purpose of this investigation was to determine the effect of the nonsteroidal anti-inflammatory drug naproxen on the elimination kinetics and anticoagulant activity of warfarin. Ten healthy men received one oral dose of 50 mg racemic warfarin alone and with naproxen, 375 mg twice daily for 17 days beginning 10 days before warfarin. Naproxen administration caused a small but statistically significant increase in the free fraction of warfarin in serum but had no significant effect on the total clearance, volume of distribution, half-life, and anticoagulant activity of warfarin. Warfarin, on the other hand, apparently enhances the serum protein binding of haproxen. There was substantial intersubject variation but very little intrasubject variation in the anticoagulant effect of warfarin. The intersubject variation of the anticoagulant effect was not related to the elimination kinetics of warfarin.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=758243&dopt=Abstract Naproxen Naprosyn





Am J Vet Res. 1995 Aug;56(8):1075-80.
Plasma and synovial fluid kinetics, disposition, and urinary excretion of naproxen in horses.

Soma LR, Uboh CE, Rudy JA, Perkowski SZ.

New Bolton Center School of Veterinary Medicine, University of Pennsylvania, Kennett Square 19348, USA.

Naproxen (+6-methoxy-[alpha-methyl]-2-naphthalene acetic acid) is a nonsteroidal anti-inflammatory drug that is used for the treatment of inflammatory conditions in horses. We developed a model that describes the drug's disposition and renal excretion, including synovial fluid disposition and elimination after IV administration in horses. The plasma disposition, after IV administration of 5 mg/kg of body weight, was described by a two-compartment model; mean +/- SD distribution and elimination half-lives were 1.42 +/- 0.42 and 8.26 +/- 2.56 hours, respectively. Plasma concentration of naproxen after IV administration of 5 mg/kg was 55.3 +/- 13.5 and 0.61 +/- 0.42 mg/L at 5 minutes and 48 hours after its administration, respectively. Steady-state volume of distribution was 0.163 +/- 0.053 L/kg, and area under the plasma concentration time-curve was 372.1 +/- 128.2 mg/h/L. The peak synovial fluid concentration of 12.68 +/- 12.39 mg/L was measured at 6 hours, and decreased to 0.71 +/- 0.38 mg/L at 36 hours after naproxen administration. The decrease of naproxen concentration in synovial fluid paralleled that in plasma. The appearance half-life of naproxen in synovial fluid was 4.64 hours, and the elimination half-life was 6.73 hours. Total body clearance was 0.015 +/- 0.006 L/h/kg. The percentage of plasma protein binding was 97.0 +/- 2.9% at plasma concentrations between 5 and 100 mg/L. This was significantly (P < 0.05) higher than the percentage of binding at plasma concentrations of 0.5, 1, and 500 mg/L, which was 75.2 +/- 11.8%. Most of the drug was excreted as glucuronidated naproxen and unconjugated desmethylnaproxen.(ABSTRACT TRUNCATED AT 250 WORDS)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8533980&dopt=Abstract Naproxen Naprosyn