J Biotechnol. 1994 Mar 31;33(2):175-82.
Enantioselective hydrolysis of racemic naproxen nitrile and naproxen amide to S-naproxen by new bacterial isolates.

Layh N, Stolz A, Bohme J, Effenberger F, Knackmuss HJ.

Institut fur Mikrobiologie der Universitat Stuttgart, Germany.

Bacteria were enriched from soil samples with succinate as a carbon source and racemic naproxen nitrile [2-(6-methoxy-2-naphthyl)propionitrile] as sole source of nitrogen. Since naproxen nitrile was only poorly soluble in water media amended with different water-immiscible organic phases were used for the enrichments. With pristane (2,6,10,14-tetramethylpentadecane) as the organic phase two bacterial strains were isolated (strain C3II and strain MP50) which were identified as rhodococci. Cells of both strains converted naproxen nitrile via naproxen amide to naproxen. From racemic naproxen nitrile Rhodococcus sp. C3II formed S-naproxen amide and subsequently S-naproxen. Racemic naproxen amide was hydrolysed to S-naproxen. Rhodococcus sp. MP50 converted racemic naproxen nitrile predominantly to R-naproxen amide and racemic naproxen amide to S-naproxen. With both strains racemic naproxen amide was converted to S-naproxen with an enantiomeric excess > 99% at a conversion rate up to 80% of the theoretical value. In strain C3II the enzymes which hydrolysed naproxen nitrile and naproxen amide were present only at a low constitutive level. In contrast, in Rhodococcus sp. MP50 these activities were induced when grown in the presence of various nitriles.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7764731&dopt=Abstract Naproxen Naprosyn





J Orthop Res. 1993 Mar;11(2):163-71.
In vivo effects of naproxen on composition, proteoglycan metabolism, and matrix metalloproteinase activities in canine articular cartilage.

Ratcliffe A, Azzo W, Saed-Nejad F, Lane N, Rosenwasser MP, Mow VC.

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

Naproxen is a nonsteroidal anti-inflammatory drug commonly used in the clinical treatment of joint disease. In this study, its effect in vivo on the biochemical composition, metabolic activities, and metalloproteinase activities of normal canine articular cartilage was analyzed. The articular cartilage from the knee joints of dogs who had been given naproxen for 4 weeks to maintain a serum level of 40-50 micrograms/ml was examined. Control animals were given a placebo. Treatment with naproxen was not found to change the composition (water, collagen, and proteoglycan) of the articular cartilage. The culture studies of cartilage explants indicated that proteoglycan synthesis rates were unaffected by the treatment with naproxen but that proteoglycan release from the tissue was suppressed. Analysis of the cartilage for matrix metalloproteinase activities showed reduced activity of neutral matrix metalloproteinase by 80%, of collagenase by 40%, and of gelatinase by 87%, with no change in activity of acid metalloproteinase or of tissue inhibitor for metalloproteinase. These findings indicate that in vivo treatment with naproxen has the capacity to modulate catabolic activities in articular cartilage.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8483029&dopt=Abstract Naproxen Naprosyn





Drug Metab Dispos. 1995 Oct;23(10):1099-103.
Stereoselective disposition of naproxen glucuronide in the rat.

Iwaki M, Bischer A, Nguyen AC, McDonagh AF, Benet LZ.

Department of Pharmacy, S-926, School of Pharmacy, University of California-San Francisco 94143-0446, USA.

The disposition of R- and S-naproxen glucuronides were investigated after intravenous administration (approximately 1.5 mg/kg) to normal male Sprague-Dawley rats and to rats pretreated with phenylmethylsulfonylfluoride, an inhibitor of esterases. The relative stability of the two glucuronides also was measured in vitro. Both diastereomers were hydrolyzed rapidly in vivo, liberating naproxen, but R-naproxen glucuronide was hydrolyzed faster than the corresponding S-diastereomer. This difference resulted in a larger plasma AUC(Nap):AUC(Nap-G) ratio for the R-glucuronide. There was, however, no marked difference in the apparent clearance of the R- and S-diastereomers. Administration of phenylmethylsulfonylfluoride had no significant effect on the disposition of the two diastereomers. In 0.15 M phosphate buffer (ph 7.4) at 37 degree C, the fastest degradation process for both diastereomers in vitro was acyl migration. Our results show that R-naproxen glucuronide is more labile than S-naproxen glucuronide in vivo and in vitro, and suggest that hydrolysis, rather than biliary excretion, is the major process leading to elimination of R-naproxen glucuronide in vivo in the rat. These results demonstrate that the rat may in certain situations be an inadequate model for studying the disposition of acyl glucuronides and that the metabolic disposition, and possibly toxicities, of diastereomeric metabolites of chiral drugs can be quite different even when the individual diastereomers have similar apparent clearances.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8654198&dopt=Abstract Naproxen Naprosyn





Riv Eur Sci Med Farmacol. 1989 Jun;11(3):263-9.
Symptomatic treatment of osteoarthrosis with two different oral preparations of naproxen.

Lacovacci F, Bosio S, Venturino G.

A new oral Naproxen retard preparation (750 mg once daily) was compared with a standard commercial formula (375 mg BID) in a population of 60 patients affected by osteoarthritis or rheumatoid arthritis. An assessment was made of the effects on the clinical parameters, inflammation indexes (ESR, PCR, urinary hydroxyproline) and general tolerance parameters after one month of treatment. Once the steady state had been reached, no significant differences were observed even 24 h after the administration of a single 750 mg dose of Naproxen retard as compared with the administration of two 375 mg doses of standard Naproxen taken every 12 hours. Both treatments induced a similar improvement in the clinical and laboratory parameters and were shown to be equally safe. However, tolerance at a gastro-enteric level was, better with the retard preparation.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2640047&dopt=Abstract Naproxen Naprosyn





J Pharm Pharmacol. 1995 Jun;47(6):462-5.
Usefulness of the pain-induced functional impairment model to relate plasma levels of analgesics to their efficacy in rats.

Hoyo-Vadillo C, Perez-Urizar J, Lopez-Munoz FJ.

Departamento de Farmacologia y Toxicologia, Centro de Investigacion y de Estudios Avanzados, Instituto Politecnico Nacional, Mexico DF, Mexico.

In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen. Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered. The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7674128&dopt=Abstract Naproxen Naprosyn





J Pharm Pharmacol. 1982 Sep;34(9):562-9.
Nabumetone (BRL 14777, 4-[6-methoxy-2-naphthyl]-butan-2-one): a new anti-inflammatory agent.

Boyle EA, Freeman PC, Mangan FR, Thomson MJ.

Nabumetone is a compound of novel structure which displays acute anti-inflammatory activity in the carrageenan-induced oedema model in rats and the ultraviolet-induced erythema model in guinea-pigs. Its activity in these tests is greater than that of aspirin but less than that of naproxen and indomethacin. In the cotton pellet-induced granuloma model in the rat, the compound is active and produces no signs of toxicity at doses much greater than the lowest effective dose, unlike aspirin, naproxen or indomethacin. Nabumetone is also active in the adjuvant-induced arthritis test in rats. In contrast to aspirin, indomethacin and naproxen, the compound is well tolerated by the stomach of fasted rats at doses in excess of those with anti-inflammatory activity. These findings could be linked to the relatively poor ability of nabumetone to inhibit the synthesis of prostaglandins in vitro and to its non-acidic structure. The compound has greater mild analgesic activity than paracetamol, is equi-active with phenylbutazone, but less active than aspirin, naproxen and indomethacin. Nabumetone also has antipyretic activity in the rabbit. No interactions with the hypothalamic-pituitary-adrenal axis have been found.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6127380&dopt=Abstract Naproxen Naprosyn





Eur J Clin Pharmacol. 1984;27(3):291-6.
Naproxen disposition in patients with alcoholic cirrhosis.

Williams RL, Upton RA, Cello JP, Jones RM, Blitstein M, Kelly J, Nierenburg D.

Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6510456&dopt=Abstract Naproxen Naprosyn