Biochem Pharmacol. 1993 Apr 22;45(8):1721-4.
Lipid peroxidation in rat liver microsomes during naproxen metabolism.

Yokoyama H, Horie T, Awazu S.

Department of Biopharmaceutics, Tokyo College of Pharmacy, Japan.

Naproxen, a non-steroidal anti-inflammatory drug, is known to be highly effective and relatively safe, but some side-effects in the liver have been reported. In the present study, the effect of naproxen metabolism on rat liver microsomes was studied by determining lipid peroxidation in terms of thiobarbituric acid reactive substances (TBA-RS), high molecular weight protein aggregates and fluorescent substances formed in the microsomal suspension containing naproxen, NADPH and MgCl2. Lipid peroxidation was found to occur at 10 mM naproxen. Production of chemiluminescence from the microsomal suspension was observed during naproxen metabolism. The time course of 6-demethyl-naproxen formation by O-demethylation of naproxen appeared to be comparable to that of the chemiluminescence production in their initial periods of production. These results suggest that the lipid peroxidation was provoked through the reactive oxygen species generated during the oxidative metabolism of naproxen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8484810&dopt=Abstract Naproxen Naprosyn





J Periodontal Res. 1991 Nov;26(6):498-501.
Inhibition of alveolar bone loss in beagles with the NSAID naproxen.

Howell TH, Jeffcoat MK, Goldhaber P, Reddy MS, Kaplan ML, Johnson HG, Hall CM, Williams RC.

Department of Periodontology, Harvard School of Dental Medicine, Boston, MA.

The non-steroidal anti-inflammatory drug(NSAID) naproxen was studied in 11 beagle dogs over a 13-month period to determine its effect on the progression of periodontitis. Following a 6-month pretreatment period, 5 dogs received naproxen daily at a dosage of 2.0 mg/kg for 1 month, then 0.2 mg/kg for 6 months. Six control dogs received a gelatin capsule daily as placebo. Standardized radiographs were used to measure the rate of bone loss during the pretreatment and treatment periods. In the control dogs, the rate of bone loss was seen to increase during the treatment period although the increase was not statistically significant. In dogs treated daily with naproxen, the rate of bone loss in the treatment period was significantly less at 4 months of treatment; however, at 7 months the difference, though lower than pretreatment rate, was not significant. When the percent change in rate of bone loss during the overall 7-month treatment period was compared with pretreatment rate, the control dogs demonstrated a 38% increase in rate of bone loss during the treatment period contrasting with a 61% decrease in bone loss rate in naproxen-treated dogs. The data indicate that the non-steroidal anti-inflammatory drug naproxen can significantly inhibit alveolar bone loss in beagles. At 4 months of treatment the rate of bone loss in the naproxen-treated dogs was significantly less than pretreatment, but at 7 months of treatment the rate was no longer statistically significantly less than baseline. This probably reflects a dose response to naproxen treatment for, after 30 days of the treatment period, the naproxen dosage was reduced 10-fold due to tolerance by the beagle.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1837054&dopt=Abstract Naproxen Naprosyn





Am Heart J. 1981 Apr;101(4):394-402.
Stabilization of cardiac lysosomal and cellular membranes in protection of ischemic myocardium due to coronary occlusion:efficacy of the nonsteroidal anti-inflammatory agent, naproxen.

Smith EF, Lefer AM.

The combined cellular membrane stabilizing and prostaglandin-inhibiting agent, naproxen, administered either 30 minutes before or after left coronary occlusion, induced significant preservation of the acutely ischemic experimental animal myocardium. A consistent extent of myocardial protection was provided as measured by ST segment elevation, plasma accumulation of CK activity, tissue CK activities, and amino-nitrogen concentrations, and ultrastructural integrity. Protection did not appear to be via hemodynamic mechanisms since naproxen neither altered pressure-rate product nor decreased coronary resistance. While the degree that inhibition of platelet thromboxane A2 generation contributes to these salutary results requires clarification due to possible simultaneous decrease of coronary endothelial PGI2 formation, the present study emphasizes the value of the concomitant special lysosomal and cellular stabilizing actions of naproxen. In contrast to acetylsalicylic acid, meclofenamate, and indomethacin which do not effect such benefit in the same experimental conditions, our results indicate that naproxen resembles the nonsteroidal anti-inflammatory agents which also possess membrane stabilizing properties, such as ibuprofen and flurbiprofen, and protects ischemic myocardium in similar adverse circumstances.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7211667&dopt=Abstract Naproxen Naprosyn





J Clin Pharmacol. 1975 Apr;15(4 Pt. 2):316-23.
Naproxen metabolism in man.

Segre EJ.

In summary, naproxen is an acidic, highly albumin-bound drug. After oral administration, it is promptly and fully absorbed. The mean half-life of the drug in man is 13 hours, close to ideal for twice-daily administration. The only metabolite detected in man is the 6-desmethyl compound. Both it and naproxen itself are excreted in the urine, primarily as conjugates. The kinetics of naproxen binding to serum albumin tend to limit attainable plasma levels. They increase little if the dose is increased beyond 500 mg twice daily, since greater concentrations are rapidly cleared. Albumin binding and competitive displacement are also responsible for potential interactions of naproxen with drugs such as warfarin, sulfonylureas, and aspirin. Experience thus far does not indicate that any of the potential interactions are clinically meaningful.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1127135&dopt=Abstract Naproxen Naprosyn





Dev Pharmacol Ther. 1982;5(3-4):143-50.
Pharmacokinetics and metabolism of naproxen in children.

Kauffmann RE, Bolliger RO, Wan SH, Oren J.

The metabolism and pharmacokinetics of orally administered naproxen were studied in 10 children aged 6-13 years. 3 patients received the drug for antipyresis and 7 for postoperative pain. The mean elimination rate constant was greater in the febrile children than the postoperative patients, 0.064 h-1 vs. 0.051 h-1. 71% of total drug recovered in urine was naproxen, and 29% was excreted as the desmethyl metabolite. 60 and 63% of naproxen and desmethyl naproxen, respectively, were excreted as conjugates. Area under the curve and fraction of dose recovered in the urine were reduced in the postoperative patients, suggesting reduced gastrointestinal absorption of the drug compared to the febrile patients.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7151646&dopt=Abstract Naproxen Naprosyn





J Chromatogr. 1992 Jul 24;578(2):239-49.
Determination of naproxen and its metabolite O-desmethylnaproxen with their acyl glucuronides in human plasma and urine by means of direct gradient high-performance liquid chromatography.

Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CP.

Department of Clinical Pharmacy, Academic Hospital Sint Radboud, Nijmegen, Netherlands.

Naproxen is metabolized in humans by O-demethylation, and by acyl glucuronidation to the 1-O-glucuronide. Naproxen, its metabolite and the conjugates can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic deglucuronidation. The glucuronide conjugates were isolated by preparative chromatography from human urine samples. Mild acidic hydrolysis of one urinary conjugate resulted in naproxen. This conjugate was also formed by alkaline isomerization of isolated naproxen acyl glucuronide, indicating that the structure of this urinary conjugate must have been naproxen isoglucuronide (4-O-glucuronide). Mild acidic hydrolysis of another urinary conjugate resulted in O-desmethylnaproxen. This conjugate was also formed by alkaline isomerisation of isolated O-desmethylnaproxen acyl glucuronide, indicating that the structure of this urinary conjugate must have been O-desmethylnaproxen isoglucuronide (4-O-glucuronide). Calibriation curves were constructed by enzymic deconjugation of samples containing different concentrations of isolated naproxen acyl glucuronide, O-desmethylnaproxen acyl glucuronide, and the isoglucuronides of naproxen and O-desmethylnaproxen by mild acidic hydrolysis. The limit of quantitation of naproxen in plasma is 1.5 microgram/ml. The limits of quantitation in urine are: naproxen, O-desmethylnaproxen, naproxen acyl glucuronide and O-desmethylnaproxen acyl glucuronide, 1 microgram/ml; the isoglucuronide of naproxen and O-desmethylnaproxen, 1.5 microgram/ml. A pharmacokinetic profile of naproxen is shown, and some preliminary pharmacokinetic parameters of naproxen obtained from two human volunteers are given.

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Scand J Rheumatol. 1995;24(6):336-41.
Comparative effects of nabumetone, naproxen, piroxicam, and diclofenac on rat gastric irritancy following acute exposure to OTC non-steroidal anti-inflammatory agents and other gastric irritants.

Carryl OR, Spangler RS.

Procter and Gamble Company, Cincinnati, Ohio, USA.

This study examined the relative effects of equally-effective anti-inflammatory doses of nabumetone, naproxen, piroxicam and diclofenac on gastric irritancy induced by over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and ibuprofen and a variety of necrotizing agents (0.6 N HCl, 0.2 N NaOH and 25% NaCl). Within one hour, aspirin 100 and 200 mg/kg and ibuprofen up to 15 mg/kg produced significant gastric mucosal injury. Aspirin 50 mg/kg produced only minimal damage that was enhanced by 5 x ID25 piroxicam and naproxen, but not by nabumetone or diclofenac. 5 x ID25 naproxen, piroxicam, and diclofenac significantly enhanced mucosal damage produced by ibuprofen 2.5 mg/kg. An equivalent anti-inflammatory dose of nabumetone failed to enhance the gastric irritancy produced by ibuprofen 2.5 mg/kg. Similarly, naproxen, piroxicam, and diclofenac enhanced the susceptibility of the gastric mucosa to the necrotizing actions of 0.6 N HCl, 0.2 N NaOH or 25% NaCl. Naproxen, piroxicam, or diclofenac are more likely than nabumetone to enhance gastric mucosal injury produced by OTC NSAIDs (aspirin and ibuprofen) or other gastric irritants.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8610216&dopt=Abstract Naproxen Naprosyn





Ital J Biochem. 1980 May-Jun;29(3):159-66.
Effect of indomethacin and naproxen on collagen cross-linking.

Arumugham R, Bose SM.

The influence of indomethacin and naproxen on rat dermal collagen cross-linking was investigated in vivo. The analyses of skins showed that the naproxen group had a decrease in percent reversibility of neutral salt-soluble collagen gel, susceptibility of insoluble collagen to denaturing agents and pronase and alpha/beta ratio of neutral salt-soluble collagen whereas the aldehyde content was significantly increased. Indomethacin was ineffective for all these parameters. The results indicated that both the inter and intra-molecular cross-linking of collagen was increased in the naproxen treated group while indomethacin did not influence the collagen cross-linking.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7451107&dopt=Abstract Naproxen Naprosyn





Arzneimittelforschung. 1975 Feb;25(2A):318-21.
[Steroid saving effect of naproxen]

[Article in German]

Mathies H.

Since for various reasons the Lansbury Index appeared inadequate to define the therapeutic efficacy of antirheumatic compounds, we chose to investigate in our trials the prednisolone saving effect in patients with rheumatoid arthritis. Our investigations with the new antirheumatic substance d-2-(6'-methoxy-2'-naphthyl)-propionic acid (naproxen) in most cases showed a prednisolone saving effect of 5 mg/day with a naproxen dose of 750 mg daily. In cases where a daily dose of 10 mg of prednisolone was necessary, a saving of 7.5 mg up to 10 mg was registered. But there were also failures and lesser saving effects. The steroid saving effect differs from one individual to another. In an additional study naproxen in a daily dose of 500 mg was compared with other antirheumatic agents (indometacin, azapropazon, and nifluminic acid) in patients not requiring steroids. The results were not uniform. In some cases naproxen was more effective, in other cases the substances mentioned were better. In these series joint function and subjective changes only were evaluated. Apart from a few cases of gastrointestinal side effects the drug was well tolerated.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1173778&dopt=Abstract Naproxen Naprosyn