Arch Intern Med. 1997 Dec 8-22;157(22):2626-31.
Gastrointestinal tract bleeding associated with naproxen sodium vs ibuprofen.

Strom BL, Schinnar R, Bilker WB, Feldman H, Farrar JT, Carson JL.

Center for Clinical Epidemiology and Biostatistics, and Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA.

BACKGROUND: The risk of gastrointestinal tract bleeding requiring hospitalization associated with naproxen sodium was compared with that with ibuprofen, using a prescription database to approximate over-the-counter dosing. OBJECTIVE: To evaluate the safety of naproxen sodium. METHODS: A claims database containing Ohio Medicaid data from January 1986 through February 1993 and Michigan Medicaid data from April 1983 through July 1993 was used to compare 101,318 patients dispensed naproxen sodium with 277,601 patients dispensed ibuprofen. Using a case-cohort design, all 59 patients from the full cohort who had been hospitalized with upper gastrointestinal tract bleeding (UGIB) that developed within 14 days after the first prescription for the study drugs were compared with a subcohort made up of a 10% random sample of subjects selected from the combined drug cohorts. RESULTS: The incidence of UGIB occurring within 14 days after the first prescription in the naproxen sodium cohort was 26 (0.026%) of 101,318 (95% confidence interval [CI], 0.017%-0.038%), compared with 33 (0.012%) of 277,601 patients (95% CI, 0.008%-0.017%) in the ibuprofen cohort. Overall, the use of naproxen sodium vs ibuprofen was associated with an adjusted relative risk of 2.0 (95% CI, 1.1-3.8). Among people with multiple prescriptions, the crude relative risk for those receiving therapy in a dose typical of over-the-counter use was 4.1 (95% CI, 1.2-13.8). CONCLUSIONS: The overall incidence of UGIB is low with both drugs. There is little additional absolute risk posed by the use of low-dose naproxen sodium, compared with low-dose ibuprofen, despite an increased relative risk. However, given the widespread use of these drugs, a substantial number of additional cases of UGIB could result from use of naproxen sodium. This increased risk should be considered, especially for patients whose baseline risk of UGIB is elevated.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9531232&dopt=Abstract Naproxen Naprosyn





Clin Pharmacol Ther. 1976 Sep;20(3):269-77.
Pharmacokinetics of naproxen overdoses.

Runkel R, Chaplin MD, Sevelius H, Ortega E, Segre E.

In earlier safety studies, naproxen, 600 mg three times daily, was administered to healthy subject without significant adverse effects. Another study demonstrated that single doses of 500 to 900 mg resulted in accelerated renal clearance and a nonlinear naproxen plasma level response after the higher doses. Our report describes the pharmacokinetics of naproxen when administered in single doses of 1, 2, 3, or 4 gm (up to eight times the clinically effective dose in rheumatoid arthritis) to healthy subjects. An increase in urinary excretion rate and continuation of the previously documented nonlinear plasma level response were observed. There were no signs that capacity to conjugate or to excrete the drug was exceeded. There were no adverse effects.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=954349&dopt=Abstract Naproxen Naprosyn





Life Sci. 1998;62(15):PL235-40.
Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat.

Muscara MN, McKnight W, Del Soldato P, Wallace JL.

Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada.

NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9566780&dopt=Abstract Naproxen Naprosyn





Res Commun Mol Pathol Pharmacol. 1998 Feb;99(2):143-54.
Glutathione disulfide formation during naproxen metabolism in the isolated rat hepatocytes.

Yokoyama H, Horie T, Awazu S.

Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.

As naproxen was found to induce lipid peroxidation in liver microsomes and isolated hepatocytes of rats during its oxidative metabolism, we studied changes of glutathione on its metabolism. Intracellular oxidized glutathione (GSSG) content increased in isolated rat hepatocytes during naproxen metabolism. The intracellular GSSG increased preceding the production of thiobarbituric acid reactive substances (TBARS) and the release of lactate dehydrogenase (LDH). The glutathione-depleted hepatocytes treated with diethymaleate (DEM) enhanced TBARS production and LDH release, compared to the untreated hepatocytes. The production of GSSG may possibly be an early stage of the naproxen-induced oxidative stress which leads to lipid peroxidation and lethal cell injury.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9583089&dopt=Abstract Naproxen Naprosyn


oarg.ucsf.edu

Prostaglandins have been reported to mediate the effects of ovariectomy on bone loss. We studied the effect of naproxen, an inhibitor of production of prostaglandins, on ovariectomy-induced bone loss. One hundred forty female Wistar rats 4.5 months of age were divided into groups of baseline, sham operation (sham), sham treated with naproxen at 10 mg/kg per day (in food), and ovariectomy treated with naproxen or estrogen as intramuscular injection of estradiol at 0.2 mg/kg body weight per week. They were killed 3, 6, and 9 months postsurgery. Bone mineral density (BMD) of the lumbar spine (L1-4), femoral neck, midshaft, and distal metaphysis was determined using dual-energy X-ray absorptiometry (DXA) in vitro. The compressive test of the L1 vertebral body and torsional test of the left femur were performed. The right femoral neck and femoral midshaft were processed undecalcified for determining cross-sectional moments of inertia. Naproxen treatment partially prevented ovariectomy-induced loss or less gain in BMD, in a significant manner, in the femoral neck cortical area, and also in L1 compressive strength and stiffness. Estrogen fully prevented these ovariectomy-induced effects. Naproxen showed no effect on ovariectomy-induced improvement in femoral torsional strength and stiffness and cross-sectional moments of inertia. No statistically significant difference was found between naproxen-treated sham rats and untreated sham rats. The data suggest that naproxen partially prevents ovariectomy-induced osteopenia.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9600785&dopt=Abstract Naproxen Naprosyn


Panther.ACP.Edu

Prescription doses of nonsteroidal antiinflammatory agents have been shown to decrease clearance and increase plasma concentrations of lithium. This study was designed to evaluate whether over-the-counter (OTC) doses of naproxen sodium or acetaminophen have the same potential to affect lithium concentration. This was a prospective, crossover, 3-phase study conducted at the Clinical Pharmacology Studies Unit of the Albany Medical Center Hospital during July and August of 1995. The 3-phase study comprised the following: phase 1, lithium carbonate (300 mg every 12 hours) alone for 7 days; phase 2, lithium and either naproxen sodium (220 mg every 8 hours) or acetaminophen (650 mg every 6 hours) for 5 days; and phase 3, a 2-day washout period followed by a crossover to lithium with the alternate drug (acetaminophen or naproxen sodium) for 5 days. Twelve healthy male volunteers were recruited, nine of whom completed the study and were included in the statistical analysis. Mean (+/-SD) plasma lithium concentrations for subjects in treatment group 1 (lithium in phase 1, lithium and naproxen sodium in phase 2, lithium and acetaminophen in phase 3) were 0.38 (+/-0.11), 0.40 (+/-0.07), and 0.36 (+/-0.11) mEq/L, respectively. Mean plasma lithium concentrations for subjects in treatment group 2 (lithium in phase 1, lithium and acetaminophen in phase 2, lithium and naproxen sodium in phase 3) were 0.43 (+/-0.05), 0.48 (+/-0.10), and 0.48 (+/-0.05) mEq/L, respectively. One-way repeated-measures analysis of variance and paired t-test showed no statistically significant differences (p>0.05) in plasma lithium concentrations during any phase of the study. The results of this study demonstrated that OTC doses of naproxen sodium and acetaminophen did not increase plasma lithium concentrations in these volunteers when taken for short periods of time.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9617983&dopt=Abstract Naproxen Naprosyn





J Pharm Biomed Anal. 1998 Aug;17(4-5):719-24.
Selective determination of naproxen in the presence of nonsteroidal anti-inflammatory drugs in serum and urine samples using room temperature liquid phosphorimetry.

Perez-Ruiz T, Martinez-Lozano C, Tomas V, Carpena J.

Department of Analytical Chemistry, University of Murcia, Spain.

A very simple, rapid and highly sensitive method is described for determining naproxen in serum and urine. This method is based on room temperature phosphorescence of naproxen in sodium dodecylsulphate micelles, with thallium(I) providing the external heavy atom and sodium sulphite acting as the oxygen scavenger. Under the optimum and experimental conditions, the range of application is 0.09-4.5 micrograms ml-1 and the limit of detection is 0.03 micrograms ml-1. The most relevant characteristic of this method is its great selectivity, e.g. naproxen can be determined in the presence of other nonsteroidal anti-inflammatory drugs (NSAIDs). The clinical applicability of this procedure has been tested, analysing naproxen in serum and urine samples. The analytical recoveries and inter- and intra assay precision data obtained demonstrate the usefulness of this procedure when used with very complex samples.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9682155&dopt=Abstract Naproxen Naprosyn