Drug Dev Ind Pharm. 2001 Oct;27(9):909-17.
Effect of water-soluble polymers on naproxen complexation with natural and chemically modified beta-cyclodextrins.

Faucci MT, Mura P.

Dipartimento di Scienze Farmaceutiche, Firenze, Italy.

The combined effect of cyclodextrins (CDs) (beta-, methyl-beta-, hydroxypropyl-beta-cyclodextrins) and water-soluble polymers (sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone K30, polyethylene glycol 6000) on naproxen solubility improvement was studied. Phase solubility analysis at 25 degrees C was used to investigate the interaction of the drug with each cyclodextrin (or polymer, alone or in the presence of the different water-soluble polymers (or cyclodextrins). The combined use of polymer and cyclodextrin was always clearly more effective in enhancing the aqueous solubility of naproxen in comparison with the corresponding drug-polymer or drug-cyclodextrin binary systems, and the solubilization enhancement was not simply additive, but synergistic. Water-soluble polymers increased the complexation efficacy of cyclodextrins toward naproxen (as shown by the increased stability constants of the complexes), which resulted in enhanced drug solubility. No previous sonication or heating treatments of the drug-cyclodextrin-polymer suspensions was necessary to obtain this favorable effect. The best results were obtained in ternary systems with beta-cyclodextrin, which had a solubilizing effect toward naproxen in the presence of 0.25% w/v of the different hydrophilic polymers examined that was improved from 25% to about 80%, depending on the type of polymer.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11763468&dopt=Abstract Naproxen Naprosyn





Drug Metab Dispos. 2002 Feb;30(2):161-6.
Conjugation of desmethylnaproxen in the rat--a novel acyl glucuronide-sulfate diconjugate as a major biliary metabolite.

Jaggi R, Addison RS, King AR, Suthers BD, Dickinson RG.

Centre for Studies in Drug Disposition, The University of Queensland, Clinical Sciences Building, Royal Brisbane Hospital, Brisbane, Queensland, Australia.

The nonsteroidal anti-inflammatory drug naproxen is primarily metabolized in humans by acyl glucuronidation to form naproxen acyl glucuronide and by O-dealkylation to form 6-O-desmethylnaproxen (DMN). DMN contains both carboxy and phenolic groups and has been shown to form acyl glucuronide and sulfate conjugates. This project aimed to investigate whether DMN formed a phenolic glucuronide and diglucuronide(s) (with both the carboxy and phenolic groups glucuronidated). Male Sprague-Dawley rats (300-350 g) with exteriorized bile flow were dosed i.v. with DMN at 50 mg/kg. Four major DMN-related peaks were detected in bile by high-performance liquid chromatography (HPLC) analysis at 225 nm, including the known acyl glucuronide and sulfate conjugates. Selective hydrolyses using acidic and alkaline conditions and digestion with beta-glucuronidase allowed tentative identification of the two unknown peaks as the phenolic glucuronide of DMN and a novel acyl glucuronide-sulfate diconjugate of DMN (i.e., formed by sulfonation of the phenolic group and glucuronidation of the carboxy group). The identities were confirmed by liquid chromatography-tandem mass spectrometry analysis of individual HPLC fractions. Total recovery of the DMN dose was approximately 80%, with the sulfate conjugate (50%) and unchanged DMN (10%) being excreted predominantly in urine and the acyl glucuronide (10%), phenolic glucuronide (6%), and acyl glucuronide-sulfate diconjugate (4%) being excreted predominantly or exclusively in bile. No evidence for a diglucuronide metabolite of DMN was found in either bile or urine of the DMN-dosed rats.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11792685&dopt=Abstract Naproxen Naprosyn


mcmail.vanderbilt.edu

BACKGROUND: Non-aspirin, non-steroidal anti-inflammatory drugs (NANSAIDs) have complex effects that could either prevent or promote coronary heart disease. Comparison of the NANSAID rofexocib with naproxen showed a substantial difference in acute myocardial infarction risk, which has been interpreted as a protective effect of naproxen. We did an observational study to measure the effects of NANSAIDs, including naproxen, on risk of serious coronary heart disease. METHODS: We used data from the Tennessee Medicaid programme obtained between Jan 1, 1987, and Dec 31, 1998, to identify a cohort of new NANSAID users (n=181 441) and an equal number of non-users, matched for age, sex, and date NANSAID use began. Both groups were 50-84 years of age, were not resident in a nursing home, and did not have life-threatening illness. The study endpoint was hospital admission for acute myocardial infarction or death from coronary heart disease. FINDINGS: During 532634 person-years of follow-up, 6362 cases of serious coronary heart disease occurred, or 11.9 per 1000 person-years. Multivariate-adjusted rate ratios for current and former use of NANSAIDs were 1.05 (95% CI 0.97-1.14) and 1.02 (0.97-1.08), respectively. Rate ratios for naproxen, ibuprofen, and other NANSAIDs were 0.95 (0.82-1.09), 1.15 (1.02-1.28), and 1.03 (0.92-1.16), respectively. There was no protection among long-term NANSAID users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1.05 (0.91-1.21). When naproxen was directly compared with ibuprofen, the current-use rate ratio was 0.83 (0.69-0.98). INTERPRETATION: Absence of a protective effect of naproxen or other NANSAIDs on risk of coronary heart disease suggests that these drugs should not be used for cardioprotection.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11809254&dopt=Abstract Naproxen Naprosyn





Clin Ther. 2001 Dec;23(12):1984-98.
Use of nonsteroidal anti-inflammatory drugs and gastroprotective agents before the advent of cyclooxygenase-2-selective inhibitors: analysis of a large United States claims database.

Schnitzer TJ, Kong SX, Mavros PP, Straus WL, Watson DJ.

Office of Clinical Research and Training, Northwestern University, Chicago, Illinois, USA.

BACKGROUND: Previous studies have shown that 20% to 40% of patients requiring nonsteroidal anti-inflammatory drugs (NSAIDs) are concomitantly prescribed gastroprotective agents (GPAs) such as proton pump inhibitors (PPIs) and H2-receptor antagonists. OBJECTIVE: The purpose of this study was to examine NSAID prescription patterns and the concurrent use of GPAs in a large national sample of patients who were prescribed NSAIDs for the first time. METHODS: Patterns of NSAID use, particularly chronic NSAID use, and of concomitant use of GPAs were examined using a large US-based prescription database. Patients with at least 1 NSAID prescription dispensed between May 1 and August 31, 1998, were identified. Persons with any NSAID prescription within 4 months prior to the first (index) prescription were excluded. The remaining patients were defined as new NSAID users and then classified as chronic users (> or = 30 days of supply of NSAIDs during the 120 days of follow-up after the first NSAID prescription) or acute users (<30 days of NSAID supply during the 120 days of follow-up). Concomitant GPA use was defined as receipt of any GPA prescription between the fill date of NSAID prescription and 125% of days of supply. NSAIDs included diclofenac/misoprostol (in a fixed combination), diclofenac, naproxen, nabumetone, ibuprofen, and "other" (comprising several less frequently prescribed agents). Patients were classified as users of a particular NSAID based on the first NSAID prescription they received. GPAs included PPIs, H2-receptor antagonists, and misoprostol. RESULTS: A total of 3,028,808 new NSAID users were identified. Chronic NSAID users (47.8% of the sample) were older than acute users. The percentage of new chronic users aged > or = 65 years for each of the NSAIDs was 41.2% for diclofenac/ misoprostol, 33.0% for nabumetone, 30.8% for diclofenac, 20.4% for naproxen, and 20.3% for ibuprofen. The percentage of women was higher among patients treated with diclofenac/misoprostol than among patients treated with all other NSAIDs (P < 0.001). During the 120 days of follow-up, the percentages of NSAID users with concomitant GPA use were 22.7% for diclofenac/misoprostol, 16.3% for diclofenac, 11.5% for naproxen, 18.0% for nabumetone, 12.3% for ibuprofen, and 14.8% for other NSAIDs. Based on days of supply, the rates of concomitant GPA use were 31.1%, 23.6%, 17.6%, 27.3%, 18.8%, and 22.5% for diclofenac/misoprostol, diclofenac, naproxen, nabumetone, ibuprofen, and other NSAID users, respectively. Among those who were taking GPAs before the NSAID index prescription date, -89% continued GPA therapy. CONCLUSIONS: Approximately 22% of the days of NSAID supply were covered by GPAs. Prior GPA use was the strongest predictor of subsequent concomitant GPA/ NSAID use. Differences in GPA use were observed among patients using different NSAIDs.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11813933&dopt=Abstract Naproxen Naprosyn


hsc.wvu.edu

CYP2C9 wild-type protein has been shown to exhibit atypical kinetic profiles of metabolism that may affect in vitro-in vivo predictions made during the drug development process. Previous work suggests a substrate-dependent effect of polymorphic variants of CYP2C9 on the rate of metabolism; however, it is hypothesized that these active site amino acid changes will affect the kinetic profile of a drug's metabolism as well. To this end, the kinetic profiles of three model CYP2C9 substrates (flurbiprofen, naproxen, and piroxicam) were studied using purified CYP2C9*1 (wild-type) and variants involving active site amino acid changes, including the naturally occurring variants CYP2C9*3 (Leu359) and CYP2C9*5 (Glu360) and the man-made mutant CYP2C9 F114L. CYP2C9*1 (wild-type) metabolized each of the three compounds with a distinctive profile reflective of typical hyperbolic (flurbiprofen), biphasic (naproxen), and substrate inhibition (piroxicam) kinetics. CYP2C9*3 metabolism was again hyperbolic for flurbiprofen, of a linear form for naproxen (no saturation noted), and exhibited substrate inhibition with piroxicam. CYP2C9*5-mediated metabolism was hyperbolic for flurbiprofen and piroxicam but linear with respect to naproxen turnover. The F114L mutant exhibited a hyperbolic kinetic profile for flurbiprofen metabolism, a linear profile for naproxen metabolism, and a substrate inhibition kinetic profile for piroxicam metabolism. In all cases except F114L-mediated piroxicam metabolism, turnover decreased and the K(m) generally increased for each allelic variant compared with wild-type enzyme. It seems that the kinetic profile of CYP2C9-mediated metabolism is dependent on both substrate and the CYP2C9 allelic variant, thus having potential ramifications on drug disposition predictions made during the development process.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11901091&dopt=Abstract Naproxen Naprosyn


cuhk.edu.hk

BACKGROUND: Naproxen is one of the most common non-steroidal anti-inflammatory drugs used by women of reproductive age. Naproxen is known to be teratogenic in animals. The aim of this study was to investigate the placental transfer of naproxen in the first trimester of human pregnancy, and to determine the amount of the drug in different embryonic compartments. METHODS: Twenty-eight patients who requested surgical termination of pregnancy in the first trimester were given two oral 500 mg doses of naproxen before the surgical procedure. Four biological samples, maternal venous blood, coelomic fluid, amniotic fluid and fetal tissue, were collected from each patient for drug analyses by high performance liquid chromatography. RESULTS: Naproxen was detected in all samples. The mean (+/- SD) concentrations were 69.5 +/- 12.2 microg/ml, 6.4 +/- 2.4 microg/g, 1.85 +/- 1.03 microg/ml and 0.14 +/- 0.11 microg/ml in maternal serum, fetal tissue, coelomic fluid and amniotic fluid respectively. The mean amniotic fluid/maternal drug ratio and fetal/maternal drug ratio were 0.002 (range 0.0005-0.0064) and 0.092 (range 0.022-0.155) respectively. There was a positive correlation between the fetal drug concentration (r = 0.59, P = 0.001), amniotic fluid drug concentration (r = 0.47, P = 0.013), amniotic fluid/maternal ratio (r = 0.536, P = 0.003) and fetal/maternal ratio (r = 0.72, P < 0.001) with advancing gestational age. CONCLUSIONS: Although naproxen can cross the placenta readily in the first trimester of human pregnancy, only a small amount was present in fetal tissues. Since there is no information on whether this small amount of naproxen would be teratogenic or not, women of reproductive age who are taking naproxen regularly should be warned of the possible fetal side-effects.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11925405&dopt=Abstract Naproxen Naprosyn





Drug Dev Ind Pharm. 2002;28(2):129-34.
Controlled-release naproxen using micronized ethyl cellulose by wet-granulation and solid-dispersion method.

Iqbal Z, Babar A, Ashraf M.

Long Island University, Brooklyn, NY, USA.

This study has been undertaken to develop a controlled-release tablet dosage form of naproxen using ethocel (ethyl cellulose) as the rate-controlling polymer. The formulations were made by employing the conventional wet-granulation method and the solid-dispersion method. Tablets made by both methods were compared for their controlled-release dissolution profiles. Both methods were useful in developing the controlled-release formulations of naproxen with desirable properties. However, the amount of polymer required to make a formulation with the desired release profile was 33% less via solid dispersion than via wet granulation. A cumulative 88% of naproxen was released from the solid-dispersion formulation, compared with 84% from the wet-granulation formulation.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11926356&dopt=Abstract Naproxen Naprosyn