Arch Pharm (Weinheim). 2002 Aug;335(8):363-6.
NO-donors (VII [1]): synthesis and cyclooxygenase inhibitory properties of N-and S-nitrooxypivaloyl-cysteine derivatives of naproxen -- a novel type of NO-NSAID.

Kartasasmita RE, Laufer S, Lehmann J.

Institute of Pharmacy, University of Bonn, Bonn, Germany.

Nitric oxide (NO)has been reported to subserve many of the same mucosal protection mechanisms as prostaglandins and is sufficient for acute gastroprotection and ulcer healing. In fact, NO-donating NSAID hybrid compounds such as the nitrooxybutyl ester of naproxen show reduced ulcerogenic activity while maintaining anti-inflammatory activity. We introduce two prototypes of novel triple-hybrid compounds consisting of cysteine which is known to enhance the activity of organic nitrates and to reduce nitrate tolerance, an NSAID (naproxen), and an organic nitrate (nitrooxypivaloic acid). L-Cysteine ethyl ester first was N-acylated in a CH(2)Cl(2)/H(2)O twophase system using the acid chlorides of naproxen or nitrooxypivaloic acid, respectively, and sodium acetate, or alternatively using the DCC-activated nitrooxy acid in absolute CH(2)Cl(2). The N-acylated intermediates were subsequently S-acylated using the acid chlorides or alternatively the carbonyldiimidazole (CDI)-activated acids again. The two naproxen-cysteine-nitrate hybrid prodrugs were screened in vitro for their cyclooxygenase inhibitory properties relative to naproxen. In this screening the N-nitrooxyacylcysteine derivative was found to be inactive in the concentration range of 0.1-10 micromol/L against both COX-1 and COX-2, while the S-nitrooxyacylcysteine derivative had only weak activity against COX-1.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12397619&dopt=Abstract Naproxen Naprosyn





Anesthesiology. 2002 Nov;97(5):1263-73.
Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia.

Hurley RW, Chatterjea D, Rose Feng M, Taylor CP, Hammond DL.

Department of Anesthesia and Critical Care, and Committee on Neurobiology, University of Chicago, Illinois, USA.

BACKGROUND: Gabapentin and pregabalin are anticonvulsants with antihyperalgesic effects in animal models of neuropathic and inflammatory nociception. This study characterized the manner in which gabapentin or pregabalin interacts with naproxen to suppress thermal hyperalgesia and inflammation in the carrageenan model of peripheral inflammation. METHODS: Gabapentin, pregabalin, naproxen, or a fixed-dose ratio of gabapentin + naproxen or pregabalin + naproxen was administered orally to rats after the induction of inflammation by intraplantar injection of lambda-carrageenan in one hind paw. Nociceptive thresholds were determined by the radiant heat paw-withdrawal test. Paw edema was measured by plethysmometry. Drug plasma concentrations were determined by a liquid chromatography-mass spectroscopy-mass spectroscopy method. RESULTS: Gabapentin, pregabalin, and naproxen alone reversed thermal hyperalgesia with ED50 values of 19.2, 6.0, and 0.5 mg/kg, respectively. Mixtures of gabapentin + naproxen in fixed-dose ratios of 50:1, 10:1, or 1:1 interacted synergistically to reverse carrageenan-induced thermal hyperalgesia. However, 1:50 gabapentin + naproxen produced only additive effects. No combination of gabapentin + naproxen decreased paw edema in a manner greater than additive. Plasma concentrations of gabapentin and naproxen were unaltered by the addition of the other drug. The mixture of 10:1 of pregabalin + naproxen interacted synergistically to reverse thermal hyperalgesia on the inflamed hind paw, whereas mixtures of 1:1 or 1:10 produced additive effects. CONCLUSIONS: These data suggest that gabapentin + naproxen and pregabalin + naproxen can interact synergistically or additively to reverse thermal hyperalgesia associated with peripheral inflammation. Therefore, the use of gabapentin or pregabalin in low-dose combinations with naproxen may afford therapeutic advantages for clinical treatment of persistent inflammatory pain.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411814&dopt=Abstract Naproxen Naprosyn


stanford.edu

Whether non-steroidal anti-inflammatory drug (NSAID)-induced suppression of bone ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, or through a yet unidentified pathway is unknown. In this study, the effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2 inhibitor on bone ingrowth and tissue differentiation are examined in vivo. Harvest chambers were implanted unilaterally in the tibiae of eight mature, New Zealand white rabbits. After a 6-week period for osseointegration of the chamber, the following oral treatments were given for 4 weeks each, followed by a harvest in each case: drinking water with no NSAID (control 1), Naproxen sodium--a COX-1 and COX-2 non-specific inhibitor at a dose of 110 mg/kg/day in the drinking water, drinking water with no NSAID (control 2), and Rofecoxib-a COX-2 inhibitor at a dose of 12.5 mg/day inserted directly into the rabbit's mouth. Harvested specimens were snap frozen, cut into serial 6 microm sections and stained with hematoxylin and eosin for general morphological characterization, and alkaline phosphatase (osteoblast marker). Sections were also processed for immunoperoxidase staining using monoclonal antibodies to identify cells expressing the vitronectin receptor (osteoclast-like cells). With drinking water alone, the percentage of bone ingrowth averaged 24.8 +/- 2.9% and 29.9 +/- 4.5% respectively. Naproxen sodium in the drinking water and oral Rofecoxib decreased bone ingrowth significantly (15.9 +/- 3.3%. p = 0.031 and 18.5 +/- 2+/-4%, p = 0.035 compared to drinking water respectively). Both Naproxen sodium (p = 0.026) and Rofecoxib (p = 0.02) decreased the number of CD51 positive osteoclast-like cells per section compared with drinking water alone. Rofecoxib decreased the area of osteoblasts per section area (p = 0.014) compared to controls, although the value for Naproxen sodium did not reach statistical significance. The results of the present study suggest that bone formation is suppressed by oral administration of an NSAID which contains a COX-2 inhibitor. COX-2 inhibitors currently taken for arthritis and other conditions may potentially delay fracture healing and bone ingrowth.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12472224&dopt=Abstract Naproxen Naprosyn


dfh.dk

Xenobiotic carboxylic acids, that via their metabolites covalently modify proteins, have been associated with serious side effects in man. Such reactive metabolites may be acyl glucuronides or alternatively, the corresponding acyl-CoA thioesters. In this study, the reaction of a model xenobiotic acyl-CoA, the naproxen-CoA, with human serum albumin (HSA), was characterized by high-performance liquid chromatography employing fluorescence and mass spectrometric detection. One mM naproxen-CoA was incubated for 6h with HSA (0.45 mM) at 37 degrees C in a 0.1M phosphate buffer (pH 7.4). The tryptic digest of the reduced and alkylated protein was analyzed in order to identify the amino acids in the sequence that were covalently modified with naproxen. Fluorescent peptides, that represented naproxen-modified peptides, were characterized using HPLC-MS-MS and HPLC-MS in zoom scan mode, which provided information on the structure and the charge of the modified peptides. The naproxen-CoA reacted predominantly with lysine 199, lysine 541, and lysine 351, which was in agreement with the binding pattern that has previously been reported for the reactive acyl glucuronides and their reaction with HSA.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12531199&dopt=Abstract Naproxen Naprosyn





Se Pu. 2000 Jan;18(1):70-2.
[Chiral separation of naproxen and flurbiprofen by capillary electrophoresis]

[Article in Chinese]

Zhu XF, Lin BC.

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.

The acidic chiral drugs naproxen and flurbiprofen were successfully separated into two enantiomers when beta-cyclodextrins (beta-CDs) were used as chiral selectors by capillary zone electrophoresis, under the conditions of 0.1 mol/L phosphate buffer with pH 4.92. The comparison of four CDs, namely beta-CD, DM-beta-CD, HP-beta-CD and TM-beta-CD for chiral separation was made. Naproxen can be separated by either beta-CD or its derivatives, while flurbiprofen can only be separated by TM-beta-CD among the CDs. The elution order of enantiomers of naproxen in different CDs was also studied, and the R form always eluted before S form when any of the four CDs was used as chiral selectors. The method of chiral separation for weak acidic compounds was also developed. It was proved that the optimum pH value for their chiral separation was about 5, close to its pKa value.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12541462&dopt=Abstract Naproxen Naprosyn


ices.on.ca

BACKGROUND: Recent debate has emerged regarding the cardiovascular safety of selective cyclooxygenase 2 inhibitors and the possible cardioprotective effect of naproxen sodium. We compared the rates of acute myocardial infarction (AMI) among elderly patients dispensed selective cyclooxygenase 2 inhibitors, naproxen, and nonselective nonnaproxen nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We conducted a population-based retrospective cohort study using administrative health care data from Ontario, Canada, from April 1, 1998, to March 31, 2001. We identified NSAID-naive cohorts of subjects aged 66 years and older in whom treatment was initiated with celecoxib (n = 15 271), rofecoxib (n = 12 156), naproxen (n = 5669), and nonnaproxen nonselective NSAIDs (n = 33 868), along with a randomly selected control cohort not exposed to NSAIDs (n = 100 000). Multivariate Cox proportional hazards models were used to compare AMI rates between study drug groups while controlling for potential confounders. RESULTS: Relative to control subjects, the multivariate model showed no significant differences in AMI risk for new users of celecoxib (adjusted rate ratio [aRR], 0.9; 95% confidence interval [CI], 0.7-1.2), rofecoxib (aRR, 1.0; 95% CI, 0.8-1.4), naproxen (aRR, 1.0; 95% CI, 0.6-1.7), or nonnaproxen nonselective NSAIDs (aRR, 1.2; 95% CI, 0.9-1.4). CONCLUSIONS: The findings of this observational study suggest no increase in the short-term risk of AMI among users of selective cyclooxygenase 2 inhibitors as commonly used in clinical practice. Furthermore, the findings do not support a short-term reduced risk of AMI with naproxen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12588209&dopt=Abstract Naproxen Naprosyn





Environ Sci Technol. 2003 Mar 15;37(6):1061-8.
Occurrence and fate of carbamazepine, clofibric acid, diclofenac, ibuprofen, ketoprofen, and naproxen in surface waters.

Tixier C, Singer HP, Oellers S, Muller SR.

Swiss Federal Institute for Environmental Science and Technology (EAWAG), Uberlandstrasse 133, CH-8600 Dubendorf, Switzerland.

Although various single-concentration measurements of pharmaceuticals are available in the literature, detailed information on the variation over time of the concentration and the load in wastewater effluents and rivers and on the fate of these compounds in the aquatic environment are lacking. We measured the concentrations of six pharmaceuticals, carbamazepine, clofibric acid, diclofenac, ibuprofen, ketoprofen, and naproxen, in the effluents of three wastewater treatment plants (WWTPs), in two rivers and in the water column of Lake Greifensee (Switzerland) over a time period of three months. In WWTP effluents, the concentrations reached 0.95 microg/L for carbamazepine, 0.06 microg/L for clofibric acid, 0.99 microg/L for diclofenac, 1.3 microg/L for ibuprofen, 0.18 microg/L for ketoprofen, and 2.6 microg/L for naproxen. The relative importance in terms of loads was carbamazepine, followed by diclofenac, naproxen, ibuprofen, clofibric acid, and ketoprofen. An overall removal rate of all these pharmaceuticals was estimated in surface waters, under real-world conditions (in a lake), using field measurements and modeling. Carbamazepine and clofibric acid were fairly persistent. Phototransformation was identified as the main elimination process of diclofenac in the lake water during the study period. With a relatively high sorption coefficient to particles, ibuprofen might be eliminated by sedimentation. For ketoprofen and naproxen, biodegradation and phototransformation might be elimination processes. For the first time, quantitative data regarding removal rates were determined in surface waters under real-world conditions. All these findings are important data for a risk assessment of these compounds in surface waters.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12680655&dopt=Abstract Naproxen Naprosyn