J Rheumatol. 1998 Dec;25(12):2417-24.
Diacerhein and rhein reduce the interleukin 1beta stimulated inducible nitric oxide synthesis level and activity while stimulating cyclooxygenase-2 synthesis in human osteoarthritic chondrocytes.

Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-Pelletier J.

Rheumatic Disease Unit, Centre hospitalier de l'Universite de Montreal, Quebec, Canada.

OBJECTIVE: To evaluate the in vitro effects of diacerhein, a new drug for the treatment of osteoarthritis (OA), and its active metabolite, rhein, on the production of nitric oxide (NO), prostaglandin (PGE2), cyclooxygenase-2 (COX-2), as well as the production and expression of the inducible nitric oxide synthase (iNOS) in human OA chondrocytes. These results were compared to those of the nonsteroidal antiinflammatory drug (NSAID) naproxen. METHODS: Human OA chondrocytes were incubated in the presence or absence of 25 units/ml recombinant human interleukin-1beta (rhIL-1beta) with or without therapeutic concentrations of diacerhein and rhein at 5, 10, and 20 microg/ml and naproxen at 30 and 90 microg/ml. Effect of the drugs was also tested on both OA chondrocytes and cartilage explants on increasing IL-1beta concentration (0-100 units/ml). The NO and PGE2 levels were determined in the culture medium using the Griess reaction and a specific ELISA, respectively. Production of COX-2 and synthesis and expression of iNOS were quantitated by Western blot and Northern blot, respectively. RESULTS: The IL- 1beta induced NO production was inhibited by both diacerhein and rhein in a time and dose dependent fashion, with statistical significance reached at the therapeutic concentration of 20 microg/ml. A decrease over 80% was found at 24, 48, and 72 h incubation. This was consistent for both chondrocytes and cartilage explants even in the presence of high IL-1beta concentration (100 units/ml). Moreover, this effect appeared to result from iNOS transcriptional and/or post-transcriptional events as indicated by a decrease in this enzyme level for both the mRNA and protein. Naproxen, however, showed only a slight inhibition of IL-1beta induced NO production at the highest dose used, 90 microg/ml. A maximum decrease of 23% in IL-1beta induced NO production was recorded after a 72 h incubation. In contrast to naproxen, which abrogated PGE2 and had no effect on COX-2 synthesis, rhein and diacerhein at 5 and 10 microg/ml produced an enhancement in their levels. CONCLUSION: Diacerhein and rhein, in contrast to an NSAID, are potent inhibitors of IL-1beta induced NO production by chondrocytes and cartilage, without reducing PGE2 production.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9858439&dopt=Abstract Naproxen Naprosyn


pharm.usyd.edu.au

The nonsteroidal anti-inflammatory drugs (NSAID), naproxen, sulindac and indomethacin, were shown to donate electrons to nitro blue tetrazolium (NBT) when irradiated with UV light in deoxygenated aqueous buffer solution (pH 7.4, 30 degrees C). The reaction was monitored spectrophotometrically by the appearance of the diformazan reduction product from NBT. The electron transfer process facilitates the decomposition of the drugs. Naproxen in the presence of NBT is photodegraded principally to the alcohol (2-[1-hydroxyethyl]-6-methoxynaphthalene) at a rate approximately 20-fold faster than when irradiated alone in deoxygenated conditions. The photoproduct from naproxen also participates in the electron transfer to NBT but at a much slower rate than naproxen. Irradiation of sulindac or indomethacin in the presence of NBT caused the slow photoreduction of NBT to diformazan. In the absence of NBT, indomethacin and sulindac are essentially unreactive when irradiated in aqueous solution. The ability of a number of NSAID to act as electron donors in their ground state was studied by observing their oxidation by potassium peroxodisulfate in pH 7.0 phosphate buffer at 50 degrees C. The HPLC analysis of the drug remaining showed that the 2-arylpropionic acid NSAID (naproxen, ibuprofen, ketoprofen and suprofen) reacted at a rate equivalent to the thermal decomposition of peroxodisulfate. The major products were the same as detected in the photooxidation of these drugs, resulting from decarboxylation and oxygen addition but also included a dimeric compound. On the other hand, the NSAID that do not contain the propionic acid substituent all reacted more slowly with peroxodisulfate, enabling specific reaction rate constants to be evaluated.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9867601&dopt=Abstract Naproxen Naprosyn





J Drug Target. 1998;6(2):105-17.
Effect of chronic bile duct obstruction and LPS upon targeting of naproxen to the liver using naproxen-albumin conjugate.

Albrecht C, Melgert BN, Reichen J, Poelstra K, Meijer DK.

Department of Clinical Pharmacology, University of Berne, Switzerland.

Naproxen covalently linked to human serum albumin (NAP-HSA) is efficiently targeted to endothelial and Kupffer cells of the liver and may offer a new therapeutic approach in the treatment of liver disease associated with inflammatory processes. In the present investigation we explored the pharmacokinetic behaviour of targeted and non-targeted naproxen as well as the pharmacokinetic properties of the active metabolite, Naproxen lysine (Nap lysine), in rats rendered fibrotic by bile duct ligation (BDL) for 4 weeks. Furthermore, we studied the effect of endotoxemia, experimentally induced by intravenous injection of 800 microg/kg lipopolysaccaride (LPS) upon the pharmacokinetics of these agents in order to investigate the feasibility of targeting naproxen to non-parenchymal cells in the inflamed and fibrotic liver. Our studies demonstrate that liver disease altered the pharmacokinetic behaviour of the different naproxen compounds. Thus, initial plasma concentrations of NAP HSA and naproxen were markedly lower in BDL rats accompanied by an increase of the volume of distribution during the terminal elimination phase (Vd(beta) BDL vs control 114 +/- 63 vs 50 +/- 7 and 202 +/- 24 vs 115 +/- 11 ml/kg for naproxen and NAP-HSA, respectively). After injection of LPS, no significant change in the pharmacokinetics of NAP-HSA was found whereas the naproxen treated control animals showed an increase in the terminal volume of distribution (176 +/- 34 vs 115 +/- 11 ml/kg) as well as an elevation of the plasma half-life (171 +/- 27 vs 116 +/- 14 min). The feasibility of targeting naproxen to the chronically diseased liver could be clearly demonstrated: 15 min after administration of the conjugate 46% and 55% of the administered dose was found in the liver of CTR and BDL rats, whereas after injection of free naproxen only 5% and 12% of the dose was detected in liver tissue, respectively. We conclude that targeting albumin-linked naproxen to non-parenchymal cells in the liver is still feasible under the pathological conditions induced in the present study. Liver fibrosis induced significant alterations in the pharmacokinetic behaviour of the studied compounds.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9886235&dopt=Abstract Naproxen Naprosyn





Biochem Pharmacol. 1999 Feb 1;57(3):247-54.
Interaction of indomethacin and naproxen with gastric surface-active phospholipids: a possible mechanism for the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs).

Giraud MN, Motta C, Romero JJ, Bommelaer G, Lichtenberger LM.

Department of Integrative Biology, Pharmacology and Physiology, University of Texas-Houston Medical School, USA.

The possibility that the molecular mechanism underlying the topical gastric irritancy of nonsteroidal anti-inflammatory drugs (NSAIDs) may involve alterations in the surface-active properties of gastric phospholipids was investigated. Indomethacin and naproxen were intragastrically administered to rats and the hydrophobicity of the luminal surface of the stomach wall was assessed by contact angle analysis. Both NSAIDs have the ability to attenuate the phospholipid-related hydrophobic properties of the gastric mucosa by more than 80-85% in a dose-dependent fashion. Potential molecular interactions between both NSAIDs and surface-active phospholipids were analyzed using fluorescent probes. Indomethacin has the ability to displace, in a dose-dependent manner, ANS (1-anilino-8-naphthalene sulphonate), a fluorescent anionic probe previously bound to the head group of phosphatidylcholine molecules. Estimations of the resonance fluorescence transfer between naproxen and the surface probe ANS or the hydrophobic probe, pyrene, bound to dipalmitoylphosphatidylcholine (DPPC) vesicles revealed that naproxen diffuses within the phospholipid bilayers. The dynamic of the gastric lipid material extracted from the surface scraping material (SSM) of the mucosa was altered by the NSAID as shown by the increase in the steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) (at 25 degrees, rSSM = 0.106+/-0.006, rssM + indomethacin = 0.137+/-0.005, and rSSM + naproxen = 0.133+/-0.007, P < 0.001). The thermodynamic behavior of a model bilayer containing DPPC was also perturbed by the NSAIDs tested. These results provide evidence that NSAIDs may reduce the ability of gastric surface-active phospholipids to form a hydrophobic protective layer.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9890551&dopt=Abstract Naproxen Naprosyn


ulg.ac.be

A capillary electrophoresis (CE) method was developed for the stereoselective determination of the non-steroidal anti-inflammatory drug (NSAID), S-naproxen, in tablets. Several beta-cyclodextrin derivatives (CDs) were tested as chiral selectors, including sulfobutyl-beta-CD (SBCD), carboxymethyl-beta-CD (CMCD), dimethyl-beta-CD (DMCD) and trimethyl-beta-CD (TMCD), in a phosphoric acid/triethanolamine pH 3 buffer. Under these conditions, the analyte was mainly present in an uncharged form and therefore, the use a neutral CD (DMCD or TMCD) alone could not lead to enantiomeric separation. On the contrary, by addition of a charged CD (SBCD or CMCD) to the running buffer, giving the analyte enantiomers an adequate mobility, chiral resolution could be achieved, although the resolution values obtained in this case were not quite satisfactory (Rs < 1.5). Dual systems, based on the use of mixtures of charged and neutral CDs, were then investigated. The SBCD/TMCD system was found to be particularly well suited to the enantioseparation of naproxen and after optimisation of the concentrations of both CDs, a resolution value of 5.4 could be obtained. The method was validated for the determination of R-naproxen (enantiomeric impurity) in the 0.1-2% range, using the racemic mixture of the analyte. A second validation was performed in the 50-150% range for the quantitation of S-naproxen. In both cases, good results with respect to linearity, precision and accuracy were obtained.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9919982&dopt=Abstract Naproxen Naprosyn





Photochem Photobiol. 1993 Mar;57(3):486-90.
Involvement of drug-derived peroxides in the phototoxicity of naproxen and tiaprofenic acid.

Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P.

Centro de Investigacion, Hospital Universitario La Fe (SVS), Valencia, Spain.

Photodegradation of naproxen and tiaprofenic acid in aqueous buffered solutions leads to decarboxylated products with ethyl, 1-hydroxyethyl and/or acetyl side chains. The photomixtures obtained in the presence of oxygen were clearly more toxic to cultured hepatocytes than those obtained under anaerobic conditions. This effect was more noticeable in the case of naproxen. Based on the composition of the oxygenated photomixtures and the relative toxicity of the different photoproducts, it is possible to account for most of the observed toxicity in the case of tiaprofenic acid but not in the case of naproxen. This is explained as a result of the presence of drug-derived peroxidic species in the photomixtures and their contribution to the observed toxicity. Peroxides were determined by the peroxidase-catalyzed oxidation of dichlorodihydrofluorescein to its fluorescent analog. The amount of peroxides present in naproxen photomixtures was much higher than in the case of tiaprofenic acid. A dose-dependent depletion of intracellular glutathione was observed when hepatocytes were incubated with peroxide-containing naproxen photomixtures. This effect was prevented by the addition of catalase or N-acetylcysteine to the culture medium.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8475183&dopt=Abstract Naproxen Naprosyn





Pharm Acta Helv. 1991;66(7):204-8.
Diffusion of naproxen in presence of beta-cyclodextrin across a silicone rubber membrane.

Orienti I, Fini A, Zecchi V, Zuman P.

Dipartimento di Scienze Farmaceutiche, Bologna, Italy.

The diffusion of Naproxen through a silicone rubber membrane has been studied for four different release systems: solution and suspension both of Naproxen and Naproxen beta-cyclodextrin coprecipitates. Differences in transport between the two forms indicate the existence of an interaction between the acid and beta-cyclodextrin in solution. Independence of the transport on pH in the case of the coprecipitate indicates rapid liberation of Naproxen from the complex prior to entering the membrane. Increase in the cumulative amount diffused for the suspension of Naproxen with increasing pH was interpreted as due to an increase in its solubility with increasing pH.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1763095&dopt=Abstract Naproxen Naprosyn