uniduesseldorf.de

PURPOSE: To synthesize new naproxen (01) derivatives with amide or ester structures or with a combination of the two (02-15). To compare their physicochemical properties with naproxen esters (16-22) and their respective skin permeation behavior. To study structure-permeation relationships via partial least squares (PLS)-analysis. METHODS: Stability, aqueous, and octanol solubility were determined. Lipophilicity and further 53 chemical descriptors were computed. A suitable in-vitro skin permeation model was developed to compare maximal flux (Jmax) of derivatives. Based on these flux data, PLS-analysis was performed to derive structure-permeation relationships. RESULTS: None of the new derivatives showed an improved flux in comparison to naproxen. This result can be explained by PLS-analysis: skin permeation increases with the solubility both in water and in octanol. For a good permeation, an optimized molecule should exhibit a small volume with a spherical shape. The surface area should be large in relation to volume, as indicated by the rugosity parameter. A clear separation between the hydrophobic and the hydrophilic domain (= high amphiphilic moment) is favorable. Lipophilicity is inversely correlated with skin permeation. CONCLUSIONS: PLS-analysis is a valuable tool to derive significant, internally predictive quantitative models for structure-permeation relationships of naproxen derivatives in the above described skin permeation assay.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11465414&dopt=Abstract Naproxen Naprosyn





Pharmacol Toxicol. 2001 Jul;89(1):43-8.
A possible mechanism of naproxen-induced lipid peroxidation in rat liver microsomes.

Ji B, Masubuchi Y, Horie T.

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.

Previous papers from our laboratory report that naproxen and salicylic acid induced lipid peroxidation in rat liver microsomes, however, the mechanism is still unclear. In the present paper, ferrous iron release, nicotinamide-adenine dinucleotide phosphate reduced form (NADPH) oxidation and hydrogen peroxide (H2O2) formation have been measured to find out which mechanisms are involved in naproxen- and salicylic acid-induced lipid peroxidation. While the increase of ferrous iron release was observed with high concentrations of naproxen, salicylic acid did not stimulate ferrous iron release. Neither of these drugs stimulated NADPH oxidation and H2O2 formation. However hexobarbital and perfluorohexane, known as uncouplers of cytochrome P450, stimulated microsomal NADPH oxidation, O2 consumption, H2O2 formation and water (H2O) formation involving four-electron oxidase reaction. These results suggest that ferrous iron release contributes to naproxen-induced microsomal lipid peroxidation and that naproxen and salicylic acid are not uncouplers of cytochrome P450. Apparently H2O2 does not play an important role in naproxen- and salicylic acid-induced microsomal lipid peroxidation.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11484909&dopt=Abstract Naproxen Naprosyn





J Microencapsul. 2001 Sep-Oct;18(5):651-62.
Response surface methodology to obtain naproxen controlled release tablets from its microspheres with Eudragit L100-55.

Zaghloul AA, Vaithiyalingam SR, Faltinek J, Reddy IK, Khan MA.

Texas Technical University Health Sciences Center, School of Pharmacy, Amarillo 79106, USA.

PURPOSE: Naproxen CR tablets have been obtained from its microspheres prepared by coprecipitation with Eudragit L100-55. The purpose of this work was to evaluate the main and interaction effects of deaggregating agent concentration (X1), compression pressure (X2) and amount of precipitating water (X3) on naproxen release. A secondary purpose was to obtain an optimized naproxen controlled release solid oral dosage form with a predictable 12 h drug release. METHOD: Eudragit L100-55 (10 g) was dissolved in 100 ml of ethyl alcohol, and 30g of naproxen was dispersed in it with stirring. Purified water (100mL, cooled to 4 degrees C) containing calcium chloride as a deaggregating agent was added to an alcoholic solution and homogenized. The mixture was filtered to obtain microspheres. Drug content analysis was performed spectrophotometrically at 332 nm. Tablets were prepared by compressing microspheres containing 500mg of naproxen after adding 1% magnesium stearate. Dissolution was performed by the USP specifications of naproxen tablets. A 3-factor 3-level Box-Behnken design was employed to get 15 experimental runs. The independent variables used were X1, X2 and X3. The dependent variables were dissolution at different time points with constraints on yield value and angle of repose of the microspheres, and hardness and thickness of the tablets. The dissolution constraints were placed such that the naproxen is released for 12 h by Higuchi's square root of time kinetics. RESULTS: The mathematical relationship obtained between X1, X2, X3 and the cumulative per cent of naproxen dissolved in 12 h with various constraints (Y5) was Y5 = 92.39 - 1.13X1 - 4.84X2 - 2.12X3 - 2.26X1X2 - 0.5X1X3 - 0.4X2X3 + 2.4X(1)(2) - 0.4X(2)(2) (R2 = 0.9). The equation shows that X1, X2 and X3 affected the release inversely, and the most significant interaction was between X1 and X2. Y5 has been maximized for optimization of naproxen release. CONCLUSIONS: Controlled release tablets of naproxen with predictable drug release characteristics were obtained by compressing its microspheres with Eudragit L100-55.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11508770&dopt=Abstract Naproxen Naprosyn





J Chromatogr A. 2001 Jul 27;924(1-2):459-64.
Enantiomeric separation of R,S-naproxen by conventional and nano-liquid chromatography with methyl-beta-cyclodextrin as a mobile phase additive.

Healy LO, Murrihy JP, Tan A, Cocker D, McEnery M, Glennon JD.

Department of Chemistry, University College Cork, Ireland.

Chiral separations of R,S-naproxen mixtures were obtained on an achiral column (ODS) with methyl-beta-cyclodextrin as a mobile phase additive using conventional and nano-LC. The optimised mobile phase composition was 20 mmol l(-1) methyl-beta-cyclodextrin, 20% (v/v) acetonitrile, and 50 mmol l(-1) sodium acetate buffer at pH 3 using hydrochloric acid for pH adjustment. In addition to UV detection at 232 nm, amperometric detection was also investigated. Without using any internal standard, the reproducibility of amperometric detection (+1.05 V vs. Ag/AgCl) over a long analysis cycle in LC was greatly improved by choosing the peak area ratio between R- and S-naproxen as the analytical readout (the relative standard deviation was 2.11%) and enantiomeric purity could be assessed directly. This method was successfully employed for enantiomeric purity assessment in commercial naproxen tablets. Finally, successful transfer from conventional LC to nano-LC was realised, resulting in over 1000-fold reduction in reagent consumption.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11521897&dopt=Abstract Naproxen Naprosyn





Arzneimittelforschung. 1975 Feb;25(2A):321-3.
[Experiences with the effect of naproxen in chronic and degenerative diseases as in overload conditions of the postural and locomotor system]

[Article in German]

Biehl G.

At the Orthopaedic University Clinic, Homburg, a total of 127 patients was treated with d-2-(6'-methoxy-2'-naphthyl)-propionic acid (naproxen) from June 1973 up to June 1974. The indications were chronic degenerative changes of the joints, muscles and tendons. In the first series naproxen was administered orally. In these 45 cases a very low rate of side effects was observed. Only 4 times nausea or vomiting occurred, which in one case had been caused by an overdosage. Generally tolerance was excellent and there was a very good relief of symptoms in early all patients. Particularly in those patients whose arthrotic alterations did not yet require surgical intervention the effect as to symptomatology was extremely good. In a second series initially 63 patients and, later on, another 19 patients were treated with naproxen suppositories. As before, concomitant medication was avoided. The therapeutic results were mostly very good to good, and only in a few cases no success was seen. It should be mentioned, however, that after application of the suppositories, a few patients noted a slight local burning after insertion of the suppository. Also blood in the feces and circulatory symptoms were reported. We believe that naproxen can achieve a very good improvement of subjective symptoms, particularly when combined with other therapeutic measures such as physiotherapy and intra- or periarticular injections. This drug should not only be used in the conservative treatment of degenerative joint diseases, but also -- as shown by our experience -- after palliative surgical procedures employed in the treatment of severe arthroses. Also in these cases a positive influence on the symptoms can be achieved.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1173779&dopt=Abstract Naproxen Naprosyn





J Clin Epidemiol. 2001 Dec;54(12):1271-4.
Hypersensitivity reactions associated with exposure to naproxen and ibuprofen: a cohort study.

McMahon AD, Evans JM, MacDonald TM.

Robertson Centre for Biostatistics, University of Glasgow, Glasgow, Scotland, UK.

The aim of the study was to evaluate the risks of hospitalisation and death due to hypersensitivity reactions associated with the NSAIDs naproxen and ibuprofen, using a record-linkage database for Tayside, Scotland (population 400,000). Cohorts of patients exposed to naproxen (n=54,038) and ibuprofen (n=79,513) were assembled. There were no deaths due to hypersensitivity. There was an increased risk of unvalidated hypersensitivity reactions during periods on-drug versus off-drug in patients exposed to naproxen and ibuprofen. However, after checking medical records, none of the three valid cases of hypersensitivity in the naproxen cohort and neither of the two in the ibuprofen cohort were judged to be due to NSAID exposure. A "worst-case" scenario gave an adjusted rate-ratio of on-drug with naproxen versus on-drug with ibuprofen of 1.63 (0.50, 5.29). The study shows that hypersensitivity reactions associated with NSAID use are rare, and provides no evidence that the risks of hypersensitivity reactions differ between naproxen and ibuprofen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11750197&dopt=Abstract Naproxen Naprosyn





Biochem Pharmacol. 2001 Dec 15;62(12):1587-95.
Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin.

Jaradat MS, Wongsud B, Phornchirasilp S, Rangwala SM, Shams G, Sutton M, Romstedt KJ, Noonan DJ, Feller DR.

Department of Pharmacology, National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677-1848, USA.

A series of nonsteroidal anti-inflammatory drugs (NSAIDs) [S(+)-naproxen, ibuprofen isomers, and indomethacin] were evaluated for their activation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma isoforms in CV-1 cells co-transfected with rat PPAR alpha and gamma, and peroxisome proliferator response element (PPRE)-luciferase reporter gene plasmids, for stimulation of peroxisomal fatty acyl CoA beta-oxidase activity in H4IIEC3 cells, and for comparative inhibition of ovine prostaglandin endoperoxide H synthase (PGHS)-1 and PGHS-2 and arachidonic acid-induced human platelet activation. Each drug produced a concentration-dependent activation of the PPAR isoforms and fatty acid beta-oxidase activity, inhibition of human arachidonic acid-induced platelet aggregation and serotonin secretion, and inhibition of PGHS-1 and PGHS-2 activities. For PPARalpha activation in CV-1 and H4IIEC3 cells, and the stimulation of fatty acyl oxidase activity in H4IIEC3 cells, the rank order of stereoselectivity was S(+)- ibuprofen > R(-)-ibuprofen; S(+)-ibuprofen was more potent than indomethacin and naproxen on these parameters. On PPARgamma, the rank order was S(+)-naproxen > indomethacin > S(+)-ibuprofen > R(-)-ibuprofen. Each drug inhibited PGHS-1 activity and platelet aggregation with the same rank order of indomethacin > S(+)-ibuprofen > S(+)-naproxen > R(-)-ibuprofen. Notably, the S(+)-isomer of ibuprofen was 32-, 41-, and 96-fold more potent than the R(-)-isomer for the inhibition of PGHS-1 activity, human platelet aggregation, and serotonin secretion, respectively. On PGHS-2, the ibuprofen isomers showed no selectivity, and indomethacin, S(+)-ibuprofen, and S(+)-naproxen were 6-, 27-, and 5-fold more potent as inhibitors of PGHS-1 than PGHS-2 activity. These results demonstrate that the mechanisms of action of NSAIDs on these cell systems are different, and we propose that the pharmacological effects of NSAIDs may be related to both their profile of inhibition of PGHS enzymes and the activation of PPARalpha and/or PPARgamma isoforms.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11755111&dopt=Abstract Naproxen Naprosyn