Clin Exp Rheumatol. 1997 Jul-Aug;15(4):393-8.
Two NSAIDs, nimesulide and naproxen, can reduce the synthesis of urokinase and IL-6 while increasing PAI-1, in human OA synovial fibroblasts.

Pelletier JP, Mineau F, Fernandes J, Kiansa K, Ranger P, Martel-Pelletier J.

Osteoarthritis Research Unit, Louis-Charles Simard Research Center, Notre-Dame Hospital, Montreal, Quebec, Canada.

OBJECTIVES: To evaluate the effect of therapeutic and pharmacologic concentrations of two non-steroidal anti-inflammatory drugs (NSAIDs), nimesulide and naproxen, on the synthesis of urokinase (uPA), plasminogen activator inhibitor (PAI-1) and interleukin-6 (IL-6) in human synovial fibroblasts isolated from osteoarthritis (OA) patients. METHODS: Urokinase, PAI-1, and IL-6 production were measured by specific ELISA. RESULTS: Nimesulide and naproxen induced a dose-dependent decrease in uPA synthesis. The two drugs, at therapeutic concentrations, exerted a stimulatory effect on the synthesis of PAI-1 whereas the synthesis of IL-6 was significantly reduced by both NSAIDs. CONCLUSION: The results of this study indicate some of the mechanisms by which nimesulide and naproxen could exert their effects on the arthritis process. The suppressive action of the two drugs on the synthesis of uPA, while stimulating PAI-1 production, may have a positive impact on the balance of plasminogen activator/inhibitor, which could help reduce cartilage catabolism.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9272300&dopt=Abstract Naproxen Naprosyn





Biopharm Drug Dispos. 1997 Oct;18(7):623-33.
Pharmacokinetic and local tissue disposition studies of naproxen-following topical and systemic administration in dogs and rats.

Suh H, Jun HW, Dzimianski MT, Lu GW.

Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602, USA.

The pharmacokinetic profiles of naproxen in blood and synovial fluid (SF) following topical and i.v. bolus administration in dogs, and the local tissue disposition of the drug following topical and oral administration in rats, were investigated to assess the feasibility of topical delivery of naproxen for local and systemic effects. The naproxen gel in poloxamer 407 (PF-127) was applied on the stifle joint of dogs, and serum and synovial fluid samples were collected. For local tissue disposition studies, the naproxen gel was applied on the dorsal skin in rats, and blood, skin, and muscle samples were taken at 3, 6, and 12 h postdose after removing the residual gel from the skin. Steady state serum concentrations occurred at approximately 20 h after topical doses and lasted for the next approximately 30 h in dogs. Similar SF-serum concentration ratios of naproxen were found between i.v. (0.61 +/- 0.16) and topical (0.55 +/- 0.14) routes of administration. Following the i.v. dose, the half-life of naproxen in SF (approximately 60 h) was significantly longer than that in serum (approximately 40 h). The bioavailability of naproxen in the topical gel was approximately 2% of the applied dose in dogs. A large accumulation of drug in the epidermis, dermis, and muscle tissue beneath the gel application site was found in rats. Isopropyl myristate (IPM) significantly increased the systemic absorption as well as the concentrations of naproxen in the underlying dermis and muscle tissues, but exerted little effect on the disposition of naproxen in the epidermis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9330782&dopt=Abstract Naproxen Naprosyn





Clin Chem. 1997 Nov;43(11):2083-90.
Differentiation between naproxen, naproxen-protein conjugates, and naproxen-lysine in plasma via micellar electrokinetic capillary chromatography--a new approach in the bioanalysis of drug targeting preparations.

Albrecht C, Reichen J, Visser J, Meijer DK, Thormann W.

Department of Clinical Pharmacology, University of Bern, Switzerland.

Pharmacotherapy through the targeting of drugs is a promising new approach that requires adequate analytical methods capable of differentiating between the free drug, the drug carrier, and metabolites. Using micellar electrokinetic capillary chromatography (MECC), we report the separation of naproxen (NAP) from NAP covalently coupled to human serum albumin or to mannosylated serum albumin and the metabolite naproxen-lysine. An assay for selective analysis of the different forms of NAP by direct plasma injection was developed with salicylate as internal standard and solute detection by laser-induced fluorescence. Compared with previously applied techniques, including HPLC and total plasma fluorescence, MECC offers the advantage that free and covalently bound NAP can be differentiated in one run and can be accurately monitored in microliter quantities of plasma. Summation of all NAP equivalents determined by MECC revealed data that compare well with those produced by total plasma fluorescence and HPLC.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9365392&dopt=Abstract Naproxen Naprosyn





J Orthop Res. 1992 Sep;10(5):647-56.
[99mTc]diphosphonate uptake and hemodynamics in experimental arthritis: effect of naproxen in the canine carrageenan injection model.

Hansen ES, He SZ, Soballe K, Kjolseth D, Henriksen TB, Hjortdal VE, Bunger C.

Department of Orthopedics, University of Aarhus, Denmark.

The impact of naproxen treatment on juxta-articular hemodynamics and bone metabolism in experimental juvenile arthritis was studied in the articular carrageenan injection model. Unilateral gonarthritis was induced for 12 weeks in eight dogs receiving naproxen (dosage, 2 mg/kg) and eight controls. Regional blood flow was assessed by the microsphere method, plasma volume by the distribution space of [125I]fibrinogen, and bone metabolism by the 2-h uptake of [99mTc]diphosphonate ([99mTc]DPD). Synovial effusion was less prominent with naproxen treatment as judged by joint fluid volume and pressure. Naproxen reduced the arthritic capsular hyperemia, almost normalized a severe blood flow increase in patella and both juxta-articular epiphyses, ameliorated an expansion of plasma volume in the patella and the distal femoral epiphysis, and normalized an increased [99mTc]DPD uptake in subchondral femoral bone and the tibial cortex. Significantly increased arteriovenous shunting in the arthritic extremity was unaffected by naproxen. The study suggests that long-term cyclooxygenase inhibition offers protection against hemodynamic and metabolic changes in juxta-articular bone secondary to synovial inflammation.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1500978&dopt=Abstract Naproxen Naprosyn





Kidney Int. 1997 Dec;52(6):1693-9.
Drug-targeting to the kidney: renal delivery and degradation of a naproxen-lysozyme conjugate in vivo.

Haas M, Kluppel AC, Wartna ES, Moolenaar F, Meijer DK, de Jong PE, de Zeeuw D.

Groningen Institute for Drug Studies (GIDS), The Netherlands.

A renal-specific controlled release of an active drug may enable a reduction of the required dose and may provide a reduction of extra-renal toxicity. To achieve renal specific targeting of the NSAID naproxen, the low-molecular-weight protein (LMWP) lysozyme was employed as carrier since it is mainly taken up and catabolized in the proximal tubules of the kidney. A conjugate was synthesized with an average coupling degree of 2 mol naproxen per 1 mol lysozyme in which the drug was directly coupled to the protein via a peptide bond. First, we investigated whether naproxen conjugation affects the renal disposition of lysozyme. As native lysozyme, the conjugate was predominantly and rapidly (within 20 min) taken up by the kidney. The subsequent decrease in renal content reflecting the renal degradation of the conjugated lysozyme molecules appeared also to be similar to that of native lysozyme with a half life of four hours. Second, the effect of lysozyme conjugation on the body distribution of naproxen was studied. An important observation with regard to the aimed reduction in extra-renal side effects was that no detectable amounts of free naproxen were present in the plasma after administration of conjugate. Conjugation of naproxen to lysozyme resulted in a pronounced (70-fold) increase of naproxen accumulation in the kidney. In agreement with the protein disposition study, the conjugate was rapidly taken up by the kidney and subsequently degraded. In conclusion, renal selective targeting of the NSAID naproxen can be obtained by conjugation with the LMWP lysozyme. This concept of drug delivery to the kidney has the potential to improve drug efficacy and safety.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9407519&dopt=Abstract Naproxen Naprosyn





Appl Biochem Biotechnol. 1997 Dec;68(3):135-42.
Surfactant effect on enhancing (S)-naproxen prodrug production from racemic naproxen by lipase.

Chang CS, Tsai SW.

Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan, Republic of China.

In the enantioselective esterification of racemic naproxen with 4-(2-hydroxyethyl) morpholine by Lipase MY in organic solvents, a productivity improvement of the desired (S)-naproxen ester from 0.42 to 0.72 mM at the reaction time of 130 h was observed, when the surfactant bis (2-ethylhexyl) sodium sulfosuccinate (AOT) was added in the reaction mixture. The presence of a small amount of exogenously added water dramatically activated the enzyme in AOT/cyclohexane-reversed micelles. Desorption of the surfactant molecule from the enzyme mass and solubilization of the enzyme into reversed micelles were used to elucidate an existing maximum of the initial rate of (S)-naproxen synthesis with the water content. Moreover, the effects of alcohol and surfactant concentration on the enzyme activity are reported.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9429297&dopt=Abstract Naproxen Naprosyn





Arch Orthop Trauma Surg. 1986;105(3):137-41.
Effects of acetylsalicylic acid and naproxen on bone resorption and formation in rats.

Solheim LF, Ronningen H, Langeland N.

The influence of acetylsalicylic acid (ASA) (150 mg/kg/12 h) and naproxen (20 mg/kg/12 h) on bone metabolism in young male rats has been studied. The doses were chosen to provide serum concentrations comparable with ordinary anti-inflammatory steady-state levels in humans. After the rats had been prelabeled with collagen- and mineral-tracing radioisotopes the rats received the drugs by gavage twice a day for 9 and 18 days. Bone resorption was measured as loss of carbon-labeled hydroxyproline (collagen) and strontium-85 (minerals). At 9 days ASA had retarded both collagen and mineral resorption in the femur by about 10% compared with controls. The resorption of both collagen and minerals was inhibited. After 18 days' treatment there were no differences regarding bone resorption, but bone formation had decreased by about 10% in the ASA-treated animals, as measured by net increases of collagen and calcium in the femur. Naproxen did not influence bone resorption or formation significantly. The results indicate an inhibitory effect of ASA on bone resorption and formation in growing rats, whereas the effect of naproxen seems negligible.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3741065&dopt=Abstract Naproxen Naprosyn