Aliment Pharmacol Ther. 1997 Feb;11(1):69-79.
NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects.

Davies NM, Roseth AG, Appleyard CB, McKnight W, Del Soldato P, Calignano A, Cirino G, Wallace JL.

Intestinal Disease Research Unit, Faculty of Medicine, University of Calgary, Alberta, Canada.

BACKGROUND: A novel class of nitric oxide-releasing nonsteroidal anti-inflammatory drug (NO-NSAID) derivatives has recently been described which exert anti-inflammatory activities but produce significantly less gastrointestinal injury than the parent NSAID from which they are derived. The present studies were performed to determine if a nitroxybutylester derivative of naproxen was less ulcerogenic to the gastrointestinal tract than its parent NSAID, and if it exerted comparable analgesic and anti-inflammatory properties to the parent NSAID. METHODS: The two drugs were compared in an acute gastric injury model, an antral ulcer model and after twice-daily administration for 18 days (small intestinal damage model). Anti-inflammatory activity was examined in the carrageenan-induced paw oedema model, while analgesia was examined in the acetic acid-induced writhing model. The pharmacokinetic profiles of naproxen vs. NO-naproxen were compared by HPLC analysis. RESULTS: NO-naproxen was found to produce significantly less gastric damage despite inducing similar increases in plasma TNF alpha to naproxen. With chronic administration, small intestinal damage was markedly less with NO-naproxen than with the parent NSAID. However, NO-naproxen exerted superior analgesic and comparable anti-inflammatory effects to naproxen. NO-naproxen was not completely converted to naproxen, but the reduced plasma levels of the latter was not the underlying reason for reduced gastrointestinal toxicity of NO-naproxen. CONCLUSION: NO-naproxen represents a novel, gastrointestinal-sparing NSAID derivative with superior analgesic and comparable anti-inflammatory properties to naproxen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9042976&dopt=Abstract Naproxen Naprosyn





Exp Anim. 1997 Apr;46(2):165-9.
Pathological evaluation of effect of anti-rheumatic drugs on type II collagen-induced arthritis in Lewis rats.

Takeshita M, Sugita T, Takata I.

Marugo Research Service, Tanabe Seiyaku Co., Ltd., Osaka, Japan.

The effects of anti-rheumatic drugs (dexamethasone 0.1 mg/kg and naproxen 5 mg/kg) were evaluated immunologically and histopathologically on type II collagen-induced arthritis in Lewis rats. Increased paw volume in the hind limbs was significantly suppressed in the groups treated with dexamethasone or naproxen, but noticeable retardation of body weight gain was observed in the group treated with dexamethasone. Serum anti-type II collagen IgG was significantly suppressed in the group treated with dexamethasone but not naproxen. Histopathological evaluation by our grading system, classification of the stages in arthritic lesion development, revealed suppression of the inflammatory changes in the tarsal joints of the animals treated with dexamethasone or naproxen. From our results, histopathological evaluation is considered to be more suitable for assessment of the efficacy of anti-rheumatic drugs on type II collagen-induced arthritis, an animal model for human rheumatoid arthritis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9145299&dopt=Abstract Naproxen Naprosyn





Arzneimittelforschung. 1997 Apr;47(4):381-4.
Absorption and distribution of naproxen in rats orally treated with naproxen betainate sodium salt monohydrate. Comparison with naproxen.

Marzo A, Ripamonti M, Benatti P, Marzo P, Wool C, Cerutti R, Reiner V.

Real s.r.l., Laboratory of Pharmacokinetics and Drug Metabolism, Como, Italy.

The S-naproxen betainate sodium salt monohydrate (naproxen-betaNa, CAS 104124-26-7, Aprenin) was synthesized to improve bioavailability and tolerability of naproxen. 24 albino rats were treated with naproxen-betaNa (84 mg/kg) and 24 with S-naproxen (naproxen) (50 mg/kg) by the oral route, the doses being equimolar. The animals were sacrificed and naproxen was assayed in timed plasma samples drawn off over a 24-h period and in tissues excised 1 h after administration. Peak concentrations of naproxen proved to be higher with naproxen-betaNa than with naproxen as such. The area under the curve of naproxen concentrations observed with the two administrations overlapped as did concentrations of the drug in the lungs, myocardium and liver. Naproxen concentrations in the gastric wall after naproxen-betaNa proved to be lower than after administration of naproxen as such, which allowed the authors to assume that naproxen-betaNa has a better gastric tolerability.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9150857&dopt=Abstract Naproxen Naprosyn





Eur J Rheumatol Inflamm. 1983;6(2):209-11.
A double blind study of antrafenine, naproxen and placebo in osteoarthrosis.

Leatham PA, Bird HA, Wright V, Seymour D, Gordon A.

Antrafenine, a new non-narcotic analgesic, has been compared at a dose of 600 mg/day to naproxen 500 mg/day and placebo in a double blind three way cross-over study on 36 patients with osteoarthrosis of the hip and/or knee. There was significant improvement with both active drugs. There was no significant difference between the two active drugs. Patients' preference at the end of the study was antrafenine 7, naproxen 10, placebo 2, no preference 9.3 patients withdrew because of concomitant illness; 2 patients withdrew because of lack of efficacy in the placebo period; 3 patients failed to attend clinic. Antrafenine is more efficacious than placebo in the treatment of osteoarthrosis of the hip and/or knee, and at the doses tested, is of comparable potency to naproxen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6673985&dopt=Abstract Naproxen Naprosyn





J Drug Target. 1997;4(5):303-10.
Targeting naproxen to non-parenchymal liver cells protects against endotoxin induced liver damage.

Lebbe C, Reichen J, Wartna E, Sagesser H, Poelstra K, Meijer DK.

Department of Clinical Pharmacology, University of Berne, Switzerland.

Non-steroidal anti-inflammatory drugs (NSAID's) could be of value in the treatment of liver disease; however, their use in this situation is limited by renal side effects. Therefore, we explored whether naproxen covalently bound to human serum albumin NAP-HSA) was able to reduce toxicity in an acute model of liver disease induced by endotoxin in rats pretreated with Corynebacterium parvum. In the isolated perfused liver of such animals endotoxin induced cholestasis (0.62 +/- 0.05 vs. 0.24 +/- 0.09 microliter.min-1.g liver-1; p < 0.05), increased vascular resistance (11300 +/- 400 vs. 311000 +/- 2000 dyn.s.cm-5; p < 0.05) and alanine aminotransferase release (22 +/- 9 vs. 149 +/- IU/l; p < 0.05). At the highest dose tested (22 mg/kg, corresponding to 6.0 mumoles naproxen), NAP-HSA normalized ALT release (21 +/- 10 IU/l: p < 0.05) while an equimolar amount of non-targeted naproxen was only partially effective (56 +/- 19 IU/l). A conventional dose of naproxen similarly prevented transaminase release. Cholestasis and increased vascular resistance were also prevented by NAP-HSA. Drug targeting by linking drugs to proteins is a potentially useful approach to maximizing drug effect while minimizing adverse events; this could be particularly useful for compounds with potentially serious adverse effects in patients with chronic liver disease such as the nonsteroidal anti-inflammatory agents used in the present study.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9169987&dopt=Abstract Naproxen Naprosyn


wvnvm.wvnet.edu

OBJECTIVE: A series of studies was undertaken to determine the cytochrome P450 isoform(s) involved in naproxen demethylation and whether this included the same isoforms reported to be involved in the metabolism of other NSAIDs. METHODS: (S)-Naproxen was incubated with human liver microsomes in the presence of a NADPH-generating system and the formation of desmethylnaproxen was measured by high-performance liquid chromatography (HPLC). To further clarify the specific isoforms involved, experiments were conducted with preparations expressing only a single P450 isoform (vaccinia virus-expressed cells and microsomes derived from a lymphoblastoid cell line, each transfected with specific P450 cDNAs) as well as inhibition studies using human liver microsomes and putative specific P450 inhibitors. RESULTS: In human liver microsomes (n = 7), desmethylnaproxen formation was observed with a mean kM of 92 (21) mumol.l-1, Vmax of 538 pmol.min-1.mg-1 protein and Cint2 (reflective of a second binding site) of 0.36 microliter.min-1.mg-1 protein. This Cint2 term was added since Eadie-Scatchard analysis suggested the involvement of more than one enzyme. Studies using putative specific P450 inhibitors demonstrated inhibition of this reaction by sulfaphenazole, (apparent Ki = 1.6 mumol.l-1), warfarin (apparent Ki = 27 mumol.l-1), piroxicam (apparent Ki = 23 mumol.l-1) and tolbutamide (apparent Ki = 128 mumol.l-1). No effect was observed when alpha-naphthoflavone and troleandomycin were employed as inhibitors, but reaction with furafylline produced, on average, a maximum inhibition of 23%. At a naproxen concentration of 150 mumol.l-1, formation of desmethylnaproxen was observed in cells expressing P450 1A2, 2C8, 2C9 and its allelic variant 2C9R144C. To further characterize these reactions, saturation kinetics experiments were conducted for the P450s 1A2, 2C8 and 2C9. The kM and Vmax for P450 1A2 were 189.5 mumol.l-1 and 7.3 pmol.min-1.pmol-1 P450, respectively. Likewise, estimates of kM and Vmax for P450 2C9 were 340.5 mumol.l-1 and 41.4 pmol. min-1.pmol-1 P450, respectively. Reliable estimates of kM and Vmax could not be made for P450 2C8 due to the nonsaturable nature of the process over the concentration range studied. CONCLUSION: Multiple cytochrome P450 isoforms (P450 1A2, 2C8 and 2C9) appear to be involved in naproxen demethylation, although 2C9 appears to be the predominant form.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9248768&dopt=Abstract Naproxen Naprosyn





J Rheumatol. 1997 Aug;24(8):1467-70.
Effects of tenidap and nonsteroidal antiinflammatory drugs on the response of cultured human T cells to interleukin 2 in rheumatoid arthritis.

Hall VC, Wolf RE.

Center of Excellence for Arthritis and Rheumatology, Louisiana State University Medical Center, Shreveport 71130, USA.

OBJECTIVE: To assess the effects of tenidap, a new oxindole class antiinflammatory compound, on the proliferative response of cultured T cells to interleukin 2 (IL-2); and to compare these effects with the antiinflammatory drugs ibuprofen, naproxen, indomethacin, piroxicam, and sulindac. METHODS: T cells were cultured with either tenidap, ibuprofen, indomethacin, naproxen, piroxicam, or sulindac in the presence of IL-2, then assayed for incorporation of tritiated thymidine. RESULTS: Tenidap, ibuprofen, and naproxen, at therapeutically attainable concentrations, significantly inhibited the proliferative response of T cells to IL-2. In contrast, indomethacin, piroxicam, and sulindac did not alter this response. Tenidap had a direct inhibitory effect on the response of activated T cells to IL-2. Both ibuprofen and naproxen interfered with the binding of IL-2 to T cells. CONCLUSION: These results suggest variable effects of different antiinflammatory drugs on lymphocyte function that may relate to the differential effectiveness of these drugs in patients with rheumatoid arthritis.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9263136&dopt=Abstract Naproxen Naprosyn