J Rheumatol. 1996 Jan;23(1):16-23.
In vitro effects of 2 antirheumatic drugs on the synthesis and expression of proinflammatory cytokines in synovial membranes from patients with rheumatoid arthritis.

Ounissi-Benkalha H, Pelletier JP, Tardif G, Mineau F, Jolicoeur FC, Ranger P, Martel-Pelletier J.

Department of Medicine, Notre-Dame Hospital, Montreal, Canada.

OBJECTIVE: To compare the effects of tenidap, a new antirheumatic drug, with a nonsteroidal anti-inflammatory drug, naproxen, on the synthesis and expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor (TNF-alpha), and interleukin-6 (IL-6) in rheumatoid synovium. METHODS: Human synovial membrane explants from patients with rheumatoid arthritis (RA) were incubated in the absence or presence of 20 micrograms/ml lipopolysaccharides (LPS) and tenidap at 50, 20 (therapeutic concentration), and 5 micrograms/ml or naproxen at 90 (therapeutic concentration) and 30 micrograms/ml. The levels of IL-1 beta, TNF-alpha, and IL-6 in the culture medium were measured by specific enzyme linked immunosorbent assays. The cytokine mRNA levels were quantitated by Northern blotting. RESULTS: In the absence of LPS, tenidap at 20 micrograms/ml produced a significant (p < 0.04) decrease in the IL-1 synthesis level. Under LPS stimulation, IL-1 beta synthesis was inhibited by tenidap at all concentrations tested (p < 0.01) and by naproxen at only 90 micrograms/ml (p < 0.01). Very small amounts of TNF-alpha could be detected only when the synovial membranes were stimulated with LPS. Tenidap significantly reduced LPS stimulated TNF-alpha synthesis; the maximum inhibition was noted at 20 micrograms/ml (69%, p < 0.002). Naproxen, at 90 micrograms/ml, reduced TNF-alpha synthesis by about 40% (p < 0.03) and values were similar to those with subtherapeutic concentrations (5 micrograms/ml) of tenidap. The spontaneous and LPS induced synthesis of IL-6 was significantly inhibited by tenidap at all concentrations tested, whereas neither concentration of naproxen demonstrated a significant effect. Tenidap induced a somewhat similar reduction pattern of IL-1 beta and IL-6 mRNA to that observed for cytokine synthesis. Naproxen only slightly reduced the LPS induced expression of IL-6, while enhancing the IL-1 beta expression. CONCLUSION: Tenidap and naproxen showed differences in their effects on cytokine synthesis and mRNA expression. Tenidap, at the therapeutic concentration, was most clearly differentiated from naproxen by its inhibition of IL-6, but was also a more potent modulator of IL-1 beta and TNF-alpha in RA synovial explants. The significance of these findings lies in the possible therapeutic benefit of proinflammatory cytokine suppression in joint disease.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8838503&dopt=Abstract Naproxen Naprosyn





J Pharm Pharmacol. 1995 Sep;47(9):708-12.
Effect of sodium naproxen on inflammatory response induced by anterior chamber paracentesis in the rabbit.

Bucolo C, Spadaro A.

Institute of Pharmacology, University of Catania, Italy.

This study evaluated the effect of sodium naproxen (a reversible competitive inhibitor of cyclo-oxygenase) and phenylephrine (a mydriatic alpha-adrenergic agent) eye drops in maintaining atropine mydriasis in the rabbit after paracentesis. Moreover, to assess the influence of these treatments on vascular and cellular inflammatory responses in the rabbit eye, several biochemical parameters were considered. Anterior chamber paracentesis significantly reduced atropine-induced mydriasis and a parallel elevation of proteins, polymorphonuclear leucocytes (PMNs), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels in the secondary aqueous humour (obtained 120 min later) was observed. A significant increase in PMNs in the aqueous humour and a parallel increase in myeloperoxidase activity, a measure of PMN infiltration, in the iris-ciliary body were detected. Atropine-induced mydriasis was maintained in rabbits treated with either sodium naproxen or phenylephrine eye drops. However, only in the former group were the inflammatory parameters significantly reduced, with the exception of aqueous LTB4 levels. The inhibition of the protein influx in the aqueous humour and of the miosis produced by sodium naproxen can be related to the high drug levels in the aqueous humour that were effective in inhibiting the cyclo-oxygenase pathway of arachidonic acid metabolism, whereas the effects on PMN infiltration appear to be independent of significant release of the potent chemotactic agent LTB4, synthesized via the 5-lipoxygenase pathway.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8583379&dopt=Abstract Naproxen Naprosyn





Fertil Steril. 1996 May;65(5):1036-43.
Effects of acetylsalicylic acid (aspirin) and naproxen sodium (naproxen) on ovulation, prostaglandin, and progesterone production in the rabbit.

Zanagnolo V, Dharmarajan AM, Endo K, Wallach EE.

Department of Gynecology and Obstetrics, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.

OBJECTIVE: To determine the effects of acetylsalicylic acid (aspirin) and naproxen sodium (naproxen) on ovulation, ovarian prostaglandins (PG), and P production in the rabbit via in vivo and in vitro studies. DESIGN: Aspirin and naproxen were administered i.v. 6.5 and 7 hours, respectively, after hCG administration to New Zealand White adult female rabbits. Laparotomy was performed 24 hours after hCG administration. For in vitro experiments, control animals underwent laparotomy 6.5 (aspirin) and 7 hours (naproxen) after hCG administration. The treated animal received aspirin and naproxen; laparotomy was performed 1 hour later. One ovary was perfused for 6 hours with aspirin or naproxen whereas the contralateral ovary served as a control and was perfused with control medium (M199; GIBCO, Grand Island, New York). Perfusate samples were collected at 1-hour intervals for PG and P determination. SETTING: A conventional laboratory setting. INTERVENTIONS: In vivo experiments used i.v. administration of 100 mg/kg aspirin and 10 and 50 mg/kg naproxen. In vitro perfusion was also carried out with 100 micrograms/mL aspirin and 10 and 50 micrograms/mL naproxen added to the perfusate. MAIN OUTCOME MEASURES: Ovulatory efficiency (no. of ovulations/no mature follicles) and ovarian vein PG and P concentration were determined. RESULTS: Ovulatory efficiency was 88% for control, 41% for in vivo aspirin-treated, and 40% (10 mg/kg) and 0% (50 mg/kg) for naproxen-treated rabbits. Aspirin and naproxen were associated with decreased ovulatory efficiency when administered in vitro to both in vivo control and in vivo treated ovaries (control-medium = 70%; control-aspirin = 14%; aspirin-medium = 34%; aspirin-aspirin = 0%; control-naproxen = 25%; naproxen-medium = 38%; naproxen = 0% with 10 microgram/mL, and control-naproxen = 13%; naproxen-medium = 0%; naproxen = 0% with 50 micrograms/mL). Prostaglandin F2 alpha was undetectable in the perfusate of those ovaries perfused of those ovaries perfused either with aspirin or naproxen. Ovarian venous concentration of P in the perfusate was similar in all groups. CONCLUSIONS: Aspirin and naproxen significantly reduced ovulatory efficiency and PG production both in vivo and in vitro in hCG-treated rabbits. A critical period of 6.5 and 7 hours after hCG administration was established.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8612831&dopt=Abstract Naproxen Naprosyn





Aliment Pharmacol Ther. 1996 Apr;10(2):133-8.
Gastric mucosal injury and adaptation to oral and rectal administration of naproxen.

Lipscomb GR, Rees WD.

Salford Royal Hospitals NHS Trust, University of Manchester School of Medicine, UK.

INTRODUCTION: Oral nonsteroidal anti-inflammatory drugs (NSAIDs) cause acute gastric mucosal injury but the relative importance of systemic and topical effect of NSAIDs to overall gastric damage remains uncertain. METHODS: Twenty-four healthy volunteers were allocated either oral or rectal naproxen 500 mg b.d. and gastroscoped before and during days 1, 7 and 28 of dosing. Macroscopic gastric damage was assessed using a modified Lanza score, mucosal blood flow recorded using laser Doppler flowmetry and prostaglandin E2 (PGE2) measured in antral mucosal biopsies. RESULTS: Maximal gastric damage occurred during the first 24 h in the oral naproxen group and was associated with a fall in antral mucosal blood flow (mean +/- S.E.M.) from 58.2 +/- 3.3 to 46.6 +/- 4.1 arbitrary units (a.u.) (P < 0.05). With continued administration of oral naproxen, gastric damage resolved and antral mucosal blood flow returned to baseline (54.2 +/- 3.7 a.u.). No macroscopic damage or significant changes in mucosal blood flow were observed during rectal administration. There was no significant difference between mucosal PGE2 concentrations in those receiving oral or rectal naproxen, falling from an initial level of 335 +/- 29 to 155 +/- 49 pg/mg at day 1 (P = 0.06) in those receiving oral naproxen and from 235 +/- 55 to 107 +/- 31 pg/mg at day 1 (P = 0.1) in those receiving rectal naproxen, and remaining suppressed throughout the study in both groups. CONCLUSIONS: These observations suggest that acute mucosal damage and changes in mucosal blood flow are caused by the topical rather than systemic actions of naproxen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8730240&dopt=Abstract Naproxen Naprosyn





Ther Drug Monit. 1996 Jun;18(3):284-7.
Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions.

Dasgupta A, Volk A.

Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque 87106, USA.

Displacement of valproic acid (90-95% bound to albumin) and carbamazepine (80% bound to albumin) by salicylate, leading to higher concentrations of pharmacologically active free drugs, has been reported. We studied the possibility of displacement of valproic acid and carbamazepine by other strongly albumin-bound nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen. We observed statistically significant displacement of carbamazepine from protein binding in uremic serum at higher therapeutic concentrations of all three antiinflammatory drugs we studied, whereas in normal serum, we observed statistically significant displacement only with 75 micrograms/ml of naproxen. For valproic acid, we observed significant displacement even at lower therapeutic concentrations with all three drugs when the study was conducted using a normal serum pool. In the uremic serum pool, we observed significant displacements only with tolmetin and ibuprofen, whereas we observed no significant displacement of valproic acid even with higher concentrations of naproxen. We conclude that tolmetin, naproxen, and ibuprofen can displace both carbamazepine and valproic acid from protein binding, but uremic serum contains an inhibitor that blocks valproic acid-naproxen interaction.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8738769&dopt=Abstract Naproxen Naprosyn





J Inorg Biochem. 1996 Sep;63(4):253-63.
Molecular mechanism of drug photosensitization: VIII. Effect of inorganic ions on membrane damage photosensitized by naproxen.

Giuffrida S, De Guidi G, Miano P, Sortino S, Condorelli G, Costanzo LL.

Dipartimento di Scienze Chimiche, Universita di Catania, Italy.

The inhibitory effect of Cu2+, Mn2+, Co2+, and I- on naproxen-induced photohemolysis was investigated. In order to better understand this effect, these ions were also tested for lipid peroxidation and protein crosslinking, which are among the main processes involved in erythrocyte membrane damage. The overall results support the hypothesis that metal cations act via a redox scavenging of the radicals which are produced on the lipid component of the membrane. This process occurs through hydrogen abstraction operated by photogenerated naproxen radicals. Moreover, copper can also act as a superoxide anion scavenger: its decay is noxious in photohemolysis, whereas it is not in lipid peroxidation. Metal cations, besides, are not able to scavenge protein crosslinking. On the other hand, iodide is able to reduce both processes because it acts as a heavy atom, favoring intersystem crossing to the unreactive triplet state of the drug, thus reducing naproxen photolysis and, as a consequence, the amount of the damaging species produced. This mechanism was supported by luminescence experiments performed in the absence and in the presence of iodide.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8757140&dopt=Abstract Naproxen Naprosyn





Analyst. 1996 Jul;121(7):909-12.
Second-derivative synchronous fluorescence spectroscopy for the simultaneous determination of naproxen and salicylic acid in human serum.

Konstantianos DG, Ioannou PC.

Laboratory of Analytical Chemistry, University of Athens, Panepistimiopolis, Greece.

Second-derivative synchronous fluorescence spectrometry was used to develop a simple, rapid and sensitive spectrofluorimetric method for the simultaneous determination of naproxen and salicylic acid in human serum. The method is based on the intrinsic fluorescence of naproxen and salicylic acid in chloroform-1% acetic acid solution. A delta gamma of 130 nm was used for the direct measurement of salicylic acid in the binary mixture, whereas naproxen was determined from direct measurements at delta gamma = 60 nm and by means of a correction equation which incorporates the concentration of salicylic acid. The range of application is 0-14 mg l-1 for naproxen and 0-13 mg l-1 for salicylic acid. The detection limits for naproxen and salicylic acid are 0.003 and 0.01 mg l-1, respectively. Serum samples are extracted into chloroform-1% acetic acid solution prior to instrumental measurement. Analytical recoveries range from 97 to 105% (mean 102%) for naproxen and from 97 to 112% (mean 103%) for salicylic acid. The within-run precision (RSD) for the method for four naproxen-salicylic acid mixtures varied from 1.2 to 6.7% and the day-to-day precision for mixtures varied from 2.1 to 5.0%.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8757923&dopt=Abstract Naproxen Naprosyn