J Immunol. 1992 Jan 15;148(2):480-4.
Modification of proinflammatory cytokine production by the antirheumatic agents tenidap and naproxen. A possible correlate with clinical acute phase response.

Sipe JD, Bartle LM, Loose LD.

Department of Biochemistry, Boston University School of Medicine, MA 02118.

The cytokines IL-6, IL-1, and TNF play a key role in the pathogenesis of rheumatoid arthritis (RA) and initiate hepatic serum amyloid A (SAA) expression after injury. To provide a possible mechanistic explanation for the previous observation that plasma SAA concentrations decreased during treatment of RA patients with tenidap, but increased during treatment with naproxen, the present study compared the effects of tenidap and naproxen on the two stages of SAA expression: cytokine production by human PBMC and cytokine-stimulated SAA synthesis by human Hep3B hepatoma cells. Tenidap inhibited production of IL-6 greater than TNF greater than IL-1; the effect of naproxen on production of all three cytokines was lesser and least on IL-6. Indeed, an increase in IL-6 production was observed after exposure to naproxen. PBMC beta-2-microglobulin production and total protein synthesis were unaffected at concentrations and times at which effects on cytokine production were observed. Cell density was a significant factor in the extent to which cytokines were stimulated by LPS. Approximately physiologic cell densities, 0.5 to 1 x 10(6) cells/ml, were optimal for stimulation of IL-1-beta and IL-6 production by LPS; however, greater amounts of TNF were produced at lower cell densities. Because neither tenidap nor naproxen inhibited SAA synthesis by cytokine-stimulated Hep3B cells and because they differ most significantly in their effect on IL-6 production, the results support a role for IL-6 in the continued stimulation of SAA production during RA.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1729367&dopt=Abstract Naproxen Naprosyn





Biol Reprod. 1988 Dec;39(5):1117-28.
Effects of inhibition of prostaglandin synthesis on uterine oxytocin receptor concentration and myometrial gap junction density in parturient rats.

Chan WY, Berezin I, Daniel EE.

Department of Pharmacology, Cornell University Medical College, New York, New York 10021.

The development of oxytocin (OT) sensitivity in the parturient uterus is associated with increases in myometrial OT receptor concentration, gap junction formation, and prostaglandin (PG) production. To investigate whether PGs mediate these responses, we measured OT responsiveness, OT receptor concentrations, and gap junction formations in uteri of Day 19, 20, 21, 22, 23 pregnant and Day 2 postpartum rats. Inhibition of endogenous PG synthesis was produced by infusion of naproxen sodium delivered by an implanted osmotic pump. Naproxen treatment, but not placebo treatment, markedly attenuated in vitro uterine PGE2, PGF2 alpha, and PGI2 releases, suppressed OT responsiveness, and prolonged gestation. The increase of OT receptor concentration that normally occurred on Day 23 term pregnancy was delayed to Day 24. Co-administration of PGF2 alpha reversed the suppressive effects of naproxen. Naproxen treatment did not significantly affect gap junction formations on Day 23 but appeared to delay both the onset and disappearance of gap junction formations. PGF2 alpha co-administration with naproxen also had no apparent effect on gap junction development. The inhibition of OT receptor formation but not gap junction formation on Day 23 in the presence of naproxen indicates that these two events are controlled independently. Furthermore, the failure of naproxen-treated rats to deliver at term suggests that gap junction formation in the absence of an increase in OT receptors is insufficient to initiate labor. It appears that increases in both OT receptor concentrations and gap junction densities may be required for labor.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2851334&dopt=Abstract Naproxen Naprosyn





Am J Obstet Gynecol. 1985 Feb 1;151(3):361-8.
The effect of a prostaglandin synthetase inhibitor on the hormonal profile and the endometrium in women.

Landgren BM, Lundstrom V, Eneroth P, Johannisson E.

A prostaglandin synthetase inhibitor, naproxen, was given continuously throughout the menstrual cycle at a dose of 250 mg twice daily to 10 healthy fertile women (group 1) and at a dose of 1000 mg per day to eight women in the secretory phase (group 2). Blood samples were withdrawn three times a week during a control cycle and during the treatment cycle. Luteinizing hormone, follicle-stimulating hormone, prolactin, estradiol, and progesterone were analyzed. Endometrial biopsies were taken in the secretory phase of the control cycle and in the treatment cycle of group 1 and on the first day of menstruation of group 2. Naproxen treatment did not suppress ovulation in any cycle and did not affect the corpus luteum function either in group 1 or in group 2. In only one of the endometrial samples taken in the secretory phase (group 1) was the density of the lysosomes increased in the treatment cycle compared to the control cycle. The specimen taken during the early menstrual period (group 2) showed an increase in glandular epithelium and height following naproxen treatment. Furthermore, a significant increase in the number of plasmolemmal vesicles per square micrometer was observed in the capillary endothelial cells after the administration of 1000 mg of naproxen per day. This suggests that the transcellular exchange of water-soluble molecules in the endothelial cells was more active after the administration of a prostaglandin synthetase inhibitor than in the control group. In spite of the significant morphologic changes observed in the naproxen-treated material the onset of menstrual bleeding could not be prevented. The mechanism of the onset of menstruation needs to be further investigated.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3918452&dopt=Abstract Naproxen Naprosyn





Life Sci. 1985 Mar 25;36(12):1157-62.
Etodolac: effect on prostaglandin concentrations in gastric mucosa of rats.

Lee D, Dvornik D.

Etodolac is a structurally novel compound exhibiting potent analgesic and anti-inflammatory activity in laboratory animals and man, with excellent G. I. tolerance. Like other nonsteroidal anti-inflammatory drugs (NSAIDs) etodolac inhibits prostaglandin (PG) biosynthesis. In view of the cytoprotective role of PGE2, we have investigated in normal rats the effect of etodolac on the gastric mucosal concentration of PGE2 as well as of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin; naproxen and piroxicam served as reference NSAIDs. The orally effective anti-inflammatory doses in the chronic arthritic rat model (3 mg/kg for etodolac and naproxen; 0.5 mg/kg for piroxicam), and their arbitrarily selected multiples of 10 were used. Rats were killed at 1, 2, 6 and 24 hr after single doses and the PG concentrations were measured by RIA. With the low dose, 2 and 6 hr after dosing, etodolac diminished the PGE2 concentration by 20-25% (vs control) while naproxen and piroxicam caused a fall of 53-65%; the difference between etodolac and the untreated control group is not statistically significant but the difference between etodolac and both piroxicam and naproxen is significant (p less than 0.001). At the high doses, the lowering in PGE2 was similar after all three drugs, i.e. about 70% at 1 and 2 hr; 50% at 6 hr, and 20-50% at 24 hr after dosing. Except for the consistently smaller reduction of concentrations after etodolac, the effects on 6-keto-PGF1 alpha concentration followed a similar pattern but the differences are not significant. The lack of the G.I. irritation of etodolac in rats and man at therapeutically effective doses may be attributed to the benefits of the relatively short-lived and slight decrease in gastric mucosal PGE2 concentrations found in this study.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3157036&dopt=Abstract Naproxen Naprosyn





Res Commun Chem Pathol Pharmacol. 1976 Oct;15(2):369-72.
Effect of naproxen on protein binding of warfarin in human serum.

Yacobi A, Levy G.

The effect of the non-steroidal anti-inflammatory agent naproxen on the protein binding of racemic warfarin in pooled human serum was determined by equilibrium dialysis. The free fraction of warfarin in serum increased practically linearly with increasing naproxen concentration. At the highest naproxen concentration tested (400 mcg/ml), the warfarin free fraction was 74% larger than the control free fraction value.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=981793&dopt=Abstract Naproxen Naprosyn





Pharm Res. 1991 Oct;8(10):1223-30.
Low molecular weight proteins as carriers for renal drug targeting: naproxen-lysozyme.

Franssen EJ, van Amsterdam RG, Visser J, Moolenaar F, de Zeeuw D, Meijer DK.

Department of Pharmacology and Therapeutics, State University of Groningen, The Netherlands.

Low molecular weight proteins (LMWPs), such as lysozyme, may be suitable carriers to target drugs to the kidney. In this study the antiinflammatory drug naproxen was covalently bound to lysozyme (1:1). Pharmacokinetics of the conjugate, naproxen-lysozyme (nap-LYSO), were compared to that of an equimolar mixture of uncoupled naproxen with lysozyme in freely moving rats. Similar plasma kinetics and organ distribution for native lysozyme and the drug conjugate were observed (Clp = 1.2 and 1.1 ml/min; t1/2,beta = 85 and 75 min, respectively). In case of the uncoupled naproxen-lysozyme mixture, a monoexponential plasma disappearance of naproxen with a t1/2 of 2.8 hr was observed, coinciding with urinary excretion of naproxen metabolites (mainly 6-desmethylnaproxen sulfate; 6-DMN-S) between 2 and 8 hr after injection. Urinary recovery of total metabolites was 59% of the naproxen dose. In contrast, after injection of covalently bound naproxen, plasma levels of the parent drug were below the detection level, whereas naproxen was recovered as 6-DMN-S in urine over a period from 4 to 30 hr. However, only 8% of the administered dose was recovered as 6-DMN-S in urine, whereas 50% of the dose was recovered as naproxen metabolites in feces. Incubation experiments using purified renal tubular lysosomal lysates revealed that naproxen-lysozyme degradation ultimately results in a stable naproxen amino acid catabolite, naproxen-lysine (nap-lys). Hepatic uptake and biliary excretion of this catabolyte were demonstrated in isolated perfused rat livers. Further, an equipotent pharmacological activity relative to parent naproxen was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1796038&dopt=Abstract Naproxen Naprosyn





Pharm Res. 1993 Jul;10(7):963-9.
Low molecular weight proteins as carriers for renal drug targeting: naproxen coupled to lysozyme via the spacer L-lactic acid.

Franssen EJ, Moolenaar F, de Zeeuw D, Meijer DK.

University Center for Pharmacy, Department of Pharmacology and Pharmacotherapy, Groningen, The Netherlands.

Low molecular weight proteins (LMWPs) are potential carriers for targeting drugs to the kidney. To test whether ester bonds are suitable for the reversible drug conjugation, the antiinflammatory drug naproxen (Nap) was conjugated to the LMWP lysozyme (LYSO) via an ester bond using an L-lactic acid spacer (Nap-lact-LYSO, 1:1:1). The distribution and degradation of the conjugate in rats were compared to those of an equimolar mixture of free drug and LMWP and of a directly coupled conjugate without spacer (Nap-LYSO). The plasma clearance of Nap-lact-LYSO closely resembled that of Nap-LYSO and LYSO itself. Its major accumulation site appeared to be the kidney as demonstrated by extracorporal gamma-camera counting of the LMWP. Renally released naproxen was excreted in the urine as 6-desmethyl-naproxen-sulfate (6-DMN-S). Apparently the kidneys represent the main sites of demethylation and sulfation after administration of the LMWP-coupled drug. In addition, the renal excretion of naproxen (including its metabolites) was significantly delayed and sustained as compared to that after injection of uncoupled naproxen. Using the L-lactic acid spacer LMWP conjugation, the renal selectivity of Nap was increased 5.6 +/- 0.41-fold. Additional in vitro studies with Nap-lact-LYSO revealed that renal generation of the parent drug coincided with formation of low molecular weight catabolites, mainly as naproxen-L-lactic acid-lysine (Nap-lact-Lys). This indicated that in vitro the rate of cleavage of the ester bond is significantly slower than digestion of the carrier backbone itself.(ABSTRACT TRUNCATED AT 250 WORDS)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8378258&dopt=Abstract Naproxen Naprosyn