J Pharm Pharmacol. 1996 May;48(5):468-73.
Anti-inflammatory activity of polyphosphazene-based naproxen slow-release systems.

Conforti A, Bertani S, Lussignoli S, Grigolini L, Terzi M, Lora S, Caliceti P, Marsilio F, Veronese FM.

Istituto di Farmacologia, Universit-a di Verona, Italy.

A biocompatible and biodegradable polyphosphazene bearing phenylalanine ethyl ester, imidazole and chlorine (10.7:1:2.5 molar ratio) as substituents of the phosphorus atoms of the polymer backbone was studied for the preparation of polymeric naproxen slow-release systems. Discs 2.5 cm in diameter and 0.5 mm (thin) or 0.65 mm (thick), loaded, respectively, with 20 and 13.5% naproxen, showed different drug release kinetics, the thin matrices releasing naproxen at a faster rate and for a shorter time. In-vivo studies in rats demonstrated the pharmacological efficacy of these two different delivery systems in the inhibition of acute or chronic inflammatory diseases. Subcutaneous implantation of the thin matrices in rats was found to reduce carrageenan oedema induced both 1 h and 7 days after implantation. Rats implanted with thick matrices showed a reduction in chronic inflammation caused by adjuvant arthritis. Approximately 78% inhibition of arthritic oedema was found 28 days after subcutaneous administration of the matrices whereas 28.7% inhibition was found after daily oral administration of naproxen. Blood levels of naproxen in arthritic rats after matrix implantation showed the presence of drug up to day 28. These positive results have encouraged us to study a controlled-release system suitable for use in man.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8799869&dopt=Abstract Naproxen Naprosyn





Biochem Pharmacol. 1996 Apr 26;51(8):1003-8.
Cytochromes P450, 1A2, and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen.

Miners JO, Coulter S, Tukey RH, Veronese ME, Birkett DJ.

Department of Clinical Pharmacology, Flinders Medical Centre, Bedford Park, Australia.

A preliminary report implicated cytochrome P450 (CYP) 2C9 in the human liver microsomal O-demethylation of S-naproxen, suggesting that this pathway may be suitable for investigation of human hepatic CYP2C9 in vitro. Kinetic and inhibitor studies with human liver microsomes and confirmatory investigations with cDNA-expressed enzymes were undertaken here to define the role of CYP2C9 and other isoforms in the O-demethylation of R- and S-naproxen. All studies utilised a newly developed sensitive and specific HPLC assay that measured the respective O-desmethyl metabolites of R- and S-naproxen in incubations of human liver microsomes and in COS cell lysates. Microsomal R- and S-naproxen O-demethylation kinetics followed Michaelis-Menten kinetics, with respective mean apparent Km values of 123 microM and 143 microM. Sulfaphenazole, a specific inhibitor of CYP2C9, reduced the microsomal O-demethylation of R- and S-naproxen by 43% and 47%, respectively, and the CYP1A2 inhibitor furafylline decreased R- and S-naproxen O-demethylation by 38% and 28%, respectively. R,S-Mephenytoin was a weak inhibitor of R- and S-naproxen O-demethylation, but other CYP isoform specific inhibitors (e.g., coumarin, diethyldithiocarbamate, quinidine, troleandomycin) had little or no effect on these reactions. cDNA-expressed CYP2C9 and CYP1A2 were both shown to O-demethylate R- and S-naproxen. Apparent Km values (92-156 microM) for the reactions catalysed by the recombinant enzymes were similar to those observed for human liver microsomal R- and S-naproxen O-demethylation. The data demonstrate that CYP2C9 and CYP1A2 together account for the majority of human liver R- and S-naproxen O-demethylation, precluding the use of either R- or S-naproxen as a CYP isoform-specific substrate in vitro and in vivo.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8866821&dopt=Abstract Naproxen Naprosyn





Am J Orthop. 1996 Sep;25(9 Suppl):7-13.
IPDAS: a novel technology brings new benefits when applied to naproxen sodium.

Devane JG, Butler J, Mulligan S.

Elan Corporation, Athlone, Ireland.

The Intestinal Protective Drug Absorption System (IPDAS) is a new oral drug delivery approach that is applicable to gastrointestinal (GI) irritant drugs, including the nonsteroidal anti-inflammatory drug (NSAID) class. Although naproxen, as the free acid or the sodium salt, has pharmacokinetic characteristics that are consistent with once-daily dosing, the GI irritant and ulcerogenic potential associated with a large bolus dose of naproxen precludes safe use of an immediate-release form. In addition, the desired pharmacodynamic activity of a once-daily dosage form of naproxen requires rapidly available naproxen for a prompt onset of analgesic activity, as well as a prolonged phase of absorption to provide 24-hour analgesic/anti-inflammatory activity. Naprelan (naproxen sodium; Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) controlled-release tablets are a unique dosage form designed to achieve the desired features of such a once-daily presentation. Through a series of in vivo studies, the pharmaceutical design features of the product have been confirmed in humans using a combination of imaging and pharmacokinetic characterization. In addition, the potential for limiting any undesirable GI adverse events has been supported by evaluation of the GI toxicity of Naprelan in specialized animal toxicity studies. Naprelan exhibited in vivo performance characteristics that support the hypothesis that, as a once-daily dosage form, it may demonstrate safety and efficacy advantages in clinical evaluation.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8886212&dopt=Abstract Naproxen Naprosyn





J Pharm Pharmacol. 1996 Aug;48(8):812-6.
Effectiveness and mode of action of isopropyl myristate as a permeation enhancer for naproxen through shed snake skin.

Suh H, Jun HW.

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

The effectiveness and mode of action of isopropyl myristate (IPM) as an enhancer for the permeation of naproxen through shed snake skin have been investigated. The highest naproxen permeability was afforded by IPM (36.2 x 10(-4) cm h-1), followed by menthol (25.0 x 10(-4) cm h-1), oleic acid (11.1 x 10(-4) cm h-1), azone (7.3 x 10(-4) cm h-1) and control (1.4 x 10(-4) cm h-1). Whereas the permeability of un-ionized naproxen (47.4 x 10(-5) cm h-1) was much greater than that of ionized naproxen (1.11 x 10(-5) cm h-1), IPM-treatment of the intact skin increased the flux of ionized naproxen significantly more (50-fold) than that of un-ionized naproxen (15-fold). The large effect of pH on the permeation of naproxen through the intact stratum corneum became insignificant after extraction of lipids from the skin. Similar permeation of naproxen through intact and delipidized skin after IPM treatment indicated that the lipid barrier of the skin was largely impaired by IPM. Direct application of IPM to skin yielded a 2.6-fold higher naproxen permeability than the application of IPM as gel. A greater amount of naproxen was absorbed from 1% test gel (pH 5) containing IPM than from 10% commercial gel (pH 7) containing no IPM. These results show that use of IPM can significantly improve the bioavailability of naproxen in topical preparations.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8887730&dopt=Abstract Naproxen Naprosyn





Photochem Photobiol. 1996 Apr;63(4):455-62.
Molecular mechanism of drug photosensitization. IX. Effect of inorganic ions on DNA cleavage photosensitized by naproxen.

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

Dipartimento di Scienze Chimiche, Universita di Catania, Italy.

Photocleavage of DNA induced by naproxen and the correlated protective effect by some inorganic ions have been considered. The presence of a DNA complex is suggested and only associated naproxen seems to be responsible for the cleavage, for which the quantum yield of single strand breaks was calculated. The inorganic ions I-, Mn2+, Co2+ and Cu2+ decrease naproxen-photoinduced DNA cleavage. Iodide acts by a heavy atom mechanism, thus inhibiting naproxen photolysis and decreasing the amount of free radicals responsible for the photocleavage both in aerobic and anaerobic conditions. Metallic ions protect only within a range of concentrations, as for higher amounts damaging processes are observed. The protective efficiency of cations decreases with the increase of free drug concentration in the bulk of the solution, due to their involvement in the scavenging of naproxen radicals generated by photolysis of the free drug. In the presence of EDTA the cations show a better protective action. The most likely hypothesis is an inhibiting effect on the damaging processes via a redox cycle. The different behaviors of copper and of the two other cations can be justified by the influence of redox potentials of free and complexed metals and by the superoxide dismutase-like activity of copper.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8934762&dopt=Abstract Naproxen Naprosyn





Eksp Klin Farmakol. 1996 Mar-Apr;59(2):35-7.
[The modification of the pharmacokinetics and analgesic effect of naproxen by cimetidine, phenobarbital and thiamine diphosphate]

[Article in Russian]

Vovk OG, Stanislavchuk NA, Pentiuk AA.

Phenobarbital in a dose of 70 mg/kg (one-time daily intraperitoneal administration for 5 days) promotes naproxen elimination from rat blood and reduces its analgesic activity. Cymetidine (intragastric one-time daily administration in a dose of 100 mg/kg for a week) inhibits naproxen elimination from blood and increases it analgesic effect. Thiamine diphosphate administered intraperitoneally in a dose of 10 mg/kg (one time a day for a week) does not change pharmacokinetic and analgesic effect of naproxene.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8974562&dopt=Abstract Naproxen Naprosyn





Arch Orthop Trauma Surg. 1986;105(1):5-10.
Effects of acetylsalicylic acid and naproxen on the mechanical properties of intact femora in rats.

Solheim LF, Ronningen H, Langeland N.

The influence of acetylsalicylic acid (ASA) and naproxen on growing bones was studied. Young male rats were used. The drugs were administered via gastric gavage twice a day for 9 or 18 days. Drug doses giving serum concentrations corresponding to ordinary anti-inflammatory steady-state levels in humans were used. There was a drug-related influence on the strength of the growing femur. After 9 days the ultimate bending moment of the distal femoral epiphyseal plate and ultimate torsional moment and stress of the femoral diaphysis increased by about 10% in the rats treated with 150 mg/kg/12 h of ASA as compared with controls. After 18 days there were no differences. The ultimate metaphyseal bending moment of the distal femur was not influenced after 9 days with this dose, but was reduced by about 10% compared with controls after 18 days. Doses of 100 mg/kg/12 h of ASA and 20 mg/kg/12 h of naproxen did not change the bone strength. The doses used were well tolerated and did not influence the bone growth or body weight of the rats. A naproxen dose of 40 mg/kg/12 h was lethal; rats that received this dose succumbed to jejunal perforations. The results indicate that ASA influences the remodeling of normally growing bones.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3707309&dopt=Abstract Naproxen Naprosyn