Pharmazie. 1999 Nov;54(11):831-6.
Diacyl glyceryl ester prodrugs for slow release in the skin: synthesis and in vitro degradation and absorption studies for naproxen derivatives.

Thorsteinsson T, Masson M, Loftsson T, Haraldsson GG, Stefansson E.

Department of Pharmacy, University of Iceland, Reykjavik, Iceland.

Diacyl glyceryl ester derivatives of naproxen were synthesized and tested for transdermal and dermal administration. Diacyl derivatives of aliphatic acids of various chain length were compared. The pharmaceutical properties of these compounds, such as lipophilicity, hydrolysis in a buffer solution at various pH values and degradation in human serum and hairless mouse skin homogenate, were investigated. All the diacyl derivatives were relatively stable in a neutral buffer solution, but were rapidly degraded to release naproxen in human serum and hairless mouse skin homogenate. The diacyl compounds could not penetrate hairless mouse skin in vitro. However, significant absorption into the skin could be measured, and this increased with increasing lipophilicity. A more than 100-fold difference in absorption was observed. The prodrugs were slowly hydrolyzed to naproxen inside the skin. The release of naproxen to the receptor compartment of diffusion cells showed that this type of prodrug could be used for controlled drug delivery.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10603609&dopt=Abstract Naproxen Naprosyn





Br J Pharmacol. 2000 Feb;129(4):681-6.
Wound collagen deposition in rats: effects of an NO-NSAID and a selective COX-2 inhibitor.

Muscara MN, McKnight W, Asfaha S, Wallace JL.

Department of Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.

Selective cyclo-oxygenase (COX)-2 inhibitors and nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit reduced toxicity in the gastrointestinal tract, but may affect wound healing in other tissues. In this study, we have compared the effects of a selective COX-2 inhibitor (celecoxib), a nitric-oxide releasing derivative of naproxen (HCT-3012) and naproxen in a model of wound collagen deposition in the rat. Polyvinyl alcohol sponges were implanted subcutaneously in rats. The rats were treated daily for 5 days with the test drugs at equieffective anti-inflammatory doses. Naproxen (10 mg kg(-1)) significantly decreased (45%) collagen deposition at the wound site relative to the vehicle-treated control group. In contrast, HCT-3012 (14.5 mg kg(-1)) significantly increased (62%) collagen deposition, while celecoxib (10 mg kg(-1)) had no effect. Naproxen and HCT-3012 suppressed prostaglandin (PG) E(2) levels at the wound site and whole blood thromboxane synthesis to similar degrees. Celecoxib had no significant effect on wound fluid PGE(2) levels, but slightly reduced whole blood thromboxane synthesis (by 17%). COX-1 mRNA and protein were expressed in the wound exudate, the skin surrounding the wound and in normal skin. In contrast, COX-2 mRNA, but not protein, was expressed in wound and normal skin. These results demonstrate that HCT-3012 can significantly enhance collagen deposition at a wound site, despite inhibiting prostaglandin synthesis to the same extent as the parent drug. Nitric oxide-releasing NSAIDs may represent a safer alternative to standard NSAIDs for use as anti-inflammatory and analgesic agents by post-surgery patients.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10683192&dopt=Abstract Naproxen Naprosyn





J Periodontal Res. 1999 Nov;34(8):473-7.
The in vitro effects of cetyltrimethylammonium naproxenate on oral and pharyngeal microorganisms of various ecological niches.

Pilloni AP, Buttini G, Giordano B, Iovene MR, di Salvo R, Buommino E, Tufano MA.

Istituto di Microbiologia, II Universita degli Studi di Napoli, Italy.

The purpose of this study was to determine the in vitro susceptibility to cetyltrimethylammonium naproxenate for various aerobic and anaerobic micro-organisms responsible for oral and pharyngeal diseases by assessing the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) or minimum fungicidal concentrations (MFCs) and by determining kill-times. The MICs of cetyltrimethylammonium naproxenate for 46 tested strains (25 reference strains and 21 clinical isolates) ranged from 8 to 500 micrograms/ml. The MIC was found to be 31.25 micrograms/ml for 36% of the reference strains. Even lower MIC values (15.63 micrograms/ml) were observed for some anaerobic strains, for Haemophilus influenzae and for Candida tropicalis. MIC and MBC values corresponded for the majority of strains tested while the MFC for C. tropicalis and C. albicans was much higher. Only 9.5% of the clinical isolates gave a MIC value of 31.25 micrograms/ml. Enterococcus faecalis, Streptococcus pyogenes and Staphylococcus aureus showed MIC at 62.5 micrograms/ml. The MIC and MBC values among the isolates were comparable, while the MFC value for the yeasts was greater. A concentration of 125 micrograms/ml of cetyltrimethylammonium naproxenate inhibited the growth of all bacteria, except Enterobacteriaceae and Pseudomonaceae, and yeasts. Cetyltrimethylammonium naproxenate shows very rapid kill-time for S. sanguis (0"), and rapid (15") for S. pyogenes, S. dysgalactiae and S. mutans and for Moraxella catarrhalis, while a longer kill-time was necessary for the other microbes tested.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10697804&dopt=Abstract Naproxen Naprosyn





Biotechnol Bioeng. 2000 Apr 5;68(1):78-83.
Enzymatic resolution of (S)-(+)-naproxen in a trapped aqueous-organic solvent biphase continuous reactor.

Xin JY, Li SB, Xu Y, Wang LL.

State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, Peoples Republic of China.

A trapped aqueous-organic biphase system for the continuous production of (S)-(+)-2-(6-methoxy-2-naphthyl) propionic acid (Naproxen) has been developed. The process consists of a stereoselective hydrolysis of the racemic Naproxen methyl ester by Candida rugosa lipase in a trapped aqueous-organic biphase system. The reaction has been carried out in a laboratory-scale continuous-flow stirred tank reactor (CSTR). The staring material has been supplied in and remaining substrate recovered by organic phase. YWG-C(6)H(5), a poorly polar synthetic support, has been employed to immobilize the lipase and to restrict the aqueous phase. Lipase immobilized on YWG-C(6)H(5) containing aqueous phase has been added into the CSTR to catalyze the hydrolysis. A dialysis membrane tube containing a continuous flow closed-loop buffer has been applied in the CSTR for the extraction of product and recruiting of the aqueous part consumed. Various reaction conditions have been studied. The activity of immobilized enzyme was effected by the polarity of support, the substrate concentration, logP value of organic phase and the product inhibition. At steady-state operating conditions, an initial conversion of 35% has been obtained. The CSTR was allowed to operate continuously for 60 days at 30 degrees C with a 30% loss of activity. The hydrolysis reaction yielded (S)-(+)-Naproxen with >90% enantiomeric excess and overall conversion of 30%. Copyright 2000 John Wiley & Sons, Inc.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10699874&dopt=Abstract Naproxen Naprosyn


uku.fi

Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c-f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a-f were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the morpholinyl- or (4-methyl-1-piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP) and quantitatively hydrolyzed (t(1/2) = 1-26 min) to naproxen in human serum. Compounds 3c-f showed higher aqueous solubility and similar lipophilicity, determined by their octanol-buffer partition coefficients (log P(app)), at pH 5.0 when compared to naproxen. At pH 7.4 they were significantly more lipophilic than naproxen. The best prodrug 3c led to a 4- and 1.5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperazinyl group yields prodrugs that are partially un-ionized under neutral and slightly acidic conditions, and thus, a desirable combination is achieved in terms of aqueous solubility and lipophilicity. Moreover, the resulting combination of biphasic solubility and fast enzymatic hydrolysis of the methylpiperazinylacyloxyalkyl derivatives gave improved topical delivery of naproxen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10780905&dopt=Abstract Naproxen Naprosyn


vanderbilt.edu

OBJECTIVE: To analyze results of treatment of osteoarthritis (OA) with acetaminophen and the nonsteroidal antiinflammatory drugs (NSAID) through a patient survey. METHODS: A 15 minute telephone survey was conducted with 300 patients, including 172 with confirmed OA. RESULTS: Twenty-four percent of patients who took acetaminophen rated it as "very helpful," compared to 31% for ibuprofen, 30% for naproxen, and 56% for diclofenac. Drug continuation beyond 24 months was reported by 33% of patients for acetaminophen, 21% for ibuprofen, 17% for naproxen, and 19% for diclofenac. Acetaminophen was significantly less likely to be discontinued because of toxicity than NSAID. Patients who indicated that they would not take a drug again, and therefore be unlikely to participate in a clinical trial involving this drug, were 26% for acetaminophen, 40% for ibuprofen, 38% for naproxen, and 28% for diclofenac. About 30% of patients who took acetaminophen reported concurrent use of ibuprofen, naproxen, or diclofenac. Among the 67% of patients who identified a drug as "most helpful," 80% named an NSAID, compared to 20% who named acetaminophen or another analgesic as the "most helpful" drug. CONCLUSION: Patients take many different drugs for OA, most of which are not continued beyond 2 years. Many patients take both acetaminophen and an NSAID. Most patients who identified a drug as "most helpful" named an NSAID rather than acetaminophen or an analgesic drug. These findings may be of value in further development of management strategies and guidelines for OA.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10782831&dopt=Abstract Naproxen Naprosyn





Rev Invest Clin. 2000 Mar-Apr;52(2):156-60.
Superoxide dismutase and Naproxen in the very late phase of carrageenan induced edema in rats.

Garcia-Gonzalez A, Morales-Hernandez RC, Porta-Gandara MA, Rubio-Cerda E, Ochoa JL.

Servicio de Medicina Interna, Hospital General de Zona No. 1, IMSS, La Paz, BCS, Mexico.

BACKGROUND: Rat hind-foot carrageenan induced edema (CIE) is a widely used model to evaluate anti-inflammatory drugs. It shows two well-defined phases, however a third not fully characterized phase has been observed. Superoxide dismutase (SOD) is a free radical-scavenger with anti-inflammatory activity. In our country there is not a specifically designed instrument to evaluate edema in CIE. METHODS: Edema was induced by intraplantar injection of carraageenan. Fours groups were evaluated: placebo, two different doses of SOD, and Naproxen. Edema was evaluated by a specially designed mercury plethismograph. Intensity of the inflammatory reaction was determined during the classical early and late phases and during the third very late phase. RESULTS: All treatments, but higher dose of SOD, showed good anti-inflammatory activity throughout early, late, and very late phases. Naproxen was more effective than SOD during first and second phase, however this difference disappeared during the third phase. In terms of equimolar basis the enzyme appeared 1,800 time more potent than Naproxen. Mercury plethysmometer performance was fine. CONCLUSIONS: The anti-inflammatory activity of SOD and Naproxen is extended until the very late phase in the CIE model. In this bioassay, this long lasting activity of the enzyme should be ascribed to a mechanism supplementary to its free radical-scavenger property. SOD may be indeed an alternative treatment in inflammatory diseases.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10846439&dopt=Abstract Naproxen Naprosyn