QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Editorial Expression of Concern All Versions of this Article: jpet.104.072843v1 311/3/1264    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fiorucci, S. Articles by Cirino, G. Search for Related Content PubMed PubMed Citation Articles by Fiorucci, S. Articles by Cirino, G. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLSALICYLIC ACID CELECOXIB NAPROXEN NITRIC OXIDE Medline Plus Health Information Joint Disorders

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Nitric Oxide (NO)-Releasing Naproxen (HCT-3012 [(S)-6-Methoxy--methyl-2-naphthaleneacetic Acid 4-(Nitrooxy)butyl Ester]) Interactions with Aspirin in Gastric Mucosa of Arthritic Rats Reveal a Role for Aspirin-Triggered Lipoxin, Prostaglandins, and NO in Gastric Protection

Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale, Faculty of Medicine, Università degli Studi di Perugia, Perugia, Italy (S.F., B.R., S.Fa., A.M.); and Dipartimento di Farmacologia Sperimentale, Faculty of Pharmacy, Università degli Studi di Napoli, Napoli, Italy (A.D.L., G.C.)

Administration of selective and nonselective cyclooxygenase (COX)-2 inhibitors to rheumatoid arthritis patients taking low doses of acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal bleeding. The present study was undertaken to investigate whether administration of HCT-3012 [(S)-6-methoxy--methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on arthritis score and interleukin-6 plasma levels, coadministration of naproxen (10 mg/kg/day) and celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates arthritis development (P < 0.01 versus arthritis alone), but markedly enhanced gastric mucosal damage caused by ASA (P < 0.01 versus ASA alone). In contrast, coadministration of HCT-3012 (15 mg/kg/day) significantly attenuated arthritis development, because HCT-3012 was equally or more effective than naproxen and celecoxib in attenuating local and systemic inflammation (P > 0.001 versus arthritis) without exacerbating gastric mucosal injury caused by ASA. Arthritis development associates with gastric COX-2 induction, mRNA and protein, and enhanced gastric prostaglandin E₂ (PGE₂) synthesis (P < 0.01 versus control rats). Although all treatments, including celecoxib, were effective in reducing gastric PGE₂ synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of aspirin-triggered lipoxin (ATL), a COX-2-derived lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with naproxen and celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P < 0.01 versus ASA alone). In contrast, whereas HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that HCT-3012 derived from NO has the potential to compensate for inhibition of PGE₂ and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and coxibs in rheumatic patients that take low doses of ASA.

Address correspondence to: Dr. Stefano Fiorucci, Clinica di Gastroenterologia ed Endoscopia Digestiva, Policlinico Monteluce, 06100 Perugia, Italy. E-mail: fiorucci{at}unipg.it

This article has been cited by other articles:

				J. KARLSSON, A. PIVODIC, D. AGUIRRE, and T. J. SCHNITZER Efficacy, Safety, and Tolerability of the Cyclooxygenase-Inhibiting Nitric Oxide Donator Naproxcinod in Treating Osteoarthritis of the Hip or Knee J Rheumatol, June 1, 2009; 36(6): 1290 - 1297. [Abstract] [Full Text] [PDF]