Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats: comparison with plain aspirin.
Takeuchi K, Ukawa H, Konaka A, Kitamura M, Sugawa Y. Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Japan.
The effects of a nitric oxide (NO)-releasing derivative of aspirin, NCX-4016, on gastric functional and ulcerogenic responses in rat stomachs were examined in comparison with those of aspirin. Topical application of aspirin (80 mM) to the stomach markedly decreased transmucosal potential difference and slightly increased luminal pH (acid back-diffusion) with minimal effect on mucosal blood flow, whereas NCX-4016 caused a marked increase in mucosal blood flow with no effect on potential difference and pH. Aspirin itself was ulcerogenic, causing damage in the mucosa when administered p.o., and it markedly potentiated gastric ulcerogenic response to hypothermic stress (28 degrees C-30 degrees C) with no effect on acid secretion when given s.c. NCX-4016, however, was not ulcerogenic by itself, did not modify the ulcerogenic response to stress and even showed a dose-dependent protection against HCl/ethanol-induced gastric lesions. When NCX-4016 was given intragastrically to pylorus-ligated rats, a large amount of NO was detected in both gastric contents and serum. NCX-4016 administered either p.o. or s.c. produced an equipotent inhibition of mucosal PGE2 generation in the stomach, as compared with aspirin. In addition, both aspirin and NCX-4016 suppressed carrageenan-induced rat paw edema. These results suggest that, unlike aspirin, the NO-releasing derivative of aspirin NCX-4016 neither had a topical irritating action on the stomach nor exerted a worsening effect on gastric ulcerogenic response to stress, but rather provided gastric protection against ethanol, despite inhibiting cyclo-oxygenase activity and showing anti-inflammatory action much as aspirin does. NCX-4016, probably by releasing NO, exerted protective effects that counteracted the potential damaging effects of cyclo-oxygenase inhibition.
IDrugs. 1998 Jun;1(2):228-31.
NCX-4016 (NicOx SA)
Huizinga TW. Academisch Ziekenhuis Leiden, Department of Rheumatology, Building 1, C4-R, PO Box 9600, 2300 RC Leiden, The Netherlands.NCX-4016, a nitric oxide non-steroidal anti-inflammatory drug (NO-NSAID) which can inhibit cyclooxygenase as well as release nitric oxide, is under development by NicOx as a potential treatment for thrombosis, inflammation and rheumatoid arthritis. It is an aspirin-nitrobutyl ester and is in phase I clinical trials as an oral antithrombotic agent in the UK [222690]. A placebo-controlled, double-blind study has been completed, which demonstrated good tolerability to NCX-4016. Studies to evaluate pharmacodynamic parameters and gastric tolerability are in progress [275922]. This compound has demonstrated a wider efficacy and tolerability than aspirin under several experimental conditions [210800]. In vitro studies have demonstrated the ability of NCX-4016 to interfere with platelet aggregation, adhesion and thromboxane B2 production. Studies in rats have also demonstrated the biological activity and gastrointestinal safety of NCX-4016 [275922]. NicOx applied for patent coverage in May 1994 and WO-09716405 specifically covers nitrated phenol esters of aspirin. NicOx specializes in the field of nitric oxide donors as therapeutic agents. The company's strategy is based on the development of new proprietary anti-inflammatory, analgesic and antithrombotic drugs with improved gastric and renal safety profiles. NicOx works with a network of outside collaborators from academia and the pharma-ceutical industry, thereby enabling rapid development whilst maintaining only a small infrastructure. The company has raised $7 million, with new investors, including Paribas Principal Investments (France) and Health Corp AB (Sweden) [273176]. The funds will be used to expand its preclinical and clinical research. NicOx is collaborating with Bayer on the development of NCX-4016, and research with other "nitro-aspirins" [281704].
