Low Direct Cytotoxicity and Cytoprotective Effects of Nitric Oxide Releasing Indomethacin

Abstract

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis. NCX 530 partially suppressed celecoxib-dependent membrane permeabilization and an inhibitor for guanylate cyclase suppressed the cytoprotective effect of NCX 530 against celecoxib. In vivo, NCX 530 alone produced fewer gastric lesions in rats than did indomethacin. A combination of the oral administration of celecoxib together with the intraperitoneal administration of indomethacin, but not of NCX 530, clearly resulted in the production of gastric lesions. The low direct cytotoxicity and the cytoprotective effect of NCX 530 observed in vitro may also act in vivo, thus ensuring that NCX 530 is safe for use on the gastric mucosa.

The Nitric Oxide Donor LA-419 [S-(6-Nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate] Prevents Intestinal Dysmotility, Bacterial Translocation, and Inflammation in a Rat Model of Enteritis

“…Moreover, several studies demonstrate a significant reduction on side effects caused by administration of NO-releasing nonsteroidal antiinflammatory drugs compared to ordinary nonsteroidal antiinflammatory drugs (Bandarage and Janero, 2001;Tomisato et al, 2005), a fact that seems to be related to a decrease of iNOS activity induced by these compounds (Rao et al, 2006). These data support our hypothesis that amelioration of inflammation induced by LA-419 may be related to the maintenance of nNOS/iNOS balance.…”

Effect of Different Cyclooxygenase Inhibitors on Gastric Adaptive Cytoprotection Induced by 20% Ethanol

“…Thus, we suggest that the differences in the ability of NSAIDs to inhibit COXs gastric and COXs from blood cell sources could reflect selectivity differences between these enzyme isoforms or alterations in available drug concentrations at the action site, and this could explain the increased PGE 2 levels observed, despite the ability of celecoxib and nimesulide to inhibit COX-2. In addition, the toxicity of an irritant is determined by both its own toxicity as well as its capacity to induce cellular stress responses, which protect cells from the irritant [20]. The administration of other NSAIDs, such as aspirin and indomethacin, induced a widespread mucosal damage and a significant increase in COX-2 mRNA expression, as well as a marked increase in COX-2 immunoreactivity in superficial mucosa, as related by Davies et al [18].…”

“…Different NSAIDs provide variable ulcerogenic properties, reflecting the ability to selectively block one of the COX isoforms, because endogenous PGs derived from both COX-1 and COX-2 are involved in the mucosal defense [19]. In addition, it has been proposed that these drugs could harm the gastric mucosa directly [20]. Therefore, we first characterized the response of gastric mucosa after exposition to several NSAIDs at doses inhibiting 80% of PGE 2 production in an inflammatory experimental model, considered as a COX-2 index [21].…”

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…The great expectation about developing NO‐NSAIDs relied on their putative ability to spare the GI tract, while maintaining therapeutic efficacy. Notably, diverse NO‐hybrids of naproxen, aspirin, diclofenac, flurbiprofen, ketoprofen, indomethacin, and ibuprofen have proved to induce less GI damage than the parent compounds in animal studies. For example, nitrofenac (diclofenac 4‐nitrooxybutylester) induced significantly less acute and chronic‐type gastric lesions in healthy rats and rabbits and exhibited reduced intestinal toxicity in healthy and colitic rats compared with diclofenac .…”