The Cyclooxygenase-Inhibiting Nitric Oxide Donator (CINOD) Compound NCX 429 Exhibits Reduced Gastrointestinal Toxicity as Compared with Naproxen in Arthritic and Aspirin-Treated Rats

Abstract

Purpose: The efficacy of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for the treatment of inflammation and pain is well recognized. Nonetheless, their long-term use poses challenges due to gastrointestinal (GI) and cardiovascular safety concerns. All NSAIDs, even COX-2 inhibitors, induce GI damage in susceptible patients, such as aspirin (ASA) users. In the constant quest for NSAIDs with improved tolerability, an approach using nitric oxide (NO) has been made. Cyclooxygenase-Inhibiting Nitric Oxide Donators (CINODs) are anti-inflammatory compounds designed to concomitantly inhibit cyclooxygenase (COX) and donate NO, with the aim of mitigating the side effects derived from COX inhibition. We studied the anti-inflammatory activity and GI tolerability of NCX 429, and reference NSAIDs naproxen and celecoxib, in rats with arthritis or pre-treated with ASA. Methods: Rats displaying Freund's complete adjuvant (FCA)-induced arthritis were orally treated for 14 days (twice daily, starting day 7 after arthritis induction) with vehicle, NCX 429 (16 mg/kg), naproxen (10 mg/kg) or celecoxib (10 mg/kg). Paw volume was measured by plethysmography. At sacrifice (day 21), stomach and intestine were excised and examined for damage (expressed as the sum of the length in mm of all lesions). In a separate setting, ASA (30 mg/kg) was administered to fasted rats 30 min before gavage with vehicle, NCX 429 (49 or 98 mg/kg), naproxen (30 mg/kg) or celecoxib (20 mg/kg). Gastric damage was measured 4 hours after drug treatment. Results: NCX 429, naproxen and celecoxib, all similarly and significantly reduced paw edema in arthritic rats. NCX 429 displayed significantly reduced gastric and intestinal damage (1.4±0.7 and 1.0±1.0 mm, respectively) than equimolar naproxen (6.2±1.8 and 8.4±3.5mm, respectively, p<0.01), and not differently from celecoxib. In fasted rats, ASA administration caused gastric mucosal damage (4.1±1.2mm, p<0.05 vs. control), which was reduced by NCX 429 (2.2±1.2mm at the maximal dose tested) but conversely exacerbated by naproxen and celecoxib (15.3±4.4 and 10.2±3.3mm, respectively, p<0.05). Conclusion: The CINOD NCX 429 shows effective anti-inflammatory activity in arthritic rats similarly to reference NSAIDs, naproxen and celecoxib. NCX 429 features a GI sparing profile over naproxen. Moreover, oppositely to naproxen and celecoxib, NCX 429 reduces ASA-induced gastric lesions, supporting the NO donating approach aimed at potentially mitigating gastric damage. This experimental evidence, needing clinical validation, would suggest a potential for CINODs in the treatment of inflammatory pathologies, especially individuals at risk for GI damage. Disclosure: Drs Bastia, Monopoli, Bolla, Viappiani - Empoyee: Company NicOx Drs Coruzzi, Guaita, Morini, Wallace - Consultant: Company NicOx. This study has been supported by a grant from NicOx SA to Drs Coruzzi and Wallace.