Gastrointestinal Profile and Efficacy in Rats of the Cyclooxygenase-Inhibiting Nitric Oxide Donator (CINOD) Compound NCX 429: 104

Purpose: The use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for pain relief in chronic inflammatory conditions is hampered by serious side effects, especially to the gastrointestinal (GI) and cardiovascular systems. Cyclooxygenase-Inhibiting Nitric Oxide Donators (CINODs) are designed with the aim of providing the efficacy of traditional NSAIDs while donating nitric oxide (NO). This NO donation is intended to improve the safety profile. Indeed, NO has been shown to stimulate mucus secretion and inhibit NSAID-dependent damage increase in the GI tract in experimental models. Aim: to confirm anti-inflammatory activity and evaluate the gastrointestinal tolerability of the CINOD NCX 429 in comparison to naproxen. Methods: Vehicle, NCX 429 (0.4-163 mg/kg) or equivalent amounts of naproxen (0.1-100 mg/kg) were orally administered to fasted rats immediately before induction of inflammation (carrageenan injection into the footpad). The paw volume was measured by plethysmography up to 4 hours post-dosing to confirm efficacy. The effect of repeated drug administration was tested by measuring gastric and intestinal lesions in rats after oral administration of vehicle, NCX 429 (0.5, 16 and 49 mg/kg) or equimolar naproxen (0.3, 10 and 30 mg/kg) bid for 5 days. Hematocrit, thromboxane (Tx)B2 and prostaglandin (PG)E2 (as marker of COX inhibition) were determined in blood samples before and at the end of the treatment. To numerically evaluate the gastric damage, the sum of the length of all lesions in mm (stomach or intestine) was determined after sacrifice (4 hours post last dosing). Results: In the carrageenan model, while both NCX 429 and naproxen similarly and dose-dependently decreased paw edema (ED50: 3.4 and 3.7 mg/kg, respectively), NCX 429 displayed reduced gastric toxicity. Particularly, NCX 429 at a full effective dose (49 mg/kg) caused significantly less lesions (6.0±1.1mm) than equimolar naproxen (34.3±6.2mm, p<0.001). In the repeated dosing experiment, both drugs similarly inhibited TxA2 and PGE2 synthesis, whereas only naproxen (30 mg/kg) significantly affected hematocrit (-11.3±1.3) and body weight (-37.2±6.0 g vs. control group). As evaluated after repeated dosing, intestinal damage score was 14.5±10.9 and 142.8±39.5mm (p<0.001) for the highest dose (49 mg/kg) of NCX 429 and equimolar naproxen, respectively. Conclusion: The CINOD NCX 429 shows COX-inhibiting activity and edema reduction as efficacious as the reference NSAID naproxen. In addition, NCX 429 is characterized by a safer GI profile in these experimental models, confirming protective activity by NO donation. If clinically confirmed, CINODs may have the potential to become a valuable therapeutic option for inflammatory conditions. Disclosure: Drs Bastia, Monopoli, Bolla & Viappiani - Employee: Company NicOx Drs Coruzzi, Guaita, Morini and Wallace - Consultant: Company NicOx.