P1121 REDUCED GASTROINTESTINAL TOXICITY OF THE CINOD NCX 429 OVER NAPROXEN IN DISEASED OR SUSCEPTIBLE RAT MODELS
Traditional non steroidal anti-inflammatory drugs (tNSAIDs) can cause severe gastrointestinal (GI) side effects and predispose to cardiovascular (CV) events. COX-2 selective inhibitors, while presenting an improved GI profile, still induce GI damage in aspirin (acetyl salicylic acid, ASA) users and share with tNSAIDs increased risk of CV events. Cyclooxygenase-inhibiting nitric oxide donators (CINODs) are new anti-inflammatory compounds designed to provide cyclooxygenase (COX) inhibition while donating nitric oxide (NO), with the aim of counteracting certain side effects due to prostaglandin suppression.
AIMS & Methods:
We assessed the anti-inflammatory activity and GI tolerability of NCX 429, a naproxen-based CINOD, in comparison to naproxen and celecoxib in rats with arthritis or pre-treated with ASA.
Arthritis was induced in male Wistar rats by injection of Freund’s complete adjuvant (FCA). Animals received orally vehicle, NCX 429 (16 mg/kg), naproxen (10 mg/kg) or celecoxib (10 mg/kg) twice daily for 14 days (from day 7 after arthritis induction) and paw volume was measured by plethysmography. Animals were sacrificed at day 21 for blind scoring of gastric and intestinal damage, expressed as the sum of the length of all lesions. In a different experiment, animals were orally treated with ASA (30 mg/kg) 30 min before oral NCX 429 (49 or 98 mg/kg), naproxen (30 mg/kg) or celecoxib (20 mg/kg) administration and sacrificed 4 hours afterwards for determination of gastric damage.
In the FCA model, NCX 429, naproxen and celecoxib similarly and significantly reduced paw edema. NCX 429 caused significantly lower gastric and intestinal damage (1.4±0.7 and 1.0±1.0, respectively) than equimolar naproxen (6.2±1.8 and 8.4±3.5, respectively, p<0.01), not differently from celecoxib.
In rats pre-treated with ASA, gastric mucosal lesions (4.1±1.2 in ASA-treated group) were significantly reduced by NCX 429 (2.2±1.2 at the maximal dose tested), whereas naproxen and celecoxib aggravated damage severity (15.3±4.4 and 10.2±3.3, respectively).
The CINOD NCX 429 inhibits FCA-induced paw edema formation with similar efficacy to naproxen and celecoxib, displaying a better gastrointestinal profile than naproxen. Moreover, the ability of NCX 429 to reduce ASA-induced gastric lesions confirms the GI safety of CINODs even in experimental settings where COX-2 inhibitors induce damage. CINODs like NCX 429 may be a valid therapeutic option for the treatment of inflammatory pathologies, especially in conditions of susceptibility to NSAID-mediated GI damage.
P1122 THE CINOD NCX 429 IS AN EFFECTIVE ANTI-INFLAMMATORY AGENT WITH IMPROVED GASTROINTESTINAL PROFILE IN ANIMAL MODELS
Non steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and pain, but their regular use can cause serious side effects to the gastrointestinal (GI) and cardiovascular (CV) systems. Cyclooxygenase inhibiting nitric oxide donators (CINODs) provide a traditional NSAID activity concomitant to nitric oxide (NO) donation, with the intent of mitigating the risk of adverse events seen with NSAIDs. In the GI tract, NO increases mucus secretion, improves blood flow and inhibits leukocyte adhesion.
AIMS & Methods:
We characterized the anti-inflammatory effects and GI toxicity profile of the new CINOD NCX 429 relative to naproxen in animal models.
Fasted rats were orally administered vehicle, NCX 429 (0.4-163 mg/kg) or naproxen (0.1-100 mg/kg) 30 minutes before injection of carrageenan into the footpad. Paw volume was measured by plethysmography, and gastric damage score determined after sacrifice by summing the length of all lesions (in mm). In a different experiment, vehicle, NCX 429 (0.5, 16 and 49 mg/kg) or equimolar naproxen (0.3, 10 and 30 mg/kg) were orally administered bid for 5 days to rats. Gastric and intestinal lesions were blindly scored after sacrifice. Blood samples were drawn before treatment and at sacrifice, for measurement of hematocrit, whole blood thromboxane (Tx)B2 and PGE2.
NCX 429 dose-dependently decreased carrageenan-induced paw edema (ED50 3.4 mg/kg), similarly to naproxen (ED50 3.7 mg/kg). NCX 429 showed reduced gastric toxicity compared to naproxen; in particular, mild mucosal lesions (6.0±1.1) were observed at 49 mg/kg, whereas equimolar naproxen induced significantly more severe gastric damage (34.3±6.2, p<0.001).
Repeated administration of NCX 429 caused significantly less intestinal damage (14.5±10.9 at 49 mg/kg) than naproxen (142.8±39.5 mm at 30 mg/kg, p<0.001). Moreover, NCX 429 did not affect hematocrit or body weight, whereas naproxen 30 mg/kg caused a significant decrease in both hematocrit (-11.3±1.3) and body weight (-37.2±6.0 g) vs. control group. NCX 429 at a dose of 49 mg/kg completely inhibited TxA2 and PGE2 synthesis, similar to equimolar naproxen.
NCX 429 inhibits COX activity and shows effective anti-inflammatory properties, similarly to naproxen. Interestingly, NCX 429 is endowed with a safer GI profile, both after single and repeated administration.
CINODs may represent a valuable therapeutic alternative to NSAIDs for the treatment of inflammatory conditions.