Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence

Abstract

Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, and hypertensive rats and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.

Figure 1. Effects of NSAIDs in rats with adjuvant arthritis.

Despite comparable suppression of paw swelling (panel A), gastric prostaglandin synthesis (panel B) and whole blood thromboxane synthesis (panel C), ATB-346 and NCX 429 did not cause significant gastric (panel D) or intestinal (panel E) damage. Celecoxib also did not cause significant GI damage. *p<0.05, **p<0.01 versus the naproxen-treated group. n = 8 per group.

Figure 2. Co-administration of naproxen or celecoxib with omeprazole and/or low-dose aspirin results in marked exacerbation of small intestinal damage.

In contrast, rats given a naproxen derivative (ATB-346 or NCX 429) did not develop significant intestinal injury when given alone or in combination with omeprazole, low-dose aspirin, or both. *p<0.05, **p<0.01 versus the corresponding group treated with NSAID alone (n≥6 per group). Aspirin and omeprazole, alone or given together, did not elicit significant intestinal damage.

Figure 3. Older (19 months of age) rats develop extensive gastric damage when given naproxen, but not when given equimolar doses of a hydrogen sulfide-releasing naproxen derivative (ATB-346) or a nitric oxide-releasing naproxen derivative (NCX 429).

***p<0.001 versus the vehicle-treated group. n =  6 rats per group.

Figure 4. Increased naproxen-induced small intestinal damage in obese versus lean rats.

Neither lean nor obese rats developed intestinal damage when given ATB-346. **p<0.01 versus the corresponding vehicle- and ATB-346-treated rats. n = 6 rats per group.

Figure 5. Severity of gastric damage induced by naproxen is similar in spontaneously hypertensive (SHR) and normotensive (WKY) rats.

ATB-346 suppressed gastric prostaglandin (PG)E₂ synthesis and whole blood thromboxane (TXB₂) synthesis as effectively as naproxen, but did not elicit gastric damage. ***p<0.001 versus the corresponding vehicle-treated group (n = 6 per group).

Figure 6. Serum and biliary levels of naproxen are significantly reduced in rats given a naproxen derivative (ATB-346 or NCX 429) as compared to the levels observed in rats given an equimolar dose of naproxen itself.

The test drugs were administered twice-daily for 2 days. *p<0.05, **p<0001 versus the naproxen-treated group. n = 4 per group.