AZD3582 PRODUCES FEWER AND SMALLER GASTRIC ULCERS THAN NAPROXEN IN THE RAT REFEEDING MODEL

Background: NSAID-induced ulcers characteristically penetrate the muscularis mucosae of the antrum. These ulcers are mimicked in the rat refeeding model, which contrasts with other models in which acute and superficial damage is induced in the corpus region of the stomach. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2 naphthyl)propanoate] is a COX-inhibiting nitric oxide donator (CINOD) being developed for the treatment of acute and chronic pain. CINODs have the potential to confer gastrointestinal tract protection through the effect of nitric oxide donation on blood flow and on mucus and bicarbonate production.Objectives: To compare AZD3582 and naproxen in the rat refeeding model of gastric antral ulcer.Methods: Male Wistar rats were fasted for 24 h, then fed for 2 h and administered AZD3582 or naproxen (both drugs at 30, 150 and 300 μmol/kg p.o), or vehicle (n= 8 per group) before being deprived of food for a further 24 h. Plasma levels of each drug were measured 3 h post-dose. The rats were killed 24 h after drug administration and their stomachs were excised. The area of antral ulceration was determined by computerized planimetry. The depth of ulceration in formalin-fixed samples was measured by histological evaluation.Results: All doses of naproxen caused formation of ulcers in the antral region of the stomach. In contrast, ulceration was seen in only 1 rat treated with AZD3582 (300 μmol/kg). Ulcers that occurred extended through the muscularis mucosae. At the lowest naproxen dose (30 μmol/kg), 1 rat exhibited an ulcer (mean area: 0.06±0.06mm), while no rat receiving an equimolar dose of AZD3582 developed an ulcer. Six rats given the middle dose of naproxen (150 μmol/kg) developed ulcers whereas no rat receiving an equimolar dose of AZD3582 developed an ulcer (mean area: 1.7±0.7 vs. 0 mm; P<0.01). One animal receiving the highest dose of naproxen (300 μmol/kg) developed an antral ulcer (mean area: 0.70±0.70 mm) as did 1 rat receiving the highest dose of AZD3582 (300 μmol/kg: mean area: 0.19±0.19 mm). No rats receiving vehicle developed ulcers. Following administration of AZD3582 (30, 150 and 300 μmol/kg, respectively) the plasma levels of its COX-inhibiting moiety increased dose-dependently (49, 251 and 387 μmol/L, respectively) and were somewhat lower than those after equimolar doses of naproxen (119, 371 and 431 μmol/L, respectively).Conclusion: In a rat model that mimics the severity of NSAID-induced ulcer formation in humans, AZD3582 produced significantly fewer and smaller ulcers than naproxen. These results are in line with results of proof of concept studies in humans, which show that AZD3582 is associated with significantly less acute gastrointestinal toxicity than naproxen at equimolar doses.Citation: , volume , supplement , year 2003, page Session: Rheumatoid arthritis – Etiology and pathogenesis/Animal models