Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects

Objective. The objective of this endoscopic study was to compare the effects on the gastroduodenal mucosa of healthy volunteers of different doses and dosing regimens of AZD3582, a cyclooxygenase-inhibiting nitric oxide donator (CINOD), with equimolar doses of naproxen. Material and methods. Healthy volunteers were enrolled in a single-centre, randomized, double-blind, crossover trial consisting of two 12-day treatment periods and employing six sequences. The groups were: AZD3582 750 mg daily versus 375 mg twice daily ( n = 25), AZD3582 375 mg twice daily versus 750 mg twice daily ( n = 25) and naproxen 250 mg twice daily versus 500 mg twice daily ( n = 25). Results. Gastroduodenal tract damage was similar with AZD3582 375 mg twice daily and 750 mg twice daily ( mean number of erosions and ulcers +/- SD: 2.889 +/- 3.95 versus 3.089 +/- 2.80, respectively; p = 0.824; 1 ulcer counted as 10 erosions). There was an indication of decreased gastroduodenal toxicity with AZD3582 750 mg daily compared with 375 mg twice daily (0.929 +/- 2.08 versus 2.719 +/- 4.75, respectively; p = 0.068). Gastroduodenal toxicity was significantly lower with AZD3582 375 mg twice daily than with naproxen 250 mg twice daily ( 2.889 +/- 3.95 versus 6.169 +/- 9.36; p < 0.05), and with AZD3582 750 mg twice daily versus naproxen 500 mg twice daily ( 3.089 +/- 2.80 versus 6.689 +/- 6.97; p < 0.05). Equimolar twice-daily doses of AZD3582 and naproxen resulted in similar naproxen plasma levels and serum thromboxane B-2 inhibition. Conclusions. AZD3582 has an improved gastroduodenal safety profile compared with equimolar doses of naproxen. The gastroduodenal effects of AZD3582 375 mg and AZD3582 750 mg twice daily are similar. A once-daily regimen of AZD3582 might be less gastrotoxic than a twice-daily regimen.