Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostaglandins. Gastrointestinal injury is a common outcome. We compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, with diclofenac, a non-specific COX inhibitor. METHODS: 655 patients with adult-onset rheumatoid arthritis of at least 6 months' duration were randomly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were assessed at baseline, every 4 weeks, and at week 24. We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available. Analysis was by intention-to-treat. FINDINGS: 430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218). The two drugs were similar in management of rheumatoid arthritis pain and inflammation. Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p<0.001). The rate of withdrawal for any gastrointestinal-related adverse event, most commonly abdominal pain, diarrhoea, and dyspepsia, was nearly three times higher in the diclofenac-treated group than in the celecoxib group (16 vs 6%; p<0.001). INTERPRETATION: Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events, and tolerability was better.

Efficacy of misoprostol in the prophylaxis of gastroduodenal lesions induced by short-term nonsteroidal antiinflammatory drug therapy in elderly patients. A multicenter double-blind, placebo-controlled trial.

Advanced age is an established risk factor for gastrointestinal toxicity of nonsteroidal antiinflammatory drugs, and the duration of use of these agents in elderly patients should be kept as short as possible. A multicenter, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of misoprostol in preventing gastrointestinal toxicity in elderly patients (> or = 65 years) given nonsteroidal antiinflammatory agents for no more than ten days. Patients who were to receive a nonsteroidal antiinflammatory agent for ten days to treat an acute rheumatic condition were randomly allocated to treatment with either a placebo or misoprostol in a dose of 200 micrograms bid. The primary efficacy criterion was the result of a gastroduodenal endoscopic evaluation done on day 10. The outcome of the rheumatic condition, changes in serum creatinine levels, and clinical safety were also evaluated. The study population included 208 subjects with a mean age of 81.4 +/- 6.4 years, of whom 81.3% were women. The misoprostol group (n = 104) and the placebo group (n = 104) were comparable at baseline. The incidence of endoscopically visible gastric lesions after ten days of nonsteroidal antiinflammatory drug therapy was significantly lower in the misoprostol group (25%) than in the placebo group (43%) (P = 0.001). In contrast, no statistically significant difference was found for the incidence of duodenal lesions between the two groups. The incidence of gastroduodenal ulcers was significantly lower (P < 0.021) in the misoprostol group (4.1%) than in the placebo group (13.5%). Changes in serum creatinine levels on day 10 versus baseline were similar in the two groups. The nonsteroidal antiinflammatory drug was well tolerated clinically when given alone or in combination with misoprostol.

SC-52458, an orally active angiotensin II-receptor antagonist: inhibition of blood pressure response to angiotensin II challenges and pharmacokinetics in normal volunteers.

This study was designed to assess in normal volunteers the potency, efficacy, and tolerability of the new nonpeptidic, orally active, angiotensin (Ang) II subtype 1 (AT1)-receptor antagonist SC-52458. After a randomized, single-blind, placebo-controlled protocol, two groups of eight healthy men ingested placebo or increasing single oral doses (10, 25, and 50 mg or 100, 150, and 200 mg) of SC-52458. Finger blood pressure (BP) was continuously monitored (Finapres), and BP response to repeated intravenous challenges with Ang II was compared with baseline BP response to the same dose of Ang II. Up to 24 h after drug intake, effects on plasma renin activity (PRA), Ang II, and aldosterone and pharmacokinetics were estimated. One, 4, and 10 h after the 200-mg dose, diastolic BP response to Ang II challenges was decreased from 30.3 to 2.6 mm Hg (mean +/- SEM; n = 8; i.e., to 8.3 +/- 1.1% of baseline response), 10.1 mm Hg (35.4 +/- 1.8%), and 17.5 mm Hg (58.7 +/- 1.8%), respectively. SC-52458 produced dose-related increases in PRA and Ang II concentrations < or = 10 h after drug intake. Plasma aldosterone concentrations tended to be decreased for < or = 24 h after SC-52458 doses of > or = 100 mg. No drug-related side effects were observed. The pharmacokinetics were linear over the dose range of 10-150 mg (t1/2 = 1.14-2.39 h). Efficacy was dose dependent, with a peak effect after 1 h. In conclusion, the novel AT1-receptor antagonist SC-52458 is well tolerated and orally active. It produces a rapid-onset inhibition of the renin-angiotensin system and reduces BP response to Ang II for > or = 10 h. These characteristics promise strong antihypertensive properties for SC-52458.

[Protective effect of misoprostol on the changes of transgastric potential difference induced by aspirin in man]. / Etude chez l'homme de l'effet protecteur du misoprostol sur les variations de la différence de potentiel transgastrique induites par l'aspirine.

The measurement of transgastric electric potential difference (DDP) is an easy and reproducible method for evaluation of the gastrotoxicity of aspirin. This randomised crossover placebo-controlled trial in 12 healthy volunteers involved study of the protective effect of misoprostol (Cytotec) against the fall in DDP induced by a gram of aspirin. One day of treatment with misoprostol 200 micrograms morning and evening led to a statistically lower fall in DDP than with the placebo: area under the curve 130 +/- 315 mV.min cf. 589 +/- 465 mV.min (p = 0.012), maximum variation 11.4 +/- 11.3 mV cf. 24.9 +/- 13.2 mV (p = 0.04). This result independent of the antisecretory action of the compound, confirms the protective effect of this prostaglandin analogue against the gastric damage caused by aspirin.