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Novel agent for OA pain does not raise blood pressure.

BERLIN -- The first of a new class of drugs, cyclooxygenase-inhibiting nitric-oxide donators, had efficacy similar to rofecoxib for pain relief in osteoarthritis but was not associated withelevations in systolic blood pressure. Dr. Thomas J. Schnitzer said at the annual European Congress of Rheumatology.

"Coxibs [cyclooxygenase-2 inhibitors] have provided an improved GI safety profile, compared with NSAIDs, but remain associated with important renal and cardiovascular side effects," he said.

The new COX-inhibiting nitric-oxide donator (CINOD), AZD3582, combines a naproxen moiety with a nitric-oxide-donating group. In preclinical studies, the addition of nitric oxide (NO) to the NSAID appeared to increase potency while showing benefits in hypertensive and ischemia reperfusion injury models. Dr. Schnitzer explained.

The compound was evaluated in a 6-week phase II efficacy study that included 645 patients with symptomatic osteoarthritis. Patients were randomized to one of six groups: AZD in dosages of 125 mg twice daily, 375 mg twice daily, or 750 mg twice daily; rofecoxib 25 mg daily; naproxen 500 mg twice daily; or placebo. The primary objective was to determine the minimal effective dose of the drug; the primary end point was within-subject improvement on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. Efficacy and safety evaluations occurred at 1, 2, 4, and 6 weeks.

Patients taking the two higher doses of AZD had significantly greater pain relief (mean WOMAC decreases of 12 mm and 13 mm, respectively) than those on placebo. The two higher doses of AZD also were similar in efficacy to rofecoxib and naproxen, while the lowest dose of AZD was similar to placebo in efficacy. Findings for stiffness, function, and overall rating by patients and researchers supported the conclusions for the primary end point, said Dr. Schnitzer, director of the Northwestern Center for Clinical Research, Northwestern University, Chicago.

General safety and tolerability were similar in all active treatment groups, except for blood pressure: At 6 weeks there was a decrease in mean supine systolic blood pressure of 4 mm Hg and 2 mm Hg in the 375-mg and 750-mg AZD groups, respectively. In contrast, there was a mean increase of 2 mm Hg in the rofecoxib group and of 1 mm Hg in the naproxen group. The differences in supine blood pressure between the AZD and rofecoxib treatment groups were statistically significant. Similar trends were observed for mean supine diastolic blood pressure, he said.

"CINODs, through NO release, may potentially counteract the detrimental effects of COX inhibition on blood pressure and may prove to be beneficial in patients with osteoarthritis and concomitant cardiovascular risk factors," Dr. Schnitzer noted in a statement.

Studies of the blood pressure destabilizing effects of COX inhibitors and NSAIDs are ongoing. In a recent long-term study following 8,538 patients with rheumatoid arthritis or osteoarthritis who were taking a nonselective NSAID, rofecoxib, or celecoxib, the risk of blood pressure increase was significantly higher for those taking rofecoxib, with an odds ratio of 2.08 (J. Rheumatol. 31[6]:1143-51, 2004).

The AZD compound, known as NO-naproxen, was developed by the French firm NiCox. It was then licensed to AstraZeneca, which supported this study and other clinical trials through phase II but declined to pursue the drug's development and returned the rights to NiCox.

Dr. Schnitzer has consulted for both AstraZeneca and NiCox, but holds no stock in the companies.


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Title Annotation:Rx; osteoarthritis
Author:Walsh, Nancy
Publication:Internal Medicine News
Geographic Code:1USA
Date:Oct 1, 2004
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