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Novel OA drug doesn't raise blood pressure.

BERLIN -- The first of a new class of drugs, cyclooxygenase-inhibiting nitric-oxide donators, showed similar efficacy to rofecoxib for pain relief in osteoarthritis but was not associated with elevations 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) compound, AZD3582, combines a naproxen moiety with a nitricoxide-donating group.

In preclinical and animal 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 of the study was to determine the minimal effective dose of the drug, and the primary end point was within-subject difference from baseline 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 than those given placebo, with mean WOMAC decreases of 12 mm and 13 mm, respectively, said Dr. Schnitzer, director of the Northwestern Center for Clinical Research at Northwestern University, Chicago.

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, he said.

Findings for stiffness, function, and overall rating by patients and investigators supported the conclusions drawn for the primary end point, he said.

General safety and tolerability were similar in all active treatment groups, with the exception of blood pressure in the two high-dose AZD groups. 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 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, Dr. Schnitzer said.

The differences in supine blood pressure between the AZD and rofecoxib treatment groups were statistically significant, he added.

Similar trends were observed for mean supine diastolic blood pressure.

"The relevance of potentially harmful effects of NSAIDs and coxibs due to an increase in arterial blood pressure is increasingly acknowledged. Even small increases of blood pressure are associated with a significantly increased incidence of cardiovascular events. In that respect, COX-inhibiting nitric-oxide donators, 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 investigating the blood pressure destabilizing effects of COX inhibitors and NSAIDs are ongoing.

In one recent long-term outcome 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).

Dr. Schnitzer disclosed that he has consulted for both NiCox, which developed the compound, and AstraZeneca, which licensed it for some time; however, he does not hold stock in either company.

Plans are underway for a phase III trial of the drug, now known as HCT 3012, beginning in 2005, NiCox chairman Michele Garufi said in a statement.
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Title Annotation:Musculoskeletal Disorders
Comment:Novel OA drug doesn't raise blood pressure.(Musculoskeletal Disorders)
Author:Walsh, Nancy
Publication:Family Practice News
Geographic Code:1USA
Date:Oct 1, 2004
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