08 - 2009

J Rheumatol. 2009 Jun;36(6):1290-7. Epub 2009 May 1.

Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee.

Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ. Sahlgrenska University Hospital/Ostra, Goteborg, Sweden.

OBJECTIVE: Naproxcinod, a cyclooxygenase-inhibiting nitric oxide donator antiinflammatory drug, was evaluated in this phase 2, double-blind, randomized, parallel group study to determine its optimal dose in patients with osteoarthritis (OA). METHODS: In total 543 patients with OA of the hip or knee were randomized to receive naproxcinod 750 mg once daily (qd), 750 mg twice daily (bid), 1125 mg bid, rofecoxib 25 mg qd, or placebo for 6 weeks. The primary efficacy variable was the within-patient change from baseline to the average of Weeks 4 and 6 in WOMAC pain subscale score. Treatment-group differences were compared using ANCOVA with factors for treatment and country, and baseline pain subscale score as a covariate. Safety endpoints included vital signs and adverse events. Treatment-group differences in mean change from baseline to Week 6 in systolic blood pressure (SBP) were compared using an ANCOVA with treatment and country as fixed factors and baseline SBP as covariate. RESULTS: All active treatments showed statistically significant reductions in WOMAC pain score compared to placebo (p < or =" 0.02)." or =" 0.02)."

Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis.

White WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M. Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut, USA. wwhite@nso1.uchc.edu

Traditional nonsteroidal anti-inflammatory drugs are associated with the destabilization of blood pressure (BP) control, particularly in hypertensive patients treated with blockers of the renin-angiotensin system. To assess the potential impact of nitric oxide donation, the effects of naproxcinod with naproxen and placebo on changes in BP were compared in a randomized clinical trial of 916 patients with osteoarthritis after 13 weeks of therapy. In addition, the effects of naproxcinod versus naproxen and placebo on systolic BP in patients with hypertension treated with renin-angiotensin system blockers were evaluated. Naproxcinod 750 mg twice daily reduced systolic BP compared to naproxen 500 mg twice daily (p <0.02).> or =10 mm Hg was greater with naproxen 500 mg (22%) compared to naproxcinod 750 mg (14%, p = 0.04), naproxcinod 375 mg (14%, p = 0.055), and placebo (15.6%, p = 0.155). In conclusion, naproxcinod did not induce elevations of BP seen with naproxen, and it had similar effects on BP to that of placebo in patients with osteoarthritis.

J Neurochem. 2009 Nov;111(3):766-76. Epub 2009 Aug 21.

NO-flurbiprofen reduces amyloid-beta, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade.

Abdul-Hay SO, Luo J, Ashghodom RT, Thatcher GR. Department of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

The non-steroidal anti-inflammatory drug flurbiprofen is a selective amyloid lowering agent which has been studied clinically in Alzheimer's disease. HCT-1026 is an ester prodrug of flurbiprofen incorporating a nitrate carrier moiety that in vivo provides NO bioactivity and an improved safety profile. In vitro, HCT-1026 retained the cyclooxygenase inhibitory and non-steroidal anti-inflammatory drug activity of flurbiprofen, but at concentrations at which levels of amyloid-beta 1-42 amino acid were lowered by flurbiprofen, amyloid-beta 1-42 amino acid levels were elevated 200% by HCT-1026. Conversely, at lower concentrations, HCT-1026 behaved as a selective amyloid lowering agent with greater potency than flurbiprofen. The difference in concentration-responses between flurbiprofen and HCT-1026 in vitro suggests different cellular targets; and in no case did a combination of nitrate drug with flurbiprofen provide similar actions. In vivo, HCT-1026 was observed to reverse cognitive deficits induced by scopolamine in two behavioral assays; activity that was also shown by a classical nitrate drug, but not by flurbiprofen. The ability to restore aversive memory and spatial working and reference memory after cholinergic blockade has been demonstrated by other agents that stimulate NO/cGMP signaling. These observations add positively to the preclinical profile of HCT-1026 and NO chimeras in Alzheimer's disease.