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.
05 - 2009
Expert Opin Biol Ther. 2009 May;9(5):649-57.
Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD).
Geusens P. University Hasselt, University Hospital, The Netherlands. piet.geusens@scarlet.be
BACKGROUND: COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs that combine the actions of the parent COX inhibitor with nitric oxide (NO), with the aim of reducing potential toxicity of the parent drug, while maintaining its analgesic and anti-inflammatory effects. AZD3582 (Naproxcinod) is the first in the class of CINODs. OBJECTIVE/METHODS: To review the effects of NO donation, CINODS in general and naproxen in osteoarthritis (OA), based on literature in PubMed. RESULTS: In preclinical and human studies, this drug produced similar analgesic and anti-inflammatory effects to its parent naproxen, with improved gastrointestinal safety in OA patients. The results of recent clinical trials, which were designed to study effects on blood pressure, are expected shortly, after peer-review. CONCLUSIONS: As naproxen is considered the safest COX inhibitor choice from a cardiovascular perspective, AZD3582 has the potential to become a new drug treatment in patients with OA, in whom pain and function are not controlled by the use of analgesics.
Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD).
Geusens P. University Hasselt, University Hospital, The Netherlands. piet.geusens@scarlet.be
BACKGROUND: COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs that combine the actions of the parent COX inhibitor with nitric oxide (NO), with the aim of reducing potential toxicity of the parent drug, while maintaining its analgesic and anti-inflammatory effects. AZD3582 (Naproxcinod) is the first in the class of CINODs. OBJECTIVE/METHODS: To review the effects of NO donation, CINODS in general and naproxen in osteoarthritis (OA), based on literature in PubMed. RESULTS: In preclinical and human studies, this drug produced similar analgesic and anti-inflammatory effects to its parent naproxen, with improved gastrointestinal safety in OA patients. The results of recent clinical trials, which were designed to study effects on blood pressure, are expected shortly, after peer-review. CONCLUSIONS: As naproxen is considered the safest COX inhibitor choice from a cardiovascular perspective, AZD3582 has the potential to become a new drug treatment in patients with OA, in whom pain and function are not controlled by the use of analgesics.
Trends Pharmacol Sci. 2009 Mar;30(3):112-7. Epub 2009 Feb 21.
Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis.
Wallace JL, Viappiani S, Bolla M. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada. wallacejohn@mcmaster.ca
Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly used medications for the treatment of the symptoms of many chronic inflammatory diseases, including osteoarthritis. Unfortunately, the toxicity of NSAIDs substantially limits their long-term use. Some newer NSAIDs, namely selective cyclooxygenase (COX)-2 inhibitors, exhibit greater gastrointestinal safety, and concomitant use of anti-secretory drugs can also reduce NSAID-induced gastropathy. However, NSAIDs also adversely affect the cardiovascular system. A new class of anti-inflammatory drugs, COX-inhibiting nitric oxide donators (CINODs), has been designed to exert similar anti-inflammatory effects as NSAIDs, but with an improved safety profile. CINODs release nitric oxide, providing protective effects in the gastrointestinal tract and attenuating the detrimental effects on blood pressure normally associated with NSAIDs. We provide an outline of the rationale for CINODs and their activity, in addition to an overview of the pre-clinical and clinical profile of the most advanced CINOD, naproxcinod.
Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis.
Trends Pharmacol Sci. 2009 Feb 19. [Epub ahead of print]
Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis.
Wallace JL, Viappiani S, Bolla M. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada.
Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly used medications for the treatment of the symptoms of many chronic inflammatory diseases, including osteoarthritis. Unfortunately, the toxicity of NSAIDs substantially limits their long-term use. Some newer NSAIDs, namely selective cyclooxygenase (COX)-2 inhibitors, exhibit greater gastrointestinal safety, and concomitant use of anti-secretory drugs can also reduce NSAID-induced gastropathy. However, NSAIDs also adversely affect the cardiovascular system. A new class of anti-inflammatory drugs, COX-inhibiting nitric oxide donators (CINODs), has been designed to exert similar anti-inflammatory effects as NSAIDs, but with an improved safety profile. CINODs release nitric oxide, providing protective effects in the gastrointestinal tract and attenuating the detrimental effects on blood pressure normally associated with NSAIDs. We provide an outline of the rationale for CINODs and their activity, in addition to an overview of the pre-clinical and clinical profile of the most advanced CINOD, naproxcinod.
Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis.
Wallace JL, Viappiani S, Bolla M. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada.
Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly used medications for the treatment of the symptoms of many chronic inflammatory diseases, including osteoarthritis. Unfortunately, the toxicity of NSAIDs substantially limits their long-term use. Some newer NSAIDs, namely selective cyclooxygenase (COX)-2 inhibitors, exhibit greater gastrointestinal safety, and concomitant use of anti-secretory drugs can also reduce NSAID-induced gastropathy. However, NSAIDs also adversely affect the cardiovascular system. A new class of anti-inflammatory drugs, COX-inhibiting nitric oxide donators (CINODs), has been designed to exert similar anti-inflammatory effects as NSAIDs, but with an improved safety profile. CINODs release nitric oxide, providing protective effects in the gastrointestinal tract and attenuating the detrimental effects on blood pressure normally associated with NSAIDs. We provide an outline of the rationale for CINODs and their activity, in addition to an overview of the pre-clinical and clinical profile of the most advanced CINOD, naproxcinod.
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