naproxen-n-butyl-nitrate and Osteoarthritis

NO-NSAIDs (or CINODs that is COX-inhibiting nitric oxide donors) are new class of antiinflammatory drugs and have a multi-pathway mechanism of action that involves cyclooxygenases (COXs) inhibition and nitric oxide (NO) donation. The first drug of this group is naproxcinod, which exerts rarely adverse effects of stomach, gut and less cardiovascular toxicity with naproxen. NO is an important mediator of endothelial function acting as a vasodilator and plays role in inflammation and pain perception that may be of relevance in osteoarthritis and in healing injures in stomach and gut. Lipoxins (LX, LXs): LXA4, LXB4 are group of lipid mediators leading to resolution of inflammation and protective influence on gastrointestinal mucosa. ATL (AT mean aspirin triggered therefore "depend on aspirin") synthesis, via COX-2, reduces the severity of damage gastrointestinal tract induced by NSAIDs. ATL also plays role in gastric adaptation during chronic aspirin administration. Antiinflammatory drugs hydrogen sulfide-releasing (H2S) (ATB-337 that consist of diclofenac linked to a hydrogen sulfide-releasing moiety) may show better efficacy and less toxicity. COX/5-LOX inhibitors and NO-NSAIDs heals symptoms of osteoarthrosis.

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Cyclooxygenase Inhibitors; Drug Interactions; Humans; Naproxen; Nitric Oxide Donors; Osteoarthritis

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.. To review the effects of NO donation, CINODS in general and naproxen in osteoarthritis (OA), based on literature in PubMed.. 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.. 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.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Naproxen; Nitric Oxide Donors; Osteoarthritis

Naproxcinod is a derivative of naproxen with similar anti-inflammatory activity, but less gastrointestinal toxicity. It is the first of a new class of analgesic and anti-inflammatory drugs known as cyclo-oxygenase-(COX)-inhibiting nitric oxide donators (CINODs) under development with NicOx in several countries. Naproxcinod is in phase III clinical development in the US for the treatment of osteoarthritis. The improved gastrointestinal tolerability of naproxcinod appears to be due to its release of nitric oxide (NO) and the consequent maintenance of tissue perfusion and integrity. Naproxcinod is available for licensing.AstraZeneca had been a worldwide licensee for naproxcinod and other CINODs. However, the results of phase II clinical trials of naproxcinod did not fulfill AstraZeneca's strategic commercial criteria for further investment and NicOx reacquired rights following AstraZeneca's decision to discontinue its involvement in 2003. NicOx was surprised by AstraZeneca's decision, and remained fully convinced of the potential of naproxcinod. NicOx is seeking new partners for development of compounds of the CINOD class. The second phase III trial (302 study) for naproxcinod in patients with osteoarthritis of the knee was initiated in April 2007. The trial will enrol approximately 1020 patients from 120 clinical sites in the US. The study is designed to confirm naproxcinod's efficacy and provide additional blood pressure data. Efficacy results are expected in mid-2008. The third phase III trial (303 study) is scheduled to start in the first half of 2007 and will assess the efficacy and safety in patients with osteoarthritis (OA) of the hip. Following pooled analysis of all three phase III trials, NicOx hopes to file an NDA in the US during the first quarter of 2009.NicOx is in ongoing discussions with regulatory authorities worldwide regarding the safety of naproxcinod and its COX-inhibiting properties. The company submitted documentation to the US FDA in August 2006 that outlined the long-term safety assessments planned for naproxcinod and has requested scientific advice on naproxcinod from the EMEA in Europe. Pending successful outcomes of the three phase III trials in patients with OA, the company anticipates that regulatory submissions in the US and Europe could be made during Q1 2009. NicOx is planning to validate a proposed development plan for Japan with the Japanese authorities in Q1 2007. Another monitoring trial is being planned by NicOx: the 305

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Humans; Naproxen; Nitric Oxide Donors; Osteoarthritis; Terminology as Topic; Treatment Outcome

Nonsteroidal anti-inflammatory drugs are associated with increases in blood pressure (BP), particularly in patients treated with antihypertensive therapy. Naproxcinod is a nitric oxide-donating cyclooxygenase inhibitor in development for osteoarthritis (OA). Thus, we characterized the effects of naproxcinod on BP in an integrated safety analysis of 3 pivotal trials of patients with OA of the hip or knee involving 2,734 patients. The changes from baseline in the systolic BP after 13 weeks of therapy with naproxcinod (375 and 750 mg), naproxen 500 mg (equipotent to naproxcinod 750 mg), or placebo twice daily were evaluated in all patients and in the subgroup taking renin-angiotensin system inhibitors. Heterogeneity testing showed no treatment-by-study interaction. The effects of naproxcinod 750 mg on the systolic BP was not different from placebo (mean change from baseline vs placebo -0.4 mm Hg, 95% confidence interval -1.6 to 0.8). Naproxen increased the systolic BP relative to placebo (mean change from baseline vs placebo +1.4 mm Hg, 95% confidence interval 0.1 to 2.7). In the renin-angiotensin system inhibitor-treated patients, the effect of naproxcinod 750 mg compared to naproxen 500 mg in the changes from baseline in the systolic BP was -4.3 mm Hg (95% confidence interval -8.5 to -0.0). In conclusion, naproxcinod had effects on BP similar to that of placebo in patients with OA. These results imply that naproxcinod would be less likely to alter systolic BP control in patients with OA than a conventional nonsteroidal anti-inflammatory drug, particularly in those treated with renin-angiotensin system inhibitor agents.

Topics: Aged; Blood Pressure; Double-Blind Method; Female; Humans; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Osteoarthritis; Treatment Outcome

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). The 2 doses of naproxcinod showed reductions from baseline in diastolic BP relative to naproxen (p <0.04) and similar changes compared to placebo. In 207 patients with hypertension treated with renin-angiotensin-blocking agents alone or with diuretics, the difference in mean change from baseline in systolic BP between naproxen 500 mg and naproxcinod 750 mg was 6.5 mm Hg in favor of naproxcinod (p <0.02). The proportion of patients in the overall population with systolic BP increases > 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.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Comorbidity; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Osteoarthritis

Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Naproxen; Nitric Oxide Donors; Osteoarthritis

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.

Topics: Animals; Blood Pressure; Cardiovascular System; Cyclooxygenase Inhibitors; Gastrointestinal Diseases; Humans; Naproxen; Nitric Oxide Donors; Osteoarthritis