Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of Osteoarthritis of the knee

ArticleinArthritis & Rheumatology 53(6):827-37 · December 2005with6 Reads
DOI: 10.1002/art.21586 · Source: PubMed
Abstract
To compare the efficacy, safety, and tolerability of AZD3582 with that of rofecoxib, naproxen, and placebo in patients with osteoarthritis (OA) of the knee, and to define the dosage of AZD3582 (125 mg, 375 mg, and 750 mg twice a day) that is noninferior in efficacy to rofecoxib. A double-blind study of 672 patients with OA of the knee was conducted. Patients who experienced increased pain on withdrawal of analgesia were randomized to receive AZD3582 125 mg, 375 mg, or 750 mg twice a day; rofecoxib 25 mg once a day; naproxen 500 mg twice a day; or placebo for 6 weeks. Efficacy, tolerability, and safety were monitored throughout the study. The primary variable was the change in Western Ontario and McMaster Universities Osteoarthritis Index pain subscale from baseline to the mean of weeks 4 and 6, comparing AZD3582 with placebo for superiority and with rofecoxib for noninferiority using a predefined margin of 10 mm. For the primary variable, AZD3582 375 mg and 750 mg were superior to placebo (least squares mean difference [95% confidence interval] -12 mm [-18, -6], P < 0.001 and -13 mm [-19, -7], P < 0.001, respectively) and were noninferior to rofecoxib (-2 mm [-8, 4], P < 0.001 and -3 mm [-9, 3], P < 0.001, respectively). AZD3582 125 mg was not significantly different from placebo for the primary variable. AZD3582 375 mg and 750 mg twice a day were superior to placebo and as effective as rofecoxib 25 mg/day in treating the signs and symptoms of OA of the knee. AZD3582 125 mg twice a day was not statistically different from placebo.
    • "In attempt to enhance the activity of NSAIDs and to minimize their potential side effect, novel NSAIDs hybrids have been developed (Kashfi 2009; Qandil 2012 ). NOreleasing NSAIDs have been shown to be effective in preclinical models of inflammation with less side effects and they have been evaluated in several clinical trials (Schnitzer et al. 2005; Fiorucci and Distrutti 2011). Similarly, H 2 S-releasing NSAIDs have been shown to have antiinflammatory properties (Kashfi and Olson 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: The development of nitric oxide (NO)- and hydrogen sulfide (H2S)-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) has generated more potent anti-inflammatory drugs with increased safety profiles. A new hybrid molecule incorporating both NO and H2S donors into aspirin (NOSH-aspirin) was recently developed. In the present study, the antinociceptive activity of this novel molecule was compared with aspirin in different models of inflammatory pain. It was found that NOSH-aspirin inhibits acetic acid-induced writhing response and carrageenan (Cg)-induced inflammatory hyperalgesia in a dose-dependent (5–150 μmol/kg, v.o.) manner, which was superior to the effect of the same doses of aspirin. NOSH-aspirin's antinociceptive effect was also greater and longer compared to aspirin upon complete Freund's adjuvant (CFA)-induced inflammatory hyperalgesia. Mechanistically, NOSH-aspirin, but not aspirin, was able to reduce the production/release of interleukin-1 beta (IL-1β) during Cg-induced paw inflammation. Furthermore, NOSH-aspirin, but not aspirin, reduced prostaglandin E2-induced hyperalgesia, which was prevented by treatment with a ATP-sensitive potassium channel (KATP) blocker (glibenclamide; glib.). Noteworthy, the antinociceptive effect of NOSH-aspirin was not associated with motor impairment. The present results indicate that NOSH-aspirin seems to present greater potency than aspirin to reduce inflammatory pain in several models. The enhanced effects of NOSH-aspirin seems to be due to its ability to reduce the production of pronociceptive cytokines such as IL-1 β and directly block hyperalgesia caused by a directly acting hyperalgesic mediator in a mechanism dependent on modulation of KATP channels. In conclusion, we would like to suggest that NOSH-aspirin represents a prototype of a new class of analgesic drugs with more potent effects than the traditional NSAID, aspirin.
    Full-text · Article · Jun 2015
    • "CINODs (Cyclo-oxygenase Inhibiting Nitric Oxide Donating drugs) represent a new class of NSAIDs; CINOD molecules consist of a traditional NSAID and a nitric oxide-donating chemical group connected by a linker. Naproxcinod is the first CINOD in clinical trials with very promising preliminary results44454647. "
    [Show abstract] [Hide abstract] ABSTRACT: Resistant hypertension is defined as uncontrolled blood pressure despite the use of three antihypertensive drugs, including a diuretic, in optimal doses. Treatment resistance can be attributed to poor adherence to antihypertensive drugs, excessive salt intake, physician inertia, inappropriate or inadequate medication, and secondary hypertension. Drug-induced hypertension, obstructive sleep apnoea, primary aldosteronism, and chronic kidney disease represent the most common secondary causes of resistant hypertension. Several drugs can induce or exacerbate pre-existing hypertension, with non-steroidal anti-inflammatory drugs being the most common due to their wide use. Obstructive sleep apnoea and primary aldosteronism are frequently encountered in patients with resistant hypertension and require expert management. Hypertension is commonly found in patients with chronic kidney disease and is frequently resistant to treatment, while the management of renovascular hypertension remains controversial. A step-by-step approach of patients with resistant hypertension is proposed at the end of this review paper.
    Full-text · Article · Mar 2011
    • "In a series of randomized, double-blind, placebocontrolled studies conducted in patients with OA on different sites, naproxcinod showed a similar potency to equimolar doses of naproxen [Karlsson et al. 2009; Lohmander et al. 2005; Schnitzer et al. 2005]. The dose of naproxcinod 750 mg twice daily showed the best balance between efficacy and safety [Karlsson et al. 2009]. "
    [Show abstract] [Hide abstract] ABSTRACT: Out of 100 patients with osteoarthritis (OA), almost 40 have a concomitant diagnosis of hypertension. Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors may trigger a rise in blood pressure (BP), which is more marked in patients with established hypertension. NSAIDs and COX-2 inhibitors attenuate the antihypertensive effect of several antihypertensive agents. Frequent BP controls are needed in treated hypertensive patients who are concomitantly receiving NSAIDs or COX-2 inhibitors because even a small increase in BP may be associated with an important rise in the risk of major cardiovascular complications. In meta-analyses, an increase in systolic BP of 5mmHg was associated with a 25% higher risk of cardiovascular events. These data have been confirmed in randomized studies with rofecoxib and celecoxib, where a modest increase in BP was associated with a significantly higher risk of cardiovascular disease. There is emerging evidence that the COX-inhibiting nitric oxide donator (CINOD) class is promising in the treatment of patients with OA. Naproxcinod, the first CINOD investigated in clinical trials, is composed of the traditional NSAID naproxen covalently bound to the nitric oxide (NO)-donating moiety butanediol mono-nitrate (BDMN). The molecule has the potential to provide a sustained release of NO. In clinical studies, naproxcinod prevented the BP rise in normotensive and hypertensive patients observed with naproxen. The BP benefit of naproxcinod over naproxen was greater in patients concomitantly receiving angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. These investigational data suggest that naproxcinod is a valuable alternative to NSAIDs and COX-2 inhibitors for treatment of OA patients.
    Full-text · Article · Aug 2010
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