tag:blogger.com,1999:blog-32227389227728493482024-02-20T00:05:08.802-08:00Naproxcinod - lab bookBlog non officiel proposant une bibliographie scientifique sur le naproxcinod de la société NicOx, depuis 1995 à aujourd'huiUnknownnoreply@blogger.comBlogger34125tag:blogger.com,1999:blog-3222738922772849348.post-14986545179260096982010-03-22T08:18:00.000-07:002010-03-22T08:21:54.907-07:002010 - 03<p>Cancer Prev Res (Phila Pa). 2009 Nov;2(11):951-6.</p><p><strong><span style="font-size:130%;">Chemopreventive efficacy of naproxen and nitric oxide-naproxen in rodent modelsof colon, urinary bladder, and mammary cancers.</span></strong></p><p>Steele VE, Rao CV, Zhang Y, Patlolla J, Boring D, Kopelovich L, Juliana MM,Grubbs CJ, Lubet RA. Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NIH, Bethesda, Maryland, USA. <a href="mailto:Steelev@mail.nih.gov">Steelev@mail.nih.gov</a></p><p>Nonsteroidal anti-inflammatory drugs (NSAID) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically, and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal ulceration and may increase cardiovascular events. Naproxen seems to cause the lowest cardiovascular events of the common NSAIDs other than aspirin. Nitric oxide (NO)-naproxen was tested based on the finding that adding a NO group to NSAIDs may help alleviate GI toxicity. In the azoxymethane-induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm in the diet reduced mean ACFs in the colon by about 45% to 60%, respectively. NO-naproxen was likewise administered in the diet at roughly equimolar doses (300 and 600 ppm) and reduced total ACF by 20% to 40%, respectively. In the hydroxybutyl (butyl) nitrosamine rat urinary bladder cancer model, NO-naproxen was given at 183 or 550 ppm in the diet, and naproxen at 128 ppm. The NO-naproxen groups had 77% and 73% decreases, respectively, in the development of large urinary bladder tumors, whereas the 128 ppm naproxen group also showed a strong decrease (69%). If treatments were started 3 months after hydroxybutyl (butyl) nitrosamine, NO-naproxen (550 ppm) and naproxen (400 ppm) were also highly effective (86-94% decreases). In the methylnitrosourea-induced mammary cancer model in rats, NO-naproxen and naproxen showed nonsignificant inhibitions (12% and 24%) at 550 and 400 ppm, respectively. These data show that both naproxen and NO-naproxen are effective agents against urinary bladder and colon, but not mammary, carcinogenesis. </p>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-3217234357759306722009-08-09T13:11:00.000-07:002010-03-22T08:39:49.143-07:0008 - 2009J Rheumatol. 2009 Jun;36(6):1290-7. Epub 2009 May 1.
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<br /><span style="font-size:130%;"><span style="FONT-WEIGHT: bold">Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee.</span></span>
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<br />Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ. Sahlgrenska University Hospital/Ostra, Goteborg, Sweden.
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<br />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)."
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<br /><strong><span style="font-size:130%;">Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis.</span></strong></strong>
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<br />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
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<br />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.
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<br />J Neurochem. 2009 Nov;111(3):766-76. Epub 2009 Aug 21.
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<br /><strong><span style="font-size:130%;">NO-flurbiprofen reduces amyloid-beta, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade.</span></strong>
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<br />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.
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<br />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.
<br />Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-60102745598951884782009-05-05T12:58:00.001-07:002009-07-20T23:49:20.309-07:0005 - 2009Expert Opin Biol Ther. 2009 May;9(5):649-57.<br /><br /><span style="font-size:130%;"><span style="FONT-WEIGHT: bold">Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD).</span></span><br /><br />Geusens P. University Hasselt, University Hospital, The Netherlands. piet.geusens@scarlet.be<br /><br />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.<br /><br /><br /><br /><p></p><p></p><p>Trends Pharmacol Sci. 2009 Mar;30(3):112-7. Epub 2009 Feb 21.</p><p><strong><span style="font-size:130%;">Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis.</span></strong></p><p>Wallace JL, Viappiani S, Bolla M. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada. <a href="mailto:wallacejohn@mcmaster.ca">wallacejohn@mcmaster.ca</a></p><p>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.</p>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-1779342661997738962009-02-27T23:31:00.000-08:002009-02-27T23:40:50.138-08:00Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis.Trends Pharmacol Sci. 2009 Feb 19. [Epub ahead of print]<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis.</span></span><br /><br />Wallace JL, Viappiani S, Bolla M. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada.<br /><br />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.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-54678631409962670222008-11-08T01:05:00.000-08:002009-02-27T23:41:26.328-08:00Risk of Myocardial Infarction and Death Associated With the Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Among Healthy Individuals: A NationwiClin Pharmacol Ther. 2008 Nov 5;<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Risk of Myocardial Infarction and Death Associated With the Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Among Healthy Individuals: A Nationwide Cohort Study.</span></span><br /><br />Fosbol E, Gislason G, Jacobsen S, Folke F, Hansen M, Schramm T, Sorensen R, Rasmussen J, Andersen S, Abildstrom S, Traerup J, Poulsen H, Rasmussen S, Kober L, Torp-Pedersen C. 1Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark.<br /><br />Use of some nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased cardiovascular risk in several patient groups, but whether this excess risk exists in apparently healthy individuals has not been clarified. Using a historical cohort design, we estimated the risk of death and myocardial infarction associated with the use of NSAIDs. Participants in the study were selected from the Danish population and were defined as healthy according to a history of no hospital admissions and no concomitant selected pharmacotherapy.<br />The source population consisted of 4,614,807 individuals, of whom 1,028,437 were included in the study after applying selection criteria. Compared to no NSAID use, hazard ratios (95% confidence limits) for death/myocardial infarction were 1.01 (0.96-1.07) for ibuprofen, 1.63 (1.52-1.76) for diclofenac, 0.97 (0.83-1.12) for naproxen, 2.13 (1.89-2.41) for rofecoxib, and 2.01 (1.78-2.27) for celecoxib. A dose-dependent increase in cardiovascular risk was seen for selective COX-2 inhibitors and diclofenac. Caution should be exercised in NSAID use in all individuals, and particularly high doses should be avoided if possible.<br />Clinical Pharmacology & Therapeutics (2008); advance online publication 5 November 2008. doi:10.1038/clpt.2008.204.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-32930409104146231792008-10-18T08:43:00.000-07:002009-02-27T23:41:58.380-08:00NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the AKt signalling pathway.Int J Cancer. 2008 Oct 15<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the AKt signalling pathway.</span></span><br /><br />Stewart GD, Nanda J, Brown DJ, Riddick AC, Ross JA, Habib FK. Prostate Research Group, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, Scotland, United Kingdom.<br /><br />Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA using RNAi. Nuclear HIF-1alpha levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1alpha translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-55524380641080908272007-11-17T01:21:00.000-08:002010-03-22T08:24:28.350-07:002007 - 11Dig Liver Dis. 2007 Nov 6; [Epub ahead of print]<br /><br /><span style="font-size:130%;"><span style="FONT-WEIGHT: bold">NSAIDs, coxibs, CINOD and H(2)S-releasing NSAIDs: What lies beyond the horizon.</span></span><br /><br />Fiorucci S, Santucci L, Distrutti E. Dipartimento di Medicina Clinica e Sperimentale, Universita di Perugia, Via E. dal Pozzo, 06122 Perugia, Italy.<br /><br />Nonsteroidal anti-inflammatory drugs are widely prescribed for treatment of pain and inflammation, despite their association with gastrointestinal complications, including bleeding and perforation. Inhibition of cyclo-oxygenases, is the main mechanism of action of aspirin and nonsteroidal anti-inflammatory drugs. Non-selective nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2. Inhibition of cyclo-oxygenase-1 derived prostanoids in the stomach represent the underlying mechanism involved in development of gastric and duodenal ulcers in patients taking nonsteroidal anti-inflammatory drugs. Selective cyclo-oxygenases-2 inhibitor (coxibs) spare cyclo-oxygenase-1 show enhanced safety profile in the gastrointestinal tract, but increase the risk of heart attack and stroke. Spurred by these findings, two coxibs, rofecoxib and valdecoxib, were withdrawn from the market. In addition to prostanoids, two gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H(2)S) exert protective effects in gastric mucosa. The inhibitory effects of NO on nonsteroidal anti-inflammatory drugs-induced leukocyte adherence have been exploited in the development of NO-releasing nonsteroidal anti-inflammatory drugs, also indicated as cyclo-oxygenase-inhibiting NO-donating drugs. Despite its non-selective profile versus cyclo-oxygenase isoenzymes, naprocyclo-oxygenase-inhibiting NO-donating drugs, the prototype of this class of anti-inflammatory agents, reduces systemic blood pressure and might have enhanced cardiovascular safety than coxibs, while causing less gastrointestinal damage than its parent drug, the naproxen. H(2)S-releasing nonsteroidal anti-inflammatory drugs derivatives have been recently developed, based on the observed ability of this gaseous mediator to cause vasodilation and to prevent leukocyte adherence. In pre-clinical settings, H(2)S-releasing nonsteroidal anti-inflammatory drugs produce less gastric damage as compared to the parent drugs. Cyclo-oxygenases-inhibiting NO-donating drugs and H(2)S-releasing nonsteroidal anti-inflammatory drugs represent examples of new anti-inflammatory drugs created through the exploitation of the beneficial effects of endogenous gaseous mediators in the gastrointestinal and cardiovascular systems.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-44204827714833521892007-09-17T06:17:00.000-07:002010-03-22T08:25:21.152-07:002007 - 08Drugs R D. 2007;8(4):255-8.<br /><br /><strong><span style="font-size:130%;">Naproxcinod: AZD 3582, HCT 3012, naproxen nitroxybutylester, nitronaproxen, NO-naproxen.</span></strong><br /><br />[No authors listed]<br /><br />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 study is a clinical endoscopy study whose objective is to confirm previous clinical findings that treatment with naproxcinod results in less gastrointestinal damage than naproxen. The trial is expected to start in 2007.The STAR Multinational Study Group has conducted a phase II gastrointestinal safety and efficacy study of naproxcinod versus naproxen in 970 patients with osteoarthritis at 80 sites in Argentina, Brazil, Hungary, Mexico, Norway, Poland, South Africa and the UK. The study was completed in November 2002.Previously, AstraZeneca had conducted a randomised, phase II trial evaluating naproxcinod's efficacy and safety among 672 subjects with symptomatic knee osteoarthritis.<br /><p> </p><p> </p><p> </p><p>Inflammopharmacology. 2007 Jun;15(3):119-23.</p><p><strong><span style="font-size:130%;">The effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.</span></strong></p><p>Walley M, Sigthorsson G, Hotz-Behofsits C, Simpson R, Bjarnason I. Guy's, King's and St Thomas' School of Medicine, Department of Gastroenterology, King's College Hospital Foundation Trust, Denmark Hill, London SE5 9PJ, London,UK. BACKGROUND: The pathogenesis of NSAID-induced enteropathy may involve dual inhibition of the cyclooxygenase (1 and 2) and a topical effect with sequential increased intestinal permeability, development of inflammation and ulcers. It has been suggested that nitric-oxide donating drugs cause significantly less gastrointestinal injury by counteracting for NSAID-induced reductions in blood flow. AIMS: To compare the effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat. METHODS: Single doses of AZD3582, naproxen (dose range 10-300 micromol/kg) or vehicle were given to male Sprague Dawley rats. Intestinal permeability (51CrEDTA) and intestinal inflammation (granulocyte marker protein) was quantitated and ulcer counts made. RESULTS: Intestinal permeability (all doses) and inflammation (highest dose of the drugs) increased significantly from control levels following naproxen and AZD3582 and there was no significant difference between the drugs. Median ulcer counts were, however, significantly (p <>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-87913612110854893572007-09-17T06:03:00.000-07:002007-09-17T06:14:04.044-07:002006 - 09Clin Ther. 2006 Sep;28(9):1279-95.<br /><br /><strong><span style="font-size:130%;">Analgesic efficacy of the cyclooxygenase-inhibiting nitric oxide donor AZD3582 in postoperative dental pain: Comparison with naproxen and rofecoxib in two randomized, double-blind, placebo-controlled studies.</span></strong><br /><br />Michael Hill C, Sindet-Pederson S, Seymour RA, Hawkesford JE 2nd, Coulthard P, Lamey PJ, Gerry Cowan C, Wickens M, Jeppsson L, Dean AD, Svensson O. University Dental Hospital, Heath Park, Cardiff, United Kingdom.<br /><br />OBJECTIVE: This study assessed the analgesic efficacy of single doses of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (AZD3582) in acute postoperative dental pain after the removal of an impacted mandibular third molar (ie, wisdom tooth). METHODS: Two randomized, placebo-controlled, double-blind studies were performed. In a dose-finding study, 242 patients were randomized to AZD3582 375, 750, 1500, or 2250 mg (n = 41, 37, 42, and 41, respectively); naproxen 500 mg (n = 39); or placebo (n = 42). In a comparator study, 282 patients were randomized to AZD3582 500 mg (n = 78) or 750 mg (n = 83), rofecoxib 50 mg (n = 80), or placebo (n = 41). Primary outcomes included time to rescue medication, time to pain relief, and mean pain intensity difference (MPID), as well as safety profile. Pain was rated on a visual analog scale. RESULTS: In the dose-finding study, 52% (126/242) were women; the mean (SD) age was 25.1 (4) years, mean weight was 69.0 kg, and the mean (SD) body mass index (BMI) was 23.7 (3) kg/m2. In the comparator study, 58% (164/282) were women; the mean (SD) age was 27 (6.4) years, mean weight was 71 kg, and mean (SD) BMI was 24.2 (3) kg/m2. In the dose-finding study, the AZD3582 750-, 1500-, and 2250-mg groups were superior to placebo in the primary variables "time to rescue medication (0-8 hours)" (hazard ratios [HRs] [95% CIs], 0.17 [0.07-0.42], P < p =" NS," p =" 0.003," p =" 0.02)," p =" 0.002)." p =" NS"> or =750 mg. The proportions of patients with vertigo and decreased orthostatic blood pressure each group were as follows: AZD3582 500 mg, 6%; AZD3582 750 mg, 12%; rofecoxib, 3%; and placebo, 5%. CONCLUSIONS: AZD3582 750 mg had similar analgesic efficacy as equimolar doses of naproxen, but noninferiority to rofecoxib was not demonstrated.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-16311332733025729932007-09-17T06:02:00.000-07:002007-09-17T06:03:08.900-07:002006 - 07Drugs R D. 2006;7(4):262-6.<br /><br /><strong><span style="font-size:130%;">Nitronaproxen: AZD 3582, HCT 3012, Naproxen Nitroxybutylester, NO-Naproxen.</span></strong><br /><br />[No authors listed]<br /><br />Nitronaproxen [AZD 3582, HCT 3012, naproxen nitroxybutylester, NO-naproxen] is a naproxen derivative with similar anti-inflammatory activity to the parent compound, but with less gastrointestinal toxicity. It is the first of a new class of analgesic and anti-inflammatory drugs known as cyclo-oxygenase-inhibiting nitric oxide donators (CINODs), which are under development by NicOx. The better gastrointestinal tolerability of nitronaproxen appears to be due to its release of nitric oxide (NO) and the consequent maintenance of tissue perfusion and integrity.Nitronaproxen is in phase III clinical development for the treatment of osteoarthritis and is available for licensing.AstraZeneca had been a worldwide licensee for nitronaproxen and other CINODs. However, the results of phase II clinical trials of nitronaproxen 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 nitronaproxen. NicOx is seeking new partners for development of compounds of the CINOD class.Nitronaproxen is in a phase III clinical trial for the treatment of osteoarthritis (OA) of the knee. The 13-week trial completed enrolment of 820 patients from 120 clinical sites in the US in May 2006. The study is designed to confirm that nitronaproxen is superior to placebo and is as effective as naproxen in relieving signs and symptoms of OA. The study will also seek to show that nitronaproxen has no adverse effect on blood pressure. An additional trial has begun that is employing ambulatory blood pressure monitoring to provide a description of the blood pressure effect of nitronaproxen over a 24-hour period in hypertensive subjects. This US trial will enrol approximately 120 volunteers with stable essential hypertension. The volunteers will not have osteoarthritis but will be between the ages of 50 and 75 years (representative of the osteoarthritis population). Results from both trials are expected in the fourth quarter of 2006.The phase II clinical programme for nitronaproxen, which included 2709 patients in five separate clinical studies, showed that the drug is a potent, safe anti-inflammatory agent, with potential for improved cardiovascular safety over NSAIDs and COX-2 selective NSAIDs. An independent advisory board recommended further development of nitronaproxen in the treatment of osteoarthritis in 2004 based on an evaluation of the full results of the phase II clinical programme.A clinical study had begun in September 2004 at the University of Pennsylvania in patients with mild essential hypertension, in which the effects of nitronaproxen and rofecoxib on arterial blood pressure would be compared. However, rofecoxib was withdrawn worldwide on 1 October 2004. It is unclear if the trial was completed. The STAR Multinational Study Group has conducted a phase II gastrointestinal safety and efficacy study of nitronaproxen versus naproxen in 970 patients with osteoarthritis at 80 sites in the following countries: Argentina, Brazil, Hungary, Mexico, Norway, Poland, South Africa and the UK. The study was completed in November 2002.AstraZeneca conducted a randomised, phase II trial evaluating the efficacy and safety of nitronaproxen among 672 subjects with symptomatic knee osteoarthritis. Results have been presented. Certain phase II trial data from 2003 had been somewhat disappointing. However, an underpowered trial and failures and deficiencies in a trial meant that it was not possible to draw conclusions from this data.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-24491888562383735982007-09-17T05:55:00.000-07:002007-09-17T05:59:16.322-07:002006 - 04Inflamm Allergy Drug Targets. 2006 Apr;5(2):121-31.<br /><br /><strong><span style="font-size:130%;">NO-NSAIDs: from inflammatory mediators to clinical readouts.</span></strong><br /><br />Fiorucci S, Antonelli E. University of Perugia, Italy.<br /><br />Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX)-2 selective inhibitors (COXIBs) are widely used drugs. However, their use is hampered by gastrointestinal, cardiovascular and renal side effects. Nitric oxide (NO)-releasing NSAIDs, NO-NSAID, are a new class of anti-inflammatory and analgesic drugs generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in humans. The combination of balanced inhibition of the two main COX isoforms with release of NO confers to NO-NSAIDs reduced gastrointestinal and cardiorenal toxicity. It is suggested that the NO, which is released as the compounds are broken down, may counteract the consequences of the NSAID-induced decrease in gastric mucosal prostaglandins. Recent clinical trials with NO-NSAIDs have provided data consistent with pre-clinical observations.<br /><br /><br /><br />Inflamm Allergy Drug Targets. 2006 Apr;5(2):115-9.<br /><br /><span style="font-size:130%;"><strong>Nitric oxide and inflammation.</strong></span><br /><br />Cirino G, Distrutti E, Wallace JL. Department of Experimental Pharmacology, Università di Napoli-Federico II, Napoli, Italy.<br /><br />There are several pre-clinical studies on the involvement of NO in inflammation. From this large amount of information it is clear that virtually every cell and many immunological parameters are modulated by NO. Thus, the final outcome is that NO cannot be rigidly classified as an anti-inflammatory or pro-inflammatory molecule. This peculiar aspect of the pathophysiology of NO has hampered the development of new drugs based on the concepts developed. Recent therapeutic approach are targeted to increase endogenous NO by activating the gene and some promising early data are available. At the present stage one of the most promising approach in the inflammation field is represented by a new class of NO-releasing compounds namely NO-NSAIDs that have recently enrolled in phase 2 clinical studies.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-14340470242472819152007-09-17T05:50:00.000-07:002007-09-17T05:53:53.000-07:002006 - 03Scand J Gastroenterol. 2006 Mar;41(3):264-73.<br /><br /><strong><span style="font-size:130%;">Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects.</span></strong><br /><br />Wilder-Smith CH, Jonzon B, Fornstedt-Wallin B, Hedman A, Karlsson P. Gastroenterology Group Practice, Brain-Gut Research Group, Berne, Switzerland.<br /><br />OBJECTIVE: The objective of this endoscopic study was to compare the effects on the gastroduodenal mucosa of healthy volunteers of different doses and dosing regimens of AZD3582, a cyclooxygenase-inhibiting nitric oxide donator (CINOD), with equimolar doses of naproxen. MATERIAL AND METHODS: Healthy volunteers were enrolled in a single-centre, randomized, double-blind, crossover trial consisting of two 12-day treatment periods and employing six sequences. The groups were: AZD3582 750 mg daily versus 375 mg twice daily (n=25), AZD3582 375 mg twice daily versus 750 mg twice daily (n=25) and naproxen 250 mg twice daily versus 500 mg twice daily (n=25). RESULTS: Gastroduodenal tract damage was similar with AZD3582 375 mg twice daily and 750 mg twice daily (mean number of erosions and ulcers+/-SD: 2.88+/-3.95 versus 3.08+/-2.80, respectively; p=0.824; 1 ulcer counted as 10 erosions). There was an indication of decreased gastroduodenal toxicity with AZD3582 750 mg daily compared with 375 mg twice daily (0.92+/-2.08 versus 2.71+/-4.75, respectively; p=0.068). Gastroduodenal toxicity was significantly lower with AZD3582 375 mg twice daily than with naproxen 250 mg twice daily (2.88+/-3.95 versus 6.16+/-9.36; p<0.05), and with AZD3582 750 mg twice daily versus naproxen 500 mg twice daily (3.08+/-2.80 versus 6.68+/-6.97; p<0.05). Equimolar twice-daily doses of AZD3582 and naproxen resulted in similar naproxen plasma levels and serum thromboxane B(2) inhibition. CONCLUSIONS: AZD3582 has an improved gastroduodenal safety profile compared with equimolar doses of naproxen. The gastroduodenal effects of AZD3582 375 mg and AZD3582 750 mg twice daily are similar. A once-daily regimen of AZD3582 might be less gastrotoxic than a twice-daily regimen.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-82132450107609359742007-09-17T04:43:00.000-07:002007-09-17T04:54:50.502-07:002005 - 12J Pharm Pharmacol. 2005 Dec;57(12):1539-54.<br /><br /><strong><span style="font-size:130%;">Clinical pharmacokinetics of the cyclooxygenase inhibiting nitric oxide donator (CINOD) AZD3582.</span></strong><br /><br />Fagerholm U, Bjarnsson MA. Clinical Pharmacology, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden.<br /><br />The clinical pharmacokinetics of the COX-inhibiting nitric oxide donator (CINOD) AZD3582 and its metabolites, including naproxen, nitric oxide and nitrate, are summarized. AZD3582 has low aqueous solubility, moderate and passive intestinal permeability and is degraded by intestinal esterases. Its oral bioavailability (F) appears to be maximally a few per cent, and increases by several-fold after food intake. Ninety-four per cent or more of an AZD3582 dose is absorbed, of which at least 9-20% appears to be taken up as intact substance. AZD3582 has a predicted plasma protein binding degree of approximately 0.1%, a half-life (t1/2) of 3 to 10 h and does not accumulate after repeated once- and twice-daily dosing. In patients AZD3582 does not provide a significantly better gastrointestinal (GI) side-effect profile than the highly permeable and locally irritating naproxen. Possible reasons for this include considerable GI uptake as naproxen, limited duration and extent of nitric oxide donation in the GI mucosa and the circulation, tolerance development (involving auto-inhibition of nitric oxide catalysing enzymes) and mucosal damage caused by nitric oxide. Blood pressure data suggest that nitric oxide is mainly donated within 3 h. The uptake of naproxen is slightly slower and lower (> or = 94% relative GI uptake and 80-85% relative F) after AZD3582 administration compared with naproxen dosing. The naproxen t1/2 and trough steady-state concentrations after AZD3582 and naproxen dosing are similar. The average systemic nitrate exposure is approximately doubled after dosing of 375 to 750 mg AZD3582 twice daily.<br /><br /><br /><br />Arthritis Rheum. 2005 Dec 15;53(6):827-37.<br /><br /><strong><span style="font-size:130%;">Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of Osteoarthritis of the knee.</span></strong><br /><br />Schnitzer TJ, Kivitz AJ, Lipetz RS, Sanders N, Hee A. Northwestern Center for Clinical Research, Chicago, Illinois 60611, USA.<br /><br />OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.<br /><br /><br /><br />Inflammopharmacology. 2005;12(5-6):521-34.<br /><br /><strong><span style="font-size:130%;">NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor.</span></strong><br /><br />Ellis JL, Augustyniak ME, Cochran ED, Earl RA, Garvey DS, Gordon LJ, Janero DR, Khanapure SP, Letts LG, Melim TL, Murty MG, Schwalb DJ, Shumway MJ, Selig WM, Trocha AM, Young DV, Zemtseva IS. NitroMed Inc., 125 Spring Street, Lexington, MA 02421-0781, USA.<br /><br />Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and to provide pain relief but suffer from a major liability concerning their propensity to cause gastric damage. As nitric oxide (NO) is known to be gastro-protective we have synthesized a NO-donating prodrug of naproxen named NMI-1182. We evaluated two cyclo-oxygenase (COX)-inhibiting nitric oxide donors (CINODs), NMI-1182 and AZD3582, for their ability to be gastro-protective compared to naproxen and for their anti-inflammatory activity. NMI-1182 and AZD3582 were found to produce similar inhibition of COX activity to that produced by naproxen. Both NMI-1182 and AZD3582 produced significantly less gastric lesions after oral administration than naproxen. All three compounds effectively inhibited paw swelling in the rat carrageenan paw edema model. In the carrageenan air pouch model all three compounds significantly reduced PGE2 levels in the pouch exudate but only NMI-1182 and naproxen inhibited leukocyte influx. These data demonstrate that NMI-1182 has comparable anti-inflammatory activity to naproxen but with a much reduced likelihood to cause gastric damage.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-3759100608632147672007-09-17T04:37:00.000-07:002007-09-17T04:41:07.523-07:002005 - 11Biochem Pharmacol. 2005 Nov 1;70(9):1343-51. Erratum in: Biochem Pharmacol. 2006 Feb 28;71(5):711.<br /><br /><strong><span style="font-size:130%;">A comparison of the cyclooxygenase inhibitor-NO donors (CINOD), NMI-1182 and AZD3582, using in vitro biochemical and pharmacological methods.</span></strong><br /><br />Young DV, Cochran ED, Dhawan V, Earl RA, Ellis JL, Garvey DS, Janero DR, Khanapure SP, Letts LG, Melim TL, Murty MG, Shumway MJ, Wey SJ, Zemtseva IS, Selig WM. Departments of Biology, 125 Spring St., Lexington, MA 02421, USA.<br /><br />Cyclooxygenase (COX, EC 1.14.99.1) inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n-butyl nitrate), for their ability to inhibit COX-1 and -2, deliver bioavailable nitric oxide, and release naproxen, using in vitro biochemical and pharmacological methods. In human whole blood, both CINODs showed inhibition, comparable to naproxen, of both COX isozymes and slowly released naproxen. Both CINODs donated bioavailable NO, as detected by cGMP induction in the pig kidney transformed cell line, LLC-PK1, but NMI-1182 was more potent by 30-100 times than AZD3582, GTN, GDN, and ISDN and considerably faster in inducing cGMP synthesis than AZD3582. The nitrate groups of GTN, NMI-1182, and AZD3582 appeared to be bioactivated via a common pathway, since each compound desensitized LLC-PK1 cells to subsequent challenge with the other compounds. Similar cGMP induction also occurred in normal, untransformed cells (human renal proximal tubule epithelial cells and hepatocytes from man, rat, and monkey); again, NMI-1182 was superior to AZD3582. NMI-1182 was also the more metabolically labile compound, releasing more absolute nitrate and nitrite (total NO(x)) in human stomach (in which NO is salutary) and liver S9 homogenates. Naproxen was also more rapidly freed from NMI-1182 than AZD3582 in human stomach, although liver S9 hydrolyzed both CINODs with similar rates. These in vitro tests revealed that NMI-1182 may be a better CINOD than AZD3582 because of its superior NO donating and naproxen liberating properties.<br /><br /><br /><br />Expert Opin Investig Drugs. 2005 Nov;14(11):1347-58.<br /><br /><strong><span style="font-size:130%;">Nitric oxide-modulating agents for gastrointestinal disorders.</span></strong><br /><br />Whittle BJ. William Harvey Research Institute, Bart's and The London, Queen Mary's School of Medicine, Charterhouse Square, London, EC1M 6BQ, UK.<br /><br />Almost 20 years after the identification of the biological role of nitric oxide (NO), the full therapeutic potential of novel agents that mimic the activity of NO or interfere with its synthesis has yet to be realised for utilities involving the gastrointestinal tract. New utilities for classical NO donors, which were used as vasodilators for decades, in the treatment of motility disorders have been explored and a product for treating anal fissure was recently launched. New classes of compounds incorporating a NO-donating moiety into standard non-steroidal anti-inflammatory drugs, the NO-non-steroidal anti-inflammatory drugs (NO-NSAIDs) or COX-inhibiting nitric oxide donors (CINODs) have also been developed. These have been shown to exhibit reduced gastrointestinal injury in experimental models, and reports on their efficacy and safety in Phase I and II studies are now available. Modulation of the inducible NO synthase isoform that generates excessive NO that can lead to subsequent cytotoxic moieties, such as peroxynitrite, may have therapeutic possibilities in a range of inflammatory diseases of the gut. Likewise, agents that promote the decomposition of peroxynitrite or removal of its other component, superoxide, may also prove to be of use. Further targets for pharmaceutical exploitation are likely to come from both genomic and molecular insights into the processes that regulate the NO system.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-80507218104552305882007-09-14T07:32:00.000-07:002007-09-17T04:27:43.475-07:002005 - 07Br J Pharmacol. 2005 Jul;145(5):679-87.<br /><br /><strong><span style="font-size:130%;">Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo.</span></strong><br /><br />Adding LC, Agvald P, Andersson LI, Jonzon B, Hoogstraate J, Gustafsson LE. Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden.<br /><br />1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitratesUnknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-75560927724921909652007-09-14T06:24:00.000-07:002007-09-17T04:21:36.945-07:002005 - 06Eur J Pharm Sci. 2005 Jun;25(2-3):229-35. Epub 2005 Mar 29.<br /><br /><strong><span style="font-size:130%;">AZD3582 increases heme oxygenase-1 expression and antioxidant activity in vascular endothelial and gastric mucosal cells.</span></strong><br /><br />Berndt G, Grosser N, Hoogstraate J, Schröder H. Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale), Germany.<br /><br />AZD3582 [4-(nitrooxy)-butyl-(2S)-2-(6-methoxy-2-naphthyl)-propanoate] is a COX-inhibiting nitric oxide donator (CINOD). Incubation of human endothelial cells (derived from umbilical cord) with AZD3582 (10-100muM) led to increased expression of heme oxygenase (HO)-1 mRNA and protein. Heme oxygenase-1 (HO-1) is a crucial mediator of antioxidant and tissue-protective actions. In contrast, naproxen (a non-selective NSAID) and rofecoxib (a selective inhibitor of COX-2), did not affect HO-1 expression. Pre-treating endothelial cells with AZD3582 at concentrations that were effective at inducing HO-1 also reduced NADPH-dependent production of oxygen radicals. Antioxidant activity in the endothelial cells persisted after AZD3582 had been washed out from the incubation medium. When added exogenously to the cells at low micromolar concentrations, the HO-1 metabolite, bilirubin, virtually abolished NADPH-dependent oxidative stress. AZD3582-induced blockade of free-radical formation was reversed in the presence of the HO-1 inhibitor, tin protoporphyrin-IX (SnPP). Similar results were obtained in human gastric mucosal cells (KATO-III). Our results demonstrate that HO-1 is a novel target of AZD3582.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-84189546074850616832007-09-14T06:14:00.000-07:002007-09-14T06:22:56.516-07:002005 - 05J Pharm Pharmacol. 2005 May;57(5):587-97.<br /><br /><strong><span style="font-size:130%;">Pre-clinical pharmacokinetics of the cyclooxygenase-inhibiting nitric oxide donor (CINOD) AZD3582.</span></strong><br /><br />Fagerholm U, Breuer O, Swedmark S, Hoogstraate J. Clinical Pharmacology, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden.<br /><br />The pre-clinical pharmacokinetics of AZD3582 (4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate) and its primary metabolites (naproxen and nitrate) were evaluated. AZD3582 had intermediate and passive intestinal permeability (40 times lower than for naproxen), high systemic plasma clearance (CL), substantial gastrointestinal hydrolysis, intermediate volume of distribution (Vss; >or=3.4 L kg-1) and half-life (t1/2; 7 h), negligible plasma protein binding (approximately 0.1%), low/intermediate oral uptake (>or=13% as intact substance) and low and varying oral bioavailability (mean 1.4% in minipigs and 3.9% in dogs). Following administration of therapeutically relevant oral doses, plasma concentrations of AZD3582 were very low (<or=13 or=" 442">40 h in rats, minipigs and dogs, respectively. The Vss and CL for naproxen were small. Plasma protein binding was extensive, and saturation was observed within the therapeutic dose and concentration range. Intake of food prolonged the systemic absorption of naproxen in the minipig. The pharmacokinetics of naproxen did not show apparent time- or gender-related dependency. Following oral dosing of [3H]-, [14C]- and [15N]-AZD3582, most [14C]- and [3H]-activity was excreted in urine and expired air, respectively. Seventeen per cent of [15N] was recovered in minipig urine as [15N]-nitrate. About 30% of [3H]-activity (naproxen and/or naproxen-related metabolites) was excreted in bile and re-absorbed. Concentrations of [14C]-activity (nitrooxy-butyl group and/or its metabolites) in milk were higher than in plasma and [3H]-activity in milk. [3H]- and [14C]-excretion data indicated that intact AZD3582 was not excreted in urine, bile or milk to a significant extent. There was no apparent consistency between tissue distribution of [14C]- and [3H]-activity in the rat, which suggests rapid and extensive metabolism of extravascularly distributed AZD3582. A substantial increase of plasma nitrate levels was found after single and repeated oral doses<br /><br /><br />Clin Pharmacol Ther. 2005 May;77(5):437-50.<br /><br /><strong><span style="font-size:130%;">Renal effects of the cyclooxygenase-inhibiting nitric oxide donator AZD3582 compared with rofecoxib and naproxen during normal and low sodium intake.</span></strong><br /><br />Huledal G, Jonzon B, Malmenas M, Hedman A, Andersson LI, Odlind B, Brater DC. Experimental Medicine, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden.<br /><br />BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) and can thereby reduce renal function, especially with respect to solute excretion and renal perfusion. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donator. Donation of nitric oxide by AZD3582 could preserve blood flow and thereby counteract the deleterious effects of COX inhibition in the gastrointestinal tract and possibly in other organ systems, including the kidney. The aim of this single-dose study was to assess the hypothesis that AZD3582 would not adversely affect renal function compared with NSAIDs. METHODS: In a parallel, randomized, double-blind fashion, a total of 60 healthy subjects (age range, 20-44 years) received 2 single doses of 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, 500 mg naproxen, or placebo (n = 12 per group). The first dose was given after a 5-day normal-sodium diet (150 mmol/d), and the second was given after a consecutive 3-day low-sodium diet (10 mmol/d). Urinary sodium excretion during normal sodium intake and glomerular filtration rate (GFR) (assessed by iohexol clearance) during sodium depletion were the primary variables measured. RESULTS: Urinary sodium excretion was reduced in all active treatment groups (maximal reduction of approximately 11 mmol/h during normal sodium intake, P < .05 versus placebo for all groups). GFR was also reduced in all active treatment groups. In sodium-depleted subjects, the mean (SD) maximal reduction in GFR during 0 to 6 hours for 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, and 500 mg naproxen was 28.1 mL/min (13.5 mL/min), 33.7 mL/min (23.3 mL/min), 25.2 mL/min (29.2 mL/min), and 41.7 mL/min (30.7 mL/min), respectively, with a statistically significant difference between 500 mg naproxen and placebo. Relative changes in sodium excretion and GFR were similar during normal sodium intake and sodium depletion during active treatment. CONCLUSION: The renal effects of 750 mg and 1500 mg AZD3582 were similar to those of 500 mg naproxen and 50 mg rofecoxib. Thus the potential for nitric oxide donation to create a renal-sparing agent was not found for AZD3582.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-17947916800307146822007-09-14T06:10:00.000-07:002007-09-14T06:12:28.633-07:002005 - 03Ann Rheum Dis. 2005 Mar;64(3):449-56. Epub 2004 Sep 2.<br /><br /><strong><span style="font-size:130%;">A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis.</span></strong><br /><br />Lohmander LS, McKeith D, Svensson O, Malmenas M, Bolin L, Kalla A, Genti G, Szechinski J, Ramos-Remus C; STAR Multinational Study Group. Department of Orthopaedics, Lund University, SE-221 85 Lund, Sweden.<br /><br />OBJECTIVE: To evaluate the gastrointestinal safety and efficacy of the COX inhibiting nitric oxide donator AZD3582 in patients with hip or knee osteoarthritis. METHODS: 970 patients were randomised (7:7:2) to AZD3582 750 mg twice daily, naproxen 500 mg twice daily, or placebo twice daily in a double blind study. The primary end point was the six week incidence of endoscopic gastroduodenal ulcers (diameter > or =3 mm). Overall damage measured on the Lanza scale was a secondary end point. Safety and tolerability assessments included endoscopic upper gastrointestinal erosions and the gastrointestinal symptom rating scale (GSRS). Efficacy was primarily assessed by WOMAC. RESULTS: The incidence of ulcers with AZD3582 was 9.7% and with naproxen 13.7% (p = 0.07, NS), v 0% on placebo. The incidence of Lanza scores >2 was higher with naproxen (43.7%) than with AZD3582 (32.2%) (p<0.001). Compared with baseline, significantly fewer ulcers and erosions developed in stomach and stomach/duodenum combined, and fewer erosions developed in stomach, duodenum, and both combined on AZD3582 than on naproxen. GSRS reflux and abdominal pain subscale scores were lower for AZD3582 than for naproxen but there was no difference for indigestion, constipation, and diarrhoea. AZD3582 was as effective as naproxen at improving WOMAC scores. Both agents were well tolerated, with no significant effects on blood pressure. CONCLUSIONS: At doses with similar efficacy in relieving osteoarthritis symptoms, the primary end point of six week endoscopic gastroduodenal ulcer incidence was not significantly different between AZD3582 and naproxen. Most secondary endoscopic gastrointestinal end points favoured AZD3582.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-10286363922469021602007-09-12T05:42:00.000-07:002007-09-14T05:01:37.228-07:002005 - 01Eur J Pharmacol. 2005 Jan 31;508(1-3):7-13. Epub 2004 Dec 28.<br /><br /><strong><span style="font-size:130%;">NSAIDs increase GM-CSF release by human synoviocytes: comparison with nitric oxide-donating derivatives.</span></strong><br /><br />Zacharowski P, Breese E, Wood E, Del Soldato P, Warner T, Mitchell J. Cardiac, Vascular and Inflammation Research, The William Harvey Research Institute, Bart's and The London, Queen Mary School of Medicine and Dentistry, London, UK.<br /><br />Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the condition of rheumatoid arthritis, where levels of prostaglandin E2 (PGE2) and granulocyte macrophage-colony stimulating factor (GM-CSF) are elevated in the synovial fluid. NO-NSAIDs are a new class of cyclooxygenase (COX)-inhibitors developed by coupling a nitric oxide (NO)-donating moiety to conventional NSAIDs. We show that, in cytokine-treated synoviocytes (from non-rheumatic patients), NO-naproxen and NO-flurbiprofen like their parent compounds concentration-dependently reduce the levels of PGE2 (an index of COX-2 activity), with a corresponding rise in the release of GM-CSF. Unlike acetylsalicylic acid (ASA), NO-ASA reduces the levels of PGE2, without increasing GM-CSF release, although cell viability is reduced at the highest concentration (1 mM). The effects of NSAIDs and NO-NSAIDs on GM-CSF release were attributable to the PGE2 mediated cyclic (c) AMP pathway because PGE2 reversed the effects of COX blockade. Second, phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-201724 (both of which elevate camp levels) decreased GM-CSF release, in the presence of PGE2. Finally, neither sodium nitroprusside nor zaprinast (both of which elevate cGMP levels) affected GM-CSF or PGE2 release. Our findings demonstrate that GM-CSF is regulated by NSAIDs and NO-NSAIDs via inhibition of COX and appears to be mediated via the cAMP pathway. NO-ASA is the exception, because it does not increase GM-CSF release, although at millimolar concentrations cell viability is reduced.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-56432343980216142432007-09-12T05:13:00.000-07:002007-09-12T05:16:31.988-07:002004 - 12J Pharmacol Exp Ther. 2004 Dec;311(3):1264-71. Epub 2004 Aug 5.<br /><br /><strong><span style="font-size:130%;">Nitric oxide (NO)-releasing naproxen (HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic Acid 4-(nitrooxy)butyl ester]) interactions with aspirin in gastric mucosa of arthritic rats reveal a role for aspirin-triggered lipoxin, prostaglandins, and NO in gastric protection.</span></strong><br /><br />Fiorucci S, Di Lorenzo A, Renga B, Farneti S, Morelli A, Cirino G. Clinica di Gastroenterologia ed Endoscopia Digestiva, Policlinico Monteluce, 06100 Perugia, Italy.<br /><br />Administration of selective and nonselective cyclooxygenase (COX)-2 inhibitors to rheumatoid arthritis patients taking low doses of acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal bleeding. The present study was undertaken to investigate whether administration of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on arthritis score and interleukin-6 plasma levels, coadministration of naproxen (10 mg/kg/day) and celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates arthritis development (P <0.01>0.001 versus arthritis) without exacerbating gastric mucosal injury caused by ASA. Arthritis development associates with gastric COX-2 induction, mRNA and protein, and enhanced gastric prostaglandin E2 (PGE2) synthesis (P <0.01 versus control rats). Although all treatments, including celecoxib, were effective in reducing gastric PGE2 synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of aspirin-triggered lipoxin (ATL), a COX-2-derived lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with naproxen and celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P <0.01 versus ASA alone). In contrast, whereas HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that HCT-3012 derived from NO has the potential to compensate for inhibition of PGE2 and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and coxibs in rheumatic patients that take low doses of ASA.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-14487650620122638002007-09-12T05:09:00.000-07:002007-09-12T05:11:03.266-07:002004 - 08J Pharmacol Exp Ther. 2004 Aug;310(2):555-62. Epub 2004 Apr 13.<br /><br /><strong><span style="font-size:130%;">The nitric oxide-releasing naproxen derivative displays cardioprotection in perfused rabbit heart submitted to ischemia-reperfusion.</span></strong><br /><br />Rossoni G, Manfredi B, Del Soldato P, Berti F. Department of Pharmacological Sciences, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.<br /><br />In this study, the pharmacological activity of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphtaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, was compared with that of naproxen in a model of acute ischemia (40 min) and reperfusion (20 min) of the rabbit heart. HTC-3012 (3-100 microM), in spite of inhibition of 6-keto-prostaglandin F(1alpha) generation by the cardiac tissues, brought about a dose-dependent normalization of coronary perfusion pressure, associated with a reduction of ventricular contracture during ischemia with remarkable improvement of left ventricular developed pressure at reperfusion. These beneficial effects were accompanied by a substantial release of nitrite/nitrate in the heart perfusates, indicating that NO has been released by HCT-3012 and donated to the cardiac tissue. These events were paralleled by a significant reduction of creatine kinase activity in heart perfusates during reperfusion. Naproxen (10-100 microM) aggravated the myocardial damage in ischemic reperfused hearts, severely depressing the postischemic ventricular dysfunction. Perfusion of the heart with N(G)-monomethyl-l-arginine (10 microM) caused a marked aggravation of myocardial damage of the reperfused hearts, and this effect was dose dependently prevented by HCT-3012 but not by naproxen. The results of the present experiments clearly indicate that HCT-3012, by donating NO, displays a noticeable anti-ischemic effect in reperfused ischemic rabbit hearts. The safer gastrointestinal profile of HCT-3012 and its ability to control experimental hypertension, suggest that this compound may have therapeutical potential in cardiovascular disease, namely in the prevention of myocardial ischemic events, and may represent a better alternative to conventional nonsteroidal anti-inflammatory drugs.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-83374616171058022152007-09-12T05:06:00.000-07:002007-09-12T05:08:39.906-07:002004 - 02Eur J Pharm Sci. 2004 Feb;21(2-3):331-5.<br /><br /><strong><span style="font-size:130%;">A common pathway of nitric oxide release from AZD3582 and glyceryl trinitrate.</span></strong><br /><br />Berndt G, Grosser N, Hoogstraate J, Schröder H. Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Street 4, 06099, Halle (Saale), Germany.<br /><br />4-(Nitrooxy)-butyl-(S)-2-(6-methoxy-2-naphthyl)-propanoate (AZD3582) is a cyclooxygenase (COX)-inhibiting nitric oxide donator (CINOD). It donates nitric oxide (NO) in biological systems through as yet unidentified mechanisms. cGMP, a marker of intracellularly generated NO, was increased up to 27-fold over basal levels by AZD3582 (1-30microM) in LLC-PK1 kidney epithelial cells. A 5h pretreatment with glyceryl tinitrate (GTN, 0.1-1microM) attenuated the cGMP response to a subsequent challenge with AZD3582 or GTN. Similarly, AZD3582 (10-30microM) pretreatment reduced the increase in cGMP on subsequent incubation with AZD3582 or GTN. In contrast, cGMP stimulation by SIN-1, which releases NO independently of enzymatic catalysis, remained unimpaired in cells pretreated with GTN or AZD3582. Our results demonstrate that AZD3582 decreases the sensitivity of the guanylyl cyclase/cGMP system to GTN and vice versa. This suggests that bioactivation pathways for organic nitrates, which involve enzymatic catalysis, may be responsible for NO donation from AZD3582.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-51697065154250216702007-09-12T04:55:00.000-07:002007-09-12T05:05:40.419-07:002003 - 11Inflammopharmacology. 2003;11(4):437-44.<br /><br /><strong><span style="font-size:130%;">The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers.</span></strong><br /><br />Jonzon B, Bjarnason I, Hawkey C, Jones J, Goddard A, Fagerholm U, Karlsson P. Experimental Medicine, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden.<br /><br />COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.<br /><br /><br /><br />Inflammopharmacology. 2003;11(4):423-8.<br /><br /><strong><span style="font-size:130%;">COX-inhibiting nitric oxide donators (CINODs) - a new paradigm in the treatment of pain and inflammation.</span></strong><br /><br />Hoogstraate J, Andersson LI, Berge OG, Jonzon B, Ojteg G. Research DMPK, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden.<br /><br />The clinical utility of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief is tempered by their propensity to cause gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators (CINODs) are a new class of drugs designed to provide analgesic efficacy through COX inhibition and gastrointestinal safety through the protective effects of controlled nitric oxide donation. Pre-clinical studies assessing the pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these studies, AZD3582 was the first CINOD to enter clinical development for the treatment of acute and chronic pain. The potential clinical utility of this new class is illustrated by a study of AZD3582 in healthy volunteers in which it caused significantly less acute gastrointestinal toxicity than an equimolar dose of naproxen. The results of the animal studies and the initial clinical study warrant long-term tolerability studies of AZD3582 along with evaluation of its anti-inflammatory and analgesic effects in humans.<br /><br /><br /><br />Gut. 2003 Nov;52(11):1537-42.<br /><br /><strong><span style="font-size:130%;">Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans.</span></strong><br /><br />Hawkey CJ, Jones JI, Atherton CT, Skelly MM, Bebb JR, Fagerholm U, Jonzon B, Karlsson P, Bjarnason IT. Division of Gastroenterology, University Hospital Nottingham, Nottingham, UK.<br /><br />BACKGROUND: Cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs that may minimise gastrointestinal toxicity compared with standard non-steroidal anti-inflammatory drugs (NSAIDs) by virtue of nitric oxide donation. METHODS: A proof of concept study of the gastrointestinal safety of AZD3582, the first CINOD available for human testing, was conducted. Thirty one subjects were randomised to receive placebo, naproxen 500 mg twice daily, or its nitroxybutyl derivative AZD3582 in an equimolar dose (750 mg twice daily) for 12 days in a double blind three period crossover volunteer study. At the start and end of each dosing period, gastroduodenal injury was assessed by endoscopy and small bowel permeability by differential urinary excretion of lactulose and L-rhamnose. Pharmacokinetic profiles were assessed at steady state. RESULTS: On naproxen, the mean total number of gastroduodenal erosions was 11.5 (and one subject developed an acute ulcer) versus 4.1 on AZD3582 (p<0.0001). More than half of the subjects had no erosions on AZD3582. Differences were seen for both the stomach and duodenum. Naproxen increased intestinal permeability (lactulose:L-rhamnose ratio 0.030 before v 0.040 after treatment) whereas AZD3582 (0.029 before, 0.029 after; p=0.006 v naproxen) and placebo (0.030 before, 0.028 after; p<0.001 v naproxen) did not. The steady state bioavailability of naproxen metabolised from AZD3582 was 95% (95% confidence interval 87-101%) of that after naproxen administration. CONCLUSIONS: This human study supports animal data showing reduced gastrointestinal toxicity with the CINOD AZD3582. The potential combination of effective pain relief and gastrointestinal protection offered by AZD3582 warrants further evaluation in human clinical studies.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-17419433200456678012007-09-12T04:52:00.000-07:002007-09-12T04:53:40.216-07:002003 - 05Dig Liver Dis. 2003 May;35 Suppl 2:S27-34.<br /><br /><strong><span style="font-size:130%;">NO-NSAIDs and cancer: promising novel agents.</span></strong><br /><br />Rigas B, Kalofonos H, Lebovics E, Vagenakis AG. American Health Foundation, 1 Dana Road, Valhalla, NY 10595, USA.<br /><br />Three potential applications of NO-donating NSAIDs in human cancer include their use: as chemopreventive agents; against already developed cancers (chemotherapy); and for the control of cancer symptoms, notably cancer pain. The evidence to date of greater safety and enhanced efficacy of NO-donating NSAIDs underscores their potential to prevent colon cancer and overcome the limitations of traditional NSAIDs. NO-donating NSAIDs affect several pathways critical to colon carcinogenesis and this may explain in part their greater efficacy in colon cancer prevention as assessed in preclinical models.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-3222738922772849348.post-13503417875699237962007-09-12T04:48:00.000-07:002007-09-12T04:51:20.331-07:002002 - 10Br J Pharmacol. 2002 Oct;137(3):295-310.<br /><br /><strong><span style="font-size:130%;">Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs.</span></strong><br /><br />Keeble JE, Moore PK. Centre for Cardiovascular Biology and Medicine, King's College, University of London, Guy's Campus, London SE1 9RT.<br /><br />This review examines the biological significance, therapeutic potential and mechanism(s) of action of a range of nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAID) and related nitric oxide-releasing donating drugs (NODD). The slow release of nitric oxide (NO) from these compounds leads to subtle changes in the profile of pharmacological activity of the parent, non-steroidal anti-inflammatory drugs (NSAID). For example, compared with NSAID, NO-NSAID cause markedly diminished gastrointestinal toxicity and improved anti-inflammatory and anti-nociceptive efficacy. In addition, nitroparacetamol exhibits hepatoprotection as opposed to the hepatotoxic activity of paracetamol. The possibility that NO-NSAID or NODD may be of therapeutic benefit in a wide variety of disease states including pain and inflammation, thrombosis and restenosis, neurodegenerative diseases of the central nervous system, colitis, cancer, urinary incontinence, liver disease, impotence, bronchial asthma and osteoporosis is discussed.Unknownnoreply@blogger.com