tag:blogger.com,1999:blog-42105351718508427372024-03-08T03:08:40.675-08:00Nitroaspirin - lab bookBlog non officiel proposant une bibliographie scientifique sur le nitroaspirine (NCX-4016) de la société NicOx, depuis 1996 à aujourd'huiUnknownnoreply@blogger.comBlogger72125tag:blogger.com,1999:blog-4210535171850842737.post-65430795311059777922010-03-22T08:12:00.000-07:002010-04-02T04:51:33.097-07:002010 - 03<p>Int Immunopharmacol. 2009 Jul;9(7-8):910-7. Epub 2009 Mar 31.</p><p><strong><span style="font-size:130%;">Comparative effects of aspirin and NO-releasing aspirins on differentiation, maturation and function of human monocyte-derived dendritic cells in vitro.</span></strong></p><p>Bufan B, Mojsilović S, Vucićević D, Vucević D, Vasilijić S, Balint B, Colić M. Institute for Medical Research, Military Medical Academy, Belgrade, Serbia; Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia. <a href="mailto:bbiljana@pharmacy.bg.ac.rs">bbiljana@pharmacy.bg.ac.rs</a></p><p>Acetylsalicilyc acid (aspirin, ASA) is a well known anti-inflammatory drug with immunomodulatory properties. NO-releasing aspirins (NO-ASA) are new compounds with anti-inflammatory properties. We studied the effects of ASA and two NO-ASA (NCX 4016 and NCX 4040) on human monocyte-derived dendritic cells (MoDC). Immature MoDC were generated in vitro from monocytes in the presence of recombinant human granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4. Mature MoDC were obtained by adding lipopolysaccharide (LPS) in cultures of immature MoDC. As we found that ASA at 4-8 mM, NCX 4016 at 400-800 microM and NCX 4040 at 4-8 microM stimulated apoptosis of monocytes and immature MoDC, sub-apoptotic concentrations of ASA (2 mM), NCX 4016 (200 microM) and NCX 4040 (2 microM) were used in experiments. Examined substances were added at the beginning of MoDC cultivation. MoDC differentiated in the presence of examined compounds had lower expression of HLA-DR, CD80, CD40 and CD54, decreased allostimulatory activity and lower production of IL-12 p40. ASA and NCX 4016 decreased production of IL-10, whereas NCX 4040 had the opposite effect. ASA inhibited the expression of CD1a and prevented downregulation of CD14, NCX 4016 stimulated the differentiation of CD1a+CD14+ and CD1a(-)CD14+ cells, whereas NCX 4040 decreased the proportion of CD1a+CD14(-) and increased the frequency of CD1a+CD14+ cells, compared to control. Maturation, both in ASA and NO-ASA treated MoDC was characterized by decreased allostimulatory activity, lower expression of CD83, HLA-DR, costimulatory molecules and CD54 and decreased production of IL-10 and IL-12 p40. In conclusion, we confirmed that ASA impairs differentiation, maturation and function of MoDC and found that NCX 4016 and NCX 4040 exerted similar, but not identical effects at about 10- and 1000-fold lower concentrations, respectively, compared to ASA.<br /></p><p></p><p></p><p></p><p> </p><p><br />Biochem Pharmacol. 2009 Nov 15;78(10):1298-304. Epub 2009 Jul 2.</p><p><strong><span style="font-size:130%;">Nitro-aspirin inhibits MCF-7 breast cancer cell growth: effects on COX-2expression and Wnt/beta-catenin/TCF-4 signaling.</span></strong></p><p>Nath N, Vassell R, Chattopadhyay M, Kogan M, Kashfi K. Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, United <a href="mailto:States.nnath@nyit.edu">States.nnath@nyit.edu</a></p><p>There is current evidence implicating the Wnt/beta-catenin/TCF pathway in breast cancer. We investigated the effect of para- and meta-positional isomers of nitric oxide-releasing aspirin (NO-ASA), and aspirin (ASA) on MCF-7 human breast cancer cell growth and beta-catenin/TCF signaling. The p- and m-NO-ASA isomers strongly inhibited cell growth and beta-catenin/TCF transcriptional activity compared to ASA; the IC50s for growth inhibition were 57+/-4, 193+/-10 and >5000microM, and for transcriptional inhibition they were 12+/-1.8, 75+/-6.5 and >5000microM for p-, m-NO-ASA and ASA, respectively. p-NO-ASA reduced the expression of Wnt/beta-catenin downstream target gene cyclin D1, and total cellular beta-catenin levels. COX-2 expression was induced by p-NO-ASA, protein kinase C inhibitors reversed this induction. p-NO-ASA blocked the cell cycle transition at S to G2/M phase. These studies suggest a targeted chemopreventive/chemotherapeutic potential for NO-ASA against breast cancer.<br /></p><p></p><p></p><p> </p><p><br /> </p><p>Int J Oncol. 2009 Oct;35(4):837-44.</p><p><strong><span style="font-size:130%;">The differential cell signaling effects of two positional isomers of theanticancer NO-donating aspirin.</span></strong></p><p>Hua A, Mackenzie GG, Rigas B. Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York 11794-5200, USA.</p><p>We studied the mechanism by which the para and meta positional isomers of nitric oxide-donating aspirin (NO-ASA) inhibit human colon cancer cell growth. These compounds are promising chemopreventive agents and represent a broader class of novel drugs. The two isomers differ drastically in their 24-h IC50s for cell growth, which are 12 microM for p-NO-ASA and 230 microM for m-NO-ASA. We examined their effects on cell signaling cascades, including predominantly the mitogen activated protein kinases (MAPKs). The principal differences between the two isomers were: a) p-NO-ASA exerts its effect earlier than m-NO-ASA; b) the predominant effect of m-NO-ASA is on ERK1/2 and Akt; whereas that of p-NO-ASA is on JNK1/2, while both activate p38, with p-NO-ASA showing a stronger and earlier effect; c) ATF-2 is more responsive to m-NO-ASA and c-Jun to p-NO-ASA; d) both isomers seem to have similar effects on AP-1 binding, the main difference between them being the timing of the effect; p-NO-ASA's effect is early and m-NO-ASA's is late; e) p-NO-ASA has an earlier and stronger effect on p21, while m-NO-ASA's effect occurs later and is weaker; and f) cell cycle changes follow the effect on p21 expression. Our findings underscore the role of positional isomerism in modulating the pharmacological effects of drugs and have potentially important implications for the further development of these chemoprevention agents.</p><p> </p><p> </p><p> </p><p></p><p></p><p>Br J Pharmacol. 2009 Sep;158(2):601-9. Epub 2009 Jul 23.</p><p><strong><span style="font-size:130%;">Antinociceptive effects of NCX-701 (nitro-paracetamol) in neuropathic rats: enhancement of antinociception by co-administration with gabapentin.</span></strong></p><p>Curros-Criado MM, Herrero JF. Departamento de Fisiología, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.</p><p>BACKGROUND AND PURPOSE: Neuropathic pain is characterized by a poor response to classic analgesics. In the present study, we have assessed the antinociceptive activity of NCX-701 (nitro-paracetamol) in neuropathic rats, after systemic and intrathecal (i.t.) administration. In addition, we analysed the possible benefit of the combination of NCX-701 and gabapentin, a well-known potent analgesic, in the treatment of neuropathic pain. EXPERIMENTAL APPROACH: The antinociceptive effects of i.v. and i.t. NCX-701 and paracetamol were studied in spinal cord neuronal responses from neuropathic adult male Wistar rats, using the recording of single motor units technique. The effect of i.v. and i.t. NCX-701 in combination with i.v. gabapentin was studied by isobolographic analysis. KEY RESULTS: The experiments showed that NCX-701, but not paracetamol, dose-dependently reduced the nociceptive responses evoked by noxious mechanical and electrical stimulation, after i.v. (ID(50) 542 +/- 5 micromol kg(-1) for noxious mechanical stimulation) or i.t. (ID(50) 932 +/- 16 nmol kg(-1)) administration. The combined administration of i.v. or i.t. NCX-701 and i.v. gabapentin induced a more intense antinociceptive effect than any of the two drugs given alone. The isobolographic analysis showed a synergistic effect. CONCLUSIONS AND IMPLICATIONS: NCX-701 is an effective antinociceptive compound in situations of neuropathy-induced sensitization, with an action mainly located in the spinal cord. The combination of NCX-701 and gabapentin induces a synergistic enhancement of the depression of nociceptive responses evoked by natural noxious stimulation. The use of NCX-701 alone or in combination with gabapentin might open up new and promising perspectives in the treatment of neuropathic pain.<br /></p><p></p><p> </p><p> </p><p><br />J Immunol. 2010 Jan 11. [Epub ahead of print]</p><p><strong><span style="font-size:130%;">NCX 4040, a Nitric Oxide-Donating Aspirin, Exerts Anti-Inflammatory Effects through Inhibition of I{kappa}B-{alpha} Degradation in Human Monocytes.</span></strong></p><p>Ricciotti E, Dovizio M, Di Francesco L, Anzellotti P, Salvatore T, Di Francesco A, Sciulli MG, Pistritto G, Monopoli A, Patrignani P. Department of Medicine and Center of Excellence on Aging, School of Medicine, "G. d'Annunzio" University and.</p><p>NO-donating aspirins consist of aspirin to which a NO-donating group is covalently linked via a spacer molecule. NCX 4040 and NCX 4016 are positional isomers with respect to the -CH(2)ONO(2) group (para and meta, respectively) on the benzene ring of the spacer. Because positional isomerism is critical for antitumor properties of NO-donating aspirins, we aimed to compare their anti-inflammatory effects with those of aspirin in vitro. Thus, we assessed their impacts on cyclooxygenase-2 activity (by measuring PGE(2) levels), protein expression, and cytokine generation(IL-1beta, IL-18, TNF-alpha, and IL-10) in human whole blood and isolated human monocytes stimulated with LPS. Interestingly, we found that micromolar concentrations of NCX 4040, but not NCX 4016 or aspirin, affected cyclooxygenase-2 expression and cytokine generation. We compared the effects of NCX 4040 with those of NCX 4016 or aspirin on IkappaB-alpha stabilization and proteasome activity in the LPS-stimulated human monocytic cell line THP1. Differently from aspirin and NCX 4016, NCX 4040, at a micromolar concentration range, inhibited IkappaB-alpha degradation. In fact, NCX 4040 caused concentration-dependent accumulation of IkappaB-alpha and its phosphorylated form. This effect was not reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase, thus excluding the contribution of NO-dependent cGMP generation. In contrast, IkappaB-alpha accumulation by NCX 4040 may involve an inhibitory effect on proteasome functions. Indeed, NCX 4040 inhibited 20S proteasome activity when incubated with intact cells but not in the presence of cell lysate supernatants, thus suggesting an indirect inhibitory effect. In conclusion, NCX 4040 is an inhibitor of IkappaB-alpha degradation and proteasome function, and it should be taken into consideration for the development of novel anti-inflammatory and chemopreventive agents.</p><p> </p><p> </p><p> </p><p>Diabetes Care. 2010 Mar 18. [Epub ahead of print]<br /><br /><strong><span style="font-size:130%;">HYPERGLYCEMIA-INDUCED PLATELET ACTIVATION IN TYPE 2 DIABETES MELLITUS IS RESISTANT TO ASPIRIN BUT NOT TO A NITRIC OXIDE-DONATING AGENT.</span></strong><br /><br />Gresele P, Marzotti S, Guglielmini G, Momi S, Giannini S, Minuz P, Lucidi P, Bolli GB, Bolli GB. Section of Internal and Cardiovascular Medicine*<br /><br />AbstractObjective. Acute, short-term hyperglycemia enhances high shear-stress-induced platelet activation in type-2-diabetes-mellitus (T2DM). Several observations suggest that platelets in T2DM are resistant to inhibition by aspirin. Our aim was to assess comparatively the effect of aspirin, a nitric oxide-donating agent (NCX 4016), their combination, or placebo on platelet activation induced by acute hyperglycemia in T2DM. Research Design and Methods. In a double-blind, placebo-controlled, randomized trial, 40 T2DM patients were allocated to aspirin 100mg, o.i.d., NCX 4016 800 mg, b.i.d., both of them, or placebo, for 15 days. On day 15, one hour after the morning dose, a four-hour hyperglycemic clamp (plasma glucose 13.9mmol/l) was performed and blood samples were collected before and immediately after it for platelet activation and cyclooxygenase-1 (COX-1) inhibition studies. Results. Acute hyperglycemia enhanced shear stress-induced platelet activation in placebo-treated patients (basal closure time 63+/-7.1sec, after hyperglycemia 49.5+/-1.4sec, -13.5+/-6.3sec, P<0.048); p="NS">Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-71924767650500527602009-05-05T12:54:00.000-07:002009-05-05T12:55:41.323-07:0005 - 2009Int J Clin Pract. 2009 May;63(5):776-89.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">New antiplatelet drugs: beyond aspirin and clopidogrel.</span></span><br /><br />Siddique A, Butt M, Shantsila E, Lip GY. Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK.<br /><br />Antiplatelet therapy remains a cornerstone of modern management of atherothrombotic vascular disease. For many years, aspirin has been the mainstay of initial antiplatelet drug management in coronary heart disease, while the need for inhibition of other platelet activation pathways has led to the development of various other antiplatelet drugs, such as clopidogrel. An improved understanding of the underlying mechanisms involved in thrombogenesis has paved the way for further development of newer antiplatelet drug therapies. Various clinical studies have probed the effectiveness and risk profile of the newer antiplatelet drugs, such as prasugrel, in comparison with currently available drugs. Some newer agents such as prasugrel are close to being approved for clinical use, whereas other agents such as cangrelor and AZD6140 are in phase 3 clinical trials. New drug classes, such as the thromboxane receptor antagonists (such as NCX-4016 and S18886), as well as platelet adhesion antagonists and thrombin receptor antagonists are similarly being evaluated for their efficacy and risk profile in phase I and II trials.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-32383554963167270032009-04-08T00:26:00.000-07:002009-04-14T23:48:53.815-07:0004 - 2009Eur J Pharmacol. 2009 Jan 14;602(2-3):215-22. Epub 2008 Nov 19.<br /><br /><span style="font-size:130%;"><strong>The nitrosylated flurbiprofen derivative HCT1026 inhibits cytokine-induced signalling through a novel mechanism of action.</strong><br /></span><br />Idris AI, Ralston SH, van't Hof RJ. Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, General Western Hospital, Edinburgh, UK.<br /><br />We have previously shown that the nitrosylated flurbiprofen derivative HCT1026 inhibits bone resorption, both in vivo and in vitro, and that its mechanism of action is independent of nitric oxide release and prostaglandin synthesis inhibition. Here we describe the effects of HCT1026 on osteoclast formation, activity, survival and cell signalling in vitro. HCT1026 strongly inhibited osteoclast formation, activity and survival in murine osteoclast cultures, whereas macrophages and osteoblasts were unaffected. HCT1026 induced osteoclast apoptosis, and this was partially prevented by increasing the concentration of receptor activator of nuclear factor kappa B ligand (RANKL). This suggests that HCT1026 inhibits bone resorption by inhibiting the effects of RANKL. In agreement with this we found that HCT1026 inhibited RANKL-induced activation of the nuclear factor kappa B (NFkappaB) and extracellular signal-regulated kinase (ERK) pathways in both osteoclast and macrophage cultures, whereas its parent compound flurbiprofen did not. In addition, HCT1026 also inhibited tumor necrosis factor (TNF)-, interleukin-1 (IL1)- and LPS-induced signalling, but not macrophage colony stimulating factor induced signalling. The pathways that are inhibited by HCT1026 all share a similar kinase complex upstream of the NFkappaB and ERK pathways, and this is the most likely target for the actions of HCT1026. Although the rationale for the modification of flurbiprofen with a nitric oxide donor group was to prevent gastro-intestinal toxicity, the resulting compound HCT1026 gained unexpected additional cytokine-inhibitory properties. As RANKL, TNF and IL1 are all important mediators of inflammation and joint destruction, compounds like HCT1026 could represent a novel class of anti-inflammatory compounds.<br /><br /><br /><br /><br />Int Immunopharmacol. 2009 Mar 30. [Epub ahead of print]<br /><br /><strong><span style="font-size:130%;">Comparative effects of aspirin and NO-releasing aspirins on differentiation, maturation and function of human monocyte-derived dendritic cells in vitro.</span></strong><br /><br />Bufan B, Mojsilović S, Vučićević D, Vučević D, Vasilijić S, Balint B, Colić M. Institute for Medical Research, Military Medical Academy, Belgrade, Serbia; Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.<br /><br />Acetylsalicilyc acid (aspirin, ASA) is a well known anti-inflammatory drug with immunomodulatory properties. NO-releasing aspirins (NO-ASA) are new compounds with anti-inflammatory properties. We studied the effects of ASA and two NO-ASA (NCX 4016 and NCX 4040) on human monocyte-derived dendritic cells (MoDC). Immature MoDC were generated in vitro from monocytes in the presence of recombinant human granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL) -4. Mature MoDC were obtained by adding lipopolysaccharide (LPS) in cultures of immature MoDC. As we found that ASA at 4-8 mM, NCX 4016 at 400-800 microM and NCX 4040 at 4-8 microM stimulated apoptosis of monocytes and immature MoDC, sub-apoptotic concentrations of ASA (2 mM), NCX 4016 (200 microM) and NCX 4040 (2 microM) were used in experiments. Examined substances were added at the beginning of MoDC cultivation. MoDC differentiated in the presence of examined compounds had lower expression of HLA-DR, CD80, CD40 and CD54, decreased allostimulatory activity and lower production of IL-12 p40. ASA and NCX 4016 decreased production of IL-10, whereas NCX 4040 had the opposite effect. ASA inhibited the expression of CD1a and prevented downregulation of CD14, NCX 4016 stimulated the differentiation of CD1a(+)CD14(+) and CD1a(-)CD14(+) cells, whereas NCX 4040 decreased the proportion of CD1a(+)CD14(-) and increased the frequency of CD1a(+)CD14(+) cells, compared to control. Maturation, both in ASA and NO-ASA treated MoDC was characterized by decreased allostimulatory activity, lower expression of CD83, HLA-DR, costimulatory molecules and CD54 and decreased production of IL-10 and IL-12 p40. In conclusion, we confirmed that ASA impairs differentiation, maturation and function of MoDC and found that NCX 4016 and NCX 4040 exerted similar, but not identical effects at about 10- and 1000-fold lower concentrations, respectively, compared to ASA.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-40379688023190013902008-12-22T10:29:00.000-08:002008-12-22T10:33:48.173-08:0012 - 2008J Physiol Pharmacol. 2008 Aug;59 Suppl 2:103-15.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Nitric oxide (NO)-releasing aspirin and (NO) donors in protection of gastric </span><span style="font-weight: bold;">mucosa against stress.</span></span><br /><br />S Kwiecien S, Pawlik MW, Brzozowski T, Konturek PC, Sliwowski Z, Pawlik WW, Konturek SJ. Department of Physiology Jagiellonian University Medical College, Cracow, Poland.<br /><br />Acute gastric mucosal lesions represent an important clinical problem. The experimental model of acute gastritis such as water immersion restraint (WRS) stress is useful tool in examination of pathomechanism of acute gastric damage. Nitric oxide (NO) plays an important role in the maintenance of gastric barrier, however the role of reactive oxygen species (ROS) in the interaction between NO and gastric mucosa integrity has been little studied. The purpose of our present study was to explain the participation of ROS in healing of WRS-induced gastric lesions accelerated by NO. Experiments were carrying out on 120 male Wistar rats. To assess gastric blood flow (GBF) laser Doppler flowmeter was used. The number of gastric lesions was established by planimetry. The colorimetric assays were used to determine gastric tissue level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the products of lipid peroxidation by ROS, as well as superoxide dismutase (SOD) activity, the enzyme scavanger of ROS. We demonstrated that 3.5 h of WRS resulted in appearance of acute gastric mucosal lesions accompanied by a significant decrease of GBF. Biological effects of ROS were estimated by measuring tissue level of MDA and 4-HNE, as well as the SOD activity. It was demonstrated that 3.5 h of WRS led to significant increase of MDA and 4-HNE mucosal level, that was accompanied by a decrease of SOD activity. Pretreatment with NO-donors (SIN-1, SNAP, nitroglycerin, NO-ASA) resulted in reduction of gastric lesions number, increment of GBF, decrease of MDA and 4-HNE tissue level and increase of SOD activity. Suppression of ROS play an important role in NO-donors action in gastroprotection against gastric acute lesions induced by 3.5 h of WRS. NO-donors cause an attenuation of lipid peroxidation as documented by a decrease of MDA and 4-HNE levels and enhancement of antioxidative properties as evidenced by increase of SOD activity.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-55209595854229349802008-10-18T08:45:00.000-07:002008-10-25T00:24:40.134-07:0010 - 2008Curr Alzheimer Res. 2008 Oct;5(5):422-31.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Fatty aspirin: a new perspective in the prevention of dementia of Alzheimer's type?</span></span><br /><br />Pomponi M, Di Gioia A, Bria P, Pomponi MF. Catholic University of Sacred Heart (UCSC), Psychiatric Department, Rome, Italy.<br /><br />Alzheimer's disease (AD) leads to a dramatic decline in cognitive abilities and memory. A more modest disruption of memory often occurs in normal aging and the same circuits that are devastated through degeneration in AD are vulnerable to sub-lethal age-related changes that alter synaptic transmission. There are numerous indications that aberrant plasticity is critically involved in Alzheimer's. Is ageing itself the major risk factor for AD? Is AD an acceleration of normal ageing? We assume that the ability of the brain is to modify its own structural organization and functioning which is liable to become impaired in ageing until it becomes dramatically impaired in Alzheimer's. Moreover, ageing can compromise the conversion of dietary alpha-linolenic acid (ALA) to docosahexaenoic acid (DHA). DHA regulates synaptogenesis and affects the synaptic structure, and synapse density is reduced in ageing. DHA and newly identified DHA-derived messenger, neuroprotecting D1 (NPD1), protect synapses and decrease the number of activated microglia in the hippocampal system. Delaying AD onset by a few years would reduce the number of the cases of dementia in the community. DHA (and NPD1?) and aspirin induce brain-derived neurotrophic factor (BDNF) protein expression and this protein has a crucial role in neuronal survival. The authors--in view of the increased neuroinflammatory reaction frequently observed during normal brain ageing--suggest the long-term use of "fatty aspirin", an association of DHA and/or NPD1 and aspirin (or nitroaspirin), to postpone, or prevent, the structural neurodegeneration of the brain.<br /><br /><br /><br />Carcinogenesis. 2008 Sep;29(9):1794-8. Epub 2008 Jun 9.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">NO-donating aspirin inhibits angiogenesis by suppressing VEGF expression in HT-29 human colon cancer mouse xenografts.</span></span><br /><br />Ouyang N, Williams JL, Rigas B. Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.<br /><br />The inhibitory effect of NO-donating aspirin (NO-ASA) on colon cancer has been demonstrated in vivo and in vitro but its mechanism is still obscure. We investigated the effect of NO-ASA on angiogenesis. Four groups of athymic mice (N = 12) bearing subcutaneous xenotransplants of HT-29 human colon cancer cells were injected intratumorally twice a week for 3 weeks with vehicle or m-NO-ASA or p-NO-ASA; the fourth group received no injections. The necrotic area of tumors, expressed as percentage of total area, was similar in the non-injected and vehicle-injected groups (51.8 +/- 2.8 versus 52.2 +/- 4.1, P > 0.05; mean +/- SEM for these and subsequent values). Compared with the vehicle group, the necrotic area of tumors was higher in the m-NO-ASA-treated (61.0 +/- 2.7, P < 0.02) and p-NO-ASA (65.8 +/- 2.4, P < 0.001)-treated groups. NO-ASA decreased microvessel density: vehicle = 11.7 +/- 0.8; m-NO-ASA = 7.8 +/- 0.6 (P = 0.0003 versus vehicle) and p-NO-ASA 6.2 +/- 0.7 (P = 0.0001 versus vehicle). The expression of vascular endothelial growth factor (VEGF) was significantly reduced in response to NO-ASA, with the p- isomer being more potent than the m-.NO-ASA altered the spatial distribution of VGEF expression, with 16.7% of the vehicle-treated xenografts displaying diminished VEGF in the inner region of the area between necrosis and the outer perimeter of the tumor, compared with those treated with m- (58.3%) or p-NO-ASA (75%, P < 0.01 for both versus control). Our findings indicate that NO-ASA suppresses the expression of VEGF, which leads to suppressed angiogenesis. The antiangiogenic activity of NO-ASA may be part of its antineoplastic effect.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-217429256112403962008-08-23T00:50:00.000-07:002008-08-23T00:53:46.252-07:002008 - 08Cardiol Rev. 2008 Sep-Oct;16(5):250-9.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Investigational antiplatelet drugs for the treatment and prevention of coronary artery disease.</span></span><br /><br />Zeidner JF, Frishman WH, Lerner RG. Department of Medicine, Johns Hopkins School of Medicine/Johns Hopkins Hospital, Baltimore, Maryland, USA.<br /><br />Antiplatelet therapy for the prevention and treatment of coronary artery disease (CAD) has undergone dramatic changes and improvements. Aspirin remains the first-line antiplatelet drug for clinical use. Newer platelet inhibitors such as the thienopyridine agents, ticlopidine and clopidogrel, have also been shown to be effective in treating CAD. There have been ongoing efforts to evaluate newer antiplatelet drugs, with the potential to improve clinical efficacy and safety. Some of the more promising antiplatelet agents include new adenosine diphosphate receptor antagonists such as prasugrel, cangrelor, and ticagrelor (AZD6140). In addition, a new thromboxane receptor antagonist, NCX-4016, a newly discovered protease-activated receptor antagonist that targets thrombin-induced platelet aggregation, and anti-von Willebrand factor aptamers show tremendous promise in refining antiplatelet therapy by targeting different receptors and molecules.<br /><br />PMID: 18708826 [PubMed - in process]Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-69493054255388351112008-05-27T07:22:00.000-07:002008-05-27T07:25:01.235-07:002008 - 05<p>Am J Physiol Endocrinol Metab. 2008 May 20<br /><br /><strong><span style="font-size:130%;">The nitric oxide-donating derivative of acetylsalicylic acid, NCX 4016, stimulates glucose transport and glucose transporters translocation in adipocytes.</span></strong><br /><br />Kaddai V, Gonzalez T, Bolla M, Lemarchand-Brustel Y, Cormont M. Unit 568, INSERM, Nice, France.<br /><br />NCX 4016 is a nitric oxide (NO)-donating derivative of acetylsalicylic acid. NO and salicylate, in vivo metabolites of NCX 4016, were shown to be potential actors in controlling glucose homeostasis. In this study, we evaluated the action of NCX 4016 on the capacity of 3T3-L1 adipocytes to transport glucose in basal and insulin-stimulated conditions. NCX 4016 induced a two fold increase in glucose uptake and the translocation of the glucose transporters GLUT1 and GLUT4 to the plasma membrane, leaving unaffected their expression. Importantly, NCX 4016 further increased glucose transport induced by a physiological concentration of insulin. This stimulatory effect of NCX 4016 appears to be mediated by its NO moiety. Indeed, it is inhibited by a NO scavenger and treatment with acetylsalicylic or salicylic acid had no effect. Although NO is involved in the action of NCX 4016, it did not mainly depend on the soluble cGMP-cyclase/protein kinase G pathway. Furthermore, NCX 4016-stimulated glucose transport did not involve the insulin signaling cascade required to stimulate glucose transport. NCX 4016 induces a small activation of the MAP kinases p38 and JNK, and no activation of other stress-activated signaling molecules including ERK, IkappaB, or AMP-activated kinases. Interestingly, NCX 4016 modified the content of S-nitrosylated proteins in adipocytes. Taken together, our results indicate that NCX 4016 induced glucose transport in adipocyte through a novel mechanism possibly involving S-nitrosylation. NCX 4016 thus possesses interesting characteristics to be considered as a candidate molecule for treatment of patients suffering from metabolic syndrome and type 2 diabetes.<br /><br /><br /><br />Nitric Oxide. 2008 Apr 23</p><p><strong><span style="font-size:130%;">Nitrates and NO-NSAIDs in cancer chemoprevention and therapy: In vitro evidence querying the NO donor functionality.</span></strong><br /><br />Dunlap T, Abdul-Hay S, Chandrasena RE, Hagos GK, Sinha V, Wang Z, Wang H, Thatcher GR.<br /><br />Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, USA.</p><p></p><p>Properties of the NO-ASA family of NO-donating NSAIDs (NO-NSAIDs), notably NCX 4016 (mNO-ASA) and NCX 4040 (pNO-ASA), reported in more than hundred publications, have included positive preclinical data in cancer chemoprevention and therapy. Evidence is presented that the antiproliferative, the chemopreventive (antioxidant/electrophile response element (ARE) activation), and the anti-inflammatory activity of NO-ASA in cell cultures is replicated by X-ASA derivatives that are incapable of acting as NO donors. pBr-ASA and mBr-ASA are conisogenic with NO-ASA, but are not NO donors. The biological activity of pNO-ASA is replicated by pBr-ASA; and both pNO-ASA and pBr-ASA are bioactivated to the same quinone methide electrophile. The biological activity of mNO-ASA is replicated by mBr-ASA; mNO-ASA and mBr-ASA are bioactivated to different benzyl electrophiles. The observed activity is likely initiated by trapping of thiol biomolecules by the quinone and benzyl electrophiles, leading to depletion of GSH and modification of Cys-containing sensor proteins. Whereas all NO-NSAIDs containing the same structural "linker" as NCX 4040 and NCX 4016 are anticipated to possess activity resulting from bioactivation to electrophilic metabolites, this expectation does not extend to other linker structures. Nitrates require metabolic bioactivation to liberate NO bioactivity, which is often poorly replicated in vitro, and NO bioactivity provided by NO-NSAIDs in vivo provides proven therapeutic benefits in mitigation of NSAID gastrotoxicity. The in vivo properties of X-ASA drugs await discovery.</p>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-13940152803769270332008-04-13T13:15:00.000-07:002008-04-13T13:18:35.937-07:002008 - 04<span style="font-size:100%;">J Transl Med. 2008 Feb 26;6:9.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols.</span></span><br /><br />Bratasz A, Selvendiran K, Wasowicz T, Bobko A, Khramtsov VV, Ignarro LJ, Kuppusamy P. Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. kuppusamy.1@osu.edu<br /><br />BACKGROUND: Ovarian carcinoma is the leading cause of mortality among gynecological cancers in the world. The high mortality rate is associated with lack of early diagnosis and development of drug resistance. The antitumor efficacy and mechanism of NCX-4040, a nitric oxide-releasing aspirin derivative, against ovarian cancer is studied. METHODS: NCX-4040, alone or in combination with cisplatin (cis-diamminedichloroplatinum, cDDP), was studied in cisplatin-sensitive (A2780 WT) and cisplatin-resistant (A2780 cDDP) cell lines as well as xenograft tumors grown in nude mice. Electron paramagnetic resonance (EPR) was used for measurements of nitric oxide and redox state. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice was used for mechanistic studies. RESULTS: Cells treated with NCX-4040 (25 microM) showed a significant reduction of cell viability (A2780 WT, 34.9 +/- 8.7%; A2780 cDDP, 41.7 +/- 7.6%; p <>Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-81849570823704584382008-01-19T00:30:00.000-08:002008-04-13T13:19:35.654-07:002008 - 01Cell Cycle. 2007 Sep 28;7(1) [Epub ahead of print]<br /><br /><span style="font-weight: bold;font-size:130%;" >NCX-4016, a nitro-derivative of aspirin, inhibits EGFR and STAT3 signaling and modulates Bcl-2 proteins in cisplatin-resistant human ovarian cancer cells and xenografts.</span><br /><br />Selvendiran K, Bratasz A, Tong L, Ignarro LJ, Kuppusamy P.<br /><br />Davis Heart and Lung Research Institute and Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.<br /><br />We have previously reported the inhibitory effect of NCX-4016, a nitro derivative of aspirin, on the proliferation of cisplatin-resistant human ovarian cancer cells, in vitro (Bratasz et al., Proc Natl Acad Sci USA 2006; 103:3914-9). In this report we present the results of our study on the mechanistic aspects of drug action including the molecular and signaling pathways involved in an in vitro cell line, as well as in a murine tumor xenograft. We report, for the first time, that NCX-4016 significantly inhibited the growth of cisplatin-resistant human ovarian cancer xenografts in mice. We observed that the inhibitory effect of NCX-4016 on cell proliferation was associated with G(1) phase cell cycle arrest with increased activity of p53, p21 and p27 proteins. NCX-4016 modulated the Bcl-2 family of proteins, and induced apoptosis by activating Bax and cytochrome c release in a time-dependent manner. In addition, NCX-4016 selectively down-regulated the phosphorylated forms of EGFR (Tyr845, Tyr992), pAkt (Ser473, Thr305), and STAT3 (Tyr705, Ser727), in vitro and in vivo. Taken together, the results clearly suggested that NCX-4016 causes significant induction of cell cycle arrest and apoptosis in cisplatin-resistant human ovarian cancer cells via down-regulation of EGFR/PI3K/STAT3 signaling and modulation of Bcl-2 family proteins. Thus, NCX-4016 appears to be a potential therapeutic agent for treating recurrent human ovarian carcinoma.<br /><br /><br /><br />Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3636-42. Epub 2007 Oct 12.<br /><br /><strong><span style="font-size:130%;">Roles of platelet and endothelial cell COX-1 in hypercholesterolemia-induced microvascular dysfunction.</span></strong><br /><br />Tailor A, Wood KC, Wallace JL, Specian RD, Granger DN.<br /><br />Department of Molecular and Cellular Physiology, Health Sciences Center, Louisiana State University, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.<br /><br />Aspirin is a common preventative therapy in patients at risk for cardiovascular diseases, yet little is known about how aspirin protects the vasculature in hypercholesterolemia. The present study determines whether aspirin, nitric oxide-releasing aspirin (NCX-4016), a selective cyclooxygenase (COX)-1 inhibitor (SC560), or genetic deficiency of COX-1 prevents the inflammatory and prothrombogenic phenotype assumed by hypercholesterolemic (HC) venules. Aspirin or NCX-4016 (60 mg/kg) was administered orally for the last week of a 2-wk HC diet. COX-1-deficient (COX-1(-/-)) and wild-type (WT) mice were transplanted with WT (WT/COX-1(-/-)) or COX-1(-/-) (COX-1(-/-)/WT) bone marrow, respectively. HC-induced adhesion of platelets and leukocytes in murine intestinal venules, observed with intravital fluorescence microscopy, was greatly attenuated in aspirin-treated mice. Adhesion of aspirin-treated platelets in HC venules was comparable to untreated platelets, whereas adhesion of SC560-treated platelets was significantly attenuated. HC-induced leukocyte and platelet adhesion in COX-1(-/-)/WT chimeras was comparable to that in SC560-treated mice, whereas the largest reductions in blood cell adhesion were in WT/COX-1(-/-) chimeras. NCX-4016 treatment of platelet recipients or donors attenuated leukocyte and platelet adhesion independent of platelet COX-1 inhibition. Platelet- and endothelial cell-associated COX-1 promote microvascular inflammation and thrombogenesis during hypercholesterolemia, yet nitric oxide-releasing aspirin directly inhibits platelets independent of COX-1.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-70085121031027528942007-11-04T01:58:00.000-07:002007-11-04T01:01:58.719-08:002007 - 11Chem Res Toxicol. 2007 Nov 1; [Epub ahead of print]<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Quinone Formation as a Chemoprevention Strategy for Hybrid Drugs: Balancing Cytotoxicity and Cytoprotection.</span></span><br /><br />Dunlap T, Chandrasena RE, Wang Z, Sinha V, Wang Z, Thatcher GR.<br /><br />Cellular defense mechanisms that respond to damage from oxidative and electrophilic stress, such as from quinones, represent a target for chemopreventive agents. Drugs bioactivated to quinones have the potential to activate antioxidant/electrophile responsive element (ARE) transcription of genes for cytoprotective phase 2 enzymes such as NAD(P)H-dependent quinone oxidoreductase (NQO1) but can also cause cellular damage. Two isomeric families of compounds were prepared, including the NO-NSAIDs (NO-donating nonsteroidal anti-inflammatory drugs) NCX 4040 and NCX 4016; one family was postulated to release a quinone methide on esterase bioactivation. The study of reactivity and GSH conjugation in model and cell systems confirmed the postulate. The quinone-forming family, including NCX 4040 and conisogenic bromides and mesylate, was rapidly bioactivated to a quinone, which gave activation of ARE and consequent induction of NQO1 in liver cells. Although the control family, including NCX 4016 and conisogenic bromides and mesylates, cannot form a quinone, ARE activation and NQO1 induction were observed, compatible with slower S N2 reactions with thiol sensor proteins, and consequent ARE-luciferase and NQO1 induction. Using a Chemoprevention Index estimate, the quinone-forming compounds suffered because of high cytoxicity and were more compatible with cancer therapy than chemoprevention. In the Comet assay, NCX 4040 was highly genotoxic relative to NCX 4016. There was no evidence that NO contributes to the observed biological activity and no evidence that NCX 4040 is an NO donor, instead, rapidly releasing NO 3 (-) and quinone. These results indicate a strategy for studying the quinone biological activity and reinforce the therapeutic attributes of NO-ASA through structural elements other than NO and ASA.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-90521295555143200062007-10-08T05:18:00.000-07:002007-10-27T09:08:23.748-07:002007 - 10J Thorac Cardiovasc Surg. 2007 Oct;134(4):1033-9.<br /><br /><strong><span style="font-size:130%;">Nitric oxide-donating aspirin (NCX 4016) inhibits neointimal thickening in a pig model of saphenous vein-carotid artery interposition grafting: a comparison with aspirin and morpholinosydnonimine (SIN-1).</span></strong><br /><br />Wan S, Shukla N, Angelini GD, Yim AP, Johnson JL, Jeremy JY. Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China.<br /><br />OBJECTIVE: Despite its proven value in reducing thrombotic complications in patients undergoing coronary artery bypass graft surgery, aspirin does not reduce the incidence of late vein graft failure. It was suggested, therefore, that co-administration of nitric oxide with aspirin may compensate for these limitations. A drug class that fulfills this pharmacologic criterion is nitric oxide-donating aspirin (NCX 4016). METHODS: The effect of administration of the aspirin-nitric oxide adduct, NCX 4016, compared with those of aspirin alone and the nitric oxide donor, morpholinosydnonimine, alone (once daily for 1 month) on thickening of saphenous vein-carotid artery interposition grafts was investigated. RESULTS: NCX 4016, at 10 mg, 30 mg, and 60 mg x kg(-1) x d(-1), inhibited neointimal thickness and area in porcine vein grafts. Aspirin alone (60 mg x kg(-1) x d(-1)) and morpholinosydnonimine alone (1 mg x kg(-1) x d(-1)), also inhibited neointimal thickness and neointimal area, although they were less potent than NCX 4016. At 30 mg x kg(-1) x d(-1), aspirin had no effect. Compared with untreated controls, NCX 4016 had little effect on medial thickness or area at 10 mg/kg or 30 mg x kg(-1) x d(-1) but had a significant effect at 60 mg x kg(-1) x d(-1). Aspirin alone and morpholinosydnonimine alone also inhibited medial thickness and area. NCX 4016 at 60 mg x kg(-1) x d(-1) and aspirin at 60 mg x kg(-1) x d(-1) increased luminal area. CONCLUSIONS: The range of properties displayed by NCX 4016 (inhibition of neointima formation, gastroprotection, antithrombotic and antiatherogenic effects) renders them potentially useful in treating both early and late vein graft failure and indicates that a clinical study on this novel drug class in patients undergoing coronary bypass grafting is warranted.<br /><br /><br /><br />Am J Physiol Heart Circ Physiol. 2007 Oct 12; [Epub ahead of print]<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Roles of platelet and endothelial cell COX-1 in hypercholesterolemia-induced microvascular dysfunction.</span></span><br /><br />Tailor A, Wood KC, Wallace JL, Specian RD, Granger DN. Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana, United States.<br /><br />Aspirin is common preventative therapy in patients at risk for cardiovascular diseases, yet little is known about how aspirin protects the vasculature in hypercholesterolemia. The present study determines whether aspirin, NO-releasing aspirin (NCX-4016), a selective COX-1 inhibitor (SC560), or genetic deficiency of COX-1 prevents the inflammatory and prothrombogenic phenotype assumed by hypercholesterolemic (HC) venules. Aspirin or NCX-4016 (60 mg/kg) was administered orally for the last wk of a 2 wk HC diet. COX-1 deficient (COX-1(-/-)) and wild type (WT) mice were transplanted with WT (WT/COX(-1-/-)) or COX-1(-/-) (COX-1(-/-)/WT) bone marrow, respectively. HC-induced adhesion of platelets and leukocytes in murine intestinal venules, observed with intravital fluorescence microscopy, was greatly attenuated in aspirin-treated mice. Adhesion of aspirin-treated platelets in HC venules was comparable to untreated platelets, while adhesion of SC560-treated platelets was significantly attenuated. HC-induced leukocyte and platelet adhesion in COX-1(-/-)/WT chimeras were comparable to SC560-treated mice, while the largest reductions in blood cell adhesion were in WT/COX-1(-/-) chimeras. NCX-4016 treatment of platelet recipients or donors attenuated leukocyte and platelet adhesion independent of platelet COX-1 inhibition. Platelet- and endothelial cell-associated COX-1 promote microvascular inflammation and thrombogenesis during hypercholesterolemia, yet NO-releasing aspirin directly inhibits platelets independent of COX-1. Key words: Aspirin, NCX-4016, cyclooxygenase, platelets, leukocytes.<br /><br /><br /><br />Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1545-52. Epub 2007 May 25.<br /><span style="font-size:130%;"><br /><span style="font-weight: bold;">Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats.</span></span><br /><br />Fu Y, Wang Z, Chen WL, Moore PK, Zhu YZ. Cardiovascular Biology Research Group, National University of Singapore.<br /><br />In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg.kg(-1).day(-1)), and NO-aspirin (56 mg.kg(-1).day(-1)). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n = 23), aspirin (n = 22), and NO-aspirin groups (n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 +/- 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 +/- 1.8 and 22.9 +/- 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemia-reperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.<br /><br /><br /><br />Biochem Soc Trans. 2007 Oct;35(Pt 5):1364-8.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Novel agents for cancer prevention based on nitric oxide.</span></span><br /><br />Rigas B. Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794-5200, U.S.A.<br /><br />NO (nitric oxide) biology has provided the impetus for the development of anticancer agents based on their ability to release NO. NO-NSAIDs (NO-donating non-steroidal anti-inflammatory drugs), consisting of a conventional NSAID to which an NO-releasing moiety is covalently attached, are promising chemopreventive agents against cancer. Compared with their parent compounds, NO-NSAIDs are up to several hundred times more potent in inhibiting the growth of cancer cell lines and prevent colon and pancreatic cancer in animal models. Their chemopreventive effect is due to inhibition of proliferation, induction of cell death and inhibition of cell-cycle-phase transitions. NO-ASA (NO-aspirin), the best-studied NO-NSAID, induces oxidative stress in target cells. Major downstream signalling effects involve the Wnt, NOS2 (nitric oxide synthase 2), MAPK (mitogen-activated protein kinase), NF-kappaB (nuclear factor kappaB) and Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) pathways. NO-NSAIDs, particularly NO-ASA, appear to be safe compounds, as suggested by many animal and early human studies. An ongoing clinical trial is designed to determine whether NO-ASA can inhibit early stages of colon carcinogenesis in subjects at risk for colon cancer. It is clinical trials that will ultimately determine the role of NO-NSAIDs in cancer prevention and perhaps treatment.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-72235914463671287162007-09-26T09:37:00.000-07:002007-09-26T09:38:00.644-07:002007 - 08Antioxid Redox Signal. 2007 Aug 30; [Epub ahead of print]<br /><span style="font-size:130%;"><br /><span style="font-weight: bold;">Nitroaspirin (NCX-4016), an NO Donor, is Antiangiogenic Through Induction of Loss of Redox-Dependent Viability and Cytoskeletal Reorganization in Endothelial Cells.</span></span><br /><br />Parinandi NL, Sharma A, Eubank TD, Kaufman BF, Kutala VK, Marsh CB, Ignarro LJ, Kuppusamy P. Department of Internal Medicine, Divisions of Cardiology and Pulmonary, Critical Care, and Sleep Medicine, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.<br /><br />We recently reported that NCX-4016, a derivative of aspirin containing a nitro moiety that releases nitric oxide (NO) in a sustained fashion in biologic systems, is a potent cytotoxic agent inhibiting the proliferation of cisplatin-resistant human ovarian cancer cells. Therefore, we hypothesize that NCX-4016 possesses antiangiogenic properties. Our study with the bovine lung microvascular endothelial cells (BLMVECs) revealed that NCX-4016 significantly induced the loss of redox-dependent cell viability in a dose- and time-dependent manner, as assayed by the redox-sensitive Alamar blue cell viability assay. Fluorescence microscopy of cells labeled with NO-specific fluorophore (DAF-FM) confirmed that NCX-4016 generated significant levels of intracellular NO. NO donors, including S-nitroso-N-acetylpenicillamine, spermine NONOate, and isosorbide dinitrite, were less effective in causing loss of cell viability. Thiol-protectant, N-acetylcysteine, significantly attenuated the NCX-4016-induced loss of cell viability, suggesting the role of alteration of thiol-redox status therein. NCX-4016 also suppressed oxygen consumption, decreased transendothelial electrical resistance (EC barrier dysfunction), and induced actin cytoskeletal reorganization in BLMVECs. The in vitro assay with human umbilical vein ECs and BLMVECs revealed that NCX-4016, in a dose-dependent manner, significantly inhibited angiogenesis with almost complete inhibition at a 100-muM concentration, suggesting that NCX-4016 can act as an antiangiogenic drug.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-10194812295674560292007-09-26T09:36:00.000-07:002007-09-26T09:37:07.628-07:002007 - 05Int J Cardiol. 2007 May 31;118(2):164-9. Epub 2006 Oct 5.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Functional effects of nitric oxide-releasing aspirin on vein conduits of diabetic patients undergoing CABG.</span></span><br /><br />Lorusso R, De Cicco G, Beghi C, Gherli T, Poli E, Corradi D, Maestri R, Bonadonna S, Mancini T, Giustina A. Experimental Cardiac Surgery Laboratory and Cardiac Surgery Unit, Civic Hospital, Brescia, Italy.<br /><br />BACKGROUND: Type 2 diabetes mellitus (DM) is known to negatively affect biological properties of venous vasculature, and, particularly, to reduce endothelium-derived nitric oxide release. This condition might influence venous graft function following coronary artery bypass surgery (CABG). The aim of this study was to evaluate the functional effects of a NO-releasing aspirin (NORA) on vein grafts (VG) of diabetics and control patients undergoing elective CABG. METHODS: In 40 consecutive ischemic heart disease patients, the effects of NORA were tested on segments of saphenous vein conduits harvested during elective CABG. Twenty patients had type-2 DM (mean age 69+/-2), whereas 20 patients had no DM (NDM) and represented the control group (mean age 67+/-4). Functional responses were tested by exposing VGs to NORA and to standard vasoactive agents in an organ-bath preparation. Histological features of VGs were also assessed by light and electronic microscopy. RESULTS: Significant impairment of endothelial-dependent vasodilation (acetylcholine induced) was documented in VGs of DM subjects. NORA induced a significant and comparable vascular relaxation in all venous segments of NDM and DM patients (56+/-12% of maximal relaxation vs 61+/-11% in the control group, respectively). Histology showed variable extent of vascular layer and cellular abnormalities in VGs of diabetics (intimal hyperplasia, calcific deposition, endothelial cell degeneration) likely responsible of the endothelial functional impairment, whereas control group VG showed preserved structures. CONCLUSIONS: This preliminary study confirms the impairment of endothelium-dependent vasodilative property of VGs in DM patients. It also indicates that NORA effectively induces vasodilation of VGs which was effective also in DM patients thereby representing a promising therapy for diabetics undergoing CABG with the use of VGs, although further studies are mandatory to conclusively assess the safety and benefits of this pharmacological agent.<br /><br /><br /><br />Int J Cardiol. 2007 May 31;118(2):170-2. Epub 2006 Sep 25.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Nitric oxide-releasing aspirin: will it say NO to atherothrombosis?</span></span><br /><br />Antoniades C, Tousoulis D, Stefanadis C.<br /><br />Aspirin is a powerful anti-platelet drug widely used in patients with coronary atherosclerosis, but its side effects and especially its toxicity for gastrointestinal tract limit its usefulness in specific groups of patients. A new category of agents, nitric oxide-releasing aspirins (such as NCX-4016), seems to provide an alternative solution. Although this drug is still at phase II clinical trials, it has provided promising results until now. When administered in vivo, it is separated into an aspirin moiety and an NO-donating complex, providing both the antithrombotic effect of aspirin and the gastroprotective effect of NO. Additionally, it increases NO bioavailability as a vascular level, and it may have the antiatherogenic properties of endogenously produced NO. Finally, recent evidence suggests that it may also improve functional aspects of vein grafts used in CABG, with possible benefit on graft patency. However, the outcome of the large ongoing trials is needed before any conclusion is made about the role of NO-releasing aspirins in cardiovascular disease.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-10774784014972537542007-09-26T08:42:00.001-07:002007-09-26T09:35:30.248-07:002007 - 04J Thromb Thrombolysis. 2007 Apr;23(2):129-33. Epub 2007 Jan 13.<br /><br /><span style="font-size:130%;"><strong>Tissue factor and nitric oxide: a controversial relationship! </strong></span><br /><br />Dusse LM, Cooper AJ, Lwaleed BA. University of Southampton, Southampton, UK.<br /><br />Tissue factor (TF) is the primary physiological initiator of blood coagulation. TF has a high-affinity for factor (F) VII resulting in the formation of (TF:FVII:FVIIa) bimolecular complex which, in the presence of Ca(2+), increases the enzymatic activity of FVIIa towards its natural substrates, FIX and FX, generating their active forms FIXa and FXa, respectively. This eventually leads to thrombin generation and a fibrin clot formation. Up-regulation of TF in injured blood vessels and atherosclerotic plaque can lead to undesirable vascular thrombosis. Nitric oxide (NO) is a free radical synthesized from L-arginine and molecular oxygen by nitric oxide synthases (NOS). NO participates in diverse physiological and pathophysiological process as an intra or extracellular messenger. A relationship between TF and NO has been proposed. Thus, models of TF regulation by NO has been studied in different cells and experimental animal models, but the results have been conflicting. The premise that NO donors can prevent TF expression in vivo has provided the foundation for a broad field of pharmacotherapeutics in vascular medicine. A new class of drugs combining a statin (inhibitors of coenzyme A reductase) with an NO-donating moiety has been described. The resulting drug, nitrostatin, has been suggested to increase the antithrombotic effects of native statin. However, it is questionable if NO release from these drugs had any significant role on TF inhibition. In summary, care must be taken in drawing conclusions about the relationship between NO and TF. Interpretation of NO studies must take several factors into consideration, including NO bioavailability, its half-life and inactivation, as well as the cell type and experimental model used.<br /><br /><br /><br />Atherosclerosis. 2007 Apr;191(2):272-5. Epub 2006 Jun 21.<br /><br /><span style="font-weight: bold;font-size:130%;" >Aspirin is a substrate for paraoxonase-like activity: implications in atherosclerosis.</span><br /><br />Santanam N, Parthasarathy S. Department of Pathology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.<br /><br />Paraoxonase 1 (PON 1) is an enzyme that is promiscuous in its ability to hydrolyze various types of substrates. It hydrolyzes aryl esters, phosphate esters, lactones, and reduces lipid peroxides to hydroxides. Aspirin is an aryl ester with a short plasma half life. We hypothesized that aspirin would be effectively hydrolyzed by PON 1 and many of its anti-atherogenic effects, at least in part, could be accounted for by its antioxidant product, salicylic acid. In this study, we determined the ability of human plasma and PON 1-rich HDL to hydrolyze acetyl ester of salicylic acid (aspirin). The ability of aspirin to compete for the hydrolysis of paraoxon and p-nitrophenylacetate was determined. In addition, nitrated aspirin was synthesized and tested directly for hydrolysis. Aspirin competed for the hydrolysis of paraoxon and p-nitrophenylacetate by HDL in a dose-dependent manner. Human plasma and HDL were also able to hydrolyse nitroaspirin and aspirin and release nitrosalicylic acid and salicylic acid, respectively. These findings suggest that salicylic acid might be generated in the plasma from aspirin. The ability of long-term treatment with aspirin to retard atherosclerosis might be dependent on the generation of free salicylic acid, a scavenger of free radicals.<br /><br /><br /><br />J Ocul Pharmacol Ther. 2007 Apr;23(2):188-95.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Susceptibility of the ocular lens to nitric oxide: implications in cataractogenesis.</span></span><br /><br />Varma SD, Hegde KR. Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.<br /><br />Oxides of nitrogen, such as nitric oxide (NO), are now biologically referred to as reactive nitrogen species. The generation of NO gives rise to several other reactive species, such as NO+, NO-, NO2, N2O3, and ONOO- and so forth, which are all capable of inflicting tissue damage. Indeed, NO generation is known to be associated with retinal degeneration and glaucoma. Its level has also been found to increase in the aqueous and vitreous humors in diabetes. We hypothesize that such an increase would have a detrimental effect on the biochemistry and metabolism of tissues, including the lens, bathed by the aqueous containing elevated levels of NO. The primary aim of our investigations was, therefore, to examine the susceptibility of the lens to damage by NO in vitro in the presence of nitroaspirin, a novel NO donating agent. The extent of physiologic damage to the lens was initially assessed by determining the integrity of its active transport mechanism. The overall status of tissue metabolism was determined by measuring the adenosine triphosphate (ATP) levels. The levels of glutathione (GSH) and glutathione disulfide, reflecting the status of its antioxidant reserve, were also determined. That NO is indeed deleterious to the lens was apparent by the inhibition of the active transport of Rb(+). This was associated with a substantial decrease in the contents of ATP and GSH, the decrease in the latter directly suggesting that the NO effects are caused by oxidative stress. That the effects are caused by NO generated from nitroaspirin was proven by a substantial increase in NO level in the medium during incubation of the lenses with nitroaspirin, as compared to the controls. The results, therefore, were highly suggestive of a contribution of the oxides of nitrogen in cataract formation associated with diabetes and other aging diseases.<br /><br /><br /><br />Eur J Pharmacol. 2007 Apr 30;561(1-3):220-5. Epub 2007 Feb 1.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Effect of aspirin, paracetamol and their nitric oxide donating derivatives on exudate cytokine and PGE2 production in zymosan-induced air pouch inflammation in rats.</span></span><br /><br />Mamuk S, Melli M. Ankara University, School of Medicine, Department of Pharmacology and Clinical Pharmacology, Morfoloji Binasi, Sihhiye 06100, Ankara, Turkey.<br /><br />Effects of different doses of aspirin, compared to equimolar doses of nitric oxide (NO)-donating aspirin (NCX 4016), and of a single dose of paracetamol, compared to an equimolar dose of NO-donating paracetamol (NCX 701) were investigated in acute zymosan-induced air pouch inflammation in rats. Treatments were administered by orogastric route, and interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) levels in the exudates were analysed 4 h after zymosan injection by enzyme immunoassay (EIA). Aspirin, at 10, 30 and 100 mg/kg doses, increased IL-1beta levels in exudates, however, only the highest dose lead to a significant increase when compared to control, whereas a significant increase in TNF-alpha level was observed at all doses tested. NCX 4016, at equimolar doses for aspirin, i.e., 18.6, 55.8 and 186 mg/kg, respectively, did not cause any changes in exudate IL-1beta or TNF-alpha levels. These effects were significantly different, when aspirin was compared with the corresponding NCX 4016 group. Nevertheless, the ability of aspirin and NCX 4016 to inhibit PGE(2) synthesis in the exudate where comparable. Although paracetamol significantly increased exudate TNF-alpha level compared to the control group and NCX 701 group, neither paracetamol, nor NCX701 treatments changed the levels of exudate IL-1beta significantly. As expected, paracetamol and NCX 701 showed poor PGE(2) inhibition. At high doses, aspirin and NCX 4016<br />decreased the number of polymorphonuclear leukocytes in the exudate. However, this inhibition was not significantly different from the control group. Paracetamol and NO-paracetamol did not cause any change in the number of polymorphonuclear leukocytes in exudate. These results indicated that aspirin and NCX 4016 possessed different effects on cytokine production or release, despite the fact that both drugs inhibited the synthesis of PGE(2) in a similar way. Unlike paracetamol, which increased exudate TNF-alpha level, NCX 701 had no effect on TNF-alpha level in the exudates.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-53663716261872590872007-09-26T08:41:00.002-07:002007-09-26T08:42:11.172-07:002007 - 03Thromb Haemost. 2007 Mar;97(3):444-50.<br /><br />Comment in: Thromb Haemost. 2007 Mar;97(3):331-3.<br /><br /><strong><span style="font-size:130%;">Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication.</span></strong><br /><br />Gresele P, Migliacci R, Procacci A, De Monte P, Bonizzoni E. Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Via Enrico dal Pozzo, I-06126 Perugia, Italy.<br /><br />Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day 1 (pre-treatment: aspirin = 3.1 +/- 0.5%, nitroaspirin = 3.9 +/- 0.7%, p = NS), and on day 28 (aspirin = 3.4 +/- 0.7%, NCX 4016 = 3.2 +/- 0.6%, p = NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = -1.15%, nitroaspirin = -1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirintreated group (-1.46%) while it was abolished in the NCX 4016-treated group (+0.79%, p = 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-1 which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-79926057043228871312007-09-26T08:41:00.001-07:002007-09-26T08:41:26.458-07:002006 - 10Drug News Perspect. 2006 Oct;19(8):485-9.<br /><br /><strong><span style="font-size:130%;">Chronicles in drug discovery.</span></strong><br /><br />Moral MA, Khurdayan VK, Bozzo J. Prous Science Medical Information Department, Barcelona, Spain.<br /><br />Chronicles in Drug Discovery features special interest reports on advances in drug discovery and development. This month we focus on the progress of the ongoing search for safe and effective chemopreventive agents. Chemoprevention is a strategy to decrease the risk of developing cancer by using agents that prevent or abrogate carcinogenic processes. Bowman- Birk inhibitor concentrate, budesonide, NCX-4016 and statins are all undergoing investigation in the clinical setting as potential chemopreventive agents for head and neck, lung, colon and breast cancers, respectively. (c) 2006 Prous Science. All rights reserved.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-90279862395921147362007-09-26T08:40:00.001-07:002007-09-26T09:32:25.588-07:002006 - 09J Cardiovasc Pharmacol. 2006 Sep;48(3):79-87.<br /><br /><strong><span style="font-size:130%;">Prevention of postischemic myocardial reperfusion injury by the combined treatment of NCX-4016 and Tempol.</span></strong><br /><br />Kutala VK, Khan M, Mandal R, Potaraju V, Colantuono G, Kumbala D, Kuppusamy P. Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, and Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA.<br /><br />Nitric oxide (NO) plays a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the concomitant production of superoxide and other reactive oxygen species (ROS) during I/R may diminish the bioavailability of NO and hence compromise the beneficial effects. The objective of this study was to investigate the protective effect of the coadministration of NCX-4016 [2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester] (an NO donor) with antioxidants Tempol, superoxide dismutase (SOD), or urate on I/R injury. Isolated rat hearts, perfused with Krebs-Henseleit buffer, were subjected to 30 minutes of global ischemia, followed by 45 minutes of reperfusion. Before the induction of ischemia, the hearts were infused for 1 minute with NCX-4016 (100 microM) either alone or in combination with Tempol (100 microM), SOD (200 U/mL), or urate (100 microM). Hearts pretreated with NCX-4016 showed a significantly enhanced recovery of function and decreased infarct size and LDH/CK release compared with the controls. However, treatment of hearts with NCX-4016 + Tempol, SOD, or urate showed a significantly enhanced recovery of heart function compared with NCX-4016 alone. The treatment of hearts with NCX-4016 + Tempol showed significantly enhanced NO generation and decreased ROS and dityrosine (a marker of peroxynitrite) formation. In conclusion, NCX-4016 in combination with Tempol demonstrated significant cardioprotection and, thus, may offer a novel therapeutic strategy to prevent I/R-mediated myocardial injury.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-26397247078119255672007-09-26T08:38:00.000-07:002007-09-29T07:12:03.962-07:002006 - 08Cardiovasc Drug Rev. 2006 Summer;24(2):148-68.<br /><br /><strong><span style="font-size:130%;">Pharmacologic profile and therapeutic potential of NCX 4016, a nitric oxide-releasing aspirin, for cardiovascular disorders.</span></strong><br /><br />Gresele P, Momi S. Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy.<br /><br />NCX 4016, 2-(acetyloxy)benzoic acid 3-[(nitrooxy)methyl]phenyl ester, is a new molecule in which a nitric oxide (NO)-releasing moiety is covalently linked to aspirin. After enzymatic metabolism, NCX 4016 releases both components. In vitro and in some animal models, these components exert their pharmacologic effects simultaneously. Nitric oxide (NO) is a small gaseous molecule that exerts several activities which may prevent atherothrombotic disorders. Moreover, it displays a protective activity on the gastric mucosa. NCX 4016 has been shown to inhibit platelet activation in vitro more effectively than aspirin, to inhibit smooth muscle cell proliferation, to exert an endothelial cell protective activity and to suppress the function of several inflammatory cells potentially involved in atherothrombosis. In animal models, NCX 4016 protected from platelet thromboembolism, prevented restenosis in atherosclerosis-prone animals, protected the heart from ischemia/reperfusion injury, and induced neoangiogenesis in critically ischemic limbs. Moreover, it displayed little or no gastric toxicity and appeared to protect stomach from noxious stimuli, including aspirin. NCX 4016 has been evaluated in healthy volunteers and found to inhibit platelet cyclo-oxygenase-1 (COX-1) similarly to or slightly less than aspirin, to raise the circulating levels of NO-degradation products, and to have little or no gastric toxicity in short term studies. In particular, in phase II studies, NCX 4016 had favorable effects on effort-induced endothelial dysfunction in intermittent claudication and on platelet-activation parameters elicited by short-term hyperglycemia in type II diabetics. In patients with type II diabetes the effects of NCX 4016 on microalbuminuria and on some hemodynamic parameters were promising. The pharmacokinetics of in vivo aspirin- and NO- released by NCX 4016, as well as the bioavailability of the two molecules, were not yet adequately studied. Also, the long-term tolerability of NCX 4016, as well as its possible effectiveness in preventing ischemic cardiovascular events and progression of atherosclerosis, should be explored.<br /><br /><br /><br />Cell Cycle. 2006 Aug;5(15):1669-74. Epub 2006 Aug 1.<br /><br /><strong><span style="font-size:130%;">Nitrogen oxide-releasing aspirin induces histone H2AX phosphorylation, ATM activation and apoptosis preferentially in S-phase cells: involvement of reactive oxygen species.</span></strong><br /><br />Tanaka T, Kurose A, Halicka HD, Huang X, Traganos F, Darzynkiewicz Z. Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, New York, USA.<br /><br />Nitric oxide-releasing acetylsalicylic acid (NO-ASA; NO-aspirin) developed as an anti-inflammatory agent that was expected to avoid some of the adverse effects of aspirin (ASA), was recently shown to be cytotoxic to cells of different tumor lines. The cytotoxic properties and potency of NO-ASA are different than those of ASA which implies that the intracellular targets for NO-ASA and ASA, and their mechanism of action, are different. The aim of the present study was to reveal whether the cytotoxicity induced by NO-ASA is mediated by damage to DNA. We observed that even brief (1 h) treatment of human B-lymphoblastoid TK6 cells with >or=5 microM NO-ASA led to DNA damage revealed by the alkaline and neutral comet assays, histone H2AX phosphorylation on Ser 139, and ATM phosphorylation on Ser 1981, a marker of activation of this kinase. The induction of H2AX phosphorylation was preferential to S-phase cells. Exposure to >or=5 microM NO-ASA for over 3 h led to apoptosis, also preferentially of S-phase cells. Apoptosis was atypical; while chromatin was highly condensed there was no evidence of nuclear fragmentation nor were the cells positive in the TUNEL assay though they did express activated caspase-3. The induction of phosphorylation of H2AX on Ser 139 by NO-ASA was markedly attenuated in the presence of N-acetyl-L-cysteine, a scavenger of reactive oxygen species (ROS). The data imply that the NO-ASA induces DNA damage through oxidative stress; the oxidation-generated lesions provide a signal for induction of H2AX phosphorylation during DNA replication, perhaps when the progressing replication forks collide with the primary lesions converting them to DNA double-strand breaks. Because neither induction of H2AX phosphorylation nor apoptosis were observed at equimolar concentrations of ASA, the NO moiety attached to ASA appeared to mediate these effects.<br /><br /><br /><br />Apoptosis. 2006 Aug;11(8):1321-30.<br /><br /><strong><span style="font-size:130%;">Molecular characterization of cytotoxic and resistance mechanisms induced by NCX 4040, a novel NO-NSAID, in pancreatic cancer cell lines.</span></strong><br /><br />Rosetti M, Tesei A, Ulivi P, Fabbri F, Vannini I, Brigliadori G, Amadori D, Bolla M, Zoli W. Istituto Oncologico Romagnolo, Meldola, Italy.<br /><br />Although non steroidal antiinflammatory drugs (NSAIDs) have been shown to be effective as chemopreventive agents, important side-effects limit their clinical use. A promising novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), has been found to be more active than classical NSAIDs. This study explored the effect of the NO-donating aspirin derivative, NCX 4040, on three human pancreatic adenocarcinoma cell lines (Capan-2, MIA PaCa-2 and T3M4). NCX 4040 activity was compared with that of NCX 4016 (an NO(2)-positional isomer of NCX 4040), SNAP (a standard NO-releasing molecule), NCX 4042 (denitrated analog of NCX 4040), and aspirin. NCX 4040 showed a striking cytocidal activity in all cell lines, already inducing significant percentages of apoptotic cells at 10 muM in Capan-2 cell lines. This study focused on the biological mechanisms of sensitivity and resistance to NCX 4040, highlighting that the cytotoxic action of this drug may be due to the hyperexpression of Bax, its translocation to the mitochondria, the release of Cytochrome C, and the activation of caspases-9 and -3, overall in a p53-independent manner. Moreover, the use of a specific COX-2 inhibitor (NS 398) in the experimental models showed that COX-2 hyperexpression could partially explain the resistance mechanisms to NCX 4040.<br /><br /><br /><br />J Submicrosc Cytol Pathol. 2006 Jun-Sep;38(2-3):149-54.<br /><br /><span style="font-size:130%;"><span style="font-weight: bold;">Ultracytochemical demonstration of soluble guanylate cyclase activation in rat aorta by NCX4016, a NO-releasing aspirin derivative.</span></span><br /><br />Rambotti MG, Mariucci G, Tantucci M, Ambrosini MV.<br /><br />Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.<br /><br />Biochemical studies demonstrate that the NO-releasing-aspirin derivative (NCX4016) stimulates soluble guanylate cyclase (sGC) activity and increases cyclic GMP (cGMP) in human platelet and monocytes by releasing NO. In the present study, an ultracytochemical technique for electron microscopy was used to investigate the effects of NCX4016 (2 mM) on sGC activity in rat thoracic aorta, using sodium nitroprusside (0.01 mM) as reference NO-donor. Guanylyl-imidodiphosphate sodium salt [Gpp(NH)p], a synthetic non-hydrolyzable analogue of GTP, was used as sGC substrate. NO-activated sGC released imidodiphosphate ions which were precipitated with lead ions, giving rise to deposits of electron-dense granules (reaction product). Ultracytochemistry allowed us to demonstrate that NCX4016 stimulated sGC activity in smooth muscle cells, and particularly in vascular endothelial cells, as sodium nitroprusside did. This result could explain the protective effects of chronic treatment with NCX4016 on aortic endothelium of diabetic rats demonstrated by scanning and transmission electron microscopy.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-7357817546959154132007-09-26T08:37:00.001-07:002007-09-26T08:38:16.775-07:002006 - 06Br J Pharmacol. 2006 Jun;148(4):517-26. Epub 2006 May 15.<br /><br /><strong><span style="font-size:130%;">Mechanism of action of novel NO-releasing furoxan derivatives of aspirin in human platelets.</span></strong><br /><br />Turnbull CM, Cena C, Fruttero R, Gasco A, Rossi AG, Megson IL. Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh.<br /><br />Incorporation of a nitric oxide (NO)-releasing moiety in aspirin can overcome its gastric side effects.We investigated the NO-release patterns and antiplatelet effects of novel furoxan derivatives of aspirin (B8 and B7) in comparison to existing antiplatelet agents. Cyclooxygenase (COX) activity was investigated in purified enzyme using an electron paramagnetic resonance-based technique. Concentration-response curves for antiplatelet agents +/- the soluble guanylate cyclase inhibitor, ODQ (50 microM) were generated in platelet-rich plasma (PRP) and washed platelets (WP) activated with collagen using turbidometric aggregometry. NO was detected using an isolated NO electrode. The furoxan derivatives of aspirin (B8, B7) and their NO-free furazan equivalents (B16, B15; all 100 microM) significantly inhibited COX activity (P < 0.01; n = 6) in vitro and caused aspirin-independent, cGMP-dependent inhibition of collagen-induced platelet aggregation in WP. B8 was more potent than B7 (PRP IC(50) = 0.62 +/- 0.1 microM for B8; 400 +/- 89 microM for B7; P < 0.0001. WP IC(50)s = 0.6 +/- 0.1 and 62 +/- 10 microM, respectively). The NO-free furazan counterparts were less potent antiplatelet agents (WP IC(50)s = 54 +/- 3 microM and 62 +/- 10 microM, respectively; P < 0.0001, B8 vs B16). Of the hybrids investigated, only B8 retained antiplatelet activity in PRP.NO release from furoxan-aspirin hybrids was undetectable in buffer alone, but was accelerated in the presence of either plasma or plasma components, albumin (4%), glutathione (GSH; 3 microM) and ascorbate (50 microM), the effects of which were additive for B7 but not B8. NO generation from furoxans was greatly enhanced by platelet extract, an effect that could largely be explained by the synergistic effect of intracellular concentrations of GSH (3 mM) and ascorbate (1 mM). We conclude that the decomposition of furoxan-aspirin hybrids to generate biologically active NO is catalysed by endogenous agents which may instil a potential for primarily intracellular delivery of NO. The blunting of the aspirin effects of furoxan hybrids is likely to be due to loss of the acetyl moiety in plasma; the observed antiplatelet effects are thereby primarily mediated via NO release. Compounds of this class might represent a novel means of inhibiting platelet aggregation by a combination of NO generation and COX inhibition.<br /><br /><br /><br />Mol Cancer Ther. 2006 Jun;5(6):1530-8.<br /><br /><strong><span style="font-size:130%;">Nitric oxide-releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets.</span></strong><br /><br />Rao CV, Reddy BS, Steele VE, Wang CX, Liu X, Ouyang N, Patlolla JM, Simi B, Kopelovich L, Rigas B. Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.<br /><br />Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAID) are promising chemoprevention agents; unlike conventional NSAIDs, they seem free of appreciable adverse effects, while they retain beneficial activities of their parent compounds. Their effect on colon carcinogenesis using carcinoma formation as an end point is unknown. We assessed the chemopreventive properties of NO-indomethacin (NCX 530) and NO-aspirin (NCX 4016) against azoxymethane-induced colon cancer. Seven-week-old male F344 rats were fed control diet, and 1 week later, rats received two weekly s.c. injections of azoxymethane (15 mg/kg body weight). Two weeks after azoxymethane treatment, rats (48 per group) were fed experimental diets containing NO-indomethacin (0, 40, or 80 ppm), or NO-aspirin (1,500 or 3,000 ppm), representing 40% and 80% of the maximum tolerated dose. All rats were killed 48 weeks after azoxymethane treatment and assessed for colon tumor efficacy and molecular changes in colonic tumors and normally appearing colonic mucosa of different dietary groups. Our results suggest that NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly suppressed both tumor incidence (P < 0.01) and multiplicity (P < 0.001). The degree of inhibition was more pronounced with NO-indomethacin at both dose levels (72% and 76% inhibition) than with NO-aspirin (43% and 67%). NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly inhibited the colon tumors' (P < 0.01 to P < 0.001) total cyclooxygenase (COX), including COX-2 activity (52-75% inhibition) and formation of prostaglandin E2 (PGE2), PGF2alpha, and 6-keto-PGF1alpha, and TxB2 from arachidonic acid (53-77% inhibition). Nitric oxide synthase 2 (NOS-2) activity and beta-catenin expression were suppressed in animals given NO-NSAID. In colonic crypts and tumors of animals fed these two NO-NSAIDs, there was a significant decrease in proliferating cell nuclear antigen labeling when compared with animals fed the control diet. The results of this study provide strong evidence that NO-NSAIDs possess strong inhibitory effect against colon carcinogenesis; their effect is associated with suppression of COX and NOS-2 activities and beta-catenin levels in colon tumors. These results pave the way for the rational design of human clinical trials.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-28993539697954049592007-09-26T08:35:00.000-07:002007-09-26T08:36:49.103-07:002006 - 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 /><strong><span style="font-size:130%;">Nitric oxide and inflammation.</span></strong><br /><br />Cirino G, Distrutti E, Wallace JL. Department of Experimental Pharmacology, Universita 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.<br /><br /><br /><br />Carcinogenesis. 2006 Apr;27(4):803-10. Epub 2005 Nov 2.<br /><br /><strong><span style="font-size:130%;">NO-donating aspirin induces phase II enzymes in vitro and in vivo.</span></strong><br /><br />Gao J, Kashfi K, Liu X, Rigas B. Division of Cancer Prevention, Department of Medicine, SUNY at Stony Brook, NY 11794, USA.<br /><br />Modulation of drug metabolizing enzymes, leading to facilitated elimination of carcinogens represents a successful strategy for cancer chemoprevention. Nitric oxide-donating aspirin (NO-ASA) is a promising agent for the prevention of colon and other cancers. We studied the effect of NO-ASA on drug metabolizing enzymes in HT-29 human colon adenocarcinoma and Hepa 1c1c7 mouse liver adenocarcinoma cells and in Min mice treated with NO-ASA for 3 weeks. In these cell lines, NO-ASA induced the activity and expression of NAD(P)H:quinone oxireductase (NQO) and glutathione S-transferase (GST). Compared with untreated Min mice, NO-ASA increased in the liver the activity (nmol/min/mg; mean+/-SEM for all) of NQO (85+/-6 versus 128+/-11, P<0.05) and GST (2560+/-233 versus 4254+/-608, P<0.005) and also in the intestine but not in the kidney; the expression of NQO1 and GST P1-1 was also increased. NO-ASA had only a marginal effect on P450 1A1 and P450 2E1, two phase I enzymes. The release of NO from NO-ASA, determined with a selective microelectrode was paralleled by the induction of NQO1 and abrogated by NO scavengers; an exogenous NO donor also induced the expression of NQO1. NO-ASA induced concentration-dependently the translocation of Nrf2 into the nucleus as documented by immunofluorescence and immunoblotting; this paralleled the induction of NQO1 and GST P1-1. Thus NO-ASA induces phase II enzymes, at least in part, through the action of NO that it releases and by modulating the Keap1-Nrf2 pathway; this effect may be part of its mechanism of action against colon and other cancers.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-63302402781082313472007-09-26T08:33:00.000-07:002007-09-26T08:35:07.524-07:002006 - 03J Pharmacol Exp Ther. 2006 Mar;316(3):1107-14. Epub 2005 Oct 31.<br /><br /><strong><span style="font-size:130%;">The effect of NCX4016 [2-acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester] on the consequences of ischemia and reperfusion in the streptozotocin diabetic rat.</span></strong><br /><br />Burke SG, Wainwright CL, Vojnovic I, Warner T, Watson DG, Furman BL. Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.<br /><br />The aim of this study was to assess the effect of chronic administration of NCX4016 [2 acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester], a nitric oxide-releasing aspirin derivative on the consequences of coronary artery occlusion in streptozotocin-diabetic rats. Rats were made diabetic by injection of streptozotocin (60 mg kg(-1)) and received insulin (2.5 U kg(-1) s.c.) daily for 4 weeks. Animals received vehicle (1 ml kg(-1) polyethylene glycol), aspirin (65.2 mg kg(-1)), NCX4016 (60 mg kg(-1)), or (iv) NCX4016 (120 mg kg(-1)) orally, once daily for the last 5 days before coronary artery occlusion (CAO). One hour after the last dose, pentobarbital-anesthetized rats were subjected to CAO for 30 min followed by 120-min reperfusion. Neither drug significantly modified initial hemodynamics or plasma glucose levels compared with vehicle treatment in either nondiabetic or diabetic rats. Neither drug modified the total ventricular premature beat (VPB) count in normal animals, although NCX4016, but not aspirin, reduced the total VPB count and the incidence of ventricular tachycardia in diabetic rats. In nondiabetic animals, both aspirin and NCX4016 reduced infarct size. However, in diabetic rats, infarct size was reduced only by the larger dose of NCX4016 (120 mg kg(-1)) but not by aspirin or the lower dose of NCX4016. These results demonstrate that the cardioprotective effects of NCX4016 are reduced in the presence of diabetes compared with the effects seen in nondiabetic animals. In summary, the present study confirms the protective effect of NCX4016 against ischemia-reperfusion injury in the normal rat heart and demonstrates for the first time its protective effect in the heart of streptozotocin-diabetic rats.<br /><br /><br /><br />Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3914-9. Epub 2006 Feb 23.<br /><br />Comment in: Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4337-8.<br /><br /><strong><span style="font-size:130%;">Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin.</span></strong><br /><br />Bratasz A, Weir NM, Parinandi NL, Zweier JL, Sridhar R, Ignarro LJ, Kuppusamy P. Center for Biomedical Electron Paramagnetic Resonance Spectroscopy and Imaging, The Dorothy M. Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA.<br /><br />Ovarian cancer is a gynecological malignancy that is commonly treated by cytoreductive surgery followed by cisplatin treatment. However, the cisplatin treatment, although successful initially, is not effective in the treatment of the recurrent disease that invariably surfaces within a few months of the initial treatment. The refractory behavior is attributed to the increased levels of cellular thiols apparently caused by the cisplatin treatment. This observation prompted us to choose a cytotoxic drug whose activity is potentiated by cellular thiols with enhanced specificity toward the thiol-rich cisplatin-resistant cells. We used NCX-4016 [2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester], a derivative of aspirin containing a nitro group that releases nitric oxide in a sustained fashion for several hours in cells and in vivo, and we studied its cytotoxic efficacy against human ovarian cancer cells (HOCCs). Cisplatin-sensitive and cisplatin-resistant (CR) HOCCs were treated with 100 microM NCX-4016 for 6 h, and/or 0.5 microg/ml cisplatin for 1 h and assayed for clonogenecity. NCX-4016 significantly reduced the surviving fractions of cisplatin-sensitive (63 +/- 6%) and CR (70 +/- 10%) HOCCs. NCX-4016 also caused a 50% reduction in the levels of cellular glutathione in CR HOCCs. Treatment of cells with NCX-4016 followed by cisplatin showed a significantly greater extent of toxicity when compared with treatment of cells with NCX-4016 or cisplatin alone. In conclusion, this study showed that NCX-4016 is a potential inhibitor of the proliferation of CR HOCCs and thus might specifically kill cisplatin-refractory cancer cells in patients with recurrent ovarian cancer.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-43638028882785176012007-09-26T05:05:00.002-07:002007-09-26T05:06:16.942-07:002005 - 12J Pharmacol Exp Ther. 2005 Dec;315(3):1331-7. Epub 2005 Sep 6.<br /><br /><strong><span style="font-size:130%;">Direct and irreversible inhibition of cyclooxygenase-1 by nitroaspirin (NCX 4016).</span></strong><br /><br />Corazzi T, Leone M, Maucci R, Corazzi L, Gresele P. Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy.<br /><br />Benzoic acid, 2-(acetyl-oxy)-3-[(nitrooxy)methyl]phenyl ester (NCX 4016), a new drug made by an aspirin molecule linked, through a spacer, to a nitric oxide (NO)-donating moiety, is now under clinical testing for the treatment of atherothrombotic conditions. Aspirin exerts its antithrombotic activity by irreversibly inactivating platelet cyclooxygenase (COX)-1. NCX 4016 in vivo undergoes metabolism into deacetylated and/or denitrated metabolites, and it is not known whether NCX 4016 needs to liberate aspirin to inhibit COX-1, or whether it can block it as a whole molecule. The aim of our study was to evaluate the effects of NCX 4016 and its analog or metabolites on platelet COX-1 and whole blood COX-2 and on purified ovine COX (oCOX)-1 and oCOX-2. In particular, we have compared the mechanism by which NCX 4016 inhibits purified oCOX enzymes with that of aspirin using a spectrophotometric assay. All the NCX 4016 derivatives containing acetylsalicylic acid inhibited the activity of oCOX-1 and oCOX-2, whereas the deacetylated metabolites and the nitric oxide-donating moiety were inactive. Dialysis experiments showed that oCOX-1 inhibition by NCX 4016, similar to aspirin, is irreversible. Reversible COX inhibitors (indomethacin) or salicylic acid incubated with the enzyme before NCX 4016 prevent the irreversible inhibition of oCOX-1 by NCX 4016 as well as by aspirin. In conclusion, our data show that NCX 4016 acts as a direct and irreversible inhibitor of COX-1 and that the presence of a spacer and NO-donating moiety in the molecule slows the kinetics of COX-1 inhibition by NCX 4016, compared with aspirin.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-77888255558749044612007-09-26T05:05:00.001-07:002007-09-26T05:05:33.492-07:002005 - 11Trends Cardiovasc Med. 2005 Nov;15(8):278-82.<br /><br /><strong><span style="font-size:130%;">Nicotinamide adenine dinucleotide phosphate oxidase: a promiscuous therapeutic target for cardiovascular drugs?</span></strong><br /><br />Muzaffar S, Shukla N, Jeremy JY. Department of Cardiac Surgery, Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, BS2 8HW Bristol, UK.<br /><br />The increased expression and activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex has emerged as a major common factor in the etiology of all forms of cardiovascular diseases since the upregulation of intravascular NADPH oxidase results in the formation of superoxide (O(2)(-)), which in turn promotes vasculopathy. An ever-increasing number of drugs commonly used in cardiovascular medicine have been shown to influence NADPH oxidase expression and activity. These include nitric oxide donors, nitroaspirin, eicosanoids, phosphodiesterase inhibitors, corticosteroids, antioxidants, and specific inhibitors. The objective of this review is to discuss these drugs in relation to the mechanisms underlying their effects on NADPH oxidase activity and the expression and therapeutic implications of these effects.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-17290411571824579092007-09-26T05:04:00.001-07:002007-09-26T05:04:32.717-07:002005 - 08J Submicrosc Cytol Pathol. 2005 Aug;37(2):205-13.<br /><br /><strong><span style="font-size:130%;">Ultrastructural investigations on protective effects of NCX 4016 (nitroaspirin) on macrovascular endothelium in diabetic Wistar rats.</span></strong><br /><br />Ambrosini MV, Mariucci G, Rambotti MG, Tantucci M, Covarelli C, De Angelis L, Del Soldato P. Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.<br /><br />The effect of a nitric oxide-donating aspirin derivative, 2-acetoxy-benzoate 3-(nitroxy-methyl)phenyl ester (NCX 4016), and aspirin on the aortic endothelium of diabetic rats was investigated by using scanning and transmission electron microscopy. Control and streptozotocin-treated rats were used. Metabolic control was assessed by measuring blood and urine metabolites, and 24-h urine volume. The ultrastructural study was performed after 7 weeks of diabetes and 6 weeks of therapy. Streptozotocin treatment induced a persistent hyperglycemia which was not influenced by the pharmacological treatments. Values of blood metabolites were in line with the diabetic status. Both scanning and transmission electron microscopy revealed that aortic endothelium was severely damaged in all diabetic rats except for the NCX 4016 treated ones. Our data document the protective effects of NCX 4016 on the vascular endothelium of diabetic rats. Since aspirin had no protective action, NCX 4016 may have exerted its beneficial action by releasing nitric oxide.Unknownnoreply@blogger.comtag:blogger.com,1999:blog-4210535171850842737.post-4987484475806371452007-09-26T05:02:00.000-07:002007-09-26T05:03:54.736-07:002005 - 03Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4185-90. Epub 2005 Mar 7.<br /><br /><strong><span style="font-size:130%;">Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination.</span></strong><br /><br />De Santo C, Serafini P, Marigo I, Dolcetti L, Bolla M, Del Soldato P, Melani C, Guiducci C, Colombo MP, Iezzi M, Musiani P, Zanovello P, Bronte V. Department of Oncology and Surgical Sciences, Oncology Section, Padua University, 35128 Padua, Italy.<br /><br />Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumor-bearing hosts, increased the number and function of tumor-antigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I/II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.<br /><br /><br /><br />Thromb Haemost. 2005 Mar;93(3):535-43.<br /><br /><strong><span style="font-size:130%;">Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice.</span></strong><br /><br />Momi S, Pitchford SC, Alberti PF, Minuz P, Del Soldato P, Gresele P. Department of Internal Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy.<br /><br />Clopidogrel plus aspirin is the treatment of choice for patients undergoing percutaneous, coronary interventions with stenting, but it does not prevent restenosis. NCX-4016, a nitric oxide-releasing aspirin (nitroaspirin), exerts a wider range of antiplatelet actions compared to aspirin, superior antithrombotic activity and reduces restenosis after arterial injury in animals. The aim of the present study was to compare the combination of nitroaspirin plus clopidogrel with aspirin plus clopidogrel in a model of platelet pulmonary thromboembolism, bleeding and intimal thickening in mice. Drugs were administered orally for 5 days; the antithrombotic effects were evaluated against collagen plus epinephrine-induced pulmonary thromboembolism, the haemorrhagic effects by tail transection bleeding time and the effects on neointima proliferation by histomorphology of photochemically injured femoral arteries. Lung platelet emboli were reduced significantly and more effectively by nitroaspirin plus clopidogrel (-56%, p<0.05 vs control) than by aspirin plus clopidogrel (-26%, p<0.05 vs control). Ex vivo platelet aggregation was inhibited maximally by nitroaspirin plus clopidogrel. Aspirin plus clopidogrel strikingly prolonged the bleeding time while nitroaspirin plus clopidogrel induced a lesser prolongation. Nitroaspirin plus clopidogrel significantly reduced intimal thickening of the femoral artery while aspirin plus clopidogrel was ineffective. Nitroaspirin plus clopidogrel is more effective and less prohaemorrhagic than aspirin plus clopidogrel in mice; provided these data are confirmed in other animal models, nitroaspirin plus clopidogrel may represent a new regimen to be tested in patients undergoing coronary revascularization procedures.Unknownnoreply@blogger.com