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CNS Drug Reviews 2003New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic... (Review)
Review
New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic non-steroidal anti-inflammatory drugs (NSAIDs) and are starting to be used not only for low to moderate intensity pain, but also for high intensity pain. Three different strategies have been followed to improve the pharmacological profile of COX inhibitors: 1. Development of COX-2 selective inhibitors. This is based on the initial hypothesis that considered COX-2 as the enzyme responsible for the generation of prostaglandins only in inflammation, and, therefore, uniquely responsible for inflammation, pain and fever. Initial expectations gave rise to controversial results, still under discussion. The second generation of these compounds is being developed and should contribute to clarifying both their efficacy and the specific functions of the COX enzymes. 2. Modified non-selective COX inhibitors. Molecules like nitro-NSAIDs or tromethamine salt derivatives have been synthesized considering that both COX-1 and COX-2 are responsible for the synthesis of prostaglandins involved either in homeostatic functions or inflammation. Nitroaspirin, nitroparacetamol or dexketoprofen trometamol are some examples of molecules that are already showing an important clinical efficacy. The modifications performed in their structures seem to lower the unwanted side effects as well as to enhance their analgesic efficacy. 3. Combined therapy of classic NSAIDs with other drugs. This strategy looks for improvements in the incidence of adverse effects or to take advantage of the synergistic enhancement of their therapeutic effects. Some of the molecules resulting from these strategies are very valuable as therapeutic agents and open a wide range of possibilities in the treatment of high intensity pain, including neuropathic pain, and opiate sparing therapy.
Topics: Adrenergic Agonists; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Caffeine; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Humans; Narcotics; Pain; Research; Steroids
PubMed: 14530796
DOI: 10.1111/j.1527-3458.2003.tb00251.x -
Polish Journal of Pharmacology 2003Excessive coagulation and impaired fibrinolysis lead to many hemostatic disorders, which enhance the risk of development of life-threatening cardiovascular diseases such... (Review)
Review
Excessive coagulation and impaired fibrinolysis lead to many hemostatic disorders, which enhance the risk of development of life-threatening cardiovascular diseases such as myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism, belonging to the most important factors influencing morbidity and mortality in civilized societies. The adverse events induced by currently used drugs, the need for regular monitoring of coagulation parameters, inconvenient, in some cases, route of administration stimulate further search for novel, effective and safe methods of therapies of these disorders. In this paper, we describe those new agents which are now under experimental and clinical study, such us prostanoids, nitroaspirin, GP IIb/IIIa receptor antagonists, thienopyridine derivatives, collagen-GPVI and von Willebrand factor-GPIb-IX contact blockers, direct thrombin inhibitors, inhibitors of thrombin-platelet interactions, factor VII inhibitors and tissue factor-factor VII contact blockers. Based on the available literature, we discuss the possible role of these agents in the future prevention and treatment of thromboembolic diseases.
Topics: Animals; Blood Coagulation; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombosis
PubMed: 14581710
DOI: No ID Found -
British Journal of Pharmacology Jan 20001. Nitroaspirin (2.5 - 50 mg kg(-1), i.p. or 2.5 - 100 mg kg(-1), p.o.) and aspirin (2.5 - 100 mg kg(-1), i.p. or p.o.) exhibit anti-inflammatory activity in the... (Comparative Study)
Comparative Study
1. Nitroaspirin (2.5 - 50 mg kg(-1), i.p. or 2.5 - 100 mg kg(-1), p.o.) and aspirin (2.5 - 100 mg kg(-1), i.p. or p.o.) exhibit anti-inflammatory activity in the carrageenan-induced hindpaw oedema model in the rat. When administered i.p., nitroaspirin was a more effective anti-oedema agent than aspirin particularly in the 'early' phase (i.e. up to 60 min) of the response. The ED(50) values for nitroaspirin and aspirin as inhibitors of the 'late' phase response (measured at 180 min) were 64.3 micromol kg(-1) and >555 micromol kg(-1), respectively. When administered p.o., neither nitroaspirin nor aspirin exhibited significant anti-inflammatory activity in the 'early' phase and were of similar potency in the 'late' phase. Thus, at the highest dose used (100 mg kg(-1), 360 min) orally administered nitroaspirin (aspirin in parenthesis) inhibited oedema formation by 46.9+/-1.6% (47.2+/-3.8%, both n=6, P<0.05). 2. Nitroaspirin and aspirin (25 - 200 mg kg(-1), p.o.) caused dose-related inhibition of the hyperalgesia to mechanical stimulation following intraplantar injection of carrageenan in the rat. ED(50) values were 365 micromol kg(-1) and 784 micromol kg(-1), respectively. Neither drug influenced the threshold for mechanical stimulation in the contralateral (i.e. untreated) hindpaw. 3. Nitroaspirin and aspirin (2.5 - 100 mg kg(-1), p.o.) caused dose-related inhibition of acetic acid induced abdominal constrictions in the mouse (ED(50) values of 154.7 micromol kg(-1) and 242.8 micromol kg(-1), respectively). 4. Nitroaspirin and aspirin (>200 mg kg(-1), p.o.) reduced the 'late' phase (but not the 'early' phase) of the formalin-induced hindpaw licking assay in the mouse. Similarly, nitroaspirin and aspirin (>50 mg kg(-1), p.o.) prolonged tail withdrawal latency following application of a noxious heat stimulus in the mouse.
Topics: Acetic Acid; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Carrageenan; Edema; Formaldehyde; Hyperalgesia; Male; Mice; Pain Measurement; Rats; Rats, Wistar; Reaction Time
PubMed: 10694241
DOI: 10.1038/sj.bjp.0703064 -
Life Sciences May 2004The metabolic fate of nitric oxide (NO) released from nitroaspirin, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX 4016), the lead compound of a new...
The metabolic fate of nitric oxide (NO) released from nitroaspirin, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX 4016), the lead compound of a new class of NO-releasing non steroidal anti-inflammatory drugs (NO-NSAIDs), has been studied in the rat following p.o. and i.p. administration of 100 mg/kg, by monitoring in plasma the bioactive storage forms of NO (S-nitrosothiols, RS-NO) and its oxidation products (nitrites/nitrates, NOx) by a chemiluminescent assay. In parallel, plasma was analyzed for unchanged drug and metabolites by reverse-phase HPLC. In orally treated rats, no unchanged drug is observed in the 0-24 h interval post-dosing, but only salicylic acid (SA), NOx and RS-NO. The time-course of SA formation parallels that of plasma NOx (plateau after 6 h). Nitrosothiols in plasma are detectable at 1 h, peak at 4 h post-administration, and decline thereafter. The results relative to i.p. administration show a more pronounced and rapid NO delivery (peak of both NOx and RS-NO at 1 h and plateau between 1 and 2 h), still coincident with the peak of SA, and the presence in plasma of NCX 4015 (a metabolite of NCX 4016 which still bears the nitrate function). In myocardial tissue from p.o. treated rats, no drug or metabolites were ever detected, and the NOx levels were always in the range of the controls. Conversely, following i.p. treatment, we observed a rapid compartmentalization within the heart of the unchanged drug, which rapidly disappears in favour of its breakdown products NCX 4015 and SA, with a concomitant rise in myocardial NOx levels up to 2 h. To check the stability of NCX 4016 in the acidic gastric milieu and to explain the different distribution of the drug following p.o. or i.p. administration, the gastric content of the orally-treated animals at different post-dosing times was analysed by HPLC. The unchanged drug was detected up to 8 h post-dosing (levels slowly decreased with time), and the only metabolite to be detected was the O-deacetylated derivative (NCX 4023), which was present in low concentrations up to 4 h post-dosing. This indicates that NCX 4016 does not undergo biotransformation in the upper part of gastrointestinal tract (no direct release of NO in this district) and that the stomach acts as a reservoir for the drug.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chromatography, High Pressure Liquid; Injections, Intraperitoneal; Male; Nitric Oxide; Rats; Rats, Wistar; Tissue Distribution
PubMed: 15094329
DOI: 10.1016/j.lfs.2003.11.018 -
Carcinogenesis May 2013The ionized cysteines present on the surfaces of many redox-sensitive proteins play functionally essential roles and are readily targeted by the reactive oxygen and...
The ionized cysteines present on the surfaces of many redox-sensitive proteins play functionally essential roles and are readily targeted by the reactive oxygen and reactive nitrogen species. Using disulfiram (DSF) and nitroaspirin (NCX4016) as the model compounds that mediate thiol-conjugating and nitrosylating reactions, respectively, we investigated the fate of p53, nuclear factor-kappaB (NF-κB) and other redox-responsive proteins following the exposure of human cancer cell lines to the drugs. Both drugs induced glutathionylation of bulk proteins in tumor cells and cell-free extracts. A prominent finding of this study was a time- and dose-dependent degradation of the redox-regulated proteins after brief treatments of tumor cells with DSF or NCX4016. DSF and copper-chelated DSF at concentrations of 50-200 µM induced the disappearance of wild-type p53, mutant p53, NF-κB subunit p50 and the ubiquitin-activating enzyme E1 (UBE1) in tumor cell lines. DSF also induced the glutathionylation of p53. The recombinant p53 protein modified by DSF was preferentially degraded by rabbit reticulocyte lysates. The proteasome inhibitor PS341 curtailed the DSF-induced degradation of p53 in HCT116 cells. Further, the NCX4016 induced a dose-dependent disappearance of the UBE1 and NF-κB p50 proteins in cell lines, besides a time-dependent degradation of aldehyde dehydrogenase in mouse liver after a single injection of 150 mg/kg. The loss of p53 and NF-kB proteins correlated with decreases in their specific binding to DNA. Our results demonstrate the hitherto unrecognized ability of the non-toxic thiolating and nitrosylating agents to degrade regulatory proteins and highlight the exploitable therapeutic benefits.
Topics: Animals; Antineoplastic Agents; Aspirin; Cell Line, Tumor; DNA-Binding Proteins; Disulfiram; HCT116 Cells; HT29 Cells; Humans; Liver; Male; Mice; NF-kappa B; Oxidation-Reduction; Proteasome Endopeptidase Complex; Rabbits; Reticulocytes; Tumor Suppressor Protein p53; Ubiquitin-Activating Enzymes
PubMed: 23354308
DOI: 10.1093/carcin/bgt032 -
Proceedings of the National Academy of... Mar 2005Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract...
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.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cancer Vaccines; Carrier Proteins; Immune System Diseases; Lipocalins; Mice; Mice, Inbred BALB C; Neoplasm Proteins; Neoplasms; Nitric Oxide Synthase; T-Lymphocytes; Time Factors
PubMed: 15753302
DOI: 10.1073/pnas.0409783102 -
Proceedings of the National Academy of... Mar 2001The objective of this study was to elucidate the mechanisms by which nitric oxide (NO) inhibits rat aortic smooth muscle cell (RASMC) proliferation. Two products of the...
The objective of this study was to elucidate the mechanisms by which nitric oxide (NO) inhibits rat aortic smooth muscle cell (RASMC) proliferation. Two products of the arginine-NO pathway interfere with cell growth by distinct mechanisms. N(G)-hydroxyarginine and NO appear to interfere with cell proliferation by inhibiting arginase and ornithine decarboxylase (ODC), respectively. S-nitroso-N-acetylpenicillamine, (Z)-1-[N-(2-aminoethyl)-N-(2-aminoethyl)-amino]-diazen-1-ium-1,2-diolate, and a nitroaspirin derivative (NCX 4016), each of which is a NO donor agent, inhibited RASMC growth at concentrations of 1-3 microM by cGMP-independent mechanisms. The cytostatic action of the NO donor agents as well as alpha-difluoromethylornithine (DFMO), a known ODC inhibitor, was prevented by addition of putrescine but not ornithine. These observations suggested that NO, like DFMO, may directly inhibit ODC. Experiments with purified, recombinant mammalian ODC revealed that NO inhibits ODC possibly by S-nitrosylation of the active site cysteine in ODC. DFMO, as well as the NO donor agents, interfered with cellular polyamine (putrescine, spermidine, spermine) production. Conversely, increasing the expression and catalytic activity of arginase I in RASMC either by transfection of cells with the arginase I gene or by induction of arginase I mRNA with IL-4 resulted in increased urea and polyamine production as well as cell proliferation. Finally, coculture of rat aortic endothelial cells, which had been pretreated with lipopolysaccharide plus a cytokine mixture to induce NO synthase and promote NO production, caused NO-dependent inhibition of target RASMC proliferation. This study confirms the inhibitory role of the arginine-NO pathway in vascular smooth muscle proliferation and indicates that one mechanism of action of NO is cGMP-independent and attributed to its capacity to inhibit ODC.
Topics: Animals; Arginine; Cell Division; Cells, Cultured; Cyclic GMP; Muscle, Smooth, Vascular; Nitric Oxide; Ornithine Decarboxylase; Polyamines; Rats
PubMed: 11259671
DOI: 10.1073/pnas.071054698 -
Journal of Inflammation (London,... Jul 2008The cytoprotective nature of nitric oxide (NO) led to development of NO-aspirins in the hope of overcoming the gastric side-effects of aspirin. However, the NO moiety...
BACKGROUND
The cytoprotective nature of nitric oxide (NO) led to development of NO-aspirins in the hope of overcoming the gastric side-effects of aspirin. However, the NO moiety gives these hybrids potential for actions further to their aspirin-mediated anti-platelet and anti-inflammatory effects. Having previously shown that novel NO-aspirin hybrids containing a furoxan NO-releasing group have potent anti-platelet effects, here we investigate their anti-inflammatory properties. Here we examine their effects upon TNFalpha release from lipopolysaccharide (LPS)-stimulated human monocytes and monocyte-derived macrophages and investigate a potential mechanism of action through effects on LPS-stimulated nuclear factor-kappa B (NF-kappaB) activation.
METHODS
Peripheral venous blood was drawn from the antecubital fossa of human volunteers. Mononuclear cells were isolated and cultured. The resultant differentiated macrophages were treated with pharmacologically relevant concentrations of either a furoxan-aspirin (B8, B7; 10 muM), their respective furazan NO-free counterparts (B16, B15; 10 muM), aspirin (10 muM), existing nitroaspirin (NCX4016; 10 muM), an NO donor (DEA/NO; 10 muM) or dexamethasone (1 muM), in the presence and absence of LPS (10 ng/ml; 4 h). Parallel experiments were conducted on undifferentiated fresh monocytes. Supernatants were assessed by specific ELISA for TNFalpha release and by lactate dehydrogenase (LDH) assay for cell necrosis. To assess NF-kappaB activation, the effects of the compounds on the loss of cytoplasmic inhibitor of NF-kappaB, IkappaBalpha (assessed by western blotting) and nuclear localisation (assessed by immunofluorescence) of the p65 subunit of NF-kappaB were determined.
RESULTS
B8 significantly reduced TNFalpha release from LPS-treated macrophages to 36 +/- 10% of the LPS control. B8 and B16 significantly inhibited monocyte TNFalpha release to 28 +/- 5, and 49 +/- 9% of control, respectively. The B8 effect was equivalent in magnitude to that of dexamethasone, but was not shared by 10 muM DEA/NO, B7, the furazans, aspirin or NCX4016. LDH assessment revealed none of the treatments caused significant cell lysis. LPS stimulated loss of cytoplasmic IkappaBalpha and nuclear translocation of the p65 NF-kappaB subunit was inhibited by the active NO-furoxans.
CONCLUSION
Here we show that furoxan-aspirin, B8, significantly reduces TNFalpha release from both monocytes and macrophages and suggest that inhibition of NF-kappaB activation is a likely mechanism for the effect. This anti-inflammatory action highlights a further therapeutic potential of drugs of this class.
PubMed: 18671842
DOI: 10.1186/1476-9255-5-12 -
British Journal of Pharmacology Jun 2006Incorporation of a nitric oxide (NO)-releasing moiety in aspirin can overcome its gastric side effects. We investigated the NO-release patterns and antiplatelet effects...
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.
Topics: Adult; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Humans; Middle Aged; Nitric Oxide; Nitric Oxide Donors; Oxadiazoles; Platelet Aggregation; Salicylic Acid
PubMed: 16702997
DOI: 10.1038/sj.bjp.0706743 -
American Journal of Physiology. Heart... Sep 2007In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat... (Comparative Study)
Comparative Study
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.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Pressure; Cyclooxygenase 1; Cyclooxygenase 2; Enzyme Inhibitors; Heart Rate; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; RNA, Messenger; Random Allocation; Rats; Rats, Wistar; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 17526656
DOI: 10.1152/ajpheart.00064.2007