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Cyclooxygenase Inhibitor (cyclooxygenase + inhibitor)
Selected AbstractsChemInform Abstract: Synthesis and Evaluation of Dithiolethiones as Novel Cyclooxygenase Inhibitors.CHEMINFORM, Issue 21 2009Shannon D. Zanatta Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious ratBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009MJ Jugus Background and purpose:, Cyclooxygenase inhibitors function to reduce levels of prostaglandin E2 (PGE2) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP3 receptor for PGE2. Experimental approach:, The activity of the EP3 receptor agonist GR63799X, and EP3 receptor antagonists, CM9 and DG041, at recombinant EP3 receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP3 receptor modulation. Key results:, GR63799X dose-dependently (0.001,1 mg·kg,1) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg·kg,1) and DG041 (30 mg·kg,1) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP3 receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9. Conclusions and implications:, These data support the EP3 receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP3 receptor activity in regulating urine flow. [source] Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2009Victor Tortorici Abstract Opiate analgesia can be hampered by a reduction in pharmacological effectiveness (tolerance), and this crucially depends on the periaqueductal gray matter (PAG). Non-opioids like metamizol (dipyrone) or aspirin also induce PAG-dependent analgesia and tolerance, but the neuronal bases of this tolerance are unknown. Metamizol is a pyrazolon derivative and cyclooxygenase inhibitor with widespread use as an analgesic in Europe and Latin America. Metamizol was microinjected into the PAG of awake male rats, and antinociception was assessed by the tail flick (TF) and hot plate (HP) tests. Microinjection twice daily for 2.5 days caused tolerance to metamizol. The rats were then anesthetized and recordings from pain-facilitating on-cells and pain-inhibiting off-cells of the rostral ventromedial medulla (RVM) were performed. PAG microinjection of morphine or metamizol depresses on-cells, activates off-cells and thus inhibits nociception, including TF and HP. In metamizol-tolerant rats, however, PAG microinjection of metamizol failed to affect on- or off-cells, and this is interpreted as the reason for tolerance. In metamizol-tolerant rats morphine microinjection into PAG also failed to affect RVM neurons or nociception (cross-tolerance). In naïve, non-tolerant rats the antinociceptive effect of PAG-microinjected metamizol or morphine was blocked when CTOP, a ,-opioid antagonist, was previously microinjected into the same PAG site. These results emphasize a close relationship between opioid and non-opioid analgesic mechanisms in the PAG and show that, like morphine, tolerance to metamizol involves a failure of on- and off-cells to, respectively, disfacilitate and inhibit nociception. Cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting. [source] Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin testEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003Mehmet Ates Abstract It is generally accepted that the phospholipase-A2 -cyclooxygenase-prostanoids-cascade mediates spinal sensitization and hyperalgesia. However, some observations are not in line with this hypothesis. The aim of the present work was to investigate whether different components of this cascade exhibit nociceptive or antinociceptive effects in the rat formalin test. Intrathecal (i.th.) injection of prostaglandin E2 (PGE2) induced a dose-dependent antinociceptive effect on the formalin-induced nociception. Furthermore, thimerosal, which inhibits the reacylation of arachidonic acid thereby enhancing arachidonic acid levels, had an antinociceptive effect rather than the expected pronociceptive effect when given i.th. While the phospholipase A2 inhibitor methyl arachidonyl fluorophosphonate (MAFP; i.th.) had a significant antinociceptive effect, its analogue palmitoyl trifluoromethyl ketone (PTFMK; i.th.) had no significant effect on the formalin-induced nociception. However, MAFP, but not PTFMK, showed a cannabinoid CB1 agonistic effect as shown by the inhibition of electrically evoked contractions of the vas deferens isolated from CB1 wild-type mice but not of that from CB1 knockout mice. The antinociceptive effect of MAFP was completely reversed by the CB1 receptor antagonist AM-251 (i.th.), thus attributing such effect to its CB1 agonistic effect. Moreover, the antinociceptive effect of the cyclooxygenase inhibitor, flurbiprofen (i.th.) was reversed by the co-administration of AM-251, but not by PGE2. Finally. the combination of phenylmethylsulfonyl fluoride (PMSF; intraperitoneal), which inhibits the degradation of anandamide through the inhibition of fatty acid amidohydrolase, with thimerosal (i.th.) produced a profound CB1 -dependent antinociception. The present results show that endocannabinoids play a major role in mediating flurbiprofen-induced antinociception at the spinal level. [source] The importance of brain PGE2 inhibition versus paw PGE2 inhibition as a mechanism for the separation of analgesic and antipyretic effects of lornoxicam in rats with paw inflammationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2009Dr Nobuko Futaki Abstract Objectives Lornoxicam is a non-selective cyclooxygenase inhibitor that exhibits strong analgesic and anti-inflammatory effects but a weak antipyretic effect in rat models. Our aim was to investigate the mechanism of separation of potencies or analgesic and antipyretic effecls of lornoxicam in relatioin to its effect on prostaglandin E2 (PGE2) production in the inflammatory paw and the brain. Methods A model of acute or chronic paw inflammation was induced by Freund's complete adjuvant injection into the rat paw. Lornoxicam (0.01,1 mg/kg), celecoxib (0.3,30 mg/kg) or loxoprofen (0.3,30 mg/kg) was administered orally to the rats and the analgesic and antipyretic effects were compared. The paw hyperalgesia was assessed using the Randall,Selitto test or the flexion test. Dorsal subcutaneous body temperature was measured as indicator of pyresis. After the measurement of activities, the rats were sacrificed and the PGE2 content in the paw exudate, cerebrospinal fluid or brain hypothalamus was measured by enzme-immunoassay. Key findings In a chronic model of arthritis, lornoxicam, celecoxib and loxoprofen reduced hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083, 3.9 and 4.3 mg/kg respectively, whereas the effective dose of these drugs in pyresis was 0.58, 0.31 and 0.71 mg/kg respectively. These drugs significantly reduced the PGE2 level in paw exudate and the cerebrospinal fluid. In acute oedematous rats, lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduced hyperalgesia to a similar extent. On the other hand, lornnoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen siginificantly reduced the pyrexia to almost the normal level. These drugs significantly reduced the PGE2 level in inflamed paw exudate lo almost the normal level. On the other hand, lornoxicam did not change PGE2 level in the brain hypothalamus, whereas celecoxib and loxoprofen strongly decreased it. Conclusions Lornoxicam exhibits strong analgesic but weak antipyretic effects in rats with paw inflammation. Such a separation of effects is related to its efficacy in the reduction of PGE2 levels in the paw and brain hypothalamus. [source] Eicosanoids mediate the laminarin-induced nodulation response in larvae of the flesh fly, Neobellieria bullataARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 1 2005Vanessa Franssens Abstract Insects have a highly developed innate immune system, including humoral and cellular components. The cellular immune responses refer to hemocyte-mediated processes such as phagocytosis, nodulation, and encapsulation. Nodulation is considered the predominant defense reaction to infection in insects. Treating third instar larvae of the grey flesh fly, Neobellieria bullata, with laminarin (,-1,3-glucan, a typical component of fungal cell walls) induced nodulation in a dose-dependent manner. This reaction was initiated very soon after injection and reached its maximal response level after 4 h. The nodules were not randomly distributed in the hemocoel, but were concentrated around the crop. The possible role of eicosanoids in this nodulation process was determined by treating larvae with the phospholipase A2 inhibitor, dexamethasone, the cyclooxygenase inhibitor, naproxen, and the lipoxygenase inhibitor, esculetin. Both dexamethasone and naproxen significantly impaired the ability of N. bullata larvae to form nodules in response to laminarin. Supplying dexamethasone-treated larvae with the eicosanoid precursor, arachidonic acid, restored the full response. On the other hand, treating larvae with esculetin did not influence the formation of nodules in response to laminarin. This is the first study that demonstrates the occurrence of a laminarin-induced nodulation response in Diptera. Phospholipase A2 and cyclooxygenase activities, both involved in prostaglandin biosynthesis, appear to play an important role in the regulation of this process. Arch. Insect Biochem. Physiol. 59:32,41, 2005. © 2005 Wiley-Liss, Inc. [source] Intervention of an inflammation amplifier, triggering receptor expressed on myeloid cells 1, for treatment of autoimmune arthritisARTHRITIS & RHEUMATISM, Issue 6 2009Yousuke Murakami Objective Triggering receptor expressed on myeloid cells 1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and accelerates tissue destruction by propagating inflammatory responses in disease related to bacterial infections. Its blockade rescues the hosts in murine models of sepsis, to clear the bacteria without impairing the host defense. The aim of this study was to investigate the involvement of TREM-1 in an autoimmune, noninfectious disease. Methods Synovial tissue specimens from the joints of patients with rheumatoid arthritis (RA) and the joints of mice with collagen-induced arthritis (CIA) were examined for TREM-1 expression, using flow cytometric analysis. Expression of TREM-1 on macrophages was induced by lipopolysaccharide, with or without a cyclooxygenase inhibitor. Rheumatoid synovial cells were stimulated with agonistic anti,TREM-1 antibodies. Recombinant adenovirus encoding the extracellular domain of TREM-1 fused with IgG-Fc (AxCATREM-1 Ig) or synthetic TREM-1 antagonistic peptides were injected to treat CIA, and the clinical manifestations of the antigen-specific T cell and B cell responses were evaluated. Results TREM-1 was expressed on CD14+ cells in rheumatoid synovial tissue and synovial macrophages from mice with CIA. Unlike murine macrophages, human monocyte/macrophages did not depend on prostaglandin E2 for up-regulation of TREM-1. Agonistic anti,TREM-1 antibodies promoted tumor necrosis factor , production from rheumatoid synovial cells. Blockade of TREM-1 using AxCATREM-1 Ig and antagonistic peptides ameliorated CIA without affecting the serum levels of anti,type II collagen antibodies or the proliferative responses of splenocytes to type II collagen. Conclusion TREM-1 ligation contributes to the pathology of autoimmune arthritis. The results of this study implied that blockade of TREM-1 could be a new approach to rheumatic diseases that is safer than the presently available immunosuppressive treatments. [source] Opposite effects of endogenous nitric oxide and prostaglandin F2, in the rat mesenteric bedAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2003H. A. Peredo Summary 1 The relationship between the effects of endogenous nitric oxide (NO) and prostanoids on the noradrenaline (NA)-induced contractions and the mechanisms involved were investigated in the rat perfused mesenteric bed, using NG -nitro- l -arginine methyl ester (l -NAME), a NO synthase inhibitor and sodium nitroprusside (SNP), a NO donor. 2 The constrictor responses to NA were reduced to 50% by the cyclooxygenase inhibitor 10 ,m indomethacin as well as by 1 ,m SNP. When indomethacin and SNP were perfused simultaneously the contractions were further reduced. 3 The NA-induced contractions were increased by the addition of 400 ,ml -NAME and the addition of either indomethacin or SNP abolished such increases. The simultaneous perfusion of both agents further reduced the contractions. 4 Removal of the endothelium increased NA-induced contractions to a similar extent as l -NAME and this increase was abolished by indomethacin as well as by SNP. 5 The perfusion of 10 ,m NA augmented the release of prostaglandin (PG) F2, by the mesenteric bed without modifications in any other prostanoid. In the presence of l -NAME, this effect was further increased. However, SNP abolished the NA-induced stimulation of PGF2, release. 6 In de-endothelialized preparations NA also stimulated PGF2, production as observed in intact preparations. This effect was more marked in the presence of l -NAME; in contrast, SNP abolished the stimulation. 7 In conclusion, the present results suggest an opposite action between NO and PGF2, on the NA-induced contractions in the rat mesenteric bed. [source] Prostanoid release and constrictor responses to noradrenaline in the rat mesenteric vascular bed in non-insulin-dependent diabetes mellitusAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2001H. A. Peredo 1,The administration of streptozotocin (STZ) to 2-day old rats induced a non-insulin-dependent diabetes mellitus (NIDDM)-like state, with mild hyperglycaemia and no alterations in body weight at the adult age. 2,In the isolated and perfused mesenteric vascular bed of NIDDM animals, the constrictor responses to either noradrenaline (NA) or potassium chloride (KCl) were not modified as compared with age-matched non-diabetic controls. 3,The reduction in NA contractions induced by the cyclooxygenase inhibitor, 10 ,M indomethacin in the control group was absent in the NIDDM rats. 4,The increase in the NA-induced contractions caused by endothelium removal was suppressed by indomethacin in the controls but not in the NIDDM group. 5,The prostanoid release from the mesenteric vascular beds of NIDDM rats was markedly reduced as compared with non-diabetic controls. Noradrenaline increased production of the constrictor prostaglandin (PG) F2, in control but not in NIDDM rats. 6,In summary, these results show that in STZ-induced NIDDM rats, there is an impairment of the prostanoid production, as well as a suppression of the role of prostanoids in the contractile effects of NA in the mesenteric vascular bed. These alterations are more severe than those previously observed in a model of insulin-dependent diabetes mellitus (IDDM), in which hyperglycaemia and reduction of body weight were more marked. The conclusion is that, in these models of diabetes and in the preparation studied, vascular alterations and modifications of glycaemia and body weight are not closely related. [source] Involvement of H2O2 in superoxide-dismutase-induced enhancement of endothelium-dependent relaxation in rabbit mesenteric resistance arteryBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003Takeo Itoh The mechanism underlying the enhancement by superoxide dismutase (SOD) of endothelium-dependent relaxation was investigated in rabbit mesenteric resistance arteries. SOD (200 U ml,1) increased the production of H2O2 in smooth muscle cells (as indicated by the use of an H2O2 -sensitive fluorescent dye). Neither SOD nor catalase (400 U ml,1) modified either the resting membrane potential or the hyperpolarization induced by acetylcholine (ACh, 1 ,M) in smooth muscle cells. In arteries constricted with noradrenaline, the endothelium-dependent relaxation induced by ACh (0.01,1 ,M) was enhanced by SOD (200 U ml,1) (P<0.01). This action of SOD was inhibited by L - NG -nitroarginine (nitric oxide (NO)-synthase inhibitor) but not by either charybdotoxin+apamin (Ca2+ -activated-K+ -channel blockers) or diclofenac (cyclooxygenase inhibitor). Neither ascorbate (50 ,M) nor tiron (0.3 mM), superoxide scavengers, had any effect on the ACh-induced relaxation, but each attenuated the enhancing effect of SOD on the ACh-induced relaxation. Similarly, catalase (400 U ml,1) inhibited the effect of SOD without changing the ACh-induced relaxation. In endothelium-denuded strips constricted with noradrenaline, SOD enhanced the relaxation induced by the NO donor 1-hydroxy-2-oxo-3-(N -methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7) (P<0.05). Ascorbate and catalase each attenuated this effect of SOD. H2O2 (1 ,M) enhanced the relaxation on the noradrenaline contraction induced by NOC-7 and that induced by 8-bromo-cGMP, a membrane-permeable analogue of guanosine 3,,5, cyclic monophosphate (cGMP). SOD had no effect on cGMP production, whether measured in endothelium-intact strips following an application of ACh (0.1 ,M) or in endothelium-denuded strips following an application of NOC-7 (0.1 ,M). It is suggested that in rabbit mesenteric resistance arteries, SOD increases the ACh-induced, endothelium-dependent relaxation by enhancing the action of NO in the smooth muscle via its H2O2 -producing action (rather than via a superoxide-scavenging action). British Journal of Pharmacology (2003) 139, 444,456. doi:10.1038/sj.bjp.0705255 [source] Perioperative Management of Medications for Psoriasis and Psoriatic Arthritis: A Review for the DermasurgeonDERMATOLOGIC SURGERY, Issue 4 2008CLAUDIA HERNANDEZ MD BACKGROUND Psoriasis affects an estimated 3% of the world's population. Many are on chronic immunosuppressive therapy for the cutaneous and joint manifestations of this disorder. The management of these medications in the perioperative period is controversial. Psoriasis and psoriatic arthritis medications can affect wound healing, hemostasis, and infection risk during cutaneous surgery. OBJECTIVES The objective of this article is to provide a critical review of various medications used for care of the psoriatic patient and their potential effect on cutaneous surgical procedures. CONCLUSIONS This review summarizes current understanding of wound healing, hemostatic effects, and infectious risks regarding many psoriasis medications including nonsteroidal anti-inflammatory drugs, cyclooxygenase inhibitors, corticosteroids, various immunosuppressants, and biologic response modifiers. Recommendations vary depending on the agent in question, type of procedure, and comorbid conditions in the patient. Caution is advised when using many of the medications reviewed due to lack of human data of their effects in the perioperative period. [source] Current concepts in cyclooxygenase inhibition in breast cancerJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2002G. Singh-Ranger BSc (Hons) MBBS MRCS (Eng) Summary The prospect that simple medications such as non-steroidal anti-inflammatory drugs (NSAIDs) could be recruited into the physician's armamentarium of anticancer drugs is intriguing, especially in the context of breast cancer, one of the leading causes of mortality in the Western world. There has consequently been a wider exploration of the role of cyclooxygenase (COX) in breast cancer, and we now accept that COX-2, one of its isoenzymes, is clearly implicated in the pathogenesis of the disease. This would seem to translate into a viable role for cyclooxygenase inhibitors in the treatment and prevention of breast cancer, but also raises issues regarding safety and tolerability of these drugs. In this article we discuss the theoretical consequences of cyclooxygenase inhibition, the significance of findings from experimental studies, large scale epidermiological investigations, and the relevance of large population studies of COX-2 inhibitors such as CLASS and VIGOR. [source] Clinical trial: the impact of cyclooxygenase inhibitors on gastrointestinal recovery after major surgery , a randomized double blind controlled trial of celecoxib or diclofenac vs. placeboALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2009D. A. WATTCHOW Summary Background, Ileus occurs after abdominal surgery and may be severe. Inhibition of prostaglandin release reduces post-operative ileus in a rat model. Aim, To determine whether prostaglandin inhibition by cyclooxygenase inhibitors, celecoxib or diclofenac, could enhance gastrointestinal recovery and reduce post-operative ileus in humans. Methods, Two hundred and ten patients undergoing elective major abdominal surgery were randomized to receive twice daily placebo (n = 67), celecoxib (100 mg, n = 74) or diclofenac (50 mg, n = 69), preoperatively and continuing for up to 7 days. Primary outcomes were hallmarks of gut recovery. Secondary outcomes were paralytic ileus, pain and complications. Results, There was no clinically significant difference between the groups for restoration of bowel function. There was a significant reduction in paralytic ileus in the celecoxib-treated group (n = 1, 1%) compared with diclofenac (n = 7, 10%) and placebo (n = 9, 13%); P = 0.025, RR 0.20, CI 0.01,0.77. Pain scores, analgesia, transfusion requirements and adverse event rates were similar between study groups. Conclusions, Perioperative low dose celecoxib, but not diclofenac, markedly reduced the development of paralytic ileus following major abdominal surgery, but did not accelerate early recovery of bowel function. This was independent of narcotic use and had no increase in post-operative complications. [source] Progesterone Regulates IL12 Expression in Pregnancy Lymphocytes by Inhibiting Phospholipase A2AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2003G. Par Par G, Geli J, Kozma N, Varga P, Szekeres-Bartho J. Progesterone regulates IL12 expression in pregnancy lymphocytes by inhibiting phospholipase A2. AJRI 2003; 49:1,5 © Blackwell Munksgaard, 2003 PROBLEM: Progesterone-induced blocking factor (PIBF) is one of the pathways that mediate the immunological effects of progesterone. PIBF inhibits natural killer (NK) cytotoxic activity. Recently we showed that neutralization of PIBF results in an increased interleukin (IL)-12 expression, which is corrected by cyclooxygenase inhibitors. As exogenous arachidonic acid (AA) voids the NK blocking effect of PIBF, it is likely that PIBF acts before the level of the cyclooxygenase enzyme. Therefore in this study we investigated the effect of PIBF neutralizing antibody and simultaneous phospholipase A2 inhibitor quinacrine (Q) treatment on IL-12 production. METHODS: Pregnancy lymphocytes were treated with anti-PIBF antibody or lipopolysaccharide (LPS) as a positive control, in the presence or absence of Q. IL-12 expression by PBMC was detected by immunocytochemistry. RESULTS: Neutralization of PIBF as well as LPS treatment resulted in an increased IL-12 expression, which was corrected by simultaneous Q treatment. Pre-treatment of lymphocytes with progesterone prevented the stimulating effect of LPS on IL-12 production. CONCLUSION: Progesterone binding of the lymphocytes is followed by the release of PIBF that inhibits AA release. The subsequent block of prostaglandin synthesis reduces IL-12 production and results in a lowered cytotoxic NK activity, which may contribute to a normal pregnancy outcome. [source] | |||||||||||||