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Indomethacin
Kinds of Indomethacin Selected AbstractsSustained increase in arterial blood pressure and vascular resistance induced by infusion of arachidonic acid in ratsACTA PHYSIOLOGICA, Issue 1 2000Kirkebø The haemodynamic responses to arachidonic acid (AA) have been investigated in seven groups of anaesthetized rats. Sodium arachidonate was infused intravenously for 4 or 20 min, and arterial blood pressure was recorded continuously. Cardiac output and organ blood flow were measured by microspheres. Infusion of arachidonate caused first a fast drop in arterial blood pressure, thereafter it increased steadily for 5,15 min towards a pressure about 25 mmHg above control level. The high pressure was maintained for at least 1 h. Repeated infusions of arachidonate gave similar responses. Inhibition of cyclo-oxygenase by indomethacin prevented the initial pressure drop to arachidonate, but not the sustained increase in pressure. Arterial pressure, total vascular resistance and blood flow in the kidneys, adrenals and spleen were significantly reduced, whereas cardiac output was not changed 4 min after start infusion of arachidonate. However, average blood pressure was significantly increased 22 and 35 min after start infusion (from 103.9 ± 2.9 to 128.1 ± 6.1 and 135.8 ± 4.6 mmHg). Mean vascular resistance increased simultaneously (from 3.5 ± 0.2 to 4.7 ± 0.4 and 5.2 ± 0.4 mmHg 100 mL,1), while cardiac output, stroke volume and heart rate were maintained or slightly reduced. The renal blood flow was significantly lowered (from average 4.9 ± 0.1 to 3.3 ± 0.2 and 4.0 ± 0.2 mL min,1). Indomethacin did not prevent the changes in vascular resistance or organ blood flow recorded after 20,35 min. On the other hand, inhibition of both cyclo-oxygenase, lipoxygenase and the cytochrome P450 pathways by eicosatetrayonic acid (ETYA) normalized all haemodynamic parameters. Likewise, the rise in pressure was prevented by 17-octadecynoic acid (17-ODYA), an inhibitor of the cytochrome P450 enzyme activity. Thus, arachidonate infusion caused a transient decrease, and then a sustained increase in arterial pressure and vascular resistance, and a long-lasting reduction in renal blood flow, possibly owing to release of a cytochrome P450 dependent vasoconstrictor metabolite of AA. [source] Enhancement of Ca2+ -regulated exocytosis by indomethacin in guinea-pig antral mucous cells: arachidonic acid accumulationEXPERIMENTAL PHYSIOLOGY, Issue 1 2006Shoko Fujiwara Ca2+ -regulated exocytosis is enhanced by an autocrine mechanism via the PGE2,cAMP pathway in antral mucous cells of guinea-pigs. The inhibition of the PGE2,cAMP pathway by H-89 (an inhibitor of protein kinase A, PKA) or aspirin (ASA, an inhibitor of cyclo-oxygenase, COX) decreased the frequency of ACh-stimulated exocytotic events by 60%. Indomethacin (IDM, an inhibitor of COX), however, decreased the frequency of ACh-stimulated exocytotic events only by 30%. Moreover, IDM increased the frequency of ACh-stimulated exocytotic events by 50% in H-89-treated or ASA-treated cells. IDM inhibits the synthesis of Prostaglandin (PGG/H) and (15R)-15-hydroxy-5,8,11 cis-13-trans-eicosatetraenoic acid (15R-HPETE), while ASA inhibits only the synthesis of PGG/H. Thus, IDM may accumulate arachidonic acid (AA). AACOCF3 or N -(p -amylcinnamoyl) anthranilic acid (ACA; both inhibitors of phospholipase A2, PLA2), which inhibits AA synthesis, decreased the frequency of ACh-stimulated exocytotic events by 60%. IDM, however, did not increase the frequency in AACOCF3 -treated cells. AA increased the frequency of ACh-stimulated exocytotic events in AACOCF3 - or ASA-treated cells, similar to IDM in ASA- and H-89-treated cells. Moreover, in the presence of AA, IDM did not increase the frequency of ACh-stimulated exocytotic events in ASA-treated cells. The PGE2 release from antral mucosa indicates that inhibition of PLA2 by ACA inhibits the AA accumulation in unstimulated and ACh-stimulated antral mucosa. The dose,response study of AA and IDM demonstrated that the concentration of intracellular AA accumulated by IDM is less than 100 nm. In conclusion, IDM modulates the ACh-stimulated exocytosis via AA accumulation in antral mucous cells. [source] Evaluation of gastric toxicity of indomethacin acid, salt form and complexed forms with hydroxypropyl-,-cyclodextrin on Wistar rats: histopathologic analysisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2009A.C. Ribeiro-Rama Abstract Indomethacin (IM) is a non-steroidal anti-inflammatory drug which inhibits prostaglandin biosynthesis. It is practically insoluble in water and has the capacity to induce gastric injury. Hydroxypropyl-,-cyclodextrin (HP-,-CD) is an alkylated derivative of ,-CD with the capacity to form inclusion complexes with suitable molecules. IM is considered to form partial inclusion complexes with HP-,-CD by enclosure of the p -chlorobenzoic part of the molecule in the cyclodextrin channel, reducing the adverse effects. The aim of this paper is to evaluate the gastric damage induced by the IM inclusion complex prepared by freeze-drying and spray-drying. A total of 135 Wistar rats weighing 224.4 ± 62.5 g were put into 10 groups. They were allowed free access to water but were maintained fasted for 18 h before the first administration until the end of the experiment. IM acid-form, IM trihydrated-sodium-salt and IM-HP-,-CD spray and freeze-dried, at normal and toxic doses, were administered through gastric cannula once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and the stomachs collected and prepared for morphological study by using the haematoxylin-eosin technique. Lesion indexes (rated 0/4) were developed and the type of injury was scored according to the severity of damage and the incidence of microscopic evidence of harm. Microscopic assessment demonstrated levels of injury with index one on 10,25%. The type of complexation method had different incidence but the same degree. The results show that IM inclusion complexation protects against gastric injury, reducing the incidence and the maximum degree of severity from 4 to 1, with a better performance of the spray-dried complex. [source] Hemicrania Continua-Like Headache Associated With Internal Carotid Artery Dissection May Respond to IndomethacinHEADACHE, Issue 1 2007Avi Ashkenazi MD Hemicrania continua (HC) is an idiopathic, chronic disorder characterized by a continuous, strictly unilateral headache associated with ipsilateral cranial autonomic symptoms. The symptoms of HC typically respond dramatically to indomethacin therapy. We describe a patient with traumatic internal carotid artery dissection, who presented with a clinical picture mimicking HC that initially responded to indomethacin. Patients with a clinical picture similar to HC should be managed with a high index of suspicion for a possible cervical arterial dissection. [source] Cough Headache, Indomethacin, and SurgeryHEADACHE, Issue 3 2004Julio Pascual MD No abstract is available for this article. [source] Chronic Bilateral Headache Responding to IndomethacinHEADACHE, Issue 10 2000Jan Hannerz MD Three patients with bilateral chronic tension-type headache (meeting IHS diagnostic criteria) responded with complete control of the headache during the more than 2 years they were treated with indomethacin. The headache recurred within 12 to 26 hours after indomethacin was stopped. Fifty milligrams of intravenous indomethacin resulted in complete relief of headache for 6.5 to 25 hours, similar to results found earlier in patients with hemicrania continua. It is concluded that there may be a subgroup of patients with bilateral chronic headache who respond to indomethacin in the group of patients otherwise diagnosed as having chronic tension-type headache. [source] Effect of inhibition of prostaglandin E2 production on pancreatic infection in experimental acute pancreatitisHPB, Issue 5 2007ANDRE S. MATHEUS Abstract Objective. Acute pancreatitis is one the important causes of systemic inflammatory response syndrome (SIRS). SIRS results in gut barrier dysfunction that allows bacterial translocation and pancreatic infection to occur. Indomethacin has been used to reduce inflammatory process and bacterial translocation in experimental models. The purpose of this study was to determine the effect of inhibition of prostaglandin E2 (PGE2) production on pancreatic infection. Materials and methods. An experimental model of severe acute pancreatitis (AP) was utilized. The animals were divided into three groups: sham (surgical procedure without AP induction); pancreatitis (AP induction); and indomethacin (AP induction plus administration of 3 mg/kg of indomethacin). Serum levels of interleukin (IL)-6 and IL-10, PGE2, and tumor necrosis factor (TNF)-, were measured 2 h after the induction of AP. We analyzed the occurrence of pancreatic infection with bacterial cultures performed 24 h after the induction of AP. The occurrence of pancreatic infection (considered positive when the CFU/g was >105), pancreatic histologic analysis, and mortality rate were studied. Results. In spite of the reduction of IL-6, IL-10, and PGE2 levels in the indomethacin group, TNF-, level, bacterial translocation, and pancreatic infection were not influenced by administration of indomethacin. The inhibition of PGE2 production did not reduce pancreatic infection, histologic score, or mortality rate. Conclusion. The inhibition of PGE2 production was not able to reduce the occurrence of pancreatic infection and does not have any beneficial effect in this experimental model. Further investigations will be necessary to discover a specific inhibitor that would make it possible to develop an anti-inflammatory therapy. [source] Successful treatment of eosinophilic pustular folliculitis with topical tacrolimusINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 8 2004Masakazu Kawaguchi We present two cases of Eosinophilic pustular folliclulitis (EPF) who were successfully treated with topical tacrolimus. Indomethacin is the most frequently used agent for the treatment of EPF, however, tacrolimus ointment may become the treatment of choice for patients with EPF. [source] Impaired EDHF-Mediated Relaxation in Porcine Pulmonary Micro-Arteries by Cold Storage with University of Wisconsin and Euro-Collins SolutionsJOURNAL OF CARDIAC SURGERY, Issue 6 2002Wei Zou Background: Vascular endothelium plays a key role in regulation of vascular tone. Hyperkalemia has been demonstrated to impair the EDHF-mediated endothelial function in coronary circulation. University of Wisconsin (UW) and Eruo-collins (EC) solutions are used for organ preservation in transplantation surgery. The potassium concentration in UW or EC solutions is as high as 125 mmol/L or 115 mmol/L, respectively. This study was designed to examine whether hyperkalemia or storage with UW and EC solutions affects the relaxation mediated by EDHF in the porcine pulmonary micro-arteries. Methods: Porcine pulmonary micro-artery rings (diameter 200,450 ,m) were studied in myograph (n = 8 in each group). After incubation with hyperkalemia (K+ 125 mmol/L, at 37° C), UW or EC solutions (at 4° C for 4 hours), EDHF-mediated relaxation induced by bradykinin (BK, ,10 to ,6.5 log M) in the presence of inhibitors for cyclooxygenase (Indomethacin, 7 ,M), nitric oxide synthase (NG -nitro- L -arginine, 300 ,M), and oxyhemoglobin (20 ,M) was compared with control (Krebs' solution) in precontraction with U46619 (,7.5 log M). Results: The EDHF-mediated relaxation to BK was 69.6 ± 6.3% compared with 97.1 ± 1.7% (p= 0.003) in control (no inhibitors). After incubation with hyperkalemia, the relaxation significantly decreased (38.6 ± 3.0% vs. 59.1 ± 7.4%, p= 0.03). Storage with UW or EC solutions also significantly decreased the relaxation (49.3 ± 7.3% vs. 65.2 ± 3.5%, p= 0.04 and 51.9 ± 8.4% vs. 60.3 ± 6.1%, p= 0.02, respectively). Conclusions: In porcine pulmonary micro-arteries, exposure to hyperkalemia or storage with UW or EC solutions at 4°C for 4 hours impairs the EDHF-mediated endothelial function. The clinical significance of this effect should be further studied. [source] Experimental study of the safety of the selective COX-2 inhibitor, celecoxib, for gastric mucosaJOURNAL OF DIGESTIVE DISEASES, Issue 2 2003Jun Ting LI OBJECTIVE: To compare the gastric mucosal damage induced by a COX-2 inhibitor, celecoxib, and a conventional NSAID, indomethacin. METHODS: A rat model of NSAID-induced gastric mucosal damage was prepared for indomethacin and celecoxib separately (n = 8). After gastric damage was induced by 100% ethanol, celecoxib was administered by gastric gavage (n = 8). Gastric mucosal concentrations of 6-keto-PGF1, and TXB2 and the lesion index (LI) were measured. Morphological changes of the gastric mucosa were assessed under light and scanning electron microscopy. RESULTS: Indomethacin caused marked gastric damage (LI: 13.38 ± 2.06) and significant reduction of the concentrations of 6-keto-PGF1, and TXB2 (P < 0.01), Celecoxib did not produce necrotic injuries on healthy gastric mucosa (LI: 0), but the mucosal injuries previously induced by ethanol worsened after its administration (LI: 37.19 ± 3.34 vs 19.90 ± 2.28, P < 0.01). CONCLUSIONS: Inhibition of COX-1 is the major mechanism of NSAIDs in producing gastric mucosal damage. As a selective COX-2 inhibitor, celecoxib does not produce toxic injuries of the healthy gastric mucosa, and is thus safer than conventional NSAID. However, when administered in the presence of an altered gastric mucosa, gastric injuries were worsened. [source] The 15-lipoxygenase-1 expression may enhance the sensitivity to non-steroidal anti-inflammatory drug-induced apoptosis in colorectal cancers from patients who are treated with the compoundsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2007Masahiro Yoshinaga Abstract Background and Aim:, Non-steroidal anti-inflammatory drugs (NSAIDs) can prevent colorectal cancer (CRC), but their effect is limited. Recent studies have shown the involvement of 15-lipoxygenase-1 (15-LOX-1) in NSAID-induced apoptosis in colorectal carcinoma cells. We evaluate whether 15-LOX-1 expression influences the sensitivity of NSAID-induced apoptosis in CRCs. Methods:, In 22 CRC surgical samples from NSAID users who had been constant for more than 5 years and 28 CRC surgical samples from NSAID non-users, the expressions of 15-LOX-1, cyclooxygenase-2 (COX-2), beta-catenin, and p53 were analyzed using immunohistochemistry. TUNEL assay was also performed for samples. The effects of the transient transfection of 15-LOX-1 cDNA on indomethacin-induced apoptosis were certified in HCT-116 cells. The effects of adding 13-S-hydroxyoctadecadinoic acid (13-S-HODE) on indomethacin-induced apoptosis were also examined in HCT-116 cells. The levels of apoptosis were determined by the analysis of the floating-cells ratio and DNA gel electrophoresis. Results:, The expression of 15-LOX-1 on CRCs from NSAID users was significantly decreased compared with those from NSAID non-users; however, the expressions of other molecules were not significantly different between two groups. The levels of TUNEL scoring in samples from NSAID users were similar to those from NSAID non-users. Indomethacin (100 ,M) induced less apoptosis in mocked cells, whereas the same concentrations of indomethacin enhanced the level of apoptosis in 15-LOX-1-transfected cells. 13-S-HODE also increased the level of indomethacin-induced apoptosis in cells. Conclusion:, Results suggest that 15-LOX-1 expression may be one of the mechanisms which enhance the sensitivity to NSAID-induced apoptosis in CRCs from patients who are treated with the compounds. [source] Protective effect of rebamipide on indomethacin-induced intestinal damage in ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2001Hiroyuki Mizoguchi Abstract Background and Aim: We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats. Methods: The animals were administered indomethacin (10 mg/kg, s.c.), and they were killed 24 h later. Rebamipide (30,300 mg/kg) was administered p.o. twice, 30 min before, and 6 h after indomethacin. Results: Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied by an increase in enterobacterial translocation, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) activities, as well as thiobarbituric acid (TBA) reactants, and these changes were significantly prevented by the supplementation with 16,16-dimethyl prostaglandin E2 (dmPGE2; 10 ,g/kg, i.v.) or the pretreatment of animals with the antibiotic ampicillin. Treatment of the animals with rebamipide dose-dependently prevented the development of intestinal lesions, and this effect was mimicked by i.v. administration of superoxide dismutase (SOD: 3000 U/kg) + catalase (CAT: 5000 U/kg). The protection by rebamipide was accompanied by a significant suppression of the increase in both MPO and iNOS activities, and a complete inhibition of the increase in TBA reactants, while SOD + CAT significantly inhibited the increase of MPO activity and TBA reactants, but not iNOS activity. The bacterial translocation following indomethacin was also significantly decreased by either rebamipide or SOD + CAT. Conclusion: These results confirmed the importance of enterobacteria and iNOS/NO in the pathogenesis of indomethacin-induced small intestinal lesions, and suggested that rebamipide prevents the development of these lesions, probably by its radical scavenging action. [source] Cyclo-oxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2000Wei-Hao Sun Abstract Background and Aims: The present study examined the effects of NS-398, a specific cyclo-oxygenase-2 inhibitor, on gastric mucosal cell kinetics and gastric wound healing following acid-induced injury. Methods: Male Sprague-Dawley rats were fasted for 24 h and then 0.6 mol/L hydrochloric acid (HCl; 1 mL) was administered into the stomach; NS-398 or indomethacin was administered to the animals 10 min after the acid. Levels of constitutive cyclo-oxygenase (COX-1) and mitogen-inducible cyclo-oxygenase (COX-2) in the gastric mucosa were analysed using western blotting and immunohistochemical staining. The grade of the lesion was assessed using planimetry and histological examination, including immunohistochemistry for proliferating cell nuclear antigen (PCNA). Results: Although there was strong expression of COX-1, there was minimal expression of COX-2 in the gastric mucosa. Expression of COX-2 was enhanced mainly in surface epithelial cells and neck cells following HCl administration. Gastric mucosal ulcers and erosions healed within 48 h, during which time the proliferative zone expanded in the control animals. Indomethacin and NS-398 suppressed the expansion of the proliferative zone and delayed the healing of the gastric injury. Conclusion: The present study demonstrated that cyclo-oxygenase-2 inhibitors delay gastric wound healing by suppressing expansion of the mucosal proliferative zone. These results provide evidence that cyclo-oxygenase-2 has an important role in gastric mucosal regeneration. [source] Effects of indomethacin on cerebral blood flow at rest and during hypercapnia: An arterial spin tagging study in humans,JOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 6 2002Keith S. St. Lawrence PhD Abstract Purpose To investigate using an arterial spin tagging (AST) approach the effect of indomethacin on the cerebral blood flow (CBF) response to hypercapnia. Materials and Methods Subjects inhaled a gas mixture containing 6% CO2 for two 5-minute periods, which were separated by a 10-minute interval, in which subjects inhaled room air. In six subjects, indomethacin (i.v., 0.2 mg/kg) was infused in the normocapnic interval between the two hypercapnic periods. Results Indomethacin reduced normocapnic gray matter CBF by 36 ± 5% and reduced the CBF increase during hypercapnia from 43 ± 9% to 16 ± 5% in gray matter (P < 0.001) and from 48 ± 11% to 35 ± 9% in white matter (P < 0.025). Conclusion The results demonstrate that an AST approach can measure the effects of indomethacin on global CBF increases during hypercapnia and suggest that an AST approach could be used to investigate pharmacological effects on focal CBF increases during functional activation. J. Magn. Reson. Imaging 2002;15:628,635. Published 2002 Wiley-Liss, Inc. [source] Improved physical stability of amorphous state through acid base interactionsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2009Chitra Telang Abstract To investigate role of specific interactions in aiding formation and stabilization of amorphous state in ternary and binary dispersions of a weakly acidic drug. Indomethacin (IMC), meglumine (MU), and polyvinyl pyrollidone (PVP) were the model drug, base, and polymer, respectively. Dispersions were prepared using solvent evaporation. Physical mixtures were cryogenically coground. XRPD, PLM, DSC, TGA, and FTIR were used for characterization. MU has a high crystallization tendency and is characterized by a low Tg (17°C). IMC crystallization was inhibited in ternary dispersion with MU compared to IMC/PVP alone. An amorphous state formed readily even in coground mixtures. Spectroscopic data are indicative of an IMC,MU amorphous salt and supports solid-state proton transfer. IMC,MU salt displays a low Tg,,,50°C, but is more physically stable than IMC, which in molecular mixtures with MU, resisted crystallization even when present in stoichiometric excess of base. This is likely due to a disrupted local structure of amorphous IMC due to specific interactions. IMC showed improved physical stability on incorporating MU in polymer, in spite of low Tg of the base indicating that chemical interactions play a dominant role in physical stabilization. Salt formation could be induced thermally and mechanically. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2149,2159, 2009 [source] Ultrasound-compacted indomethacin/polyvinylpyrrolidone systems: Effect of compaction process on particle morphology and dissolution behaviorJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2002Adamo Fini Abstract Indomethacin (IMC)/polyvinylpyrrolidone systems were prepared under different technological conditions, using co-evaporation, kneading, traditional, and ultrasound (US) compaction. The materials thus obtained were milled and sieved and the powders were analyzed by using scanning electron microscopy to evaluate the morphology of the final particles and the fractal dimension of the particle contour. In the case of US-treated particles, scanning electron micrographs suggest that IMC could have partially covered the excipient granule surface, which appears lustrous and smooth, whereas after co-evaporation, the particles display a stratified structure. The external color of the granules, the hot stage microscopy examination, and the absence of the melting peak of the drug in thermograms supports the idea that IMC converts into an amorphous form under US discharge. Each technological treatment performed on the binary mixtures increases the dissolution rate of the drug, with respect to the pure drug and the physical mixture, but to a lesser extent than US compaction. US compaction and co-evaporation produce comparable results in improving the release of the drug. Polyvinylpyrrolidone offers better results than ,-cyclodextrin in promoting the dissolution of IMC, when both systems are compacted under US. © 2002 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:1880,1890, 2002 [source] Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymersJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2001Angus Forster Indomethacin, lacidipine, nifedipine and tolbutamide are poorly soluble in water and may show dissolution-related low oral bioavailability. This study describes the formulation and characterization of these drugs as glass solutions with the amorphous polymers polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-co-vinyl acetate by melt extrusion. The extrudates were compared with physical mixtures of drug and polymer. X-ray powder diffraction, thermal analysis, infrared spectroscopy, scanning electron microscopy, HPLC, moisture analysis and dissolution were used to examine the physicochemical properties and chemical stability of the glass solutions prepared by melt extrusion at a 1:1 drug/polymer ratio. Depending on the temperature used, melt extrusion produced amorphous glass solutions, with markedly improved dissolution rates compared with crystalline drug. A significant physicochemical interaction between drug and polymer was found for all extrudates. This interaction was caused by hydrogen bonding (H-bonding) between the carbonyl group of the pyrrole ring of the polymer and a H-donor group of the drug. Indomethacin also showed evidence of H-bonding when physical mixtures of amorphous drug and PVP were prepared. After storage of the extrudates for 4,8 weeks at 25°C/75% relative humidity (RH) only indomethacin/polymer (1:1) extrudate remained totally amorphous. All extrudates remained amorphous when stored at 25°C/< 10% RH. Differences in the physical stability of drug/polymer extrudates may be due to differences in H-bonding between the components. [source] The effects of smoking and indomethacin on small intestinal permeabilityALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2000Suenaert Background: Smoking modulates inflammatory bowel disease, protecting from ulcerative colitis on the one hand and worsening the course of Crohn's disease on the other. This influence might occur through changes in intestinal permeability, because permeability is increased in most patients with Crohn's disease. Aim: To study the influence of smoking on small intestinal permeability and its increase induced by indomethacin. Methods: 50 smokers and 50 nonsmokers underwent a 51Cr-EDTA basal permeability test and the same test after challenge with indomethacin 125 mg p.o. Results: Small intestinal permeability was the same in smokers (median 1.22%; IQR 1.00,1.58) and nonsmokers (1.24%; 0.94,1.66). Basal small intestinal permeability was lower in females (1.09%; 0.87,1.33) than in males (1.48%; 1.18,1.88). Indomethacin challenge increased permeability by 110% (71,141) in smokers, vs. 156% (78,220) in the nonsmokers (P=0.04). Conclusion: Smoking reduces the effect of NSAID on small intestinal permeability. It is therefore unlikely that the adverse effect of smoking on Crohn's disease is related to its influence on intestinal permeability. [source] Leishmania donovani -induced macrophages cyclooxygenase-2 and prostaglandin E2 synthesisPARASITE IMMUNOLOGY, Issue 4 2001Claudine Matte Prostaglandin E2 (PGE2) secretion during Leishmania infection has been reported. However, the signalling mechanisms mediating this response are not well understood. Since cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2) are involved in PGE2 synthesis in response to various stimuli, the implication of these enzymes was evaluated in Leishmania -infected phorbol myristate acetate-differentiated U937 human monocytic cell line. Time-course experiments showed that PGE2 synthesis increased significantly in parallel with COX-2 expression when cells were incubated in the presence of Leishmania donovani promastigotes or lipopolysaccharides (LPS). Increase in cPLA2 mRNA expression was only detected when cells were stimulated with LPS. Indomethacin, genistein, and H7, which are antagonists of COX-2, protein tyrosine kinase (PTK) and protein kinase C (PKC), respectively, inhibited PGE2 production induced by L. donovani and LPS. However, only H7 inhibited COX-2 mRNA synthesis, and there was a significant correlation between PGE2 inhibition and reduced COX-2 expression. Collectively, our results indicate that infection of U937 by L. donovani leads to the generation of PGE2 in part through a PKC-dependent signalling pathway involving COX-2 expression. They further reveal that PTK-dependent events are necessary for Leishmania -induced PGE2 generation, but not for COX-2 expression. A better understanding of the mechanisms by which Leishmania can induce PGE2 production could provide insight into the pathophysiology of leishmaniasis and may help to improve therapeutic approaches. [source] UV Erythema Reducing Capacity of Mizolastine Compared to Acetyl-salicylic Acid or both Combined in Comparison to Indomethacin,,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2001Jens-Uwe Grundmann ABSTRACT UV light exerts hazardous effects such as induction of skin cancer and premature skin aging. In this study we evaluated an assumptive anti-inflammatory effect of the nonsedative histamine H1-receptor antagonist, mizolastine, on UV-induced acute sunburn reaction. Therefore, a clinical, randomized, double-blind, four-arm, crossover study was conducted in healthy young female volunteers (skin type II) comparing the UV sensitivity under mizolastine, acetyl-salicylic acid (ASA), indomethacin or a mizolastine/ASA combination. Moreover, HaCaT keratinocytes were incubated with mizolastine under various UV treatment modalities in vitro to study its effect on the release of inflammatory cytokines, i.e. interleukin (IL)-1,, IL-6 and tumor necrosis factor , (TNF-,). All three drugs were effective in suppressing the UVB-, UVA- and combined UVA/UVB-erythema. However, the strongest effects were observed using the combined treatment with both 250 mg ASA and 10 mg mizolastine. An inhibitory effect in vitro of 10 nM mizolastine upon UV-induced cytokine release from HaCaT keratinocytes was observed for IL-1, at 24 h after 10 J/cm2 UVA1, for IL-6 at 48 h after 10 J/cm2 UVA1 and 30 mJ/cm2 UVB, and also for TNF-, at 4 h after 10 J/cm2 UVA, 10 J/cm2 UVA1 and 30 mJ/cm2 UVB, respectively. The combination of mizolastine and ASA can be strongly recommended as a protective measure against UV erythema development with a lower unwanted side effect profile than that of the hitherto treatment modality, i.e. indomethacin. [source] Rapid induction of peroxisome proliferator,activated receptor , expression in human monocytes by monosodium urate monohydrate crystalsARTHRITIS & RHEUMATISM, Issue 1 2003Tohru Akahoshi Objective Peroxisome proliferator,activated receptor , (PPAR,) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR, in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR, expression by monosodium urate monohydrate (MSU) crystal,stimulated monocytes, and we studied the effects of PPAR, ligands on crystal-induced acute inflammation. Methods PPAR, expression by MSU crystal,stimulated human peripheral blood mononuclear cells was determined by reverse transcription,polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR, ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated. Results MSU crystals rapidly and selectively induced PPAR, expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR, was functional, since a PPAR, ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR,, 15-deoxy-,12,14 -prostaglandin J2 (15deoxy-PGJ2), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ2 significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal,induced acute inflammation. Conclusion Rapid induction of PPAR, expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout. [source] Anti-Inflammatory and Analgesic Activities of the Aqueous Extract of Acacia karroo Stem Bark in Experimental AnimalsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2008Adeolu A. Adedapo The extract at 100 and 200 mg/kg reduced significantly the formation of oedema induced by carrageenan and histamine. In the acetic acid-induced writhing model, the extract showed a good analgesic effect characterized by a significant reduction in the number of writhes with two doses (100 and 200 mg/kg) used when compared to the untreated control group. In the tail immersion test, the extract at the doses used (100 and 200 mg/kg) increased reaction time to pain after 30 min. of oral administration of the extract. Indomethacin at 10 mg/kg served as reference drug in all these tests. The results gave a scientific basis to the traditional uses of Acacia karroo mainly for wound poultices, eye treatments and cold remedies. [source] Adverse effects of tocolytic therapyBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 2005Steve Caritis The rationale for using tocolytics in preterm labour is to enable transfer of the mother to a tertiary centre and to prolong pregnancy sufficiently so that glucocorticoids can be administered to the mother. There is little question that these short term objectives can be achieved with contemporary tocolytics. Whether tocolytics can maintain pregnancy for sufficient periods to enable in utero maturation to occur remains an unresolved question. When a decision is made to use tocolytics, the clinician is faced with a multitude of choices with side effects, efficacy and ease of administration generally being the most important considerations. Placebo-controlled studies suggest that the ,-agonists, prostaglandin inhibitors and atosiban are effective in prolonging pregnancy for 24,48 hours. Of these three agents, atosiban has the best safety profile. There are no placebo-controlled studies with calcium channel blockers or nitric oxide donors. However, because of their ease of use and efficacy compared with the ,-agonists, calcium channel blockers are widely used. Calcium channel blockers appear to have a better safety profile than the ,-agonists, but there are still significant cardiovascular side effects associated with their use. Indomethacin, although proven to be efficacious, has a safety profile that limits its utility for other than short courses. Magnesium sulphate is the most commonly used tocolytic in the United States, despite a lack of evidence for its efficacy. Although magnesium sulphate appears to have a good safety profile, serious side effects have been reported with its use. The choice of tocolytics is commonly based on personal preference. Whichever tocolytic is chosen, the fundamental parturitional process is not reversed by contemporary treatment, rather a reduction in uterine response to a stimulant; thus, the expectations of tocolytic treatment need to be reconsidered. [source] Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacinBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2007A E Chávez-Piña Background and purpose: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. Experimental approach: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7,83.8 ,mol kg,1) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E2 and leukotriene (LT) B4 levels in exudates, and whole blood thromboxane (TX) B2 synthesis were measured. Key results: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE2 and TXB2 synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB4 production in the airpouch. Conclusions and implications: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB4 production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin. British Journal of Pharmacology (2007) 152, 930,938; doi:10.1038/sj.bjp.0707451; published online 17 September 2007 [source] AT2 receptor-dependent vasodilation is mediated by activation of vascular kinin generation under flow conditionsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002Jun Katada Physiological roles of angiotensin II type 2 receptor (AT2) are not well defined. This study was designed to investigate the mechanisms of AT2 -dependent vascular relaxation by studying vasodilation in pressurized and perfused rat mesenteric arterial segments. Perfusion of angiotensin II in the presence of AT1 antagonist elicited vascular relaxation, which was completely dependent on AT2 receptors on endothelium. FR173657 (>1 ,M), a bradykinin (BK) B2 -specific antagonist, significantly suppressed AT2 -dependent vasodilation (maximum inhibition: 68.5% at 10 ,M). Kininogen-deficient Brown Norway Katholiek rats showed a significant reduction in AT2 -mediated vasodilatory response compared with normal wild-type Brown Norway rats. Indomethacin (>1 ,M), aprotinin (10 ,M) and soybean trypsin inhibitor (10 ,M) also reduced AT2 -dependent vasodilation. Our results demonstrated that stimulation of AT2 receptors caused a significant vasodilation through local production of BK in resistant arteries of rat mesentery in a flow-dependent manner. Such vasodilation counterbalances AT1 -dependent vasoconstriction to regulate the vascular tone. British Journal of Pharmacology (2002) 136, 484,491; doi:10.1038/sj.bjp.0704731 [source] Retinal and optic nerve oxygenation and carbonic anhydrase inhibitionACTA OPHTHALMOLOGICA, Issue 2009M LA COUR Purpose To study the effects of carbonic anhydrase inhibition on porcine retinal and optic nerve oxygenation under physiological conditions and in experimental models of ischemia. Methods Polarographic oxygen electrodes were used to measure the oxygen tension in the vitreous 500 microns in front of the optic nerve and retina. Retinal ischemia was produced by diathermia of the superior arcade vein, producing a branch retinal vein occlusion, BRVO. Optic nerve ischemia was produced by intravenous administration of 100 mg Indomethacin intravenously. Results One week after induction of BRVO, the oxygen tension over BRVO affected retina was significantly decreased by 29%. Administration of the carbonic anhydrase inhibitor dorzolamide (500 mg) caused a significant increase in the oxygen tension over BRVO affected retina, and in effect restored this tension to normal values (n=5). Intravenous administration of 300 mg Indomethacin caused a decrease of optic nerve oxygen tension by 41%. Subsequent administration of 500 mg dorzolamide increased the optic nerve oxygen tension, albeit not to normal levels (n=6). Conclusion Carbonic anhydrase inhibition increases the oxygen tension in the retina and optic nerve. In BRVO affected retina, carbonic anhydrase inhibition restores oxygen tension to normal levels. [source] New Procedure for Obtaining Indomethacin (VII)CHEMINFORM, Issue 9 2006I. V. Magedov 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, please click on HTML or PDF. [source] Effects of prostaglandins on form deprivation myopia in the chickACTA OPHTHALMOLOGICA, Issue 5 2000Niyun Jin ABSTRACT. Purpose: To investigate the possible role of endogenous prostaglandins in the development of form deprivation myopia, as well as the effects of exogenous prostaglandins using atropine as a positive control. Methods: Monocular form deprivation was accomplished by mounting a translucent occluder on one eye of 2,3 day old chicks for 1,4 weeks. Ocular occlusion for 1,2 weeks was used for pharmacological blocking experiments. The axial length of the eye was measured by ultrasonography. Results: Indomethacin, administered intramuscularly, subconjunctivally or intra-vitreally had no significant effect on myopia development. Exogenous PGE2, PGF2, and latanoprost acid administered subconjunctivally, or topically as isopropyl ester eyedrops had no statistically significant effect on the myopia development. However, PGF2, significantly (p<0.01) attenuated the development of myopia after intravitreal injection. The other two prostaglandins had no statistically significant effect. Conclusions: Endogenous prostaglandins are unlikely to play a significant role in the development of form deprivation myopia in the chick. However, PGF2, suprisingly seems to retard the development of form deprivation myopia, but only when administered intravitreally. Whether the mechanism of the myopia retardation is direct or indirect remains unknown. [source] Does indomethacin for closure of patent ductus arteriosus affect cerebral function?ACTA PAEDIATRICA, Issue 10 2010A Flisberg Objective:, To study whether indomethacin used in conventional dose for closure of patent ductus arteriosus affects cerebral function measured by Electroencephalograms (EEG) evaluated by quantitative measures. Study design:, Seven premature neonates with haemodynamically significant persistent ductus arteriosus were recruited. EEG were recorded before, during and after an intravenous infusion of 0.2 mg/kg indomethacin over 10 min. The EEG was analysed by two methods with different degrees of complexity for the amount of low-activity periods (LAP, "suppressions") as an indicator of affection of cerebral function. Results:, Neither of the two methods identified any change in the amount of LAPs in the EEG as compared to before the indomethacin infusion. Conclusion:, Indomethacin in conventional dose for closure of patent ductus arteriosus does not affect cerebral function as evaluated by quantitative EEG. [source] Spontaneous localized intestinal perforation and intestinal dilatation in very-low-birthweight infantsACTA PAEDIATRICA, Issue 11 2006Tsugumichi Koshinaga Abstract Aim: To elucidate how spontaneous localized intestinal perforation (SLIP) is related to intestinal morphological features such as dilatation in very-low-birthweight (VLBW) infants. Methods: The medical records of 13 VLBW infants (<1500 g) undergoing laparotomy between 1983 and 2003 for presumed SLIP were retrospectively reviewed. Clinical findings including maternal, prenatal and perinatal factors were analysed, and the clinical and surgical findings upon laparotomy were compared. Results: Postnatal pathological conditions included patent ductus arteriosus (n= 7), sepsis (n= 2), respiratory distress syndrome (n= 7), intraventricular haemorrhage (n= 2), an indwelling catheter via the umbilical vein (n= 1) and pneumonia (n= 1). Indomethacin was used in seven neonates with patent ductus arteriosus, and dexamethasone preventive therapy was employed in one neonate for bronchopulmonary dysplasia. Operative findings revealed a localized small punched-out perforation in the ileum. Five patients had intestinal dilatation: two with a perforation in the middle of the dilated intestine, and three with a perforation proximal to the region of dilatation. The muscularis propria was absent in the dilated intestine of four patients. Conclusion: This study found no significant relationship between perforation and dilatation of the intestine. Perforation may occur in any portion of the ischaemic intestine when circulatory failure becomes severe, and is not necessarily restricted to the dilated intestine. We believe that SLIP and intestinal dilatation may occur on the same basis in low-birthweight infants; however, the disease process may be aetiologically different. [source] | ||||||||||||||||||||||||||||||||||||||||