Tesi: "Indomethacin"

1

Hollingsworth, Simon John. "Protentiation of methotrexate cytotoxicity by indomethacin". Thesis, King's College London (University of London), 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281631.

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2

Martin, Steven William. "Study of indomethacin-induced gastric mucosal damage". Thesis, University of Southampton, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316437.

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3

Brodowicz, Gary Ray. "Exercise training, indomethacin, and isoproterenol-induced myocardial necrosis /". The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487265555440899.

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4

Priebe, Milissa Ann. "Clinical implications of indomethacin superfused over the capillaries of frogs with activated white blood cells". Thesis, Montana State University, 2010. http://etd.lib.montana.edu/etd/2010/priebe/PriebeM0510.pdf.

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Treatment for inflammation is controversial. The purpose of this study was to investigate the effect of indomethacin on capillary permeability in animals with signs of systemic inflammation. We hypothesized that the permeability of an individual capillary would be lower after a shear stress challenge in the presence of indomethacin when evidence of systemic infection was present in the animal. Frogs (n=13) were pithed and the mesentery was exposed, hydraulic conductivity (L p) was assessed at 30 cm Hâ‚‚O using the modified Landis technique after an abrupt change in shear stress. Two capillaries from each frog were used; one was a control and one with indomethacin superfused over the tissue. The frogs showed a systemic infection (nitro blue tetrazolium activation) but individual capillaries had no evidence of rolling or sticking white cells. There was a significant decrease in L p (P=0.002) when comparing the control and treatment vessels. The results of the analysis indicate capillary L p assessed in mesentery of infected frogs, decreased when exposed to shear stress and indomethacin. The data imply that gaps between endothelial cells may get smaller when indomethacin is introduced into the system decreasing the flow of fluids out of the capillary.

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5

Chokshi, Rina. "Evaluation of hot-melt extrusion technology to improve dissolution rates of poorly water soluble drugs /". View online ; access limited to URI, 2004. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3145415.

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6

Kelly, David Andrew. "Changes in jejunal villous blood flow in response to indomethacin". Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286454.

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7

Tan, Aiguo. "Thioredoxin-1 attenuates indomethacin-induced gastric mucosal injury in mice". Kyoto University, 2008. http://hdl.handle.net/2433/135862.

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8

Warwick, Barry School of Chemical Engineering &amp Industrial Chemistry UNSW. "Synthesis, purification and micronisation of copper indomethacin using dense gas technology". Awarded by:University of New South Wales. School of Chemical Engineering and Industrial Chemistry, 2001. http://handle.unsw.edu.au/1959.4/17876.

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The primary aim of this work was to provide an alternative method of synthesis of the non-steroidal anti-inflammatory drug copper indomethacin (Cu-Indo) and to produce alternative forms of the drug to increase its marketability. Dense gases as anti-solvents were used to achieve these aims. The study involved the synthesis, purification, micronisation and co-precipitation of Cu-Indo with polyvinylpyrrolidone (PVP) using dense carbon dioxide as an anti-solvent. Initially the volumetric and solubility behaviours of the solvent???anti-solvent systems were investigated to determine the optimum processing conditions. The solubility of Cu-Indo in an expanded solution was found to be a complex function of the solvent and other solutes. Copper indomethacin was successfully synthesised and purified in a single vessel using dense carbon dioxide as an anti-solvent. Drug yields of 98 % and purities near 100 % were achieved at optimum conditions with the advantages of less residual solvent in the drug, less solvent waste, reduced processing time and increased yields over the conventional synthesis process. Copper indomethacin was produced in a variety of morphologies and particle sizes using dense carbon dioxide as an anti-solvent. An investigation of the effect of process parameters on the particle characteristics showed that solute concentration was the dominant variable. Spherical particles with diameters less than 8 mm were obtained at optimum conditions. The immediate benefit of micronising Cu-Indo was demonstrated with an eight fold increase in dissolution rate when compared to the conventionally produced drug. Polyvinylpyrrolidone was successfully co-precipitated with Cu-Indo using dense carbon dioxide as an anti-solvent. The PVP???Cu-Indo co-precipitates were found to increase the solubility of the drug in ethanol with a 36 fold solubility enhancement at optimum conditions. The use of dense carbon dioxide as anti-solvent in this work demonstrates the potential of the GAS and ASES processes in the pharmaceutical industry. Copper indomethacin was synthesised, purified and micronised in a single vessel at a substantial saving in terms of time and solvent usage. The micronisation of Cu-Indo and the formation of the PVP???Cu-Indo co-precipitate provided alternative forms of the drug substantially increasing its marketability.

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9

Roberts, A. A. "The polymerisation state of sodium hyaluronate and the in vivo and in vitro influence of indomethacin". Thesis, University of Salford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381738.

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10

Battu, Ganga Rao. "Anti-inflammatory and phytochemical studies of a Kenyan traditional medicinal plant, Commiphora kua". Thesis, University of Strathclyde, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366837.

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11

Cattani, Vitória Berg. "Avaliação farmacocinética do éster etílico de indometacina nanoencapsulado e da indometacina formada in vivo". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2007. http://hdl.handle.net/10183/10874.

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Objetivos: Avaliar a farmacocinética do éster etílico de indometacina (IndOEt) em ratos Wistar, após sua administração oral (p.o) e intravenosa (i.v.) nas formas livre ou nanoencapsulada, e monitorar a formação de indometacina (IndOH) in vivo. Metodologia: Os protocolos experimentais foram aprovados pelo Comitê de Ética em Pesquisa da UFRGS (2005478). Nanocápsulas (NC) contendo IndOEt (IndOEt- NC) foram administradas p.o. (10 mg/kg) e i.v. bolus (5 mg/kg) a ratos machos Wistar (n = 5 a 7/grupo) e as concentrações plasmáticas de IndOEt e IndOH resultantes foram determinadas por CLAE com detecção por UV, empregando-se metodologia validada. Os grupos controle foram tratados com suspensão aquosa de IndOEt (10 mg/kg), com ou sem polissorbato 80, ou com IndOH pelas vias i.v. ou p.o. (10 mg/kg) (n = 7 a 11/grupo). Os perfis plasmáticos individuais foram avaliados por abordagem não-compartimental e compartimental utilizando os softwares Excel® 2003 e Scientist® 2.01, respectivamente, para a determinação dos parâmetros farmacocinéticos, que foram comparados estatisticamente utilizando-se teste “t” de Student ou ANOVA (α = 0,05). A avaliação do local de absorção p.o. de IndOEt-NC foi realizada pela quantificação de IndOEt e IndOH no plasma periférico e da veia porta, homogeneizado de fígado e de parede, bem como conteúdo, de porções do intestino delgado (n= 4/tempo) após a administração oral da formulação. Resultados e Discussão: Após a administração de IndOEt-NC por ambas as vias, apenas a IndOH foi detectada, indicando uma rápida hidrólise do éster. Em todos os casos, o IndOEt não alterou os parâmetros farmacocinéticos da IndOH, exceto a biodisponibilidade. Os perfis plasmáticos de IndOH i.v. foram descritos pelo modelo de 2 compartimentos, e os orais, pelo de 1 compartimento com absorção de primeira ordem. A avaliação da absorção oral de IndOEt-NC evidenciou que o IndOEt é, provavelmente, liberado e hidrolisado ainda na luz do trato gastrintestinal, sendo a IndOH formada in vivo e absorvida. Conclusões: O IndOEt nanoencapsulado ou não, quando administrado pelas vias oral e i.v., é rapidamente convertido a IndOH. A IndOH é, portanto, responsável pela atividade antiedematogênica relatada para o IndOEt-NC.
Objective: To evaluate the pharmacokinetics of either nanoencapsulated (NC) or free indomethacin ethyl ester (IndOEt) after intravenous (i.v.) and oral (p.o.) administration to Wistar rats and to determine the pharmacokinetics of indomethacin (IndOH) formation. Methodology: Animal experiments were approved by UFRGS Ethics in Research Committee (# 2005478). The pharmacokinetics was investigated in male Wistar rats after oral and i.v. administration of IndOEt-NC (10 mg/kg and 5 mg/kg, respectively) (n = 5-7/group) and IndOEt and IndOH plasma concentrations were determined by a validated HPLC with UV detection method. The control groups were treated with IndOEt aqueous suspension (10 mg/kg p.o.) or with IndOH aqueous suspension by the p.o. or i.v. routes (10 mg/kg) (n = 7 -11/group). Noncompartmental and compartmental approaches were used for individual profiles analysis using Excel® 2003 or Scientist® 2.01 softwares, respectively. The site of IndOEt-NC oral absorption was investigated in peripheral and portal vein plasma, hepatic tissue, intestine epithelia, and lumen content (n = 4/time). Results and Discussion: After IndOEt administration by both routes, only IndOH was detected in plasma, suggesting a fast hydrolysis of the ester. The IndOH parameters after administration of IndOEt and IndOH were similar, except for the bioavailability. The pharmacokinetic parameters of IndOH were modeled by two compartment open model after i.v. dosing and by one compartment with first order absorption after oral administration. After oral administration, IndOEt-NC was converted in IndOH in the gastrointestinal tract and then absorbed as such. Conclusions: After i.v. and oral administration, either IndOEt-NC or the free drug is quickly converted in IndOH. After oral administration, IndOEt-NC is released and hydrolyzed to IndOH following its absorption at the gastrointestinal tract. Therefore, the IndOH is responsible for antiendematogenic activity reported for IndOEt-NC.

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12

Alexis, Neil. "Effects of indomethacin pretreatment on short-term ozone exposure in asthmatics". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0028/NQ35098.pdf.

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13

Sridhar, Vishak. "Solubility Improvement by Solid Dispersion and Their Characterization: Indomethacin and Phenytoin". University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1364173208.

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14

Koomer, Ajoy Neau Steven H. Johnston Thomas P. "Development of a novel immunological assay to assess the pharmacological interactions between [beta]--lactams and their microbial targets (Part I) ; Crystallization kinetics of amorphous indomethacin and felodipine studied by model-fitting and model-free approaches (Part II)". Diss., UMK access, 2005.

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Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2005.
"A dissertation in pharmaceutical sciences and chemistry." Advisor: Steven H. Neau and Thomas P. Johnston. Typescript. Vita. Description based on contents viewed Mar. 12, 2007; title from "catalog record" of the print edition. Includes bibliographical references (leaves 97-108). Online version of the print edition.

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15

Lean, Jennifer Maree. "Mechanical stimulation of bone formation in the rat". Thesis, St George's, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263682.

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16

Slavin, Paul Anthony. "Crystallisation and polymorphism of the pharmaceutical indomethacin from simple and complex solvents". Thesis, University of Strathclyde, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273431.

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17

Panter, Katerine Ruth. "Cyclooxygenase expression and inhibition and tocolysis in preterm labour". Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391614.

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18

OsÃrio, CÃsar Braga de Holanda. "Atividade gastroprotetora do hidroxicitronelal em modelos de lesÃo gÃstrica aguda em camundongos". Universidade Federal do CearÃ, 2011. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=7985.

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FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico
O hidroxicitronelal Ã um composto amplamente usado como fragrÃncia em cosmÃticos. Este composto pode ser obtido a partir da semi-sÃntese do citronelal, um terpeno isolado do Ãleo essencial de citronela (Cymbopogon marginatus) ou de cidreira (Melissa officinalis), e tambÃm vÃrias outras plantas. O objetivo deste estudo Ã demonstrar a atividade gastroprotetora do hidroxicitronelal em modelos de lesÃo gÃstrica aguda. A manipulaÃÃo dos animais e os protocolos experimentais foram registrados no ComitÃ de Ãtica Institucional (CEPA) sob o nÃmero 052/2011. Foram utilizados camundongos swiss, que foram divididos em grupos de 8 (n = 8), e foram submetidos a um perÃodo de jejum de 16h, entÃo foram tratados com HC nas doses de 0.5; 2.5 e 12,5 mg/Kg ou NAC (750 mg/Kg). ApÃs 30 minutos os animais receberam 0,2 ml de etanol absoluto v.o. E apÃs 30 min, os animais foram sacrificados, os estÃmagos removidos e analisados para determinaÃÃo do Ãndice de lesÃo ou feito homogenatos para a dosagem de GSH (glutationa reduzida). A fim de se investigar o envolvimento das prostaglandinas, NO e dos canais de potÃssio, antes do tratamento com HC os animais receberam L-NAME(20mg/Kg) e/ou L-arginina(600mg/Kg), indometacina (10mg/Kg) e/ou misoprostol(0.03Âg/Kg), Glibenclamida(5mg/Kg) e/ou DiazÃxido(3mg/Kg). Para investigar a participaÃÃo dos receptores TRPV1 , os animais receberam capsaicina(0,3mg/Kg) e/ou capsazepina(5mg/Kg). No modelo de Ãlcera gÃstrica induzida por AINEs, os animais foram tratados com HC (12.5; 50 e 200 mg/Kg) ou Cimetidina (100 mg/Kg) 30 min antes do tratamento com indometacina (60 mg/Kg), e depois de 6h os animais foram sacrificados, os estÃmagos removidos e analisados sob o critÃrio de escores de lesÃo. No modelo de lesÃo por etanol, HC nas doses de 0,5; 2.5 e 12 mg/Kg foi capaz de inibir a lesÃo em 31; 53 e 69% respectivamente. HC tambÃm recuperou os nÃveis de GSH na mucosa em 31.19% quando comparados com o grupo lesÃo. L-NAME, Glibenclamida e Indometacina foram capazes de reverter o efeito de HC, demonstrando o envolvimento das Prostaglandinas, NO e dos canais de potÃssio, em seu mecanismo de aÃÃo. Capsazepina foi inefetiva em reverter o efeito de HC, assim excluindo o possÃvel envolvimento dos receptores TRPV1. No modelo de lesÃo por AINEs, HC nas doses testadas reduziu os escores de lesÃo em 28.8, 56.3, e 84.1% respectivamente. Podemos concluir que HC possui uma atividade farmacolÃgica gastroprotetora sobre a mucosa do estÃmago. Essa proteÃÃo parece ser mediada em parte pela modulaÃÃo de Prostaglandina/NO/ KATP, que Ã de papel fundamental na manutenÃÃo do fluxo sanguÃneo e na defesa da mucosa gÃstrica.
The hydroxycitronellal is a compound widely used as fragrance in cosmetics. This compound can be obtained by semi-synthesis from citronellal, a terpenoid isolated from essential oil of citronella (Cymbopogon marginatus) or Balm (Melissa officinalis), and also found in other plants. The aim of this study is to demonstrate the gastroprotective of hydroxycitronellal in gastric ulcer models. Animal handling and experimental protocols were registered on the Institutional Ethics Committee (CEPA) under number 052/2011. Swiss mice were used, were divided into groups of 8 (n = 8), and undergo fasting of 16h, then were treated with HC in doses 0.5; 2.5 and 12,5 mg/Kg or NAC (750 mg/Kg). After 30 min they received 0, 2 ml of absolute ethanol per oral and after 30 min, the animals were sacrificed and stomachs removed and analyzed the lesion index and dosage of GSH (reduced glutathione). In order to investigate the involvement of prostaglandins, NO and potassium channels, before treatment with HC animals received L-NAME (20mg/Kg) or L-arginine (600mg/Kg), indomethacin (10mg/Kg) or misoprostol (0.03Âg/Kg), Glibenclamide (5mg/Kg) or Diazoxide (3mg/Kg). To investigate the participation of TRPV1 receptors, animals received capsaicin (0,3mg/Kg) or capsazepina (5mg/Kg). In the model of injury by NSAIDâs, the animals were treated with HC (12.5; 50 and 200 mg/Kg) or Cimetidine (100 mg/Kg) 30 min before treatment with indomethacin (60 mg/Kg), and after 6h animals were sacrificed and stomachs removed and examined under-rated scores. In model of injury by ethanol, HC at the doses 0,5; 2.5 and 12 mg/Kg was able to prevent injury in 31.0; 52.9 and 69.3% respectively. HC also restored the GSH levels in mucosa in 31.19% compared to the ethanol group. LNAME, Glibenclamide and Indometacin were able to reverse the protective effect of HC, demonstrating the involvement of Prostaglandins, NO and potassium channels in its mechanism of action. Capsazepine was unable to reverse the effect of HC, thus excluding a possible involvement of TRPV1 receptors. In the model of injury by NSAIDâs, HC in tested doses reduces the injury scores in 28.8, 56.3, and 84.1%respectively. We can conclude that the HC has pharmacological activity with gastroprotetor effect in the gastric mucosa. This protection appears to be mediated in part by modulation of Prostaglandin/NO/KATP, which is of great importance in mucosal defense and in maintaining blood flow to the stomach.

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19

Ju, Changqing. "Reactive iminoquinone metabolites of indomethacin and carbamazepine, implications for drug-induced idiosyncratic reactions". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0007/NQ41183.pdf.

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20

Patel, Dhaval D. "KINETICS AND MECHANISMS OF CRYSTAL GROWTH INHIBITION OF INDOMETHACIN BY MODEL PRECIPITATION INHIBITORS". UKnowledge, 2015. http://uknowledge.uky.edu/pharmacy_etds/47.

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Supersaturating Drug Delivery Systems (SDDS) could enhance oral bioavailability of poorly water soluble drugs (PWSD). Precipitation inhibitors (PIs) in SDDS could maintain supersaturation by inhibiting nucleation, crystal growth, or both. The mechanisms by which these effects are realized are generally unknown. The goal of this dissertation was to explore the mechanisms underpinning the effects of model PIs including hydroxypropyl β-cyclodextrins (HP-β-CD), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP) on the crystal growth of indomethacin, a model PWSD. At high degrees of supersaturation (S), the crystal growth kinetics of indomethacin was bulk diffusion-controlled, which was attributed to a high energy form deposited on the seed crystals. At lower S, indomethacin growth kinetics was surface integration-controlled. The effect of HP-β-CD at high S was successfully modeled using the reactive diffusion layer theory. The superior effects of PVP and HPMC as compared to HP-β-CD at high S were attributed to a change in the rate limiting step from bulk diffusion to surface integration largely due to prevention of the high energy form formation. The effects of PIs at low S were attributed to significant retardation of the surface integration rate, a phenomenon that may reflect the adsorption of PIs onto the growing surface. PVP was selected to further understand the relationship between adsorption and crystal growth inhibition. The Langmuir adsorption isotherm model fit the adsorption isotherms of PVP and N-vinylpyrrolidone well. The affinity and extent of adsorption of PVP were significantly higher than those of N-vinylpyrrolidone, which was attributed to cooperative interactions between PVP and indomethacin. The extent of PVP adsorption on a weight-basis was greater for higher molecular weight PVP but less on a molar-basis indicating an increased percentage of loops and tails for higher molecular weight PVPs. PVP significantly inhibited indomethacin crystal growth at high S as compared to N-vinylpyrrolidone, which was attributed to a change in the growth mechanism resulting in a change in the rate limiting step from bulk diffusion to surface integration. Higher molecular weight PVPs were better inhibitors than lower molecular weight PVPs, which was attributed to a greater crystal growth barrier provided by a thicker adsorption layer.

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21

Thurmond, Thane S. "Indomethacin Reduces Splenic Red Pulp Macrophage Populations in Female New Zealand White Rabbits". Digital Commons @ East Tennessee State University, 1995. https://dc.etsu.edu/etd/2807.

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In an effort to elucidate the mechanism by which indomethacin (IN) attenuates the stimulatory effect of estradiol (E$\sb2$) on rabbit splenic red pulp macrophages (RPM), thirty-nine female New Zealand White rabbits were divided into 10 groups: ovariectomized (OVX), OVX/IN at 0.1 and 5.0 mg/kg body weight (bw)/day; sham OVX (SOVX), SOVX/IN at 0.1 and 5.0 mg/kg bw/day; OVX/25 mg E2, OVX/25 mg E$\sb2$/IN at 0.1 and 5.0 mg/kg bw/day; intact Control. Quantitative changes in RPM population in response to the treatments were measured using a 0 to 4 histologic grading scale. Estradiol treatment resulted in increased RPM grade when compared to the OVX non-E$\sb2$ groups. Indomethacin addition decreased mean RPM grade in the SOVX/IN 5.0 group when compared to its E$\sb2$ control group. Indomethacin administration had no significant effect on levels of PGE$\sb2$ in the spleen, blood or urine (p $>$.05). Hematocrits were reduced in both OVX and OVX/E$\sb2$ groups and this decrease was exacerbated by the high IN dose. The results from this study suggest that the effect of IN on E$\sb2$-induced RPM activation may be mediated through a non-prostaglandin pathway. The observed hematocrit changes are possibly the result of direct action of IN and E$\sb2$ on erythrocytes. To further investigate whether a direct interaction of IN and E$\sb2$ with rabbit erythrocytes may be responsible for the decreases in hematocrit observed in vivo, an in vitro study was conducted to determine the effect of these drugs on erythrocyte fragility characteristics. Two ml aliquots of treated New Zealand White rabbit whole blood were assayed as; Control, IN (9.6 $\mu$g/ml), E$\sb2$ (500 pg/ml) and IN plus E$\sb2$, for changes in erythrocyte fragility. Osmotic (OF) and mechanical (MF) fragility were evaluated under approximate physiological conditions by measurement of hemoglobin release at 545 nm. Blood samples at 39.5$\sp\circ$C were assayed immediately after drug addition (initial) and again 4 hours after incubation (final). Eight replicates of each experiment were run. Results of the OF assays showed a significant increase (p $<$.05) in mean 50% hemolysis point between IN (final) and IN plus E$\sb2$ (final) when compared to their mean initial values and to the mean final Control value. The OF hemolysis dispersion was increased by IN and IN plus E$\sb2$ treatment when final values were compared to initial values. The mean final values for MF increased with IN, E$\sb2$ and IN plus E$\sb2$ treatment versus the mean final Control value (p $<$.05). While the increase in MF from IN was greater than that from E$\sb2$, the MF from the combination (IN plus E$\sb2$) was not greater than from IN alone (p $>$.05). The IN-induced increases in both OF and MF indicate a difference in degrees of interaction with the erythrocyte from that of E$\sb2$, which only affected MF and whose effect was not additive or synergistic with that of IN. The in vitro experimental results demonstrate that the increased fragility produced by IN and E$\sb2$ on rabbit erythrocytes may account for the observed in vivo reduction in hematocrit. Increased erythrocyte fragility would also lead to their accelerated clearance from the circulation by splenic RPM and subsequent increases in activity of these macrophages. This elevation in splenic RPM population may also be enhanced by direct E$\sb2$ stimulation of macrophage proliferation.

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22

Aldosari, Basmah Nasser Abdullah. "Development and evaluation of self-nanoemulsifying drug delivery systems for oral delivery of indomethacin". Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10044225/.

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In this study, indomethacin-loaded self-nanoemulsifying drug delivery systems (SNEDDS) were developed in liquid, solid and carrier-mediated formulations in order to improve the solubility of this model poorly water soluble drug. Liquid SNEDDS based on CapryolTM 90 (oil phase), Cremophor® RH 40 (surfactant) and Transcutol® HP (co-surfactant) were thermodynamically stable and produced clear nanoemulsions upon dilution. Optimized liquid formulations were transformed into solid SNEDDS by adsorption onto the inert carriers Syloid® XDP 3150, Neusilin® US2 and Florite® PS-200. Ratios of adsorbent: liquid SNEDDS of 1:1.5 and 1:2 resulted in solid SNEDDS formulations that exhibited fair to passable powder flow properties. Carrier-based solid SNEDDS formulations were developed using the solid self-emulsifying carriers Gelucire® 44/14 and Gelucire® 48/16 and prepared by hot melt extrusion. The absorbent-based solid SNEDDS maintained the self-nanoemulsification properties of the original liquid SNEDDS formulations, with solid state analysis suggesting that the drug had remained in a dissolved state within these formulations. Similarly, physical characterization of the carrier-based solid SNEDDS formulations indicated that the drug was molecularly dispersed within the system and that the self-nanoemulsifying properties of the carrier were unchanged. The only exception was those formulations prepared at the highest drug: carrier ratio (3: 10). For both absorbent-based and carrier-based solid SNEDDS, the in vitro dissolution efficiency was significantly higher than that obtained for the pure drug. However, incorporation of adsorbents into Gelucire®-based solid SNEDDS formulations resulted in reduced dissolution of the drug. Gelucire®48/16-based solid SNEDDS prepared at 50oC were more physically stable to storage at 30oC/75% RH for 6 months than formulations processed at 40oC, suggesting that complete melting of the carrier during manufacture is essential for production of physically stable formulations. Overall, a range of liquid, solid and carrier-based SNEDDS formulations were successfully developed and offer useful alternatives to improving the solubility of poorly water-soluble drugs.

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23

Kinney, Sarah. "The effect of indomethacin on physical activity in a mouse model of cancer cachexia". Connect to resource, 2009. http://hdl.handle.net/1811/37109.

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24

Havinga, Riana. "The effect of pharmaceutical excipients on the release of indomethacin from chitosan beads / Riana Havinga". Thesis, North-West University, 2006. http://hdl.handle.net/10394/4.

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Contents: Chitosan -- Controlled drug delivery -- Indomethacin -- Inotropic gelation -- Tripolyphosphate (TPP) -- Explotab® -- Ac-Di-Sol® -- Vitamin C
Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

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25

Kayser, Stephan. "Influence of prostaglandins, omeprazole and indomethacin on healing of experimental gastric ulcers in the rat /". [S.l : s.n.], 1988. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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26

Tandt, Ludo Alfons Germaan Luc. "The evaluation of indomethacin and theophylline oral controlled/modified-release dosage forms in vitro-in vivo correlations". Thesis, Rhodes University, 1992. http://hdl.handle.net/10962/d1003272.

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Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.

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27

Staigmiller, Carmen Kay. "The effect of indomethacin on healthy frog capillaries following a shear stress stimulus: potential clinical implications". Thesis, Montana State University, 2010. http://etd.lib.montana.edu/etd/2010/staigmiller/StaigmillerC0510.pdf.

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When cultured endothelial cells are stimulated by shear stress they release prostaglandins. One of the effects of prostaglandin release is vasodilation. The effect of prostaglandins on hydraulic conductivity (Lp) is not known. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that is known to block prostaglandins. The purpose of this study was to evaluate the effect of indomethacin on endothelial cells of a true capillary. It was hypothesized that in an intact healthy capillary, superfused with indomethacin, there will be a decrease in capillary Lp after a shear stress stimulus. The mesentery of healthy North American leopard frogs (n=16) was exposed and a capillary was cannulated. Using the modified Landis technique Lp was assessed, after a shear stress stimulus, in a control capillary and a capillary that was exposed to indomethacin. There was not a significant decrease (P=0.13) in Lp when comparing the control vessels with treatment vessels. Data from this study suggest that prostaglandins are not involved with the response of Lp to shear stress in healthy frogs. Since Lp did not decrease in the presence of indomethacin, it is probable that other processes are affecting the response of the endothelium. The clinical implications of this study are important because of the potentially devastating impact of the toxic effects of NSAIDs.

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28

Genari, Bruna. "Sistema adesivo odontológico com nanocápsulas contendo fármacos". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/152698.

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O objetivo da presente tese foi desenvolver um adesivo com nanocápsulas (NCs), contendo indometacina, e um sistema adesivo com nanocápsulas (NC), contendo indometacina e triclosan, e avaliar suas propriedades. As NCs foram produzidas por meio do método de deposição de polímero, secas e caracterizadas quanto ao tamanho de partículas, à forma, quantidade de fármaco encapsulado e citotoxicidade. Uma resina adesiva foi formulada. Foram adicionadas ao adesivo 1%, 2%, 5% e 10% de NCs em massa, e um grupo permaneceu sem NC. As NCs, contendo indometacina e triclosan, foram também incorporadas no primer comercial a 2% em peso e um grupo permaneceu sem NCs. Os adesivos foram avaliados quanto ao GC imediato e tardio, à degradação em solvente, liberação dos fármacos, difusão de indometacina pela dentina e resistência de união. O adesivo com 10% de NCs, contendo indometacina, foi também avaliado quanto à ação anti-inflamatória em modelo animal. O primer e o adesivo com as diferentes concentrações de NCs, contendo indometacina e triclosan, foram avaliados quanto à liberação dos fármacos, difusão de indometacina pela dentina, ao efeito antimicrobiano, grau de conversão (GC) in situ, ângulo de contato e à resistência de união à microtração. Os dados foram analisados por ANOVA, Tukey e teste t. As NCs apresentaram forma esférica e viabilidade celular acima de 80%. As NCs, contendo indometacina, apresentaram diâmetro médio de 165 nm e as NCs, contendo indometacina e triclosan, 159 nm. O adesivo, contendo 10% de NCs com indometacina, apresentou efeito anti-inflamatório. A incorporação de NCs não alterou o GC, que variou de 63,63 ± 1,01% a 70,50 ± 2,08%. A degradação em solvente não foi alterada com 2% de NCs. Tanto os adesivos quanto o primer apresentaram liberação controlada. A indometacina permeou através da dentina. O adesivo e primer também apresentaram efeito antimicrobiano. A incorporação de NCs no primer e no adesivo não influenciou o GC in situ nem a resistência de união imediata, em comparação aos materiais sem NCs. O uso concomitante do primer e adesivo com NCs aumentou o ângulo de contato e diminuiu a resistência de união longitudinal. Conclui-se que o uso do adesivo com a incorporação de NCs tem potencial para proporcionar ações terapêuticas à adesão dentinária.
The aim of the present thesis was to develop an adhesive with nanocapsules (NCs) containing indomethacin and an adhesive system with nanocapsules containing indomethacin and triclosan and to evaluate their properties. NCs were prepared by the interfacial deposition of preformed polymer technique, dried and characterized regarding particle size, encapsulated drug content and cytotoxicity. Adhesive resin was produced. Concentrations of 1%, 2%, 5% and 10% of NCs were added in the adhesive and a group was maintained with no NCs. Indomethacin and triclosan-loaded NCs were also incorporated into a commercial primer in a concentration of 2% and a group was maintained with no NCs. Adhesives were evaluated regarding immediate and late degree of conversion (DC), degradation in solvent, drug release, indomethacin diffusion through dentin and bond strength. The adhesive with 10% of NCs containing indomethacin was also evaluated regarding the anti-inflammatory effect in an animal model. Primer and adhesive with different concentrations of NCs containing indomethacin and triclosan were evaluated regarding drug release, indomethacin diffusion through dentin, antimicrobial effect, in situ degree of conversion, contact angle and bond strength. Data were analyzed through ANOVA, Tukey post-hoc and t-test.NCs presented a spherical shape and cell viability higher than 80%. NCs containing indomethacin presented an averaged size of 165 nm and NCs containing indomethacin and triclosan, 159 nm. The adhesive with 10% of NCs containing indomethacin presented anti-inflammatory effect. The incorporation of NCs presented no alteration of DC, varying from 63.63 ± 1.01% a 70.50 ± 2.08%. Degradation in solvent suffers no influence of NCs with 2% of NCs. Adhesives and primer presented controlled drug release. Indomethacin diffused through dentin. Adhesive and primer also presented an antimicrobial effect. The incorporation of NCs in adhesive and primer showed no influence on in situ DC and immediate bond strength compared to materials with no NCs. The use in combination of primer and adhesive with NCs resulted in higher contact angle and lower longitudinal bond strength. It is possible to conclude that the use adhesive with incorporation of NCs has potential to provide therapeutic effects on dentin adhesion.

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29

Kemper, Oliver [Verfasser], e Marcus [Akademischer Betreuer] Jäger. "Einfluss von Indomethacin und Iloprost auf die Proliferation und Differenzierung mesenchymaler Progenitorzellen / Oliver Kemper ; Betreuer: Marcus Jäger". Duisburg, 2017. http://d-nb.info/1128593890/34.

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30

Silva, Marcos AntÃnio Martins da. "Evaluation of the effect of damage on the intestinal thalidomide and liver in rats induced by indomethacin wistar". Universidade Federal do CearÃ, 2011. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=10496.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
O uso clÃnico de indometacina, embora eficaz na supressÃo da dor, febre e inflamaÃÃo, Ã frequentemente associado a efeitos deletÃrios sobre o sistema gastrointestinal, hematolÃgico e renal, que limitam o seu uso terapÃutico. Este estudo analisou se a talidomida poderia reduzir a letalidade induzida pela indometacina e as alteraÃÃes hematolÃgicas e bioquÃmicas no sangue, os danos intestinais, alÃm do efeito da talidomida sobre o epitÃlio intestinal e o aumento nos nÃveis de fibrinogÃnio plasmÃtico induzido pela indometacina em ratos. Os ratos foram tratados com indometacina (5,0 mg/kg), talidomida 100,0 mg/kg e 200,0 mg/kg, e ampicilina (200,0 mg/kg), via oral, num perÃodo de cinco dias. Os animais foram submetidos Ã coleta de sangue no quinto dia de tratamento, mediante a punÃÃo do plexo-orbital do olho. Os parÃmetros estudados foram: eritrograma, contagem de leucÃcitos, tempo de protrombina (TP), tempo de tromboplastina parcial ativada (TTPA), fibrinogÃnio, contagem de plaquetas, cultura do lavado peritoneal e dosagem de mieloperoxidase (MPO) nesse lavado, avaliaÃÃo hepÃtica (ALT, AST, FA, GGT) e glicose. Os resultados do TP, TTPA, antitrombina, contagem de plaquetas, mantiveram-se normais em relaÃÃo ao grupo controle. Nos animais tratados com indometacina, observamos um aumento (p <0,001) nos nÃveis de fibrinogÃnio (637,50Â13,19 mg/dL) sendo o mesmo revertido pelo tratamento com talidomida 100,0 mg/kg e 200,0 mg/kg, (381,80 Â 50,79 mg/dL; 389,30Â 65,13 mg/dL) respectivamente. Os animais que receberam indometacina apresentaram positividade em 100% das culturas realizadas para enterobactÃrias, demonstrando assim a presenÃa de bactÃrias do trato gastrintestinal na cavidade peritoneal. A atividade da MPO no lÃquido peritoneal dos ratos que receberam indometacina (5,0 mg/kg, v.o, 5d) foi significativamente maior (1217 Â 341,4 U/mL) quando comparada com o grupo-controle (3,33 Â 3,33 U/mL). O tratamento com talidomida (100 e 200 mg / kg, v.o, 5d) reduziu significativamente (p <0,05) este aumento (375,8 Â 149,1 U/ mL), sendo a inibiÃÃo de 69,2%. Os resultados demonstram que a lesÃo intestinal inflamatÃria induzida pela indometacina foi revertida parcialmente pelo tratamento com a talidomida. AlÃm disso, os dados obtidos evidenciam o efeito hepatoprotetor da talidomida contra a indometacina, provavelmente por sua atividade antiinflamatÃria diminuindo ou minimizando o aumento do fibrinogÃnio e recrutamento leucocitÃrio no ambiente hepÃtico.
The clinical use of indomethacin, although effective in suppressing pain, fever and inflammation is often associated with deleterious effects for the gastrointestinal system, and hematological and renal functions, which limit its therapeutic use. This study examined in rats whether thalidomide could reduced the lethality induced by indomethacin and hematological, biochemical, blood, and intestinal damage. This study analyzed the effect of thalidomide on the intestinal epithelium and increased levels of plasma fibrinogen induced by indomethacin in rats. The rats were treated with indomethacin (5.0 mg / kg), thalidomide 100.0 mg / kg or 200.0 mg / kg, and ampicillin (200.0 mg / kg) orally over a period of 5 days. The animals were submitted to blood collection on the fifth day of treatment by puncturing the orbital plexus of the eye, after being anesthetized with ether. The blood was placed in tubes containing anticoagulant, EDTA, sodium citrate and 3.8% in tubes without anticoagulant. The parameters studied were: erythrogram, leukocyte count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, platelet count, and culture of peritoneal lavage, measurement of MPO and evaluation of liver function (ALT, AST, FA, GGT and glucose). The results of the PT, APTT, antithrombin, platelet counts remained normal in the control group. In animals treated with indomethacin, we observed a significant increase (p <0.001) in fibrinogen levels (637.50 Â 13.19 mg / dL) and this increase reversed by treatment with thalidomide 100.0 mg / kg or 200.0 mg / kg, (381.80 Â 50.79 mg / dL, 389.30 Â 65.13 mg / dL, respectively). Animals that received indomethacin were positive in 100% of the cultures performed for enterobacteria, thus demonstrating the presence of bacteria in the gastrointestinal tract into the peritoneal cavity, probably due to a drug-induced intestinal perforation. The MPO activity in peritoneal fluid of rats given indomethacin (5.0 mg / kg, po, 5d) was significantly higher (1217 Â 341.4 U / mL) compared with the control group (3.33 Â 3, 33 U / mL). Treatment with thalidomide (100 or 200 mg / kg, vo, 5d) significantly reversed this effect (p <0.05), (375.8 Â 149.1 U / mL). As inhibition of 69.2%. The results showed that inflammatory intestinal injury in rats induced by indomethacin was partially reversed by treatment with thalidomide. In addition, the data showed a hepatoprotective effect of thalidomide against indomethacin, by its anti-inflammatory activity that might prevent the increase of fibrinogen and leukocyte recruitment in the liver environment.

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31

Wersig, Tom [Verfasser], Karsten [Gutachter] Mäder, Jörg [Gutachter] Kressler e Achim [Gutachter] Göpferich. "Poly(glycerol adipate) - indomethacin conjugates for modified drug release / Tom Wersig ; Gutachter: Karsten Mäder, Jörg Kressler, Achim Göpferich". Halle (Saale) : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2019. http://d-nb.info/1210729660/34.

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32

Rios, Emiliano Ricardo Vasconcelos. "Pharmacologicals effects of the esculin in animal models of gastric injury and possible machanisms involved". Universidade Federal do CearÃ, 2009. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4509.

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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico
Ulcer can be defined as a chronic inflammatory disease of the stomach and duodenum, which appears as a lesion in the digestive tract, which extends through the mucosa muscle or more deeply. The ulcer usually occurs because of an imbalance between protective and agrssive factors of the mucosa. Esculin (ESC) (6.7-Dihydroxycoumarin-6-O-Glucoside) was evaluated in models ethanol or indomethacin-induced gastric lesions in mice. Esculin (12.5, 25 and 50 mg/kg, p.o.) significantly reduced gastric lesions induced by absolute ethanol (0.2 mL/animal) at 69.96, 72.94 and 79.33% respectively, showing no relationship dose-response at the doses studied. This gastroprotection was also evaluated microscopically showing that the ESC (25 mg/kg, p.o.) decreased the cell loss in the mucosa, submucosal edema and hemorrhage. Esculin (25 and 50 mg/kg, p.o.) also reduced significantly the gastric lesions induced by indomethacin (20 mg/kg, p.o.). Gastroprotective mechanism of ESC was examined in the dose of 25 mg/kg, in the model of gastric lesions induced by ethanol in mice. In animals pretreated with L-NAME (10 mg/kg, sc), an inhibitor of nitric oxide synthase, or with glibenclamide (5 mg/kg, i.p.), a drug that blocks ATP-dependent potassium channels, or indomethacin (10 mg/kg, p.o.), a nonselective inhibitor of cyclooxygenase, the gastroprotective effect of ESC was inhibited significantly, suggesting the involvement, at least in part, of nitric oxide, activation of potassium channels and endogenous prostaglandins in gastroprotective effect of ESC. Otherwise, the gastroprotective effect of ESC (25 mg/kg, p.o.) was not reversed in animals pretreated with capsazepine (5 mg/kg, i.p.), an antagonist of vanilloid receptor TRPV-1, demonstrating that there is activation of these receptors in the mechanism of action of ESC. This work was also evaluated the antioxidant mechanism of ESC as gastroprotective agent, against ethanol-induced lesions. Under our experimental conditions, the model of induction of ethanol injury caused changes in the antioxidant system of the gastric mucosa of mice as the decrease in the levels of sulfhydryl groups (GSH) and activity of superoxide dismutase (SOD), also showed increased activity catalase (CAT), the activity of myeloperoxidase (MPO) and the concentration of species that react with thiobarbituric acid (TBARS) as index of lipid peroxidation (LPO). Esculin in the model of ethanol did not interfere with the concentration of GSH, but increased SOD activity, allowed the restoration of normal CAT activity, normal levels of LPO and MPO activity. The data suggest that the ESC promotes gastroprotection against gastric lesions induced by ethanol or indomethacin in mice whose mechanisms include the involvement of endogenous prostaglandins, nitric oxide, and or, of KATP channels, as well as an antioxidant activity.
A Ãlcera pÃptica pode ser definida como sendo uma doenÃa inflamatÃria crÃnica do estÃmago e duodeno, que se apresenta como uma lesÃo na mucosa do trato digestivo, que se estende atravÃs da musculatura da mucosa ou mais profundamente. A Ãlcera pÃptica geralmente ocorre devido a um desequilÃbrio entre os fatores de defesa e agressores da mucosa. Este trabalho teve como objetivo avaliar a atividade gastroprotetora da esculina, (6,7-diidroxicumarina-6-o-glicosÃdio), e identificar os mecanismos farmacolÃgicos envolvidos. A esculina foi avaliada em modelos de lesÃes gÃstricas induzidas por etanol absoluto (0,2 mL/animal) em camundongos swiss, nas doses 12,5, 25 e 50 mg/kg, v.o., os resultados mostraram a reduÃÃo das lesÃes gÃstricas induzidas por etanol em 69,96, 72,94 e 79,33 % respectivamente, nÃo mostrando relaÃÃo dose-resposta nas doses estudadas. Esta gastroproteÃÃo tambÃm foi avaliada microscopicamente mostrando que a ESC (25 mg/kg, v.o.) diminuiu a perda celular na mucosa, formaÃÃo de edema na submucosa e hemorragia. A ESC (25 e 50 mg/kg, v.o.), tambÃm, foi avaliada no modelo de lesÃo gÃstrica induzida por indometacina (20 mg/Kg, v.o.), mostrando uma reduÃÃo das lesÃes gÃstricas. O mecanismo gastroprotetor da ESC foi analisado na sua dose de 25 mg/Kg, em modelo de lesÃes gÃstricas induzidas por etanol em camundongos. Em animais prÃ-tratados com L-NAME (10 mg/Kg, s.c.), um inibidor da Ãxido nÃtrico sintase, ou com glibenclamida (5 mg/Kg, i.p.), droga bloqueadora de canais de potÃssio ATP-dependentes, ou indometacina (10 mg/Kg, v.o.), um inibidor nÃo seletivo da ciclooxigenase, o efeito gastroprotetor da ESC foi inibido significativamente, sugerindo o envolvimento, pelo menos em parte, do Ãxido nÃtrico, ativaÃÃo dos canais de potÃssio e prostaglandinas endÃgenas no efeito gastroprotetor da ESC. De outra forma, o efeito gastroprotetor da ESC (25 mg/Kg, v.o.) nÃo foi revertido em camundongos prÃ-tratados com capsazepina (5 mg/Kg, i.p.), um antagonista dos receptores vanilÃides TRPV-1, demonstrando assim que nÃo hÃ ativaÃÃo destes receptores no mecanismo de aÃÃo da ESC. Neste trabalho tambÃm foi avaliado a aÃÃo antioxidante da ESC como mecanismo gastroprotetor contra as lesÃes induzidas por etanol. Sob nossas condiÃÃes experimentais, o modelo de induÃÃo de lesÃo por etanol provocou alteraÃÃo no sistema antioxidante da mucosa gÃstrica dos camundongos, como a diminuiÃÃo nos nÃveis de grupamentos sulfidrila (GSH) e atividade da superÃxido dismutase (SOD), tambÃm observamos aumento da atividade da catalase (CAT), da atividade da mieloperoxidase (MPO) e da concentraÃÃo de espÃcies que reagem com o Ãcido tiobarbitÃrico (TBARs), como Ãndice de peroxidaÃÃo lipÃdica (LPO). A ESC no modelo de etanol nÃo interferiu com a concentraÃÃo de GSH, mas aumentou a atividade da SOD, permitiu o restabelecimento da atividade normal da CAT e de patamares normais de LPO e de atividade da MPO. Os dados obtidos sugerem que a ESC promove gastroproteÃÃo contra as lesÃes gÃstricas induzidas por etanol ou indometacina em camundongos, por mecanismos que incluem o envolvimento de prostaglandinas endÃgenas, Ãxido nÃtrico, e ou, dos canais de KATP, alÃm de uma aÃÃo antioxidante.

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33

Smith, Lucille Lakier. "The role of inflammation in delayed muscle soreness (DMS) and the effects of indomethacin on DMS and perceived exertion". Diss., Virginia Polytechnic Institute and State University, 1986. http://hdl.handle.net/10919/71190.

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PART I: MARKERS OF INFLAMMATION IN DELAYED MUSCLE SORENESS Fifty-five untrained males were assigned to an experimental (E) or a control group (C), to re-examine the concept that DMS represents an acute inflammatory response. Subjects were assigned to receive either Indocin (Id; 100 mg per day) for 2 days prior to the treatment and a placebo (P) for 2 days after (Id-P); or the reverse combination (P-Id); or Id for- 4 days (Id-Id); or placebo (P-P). On the treatment day, to induce DMS, E subjects performed 30 min of bench-stepping with one leg leading throughout; C subjects rested for 30 min. Immediately before and after stepping/resting, all subjects used their right and left leg to perform 19 maximal and 15 submaximal repetitions on the Cybex II. Blood samples were collected -5 min before, immediately after bench stepping (0 h), 2 h after and 24, 48 and 72 h, to evaluate WBC. DMS was also monitored 0, 24, 48 and 72 h. All E subjects experienced a significant amount of DMS (p<.01) which peaked at 48 h after exercise (E=7.58 ± .79 vs 0 for C, X±SEM); however, no significant differences in soreness perception were observed between drug and placebo groups. Total WBC count ( cells/mm³ ) was significantly greater at 0 h (8,340±380) than at -5 min (6,699±365) for both E and C; this increase was most likely a response to Cybex exercise. At 2 h there was a significant increase in total WBC count for E ( 9,603±389) and no change for C ( 8,336±273}. Neutrophils increased significantly at 2 h for E only (6,428±375 vs 4,988±261 for C}. Bench-stepping leads to increases in DMS and increases in WBC count, particularly in neutrophils, 2 h after stepping; this data suggests that inflammation is involved in DMS. PART II: EFFECT OF AN ASPIRIN-LIKE DRUG ON PERCEIVED EXERTION DURING BENCH STEPPING The object of this study was to determine whether perceived exertion (RPE) for the limb performing predominantly positive work was significantly greater than for the limb performing predominantly negative work, during 30 min of bench stepping. A second objective was to determine the effects of indomethacin (Id) on RPE. Thirty-nine males were randomly assigned to a drug (Id) or placebo (P) group and administered 150 mg indomechacin or placebo, beginning 36 h prior to stepping. Results indicated no significant differences between RPE for "concentric" and "eccentric" limbs of the P group inspite of the fact that the metabolic demand of the "concentric" limb was much greater. Indomethacin did not significantly alter RPE during stepping however, when RPE scores were totaled over the entire bench stepping period, the Id condition was associated with a greater (p < .01) psychological cost for the "concentric" leg effort as compared to P; this indicated that indomethacin might alter effort sense related to concentric contractions.
Ph. D.

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34

Chennamaneni, Snigdha. "FROM NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSIAD) INDOMETHACIN TO ANTI-CANCER AGENTS: DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MECHANISM INVESTIGATION". Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1421084668.

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35

Buchmeier, Eva Lotte [Verfasser]. "Der medikamentöse Verschluss des Ductus arteriosus Botalli : eine retrospektive Studie zum Vergleich von Indomethacin und Ibuprofen / Eva Lotte Buchmeier". Köln : Deutsche Zentralbibliothek für Medizin, 2011. http://d-nb.info/1016179324/34.

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36

Cuppini, Marla. "Síntese e caracterização de uma nova pasta endodôntica com sistemas carreadores de fármacos". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/179834.

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O objetivo do presente estudo foi sintetizar e caracterizar um material reparador para uso endodôntico com propriedades anti-inflamatória, antimicrobiana e remineralizante. A pasta experimental tem como propósito ser um sistema carreador de fármacos para regiões de difícil acesso em Odontologia. A apresentação do material é em forma de pó:líquido. No pó se encontra α-fosfato tricálcico, tungstato de cálcio e microesferas de amoxicilina (AMX-MS), já no líquido estão contidas nanocápsulas de indometacina (IndOHNC). A pasta experimental foi testada em relação a suas características físicoquímicas e biológicas. As AMX-MS obtiveram tamanho de 1,604 μm ± 0,08, forma esférica confirmada por MEV e teor da droga foi 1,63 mg g-1. As IndOHNC obtiveram tamanho de 162 ± 7,5 nm e forma esférica confirmada por MET. O teor do fármaco foi de 1 mg mL-1 ± 0,02. O escoamento da pasta foi de 18.56 ± 0.29, a espessura de película obtida foi 33 μm e radiopacidade de 1,81 mmAl. A pasta experimental demonstrou atividade antibacteriana contra o Enterococcus faecalis. A maior concentração de pasta experimental apresentou o maior valor em relação à viabilidade celular, com 187,03% no teste SRB. A atividade da enzima fosfatase alcalina e a formação de nódulos mineralizados obtiveram um gradual aumento em função do tempo. A migração celular demonstrou fechamento da ferida, e a pasta experimental foi capaz de acelerar o processo (p<0.05). Em conclusão, a pasta experimental demonstrou propriedades físico químicas e biológicas confiáveis, podendo ser um material promissor para o reparo da região periapical.
The aim of this study was to synthesize and characterize a new reparative material with anti-inflammatory, antimicrobial and remineralizing properties. The reparative material was developed to be a drug delivery system for regions with difficult access in Dentistry. The formulation is presented in powder/liquid. The powder is composed of α-tricalcium phosphate, calcium tungstate and amoxicillin microspheres (AMX-MS). The liquid is composed of nanocapsules containing indomethacin (IndOH-NC). The physicochemical and biological properties of the experimental endodontic paste were evaluated. The AMX-MS obtained a mean size of 1.604 μm ± 0.08, spherical shape and the encapsulation capacity was 1.63 mg g-1. IndOH-NCs obtained a mean size of 162 ± 7.5 nm and spherical shape confirm by MET. The content of the encapsulated drug was 1 mg mL-1 ± 0.02. The experimental paste flow was 18.56 ± 0.29 mm, mean film thickness was 33 μm and radiopacity equivalent to 1.81 mmAl. The experimental paste showed antibacterial activity against Enterococcus faecalis. The highest concentration of experimental paste presented the highest value in cell viability (187.03% in SRB test). The activity of the phosphatase alkaline enzyme and the formation of mineralized nodules showed a gradual increase as a function of time. Cell proliferation showed continuous wound closure, and the experimental paste was able to accelerate the process (p<0.05). In conclusion, the experimental paste demonstrated reliable physicochemical and biological properties, and it could be a promising material for periapical region repair.

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37

Dussault, Isabelle. "Natural killer (NK) cells in normal and leukemic infant, young adult and aged mice : effects of interleukin-2 and indomethacin". Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28443.

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This work was aimed, firstly, at studying the effects or a form of immunotherapy utilizing the cytokine, interleukin-2 and the non-steroid, anti-inflammatory drug, indomethacin, on natural killer (NK) cells in young adult mice bearing a tumor of hemopoietic origin, i.e., lymphomas and leukemias. In the hands of others, recently, this form of immunotherapy has had strikingly ameliorative influences in mice and man bearing solid (melanoma) tumors. The second aim of this project was to test the universality, with respect to age, of this form of immunotherapy in mice bearing a tumor of hemopoietic origin. The third goal was to investigate the mechanism(s) responsible for the well known lack of NK cell functional activity in normal infant and aged mice. Under various combinations and applications of the cytokine and drug, in both normal and erythroleukemic mice, the following parameters were measured: (i) quantitation of NK cells in the bone marrow and spleen, and (ii) the lytic activity of those cells in all cases. In some cases, their (i) proliferative capacity, (ii) target binding capacity and (iii) microenvironmental influences were also assessed. The project has shown that rIL-2+indomethacin treatment of tumor-bearing young adult mice significantly elevated NK cell numbers and their function, reduced tumor cell numbers and increased the life span of such mice. However, in tumor-bearing infant mice, the drug and/or cytokine increased life span and stimulated NK cell numbers was/were unable to induce NK cell functional (lytic) activity from these numerically increased NK cells. Finally, tumor-bearing aged mice were totally unresponsive to such treatments. These results indicate that this form of immunotherapy is very effective in stimulating NK cells in mice bearing erythroleukemia. However, this form of immunotherapy is not universal with respect to age. The lack of NK cell functional activity in normal infant. and aged mice results from different mechanisms. Wher

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38

Bockelmann, Petra Karla. "Analise histoquimica, ultra-estrutural e morfometrica do efeito de drogas anti-inflamatorias não esteroides (naproxeno e indometacina) sob a regeneração da nadadeira caudal de teleosteo, Cyprinus carpio (carpa)". [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317614.

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Orientador: Ivanira Jose Bechara
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: As nadadeiras caudais de teleósteos, quando parcialmente amputadas, passam por um rápido processo de regeneração chamado de regeneração epimórfica, caracterizado pela formação de uma massa de células indiferenciadas, diferenciação dessas células, síntese e deposição de matriz extracelular e restauração morfológica. A regeneração da nadadeira é extremamente sensível a fatores físicos e químicos externos, tais como variações na temperatura, intensidade da luz, ação de alguns agentes contaminantes ambientais e ação de algumas drogas que podem interferir na capacidade regenerativa das nadadeiras dos peixes teleósteos. Existem relatos na literatura, que drogas anti-inflamatórias não esteróides, podem interferir de alguma forma na restauração tecidual de diversos organismos, uma vez que inibem a ação da enzima ciclooxigenase e, conseqüentemente, a conversão do ácido araquidônico em prostaglandina, elementos que desempenham funções importantes na proteção celular, crescimento, angiogênese e produção de matriz extracelular. Em vista disso, este trabalho teve como objetivo avaliar os efeitos de drogas antiinflamatórias não esteróides, naproxeno e indometacina, durante o processo regenerativo da nadadeira caudal de peixe teleósteo Cyprinus carpio (carpa). Para isso, foram montados experimentos com cinco grupos: grupo formado com peixes que serviram como controle, grupo formado com peixes que entraram em contato com o naproxeno, na dose de 15,6 mg/L, e três grupos formados por peixes que tiveram contato com a indometacina nas doses 10, 20 e 30 mg/L cada. Os peixes foram anestesiados e suas nadadeiras caudais foram amputadas transversalmente e, após a amputação os peixes foram divididos entre os cinco grupos e permaneceram nos aquários até que a regeneração ocorresse. Os animais foram anestesiados, sacrificados e as nadadeiras em regeneração foram excisadas e fixadas em intervalos de 1, 2, 4, 5, 6, 8, 10 e 12 dias após a amputação. As amostras foram processadas para permitir uma análise histoquímica, ultra-estrutural e morfométrica das possíveis alterações no processo regenerativo da nadadeira caudal de teleósteo em contato com as drogas em questão. Os grupos tratados com o naproxeno e a indometacina utilizada na dose de 10 mg/L apresentaram o processo de regeneração de forma semelhante ao grupo controle, ou seja, não afetaram a formação da capa epidermal, a formação do blastema, a diferenciação das células blastemais, bem como a síntese, deposição, organização e mineralização dos componentes da matriz lepidotriquial e a síntese das actinotriquias durante o processo regenerativo da nadadeira caudal. No entanto, os peixes tratados com a indometacina nas doses de 20 e 30 mg/L apresentaram um atraso no processo de regeneração da lepidotriquia e da actinotriquia quando comparados com os peixes do grupo controle. Estudos mais detalhados sobre os mecanismos de ação das drogas anti-inflamatórias não esteróides e a ação dessas drogas sob a expressão ou a inibição da expressão de alguns genes envolvidos no processo de regeneração da nadadeira caudal de teleósteo talvez possam responder a razão das diferenças de efeitos entre essas duas drogas
Abstract: The fins of teleosts, when partially amputated, they pass for a quick regenerative process called epimorphic regeneration, characterized by the formation of a mass of undifferentiated cells, by the differentiation of these cells, by the synthesis and the deposition of the extracellular matrix and morphological restoration. The regeneration of the fin is extremely sensitive to external physical and chemical factors such as temperature variations, light intensity, the action of some environmental contaminants and the action of some drugs that can interfere in the regenerative capacity of teleost fins. There are some studies that show that nonsteroids anti-inflammatory drugs can interfere somehow in the tissue restoration of many organisms, as they inhibit the action of ciclooxygenase enzyme and, consequently, the conversion of arachidonic acid in prostaglandins, elements that execute important roles in cell protection, growth, angiogenesis and in the production of extracellular matrix. In this sense, this study aimed to evaluate the effects of nonsteroid anti-inflammatory drugs, naproxen and indomethacin, during the regenerative process of the teleost tail fin Cyprinus carpio (carp). Therefore, experiments were undertaken in five groups: the control group fish, group of fish in touch with naproxen in doses of 15.6 mg/L, and three groups of fish in contact with indomethacin in doses of 10, 20 and 30 mg/L each. The fish were anesthetized and their fins transversally amputated and, after amputations the fish were divided among the five groups described above and were left in the aquaria until the occurrence of regeneration. The animals were anesthetized, sacrificed and the regenerating fins excised and fixed in intervals of 1, 2, 4, 5, 6, 8, 10 and 12 days after amputation. The samples were processed in order to permit a histochemical, ultra-structural and morphometric analysis of the possible alterations in the regenerative process of the tail fin of the teleosts in contact with the drugs mentioned above. The group treated with naproxen and indomethacin in a 10 mg/L dose showed a regenerative process similar to the control group, thus, it did not affect the formation of the epidermal layer, the formation of blastema, and the differentiation of blastemal cells, as well as its synthesis, deposition, organization and mineralization of the lepidotrichial matrix and the synthesis of actinotrichia during the process of regeneration of the tail fin. However, the fish treated with indomethacin in doses of 20 and 30 mg/L presented a delay in the regenerative process of the lepidotrichia and actinotrichia when compared to the control group fish. Detailed studies about the mechanisms of nonsteroids anti-inflammatory drugs action and the action of these drugs under the expression or inhibition of expression of some genes involved in the teleost tail fin regenerative process could explain more precisely the reason of the differences of effect between these two drugs
Doutorado
Histologia
Doutor em Biologia Celular e Estrutural

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Cerqueira, Gilberto Santos. "Efeitos farmacolÃgicos e possÃveis mecanismos de aÃÃo da hecogenina em modelos animais de lesÃo gÃstricas". Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=10313.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Este estudo investiga os efeitos gastroprotetores da hecogenina, uma saponina esterÃide, isolada de Agave sisalana, em modelos experimentais de Ãlcera gÃstrica. Camundongos Swiss machos foram utilizados nos modelos de Ãlcera gÃstrica induzida pelo etanol e indometacina. Para identificarmos os mecanismos de aÃÃo da hecogenina, os papÃis de Ãxido nÃtrico (NO), do grupos sulfidrilicos nÃo protÃicos (GSH), dos canais de K+ ATP e das prostaglandinas foram tambÃm investigados assim como determinaÃÃes da peroxidaÃÃo lipÃdica (TBARS) e dos nÃveis de nitrito no estÃmago de animais tratados com hecogenina e de grupos controle foram realizadas. AlÃm disso, foi avaliado o efeito da hecogenina sobre a contagem de mastÃcitos, bem como sobre a liberaÃÃo da mieloperoxidase (MPO), um biomarcador de inflamaÃÃo foram estudados em neutrÃfilos humanos in vitro. Foram avaliados a atividade antimicrobina para o Helicobacter pylori e a expressÃo de COX-2, TNF-α, IL-1β, Ãxido nÃtrico sintase induzida (iNOS), NF-kB-p50 NLS (sequÃncia de localizaÃÃo nuclear) atravÃs da tÃcnica de imunohistoquÃmica em modelo de Ãlcera gÃstrica agudo e crÃnico. Os nossos resultados mostraram que a hecogenina (15, 30,60 e 90 mg/ kg, p.o.) administrada de forma aguda, antes do etanol ou indometacina, exibiu um potente efeito gastroprotetor, bem como reduziu o nÃmero de mastÃcitos. Embora os prÃ-tratamentos com L-NAME, um inibidor de iNOS, e capsazepina, um agonista do receptor TRPV1, nÃo foram capazes de reverter o efeio da hecogenina, este foi revertido por glibenclamida, um bloqueador de K+ATP e por indometacina no modelo de Ãlcera induzida por etanol. O prÃ-tratamento com hecogenina reduziu de modo significativo os nÃveis de GSH, peroxidaÃÃo lipÃdica e nitrito no modelo de lesÃo gÃstrica induzida por etanol. A droga por si sÃ aumentou a expressÃo de COX-2, e este efeito foi ainda melhor na presenÃa de etanol tendo diminuido tambÃm a liberaÃÃo de MPO. A hecogenina nÃo demonstrou efeitos significativos sobre o modelo de ligadura do piloro e trÃnsito intestinal em camundongos. No modelo crÃnico, o tratamento com a hecogenina foi capaz de melhorar a cicatrizaÃÃo de Ãlceras gÃstricas induzidas pelo Ãcido acÃtico promovendo significativa regeneraÃÃo da mucosa gÃstrica. Ademais, hecogenina 90 mg/Kg diminuiu a marcaÃÃo imunohistoquÃmica para TNF-α, NOSi, IL-1β, NF-kB-p50 NLS na mucosa gÃstrica tanto em experimento agudo como no crÃnico. Em conclusÃo, os resultados obtidos indicam que a hecogenina possui atividade gastroprotetora em modelos agudo e crÃnico e capacidade de promover cicatrizaÃÃo de Ãlcera da mucosa gÃstrica. AlÃm disso, demonstramos que a hecogenina apresenta um efeito gastroprotetor significativo que parece ser mediado pela abertura de canais de K+ATP pela via COX- 2/PG. AlÃm disso, as propriedades antioxidantes e anti-inflamatÃrias podem desempenhar um papel no efeito gastroprotetor da droga. Constata-se tambÃm que o efeito anti-Ãlcera pode ser devido Ãs suas propriedades de aumentar o mecanismo de defesa da mucosas e atravÃs da supressÃo da inflamaÃÃo mediada por TNF-α, NOSi, IL-1β, NF-kB.
This study investigates the gastroprotective effects of hecogenin, a steroid saponin isolated from Agave sisalana, on experimental models of gastric ulcer. Male Swiss mice were used in the models of ethanol- and indometacin-induced gastriculcer. To clarify the hecogenin mechanism of action, the roles of nitric oxide (NO), sulfhydryls (GSH), K+ATP channels and prostaglandins were also investigated, and measurements of lipid peroxidation (TBARS assay) and nitrite levels in the stomach of hecogenin-treated and untreated animals were performed. Furthermore, the effects of hecogenin on myeloperoxidase (MPO) release from human neutrophils were assessed in vitro. Our results showed that hecogenin (3.1, 7.5, 15, 30, 60 and 90 mg/kg, p.o.) acutely administered, before ethanol or indomethacin, exhibited a potent gastroprotective effect. Although the pretreatments with L-NAME, an iNOS inhibitor, and capsazepine, a TRPV1 receptor agonist, were not able to reverse the hecogenineffect, this was reversed by glibenclamide, a K+ATP blocker, and indomethacin in the model of ethanol-induced gastric lesions. The hecogenin pretreatment normalized GSH levels and significantly reduced lipid peroxidation and nitrite levels in the stomach, as evaluated by the ethanol-induced gastric lesion model. The drug alone increased COX-2 expression and this effect was further enhanced in the presence of ethanol. It also decreased MPO release and significantly protected the gastric mucosa. In conclusion, we showed that hecogenin presents a significant gastroprotective effect that seems to be mediated by K+ATP channels opening and the COX-2/PG pathway. In addition, its antioxidant and anti-inflammatory properties may play a role in the gastroprotective drug effect.

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Moura, Renata Kely de Paulo. "Avaliação in vitro das características de liberação de indometacina a partir de dispositivos oculares implantáveis". Universidade Federal da Paraíba, 2010. http://tede.biblioteca.ufpb.br:8080/handle/tede/6857.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
The anatomy and physiology of the eye, together with its protective barriers represent challenges to effective ocular drug delivery systems. The pharmacological treatment of eye diseases had been limited to conventional drug formulations, which are not satisfactory for diseases affecting the posterior segment of the eye. The delivery of therapeutic doses at tissues from the posterior segment in order to minimize adverse systemic and regional effects is the main goal in the treatment of ocular diseases. With this aim, several studies have been conducted to develop new ocular drug delivery systems, such as those involving ocular implants. These implants are prepared using a variety of different polymers that can be either biodegradable or non-biodegradable. Polymers derived from lactic and glycolic acid have revealed to be promising materials for the formulation of ocular implants, mainly due to their biocompatibility and biodegradability. In this study, two different biodegradable indomethacin implants formulated based on a copolymer of lactic/glicolic acid (PLGA 50:50) and D,L-lactic acid (D,L-PLA) were characterized by differential scanning calorimetry (DSC), in vitro release using dissolution apparatus and scleral diffusion (from rabit´s eye) using Franz chambers. The study was done in collaboration with 3T Biopolymers (São Paulo, Brazil) that provided samples of the polymers and implants for analyses. The results of the validation of the HPLC method for indomethacin quantification were within the limits set forth by Brazilian legislation (RE 899, 2003, ANVISA). The results of DSC analysis revealed absence of any evidence of physico-chemical interactions between the drug and polymer. The suppression of the indomethacin melting peak is probably due to changes from the crystalline to the amorphous state of the drug following lyophilization or by dilution effects. Preliminary in vitro release data revealed a triphasic profile for indomethacin release from the PLGA-based implants and a biphasic one for the PLA implants. The implants formulated with PLGA promoted a faster release of indomethacin (103.64%) compared with implants formulated with PLA (49.9%) during the thirty days of the experiment. The release profile of indomethacin was determined by the rate of degradation of polymers, which also determined the scleral diffusion of indomethacin from PLGA and PLA (1.7 x 10-5 cm / s and 0.24 x 10-5 cm / s, respectively). The scleral diffusion experiments using Franz difusion chambers have shown that the rabit sclera is permeable to indomethacin and polarized light microscopy revealed that the structure of the scleral collagen fibers were not significantly altered during the diffusion experiments. The drug-release systems studied were able to release indomethacin in a sustained fashion, serving as a model for the formulation of indomethacin implants that could be used in the future for the treatment of ocular diseases such as the cystoid macular edema.
A anatomia e fisiologia do olho e suas barreiras protetoras representam um desafio para o desenvolvimento de sistemas de transporte de drogas oftálmicas efetivos. O tratamento farmacológico de doenças oculares tem se limitado às formas convencionais de administração que não são satisfatórias para o tratamento de doenças que acometem o segmento posterior do bulbo do olho. O transporte de doses terapêuticas para os tecidos do segmento posterior do olho, que minimize os efeitos colaterais sistêmicos e locais, é o principal objetivo no tratamento de doenças oculares. Visando atingir este objetivo, estudos têm sido feitos no sentido de desenvolver novos sistemas de liberação de fármacos para o olho, entre estes estão os implantes. Esses implantes são preparados a partir de diferentes polímeros, os quais podem ser biodegradáveis ou não biodegradáveis. Os polímeros derivados dos ácidos lático e glicólico têm se revelado bastante promissores devido, principalmente, às suas características de biocompatibilidade e biodegradabilidade. Neste trabalho, dois diferentes implantes de indometacina formulados a partir do copolímero ácido lático / ácido glicólico (PLGA 50:50) e do polímero derivado do ácido D,L-lático (PLA), através de liofilização da mistura polímero-fármaco, foram fornecidos pela empresa 3T Biopolímeros (São Paulo - SP) e avaliados através de DSC, estudos de liberação in vitro usando aparato de dissolução e estudos de difusão através de esclera de coelho utilizando câmaras de Franz. Os resultados da validação do método CLAE para quantificação da indometacina apresentaram-se dentro dos limites estabelecidos pela legislação brasileira (Resolução RE 899, 2003, ANVISA). As análises de DSC mostraram a ausência aparente de interações químicas e físicas entre o fármaco e os polímeros, sendo sugerido que o desaparecimento do pico de fusão da indometacina tenha ocorrido pela amorfização do fármaco durante o processo de liofilização ou pela diluição do fármaco no polímero. Os estudos preliminares de liberação in vitro demonstraram um perfil trifásico para os implantes formulados com PLGA e um perfil bifásico para àqueles formulados com PLA. Os implantes formulados com PLGA promoveram uma liberação mais rápida da indometacina (103,64%) quando comparado com os implantes formulados com PLA (49,9%) durante os trinta dias de experimento. O perfil de liberação da indometacina foi determinado pela velocidade de degradação dos polímeros, que também determinou a difusão escleral da indometacina a partir do PLGA e do PLA (1,7 x 10-5 cm/s e 0,24 x 10-5 cm/s, respectivamente). Os estudos de difusão escleral mostraram que a esclera de coelho é permeável à indometacina e a microscopia de luz polarizada mostrou que a estrutura das fibras colágenas da esclera não foram significativamente alteradas durante o estudo de difusão nas câmaras de Franz. Os sistemas de liberação de fármacos avaliados foram capazes de liberar a indometacina de forma prolongada, servindo como um modelo para formulação de implantes de indometacina que podem ser futuramente utilizados para tratamento de doenças como edema macular cistóide.

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Venturin, Gabriela Lovizutto [UNESP]. "Níveis de arginase, óxido nítrico e o efeito da pge2 na produção de tnf-α em linfonodo de cães com leishmaniose visceral". Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/144048.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Visceral leishmaniasis (VL) is a chronic disease that can be fatal to humans and dogs. The disease is caused by the intracellular parasite Leishmania infantum and is transmitted by the bite of the sandfly (phlebotomines). In dogs, VL is observed as an intense chronic inflammatory reaction in the liver, spleen, skin, bone marrow and lymph nodes. Arginase activity is important in VL because an increase of this enzyme may contribute to the multiplication of the parasite and a reduction of nitric oxide (NO) synthesis, predisposing a macrophage to infection. Prostaglandin E2 (PGE2) can play a regulatory role in the production of tumor necrosis factor (TNF-α) and interleukin-10 (IL-10), however, there have been no studies in dogs with LV. This study aimed to evaluate the arginase activity in adherent macrophages cultivated from the lymph nodes of 18 healthy and 23 naturally infected dogs and to examine levels of NO and PGE2 in the supernatant of these cultures. The regulatory effect of PGE2 on the production of TNF-α and IL-10 was also evaluated in supernatants of total lymph node leukocytes cultures. These results help to clarify the mechanisms of the immune response in CVL.
FAPESP: 2013/066849

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Venturin, Gabriela Lovizutto. "Níveis de arginase, óxido nítrico e o efeito da pge2 na produção de tnf-α em linfonodo de cães com leishmaniose visceral /". Araçatuba, 2015. http://hdl.handle.net/11449/144048.

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Resumo:A leishmaniose visceral (LV) é uma doença crônica que pode ser fatal para os humanos. A doença é causada por um parasita intracelular, Leishmania infantum e é transmitida pela picada do mosquito flebótomo. Em cães com LV observa-se uma intensa reação inflamatória crônica no fígado, baço, pele, medula óssea e gânglios linfáticos. A atividade arginase é importante na LV, pois o aumento dessa enzima pode contribuir para a multiplicação do parasita e para a redução da síntese de óxido nítrico (NO), predispondo o macrófago à infecção. A prostaglandina E2 (PGE2) pode regular a produção do fator de necrose tumoral alfa (TNF-α) e da interleucina-10 (IL-10), porém nenhum estudo ainda foi realizado em cães com LV. O presente estudo teve como objetivo avaliar a atividade arginase em macrófagos aderentes de cultura de linfonodos de 23 cães naturalmente infectados e 18 saudáveis, e os níveis de NO e PGE2 no sobrenadante dessas culturas. O efeito regulatório de PGE2 na produção de TNF-α e IL-10 também foi avaliado em cultura de leucócitos totais de linfonodo. Esse estudo ajuda a esclarecer o mecanismo da resposta imunológica na LVC.
Abstract:Visceral leishmaniasis (VL) is a chronic disease that can be fatal to humans and dogs. The disease is caused by the intracellular parasite Leishmania infantum and is transmitted by the bite of the sandfly (phlebotomines). In dogs, VL is observed as an intense chronic inflammatory reaction in the liver, spleen, skin, bone marrow and lymph nodes. Arginase activity is important in VL because an increase of this enzyme may contribute to the multiplication of the parasite and a reduction of nitric oxide (NO) synthesis, predisposing a macrophage to infection. Prostaglandin E2 (PGE2) can play a regulatory role in the production of tumor necrosis factor (TNF-α) and interleukin-10 (IL-10), however, there have been no studies in dogs with LV. This study aimed to evaluate the arginase activity in adherent macrophages cultivated from the lymph nodes of 18 healthy and 23 naturally infected dogs and to examine levels of NO and PGE2 in the supernatant of these cultures. The regulatory effect of PGE2 on the production of TNF-α and IL-10 was also evaluated in supernatants of total lymph node leukocytes cultures. These results help to clarify the mechanisms of the immune response in CVL.
Orientador:Valéria Marçal Felix de Lima
Banca:Alexandra Ivo de Medeiros
Banca:Caris Maroni Nunes
Mestre

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Schütz, Antonio Beltrão. "Estudo comparativo do mecanismo de ação e dos efeitos farmacológicos do tenoxicam, indometacina, dexametasona e metotrexato no processo inflamatório agudo e crônico". Universidade de São Paulo, 1996. http://www.teses.usp.br/teses/disponiveis/25/25136/tde-30052006-163226/.

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Aprofundamos o estudo dos efeitos farmacológicos da dexametasona, indometacina e tenoxicam e de uma droga citostática (metotrexato), assim como a análise dos mecanismos envolvidos na estimulação flogógena causada por agentes de intensidades fraca, média e forte. Para isso. empregamos o teste edemogênico, que demonstrou ser os fármacos antiinflamatórios não esteróides (tenoxicam e indometacina), os de maior potência na inibição da exsudação plasmática induzida pela paracoccidioidina. Todavia, com agentes flogógenos de intensidade média (carragenina), o metotrexato foi o medicamento mais potente; enquanto que com a placa microbiana dental (agente forte), a dexametasona e a indometacina foram os de maior potência antiinflamatória. Por meio da análise histomorfométrica relativa dos granulomas induzidos por esse último agente, verificamos, até 14 dias, a maior potência antiinflamatória apresentada pelo tenoxicam, comparativamente à da indometacina - em relação à inibição da região central de necrose supurativa-, demonstrando efeito semelhante ao da dexametasona; não obstante, nesse período experimental, em relação à inibição da densidade do volume do tecido granulomatoso, os fármacos mais potentes terem sido a indometacina e a dexametasona. Após 14 dias, foi constatada diferença não significativa (p>0.05) entre o efeito apresentado pelo tenoxicam e o da indometacina. O acentuado efeito apresentado pelos NSAIDs em relação à inibição da densidade de volume dos macrófagos, semelhante ao do metotrexato, sugeriu que os NSAIDs inibiram a proliferação das células progenitoras mielóides dos monócitos/macrófagos. Também agiram tanto aumentando (21 dias) como inibindo (28 dias) a densidade de volume ocupada pelas fibras colágenas; enquanto que a dexametasona apresentou efeito contrário. Tais resultados indicaram que no processo inflamatório induzido por agentes flogógenos de intensidade forte (PMD), estimulores da acentuada produção de LTs e PGs, o emprego de antiinflamatórios esteróides e não esteróides foi vantajosa em relação ao fármaco citostátco.
Was studied comparatively the mechanisms of action and the antiinflammatory effect presented by dexamethasone, tenoxican, indomethacin and methotrexate in acute and chronic inflammation induced by agent flogogenous of minim, media and elevated intensity. With the employ of edemogenic test was verified that the effect presented by nonsteroid antiinflammatory (tenoxican and indomethacin), in relation to inhibition of the plasmatic exsudation induced by paracoccidioidin, was more potent than other medicaments tested. Meanwhile, in the inhibition of the acute inflammation caused by carrageenan and dental microbian plaque, methotrexate, dexamethasone and indomethacin were the most potent pharmacs, respectively. The injection of the dental microbian plaque in the air pouch model induced two experimental granulomas susceptive to the antiinflammatory effects presented for the pharmacs tested, which were utilized in the determination of the weights and of the volume density occupied by structures presents in the periods experimental of 7, 14, 21 and 28 days. With relation the inhibition of the differential mid and dry weights, methotrexate and dexamethasone followed by indomethacin and tenoxican were the most effective pharmacs in decrescent order of potency. The histomorphometric studies of the volume density of the granulomatous tissue revealed that indomethacin reduced this structure comparatively to the tenoxican at 14 days. After this experimental period tenoxican presented the most potent anti-inflammatory effect; however, without significant statistical difference to indomethacin. Tenoxican too presented elevated inhibitory effect of the volume density of the region of supurative necrose (similar to dexamethasone) particularly along to first week. NSAIDs also showed in relation the inhibition of volume density of the collagen effect stimulator (21 days) and inhibitor (28 days), while that dexamethasone revealed contrary effect. The accentuate inhibitory effect of the volume density of macrophages presented by NSAIDs was similar to methotrexate, indicating that these medicaments possibly presented anti-mitotic effect to the progenitors myeloid cells of monocytes/macrophages. These results indicated that in the inflammatory process induced by flogogenous of strong intensity, stimulators of increased production of LTS and PGs, the administration of steroids and non-steroids anti-inflammatory was advantageous in relation to methotrexate.

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44

Robinson, Fiona. "Approaches to Understanding the Milling Outcomes of Pharmaceutical Polymorphs, Salts and Cocrystals. The Effect of Different Milling Techniques (Ball and Jet) on the Physical Nature and Surface Energetics of Different Forms of Indomethacin and Sulfathiazole to Include Computational Insights". Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5412.

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The process of milling drugs to obtain samples with a desirable particle size range has been widely used in the pharmaceutical industry, especially for the production of drugs for inhalation. However by subjecting materials to milling techniques surfaces may become thermodynamically activated which may in turn lead to formation of amorphous material. Polymorphic conversions have also been noted after milling of certain materials. Salt and cocrystal formation is a good way of enhancing the properties of an API but little or no work has been published which investigates the stability of these entities when subjected to milling. Different milling techniques (ball and jet) and temperatures (ambient and cryogenic) were used to investigate the milling behaviour of polymorphs, salts and cocrystals. All materials were analysed by XRPD and DSC to investigate any physical changes, i.e. changes in melting point and by inverse gas chromatography (IGC) to investigate whether any changes in the surface energetics occurred as a result of milling. Another aim of this thesis was to see if it was possible to predict the milling behaviour of polymorphs by calculating the attachment energies of the different crystal facets using Materials Studio 4.0. These results were compared to the IGC data to see if the predicted surface changes had occurred. The data collected in this study showed that different milling techniques can have a different effect on the same material. For example ball milling at ambient temperature and jet micronisation of the SFZ tosylate salt caused a notable increase in the melting point of the material whereas ball milling at cryogenic temperatures did not cause this to happen. The IGC data collected for this form also showed a contrast between cryomilling and the other two techniques. The study also showed that the formation of salts and cocrystals does not necessarily offer any increased stability in terms of physical properties or surface energetics. Changes in melting point were observed for the SFZ tosylate salt and the IMC:Benzamide cocrystal. Changes in the specific surface energies were also observed indicating that the nature of the surfaces was also changing. The materials which appeared to be affected the least were the two stable polymorphs, gamma IMC and SFZ III. The computational approach used has many limitations. The software does not allow for conversion to the amorphous form or polymorphic conversions. Such conversions were seen to occur, particularly for the metastable polymorphs used, meaning that this computational approach may only be suitable for stable polymorphs.

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45

Andrade, Toni Carvalho de. "Estudo da granulação por solidificação de materiais fundidos em leito fluidizado utilizando dispersão sólida de indometacina". Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/60/60137/tde-29072009-115330/.

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A preparação de partículas pela técnica de granulação por solidificação de material fundido em leito fluidizado tem se destacado no âmbito da indústria farmacêutica. As vantagens do uso deste método têm atraído muitos pesquisadores para aprimorar e colocar em prática tal técnica de preparo. A principal vantagem deste processo é dispensar o uso de solventes e diminuir o tempo de preparo dos granulados para compressão. O objetivo do presente trabalho foi o desenvolvimento e estudo desta técnica de granulação, usando a lactose tipo spray-dried como substrato e como agente aglutinante uma dispersão do polímero polietilenoglicol 4000 contendo indometacina como fármaco modelo. Outra motivação para este trabalho foi realizar a caracterização físico-química dos granulados obtidos e avaliar um possível aumento da solubilidade deste fármaco de classe II. Resultados obtidos durante estudos preliminares mostram que a solubilidade da indometacina foi consideravelmente aumentada com o uso do PEG e análises físico-química indicaram que não há interação entre a indometacina e o PEG. O método utilizado na granulação consistiu na atomização da dispersão liquefeita de PEG 4000 contendo 25% de indometacina sobre o substrato a fim de obter grânulos contendo estes três componentes. Um estudo prévio da fluidodinâmica da lactose provou ser predominante o regime de leito fluidizado. Para viabilizar a obtenção destas dispersões sólidas, foram estudadas as variáveis do processo como vazão da dispersão carreador/fármaco, vazão do ar de atomização e quantidade total de dispersão adicionada, aplicando para tal um planejamento fatorial tipo Box-Behnken. O leito fluidizado se mostrou eficiente para a granulação e os granulados obtidos foram considerados de boa qualidade baseando-se na sua caracterização por densidades aparente e compactada, fluidez, distribuição granulométrica, doseamento do fármaco e perfil de dissolução in-vitro. Granulados de dois tamanhos médios diferentes e com ótima fluidez foram escolhidos para as análises seguintes. A integridade e ausência de interação do fármaco com os demais componentes destes granulados foram comprovadas por calorimetria exploratória diferencial, difração de raios-X, infravermelho, microscopia de plataforma quente e microscopia de varredura eletrônica. As micrografias mostraram visivelmente que as formas dos cristais de indometacina presentes no granulado apresentaram as características da forma y (II), que é a mesma da indometacina padrão. A dissolução de cápsulas gelatinosas duras contendo os lotes de grânulos escolhidos mostraram que no meio tampão fosfato (pH 7,2) foi liberado até 99% da indometacina. Porém, em meio HCl 0,1N; obteve-se liberação de até 28% da indometacina, o que corresponde a um aumento de 14,5 vezes a liberação obtida com a indometacina padrão.
Recently, there is a renewed interest in the fluidized bed hot melt granulation for the preparation of solid dosage forms in the pharmaceutical industry and academy. The several advantages of this technique have attracted may researchers, but the main advantage are undoubtedly the solvent free operation and the short processing times. The aim of this work was to develop and study this granulation technique using spray-dried lactose as substrate and a dispersion of indomethacin in hot melted polyethylene glycol 4000 and as the binder. Another goal in this work was to characterize the granules obtained and to evaluate any increase in indomethacin solubility in the solid dispersions. The results of preliminary evaluation of indomethacin/polyethylene glycol physical mixtures and solid dispersions showed a considerable increase in the drug solubility, while no chemical or physical interaction with the carrier could be observed. Before the granulation experiments the fluid dynamic behavior of the lactose was characterized as fluidization regime. The method of granulation consisted in the atomization of hot melted polyethylene glycol containing 25% of indomethacin onto the fluidized bed of lactose. In order to study the granulation process, a Box-Behnken design was applied to verify the effects of spray air flow rate, drug/carrier feed rate and total amount of drug/carrier added to granules. The fluidized bed showed to be an effective method for hot melt granulation and the granules quality can be considered adequate, based on their characteristics of apparent and compacted densities, flowability, particle size distribution, indomethacin content and in-vitro dissolution profile. From the whole set of experiments, two granule batches were chosen based on their mean particle sizes and excellent flow indexes, to verify any drug/PEG/lactose interaction during the granulation process. The non existence of interaction was proved by differential scanning calorimetry, X-ray powder diffraction, Fourier transform Infra-red, hot stage microscopy and scanning electron microscopy. The scanning electron microscopy showed that indomethacin crystals with the characteristic shape of the form y (II) could be observed in the granules, indicating that its crystalline form did not change during processing. The dissolution profiles of indomethacin from hard gelatin capsules containing the granules showed the release of 99% of the drug in phosphate buffer media (pH 7.2). However, in acidic media (HCl 0,1N) 28% of the total indomethacin was released, which corresponded to a 14.5 fold increase when compared to the pure indomethacin release under the same conditions.

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46

Shergill, Sarbjit. "An investigation of the anti-inflammatory activity and gastro-toxicity of indomethacin (1%), ibuprofen (5%) and felbinac (3%) topical formulations using carrageenan-induced rat paw oedema and ultra-violet induced erythema models of inflammation". Thesis, Liverpool John Moores University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725120.

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Orally administered non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used in the management of several rheumatic disorders. However, one of the major drawbacks to their use has been the severity of the adverse reactions, in particular the gastro-toxicity associated with oral administration. Topical formulations of NSAIDs were introduced in an attempt to overcome the systemically mediated gastro-toxic effects of oral delivery. It was claimed that topical delivery localised the drug at the site of action and therefore reduced the gastro-toxic effects. These claims were investigated, using carrageenan-induced rat paw oedema arid U.V.- induced erythema models of inflammation. The aim of this study was to determine whether the topical NSABD formulations under investigation produced their beneficial effects locally or systemically, and if topical delivery afforded any benefits with regard to gastro-toxicity. Following topical administration of the NSAID the drug did not remain localised within the tissue and the plasma drug levels achieved were comparable to those produced orally. Hence the number of lesions observed after topical administration were not significantly different to those caused by oral administration. In carrageenan-induced rat paw oedema plasma drug levels appeared to be a critical factor in producing a beneficial anti-inflammatory effect. However, in U.V.-induced erythema tissue drug levels relate to significant anti-inflammatory activity. Therefore, it can be concluded that the topical NSAID formulations under investigation appear to have both systemically arid locally mediated anti-inflammatory effects and that they do not afford any benefits in terms of reducing gastro-toxic effects. The site of action is probably dependent upon the type of end-point inflammatory response (oedema or erythema) and the mediators responsible for the inflammatory response.

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47

Badri, Waisudin. "Preparation of polymeric nanoparticles for topical anti-inflammatory applications". Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1095/document.

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L'objectif de cette thèse est d’encapsuler l'indométacine dans des nanoparticules polymériques en association à l’huile essentielle de Nigella Sativa L. extraite à partir de ses graines afin d’optimiser son utilisation par voie cutanée et potentialiser son activité anti-inflammatoire.Pour ce faire, des nanoparticules à base de poly-epsilon-caprolactone ont été préparées par nanoprécipitation. Une étude systématique a été menée pour comprendre l'effet de la variation des paramètres de préparation sur les propriétés colloïdales des nanoparticules obtenues. Une fois les différents paramètres optimisés, l'indométacine et l'huile essentielle de Nigella Sativa L. ont été encapsulées séparément dans les nanoparticules polymériques. Puis, l’ensemble, indométacine et huile essentielle de Nigella Sativa L. a été encapsulé. Les nanoparticules préparées ont à chaque fois été caractérisées notamment en termes de stabilité et de performance d’encapsulation. Ensuite, nous avons mené une étude ex vivo et in vivo des nanoparticules obtenues afin d’évaluer le potentiel de pénétration cutanée d’une part, et le potentiel clinique dans la prise en charge de l’inflammation
The objective of this PhD thesis was to extract the Nigella Sativa L. Seeds Essential Oil and its encapsulation together with indomethacin within polymeric nanoparticles in order to reduce taken amount and to enhance indomethacin cutaneous penetration, and anti-inflammatory activity. To this direction poly-epsilon-caprolactone based nanoparticles were designed using nanoprecipitation method. A systematic study was performed to figure out the effect of process and formulation parameters on the characteristics of obtained nanoparticles. Once the effects of all parameters were studied, then indomethacin and Nigella Sativa L. Seeds Essential Oil was encapsulated separately. Consequently, both together indomethacin and Nigella Sativa L. Seeds Essential Oil was encapsulated. Then prepared nanoparticles were characterized in terms of stability, encapsulation efficiency. In addition, ex vivo skin penetration and in vivo anti-inflammatory activity of designed nanoparticles was investigated

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Costa, Juslene Aparecida Oliveira da. "Avaliação da Atividade Protetora Gástrica do Extrato Hidroalcoólico da Semente de Girassol". Universidade Jose do Rosario Vellano, 2009. http://tede2.unifenas.br:8080/jspui/handle/jspui/82.

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Made available in DSpace on 2016-05-02T13:54:48Z (GMT). No. of bitstreams: 1 JusleneAparecidaOliveiraCosta-dissertacao.pdf: 896769 bytes, checksum: 1744062ba6c85af80f07a70043a38f54 (MD5) Previous issue date: 2009-10-09
Helianthus annus is a plant known as "sunflower". The use of plants as medicine for human use dates back to the old age. The hydroalcoholic extract of sunflower seed (HESS) has been indiscriminately used for gastric lesions, without scientific support to validate their action. This study assessed quantitatively and qualitatively the probable gastric protection of HESS in stress, and in the use of ethanol and indomethacin; checked the acidity (pH) through the gastric pylorus ligation (gastric residue, either pure or added with water); and compared differences in pH values in both techniques. A total of 120 rats (5 in each group) of the species Rattus norvegicus albinus, weighing 150-230g,were divided into 24 groups, which received the following treatments: HESS: 250mg/kg, 500mg/kg, 1000mg/kg and 2000mg / kg; ethanol; cimetidine; indomethacin; water; cimetidine and ethanol; cimetidine and endomethacin; pylorus ligation and water; pylorus ligation and cimeditine; HESS and ethanol; HESS and indomethacin; pylorus ligation and HESS. The results were submitted to analysis of variance (ANOVA) followed by Tukey test for evaluation of gastric lesions, and Kruskal-Wallis test followed by Dunn, to evaluate the gastric pH, with a statistically significance at p <0.05. This work was approved by the Ethics Committee of the Universidade José do Rosário Vellano, with protocol no. 04 A / 2009. The results showed that HESS 250 mg/kg and 1000mg/kg suggests probable gastric protection in stress. In the ethanol-induced gastric ulcer model, the doses of 250 and 1000 mg / kg showed probable gastric protection; the HESS 250 mg / kg + indomethacin, the dose of 250 mg / kg suggests gastric protection. Regarding the pH, the gastric residue, when pure, is more acidic than water, thus indicating that the model of addition of 3 ml of water is increasing the pH, thus proving that the pure pH model is more appropriate and more practical. Therefore, the data obtained in this study show that HESS probably provides gastric protection at certain doses. So, the results show that the sunflower,should be further studied for the development of phytomedicines or new chemicals with antiulcerogenic activity.
Helianthus annus é uma planta conhecida como girassol . A utilização das plantas, como medicamento para o tratamento das enfermidades que acometem a espécie humana remonta à idade antiga. O uso do extrato hidroalcoólico de semente de girassol (EHSG) para lesões gástricas é utilizado de forma indiscriminada, sem base em estudos científicos que tenham validado sua ação. O presente estudo tem como objetivo comparar quantitativamente e qualitativamente a provável proteção gástrica do EHSG com a cimetidina, frente ao estresse, ao uso da indometacina e do etanol e o pH gástrico por meio da ligadura pilórica (resíduo gástrico puro e com adição de água). Foram estudados 120 ratos (5 em cada grupo) da espécie Rattus norvegicus albinus, com peso de 150-230g, divididos em 24 grupos distintos, os quais receberam o EHSG nas dosagens de 250mg/kg, 500mg/kg, 1000mg/kg e 2000mg/kg, etanol 0,5ml, cimetidina 150mg/ml, indometacina 20mg/Kg e água 1ml. Estes grupos foram submetidos à associação da cimetidina com etanol e indometacina, às 4 dosagens do EHSG com etanol 70% e indometacina, aos grupos submetidos à ligadura pilórica e administração de água, cimetidina e às 4 dosagens de EHSG. As análises estatísticas dos resultados foram realizadas por meio de análise de variância (ANOVA), seguidas pelo teste de Tukey, para avaliação das lesões no estômago, e Kruskal-Wallis, seguido pelo teste Dunn, para avaliação do pH do estômago, utilizando diferença estatisticamente significante para p<0,05. O presente trabalho foi encaminhado e aprovado pelo Comitê de Ética em Pesquisa da Universidade José do Rosário Vellano, com o protocolo 04 A / 2009. Os resultados do estudo mostraram que o EHSG nas dosagens 250 e 1000mg/kg sugerem proteção contra as lesões gástricas no estresse. No modelo de indução de úlcera gástrica por etanol, as dosagens de 250 e 1000 mg/kg apresentaram provável proteção gástrica; no grupo utilizando EHSG 250 mg/kg + indometacina, a dosagem de 250 mg/kg sugere proteção gástrica. Em relação ao valor de pH, o resíduo gástrico, quando verificado puro, mostrou-se mais ácido que pelo modelo da adição de água, significando que este último aumentou o pH, verificando assim que o modelo do resíduo gástrico puro é mais indicado e mais prático. Portanto, os resultados obtidos no presente estudo apontam provável efeito protetor gástrico do EHSG em determinadas doses. Assim, pode-se concluir que a planta em questão constitui interessante alvo de estudo, visando ao desenvolvimento de fitomedicamentos ou à busca de novas entidades químicas com ação antiulcerogênica.

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49

BRUNELLI, CLAUDIA. "Mechanisms of translational control during Rhabdovirus infection". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/202253.

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Molti virus hanno evoluto sofisticate strategie per il controllo dell’apparato traduzionale della cellula ospite, in modo da bloccare la sintesi proteica cellulare e favorire la traduzione dei messaggeri virali. I meccanismi molecolari alla base di questo controllo sono in gran parte sconosciuti. Nel presente lavoro abbiamo studiato l’effetto dell’infezione virale su fattori cellulari che controllano l’inizio della traduzione cap-dipendente, usando come modello cellule di rene di scimmia MA104 infettate con il Virus della Stomatite Vescicolare (VSV), un rhabdovirus che è noto causare un blocco rapido e selettivo della traduzione degli mRNA cellulari. In particolare il nostro studio si è focalizzato sulle modificazioni indotte dal VSV al fattore di inizio della traduzione eIF4E. eIF4E è regolato sia direttamente, attraverso processi di fosforilazione, che indirettamente attraverso il legame con le proteine inibitorie 4E-BPs. L’infezione con VSV causava una marcata riduzione nei livelli di fosforilazione delle 4E-BPs, correlata al blocco dell’attività della chinasi mTOR, a partire da 4 ore p.i.. E’ noto che nello stato defosforilato le 4E-BPs legano eIF4E, impedendogli di entrare a far parte del complesso eIF4F funzionale. Abbiamo inoltre analizzato l’effetto dell’infezione con VSV sulla proteina da stress HSP27 che è stata recentemente implicata nella regolazione di eIF4E. L’analisi in Western blot ha dimostrato che l’infezione con il VSV è in grado di indurre a partire da 2 ore p.i. la fosforilazione di HSP27 associata all’attivazione della MAPK p38. Infine, oltre ai cofattori di eIF4E e HSP27, abbiamo dimostrato che il virus è in grado di indurre la fosforilazione transiente del fattore eIF4E stesso a 4 ore p.i.. Questi risultati indicano che il virus VSV ha evoluto diverse strategie per modificare la funzionalità di eIF4E, alterando il fattore ad almeno tre livelli diversi: 1) inducendo la defosforilazione delle 4E-BPs; 2) causando un aumento della fosforilazione della proteina HSP27; 3) modificando i livelli di fosforilazione del fattore stesso. E’ ipotizzabile che le diverse alterazioni prodotte dal virus siano necessarie per il reclutamento selettivo dei messaggeri virali nel complesso di inizio della traduzione eIF4F. Un secondo obiettivo del progetto è stato identificare molecole antivirali che agiserro sull’espressione delle proteine virali. In particolare abbiamo studiato i meccanismi molecolari e le vie di segnalazione potenzialmente coinvolte nell’attività antivirale del farmaco anti-infiammatorio non-steroideo (NSAID) indometacina, nei confronti dell’espressione delle proteine del VSV. L’indometacina è un inibitore degli enzimi ciclo-ossigenasi 1 e 2 ampiamente usato in trattamenti clinici per la sua potente azione anti-infiammatoria e anti-dolorifica. Oltre ad avere attività antiinfiammatoria, l’indometacina ha anche un’azione antivirale nei confronti di molti patogeni virali umani; tuttavia, il meccanismo di azione antivirale non è ancora chiarito. Abbiamo dimostrato che l’indometacina agisce a livello della sintesi proteica, inducendo rapidamente la fosforilazione della subunità α del fattore di inizio traduzionale eIF2, il complesso multi proteico responsabile del reclutamento del tRNA iniziatore (Met-tRNAi) a livello della subunità ribosomale 40S in maniera GTP-dipendente. Abbiamo dimostrato che l’indometacina attiva in maniera diretta la chinasi PKR (dsRNA-dependent protein kinase), un enzima con un ruolo critico nella difesa dell’ospite nei confronti delle infezioni virali, causando una rapida (< 5 minuti) fosforilazione di eIF2α. Durante l’infezione con il VSV questa fosforilazione di eIF2α mediata da PKR induce il blocco della sintesi proteica virale e della replicazione virale, proteggendo inoltre la cellula ospite dall’effetto citopatico indotto dal virus. L’indometacina non modula la funzione delle altre chinasi di eIF2α PERK e GCN2, ed è risultata essere incapace di causare la fosforilazione di eIF2α in cellule knock-out per PKR. Inoltre, il silenziamento di PKR tramite RNA-interference in cellule umane previene la fosforilazione di eIF2α e impedisce l’effetto antivirale dell’indometacina. Questi risultati identificano PKR come un bersaglio critico per l’attività antivirale dell’indometacina, suggerendo che la fosforilazione di eIF2α possa essere un elemento chiave nell’attività antivirale ad ampio spettro di tale farmaco.
Modulation of the host cell translational machinery by viruses is a crucial part of the virus strategy to replicate. Many viruses can selectively inhibit host translation and still use the host translation machinery to synthesize their own proteins. In particular, some rhabdoviruses cause a dramatic shut-off of host cell protein synthesis. Rhabdoviruses are enveloped RNA viruses widely distributed in nature, belonging to the Rhabdoviridae family. They represent the simplest of the non-segmented negative-stranded (NNS) RNA viruses, and have a wide host range, infecting reptiles, fish, insects, plants and mammals, including man. The main member of the Rhabdoviridae family is the rabies virus. Rabies is a disease diffused in the world and, even though there is an effective vaccine, the disease cannot be controlled because of the presence of the virus in wild animals. Vesicular Stomatitis virus (VSV) is the main model used in rhabdovirus experimental studies. Following viral penetration and uncoating, VSV primary mRNAs are synthesized in the host cell cytoplasm by the virus-associated RNA-dependent RNA polymerase. When viral proteins begin to accumulate, progeny viral genomes are replicated and used for secondary transcription. mRNA from both primary and secondary transcription are similar in structure to host messengers, containing a cap at the 5’-end and a 3’-poly(A) tail similar in length to host mRNAs. During VSV replication host translation is rapidly inhibited. The molecular basis of the mechanism causing the host protein synthesis shut-off is still largely unknown. The aim of this project was to investigate the mechanisms underlying the shut-off of cellular protein synthesis induced by VSV, with the double objective to elucidate the viral strategy for selective translation, and to identify novel targets for antiviral compounds interfering with viral protein expression. A key regulatory step during translation is the initiation, that requires several initiation factors. One of the rate-limiting factors of cap-dependent initiation during viral infection is the mRNA 5’ cap-binding protein eIF4E, a component of the eIF4F complex. Therefore most of this study was focused to analyze several signalling pathways that may lead to the alteration of eIF4E activity in our model. The results obtained suggest that VSV interferes with eIF4E at multiple levels: 1) inducing a transient eIF4E phosphorylation at 4 hours p.i.; 2) inducing 4E-BP1 dephosphorylation, an event that is known to lead to dissociation of eIF4E from the eIF4F complex, thus inhibiting host protein synthesis; 3) inducing at 2 hours p.i. the phosphorylation of HSP27, a small heat shock protein that has been recently involved in translation regulation, by modulating the availability of eIF4E and eIF4G for cap-dependent translation. These results indicate that this factor may play a key role in the virus-induced shut-off of the host cell protein synthesis. The mechanisms by which VSV is able to synthesize its proteins under these conditions is not known, even though it can be hypothesized that the peculiar viral mRNAs structure, characterized by short 5’-UTR regions lacking elaborate secondary structure, could be responsible for preferential translation. A second objective of the project was to identify antiviral molecules targeting viral protein expression. We have now identified different cycloxygenase (COX) inhibitors which interfere with VSV protein expression. Among these, we investigated the molecular mechanisms and the signalling pathways potentially involved in the antiviral activity of the non-steroidal antiinflammatory drug indomethacin. Indomethacin is a cyclooxygenase-1 and -2 inhibitor widely used in the clinic for its potent anti-inflammatory and analgesic properties. In addition to antiinflammatory/analgesic action, indomethacin also possesses antiviral activity against several human viral pathogens; however, the mechanism of the antiviral action remained elusive. We demonstrate that indomethacin acts at the translational level, by rapidly inducing the phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2), the multiprotein complex responsible for recruiting the initiator Met-tRNAi to the 40S ribosomal subunit in a GTP-dependent manner. We found that indomethacin directly activates the double-stranded RNA (dsRNA)-dependent protein kinase PKR, an enzyme that plays a critical role in the host antiviral defence and survival, causing rapid (< 5 minutes) phosphorylation of eIF2α. During VSV infection, PKR-mediated eIF2α phosphorylation resulted in shutting-off viral protein translation and blocking viral replication while protecting host-cells from virus-induced damage. Indomethacin did not affect eIF2α kinases PERK and GCN2, and was unable to trigger eIF2α-phosphorylation in PKR knock-out cells. In addition, small interfering RNA-mediated PKR-gene silencing prevented eIF2α phosphorylation and dampened the antiviral effect in indomethacin-treated human cells. The results identify PKR as a critical target for the antiviral activity of indomethacin and indicate that eIF2α phosphorylation could be a key element in the broad-spectrum antiviral activity of the drug.

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Santos, Fernanda Regina Ribeiro. "Ciclooxigenase-2 modula in vivo a expressão de marcadores da osteoclastogênese e genes envolvidos no metabolismo ósseo em resposta ao lipopolissacarídeo bacteriano". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/58/58135/tde-04072012-135640/.

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Abstract (sommario):

Durante a resposta inflamatória, diversos mediadores são liberados localmente com o objetivo de estimular a resposta imune celular e humoral. Por meio da ação das enzimas ciclooxigenases e lipoxigenases ocorrerão modificações estruturais na cadeia do ácido araquidônico levando a síntese de prostaglandinas ou leucotrienos e lipoxinas, respectivamente. Tais mediadores são responsáveis pela regulação da expressão dos genes RANK, RANKL e OPG, moduladores da osteoclastogênese. Dessa maneira, o objetivo deste estudo foi avaliar a expressão do RNA mensageiro (RNAm) para as enzimas envolvidas no metabolismo do ácido araquidônico, ciclooxigenase-2 (COX-2) e 5- lipoxigenase (5-LO), e para os mediadores da osteoclastogênese (RANK, RANKL e OPG) no tecido ósseo, após inoculação de lipopolissacarídeo bacteriano (LPS) nos canais radiculares de molares de camundongos. Posteriormente foi investigado o efeito do bloqueio farmacológico da via COX-2 induzida pelo LPS, na expressão de mediadores da osteoclastogênese e de genes envolvidos no metabolismo ósseo. Foram utilizados 144 camundongos C57BL/6, com 6 semanas de idade, pesando de 18 a 20 gramas, nos quais os canais radiculares dos primeiros molares foram inoculados com uma solução contendo lipopolissacarídeo bacteriano de E. coli (0,1, 1,0 e 10mg/ml). Decorridos os períodos experimentais de 7, 14, 21 e 28 dias, os animais foram submetidos à eutanásia e os blocos contendo dente e osso foram removidos para extração do RNA total. Em seguida, foi realizada a avaliação da expressão gênica por meio de transcrição reversa e reação da polimerase em cadeia em tempo real (qRT-PCR). A análise global da expressão de RNAm para proteínas envolvidas no metabolismo ósseo foi realizada por meio de um ensaio de PCR Array (Osteogenesis RT² Profiler PCR Array). Os valores de expressão relativa de cada RNAm, para cada grupo, foram comparados por meio da análise de variância (ANOVA) de duas vias seguido pelo pós-teste de Bonferroni ou por ANOVA de uma via seguido pelo pós-teste de Dunnett (&alpha = 0,05). A inoculação de LPS nos canais radiculares de molares de camundongos foi capaz de induzir a expressão dos genes PTGS2 e ALOX5, responsáveis pela codificação das enzimas COX-2 e 5-LO, envolvidas no metabolismo do ácido araquidônico, concomitantemente à modulação da expressão dos genes TNFRSF11A, TNFSF11 e TNFRSF11B, responsáveis pela codificação dos moduladores da osteoclastogênese RANK, RANKL e OPG, respectivamente. A administração de Indometacina, um inibidor não seletivo de COX-2, inibiu a expressão de RNAm para RANK e RANKL e estimulou a expressão de OPG durante os períodos iniciais de resposta à inoculação de LPS nos canais radiculares. A inibição da via COX-2 de metabolismo do ácido araquidônico nos períodos iniciais de resposta à inoculação de LPS nos canais radiculares modulou diferencialmente a expressão de genes envolvidos no catabolismo e anabolismo ósseo, indicando possíveis papéis para os mediadores derivados no ácido araquidônico na regulação do metabolismo ósseo. Estes resultados sugerem alvos terapêuticos importantes para intervenção precoce em doenças inflamatórias, como lesões periapicais para evitar a reabsorção do tecido ósseo.
During an inflammatory response, several mediators are locally released in order to stimulate cellular and humoral immune response. Through the action of cyclooxygenase and lipoxygenase enzymes structural changes occur in the arachidonic acid chain leading to synthesis of prostaglandins or leukotrienes and lipoxins, respectively. Such mediators are responsible for the regulation of RANK, RANKL and OPG gene expression, osteoclastogenesis modulators. Thus, the objective of this study was to evaluate the expression of messenger RNA (mRNA) for the enzymes involved in arachidonic acid metabolism, cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), and the osteoclastogenesis mediators (RANK, RANKL and OPG) in bone tissue after injection of bacterial lipopolysaccharide (LPS) in murine dental root canals. Then, COX-2 pathway was pharmacologically blocked for investigation of expression of osteoclastogenesis mediators and genes involved in bone metabolism. We used 144 C57BL/6 mice, 6 weeks-old, weighing 18-20 grams, which had the first molars root canals inoculated with a solution containing LPS from E. coli (0.1, 1.0 and 10 mg/ml). After 7, 14, 21 and 28 days the animals were euthanized and the tooth-and-bone blocks were removed for total RNA extraction. Subsequently, the evaluation of gene expression was performed by reverse transcription and polymerase chain reaction in real time (qRT-PCR). Global analysis of mRNA expression for proteins involved in bone metabolism was performed using PCR arrays (Osteogenesis RT² Profiler PCR Array). The values for relative expression of each mRNA for each group were compared using two-way analysis of variance (ANOVA) followed by Bonferroni post-test or one-way ANOVA followed by Dunnett\'s test (α=0.05). The injection of LPS into the root canals was induced expression of genes PTGS2 and ALOX5, responsible for encoding COX-2 and 5-LO enzymes, involved in the metabolism of arachidonic acid, simultaneously to the modulation of gene expression of TNFRSF11A, TNFSF11 and TNFRSF11B, responsible for encoding the osteoclastogenesis modulators RANK, RANKL and OPG, respectively. Administration of Indomethacin, a non-selective inhibitor of COX-2, inhibited the expression of mRNA for RANK and RANKL and stimulated the expression of OPG during the initial response to the root canals contamination with LPS. Inhibition of the COX-2 pathway from arachidonic acid metabolism in the initial periods of response to LPS injection into the root canals differentially modulated the expression of genes involved in bone catabolism and anabolism, indicating possible roles for mediators derived from arachidonic acid in the regulation of bone metabolism. These results suggest important therapeutic targets for early intervention in inflammatory diseases such as apical periodontitis to avoid resorption of bone tissue.

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Tesi sul tema "Indomethacin"

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