ABSTRACT The non-steroidal anti-inflammatory drug (NSAID), diclofenac, has been associated with a high risk for cardiovascular events in observational studies. However, majority of studies identifying this association were conducted when diclofenac was the only NSAID that could be obtained as a combination product (i.e., formulated with misoprostol). As a result, channelling bias might have resulted if prescribers selected the combination of diclofenac/misoprostol (Diclo-Miso) in patients with poor health status frequently than other NSAID products. The main purpose of this study was to identify evidence for channelling bias in a cohort of patients with coronary heart disease (CHD) prescribed NSAIDs. Three independent, retrospective analyses were carried out using Saskatchewan’s health administrative databases. Patients were eligible if they were hospitalized with CHD event between January 1, 1994 and December 31, 2008. In the first analysis, a time series was conducted to examine trends in the use of NSAIDs following discharge from original hospitalization. In the second analysis, multivariate logistic regression models were constructed to identify characteristics of patients prescribed with Diclo-Miso in comparison to single-entity diclofenac. Finally, a nested case-control study was conducted to examine the risk for recurrent myocardial infarction (MI)/ Unstable Angina (UA) or death among patients prescribed with Diclo-Miso versus single-entity diclofenac. For each case, up to five controls were matched by age and sex. Between 1994 and 2008, NSAIDs were used by 20.1% (3,099/15,393) of patients in the year following discharge from their original MI/UA hospitalization. Use of these agents was relatively stable until 2004 when the COX-2 selective agent rofecoxib was withdrawn from the market. Following this date (i.e., September 30, 2004), the use of Diclo-Miso and single-entity diclofenac appeared to follow different trends. However, available patient and disease specific factors could not explain diverging utilization trends. Further, no differences were observed in the risk of experiencing recurrent MI/UA between patients receiving Diclo-Miso (OR 0.88, 95% CI 0.72-1.08, p=0.22) or single-entity diclofenac (OR 0.78, 95% CI 0.60-1.00, p=0.06) versus patients not exposed to NSAIDs. Based on the study’s result, channelling bias does not appear to be a major threat to the analysis of cardiovascular toxicity of diclofenac products.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for systemic control of acute and chronic pain and inflammation (Lin et ah, 2000:1129), but usage problems and side-effects that occur during the post-marketing phase of these drugs are well documented (Thiefin & Beaugerie, 2005:287). Following the demonstration of the value of anti-inflammatory therapy in diseases like rheumatoid arthritis (Boardman & Dudley Hart, 1967:268), new NSAIDs appeared on the market (Dieppe et al., 2004:867), and the indications steadily broadened from inflammatory diseases to almost any painful condition. Studies have indicated that NSAID-associated serious upper gastro-intestinal (GI) adverse events result in 103 000 hospitalisations (Bombardier, 2002:4) and 165 000 deaths per year in the United States. A study in South Africa in 2002 indicated that NSAID utilisation contributed considerably to the total cost of all medicine items from a medicine claim database in the private health care sector (Joubert, 2002:260). The objective of this study was to determine the prevalence and cost of non-steroid anti-inflammatory drugs in a section of the private health care sector, and specifically to determine the prevalence, usage and cost of Coxib (Specific cyclo-oxygenase-2 inhibitor) medicine items before and after the withdrawal of Vioxx® from the market in September 2004 (Merck, 2004). Data from two medicine claim databases for the years 2004, 2005 and 2006 (medicine claim database I) and the years 2005 and 2006 (medicine claim database M), were analysed by means of a retrospective drug utilisation review (DUR) study. The usage of Coxib medicine items was determined, and compared for the periods before and after the withdrawal of Vioxx® in September 2004. It was found that between 9 and 10.5 per cent of prescriptions dispensed through both medicine claim database I and medicine claim database M during the study period were NSAID prescriptions. NSAID medicine items on medicine claim database I represented between 3.9 % (R25 942 986) and 2.9 % (R8 073 034) of the total cost of all medicine items claimed from 2004 to 2006. NSAIDs represented 3.1 % (R58 290 412) and 2.8 % (R57 752 267) of the cost of all medicine items claimed through medicine claim database M during 2005 and 2006 respectively, indicating similar trends in the two medicine claim databases. The prevalence of Coxibs on medicine claim database I decreased from almost 20 % (47 938) in 2004 to 8.4 % (13 276) in 2005, but showed an increase again to 10.9 % (12 355) in 2006. The prevalence of both cyclo-oxygenase (COX) inhibitors, and Coxibs demonstrated a change during 1 September 2004 to 31 December 2004 when COX-inhibitors showed an increase in use, while Coxibs showed and almost equal but opposite trend with a decrease in use. This could possibly be related to perceptions of providers and public with regard to Coxibs and their related safety after the withdrawal of Vioxx® on 30 September 2004 (Merck, 2004) and other Coxibs such as Bextra® (FDA, 2005) in 2005 in USA. It is concluded that most patients who were using Coxibs before the withdrawal of Vioxx®, substituted Coxibs for COX-inhibitors, that are known for their possible gastro-intestinal side-effects. Recommendations for future research regarding NSAID use were also made, and included an investigation of the usage of Coxibs in different age groups, as well as the combination of NSAIDs with gastro-protective medicines in long-term use. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2009.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for systemic control of acute and chronic pain and inflammation (Lin et ah, 2000:1129), but usage problems and side-effects that occur during the post-marketing phase of these drugs are well documented (Thiefin & Beaugerie, 2005:287). Following the demonstration of the value of anti-inflammatory therapy in diseases like rheumatoid arthritis (Boardman & Dudley Hart, 1967:268), new NSAIDs appeared on the market (Dieppe et al., 2004:867), and the indications steadily broadened from inflammatory diseases to almost any painful condition. Studies have indicated that NSAID-associated serious upper gastro-intestinal (GI) adverse events result in 103 000 hospitalisations (Bombardier, 2002:4) and 165 000 deaths per year in the United States. A study in South Africa in 2002 indicated that NSAID utilisation contributed considerably to the total cost of all medicine items from a medicine claim database in the private health care sector (Joubert, 2002:260). The objective of this study was to determine the prevalence and cost of non-steroid anti-inflammatory drugs in a section of the private health care sector, and specifically to determine the prevalence, usage and cost of Coxib (Specific cyclo-oxygenase-2 inhibitor) medicine items before and after the withdrawal of Vioxx® from the market in September 2004 (Merck, 2004). Data from two medicine claim databases for the years 2004, 2005 and 2006 (medicine claim database I) and the years 2005 and 2006 (medicine claim database M), were analysed by means of a retrospective drug utilisation review (DUR) study. The usage of Coxib medicine items was determined, and compared for the periods before and after the withdrawal of Vioxx® in September 2004. It was found that between 9 and 10.5 per cent of prescriptions dispensed through both medicine claim database I and medicine claim database M during the study period were NSAID prescriptions. NSAID medicine items on medicine claim database I represented between 3.9 % (R25 942 986) and 2.9 % (R8 073 034) of the total cost of all medicine items claimed from 2004 to 2006. NSAIDs represented 3.1 % (R58 290 412) and 2.8 % (R57 752 267) of the cost of all medicine items claimed through medicine claim database M during 2005 and 2006 respectively, indicating similar trends in the two medicine claim databases. The prevalence of Coxibs on medicine claim database I decreased from almost 20 % (47 938) in 2004 to 8.4 % (13 276) in 2005, but showed an increase again to 10.9 % (12 355) in 2006. The prevalence of both cyclo-oxygenase (COX) inhibitors, and Coxibs demonstrated a change during 1 September 2004 to 31 December 2004 when COX-inhibitors showed an increase in use, while Coxibs showed and almost equal but opposite trend with a decrease in use. This could possibly be related to perceptions of providers and public with regard to Coxibs and their related safety after the withdrawal of Vioxx® on 30 September 2004 (Merck, 2004) and other Coxibs such as Bextra® (FDA, 2005) in 2005 in USA. It is concluded that most patients who were using Coxibs before the withdrawal of Vioxx®, substituted Coxibs for COX-inhibitors, that are known for their possible gastro-intestinal side-effects. Recommendations for future research regarding NSAID use were also made, and included an investigation of the usage of Coxibs in different age groups, as well as the combination of NSAIDs with gastro-protective medicines in long-term use. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2009.

Made available in DSpace on 2014-06-11T19:32:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-14Bitstream added on 2014-06-13T19:42:31Z : No. of bitstreams: 1 vizioli_eo_dr_arafcf.pdf: 7064778 bytes, checksum: e872f0937bcd407f465d83cdf5ba7ec6 (MD5) / Universidade Estadual Paulista (UNESP) / A inflamação é uma reação de defesa e reparo fisiológico, importante em resposta a agressões físicas, químicas ou biológicas ao organismo, que geram o aparecimento dos quatro sinais cardinais dor, edema, calor, rubor, incluindo, muitas vezes a perda de função do tecido ou órgão. O processo inflamatório agudo é imediato e inespecífico contra o agente agressor, podendo evoluir para crônico, caso haja a permanência do agente agressivo e é caracterizado pelo aumento de celularidade e outros elementos teciduais. Várias substâncias estão envolvidas no processo inflamatório, como a prostaglandinas, histamina, serotonina e citocinas pró-inflamatórias como IL-1b, 1L-6, IL-8, TNF-a, NF-kB. Estima-se que exista na terapêutica, mais de 50 antiinflamatórios não esteróides (AINEs) diferentes, mas nenhum deles totalmente destituído de efeitos tóxicos, como a gastrotoxicidade, mesmo os compostos mais novos, seletivos para receptores COX2, como o celecoxibe. Por este motivo nenhum AINEs é recomendado para utilização em processos inflamatórios crônicos. Neste sentido, Vizioli (2006) e Castro (2008), planejaram pró-fármacos taurínicos e híbridos ftalimídicos, respectivamente, obtendo resultados promissores como antiinflamatórios potenciais destituídos de gastrotoxicidade. O presente trabalho visa realizar os testes pré-clinicos de atividade antiinflamatória aguda e crônica. Os resultados demostraram que que todos os derivados testados não apresentam gastrotoxicidade em relação ao padrão AINE testado, sem alteração significativa da resposta inflamatória aguda, com exceção do derivado de ibuprofeno N-(1,3-dioxo-1,3-diidro-2H-isoindol-2-il)-2-(4-isobutilfenil) propanamida, que demonstrou atividade inferior. Em estudo de atividade inflamatória crônica... / Inflammation is a defense and repair physiologic reaction important in response to an physical, chemical or biological aggression of the body, providing the appearance of the four cardinal signs of pain, swelling, heat, redness, including often the loss of function of the tissue or organs. The acute inflammatory process is immediate and nonspecific against the aggressive agent and it is characterized by increased cellular and other tissue elements. Series of substances are involved in the inflammatory process such as prostaglandins, histamine, serotonin and pro-inflammatory cytokines such as 1L-6, IL-8, a-TNF, NF- kB. It is estimated that exists more than 50 different non steroidal anti-inflammatory drugs (NSAIDs) drugs in the market, but none of them are wholly without side effects such as gastro toxicity, even the newer compounds, selective to COX2 receptors, as the celecoxib. For this reason none of NSAIDs is recommended for use in chronic inflammatory diseases. In this sense, Vizioli (2006) and Castro (2008), planned new taurine prodrugs and phtalimide hybride NSAIDs, respectively, showing promising results as anti-inflammatory without toxicity. This work aims to accomplish pre-clinical assay by acute and chronic models of inflammation. The results showed that all derivatives tested have no gastro toxicity when compared with the NSAIDs standard. No significant inflammatory response was observed with the exception toibuprofen derivative N-(1,3-dioxo-1,3-diidro-2H-isoindol-2-il)-2-(4-isobutilfenil) propanamide, which showed less activity. In the chronic inflammatory study activity all compounds phthalimide and taurine showed increase of activity compared to standard NSAIDs with decrease of the mortality and exclusion of the clinical signals such as bleeding, weight loss, and increased defecation rate... (Complete abstract click electronic access below)

Master of Science / Department of Clinical Sciences / Gregory F. Grauer / Prostaglandins play many important roles in the kidney including regulation of renal blood flow, glomerular filtration, renin release, and sodium excretion. Upon activation of the renin angiotensin aldosterone system (RAAS), prostaglandin upregulation becomes critical to offset the vasoconstrictive effects of norephinephrine, angiotensin II, and vasopressin. Nonsteroidal anti-inflammatory drugs (NSAIDs) produce both their beneficial and detrimental effects through inhibition of the cyclooxygenase enzyme and subsequent interference with prostaglandin production. Healthy canine kidneys express both COX-1 and COX-2, although basal COX-2 expression in dogs is significantly higher than in other species. Nonsteroidal anti-inflammatory drugs that spare COX-1 have exhibited less gastrointestinal toxicity, but no NSAID has been proven safe for the kidney. The kidney is the organ with the second highest reports of adverse drug events, which is usually manifested as functional changes. However, structural changes including renal papillary necrosis, can occasionally be observed. Dogs with chronic kidney disease could be expected to be at increased risk for NSAID-related adverse drug effects. As nephrons and renal reserve are lost in chronic kidney disease, the canine kidney becomes more dependent on COX-2 for production of prostaglandins. Inasmuch as the prevalence of both CKD and OA increases with age, it is expected that many dogs being treated with NSAIDs for OA will have loss of renal reserve and/or early stage CKD. If administration of an NSAID is required for long term treatment of osteoarthritis, frequent monitoring of blood pressure and renal parameters, as well as hepatic enzymes are recommended.

Made available in DSpace on 2014-06-11T19:29:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-11-22Bitstream added on 2014-06-13T20:19:22Z : No. of bitstreams: 1 eberle_as_me_botfm.pdf: 395672 bytes, checksum: c52ffaf5efef264884d6ad1f77cee96b (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fármacos antiinflamatórios, inibidores da síntese de prostaglandinas, são muitas vezes administrados imediatamente antes da cirurgia, ou durante a mesma, para tratamento de dor pós-operatória. Se ocorrer hemorragia intraoperatória, o rim estaria sem a ação protetora das prostaglandinas, com possibilidade de pior lesão isquêmica. Entretanto, estudo mostrou menor lesão com o antiinflamatório cetoprofeno nessa situação. Em vista disso, o objetivo deste estudo foi pesquisar a expressão renal de citocinas TNFα e IL-1, em ratos que receberam cetoprofeno antes de serem submetidos à hemorragia aguda sem ressuscitação fluídica, relacionando esta expressão com o resultado histológico. Método. Este trabalho foi desenvolvido com 20 ratos Wistar machos, anestesiados com pentobarbital sódico, 50 mg. kg-1 por via intraperitoneal, e divididos em dois grupos submetidos a sangria de 30% da volemia, realizada em três momentos com tempo de 10 minutos entre eles. No grupo G1, 10 animais permaneceram apenas com infusão venosa contínua de solução de Ringer com lactato para reposição de perdas mínimas. No grupo G2, 10 animais também receberam, por via venosa, cetoprofeno 1,5 mg. kg-1, 60 minutos antes da hemorragia. Os atributos estudados foram: pressão arterial média, temperatura retal, hematócrito, concentrações séricas de TNF-α e IL-1, análise histológica do rim, imunomarcações teciduais renais de TNF-α e IL-1. Resultados. Os animais foram homogêneos quanto ao peso. Em G1, a redução da pressão arterial média foi intensa e em G2 houve redução, porém não significativa. Ambos os grupos já antes da hemorragia apresentaram animais com hipotermia, a qual foi mais intensa em G2. Em G2, o hematócrito foi significativamente maior que em G1. Os valores séricos de TNF-α já estavam elevados quando da hemorragia, em G1 e G2, porém muito mais neste último... / Anti-inflammatory drugs, inhibitors of prostaglandins synthesis, are several times administered immediately before or during surgery for postoperative pain relief. In case of intraoperative hemorrhage, the kidney would lose the protective action of the prostaglandin, with the possibility of a worse ischemic lesion. In this case, however, study has shown a smaller lesion with the use of the antiinflammatory drug ketoprofen. The aim of this study was to research the renal expression of cytokines TNF- and IL-1 in rats which have received ketoprofen before being submitted to acute hemorrhage without fluid resuscitation, connecting this expression with the histological result. Method: This study was developed with 20 male Wistars rats, anesthetized with 50 mg.kg-1 of sodium pentobarbital intraperitoneal, and divided in two groups submitted to a 30% volemia bleeding, performed in three moments with a 10 minutes lapse between them. In the group G1, 10 animals remained only with continuous venous infusion of lactated Ringer solution to replace the minimum loss. In the group G2, 10 animals received 1,5 mg.kg-1 of ketoprofen intravenously as well, 60 minutes before the hemorrhage. The attributes studied were: medium artery blood pressure, rectal temperature, hematocrit, serum concentration of cytokines TNF- and IL-1, histological analysis of the kidney, immunostaining of TNF- and IL-1 in renal tissues. Results: The animals were homogeneous in weight. The group G1 showed an intense reduction of the medium artery blood pressure while the group G2 showed a non significative reduction. The animals in both groups had already presented hypothermia before the hemorrhage, which was more intense in group G2. Also in this group, the hematocrit was considerably larger than in group G1. The serum values of TNF- were already high at the time of first hemorrhage... (Complete abstract click electronic access below)

Orientador: Yara Marcondes Machado Castiglia / Banca: Maria Rita Parisi Fortes / Banca: Luiz Vicente Garcia / Resumo: Fármacos antiinflamatórios, inibidores da síntese de prostaglandinas, são muitas vezes administrados imediatamente antes da cirurgia, ou durante a mesma, para tratamento de dor pós-operatória. Se ocorrer hemorragia intraoperatória, o rim estaria sem a ação protetora das prostaglandinas, com possibilidade de pior lesão isquêmica. Entretanto, estudo mostrou menor lesão com o antiinflamatório cetoprofeno nessa situação. Em vista disso, o objetivo deste estudo foi pesquisar a expressão renal de citocinas TNFα e IL-1, em ratos que receberam cetoprofeno antes de serem submetidos à hemorragia aguda sem ressuscitação fluídica, relacionando esta expressão com o resultado histológico. Método. Este trabalho foi desenvolvido com 20 ratos Wistar machos, anestesiados com pentobarbital sódico, 50 mg. kg-1 por via intraperitoneal, e divididos em dois grupos submetidos a sangria de 30% da volemia, realizada em três momentos com tempo de 10 minutos entre eles. No grupo G1, 10 animais permaneceram apenas com infusão venosa contínua de solução de Ringer com lactato para reposição de perdas mínimas. No grupo G2, 10 animais também receberam, por via venosa, cetoprofeno 1,5 mg. kg-1, 60 minutos antes da hemorragia. Os atributos estudados foram: pressão arterial média, temperatura retal, hematócrito, concentrações séricas de TNF-α e IL-1, análise histológica do rim, imunomarcações teciduais renais de TNF-α e IL-1. Resultados. Os animais foram homogêneos quanto ao peso. Em G1, a redução da pressão arterial média foi intensa e em G2 houve redução, porém não significativa. Ambos os grupos já antes da hemorragia apresentaram animais com hipotermia, a qual foi mais intensa em G2. Em G2, o hematócrito foi significativamente maior que em G1. Os valores séricos de TNF-α já estavam elevados quando da hemorragia, em G1 e G2, porém muito mais neste último... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Anti-inflammatory drugs, inhibitors of prostaglandins synthesis, are several times administered immediately before or during surgery for postoperative pain relief. In case of intraoperative hemorrhage, the kidney would lose the protective action of the prostaglandin, with the possibility of a worse ischemic lesion. In this case, however, study has shown a smaller lesion with the use of the antiinflammatory drug ketoprofen. The aim of this study was to research the renal expression of cytokines TNF- and IL-1 in rats which have received ketoprofen before being submitted to acute hemorrhage without fluid resuscitation, connecting this expression with the histological result. Method: This study was developed with 20 male Wistars rats, anesthetized with 50 mg.kg-1 of sodium pentobarbital intraperitoneal, and divided in two groups submitted to a 30% volemia bleeding, performed in three moments with a 10 minutes lapse between them. In the group G1, 10 animals remained only with continuous venous infusion of lactated Ringer solution to replace the minimum loss. In the group G2, 10 animals received 1,5 mg.kg-1 of ketoprofen intravenously as well, 60 minutes before the hemorrhage. The attributes studied were: medium artery blood pressure, rectal temperature, hematocrit, serum concentration of cytokines TNF- and IL-1, histological analysis of the kidney, immunostaining of TNF- and IL-1 in renal tissues. Results: The animals were homogeneous in weight. The group G1 showed an intense reduction of the medium artery blood pressure while the group G2 showed a non significative reduction. The animals in both groups had already presented hypothermia before the hemorrhage, which was more intense in group G2. Also in this group, the hematocrit was considerably larger than in group G1. The serum values of TNF- were already high at the time of first hemorrhage... (Complete abstract click electronic access below) / Mestre

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / The use of PET as a support material for TiO2 films in advanced oxidation processes (AOPs) for water treatment was investigated. A green, low-cost immobilization procedure was developed and the amount of deposited photocatalyst ranged from 0.036 to 0.202 mg per cm2 PET. Photocatalytic activity of the films was evidenced by degrading paracetamol solutions under UV radiation. The highest kinetic constants were observed for at least 0.09 mg TiO2 per cm2 PET. Scan Electron Microscopy (SEM) and Energy-Dispersive X-ray (EDX) analyses indicated 0.15 mg TiO2 per cm2 PET as enough to provide complete covering of the PET support. Characterization analyses were performed with a film after 30 h of use in a UV/TiO2/O3 reactor. According to SEM analyses, the photocatalyst was not detached from the PET support, while EDX and gravimetric data indicated the possibility of the TiO2 to have been contaminated by compounds present in the solution during the treatment. Further experiments were performed, concerning the study of the degradation of the pharmaceuticals paracetamol, ibuprofen, ketoprofen, and naproxen. Degradation studies were carried out in a pilot-scale reactor, by using several AOPâs, namely direct photolysis, heterogeneous photocatalysis, and ozonation, either individually or simultaneously. Special attention was given to the identification of significant factors considered, in order to contribute to the optimization of systems in which such AOPs or their combination can be used. Also, the detection and indication of degradation products is presented. / O uso de PET (politereftalato de etileno) como material de suporte para filmes de TiO2 foi estudado. Um procedimento de baixo custo e ambientalmente correto foi desenvolvido para a obtenÃÃo dos filmes e a quantidade de fotocatalisador depositada variou de 0,036 a 0,202 mg por cm2 de PET. A atividade fotocatalÃtica dos filmes obtidos foi evidenciada por ensaios de degradaÃÃo de paracetamol sob radiaÃÃo UV. As maiores constantes cinÃticas foram observadas quando 0.09 mg de TiO2 ou mais foram depositados por cm2 PET. AnÃlises por microscopia eletrÃnica de varredura (MEV) e energia dispersive de raios-X (EDX) indicaram que 0,15 mg de TiO2 por cm2 de PET foram suficientes para completa cobertura do suporte. AnÃlises de caracterizaÃÃo tambÃm foram realizadas em filmes com mais de 30 h de uso em sistema UV/TiO2/O3. De acordo com as anÃlises de MEV, o fotocatalisador nÃo foi removido do suporte de PET, enquanto dados de EDX e de anÃlise gravimÃtrica indicaram a probabilidade de contaminaÃÃo dos filmes por compostos presentes na soluÃÃo durante o tratamento. Outros experimentos foram realizados, relacionados ao estudo da degradaÃÃo dos fÃrmacos paracetamol, ibuprofeno, cetoprofeno e naproxeno. Os estudos de degradaÃÃo foram realizados em reator em escala piloto, utilizando-se diversos POAs (fotÃlise direta, fotocatÃlise heterogÃnea, ozonizaÃÃo) de forma individual ou simultaneamente. AtenÃÃo especial foi dada à identificaÃÃo dos fatores significativos, dentre aqueles considerados nos ensaios, de modo a contribuir para a otimizaÃÃo de sistemas em que estes POAs venham a ser utilizados. A detecÃÃo e indicaÃÃo de provÃveis produtos de degradaÃÃo tambÃm à apresentada.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are currently widely used as fever and pain relief in patients with arthritis and other inflammatory symptoms. NSAIDs effect by inhibiting cyclooxygenase-1 (COX-1) and/or cyclooxygenase-2 (COX-2). COX isozymes (COXs) are key enzymes in the biosynthesis of prostaglandin H2 (PGH2) from arachidonic acid (AA). It is now clear that prostaglandin E2 (PGE2), one of the downstream products of PGH2, is the main mediator in both chronic and acute inflammation. Microsomal prostaglandin E synthase (mPGES-1) is the terminal enzyme of COX-2 in the PGE2 biosynthesis pathway. Different from other two constitutively expressed PGE2 synthase (PGES), mPGES-2 and cPGES, mPGES-1 is induced by pro-inflammatory stimuli and responsible for the production of PGE2 related to inflammation, fever and pain. For these reasons, selective inhibition of mPGES-1 is expected to suppress inflammation induced PGE2 production and, therefore, will exert anti-inflammatory activity while avoid the side effects of COXs inhibitors, such as gastrointestinal (GI) toxicity, and cardiovascular events. A combination of computational and experimental approaches was used to discovery mPGES-1 inhibitors with new scaffolds. The methods used include molecular docking, molecular dynamic simulation, molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculation, and in vitro activity assays. Our large-scale structure-based virtual screening was performed on compounds in the NCI libraries, containing a total of ~260,000 compounds. 7 compounds have been determined for their IC50 values (about 300 nM to 8000 nM). What’s more, these new inhibitors of mPGES-1 identified from virtual screening did not shown significant inhibition against COX isozymes even at substantially high concentrations (e.g. 100 µM). Rational methodology for drug design and organic synthesis were applied to generate three series of mPGES-1 inhibitors with different scaffolds. In total, about 200 compounds were synthesized and tested for their in vitro inhibition against human mPGES-1. Compounds with high potency against human mPGES-1 were further screened for their inhibition against mouse mPGES-1 and selectivity of human mPGES-1 over COXs. Several compounds were identified as submicromolar inhibitors against human mPGES-1 with high selectivity over COXs. In general, we have successfully identified a library of compounds as potent mPGES-1 inhibitors without significant inhibition against COXs. Structure information and in vitro activity evaluation data generated from the virtual screening and the library of compounds will be used to guide future design and synthesis of the mPGES-1 inhibitors.

Made available in DSpace on 2016-05-02T13:54:45Z (GMT). No. of bitstreams: 1 Patricia Costa.pdf: 508722 bytes, checksum: a02bd42feee52e02068566c6c8bdfd6e (MD5) Previous issue date: 2010-04-16 / The treatment of several affections of the musculoskeletal system with anti-inflammatory drugs is very frequent. However, the effects of such drugs on boné neoformation and osseointegration after fractures or bone surgeriesare not well understood yet. This study aimed at evaluating the effect of ketoprofen (NSAID) and dexamethasone (SAID) on osteogenesis around a dense hydroxiapatite (DHA) implant in the left tibia and left parietal bone, and on the femur bone resistance. Fifteen fifty-day-old Wistar rats (Rattus norvegicus albinus) weighing on average 250±30 g were used. The animals were separated into three groups (n=5): control (CT); non-steroidal anti-inflammatoryl (NSAID); and steroidal anti-inflammatory (SAID). After anesthesia with IM ketamine/xylazine, a 3 mm cavity was made in the left parietal bone and in the proximal epiphysis of the left tibia. A DHA bioceramic was implanted in the tibia. The periosteum and the skin were repositioned by suturing their borders. The animals were treated subcutaneously during 30 days as follows: NSAID group: ketoprofen at the dose of 12/Kg/day; SAID group: dexamethasone, 0,10 mg/kg/day. The CT group received saline through the same route. All the animals received the same solid diet and water ad libitum. The daily water and ration consumption were calculated to evaluate the animals nutritional conditions. After 30 days of experiment, the animals wereeuthanized, and their femurs collected for the mechanical test, while their tibia and parietal sites were prepared for the histomorphometrical analysis. The daily consumption of water and ration was satisfactory, showing neither dehydration nor protein undernourishment. Microscopically, the SAID and NSAID groups showed a lower volume of neoformed bone. In addition, the NSAID and SAID group femurs required lower maximum force for complete rupture when compared with the CT group. It was concluded that ketoprofen and dexamethasone interfered with osteogenesis and decreased bone resistance by altering the bone tissue metabolism, mainly by inhibiting the COX-2 and decreasing prostaglandins. Therefore, the use of ketoprofen and dexamethasone after boné surgeries can compromise the stability and maintenance of implants. / O tratamento de diversas afecções do sistema musculoesquelético com anti-inflamatórios é muito freqüente. Entretanto, os efeitos da utilização dessas drogas na neoformação óssea e osseointegração após fraturas ou cirurgias ósseas permanecem pouco esclarecidos. O objetivo deste estudo foi avaliar o efeito do cetoprofeno (AINES) e da dexametasona (AIES) na osteogênese ao redor de implante de hidroxiapatita densa (HAD) na tíbia esquerda, no osso parietal esquerdo, e na resistência óssea do fêmur. Utilizaram-se 15 ratos (Rattus norvegicus albinus, Wistar), pesando em média 250±30 g, com 50 dias de idade. Os animais foram divididos aleatoriamente em três grupos (n=5): controle (CT), anti-inflamatório não esteroidal (AINES) e anti-inflamatório esteroidal (AIES). Após a anestesia com quetamina/xilazina IM, foi produzido no osso parietal esquerdo e na epífise proximal da tíbia esquerda uma cavidade de 3 mm. Na cavidade da tíbia foi implantada a biocerâmica hidroxiapatita densa. O periósteo e a pele foram reposicionados através da sutura de suas bordas. Os animais do grupo AINES foram submetidos ao tratamento com cetoprofeno na dose de 12 mg/Kg/dia, e os do grupo AIES receberam doses de 0,10 mg/kg/dia de dexametasona por via subcutânea durante 30 dias. Os animais do grupo CT receberam solução salina pela mesma via de administração. Todos os animais receberam a mesma dieta sólida e água ad libitum. Foram calculados os consumos diários de água e ração para avaliar o estado nutricional dos animais. Após 30 dias de experimento os animais sofreram eutanásia, os fêmures coletados, para teste mecânico, e os locais do implante das tíbias e o osso parietal, para análise histomorfométrica. O consumo diário de água e de ração foi satisfatório entre os grupos, mostrando não haver desnutrição protéica e desidratação. Microscopicamente observamos menor volume de osso neoformado nos animais dos grupos AINES e AIES. Além disso, os animais dos grupos AINES e AIES necessitam de menor força máxima para a ruptura completa dos fêmures quando comparados com o grupo CT. Concluímos que o cetoprofeno e a dexametasona interferiram na osteogênese e ao redor do implante de HAD e no osso parietal, e diminuiu a resistência óssea por alterar o metabolismo do tecido ósseo, principalmente pela inibição da COX2 e diminuição das prostaglandinas. Assim,o uso do cetoprofeno e da dexametasona pós-cirurgias ósseas pode comprometer a estabilidade e manutenção do implante.