No description available.

Colorectal carcinoma is an important, feasible and attractive target for chemoprevention because a) it is a major cause of mortality in the United States and in other developed countries worldwide, b) there is a high mortality associated with advanced disease, c) there is a well described molecular carcinogenesis pathway and d) recent advances in molecular genetics will improve the ability to identify high-risk subjects. Epidemiological data, colonoscopic screening and advances in molecular genetics has made possible the identification and selection of subjects at increased risk of developing colorectal cancer. Due to this new information it may be possible to impede malignant cellular transformation with drugs. Such intervention with relatively simple maneuvers, such as a low daily dose of aspirin, can potentially reduce mortality from colorectal cancer. Prospective trials need to confirm experimental and epidemiological data supporting the efficacy of aspirin and other NSAID as chemopreventive agents before they can be used in the general population at risk. To use cancer chemopreventives effectively and safely in an asymptomatic population, the risks should be minimized and the benefits maximized by determination of optimal dose, schedule and chemopreventive mechanism of the NSAID. By linking the putative mechanism of drug action to effect endpoints, we expect to know whether the chemopreventive intervention is likely to be effective in a given individual.

Twenty-four healthy, mixed breed dogs were divided into four groups. Group I received a placebo PO BID, group II received an average 16.5 (range, 15.1-17.8) mg/kg buffered aspirin PO BID, group III received an average 2.2 (range, 2.0-2.4) mg/kg carprofen PO BID, and group IV received an average 12.8 (range, 11.7-13.8) mg/kg etodolac PO QD (with a placebo in the P.M.). All treatments continued for 28 consecutive days. Gastroduodenal endoscopy was performed on days – 9, 0, 5, 14 and 28. Multiple gastric biopsies were obtained endoscopically on day – 9 to determine each dog's Helicobacter spp. status. Five areas, consisting of four regions in the stomach and one in the proximal duodenum, were evaluated endoscopically, and each was assigned a score from 1 to 11 based on qualitative assessment of submucosal hemorrhage, erosion, or ulceration. These scores for each region were then summed to give a total score for each endoscopic evaluation. Erosions and submucosal hemorrhages were seen in all dogs receiving aspirin. Only minor gastric lesions were observed in the carprofen, etodolac, and control groups. No adverse clinical signs were noted in any dog given any treatment during the course of the study. There was no predilection site for lesion development in any group. Median total score on days 0, 5, 14, and 28 were as follows: group I, 5.0, 5.0, 5.0, 5.0; group II, 5.0, 27.0, 26.0, 27.5; group III, 5.0, 5.0, 6.0, 5.0; group IV, 5.0, 7.0, 5.0, 5.0, respectively. There was no significant difference between dogs receiving carprofen, etodolac, or placebo. The administration of carprofen, etodolac, or placebo to healthy dogs resulted in significantly less gastroduodenal lesion development than in dogs receiving buffered aspirin. Thirty healthy, random source, dogs were evaluated to determine the prevalence of Helicobacter spp., and to compare the ‘Campylobacter-like organism’ test (CLOtest®) to histopathologic identification of Helicobacter spp. organisms. Gastric mucosal biopsies from each of four gastric regions (cardia, pyloric antrum, greater curvature, and angularis incisura) were obtained endoscopically for use in the CLOtest® and for histopathologic evaluation. Twenty-seven of 30 dogs (90%) were positive for spiral bacteria suspected to be Helicobacter spp. by histopathologic evaluation in at least one of the four gastric regions. Three dogs (10%) were negative for Helicobacter spp. in all gastric regions by histopathologic evaluation. The CLOtest® was found to have a sensitivity, specificity, and positive predictive value of 84%, 81%, and 92%, respectively, when compared to histopathologic evaluation. When only the angularis incisura was evaluated, the sensitivity, specificity, and positive predictive value increased to 92%, 94%, and 96%, respectively. The angularis incisura had the highest, whereas the pyloric antrum had the lowest, prevalence of positive test results when compared to dogs determined to be overall Helicobacter spp. positive (histopathologic positive in at least one gastric region). The results of this study suggest the prevalence of Helicobacter spp. in apparently healthy dogs is high. For accurate and economical detection of Helicobacter spp. in a dog undergoing upper gastrointestinal endoscopy, a tissue sample should be taken from the angularis incisura for CLOtest® sampling. / Master of Science

Made available in DSpace on 2017-07-24T19:22:23Z (GMT). No. of bitstreams: 1 Alessandro Hyczy Lisboa.pdf: 2109633 bytes, checksum: 0d2cb7a9b350004abdf50ad1c2c53d2b (MD5) Previous issue date: 2012-08-03 / The objective of this study was to compare the existing level of anxiety in patients undergoing different surgical procedures on an outpatient basis, and determine the prevalence of third molar position, establishing its position and inclination, in relation to the classification of Winter and to the classification of Pell & Gregory, and to evaluate the effect of the preemptive use of ibuprofen associated with arginine, etoricoxib and dexamethasone in controlling pain after extraction of mandibular third molar. To evaluate the existence of differences in degree of anxiety in patients undergoing different forms of surgical procedures, the patients were selected (n = 60) who required extractions of third molars, which were compared with others (n = 62) that underwent simple dental extractions. The results indicate that there was no association between anxiety level and gender, but to evaluate the type of surgery used was found that patients undergoing conventional extractions indicated greater levels of anxiety than patients undergoing surgery for third molars. For the radiographic classification, radiographs were analyzed from 1150 third molars which were related to the classification of Winter as its angle to the long axis of the adjacent second molar and Pell & Gregory that determines its position in relation to the branch the mandible and the occlusal plane of the second molar. It was observed that the position was the most common mesioangular (28,52%) as classified by Winter,according to the classification of Gregory & Pell, 27,30% were Class II and 29,82% were in position A. In this randomized clinical trial, parallel and blind study, patients were divided into 4 groups (G): G1 received 600mg of ibuprofen with 555mg of arginine, G2 received 90 mg etoricoxib, G3 who received 8 mg dexamethasone, and G4 received placebo, all administered orally 90 minutes before surgery. Pain intensity was evaluated on a numerical scale of 101 points (101P) and the four point verbal rating scale (VRS) after 2, 4, 6, 8, 12, 24, 36 and 48 hours. Statistical analysis was performed with the Kruskall-Wallis, ANOVA and chi-square test (p 0.05). In the first stage patients were divided into G1 (n = 10), G2 (n = 9), G3 (n = 10) and G4 (n = 13) and it is concluded that all the protocols shown evaluated to be superior to placebo the first 4 hours, and the use of dexamethasone or etoricoxib resulted in lower consumption of rescue analgesia. In the second phase, we selected 60 patients who were randomly divided into 15 for each group. The G4 group had higher pain intensity than the other groups in the 2, 4, 12 and 48 hours. The G3 had more pain than G2 after 2 hours, as well as in relation to G1 after 2 and 4 hours. Again it was observed that all the protocols evaluated proved superior to placebo for both scales and used at different times after surgery, for controlling postoperative pain. / O objetivo deste trabalho foi comparar o nível de ansiedade existente em pacientes submetidos a distintos procedimentos cirúrgicos em âmbito ambulatorial; verificar a prevalência da posição de terceiros molares inferiores, estabelecendo a sua posição e inclinação, em relação às classificações de Winter e de Pell & Gregory; e verificar o efeito da utilização preemptiva de ibuprofeno associado à arginina, etoricoxibe e dexametasona no controle da dor pós exodontia de terceiros molares inferiores. Para avaliar a existência de diferença no grau de ansiedade em pacientes submetidos a distintas modalidades de procedimentos cirúrgicos, foram selecionados pacientes (n=60) que necessitavam de exodontias de terceiros molares, os quais foram comparados com outros (n=62) que foram submetidos a exodontias simples. Os resultados apontam que não houve associação entre nível de ansiedade e gênero, porém ao avaliar a modalidade de cirurgia empregada encontrou-se que os pacientes submetidos à exodontias convencionais denotaram maior grau de ansiedade do que os pacientes submetidos a cirurgias de terceiros molares. Para a classificação radiográfica, foram analisadas radiografias de 1150 terceiros molares inferiores os quais foram relacionados com a classificação de Winter quanto a sua angulação em relação ao longo eixo do segundo molar adjacente e de Pell & Gregory que determina a sua posição em relação com o ramo da mandíbula e ao plano oclusal do segundo molar. Observou-se que a posição mais comum foi a mesioangular (28,52%), segundo a classificação de Winter, e de acordo com a classificação de Pell & Gregory, 27,30% estavam em Classe II e 29,82% estavam em posição A. Nesse um estudo clínico randomizado, paralelo e cego os pacientes foram divididos em 4 grupos (G): G1 que recebeu 600mg de ibuprofeno com 555mg de arginina, G2 que recebeu 90 mg de etoricoxibe, G3 que recebeu 8 mg de dexametasona, e o G4 que recebeu placebo, todos administrados por via oral 90 minutos antes da cirurgia. A intensidade da dor foi avaliada pela escala numérica de 101 pontos (101P) e a escala verbal de 4 pontos (VRS) após 2, 4, 6, 8, 12, 24, 36 e 48 horas. A análise estatística foi feita com os testes de Kruskall-Wallis, ANOVA e Qui-quadrado (p0,05). Na primeira fase os pacientes foram divididos em G1 (n=10), G2 (n=9), G3 (n=10) e G4 (n=13) e conclui-se que todos os protocolos avaliados mostraram-se superior ao placebo nas primeiras 4 horas, sendo que o uso do etoricoxibe ou da dexametasona resultaram em menor consumo de analgésicos resgate. Na segunda fase foram selecionados 60 pacientes, que foram randomicamente divididos em 15 para cada grupo. O grupo G4 apresentou maior intensidade de dor do que os demais grupos, nos períodos de 2, 4, 12 e 48 horas. O G3 apresentou maior intensidade de dor do que G2 após 2 horas, bem como em relação ao G1 após 2 e 4 horas. Novamente observou-se que todos os protocolos avaliados mostraram-se superior ao placebo em ambas as escalas utilizadas e em diferentes momentos após a cirurgia, para o controle da dor pós-operatória.

Os compostos de coordenação de rutênio têm recebido grande atenção para tratamento do câncer. Em particular, estudos do grupo mostraram que um metalofármaco de dirutênio(II,III) com o fármaco anti-inflamatório não-esteróide ibuprofeno apresenta boa atividade para tumor cerebral maligno. Neste contexto, o presente trabalho teve como objetivo ampliar os estudos com a obtenção de novos complexos, investigar as interações dos metalofármacos com moléculas de interesse biológico e preparar materiais híbridos destes com ciclodextrina. Desenvolveu-se metodologia sintética para a preparação de dois novos metalofármacos de dirutênio(II,III) de fórmula geral [Ru2(O2CR)4Cl], em que O2CR = cetoprofenato (cet) ou fenbufenato, a partir do precursor [Ru2(O2CH3)4Cl]. Os novos complexos foram caracterizados principalmente por meio de técnicas espectroscópicas, difratometria de raios x e análise térmica. Estudos de reatividade foram realizados para a espécie [Ru2(O2CH3)4(H2O)2]+, obtida a partir do precursor [Ru2(O2CH3)4Cl] em solução aquosa. Constantes de equilíbrio e parâmetros termodinâmicos para as reações de substituição axial água-cloreto, e também parâmetros cinéticos das reações deste complexo com os aminoácidos glicina, triptofano, cisteína e histidina, e com os agentes redutores glutationa e ácido ascórbico, foram determinados. Estudos sobre as interações com a proteína albumina do soro humano (HSA) foram efetuados para os complexos [Ru2(O2CH3)4Cl] e [Ru2(cet)4Cl], e também para o derivado análogo de ibuprofenato (ibp), [Ru2(ibp)4Cl]. Novos materiais híbridos contendo os complexos [Ru2(O2CR)4Cl] (O2CR = ibuprofenato ou cetoprofenato) e hidroxipropil-β-ciclodextrina foram obtidos, usando-se a técnica de spray-drying, e caracterizados. / Ruthenium compounds have received great attention for cancer therapy. In particular, studies from our research group have found that a metallodrug of diruthenium(II,III) with the non-steroidal anti-inflammatory drug ibuprofen, has good activity for malignant brain tumor. In this context, the main purposes of this work were to improve these studies, to investigate some interactions of these metallodrugs with biologically relevant molecules, and also to prepare hybrid materials of these complexes with cyclodextrin. Synthetic methodologies were developed to prepare two novel diruthenium(II,III) metallodrugs, with the general formula [Ru2(O2CR)4Cl], where O2CR = ketoprofen (ket) or fenbufen starting from the precursor [Ru2(O2CH3)4Cl]. The novel complexes were characterized mainly by spectroscopical techniques, X-rays difractometry and termal analysis. Reactivity studies were performed for the species [Ru2(O2CH3)4(H2O)2]+ obtained from the precursor [Ru2(O2CH3)4Cl] in aqueous solution. Equilibrium constants and thermodynamic parameters for water-chloride axial substitutions, and also kinetic parameters for the reactions of this complex with the amino acids glycine, tryptophan, cysteine and histidine, and the reducing agents glutathione and ascorbic acid, were determined. Studies on the interactions with the human serum albumin (HSA) protein were performed for the complexes [Ru2(O2CH3)4Cl] and [Ru2(ket)4Cl], and also for the analogue derivative of the ibuprofen drug (ibp), [Ru2(ibp)4Cl]. Novel hybrid materials containing complexes [Ru2(O2CR)4Cl] (O2CR = ibuprofenato or ketoprofenato) and β-hydroxypropyl-cyclodextrin were prepared by using spray-drying technique and characterized.

Chronic inflammation is intimately linked with cancer development and progression and therefore reducing or eliminating inflammation represents a logical treatment and prevention strategy. Studies have shown that anti-inflammatory agents have anti-tumour effects in cancers, with reduced metastases and mortality. Current use of anti-inflammatory agents in the treatment and prevention of cancer is limited by their toxicity and side effects. The emerging field of nanotechnology allows the fundamental properties of a drug to be altered, creating a product with improved reactivity and bioavailability, leading to more targeted treatments and reduced dosage. In the present study, the genotoxic effects of three commonly used anti-inflammatory drugs; aspirin, ibuprofen and hydrocortisone, in their bulk and nano forms were evaluated on peripheral blood lymphocytes of healthy donors using the comet assay and the micronucleus assay. In order to determine any anti-cancer effects, these agents were also tested in peripheral blood lymphocytes in patients with haematological cancers. The glucocorticoid hydrocortisone was also evaluated for anti-oxidant capacity. Our results demonstrate that the nano versions of each drug produced a different response than the bulk counterpart, indicating that a reduction in particle size had an impact on the reactivity of the drug. Our results also indicate that the nano versions of each drug were less genotoxic than the bulk formulation, further emphasising the potential of nanoparticles as an improvement to current treatment options. We also found an anti-oxidant effect with hydrocortisone, with a more profound effect seen with the nano formulation.

As the principal pro-inflammatory prostanoid, prostaglandin E2 (PGE2) serves as mediator of pain and fever in inflammatory reactions. The biosynthesis of PGE2 starts from arachidonic acid (AA). Cyclooxygenase (COX)-1 and/or COX-2 converts AA to prostaglandin H2 (PGH2), and PGE2 synthases transform PGH2 to PGE2. Current mainstream approach for treating inflammation-related symptoms remains the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). As both categories shut down the biosynthesis of all downstream prostanoids, their application renders several deleterious effects including gastrointestinalulceration and cardiovascular risk. Microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors, specifically blocking the production of inflammation-related PGE2, are expected to reduce the adverse effects while retain the anti-inflammation activity. Although several compounds have been reported, only a few have entered clinical trials and none was on the market. Particularly, most of the reported human mPGES-1 inhibitors were not active for wild-type mouse/rat mPGES-1 enzymes, which prevents using the well-established mouse/rat models of inflammation in preclinical studies. Therefore, we expect our designed inhibitors to also be potent against mouse mPGES-1 and thus is suitable for preclinical testing in wild-type mice.

Made available in DSpace on 2014-07-29T16:11:53Z (GMT). No. of bitstreams: 1 Dissertacao Fabiula.pdf: 1283219 bytes, checksum: 9daa5fd6fda20c31ea6e9dd5731a9e99 (MD5) Previous issue date: 2009-09-18 / Inflammation is a local reaction of tissue involving neurological, vascular, humoral and cellular reactions to eliminate the causal agents and reduce the cellular damages. Prostaglandins, thromboxanes and leukotrienes are examples of chemical inflammation mediators, resulting for the action of the enzyme phospholipase A2 (PLA2). The PLA is a enzyme that hydrolyses membrane phospholipids in the sn-2 position resulting in lisophospholipids and arachidonic acid (AA), taking a key role in the production of lipidic inflammatory mediators. The research and development of new chemical entities security, effective and that presents less side effects to the particular therapeutic target, constituted the principal objective of technological innovation in pharmaceuticals industry. Due the side effects of selective inhibitors of the production of eicosanoids currently presents in the market, control of production of AA by inhibiting PLA2 is a useful treatment for pathological conditions that are caused by mediators of the AA. In this work synthetic routes were studied to obtain new candidates prototypes of anti-inflammatory drugs obtained by rational planning of new piperazines derivatives originally designed from nerolidylcatechol (25) and arilsulfonilpiperazines (26) to presents the inhibitory profile of secreted PLA2 enzyme. The final synthesized compound, N-(benzo[d][1,3]dioxol-5-aryl) acetamide (18), E-N-(3,7-dimetylocta-2,6-dienyl) benzo[d] [1,3]dioxol-5-amine (19), (E)-N-(6-dienil,3,7-dimetilocta-2)aminobenzeno (20), (E)-4-(6-dienil,3,7-dimetilocta-2)(aminometil)fenol (21) e (E)-(N)-(6-dienil,3,7-dimetilocta-2)-N-(4-idroxifenil)metanosulfanoamida (22) were submitte to in vitro pharmacological assays to evaluated the enzymatic inhibition of sPLA2 and characterization by hydrogen nuclear magnetic resonance (RMN 1H) and the 13 carbon nuclear magnetic resonance (RMN 13C). Based on the obtained results by pharmacological assays can be concluded that the final synthesized compounds (18, 19, 21, 22) presents good anti-inflammatory profiles. As the synthetic methods employed to obtain the final molecules (18-22) the results showed be viable in its execution enable an obtainment of compounds with appropriate yields and efficiency in the profile of purification / A inflamação é uma reação local dos tecidos envolvendo reações neurológicas, vasculares, humorais e celulares, objetivando eliminar o agente causal e diminuir o dano celular. As prostaglandinas, tromboxanos e leucotrienos, são exemplos de mediadores químicos da inflamação, originados a partir da ação da enzima fosfolipase A2 (PLA2). A PLA2 é uma enzima que hidrolisa fosfolipídios presentes na membrana celular na posição sn-2 produzindo lisofosfolipídios e ácido araquidônico, tendo um papel chave na produção de mediadores lipídicos inflamatórios. A pesquisa e desenvolvimento de novas entidades químicas seguras, eficazes e que apresentem menos efeitos colaterais para um determinado alvo terapêutico, constituí o principal objeto de inovação tecnológica das indústrias farmacêuticas. Devido aos efeitos colaterais dos inibidores seletivos da produção de eicosanóides presentes atualmente no mercado, o controle da produção de ácido araquidônico (AA) pela inibição da PLA2 surge como um vantajoso tratamento para as condições patológicas que são causadas pelos mediadores do AA. Neste trabalho foram estudadas rotas sintéticas para obtenção de novos candidatos a protótipos de fármacos anti-inflamatórios obtidos por meio do planejamento racional de novos derivados piperazínicos originalmente desenhados a partir do nerolidilcatecol (16) e do arilsulfonilpiperazina (17) para apresentarem perfil inibitório da enzima PLA2 secretada. Os compostos finais sintetizados, N-(benzo[d][1,3]dioxol-5-aril) acetamida (18), E-N-(3,7-dimetilocta-2,6-dienil) benzo[d] [1,3]dioxol-5-amina (19), (E)-N-(6-dienil,3,7-dimetilocta-2)aminobenzeno (20), (E)-4-(6-dienil,3,7-dimetilocta-2)(aminometil)fenol (21) e (E)-(N)-(6-dienil,3,7-dimetilocta-2)-N-(4-idroxifenil)metanosulfanoamida (22) foram submetidos a ensaios farmacológicos in vitro para avaliação da inibição enzimática da sPLA2 e caracterização por meio de Ressonância Magnética Nuclear de Hidrogênio (RMN 1H) e de Carbono (RMN 13C). Baseados nos resultados obtidos por meio dos ensaios farmacológicos concluimos que os compostos sintetizados (18, 19, 21, 22) apresentaram perfil anti-inflamatório esperado. Quanto às metodologias sintéticas empregadas para obtenção dos compostos finais (18-22) os resultados obtidos demonstraram serem esta viáveis nas suas execuções permitindo a obtenção de compostos com rendimentos adequados e com eficiência no perfil de purificação

Os compostos de coordenação de rutênio têm recebido grande atenção para tratamento do câncer. Em particular, estudos do grupo mostraram que um metalofármaco de dirutênio(II,III) com o fármaco anti-inflamatório não-esteróide ibuprofeno apresenta boa atividade para tumor cerebral maligno. Neste contexto, o presente trabalho teve como objetivo ampliar os estudos com a obtenção de novos complexos, investigar as interações dos metalofármacos com moléculas de interesse biológico e preparar materiais híbridos destes com ciclodextrina. Desenvolveu-se metodologia sintética para a preparação de dois novos metalofármacos de dirutênio(II,III) de fórmula geral [Ru2(O2CR)4Cl], em que O2CR = cetoprofenato (cet) ou fenbufenato, a partir do precursor [Ru2(O2CH3)4Cl]. Os novos complexos foram caracterizados principalmente por meio de técnicas espectroscópicas, difratometria de raios x e análise térmica. Estudos de reatividade foram realizados para a espécie [Ru2(O2CH3)4(H2O)2]+, obtida a partir do precursor [Ru2(O2CH3)4Cl] em solução aquosa. Constantes de equilíbrio e parâmetros termodinâmicos para as reações de substituição axial água-cloreto, e também parâmetros cinéticos das reações deste complexo com os aminoácidos glicina, triptofano, cisteína e histidina, e com os agentes redutores glutationa e ácido ascórbico, foram determinados. Estudos sobre as interações com a proteína albumina do soro humano (HSA) foram efetuados para os complexos [Ru2(O2CH3)4Cl] e [Ru2(cet)4Cl], e também para o derivado análogo de ibuprofenato (ibp), [Ru2(ibp)4Cl]. Novos materiais híbridos contendo os complexos [Ru2(O2CR)4Cl] (O2CR = ibuprofenato ou cetoprofenato) e hidroxipropil-β-ciclodextrina foram obtidos, usando-se a técnica de spray-drying, e caracterizados. / Ruthenium compounds have received great attention for cancer therapy. In particular, studies from our research group have found that a metallodrug of diruthenium(II,III) with the non-steroidal anti-inflammatory drug ibuprofen, has good activity for malignant brain tumor. In this context, the main purposes of this work were to improve these studies, to investigate some interactions of these metallodrugs with biologically relevant molecules, and also to prepare hybrid materials of these complexes with cyclodextrin. Synthetic methodologies were developed to prepare two novel diruthenium(II,III) metallodrugs, with the general formula [Ru2(O2CR)4Cl], where O2CR = ketoprofen (ket) or fenbufen starting from the precursor [Ru2(O2CH3)4Cl]. The novel complexes were characterized mainly by spectroscopical techniques, X-rays difractometry and termal analysis. Reactivity studies were performed for the species [Ru2(O2CH3)4(H2O)2]+ obtained from the precursor [Ru2(O2CH3)4Cl] in aqueous solution. Equilibrium constants and thermodynamic parameters for water-chloride axial substitutions, and also kinetic parameters for the reactions of this complex with the amino acids glycine, tryptophan, cysteine and histidine, and the reducing agents glutathione and ascorbic acid, were determined. Studies on the interactions with the human serum albumin (HSA) protein were performed for the complexes [Ru2(O2CH3)4Cl] and [Ru2(ket)4Cl], and also for the analogue derivative of the ibuprofen drug (ibp), [Ru2(ibp)4Cl]. Novel hybrid materials containing complexes [Ru2(O2CR)4Cl] (O2CR = ibuprofenato or ketoprofenato) and β-hydroxypropyl-cyclodextrin were prepared by using spray-drying technique and characterized.

in Hradec Králové Student: Johana Urbanová Supervisor: PharmDr. Jana Mandíková, Ph.D. = 38.02 μM), lowest indometacin μM