published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Thesis (M. Med. Sc.)--University of Hong Kong, 2007.

Thesis (M.Sc.)--Dalhousie University, 1999. / Includes bibliographical references.

Made available in DSpace on 2016-08-19T17:47:09Z (GMT). No. of bitstreams: 1 Rachel Melo Ribeiro.pdf: 542816 bytes, checksum: 97d23f29c7aaa773c7cec34818b5ed2f (MD5) Previous issue date: 2007-04-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This work was carried out to evaluate the effect of sheets of Syzygium jambolanum DC (jambolan) in blood pressure (BP) and reactivity of vascular smooth muscle and non-vascular of normotensive rats. The extract hidroalcóolico (EH; ethanol 70%) was obtained by maceration from the dried leaves of Syzygium jambolanum DC to evaluate blood pressure in conscious rats and preparations isolated from deferent duct or thoracic aorta of rats. The EH was submitted the division with solvent using chloroform / water (2:1 v / v) to obtain the fractions chloroform (FC) and water (FMD) and assessment of vascular reactivity-ring mesenteric artery. The oral administration of EH (0.1 g / kg / day or 0.2 g / kg / day) induced a significant reduction of the PA in rats with normal conscious. In preparations of duct deferentes isolated from rats, EH 0.05, 0.1 and 0.25 mg / ml reduced the effect maximum (Emax) induced by norepinephrine (NE) at 22.2, 45.4 and 81.5%, respectively. In ducts deferentes previously contracted with the CE75% noradrenaline (3x10-4 M) the EH (0.2 to 14 mg / ml) induced relaxation, dependent on concentration, which reached 69%, with the largest concentration. In arteries aorta thoracic isolated from rats, EH 0025, 0.05 and 0.1 mg / ml moved to the right, the cumulative concentration-response curves of calcium (Ca + +) at 7.7, 2.8 and 5.2 times, respectively. This effect of EH was accompanied by a reduction in the Emax 30.5; 56.4 and 78.4% respectively. The FA (0.1, 0.25 and 0.5 mg / ml) reduced the effect maximum (Emax) of 6.5 in NE, 15.7 and 51.9% visited the curve to the right in 2.0, 2.8 and 3.5 times respectively. The FC 0.5 mg / ml reduced the Emax of 25.8% in NE. The FC (0.1 and 0.25 mg / ml) reduced the Emax of concentration-response curve cumulative calcium (Ca + +) at 21.1 and 47.1% and moved to right on 3 and 4 times, respectively. In addition, the FC (0.01 to 1.0 mg / ml) induced relaxation, dependent on concentration, mesenteric artery pre-contracted with calcium (≅ EC75), the maximum concentration (1mg/ml), in the absence or presence of the blocker of potassium channels (Tetraetilamônio-TEA), 97.4 and 99.6% respectively. Together, these results suggest that the effect of lowering the EH Syzygium DC can jambolanum be related to activity relaxing blood presented by the FC in rings of artery mesenteric pre-contracted with calcium. Thus this work contributes to hypotensive confirmation of the activity of the leaves of Syzygium jambolanum DC Maranhão employed by the population. / O presente trabalho foi desenvolvido com o objetivo de avaliar o efeito das folhas de Syzygium jambolanum D.C. (jambolão) na pressão arterial (PA) e na reatividade da musculatura lisa vascular e não-vascular de ratos normotensos. O extrato hidroalcóolico (EH; etanol 70%) foi obtido por maceração a partir das folhas secas de Syzygium jambolanum D.C. para avaliação da pressão arterial de ratos conscientes e em preparações isoladas de ducto deferente ou aorta torácica de ratos. O EH foi submetido a fracionamento com solvente usando clorofórmio/água (2:1 v/v) para obtenção das frações clorofórmica (FC) e aquosa (FA) e avaliação da reatividade vascular de anéis de artéria mesentérica. A administração oral de EH (0,1 g/kg/dia ou 0,2 g/kg/dia) induziu uma significante redução da PA em ratos conscientes normotensos. Em preparações de ducto deferentes isolados de ratos, o EH 0,05; 0,1 e 0,25 mg/ml reduziu o efeito máximo (Emax) induzido pela noradrenalina (NE) em 22,2; 45,4 e 81,5%, respectivamente. Em ductos deferentes previamente contraídos com a CE75% de noradrenalina (3x10-4 M) o EH (0,2 a 14 mg/ml) induziu relaxamento, dependente de concentração, que atingiu 69%, com a maior concentração utilizada. Em artérias aorta torácica isoladas de ratos, o EH 0,025; 0,05 e 0,1 mg/ml deslocaram, para a direita, as curvas concentração-resposta cumulativas de cálcio (Ca++) em 7,7; 2,8 e 5,2 vezes, respectivamente. Este efeito do EH foi acompanhado pela redução do Emax em 30,5; 56,4 e 78,4%, respectivamente. A FA (0,1; 0,25 and 0,5 mg/ml) reduziu o efeito máximo (Emax) da NE in 6,5; 15,7 e 51,9% deslocaram a curva para a direita em 2,0; 2,8 e 3,5 vezes, respectivamente. A FC 0,5 mg/ml reduziu o Emax da NE em 25,8%. A FC (0,1 e 0,25 mg/ml) reduziu o Emax da curva concentração-resposta cumulativa de cálcio (Ca++) em 21,1 e 47,1% e deslocou para a direita em 3 e 4 vezes, respectivamente. Em adição, a FC (0,01 a 1,0 mg/ml) induziu relaxamento, dependente de concentração, em artéria mesentérica pré-contraída com cálcio (≅EC75), na máxima concentração (1mg/ml), na ausência ou presença do bloqueador dos canais de potássio (Tetraetilamônio -TEA), de 97,4 e 99,6%, respectivamente. Em conjunto, estes resultados sugerem que o efeito hipotensor do EH de Syzygium jambolanum D.C. pode estar relacionado à atividade vasorrelaxante apresentada pela FC em anéis de artéria mesentérica pré-contraídas com cálcio. Desta forma o presente trabalho contribui para a confirmação da atividade hipotensora das folhas de Syzygium jambolanum D.C. empregada pela população maranhense.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-04-04T17:11:51Z No. of bitstreams: 1 LIARA MERLUGO.pdf: 1163654 bytes, checksum: 112650b0950a34ee9e23411aa8adcab1 (MD5) / Made available in DSpace on 2016-04-04T17:11:51Z (GMT). No. of bitstreams: 1 LIARA MERLUGO.pdf: 1163654 bytes, checksum: 112650b0950a34ee9e23411aa8adcab1 (MD5) Previous issue date: 2015-03-12 / O gênero Erythrina está presente mundialmente nas regiões tropicais e subtropicais. Estudos fitoquímicos utilizando vários órgãos dessas plantas, demostraram a presença de alcaloides, flavonoides, pterocarpanos e triterpenóides. Várias espécies são encontradas no Brasil, dentre elas Erythrina falcata e Erythrina crista-galli, conhecidas popularmente como “corticeira” e utilizadas medicinalmente devido à ação sedativa, ansiolítica, anti-inflamatória e antihipertensiva. Este trabalho objetivou estudar a composição química de extratos vegetais obtidos de folhas de E. falcata e E. crista-galli e ainda, avaliar o potencial hipotensor in vivo de extratos de E. falcata. Inicialmente, após coleta do material, as folhas foram selecionadas, submetidas à secagem e trituradas. Então, foram submetidas à extração por maceração exaustiva utilizando etanol 40% (v/v) e por infusão utilizando água a 100 °C. Para a caracterização em termos de fenólicos totais e conteúdo de flavonoides, os extratos foram quantificados por espectrofotometria. Para o ensaio cromatográfico, os extratos foram analisados por CLAE em sistema de fase reversa, com fase móvel consistindo de acetonitrila:água em eluição por gradiente e fluxo de 1,0 mL/min. Para a análise por CLUEESI- MS, a fase móvel foi composta de mistura de acetonitrila:metanol (4:1) e ácido fórmico pH 3,0, com eluição por gradiente e fluxo de 0,2 mL/min. A detecção por espectrometria de massas foi conduzida a partir das seguintes condições: N2 como nebulizante; energia de colição 4.0 eV; temperatura da fonte do eletrospray e do gás de solvatação 100°C e 120°C, respectivamente; voltagem do capilar 3000V; voltagem do cone 40V. Os espectros de massas foram obtidos na faixa de m/z 200-800. A avaliação dos efeitos hemodinâmicos foi realizadaem ratos wistar normotensos, anestesiados com uretana (1,4 mg/Kg), via canulação da artéria carótida (para a verificação da PAS, PAD e FC) e veia jugular (para administração do extratose drogas). A avaliação do potencial hipotensor da E. falcata foi investigada através da realização de uma curva crescente de administração dos extratos e os possíveis mecanismos de ação envolvidos foram analisados através da administração de diferentes drogas sendo elas: L-NAME (30 mg/kg); losartana (10 mg/Kg); hexametônio (20mg/Kg) e propranolol (5mg/kg). Os teores de fenólicos totais para E. falcata e E. crista-galli estiveram na faixa de 1,3193 – 1,4989 mgEAG/mL para os extratos obtidos por maceração e de 0,8771 – 0,9506 mgEAG/mL para as infusões. Em flavonoides totais, os conteúdos estiveram na faixa de 7,7829 – 8,1976 ER mg/g para os extratos obtidos por maceração e 9,3471 – 10,4765 ER mg/g para as infusões. Na determinação por CLUE-MS, os dados de íon molecular e fragmentos de massa indicaram a composição predominante em alcaloides, sugerindo-se os componentes erythristemine, 11β-methoxyglucoerysodine, erysothiopine, 11β- hydroxyerysodine–glicose e 11-hydroxyerysotinone-ramnosídeo. O extrato aquoso da E. falcata mostrou-se um potente hipotensor dose-dependente, causando uma queda na PAS de 23 a 35% e na PAD de 32 a 49% para ambos os extratos estudados, sem influenciar a FC, podendo este efeito estar relacionado com a via dos receptores β-adrenérgicos. / The genus Erythrina is present worldwide in tropical and subtropical regions. Phytochemical studies using various organs of these plants demonstrated the presence of alkaloids, flavonoids, pterocarpans and triterpenoids. Several species are found in Brazil, among them Erythrina falcata and Erythrina crista-galli, which are popularly known as “corticeira” and. used medicinally due to it action as sedative, anxiolytic, anti-inflammatory and antihypertensive. The present study aimed to investigate the chemical composition of extracts obtained from leaves of E. falcata and E. crista-galli, and still, to evaluate the hypotensive potential in vivo of E. falcata extracts. Initially, after collection of material plant, the leaves were selected, submitted to dryness and powdered. Then, submitted to extration by exhaustive maceration using ethanol 40% (v/v) and by infusion using water at 100 °C. For characterization in terms of phenolics and flavonoid content, the extracts were quantified by spectrophotometry. For chromatographic assay, the extracts were analysed by HPLC in reversed phase system, with a mobile phase consisting of acetonitrile:water in gradient elution and flow rate of 1.0 mL/min. For analysis by UPLC-ESI-MS, the mobile phase consisted in a mixture of acetonitrile:methanol (4:1) and 0.1% formic acid pH 3.0, with a elution by gradient and flow rate of 0.2 mL/min. The MS detection was performed following the conditions: N2 as nebulizing; collision energy 4.0 eV; temperature of electrospray source and desolvation gas 100°C and 120°C, respectively; capillary voltage 3000V; sample cone 40V. Mass spectra were recorded in the range of m/z 200-800. The evaluation of the hemodynamic effects was performed in normotensive Wistar rats, anesthetized with urethane (1.4 mg/kg) by cannulation of the carotid artery (for verification of SBP, DBP and HR) and jugular vein (for administration of the extracts and drugs). The hypotensive potential of E. falcata was investigated by conducting a growing curve administration of the extracts and the possible mechanisms involved were analyzed by administering different drugs such as: L-NAME (30 mg/kg); losartan (10 mg/kg); hexamethonium (20 mg/kg) and propranolol (5 mg/kg). The total phenolics content for E. falcata and E. crista-galli was from 1.3193 to 1.4989 mgGAE/mL for maceration and 0.8771 to 0.9506 mgGAE/mL for infusions. In total flavonoid, the content was from 7.7829 to 8.1976 mg RE/g for maceration and 9.3471 to 10.4765 RE mg/g for infusions. The molecular ions and mass fragments obtained by UPLCMS indicated the predominant composition in alkaloids, suggesting the components erythristemine, 11β-methoxyglucoerysodine, erysothiopine, 11β-hydroxyerysodine-glucose and 11-hydroxyerysotinone-rhamnoside. The aqueous extract of E. falcata showed to be a potent dose-dependent hypotensive, decreasing the SBP in 23 to 35% and DBP in 32 to 49% for both extracts, without influence in HR, and this effect may be due to the route of β- adrenergic receptors.

Angiotensin-converting enzyme (ACE) inhibitors are some of the most commonly prescribed medications for hypertension. They are cited in many papers as the treatment most often recommended by guidelines and favoured over other antihypertensive drugs as first-line agents especially when other high-risk conditions are present, such as diabetic nephropathy. The development of captopril (CPT) was amongst the earliest successes of the revolutionary concept of structure-based drug design. Due to its relatively poor pharmacokinetic profile or short half-life of about 1 hour, the formulation of sustained-release microcapsule dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Currently, CPT is mainly administered in tablet form. One of the difficulties of CPT formulation has been reported to be its instability in aqueous solutions. CPT is characterized by a lack of a strong chromophore and, therefore, not able to absorb at the more useful UV–Vis region of the spectrum. For this reason, an accurate, simple, reproducible, and sensitive HPLC-ECD method was developed and validated for the determination of CPT in dosage forms. The method was successfully applied for the determination of CPT in commercial and developed formulations. Possible drug-excipient and excipient-excipient interactions were investigated prior to formulating CPT microcapsules because successful formulation of a stable and effective solid dosage form depends on careful selection of excipients. Nuclear magnetic resonance spectroscopy, Fourier transform infra-red spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used for the identification and purity testing of CPT and excipients. The studies revealed no thermal changes during stress testing of binary and whole mixtures which indicate absence of solid state interactions. There were no shifts, appearance and disappearance in the endothermic or exothermic peaks and on the change of other associated enthalpy values on thermal curves obtained with DSC method. Characteristic peaks for common functional groups in the FT-IR were present in all the mixtures indicating the absence of incompatibility. The techniques used in this study can be said to have been efficient in the characterization and evaluation of the drug and excipients. The technique of microencapsulation by oil-in-oil was used to prepare CPT microcapsules. The effects of polymer molecular weight, homogenizing speed on the particle size, flow properties, morphology, surface properties and release characteristics of the prepared CPT microcapsules were examined. In order to decrease the complexity of the analysis and reduce cost response surface methodology using best polynomial equations was successfully used to quantify the effect of the formulation variables and develop an optimized formulation thereby minimizing the number of experimental trials. There was a burst effect during the first stage of dissolution. Scanning electron microscopy (SEM) results indicated that the initial burst effect observed in drug release could be attributed to dissolution of CPT crystals present at the surface or embedded in the superficial layer of the matrix. During the preparation of microcapsules, the drug might have been trapped near the surface of the microcapsules and or might have diffused quickly through the porous surface. The release kinetics of CPT from most formulations followed Fickian diffusion mechanism. SEM photographs showed that diffusion took place through pores at the surface of the microcapsules. The Kopcha model diffusion and erosion terms showed predominance of diffusion relative to swelling or erosion throughout the entire test period. Drug release mechanism was also confirmed by Makoid-Banakar and Korsmeyer-Peppas models exponents which further support diffusion release mechanism in most formulations. The models postulate that the total of drug release is a summation of a couple of mechanisms; burst release, relaxation induced controlled-release and diffusional release. Inspection of the 2D contour and 3D response surfaces allowed the determination of the geometrical nature of the surfaces and further providing results about the interaction of the different variables used in central composite design (CCD). The wide variation indicated that the factor combinations resulted in different drug release rates. Lagrange, canonical and mathematical modelling were used to determine the nature of the stationery point of the models. This represented the optimal variables or stationery points where there is interaction in the experimental space. It is difficult to understand the shape of a fitted response by mere inspection of the algebraic polynomial when there are many independent variables in the model. Canonical and Lagrange analyses facilitated the interpretation of the surface plots after a mathematical transformation of the original variables into new variables. In conclusion, these results suggest the potential application of Eudragit® / Methocel® microcapsules as suitable sustained-release drug delivery system for CPT.

Submitted by Erika Demachki (erikademachki@gmail.com) on 2017-04-25T16:50:08Z No. of bitstreams: 2 Dissertação - Milton Junio Cândido Bernardes - 2012.pdf: 1056534 bytes, checksum: f6f739a120711136b922612ab0c4029c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Erika Demachki (erikademachki@gmail.com) on 2017-04-25T16:51:18Z (GMT) No. of bitstreams: 2 Dissertação - Milton Junio Cândido Bernardes - 2012.pdf: 1056534 bytes, checksum: f6f739a120711136b922612ab0c4029c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-04-25T16:51:18Z (GMT). No. of bitstreams: 2 Dissertação - Milton Junio Cândido Bernardes - 2012.pdf: 1056534 bytes, checksum: f6f739a120711136b922612ab0c4029c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2012-12-19 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Aspidosperma subincanum Mart. is a medicinal herb that is known to be useful for the treatment of cardiovascular-related illnesses. However, its effects and pharmacological mechanisms of action have not been studied. The aim of the present study was to determine the effect of an ethanol extract of Aspidosperma subincanum Mart. (EEAS) on blood pressure (in vivo) and vascular tension (in vitro) in the rat thoracic aorta. Catheters were inserted into the right femoral vein and artery of anesthetized rats for EEAS infusion and the measurement of blood pressure, heart rate and aortic blood flow (flow probes were placed around the aorta). Moreover, the vasodilator effect of EEAS in isolated pre-contracted rat aortas was examined. Intravenous infusion of EEAS resulted in significant and dose-dependent hypotension, bradycardia and increased aortic blood flow. In isolated arteries, EEAS (0-27μg/mL) induced a concentration-dependent relaxation of pre-contracted aortic rings; endothelial denudation potentiated this effect. Pre-treatment of the aortic rings with ODQ, an inhibitor of soluble guanylyl cyclase (sGC); MDL-12,330A, an inhibitor of adenylyl cyclase (AC); or CPA, a SERCA inhibitor, reduced EEAS-induced vasorelaxation. Treatment with an EEAS impaired contractions induced by phenylephrine (an adrenergic agonist) and Bay K 8644 (an L-type Ca(2+) channel activator). The blockade of K(+) channels with tetraethylammonium, clotrimazole, glibenclamide or 4-aminopyridine reduced the relaxation stimulated by EEAS. These findings suggest that EEAS induces hypotension associated with bradycardia. EEAS induces endothelium-independent vascular relaxation. The sGC/cGMP and AC/cAMP pathways, SERCA activation and Ca(2+) and K(+) flux across the sarcolemma, are likely involved in this relaxation. / O Aspidosperma subincanum Mart. é uma planta medicinal que é conhecida por ser utilizada para o tratamento de doenças relacionadas com o sistema cardiovascular. No entanto, seus efeitos e mecanismos de ação farmacológicos não estão muito bem elucidados. O objetivo do presente estudo foi determinar o efeito do Extrato Etanólico do Aspidosperma Subincanum Mart. (EEAS) sobre a pressão arterial (in vivo) em ratos anestesiados e da pressão arterial (in vitro) em artéria aorta torácicas de ratos. Para a realização do protocolos experimentais foram inseridos cateteres na veia e artéria femural direita de ratos anestesiados para que pudesse ser realizada a infusão do EEAS e a verificação da pressão arterial, frequência cardíaca e fluxo sanguíneo aórtico; foram inseridas sondas de fluxo e posicionadas em torno da aorta. Além da pressão foi verificado o efeito vasodilatador do EEAS em anéis de aortas isoladas de ratos pré-contraídas com vasoconstritor. A infusão intravenosa do EEAS resultou em significativa hipotensão, bradicardia e aumento do fluxo aórtico dose-dependente. Em artérias isoladas, o EEAS (0-27μg/mL) induziu relaxamento concentração-dependente em anéis de aorta pré-contraídas com agonista contrátil; foi potencializado o relaxamento nos anéis de aorta sem endotélio. O pré-tratamento dos anéis isoladas de aorta com ODQ, um inibidor da guanilato clicase solúvel (sGC), MDL – 12,330A um inibidor da adenilato ciclase (AC) e CPA um inibidor da bomba do retículo sarcoplasmático, reduziram o vasorelaxamento induzido pelo EEAS. O EEAS foi capaz de diminuir o efeito ocasionado pelo tratamento com fenilefrina (um agonista adrenérgico) e Bay K 8644 (ativador dos canais de Calcio do tipo L) de forma concentração-dependente. O bloqueio dos canais de K+ com tetraetilamonio, clotrimazol, glibenclamida ou 4-aminopiridina reduziu o relaxamento estimulado pelo EEAS. Estes achados sugerem que o EEAS induz hipotensão associada à bradicardia e o relaxamento independente do endotélio vascular. As vias do cGMP/sGC e cAMP/AC foram ativadas e a SERCA e os canais de K+ possivelmente estão envolvidos neste relaxamento.

Conclusions: In the same number of people treated, the number of CVD events avoided for the overall risk approach is always larger than that of the blood pressure approach. The additional benefits of overall risk approach compared with the blood pressure approach decreases as the percentage of people from the total population is increased. If the current practice and hypertension guidelines in China are shifted to the overall risk approach, many more CVD events could be avoided with the same resources used. / Methods: The sample used in the analyses includes a subsample of 38,673 persons from the 2002 China National Nutrition and Health Survey, who were 30-74 years old, without previous CVD, and had data on all major CVD risk factors. CVD risks of the patients selected by each approach are predicted using suitable risk prediction equation. The RRR of anti-hypertensive drug treatment derived from meta-analyses of RCTs. The difference in the absolute effectiveness between the two approaches is used to quantify how many more CVD events can be prevented in 1000 people treated by the ORA as compared to the BPA. / Objective: To estimate and compare the number of major cardiovascular events that could be avoided by shifting the blood pressure approach to the overall risk approach if the same percentage of people in a large, representative Chinese population is treated with anti-hypertensive drugs. / Results: When 2.5%, 5.5%, 10.1%, 15.5%, 20.7%, 25.7% or 33.0% of the 38,673 subjects were treated by anti-hypertensive drugs by using the two approaches respectively, 22 (95%CI: 17∼28), 13 (11∼16), 9 (8∼10), 7 (6∼8), 6 (5∼7), 5 (4∼6), or 4 (3∼4) more CVD events could be avoided in every 1000 people treated if the blood pressure approach is shifted to the overall risk approach, which is in general a 15% to 25% increase in CVD events prevented. / Qin, Ying. / Adviser: Jin Ling Tang. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 116-121). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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