No description available.

Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / BACKGROUND: Although novel anticoagulant drugs have proven safety and efficacy profiles from Phase III clinical trials, those patients with significant kidney disease were excluded. The lack of knowledge about incidence, severity and risk factors for severe renal dysfunction in patients requiring oral anticoagulation impedes development of strategies to mitigate risks of hemorrhage associated with renally-eliminated novel oral anticoagulants. METHODS: Patients taking warfarin for atrial fibrillation (AF) or venous thromboembolism (VTE) were consecutively enrolled from January 2007 to December 2010. Baseline kidney function was assessed and patients were followed to their first decline in Glomerular Filtration Rate (GFR) to < 30 ml/min estimated by the Cockcroft-Gault calculation. Independent risk factors for development of severe kidney dysfunction were assessed by multivariate analysis. RESULTS: Of 787 patients identified, 34 were excluded for baseline eGFR < 30 ml/min. The mean age of the cohort was 71 years. At baseline, 23% (n=174) had moderate renal impairment, or Stage 3 CKD (eGFR 30-59 ml/min), while 31% had mild disease. Overall, those with hypertension, congestive heart failure (CHF), diabetes mellitus (DM), and coronary artery disease (CAD) were 74%, 33%, 31%, 24%, and 9% of the cohort, respectively. A decline in eGFR to < 30 ml/min (the primary outcome) occurred in 91 patients, 25% of which happened within 5.3 months. Of those with baseline Stage 3 CKD, 37% experienced the primary outcome. In multiple logistic regression analysis, a baseline eGFR 30–59 ml/min conferred a greater than 14-fold increased risk in the development of eGFR < 30 ml/min (OR 14.5, 99% CI: 5.3 to 39.8, P<0.001) during the warfarin exposure period. CAD was associated with a greater than two-fold increased risk (OR 2.2, 95% CI 1.1 to 4.4, P=0.004). After adjusting for baseline kidney function, age was not an independent risk factor for a decline in eGFR to < 30 ml/min. CONCLUSIONS: Acute and chronic renal dysfunction is common among individuals on chronic warfarin therapy. Better understanding of the fluctuations in renal function would inform patient selection and monitoring strategies for optimal use of novel anticoagulants. / 2999-01-01

Estudo exploratório, de delineamento longitudinal, com 81 pacientes em uso de anticoagulante oral e que foram avaliados durante internação e dois meses após a alta. Os objetivos foram acompanhar a evolução quanto á terapia de anticoagulação oral e adesão ao tratamento; comparar o estado geral de saúde e a presença de sintomas de ansiedade e depressão. Foram utilizados instrumentos específicos para avaliar adesão ao tratamento medicamentoso (Medida de Adesão aos Tratamentos), estado geral de saúde (Escala Visual Analógica) e presença de sintomas de ansiedade (HADS-Ansiedade) e depressão (HADS- Depressão). As análises estatísticas realizadas foram: Teste t de Student pareado para comparar as médias do estado geral de saúde e da HADS; Modelo Linear de Efeitos Mistos para analisar a associação entre estado geral de saúde, ansiedade, depressão e tempo de avaliação no estudo. O nível de significância adotado foi 0,05. Entre os participantes, 54,3% eram mulheres, com idade média de 59,5 anos e nível médio de instrução de 5,1 anos. A principal indicação clínica para uso do medicamento foi formação de trombos (34,6%), sendo a varfarina o anticoagulante oral mais utilizado (97,5%). Dois meses após a alta, todos os pacientes foram classificados como aderentes ao tratamento e 42% mantiveram o INR na faixa terapêutica. As diferenças entre as médias do estado geral de saúde, HADS-Ansiedade e HADS-Depressão durante a internação e dois meses após a alta não foram estatisticamente significantes (p=0,78; p=0,27 e p=0,40, respectivamente). Em relação á presença de ansiedade, quando associamos as duas variáveis de forma categórica, com e sem sintomas, e o tempo de avaliação, 38 (46,9%) pacientes foram classificados como \"sem sintomas\" de ansiedade e 22 (27,1%) \"com sintomas\", sendo esta associação estatisticamente significante (p<0,001). Para depressão, a maioria (55; 67,9%) foi classificada como \"sem sintomas\" e 11 (13,6%) \"com sintomas\", sendo tal associação estatisticamente significante (p<0,001). Ao analisarmos as médias do estado geral de saúde segundo tempo e grupo de sintomas, resultados estatisticamente significantes foram obtidos apenas quando comparamos os valores entre os grupos sem sintomas de depressão (M=80,5; D.P.=23,46) e com sintomas (M=62,5; D.P.=26,07) (p=0,021), dois meses após a alta e quando comparamos as médias do grupo com sintomas de depressão, na internação (M= 75,37; D.P.=25,02) e dois meses após a alta (M=62,5; D.P.=26,07) (p=0,046). Identificar o perfil clínico de pacientes em uso de anticoagulante oral, desde a internação até dois meses de seguimento ambulatorial; conhecer sua percepção sobre estado de saúde, presença de sintomas de ansiedade e de depressão e a adesão ao tratamento são ações importantes a serem consideradas no atendimento desses pacientes. Tais resultados poderão ser utilizados para nortear mudanças na organização do ambulatório de anticoagulação oral e no planejamento da assistência de enfermagem a tais pacientes. / This exploratory and longitudinal research involved 81 patients under oral anticoagulation treatment, who were evaluated during hospitalization and two months after discharge. The objectives were to follow the patients\' clinical evolution, considering the oral anticoagulation therapy and treatment adherence; and to compare the general health condition and the presence of anxiety and depression symptoms. Specific instruments were used to assess adherence to medication treatment (Treatment Adherence Measure), general health condition (visual analogue scale) and the presence of anxiety (HADS-Anxiety) and depression symptoms (HADS-depression). For the sake of statistical analysis, the following were applied: Student\'s paired t-test to compare the mean scores for the general health condition and HADS scores; the Linear Fixed Effects Model to analyze the association between general health condition, anxiety, depression and research moment. Significance was set at 0.05. Among the participants, 54.3% were women, with a mean age of 59.5 years and a mean education time of 5.1 years. The main clinical indication for medication use was the formation of thrombi (34.6%), with warfarin as the most used oral anticoagulant drug (97.5%). AT two months after discharge, all patients were classified as adherent to the treatment and 42% maintained their INR within the therapeutic range. The differences between the mean general health, HADS-Anxiety and HADS-Depression scores during hospitalization and two months after discharge were not statistically significant (p=0.78; p=0.27 and p=0.40, respectively). As regards the presence of anxiety, when the two variables are associated categorically, with and without symptoms, and the research moment, 38 (46.9%) patients were classified as \"without symptoms\" of anxiety and 22 (27.1%) \"with symptoms\", with a statistically significant association (p<0.001). As for depression, the majority (55; 67.9%) was classified as \"without symptoms\" and 11 (13.6%) \"with symptoms\", a statistically significant association (p<0.001). The analysis of the mean general health condition scores according to the research moment and group of symptoms only revealed statistically significant results when comparing the groups without (M=80.5; S.D.=23.46) and with symptoms (M=62.5; S.D.=26.07) (p=0.021) two months after the discharge and when comparing the mean scores for the group with depression symptoms during hospitalization (M= 75.37; S.D.=25.02) and two months after the discharge (M=62.5; S.D.=26.07) (p=0.046). Identifying the clinical profile of patients under oral anticoagulant therapy since hospitalization and after two months of outpatient monitoring and getting to know their perceived health condition, presence of anxiety and depression symptoms and treatment adherence are important actions for consideration in care delivery to these patients. These results can be used to guide changes in the organization of the oral anticoagulation outpatient clinic and in nursing care planning for these patients.

Estudo exploratório, de delineamento longitudinal, com 81 pacientes em uso de anticoagulante oral e que foram avaliados durante internação e dois meses após a alta. Os objetivos foram acompanhar a evolução quanto á terapia de anticoagulação oral e adesão ao tratamento; comparar o estado geral de saúde e a presença de sintomas de ansiedade e depressão. Foram utilizados instrumentos específicos para avaliar adesão ao tratamento medicamentoso (Medida de Adesão aos Tratamentos), estado geral de saúde (Escala Visual Analógica) e presença de sintomas de ansiedade (HADS-Ansiedade) e depressão (HADS- Depressão). As análises estatísticas realizadas foram: Teste t de Student pareado para comparar as médias do estado geral de saúde e da HADS; Modelo Linear de Efeitos Mistos para analisar a associação entre estado geral de saúde, ansiedade, depressão e tempo de avaliação no estudo. O nível de significância adotado foi 0,05. Entre os participantes, 54,3% eram mulheres, com idade média de 59,5 anos e nível médio de instrução de 5,1 anos. A principal indicação clínica para uso do medicamento foi formação de trombos (34,6%), sendo a varfarina o anticoagulante oral mais utilizado (97,5%). Dois meses após a alta, todos os pacientes foram classificados como aderentes ao tratamento e 42% mantiveram o INR na faixa terapêutica. As diferenças entre as médias do estado geral de saúde, HADS-Ansiedade e HADS-Depressão durante a internação e dois meses após a alta não foram estatisticamente significantes (p=0,78; p=0,27 e p=0,40, respectivamente). Em relação á presença de ansiedade, quando associamos as duas variáveis de forma categórica, com e sem sintomas, e o tempo de avaliação, 38 (46,9%) pacientes foram classificados como \"sem sintomas\" de ansiedade e 22 (27,1%) \"com sintomas\", sendo esta associação estatisticamente significante (p<0,001). Para depressão, a maioria (55; 67,9%) foi classificada como \"sem sintomas\" e 11 (13,6%) \"com sintomas\", sendo tal associação estatisticamente significante (p<0,001). Ao analisarmos as médias do estado geral de saúde segundo tempo e grupo de sintomas, resultados estatisticamente significantes foram obtidos apenas quando comparamos os valores entre os grupos sem sintomas de depressão (M=80,5; D.P.=23,46) e com sintomas (M=62,5; D.P.=26,07) (p=0,021), dois meses após a alta e quando comparamos as médias do grupo com sintomas de depressão, na internação (M= 75,37; D.P.=25,02) e dois meses após a alta (M=62,5; D.P.=26,07) (p=0,046). Identificar o perfil clínico de pacientes em uso de anticoagulante oral, desde a internação até dois meses de seguimento ambulatorial; conhecer sua percepção sobre estado de saúde, presença de sintomas de ansiedade e de depressão e a adesão ao tratamento são ações importantes a serem consideradas no atendimento desses pacientes. Tais resultados poderão ser utilizados para nortear mudanças na organização do ambulatório de anticoagulação oral e no planejamento da assistência de enfermagem a tais pacientes. / This exploratory and longitudinal research involved 81 patients under oral anticoagulation treatment, who were evaluated during hospitalization and two months after discharge. The objectives were to follow the patients\' clinical evolution, considering the oral anticoagulation therapy and treatment adherence; and to compare the general health condition and the presence of anxiety and depression symptoms. Specific instruments were used to assess adherence to medication treatment (Treatment Adherence Measure), general health condition (visual analogue scale) and the presence of anxiety (HADS-Anxiety) and depression symptoms (HADS-depression). For the sake of statistical analysis, the following were applied: Student\'s paired t-test to compare the mean scores for the general health condition and HADS scores; the Linear Fixed Effects Model to analyze the association between general health condition, anxiety, depression and research moment. Significance was set at 0.05. Among the participants, 54.3% were women, with a mean age of 59.5 years and a mean education time of 5.1 years. The main clinical indication for medication use was the formation of thrombi (34.6%), with warfarin as the most used oral anticoagulant drug (97.5%). AT two months after discharge, all patients were classified as adherent to the treatment and 42% maintained their INR within the therapeutic range. The differences between the mean general health, HADS-Anxiety and HADS-Depression scores during hospitalization and two months after discharge were not statistically significant (p=0.78; p=0.27 and p=0.40, respectively). As regards the presence of anxiety, when the two variables are associated categorically, with and without symptoms, and the research moment, 38 (46.9%) patients were classified as \"without symptoms\" of anxiety and 22 (27.1%) \"with symptoms\", with a statistically significant association (p<0.001). As for depression, the majority (55; 67.9%) was classified as \"without symptoms\" and 11 (13.6%) \"with symptoms\", a statistically significant association (p<0.001). The analysis of the mean general health condition scores according to the research moment and group of symptoms only revealed statistically significant results when comparing the groups without (M=80.5; S.D.=23.46) and with symptoms (M=62.5; S.D.=26.07) (p=0.021) two months after the discharge and when comparing the mean scores for the group with depression symptoms during hospitalization (M= 75.37; S.D.=25.02) and two months after the discharge (M=62.5; S.D.=26.07) (p=0.046). Identifying the clinical profile of patients under oral anticoagulant therapy since hospitalization and after two months of outpatient monitoring and getting to know their perceived health condition, presence of anxiety and depression symptoms and treatment adherence are important actions for consideration in care delivery to these patients. These results can be used to guide changes in the organization of the oral anticoagulation outpatient clinic and in nursing care planning for these patients.

Made available in DSpace on 2014-12-17T14:03:28Z (GMT). No. of bitstreams: 1 JulianaMCS.pdf: 573830 bytes, checksum: 9b4db031d8ca76bd1eed966ee42dfb5b (MD5) Previous issue date: 2008-11-25 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Sulfated polysaccharides (PS) are biomolecules with a great biotechnological potential. There are few data about PS from high plants. In addition, pharmacological activities of PS from plants have not been carrying out. The aim of this work was extract PS from the angiosperm Halodule wrightii and study their anticoagulant and antioxidant activities. Histological analysis showed the presence of the PS manly in the roots. A polysaccharide-rich extract was obtained from H. wrightii by proteolysis followed by methanol and TCA precipitation. Chemical, infra-red analysis and agarose gel electrophoresis in 1.3 diaminopropane acetate buffer confirmed the presence of sulfated polysaccharides made by glucose, galactose, xylose and sulfate residues in the proportion 1: 0,9: 1: 1. In addition polyacrilamide electrophoresis have shown that extract is mainly compose by 11kDa sulfated polysaccharides. Pharmacological analysis have shown total antioxidant capacity (CAT) that resulted in 15,21 &#956;g for equivalent of ascorbic acid, scavenging activity of the DPPH radical with 41,36 % of scavenging, activity of reducing power with the maximum of 0,290 nm (50 % of vitamin C activity) and scavenging activity superoxide radical (O2-) with a maximum of 32,23 %. Chelating activity of metal less than 4% and scavenging activity of the radical hydroxyl (OH-) less than 2%. Time of activated partial tromboplastin (aPTT) doubling the time of coagulation from 20&#956;g of and protrombin time (PT) was not present. The data indicate that PS from Halodule wrightii could be considered for future applications in medicine, food production or cosmetic industry / Os polissacar?deos sulfatados (PS) s?o biomol?culas com um grande potencial biotecnol?gico por apresentarem uma diversidade estrutural e farmacol?gica muito grande. Poucos s?o os relatos da exist?ncia destes pol?meros em vegetais superiores, al?m disso, ainda n?o se tem relatos da identifica??o de atividades antioxidantes e anticoagulantes com PS extra?dos destes vegetais. Com o intuito de verificar a presen?a destes polissacar?deos em angiospermas marinhas conhecidas popularmente como capim do mar, foi coletada a esp?cie marinha Halodule wrightii. As por??es vegetativas (folha, caule e raiz) n?o foram separadas sendo preparado inicialmente um extrato denominado de extrato bruto (EB). Ap?s descontamina??o prot?ica o material obtido foi chamado de extrato de polissacar?deos totais (EPT). A presen?a destes polissacar?deos foi investigada e confirmada por an?lises qu?micas, espectroscopia de infravermelho e eletroforese em gel de agarose sendo denominados de extrato rico em polissacar?deos sulfatados (EPS). A an?lise histol?gica da localiza??o dos PS resultou na presen?a destes polissacar?deos principalmente na epiderme da por??o vegetativa raiz. As an?lises qu?micas mostraram que os polissacar?deos contem glicose, galactose, xilose e sulfato na propor??o de 1: 0,9: 1: 1 e massa molecular de aproximadamente 11 kDa. Os grupos sulfatos est?o provavelmente ligados principalmente em C2 de um monossacar?deo. Testes de atividade antioxidante demonstraram que os PS de H. wrightii n?o apresentaram resultado para o teste de capacidade antioxidante total pelo m?todo CAT. Desta forma foi utilizada a atividade de seq?estro do radical DPPH indicado na literatura por dosar a capacidade antioxidante total que resultou em 41,36%. O seq?estro do ?on super?xido tamb?m foi realizado e resultou em 32,23% assim como o poder redutor que equivaleu a 50% da atividade da Vit. C. N?o houve atividade de seq?estro do radical hidroxila assim como atividade quelante de metal. O teste de atividade anticoagulante (aPTT) mostrou que EPS dobra o tempo de coagula??o com 20 &#61549;g, que ? apenas 2,5 vezes a quantidade da Clexane? (heparina de baixo peso molecular). Para o tempo de protrombina (PT) H.wrightii n?o apresentou atividade. Os dados indicam que EPS possuem um potencial biotecnol?gico anticoagulante e antioxidante e que futuras an?lises se fazem necess?rias para confirmarem esse potencial

Made available in DSpace on 2014-12-17T14:03:29Z (GMT). No. of bitstreams: 1 JulianaMCS.pdf: 573830 bytes, checksum: 9b4db031d8ca76bd1eed966ee42dfb5b (MD5) Previous issue date: 2008-11-25 / Sulfated polysaccharides (PS) are biomolecules with a great biotechnological potential. There are few data about PS from high plants. In addition, pharmacological activities of PS from plants have not been carrying out. The aim of this work was extract PS from the angiosperm Halodule wrightii and study their anticoagulant and antioxidant activities. Histological analysis showed the presence of the PS manly in the roots. A polysaccharide-rich extract was obtained from H. wrightii by proteolysis followed by methanol and TCA precipitation. Chemical, infra-red analysis and agarose gel electrophoresis in 1.3 diaminopropane acetate buffer confirmed the presence of sulfated polysaccharides made by glucose, galactose, xylose and sulfate residues in the proportion 1: 0,9: 1: 1. In addition polyacrilamide electrophoresis have shown that extract is mainly compose by 11kDa sulfated polysaccharides. Pharmacological analysis have shown total antioxidant capacity (CAT) that resulted in 15,21 &#956;g for equivalent of ascorbic acid, scavenging activity of the DPPH radical with 41,36 % of scavenging, activity of reducing power with the maximum of 0,290 nm (50 % of vitamin C activity) and scavenging activity superoxide radical (O2-) with a maximum of 32,23 %. Chelating activity of metal less than 4% and scavenging activity of the radical hydroxyl (OH-) less than 2%. Time of activated partial tromboplastin (aPTT) doubling the time of coagulation from 20&#956;g of and protrombin time (PT) was not present. The data indicate that PS from Halodule wrightii could be considered for future applications in medicine, food production or cosmetic industry / Os polissacar?deos sulfatados (PS) s?o biomol?culas com um grande potencial biotecnol?gico por apresentarem uma diversidade estrutural e farmacol?gica muito grande. Poucos s?o os relatos da exist?ncia destes pol?meros em vegetais superiores, al?m disso, ainda n?o se tem relatos da identifica??o de atividades antioxidantes e anticoagulantes com PS extra?dos destes vegetais. Com o intuito de verificar a presen?a destes polissacar?deos em angiospermas marinhas conhecidas popularmente como capim do mar, foi coletada a esp?cie marinha Halodule wrightii. As por??es vegetativas (folha, caule e raiz) n?o foram separadas sendo preparado inicialmente um extrato denominado de extrato bruto (EB). Ap?s descontamina??o prot?ica o material obtido foi chamado de extrato de polissacar?deos totais (EPT). A presen?a destes polissacar?deos foi investigada e confirmada por an?lises qu?micas, espectroscopia de infravermelho e eletroforese em gel de agarose sendo denominados de extrato rico em polissacar?deos sulfatados (EPS). A an?lise histol?gica da localiza??o dos PS resultou na presen?a destes polissacar?deos principalmente na epiderme da por??o vegetativa raiz. As an?lises qu?micas mostraram que os polissacar?deos contem glicose, galactose, xilose e sulfato na propor??o de 1: 0,9: 1: 1 e massa molecular de aproximadamente 11 kDa. Os grupos sulfatos est?o provavelmente ligados principalmente em C2 de um monossacar?deo. Testes de atividade antioxidante demonstraram que os PS de H. wrightii n?o apresentaram resultado para o teste de capacidade antioxidante total pelo m?todo CAT. Desta forma foi utilizada a atividade de seq?estro do radical DPPH indicado na literatura por dosar a capacidade antioxidante total que resultou em 41,36%. O seq?estro do ?on super?xido tamb?m foi realizado e resultou em 32,23% assim como o poder redutor que equivaleu a 50% da atividade da Vit. C. N?o houve atividade de seq?estro do radical hidroxila assim como atividade quelante de metal. O teste de atividade anticoagulante (aPTT) mostrou que EPS dobra o tempo de coagula??o com 20 ug, que ? apenas 2,5 vezes a quantidade da Clexane? (heparina de baixo peso molecular). Para o tempo de protrombina (PT) H.wrightii n?o apresentou atividade. Os dados indicam que EPS possuem um potencial biotecnol?gico anticoagulante e antioxidante e que futuras an?lises se fazem necess?rias para confirmarem esse potencial

Made available in DSpace on 2014-12-17T14:13:41Z (GMT). No. of bitstreams: 1 NednaldoDS_TESE.pdf: 2321205 bytes, checksum: c08caa8155a3fd7b840048363939c371 (MD5) Previous issue date: 2012-03-19 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Sulfated polysaccharides (SP) are widely distributed in animals and seaweeds tissues. These polymers have been studied in light of their important pharmacological activities, such as anticoagulant, antioxidant, antitumoral, anti-inflammatory, and antiviral properties. On other hand, SP potential to synthesize biomaterials like as nanoparticules has not yet been explored. In addition, to date, SP have only been found in six plants and all inhabit saline environments. However, the SP pharmacological plant activities have not been carrying out. Furthermore, there are no reports of SP in freshwater plants. Thus, do SP from marine plants show pharmacological activity? Do freshwater plants actually synthesize SP? Is it possible to synthesize nanoparticles using SP from seaweed? In order to understand this question, this Thesis was divided into tree chapters. In the first chapter a sulfated polysaccharide (SPSG) was successfully isolated from marine plant Halodule wrightii. The data presented here showed that the SPSG is a 11 kDa sulfated heterogalactan contains glucose and xylose. Several assays suggested that the SPSG possessed remarkable antioxidant properties in different in vitro assays and an outstanding anticoagulant activity 2.5-fold higher than that of heparin Clexane? in the aPTT test; in the next chapter using different tools such as chemical and histological analyses, energy-dispersive X-ray analysis (EDXA), gel electrophoresis and infra-red spectroscopy we confirm the presence of sulfated polysaccharides in freshwater plants for the first time. Moreover, we also demonstrate that SP extracted from E. crassipes root has potential as an anticoagulant compound; and in last chapter a fucan, a sulfated polysaccharide, extracted from the brown seaweed was chemically modified by grafting hexadecylamine to the polymer hydrophilic backbone. The resulting modified material (SNFuc) formed nanosized particles. The degree of substitution for hydrophobic chains of 1H NMR was approximately 93%. SNFfuc-TBa125 in aqueous media had a mean diameter of 123 nm and zeta potential of -38.3 ? 0.74 mV, measured bydynamic light scattering. Tumor-cell (HepG2, 786, H-S5) proliferation was inhibited by 2.0 43.7% at SNFuc concentrations of 0.05 0.5 mg/ mL and RAEC non-tumor cell line proliferation displayed inhibition of 8.0 22.0%. On the other hand, nanogel improved CHO and RAW non-tumor cell line proliferation in the same concentration range. Flow cytometric analysis revealed that this fucan nanogel inhibited 786 cell proliferation through caspase and caspaseindependent mechanisms. In addition, SNFuc blocks 786 cell passages in the S and G2-M phases of the cell cycle / Os polissacar?deos sulfatados (PS) s?o amplamente distribu?dos em animais e tecidos de algas. Estes pol?meros t?m sido estudados em fun??o da import?ncia de suas atividades farmacol?gicas, tais como: anticoagulante, antioxidante, antitumoral, anti-inflamat?ria e as propriedades antivirais. Contudo, o potencial dos PS para sintetizar biomateriais, tais como nanopart?culas, ainda ? pouco explorado. At? ent?o, os PS s? foram encontrados em seis plantas e todas habitam ambientes salino. N?o havendo relatos de PS em plantas de ?gua doce. O que nos levou aos seguintes questionamentos: Os PS extraidos de vegetais marinhos n?o apresentam atividades farmacol?gicas? Os vegetais de ?gua doce realmente sintetizam PS? ? poss?vel sintetizar nanopart?culas utilizando PS a partir de algas marinhas? Para melhor entender as quest?es, esta tese foi dividida em tr?s cap?tulos. No primeiro cap?tulo, um polissacar?deo sulfatado (SPSG) foi isolado a partir de um vegetal marinho Halodule wrightii. Os dados aqui apresentados mostram que o SPSG ? uma heterogalactana sulfatada de 11 kDa constituida de glucose e xilose. Os ensaios realizados sugerem que o SPSG possue propriedades antioxidantes not?veis em diferentes ensaios in vitro e uma excelente actividade anticoagulante de 2,5 vezes mais elevadas do que a de heparina Clexane ? no teste APTT. No cap?tulo seguinte, utilizando ferramentas diferentes, tais como an?lises qu?micas e histol?gicas, an?lise de dispers?o de raios-X (EDXA), eletroforese em gel e espectroscopia de infra-vermelho,confirmamos, em primeira m?o, a presen?a de polissacar?deos sulfatados em vegetais de ?gua doce. Al?m de demonstrarmos que o PS extra?do a partir da raiz de E. crassipes tem potencial como um composto anticoagulante.No ?ltimo cap?tulo uma fucana, um polissac?rido sulfatado, extra?do a partir de uma alga marrom, foi quimicamente modificada por adi??o de hexadecilamina ? cadeia principal do pol?mero hidrof?lico. O material resultante (SNFuc) forneceu part?culas nanom?tricas. O grau de substitui??o para as cadeias hidrof?bicas de 1H RMN foi de aproximadamente 93%. SNFuc em meios aquosos tinha um di?metro m?dio de 123 nm e potencial zeta de -38,3 ? 0,74 mV. Os ensaios com c?lulas tumorais (HepG2, 786, H-S5) demonstrou a ocorr?ncia de uma inibi??o que variou de 2,0-43,7% em concentra??es diferentes de SNFuc (0,05-0,5 mg / mL) resultado semelhante foi obtido com a RAEC monstrando uma inibi??o entre 8,0-22,0%. Por outro lado, o nanogel estimulou a prolifera??o de linhagens celulares n?o tumorais como CHO e RAW nas mesmas concentra??es. An?lise por citometria de fluxo revelou que este nanogel de fucana inibiu a prolifera??o celular de 786 por mecanismos dependentes e independentes de caspases. Al?m disso, bloqueou a passagens da c?lula 786 na fase S e G2-M do ciclo celular / 2020-01-01

Cette thèse est consacrée à la modélisation mathématique de la coagulation sanguine et de la formation de thrombus dans des conditions normales et pathologiques. La coagulation sanguine est un mécanisme défensif qui empêche la perte de sang suite à la rupture des tissus endothéliaux. C'est un processus complexe qui est règlementé par différents mécanismes mécaniques et biochimiques. La formation du caillot sanguin a lieu dans l'écoulement sanguin. Dans ce contexte, l'écoulement à faible taux de cisaillement stimule la croissance du caillot tandis que la circulation sanguine à fort taux de cisaillement la limite. Les désordres qui affectent le système de coagulation du sang peuvent provoquer différentes anomalies telles que la thrombose (coagulation exagérée) ou les saignements (insuffisance de coagulation). Dans la première partie de la thèse, nous présentons un modèle mathématique de coagulation sanguine. Le modèle capture la dynamique essentielle de la croissance du caillot dans le plasma et le flux sanguin quiescent. Ce modèle peut être réduit à un modèle qui consiste en une équation de génération de thrombine et qui donne approximativement les mêmes résultats. Nous avons utilisé des simulations numériques en plus de l'analyse mathématique pour montrer l'existence de différents régimes de coagulation sanguine. Nous spécifions les conditions pour ces régimes sur différents paramètres pathophysiologiques du modèle. Ensuite, nous quantifions les effets de divers mécanismes sur la croissance du caillot comme le flux sanguin et l'agrégation plaquettaire. La partie suivante de la thèse étudie certaines des anomalies du système de coagulation sanguine. Nous commençons par étudier le développement de la thrombose chez les patients présentant une carence en antihrombine ou l'une des maladies inflammatoires. Nous déterminons le seuil de l'antithrombine qui provoque la thrombose et nous quantifions l'effet des cytokines inflammatoires sur le processus de coagulation. Puis, nous étudions la compensation de la perte du sang après un saignement en utilisant un modèle multi-échelles qui décrit en particulier l'érythropoïèse et la production de l'hémoglobine. Ensuite, nous évaluons le risque de thrombose chez les patients atteints de cancer (le myélome multiple en particulier) et le VIH en combinant les résultats du modèle de coagulation sanguine avec les produits des modèles hybrides (discret-continues) multi-échelles des systèmes physiologiques correspondants. Finalement, quelques applications cliniques possibles de la modélisation de la coagulation sanguine sont présentées. En combinant le modèle de formation du caillot avec les modèles pharmacocinétiques pharmacodynamiques (PK-PD) des médicaments anticoagulants, nous quantifions l'action de ces traitements et nous prédisons leur effet sur des patients individuels / This thesis is devoted to the mathematical modelling of blood coagulation and clot formation under flow in normal and pathological conditions. Blood coagulation is a defensive mechanism that prevents the loss of blood upon the rupture of endothelial tissues. It is a complex process that is regulated by different mechanical and biochemical mechanisms. The formation of the blood clot takes place in blood flow. In this context, low-shear flow stimulates clot growth while high-shear blood circulation limits it. The disorders that affect the blood clotting system can provoke different abnormalities such thrombosis (exaggerated clotting) or bleeding (insufficient clotting). In the first part of the thesis, we introduce a mathematical model of blood coagulation. The model captures the essential dynamics of clot growth in quiescent plasma and blood flow. The model can be reduced to a one equation model of thrombin generation that gives approximately the same results. We used both numerical simulations and mathematical investigation to show the existence of different regimes of blood coagulation. We specify the conditions of these regimes on various pathophysiological parameters of the model. Then, we quantify the effects of various mechanisms on clot growth such as blood flow and platelet aggregation. The next part of the thesis studies some of the abnormalities of the blood clotting system. We begin by investigating the development of thrombosis in patients with antihrombin deficiency and inflammatory diseases. We determine the thrombosis threshold on antithrombin and quantify the effect of inflammatory cytokines on the coagulation process. Next, we study the recovery from blood loss following bleeding using a multiscale model which focuses on erythropoiesis and hemoglobin production. Then, we evaluate the risk of thrombosis in patients with cancer (multiple myeloma in particular) and HIV by combining the blood coagulation model results with the output of hybrid multiscale models of the corresponding physiological system. Finally, possible clinical applications of the blood coagulation modelling are provided. By combining clot formation model with pharmacokinetics-pharmacodynamics (PK-PD) models of anticoagulant drugs, we quantify the action of these treatments and predict their effect on individual patients