Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, 2008. / Submitted by Diogo Trindade Fóis (diogo_fois@hotmail.com) on 2009-09-17T15:54:56Z No. of bitstreams: 1 Tese_DioneMarcalLima.pdf: 1570423 bytes, checksum: 13048c5dcea69a1836fe50a5987e123d (MD5) / Approved for entry into archive by Guimaraes Jacqueline(jacqueline.guimaraes@bce.unb.br) on 2010-06-23T11:00:43Z (GMT) No. of bitstreams: 1 Tese_DioneMarcalLima.pdf: 1570423 bytes, checksum: 13048c5dcea69a1836fe50a5987e123d (MD5) / Made available in DSpace on 2010-06-23T11:00:43Z (GMT). No. of bitstreams: 1 Tese_DioneMarcalLima.pdf: 1570423 bytes, checksum: 13048c5dcea69a1836fe50a5987e123d (MD5) Previous issue date: 2008-02-15 / A estabilidade de uma formulação farmacêutica pode ser considerada um fator determinante para garantir a qualidade de um medicamento e conseqüentemente sua eficácia no tratamento. O anti-hipertensivo enalapril é um pró-fármaco que, ao ser absorvido, é hidrolisado a enalaprilato, agente que atua bloqueando a transformação de angiotensina I em angiotensina II, sendo a substância responsável pela ação farmacológica. A estabilidade das formulações contendo o maleato de enalapril pode ser afetada quando expostas a altos níveis de temperatura e umidade, sendo observada a formação de dois produtos de degradação: enalaprilato e dicetopiperazina. Neste trabalho, estudo de estabilidade pelo envelhecimento acelerado e a determinação da concentração plasmática do fármaco foram utilizados para avaliar a qualidade de diferentes especialidades farmacêuticas (Referência, Genéricos e Similares) do maleato de enalapril, na forma de comprimidos de 20 mg. A constatação de que o maleato de enalapril pode ser facilmente degradado em condições ambientais adversas foi comprovada através da verificação do teor inadequado de enalapril em cinco das nove especialidades avaliadas ao final do ensaio de estabilidade pelo envelhecimento acelerado. Além disso, na avaliação do perfil de dissolução das amostras nos diferentes tempos do ensaio de estabilidade, foram observadas diferenças no modelo de liberação do fármaco quando comparado ao produto Referência e a dissolução ao final de 30 minutos do teste mostrou-se comprometida pela degradação do princípio ativo. As alterações observadas no teor e perfil de dissolução do enalapril em alguns dos medicamentos analisados no estudo pode ser um indicativo de comprometimento da biodisponibilidade in vivo. No ensaio in vivo, concentrações plasmáticas mais baixas foram determinadas nas amostras obtidas dos pacientes tratados com o produto Genérico ou Similar, reforçando a hipótese de que o teste de bioequivalência pode não ser considerado um parâmetro definitivo na determinação da qualidade do produto para fármacos de alguns grupos farmacológicos, indicando a necessidade de que, em alguns casos, ensaios in vivo devam ser realizados em condições clínicas normais. __________________________________________________________________________________________ ABSTRACT / The stability of a pharmaceutical formulation can be a major factor in assuring the quality of a drug product and, as a consequence, the efficacy of the treatment. Enalapril is an anti-hypertensive pro-drug that, after being absorbed, is hydrolised into enalaprilat, an agent responsible for blocking the conversion of angiotensin I into angiotensin II. Stability of formulations containing enalapril maleate can be affected when exposed to high levels of temperature and humidity, with the formation of two degradation products: enalaprilat and diketopiperazine. In this work, the quality of different commercially available tablets of 20mg of enalapril maleate (Reference, generic and similar products) was evaluated by both an accelerated stability study and by monitoring the plasma concentration of this drug in patients. Previous indications that enalapril can be easily decomposed under adverse environmental conditions were proven by the results of the accelerated stability studies obtained in this work, in which five out of the nine samples analyzed did not exhibit the specified amount of drug. In addition, the evaluation of the dissolution profile of the tables showed marked differences in the drug release mechanism. Also, at the end of 30 minutes of the test, the dissolution was altered by the degradation of the drug. During the clinical study, lower plasma concentrations were found in patients under treatment with generic and similar products. Changes observed in the drug concentration and dissolution profile for some of the samples in this study may be an indication of a compromised bioavailability.

Submitted by Fernanda Rodrigues de Lima (fernanda.rlima@ufpe.br) on 2018-08-27T19:33:14Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) DISSERTAÇÃO Edjair Vicente Cabral.pdf: 986887 bytes, checksum: 58cdb36341ddcddd9d04854e89d41b64 (MD5) / Approved for entry into archive by Alice Araujo (alice.caraujo@ufpe.br) on 2018-09-05T20:23:56Z (GMT) No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) DISSERTAÇÃO Edjair Vicente Cabral.pdf: 986887 bytes, checksum: 58cdb36341ddcddd9d04854e89d41b64 (MD5) / Made available in DSpace on 2018-09-05T20:23:56Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) DISSERTAÇÃO Edjair Vicente Cabral.pdf: 986887 bytes, checksum: 58cdb36341ddcddd9d04854e89d41b64 (MD5) Previous issue date: 2011-02-24 / CAPES / FACEPE / Foram investigados os mecanismos renais que permeiam a hipertensão induzida pela sobrecarga perinatal de Na⁺, bem como, os efeitos de um tratamento de curta duração com o enalapril, em termos de reprogramação de alterações moleculares no rim e dos mecanismos responsáveis pela hipertensão. Ratos machos adultos Wistar foram obtidos de mães mantidas, durante a gravidez e lactação, com dieta padrão e água potável, o grupo controle, ou com NaCl 0,17 M, o grupo salina. O enalapril (100 mg/l) foi administrado durante três semanas, após o desmame. A prole de mães que beberam salina apresentou túbulos proximais com atividade aumentada da (Na⁺+K⁺)ATPase sem alterações na expressão da subunidade alfa. A atividade da Na⁺-ATPase insensível a ouabaina permaneceu inalterada, mas sua resposta à angiotensina II (ANG II) foi perdida. A atividade das proteína kinase C (PKC), da proteína kinase dependente de AMPc (PKA) e as substâncias reativas ao ácido tiobarbitúrico (TBARS) apresentaram-se aumentadas, enquanto a expressão de receptores AT₂ apresentou-se diminuída e a expressão de receptores AT₁ apresentou-se inalterada. O tratamento com enalapril reduziu as atividades de ambas bombas e as atividades da PKC e PKA na prole que foi exposta ao sódio durante o período perinatal. Adicionalmente, o tratamento com enalapril reduziu a expressão de receptores AT₂ e aumentou os níveis de TBARS no rim. A atividade reduzida da PKA na prole tratada com salina mais enalapril foi acompanhada por recuperação da atividade estimulatória, mas não da inibitória, no que diz respeito a ação da ANG II sobre a enzima Na⁺-ATPase. A prole de mães tratadas com salina apresentou, aos 90 dias, pressão arterial mais elevada do que a prole de mães controle. O tratamento com enalapril preveniu a hipertensão. No entanto, os efeitos paralelos, como a diminuição da atividade da PKA e da PKC, assim como dos receptores AT₂ e o aumento de TBARS podem prejudicar a função renal na idade adulta. / The renal mechanisms underlying perinatal Na⁺ overload-induced hypertension were investigated, as were the effects of short treatment with enalapril in terms of the reprogramming of molecular alterations in the kidney and the onset of hypertension. Male adult Wistar rats were obtained from dams maintained throughout pregnancy and lactation on a standard diet and drinking water (control) or 0.17 M NaCl (saline group). Enalapril (100 mg/l) was administered for three weeks after weaning. Ninety day old offspring from dams that drank saline presented with proximal tubules exhibiting increased (Na⁺+K⁺)ATPase activity without alterations in α-subunit expression. Ouabain-insensitive Na⁺-ATPase activity remained unchanged but its response to angiotensin II (ANG II) was lost. Protein kinase C (PKC), cAMPdependent protein kinase (PKA) and renal thiobarbituric acid reactive substances (TBARS) increased, AT₂ receptor expression decreased and AT₁ receptor expression remained unchanged. Early treatment with enalapril reduced the activities of both pumps, and reduced PKC and PKA activities depending on whether the offspring were exposed to high Na+ perinatally. In addition, treatment with enalapril lowered AT₂ receptor expression and increased local TBARS. Reduced PKA activity in enalapril-treated saline offspring was accompanied by a recovery of the stimulatory, but not the inhibitory, response to ANG II. The ninety day old saline offspring had higher blood pressure than controls and early enalapril administration blocked the onset of hypertension, indicating reprogramming of (Na⁺+K⁺)ATPase. Enalapril was beneficial in decreasing Na+ reabsorption and preventing hypertension in adult offspring. However, side effects including down-regulation of PKA, PKC and AT₂ receptors, and increasing TBARS could impair renal function in later life.

Submitted by Pedro Barros (pedro.silvabarros@ufpe.br) on 2018-08-28T20:35:28Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) TESE Edjair Vicente Cabral.pdf: 4514898 bytes, checksum: 96c4588a2d09e08f62367b1180ade494 (MD5) / Approved for entry into archive by Alice Araujo (alice.caraujo@ufpe.br) on 2018-09-05T22:07:17Z (GMT) No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) TESE Edjair Vicente Cabral.pdf: 4514898 bytes, checksum: 96c4588a2d09e08f62367b1180ade494 (MD5) / Made available in DSpace on 2018-09-05T22:07:17Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) TESE Edjair Vicente Cabral.pdf: 4514898 bytes, checksum: 96c4588a2d09e08f62367b1180ade494 (MD5) Previous issue date: 2014-11-28 / CAPES / Elevada ingestão de sódio durante o desenvolvimento induz na prole disfunções cardiovasculares e renais. Intervenções durante o período pós-natal podem prevenir tais alterações. Neste trabalho foram investigados se o enalapril, um inibidor da enzima conversora de angiotensina ou o α-tocoferol, administrados por 3 semanas após o desmame previnem alterações programadas pela sobrecarga de sódio pré-natal. Adicionalmente, foi avaliado o efeito do α-tocoferol quando administrado em um período mais precoce, durante a lactação. O protocolo experimental foi dividido da seguinte forma: i) ratos machos adultos Wistar foram obtidos de mães mantidas, durante a gravidez e lactação, com NaCl 0,17 M e ii) ratos machos obtidos de mães mantidas com solução de NaCl 0,3 M, desde 20 dias antes do acasalamento até o parto. A prole de mães que receberam salina 0,17 M durante o período perinatal apresentou nos túbulos proximais: atividade aumentada e maior expressão da subunidade alfa da (Na⁺-K⁺)-ATPase, atividade da Na⁺-ATPase insensível a ouabaína permaneceu inalterada, no entanto, sua resposta à Angiotensina II (AngII) foi perdida. A atividade das proteínas kinases C e A e as substâncias reativas ao ácido tiobarbitúrico (TBARS) apresentaram-se aumentadas, assim como a densidade de colágeno e a expressão de AngII. O tratamento com enalapril reverteu praticamente todas as alterações produzidas pela sobrecarga salina, no entanto, produziu no grupo controle alterações de função renal. A prole de mães que receberam salina 0,3 M durante a gestação apresentou, sobretudo alterações do desenvolvimento cardíaco, as quais foram somadas aos efeitos do α-tocoferol pós-natal. O α-tocoferol produziu elevação da pressão arterial, hiporesponsividade à AngII e atrofia cardíaca, e quando associado ao tratamento pré-natal com salina produziu redução na sensibilidade do baroreflexo. Conclusão: A duração do tratamento perinatal, ou seja, somente pré-natal ou pré-natal mais período do aleitamento parecem decisivos na extensão de efeitos sobre a função renal. Por outro lado, o tratamento com enalapril ou α-tocoferol durante o período pós-natal pode reverter alterações produzidas pela sobrecarga de sódio perinatal, no entanto pode programar alterações funcionais cardíaca e renal que são irreversíveis. / Maternal high sodium intake over pregnancy leads to renal and cardiovascular dysfunctions in the offspring. Early interventions could prevent some of these dysfunctions. This work investigated whether the enalapril, an angiotensin converting enzyme inhibitor, or the α-tocopherol, administered for 3 weeks after the weaning, prevent alterations provoked by prenatal sodium overload. Additionally, it was investigated the α-tocopherol effect administered over lactation. The experimental protocol was as it follows: i) Adult male Wistar rats were born from dams provided during pregnancy and lactation with 0.17 M NaCl solution and; ii) adult male rats were born from dams provided 0.3 M NaCl, from 20 days before pregnancy up to parturition. The offspring of dams on 0.17 M NaCl showed in the proximal renal tubules: increased activity of (Na⁺+K⁺)ATPase, increased expression of the α subunit of this enzyme, unaltered activity of Na+-ATPase, hyporesponsiveness of Na⁺-ATPase to angiotensin II, increased activity of PKC and PKA and increased levels of tiobarbituric acid reactive substances (TBARS). In the kidney, they showed increased content of collagen and angiotensin II. Enalapril prevented molecular alterations produced by sodium overload; however it changed renal function in control rats. The offspring of mothers that received 0.3M saline over pregnancy exhibited changes in cardiac development that were summed up to postnatally administered α-tocopherol effects. α-Tocopherol led to hyporesponsiveness to angiotensin II-induced hypertension and cardiac atrophy. When it was associated with prenatal treatment with sodium overload, α-tocopherol led to an attenuation in the baroreflex sensitivity. Conclusion: The sodium overload length, it means, only prenatal or prenatal plus postnatal over lactation, seem crucial to the extension of cardiovascular and renal effects. On the other hand, treatment with enalapril or α-tocopherol, at early periods of development, may prevent alterations provoked by sodium overload during perinatal period. However, these substances may programming irreversible changes in renal and cardiac function.

Background: Heart failure (HF) is a global pandemic with a rising prevalence rate in low- and middle-income countries (LMICs). Poor medication adherence contributes to the impact of chronic diseases such as HF. However, there are sparse adherence data on HF patients in sub-Saharan Africa (SSA). This is problematic as African HF patients have a high mortality rate, which is poorly understood. Poor medication adherence could contribute to the high mortality rate of African HF patients. Objective adherence measures are better than subjective measures (for example, patient recall) at predicting outcomes. In addition, the adherence method should be applicable to resource-scarce settings. Novel multiplex assays were developed to quantify carvedilol, enalaprilat and perindoprilat in dried blood spots (DBS) and correlated with plasma. Carvedilol, enalapril and perindopril are medications commonly used to treat HF, with enalaprilat and perindoprilat being the active metabolites of enalapril and perindopril, respectively. The developed assays were then evaluated in terms of their ability to discern between non-adherent and adherent patients and their suitability for use in resource-scarce settings. Method: The DBS and plasma assays were validated per the United States Food and Drug Administration (FDA) guidelines. The plasma assay was validated over a calibration range of 0.2–200 ng/mL for carvedilol, enalaprilat and perindoprilat. The DBS assay was validated over a range of 1.00–200 ng/mL for the three analytes. The DBS assays were correlated with plasma concentrations in a pilot intensive pharmacokinetic study of six patients. The correlation was determined using Deming regression, with Bland–Altman analysis used to establish agreement between observed and calculated plasma concentrations. Calculated plasma concentrations were obtained using the Deming regression equations describing the relationship between DBS and plasma concentrations. Results: Accuracy, precision, selectivity and sensitivity were proven with complete and reproducible extraction recovery at all concentrations tested for both assays. Stability of the analytes in the matrix and throughout sample processing was proven for both assays. The full range of plasma pharmacokinetic samples could be quantified for all analytes, with the lower limit of quantification (LLOQ) of 0.2 ng/mL proving to be sufficient. The pharmacokinetic pilot study's full range of DBS concentrations could be quantified for enalaprilat but not for carvedilol and perindoprilat. The LLOQ of 1.00 ng/mL was not sensitive enough to quantify the lowest concentrations of some patients for these two analytes. Good correlations were observed between DBS and plasma pharmacokinetic samples, with the Pearson's correlation coefficient (r) greater than 0.94 for all analytes. The difference between the observed and calculated plasma concentrations was less than 20% of their mean for > 67% of samples for all analytes, indicating good agreement between observed and calculated plasma concentrations for all analytes. Conclusions: The plasma assay is suited for evaluating patient adherence to carvedilol, enalapril and perindopril medication. The assay is robust and sensitive enough to discern between those who are adherent and non-adherent. Due to the wealth of pharmacokinetic data available for the analytes in plasma, through pharmacokinetic modelling, it is possible to determine the most appropriate dose and weight-specific adherence interpretation for that patient rather than relying on a general cut-off value. In other words, adherence interpretation can be individualised based on a patient's own dose and weight. Plasma as a matrix, however, is not very amenable to resource-scarce settings. The matrix requires strict storage and transport conditions, so creating additional logistic difficulties and expenses in resource-scarce and remote locations. These are difficulties that would have to be accommodated to use the assay. It was found that the DBS assay is more suitable as a screening assay for carvedilol and perindoprilat than as an assay to gauge adherence. The assay is suitable as an adherence determining assay for enalaprilat, however. The prolonged terminal half-life of enalaprilat allows sufficient DBS concentrations to track adherence. The DBS assay's higher LLOQ and the higher concentration of the analytes in plasma versus that of whole blood places the assay at a stark disadvantage in terms of sensitivity relative to the plasma assay. DBS samples have a significant advantage over plasma samples in their less stringent storage and transport requirements. As a matrix, DBS is far more conducive to remote and resource-scarce areas when compared to plasma. The robustness of both assays was proven with cross-validation using actual clinical samples. Good agreement between observed and calculated plasma concentrations means that DBS concentrations, once normalised, can be used interchangeably with plasma samples. DBS samples can be collected at the sampling sites, taking advantage of the DBS matrix's less stringent storage and transportation requirements. Once the samples are analysed, the concentrations can be converted to plasma concentrations, which can be interpreted more efficiently in terms of adherence. However, this would only be feasible for enalaprilat, as the DBS assay for the carvedilol and perindoprilat analytes lacked sensitivity to reflect ingestion within the last 24 hours.

La validación de un método analítico, constituye un instrumento importante para garantizar la calidad del medicamento, En el presente trabajo se demostró la aplicabilidad del método analítico propuesto por la USP 26, aun introduciendo cambios significativos, para el análisis del Enalapril Maleato por cromatografía liquida de alta Performance (HPLC) en el Perú, el cual seguidamente se validó. Con el cual se establece una evidencia documentada de que el método analítico es capaz de cumplir en forma consistente y repetitiva las especificaciones establecidas. Se presentan los resultados obtenidos en la validación del método analítico por cromatografía liquida de alta performance (HPLC). Previo al inicio de la validación, se realizó un ensayo de adaptabilidad del sistema, con el cual se comprobó el buen funcionamiento del sistema de bombeo, inyector, horno y detector. El método fue validado, siguiendo una metodología de trabajo elaborado previamente en un protocolo de validación, donde se analizaron diferentes parámetros como son: Selectividad, Linealidad, Precisión, Exactitud, Rango y la adecuación del sistema. Definidas las condiciones, se inicia los análisis para la evaluación de los parámetros de validación y se demuestra mediante el diseño experimental y los procedimientos estadísticos empleados, que el método analítico propuesto es selectivo, porque no se evidencian que los productos de degradación interfieran en el análisis del principio activo, además se obtiene un porcentaje de pureza de pico del 100%; es lineal porque se obtiene un coeficiente de correlación r = 0,99987; es precisa ya que para la repetibilidad se obtiene una RSD de 0,64%; y para la reproducibilidad se obtiene una RSD de 0,88%; y finalmente es exacto porque se obtiene un porcentaje de recuperación de 99,88%. Cumpliendo los parámetros de validación establecidos en las obras oficiales, se comprobó de esta forma la validez del método analítico. / --- The validation of an analytic method, constitutes an important instrument to guarantee the quality of the medication, Presently work was demonstrated the applicability of the analytic method proposed by the USP 26, even introducing significant changes, for the analysis of the Enalapril Maleato for cromatografía liquidates of high Performance (HPLC) in the Peru, the one which subsequently you been worth. With which settles down a documented evidence that the analytic method is able to complete in consistent and repetitive form the established specifications. The results are presented obtained in the validation of the analytic method by cromatografía it liquidates of high performance (HPLC). Previous to the beginning of the validation, one carries out a rehearsal of adaptability of the system, with which was proven the good operation of the system of pumping, injector, oven and detecting. The method was validated, following a work methodology elaborated previously in a validation protocol, where different parameters were analyzed like they are: Selectivity, Linealidad, Precision, Accuracy, Range and the adaptation of the system. Defined the conditions the analyses begin for the evaluation of the validation parameters and it is demonstrated by means of the experimental design and the procedures statistical employees that the Selective proposed analytic method because they are not evidenced that the degradation products interfere in the analysis of the active principle, a percentage of purity of pick of 100% is also obtained; it is lineal because one obtains a correlation coefficient r = 0,99987; it is he/she specifies since for the repetibilidad a RSD of 0,64% it is obtained; and for the reproducibilidad a RSD of 0,88% is obtained; and finally it is exact because one obtains a percentage of recovery of 99,88%. Completing the established validation parameters in the official works, he/she was proven this way the validity of the analytic method. / Tesis

La validación de un método analítico, constituye un instrumento importante para garantizar la calidad del medicamento, En el presente trabajo se demostró la aplicabilidad del método analítico propuesto por la USP 26, aun introduciendo cambios significativos, para el análisis del Enalapril Maleato por cromatografía liquida de alta Performance (HPLC) en el Perú, el cual seguidamente se validó. Con el cual se establece una evidencia documentada de que el método analítico es capaz de cumplir en forma consistente y repetitiva las especificaciones establecidas. Se presentan los resultados obtenidos en la validación del método analítico por cromatografía liquida de alta performance (HPLC). Previo al inicio de la validación, se realizó un ensayo de adaptabilidad del sistema, con el cual se comprobó el buen funcionamiento del sistema de bombeo, inyector, horno y detector. El método fue validado, siguiendo una metodología de trabajo elaborado previamente en un protocolo de validación, donde se analizaron diferentes parámetros como son: Selectividad, Linealidad, Precisión, Exactitud, Rango y la adecuación del sistema. Definidas las condiciones, se inicia los análisis para la evaluación de los parámetros de validación y se demuestra mediante el diseño experimental y los procedimientos estadísticos empleados, que el método analítico propuesto es selectivo, porque no se evidencian que los productos de degradación interfieran en el análisis del principio activo, además se obtiene un porcentaje de pureza de pico del 100%; es lineal porque se obtiene un coeficiente de correlación r = 0,99987; es precisa ya que para la repetibilidad se obtiene una RSD de 0,64%; y para la reproducibilidad se obtiene una RSD de 0,88%; y finalmente es exacto porque se obtiene un porcentaje de recuperación de 99,88%. Cumpliendo los parámetros de validación establecidos en las obras oficiales, se comprobó de esta forma la validez del método analítico. / The validation of an analytic method, constitutes an important instrument to guarantee the quality of the medication, Presently work was demonstrated the applicability of the analytic method proposed by the USP 26, even introducing significant changes, for the analysis of the Enalapril Maleato for cromatografía liquidates of high Performance (HPLC) in the Peru, the one which subsequently you been worth. With which settles down a documented evidence that the analytic method is able to complete in consistent and repetitive form the established specifications. The results are presented obtained in the validation of the analytic method by cromatografía it liquidates of high performance (HPLC). Previous to the beginning of the validation, one carries out a rehearsal of adaptability of the system, with which was proven the good operation of the system of pumping, injector, oven and detecting. The method was validated, following a work methodology elaborated previously in a validation protocol, where different parameters were analyzed like they are: Selectivity, Linealidad, Precision, Accuracy, Range and the adaptation of the system. Defined the conditions the analyses begin for the evaluation of the validation parameters and it is demonstrated by means of the experimental design and the procedures statistical employees that the Selective proposed analytic method because they are not evidenced that the degradation products interfere in the analysis of the active principle, a percentage of purity of pick of 100% is also obtained; it is lineal because one obtains a correlation coefficient r = 0,99987; it is he/she specifies since for the repetibilidad a RSD of 0,64% it is obtained; and for the reproducibilidad a RSD of 0,88% is obtained; and finally it is exact because one obtains a percentage of recovery of 99,88%. Completing the established validation parameters in the official works, he/she was proven this way the validity of the analytic method.

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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Farmacologia. / Made available in DSpace on 2012-10-24T19:38:47Z (GMT). No. of bitstreams: 1 262372.pdf: 1124134 bytes, checksum: d9aa69015b1a7db3d97d6d6af8598eb0 (MD5) / A sepse consiste em uma síndrome de resposta inflamatória sistêmica secundária à infecção. A angiotensina II além de ser um importante vasoconstritor liberado durante a sepse, também possui efeitos pró-inflamatórios. O tratamento de animais que tiveram a condição de sepse induzida através da cirurgia de ligadura e perfuração do ceco (CLP), com as doses de 0,25 mg/kg ou 15 mg/kg de losartan, um antagonista dos receptores AT1 de angiotensina, duas horas após a CLP, mostrou nas análises feitas 4 horas após o tratamento, que ambas as doses reduziram a inflamação nos animais sépticos. Nenhuma das doses alterou a hiporreatividade a fenilefrina. A maior dose causou queda da pressão arterial média (PAM) e piora da função renal. Por outro lado, análises feitas 22 horas após o tratamento mostraram que a menor dose não interferiu na PAM, melhorou a hiporreatividade aos agentes vasoconstritores fenilefrina e angiotensina II e permaneceu reduzindo a inflamação. Esta dose não alterou os níveis plasmáticos de creatinina, uréia e NOx que se encontravam elevados nos animais sépticos. A maior dose promoveu uma considerável queda da PAM dos animais e piora da hiporreatividade a fenilefrina e a angiotensina II. Como comparativo, o tratamento precoce dos animais sépticos com a dose de 0,25 mg/kg de enalapril (inibidor da enzima conversora de angiotensina) mostrou os mesmos resultados apresentados pelo losartan. A administração das duas doses de losartan, em momento tardio da sepse (8 horas após a CLP) com análises feitas 16 horas após o tratamento, mostrou que a dose baixa não melhorou e a maior dose permaneceu piorando a hiporreatividade a fenilefrina e a angiotensina II. Portanto, o tratamento precoce com uma baixa dose de losartan foi capaz de melhorar alguns parâmetros na sepse. Assim, uma interferência de forma adequada no sistema renina-angiotensina pode fornecer importantes ferramentas que auxiliem na compreensão e no tratamento da sepse.

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