Development and validation of alternative methods by non-aqueous acid-base titration and derivative ultraviolet spectrophotometry for quantification of sildenafil in raw material and tablets

Sildenafil citrate (SILC) is a potent phosphodiesterase-5 inhibitor used for erectile dysfunction and pulmonary hypertension. This study shows two simple, fast and alternative analytical methods for SILC determination by non-aqueous titration and by derivative ultraviolet spectrophotometry (DUS) in active pharmaceutical ingredient and/or dosage forms. The quantitation method of SILC active pharmaceutical ingredient by non-aqueous acid-base titration was developed using methanol as solvent and 0.1 mol/L of perchloric acid in acetic acid as titrant. The endpoint was potentiometrically detected. The non-aqueous titration method shows satisfactory repeatability and intermediate precision (RSD 0.70-1.09%). The neutralization reaction occurred in the stoichiometric ratio 1:1 in methanol. The determination of SILC active pharmaceutical ingredient or dosage forms by DUS was developed in the linear range from 10 to 40 µg/mL, in 0.01 mol/L HCl, using the first order zero-peak method at λ 256 nm. The DUS method shows selectivity toward tablets excipients, appropriate linearity (R2 0.9996), trueness (recovery range 98.86-99.30%), repeatability and intermediate precision in three concentration levels (RSD 1.17-1.28%; 1.29-1.71%, respectively). Therefore, the methods developed are excellent alternatives to sophisticated instrumental methods and can be easily applied in any pharmaceutical laboratory routine due to simple and fast executions

PLGA-corosolic acid implants for potential application in ocular neovascularization diseases

Angiogenesis is the formation of new blood vessels from preexisting vasculature. Uncontrolled angiogenesis is associated with progression of several ocular pathologies, such as diabetic retinopathy and macular degeneration. Thus, the inhibition of this process consists in an interesting therapeutic target. Corosolic acid (CA) is a natural derivative of ursolic acid, found in many medicinal herbs and exhibits numerous biological properties, including the antiangiogenic activity. The present study reports the production of CA-loaded poly d,l-lactidecoglycolide acid (PLGA) devices by melt technique. HPLC-UV method was developed and validated to evaluate the uniformity and the release profile of the developed systems. The devices were also characterized by Fourier transform infrared spectroscopy, thermal analysis, and scanning electron morphology. It was studied the antiangiogenic activity of the CA-polymer system, using an in vivo model, the chorioallantoic membrane assay (CAM). CA was dispersed uniformly in the polymer matrix and no chemical interaction between the components of the formulation was verified. The implants presented a sustained release of the drug, which was confirmed by the morphological study and demonstrated an antiangiogenic activity. Therefore, the developed delivery system is a promising therapeutic tool for the treatment of ocular diseases associated with neovascularization or others related to the angiogenic process

6ª Diretriz de monitorização ambulatorial da pressão arterial e 4ª diretriz de monitorização residencial da pressão arterial

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Diretrizes Brasileiras de Medidas da Pressão Arterial Dentro e Fora do Consultório – 2023

Hypertension is one of the primary modifiable risk factors for morbidity and mortality worldwide, being a major risk factor for coronary artery disease, stroke, and kidney failure. Furthermore, it is highly prevalent, affecting more than one-third of the global population. Blood pressure measurement is a MANDATORY procedure in any medical care setting and is carried out by various healthcare professionals. However, it is still commonly performed without the necessary technical care. Since the diagnosis relies on blood pressure measurement, it is clear how important it is to handle the techniques, methods, and equipment used in its execution with care. It should be emphasized that once the diagnosis is made, all short-term, medium-term, and long-term investigations and treatments are based on the results of blood pressure measurement. Therefore, improper techniques and/or equipment can lead to incorrect diagnoses, either underestimating or overestimating values, resulting in inappropriate actions and significant health and economic losses for individuals and nations. Once the correct diagnosis is made, as knowledge of the importance of proper treatment advances, with the adoption of more detailed normal values and careful treatment objectives towards achieving stricter blood pressure goals, the importance of precision in blood pressure measurement is also reinforced. Blood pressure measurement (described below) is usually performed using the traditional method, the so-called casual or office measurement. Over time, alternatives have been added to it, through the use of semi-automatic or automatic devices by the patients themselves, in waiting rooms or outside the office, in their own homes, or in public spaces. A step further was taken with the use of semi-automatic devices equipped with memory that allow sequential measurements outside the office (ABPM; or HBPM) and other automatic devices that allow programmed measurements over longer periods (HBPM). Some aspects of blood pressure measurement can interfere with obtaining reliable results and, consequently, cause harm in decision-making. These include the importance of using average values, the variation in blood pressure during the day, and short-term variability. These aspects have encouraged the performance of a greater number of measurements in various situations, and different guidelines have advocated the use of equipment that promotes these actions. Devices that perform HBPM or ABPM, which, in addition to allowing greater precision, when used together, detect white coat hypertension (WCH), masked hypertension (MH), sleep blood pressure alterations, and resistant hypertension (RHT) (defined in Chapter 2 of this guideline), are gaining more and more importance. Taking these details into account, we must emphasize that information related to diagnosis, classification, and goal setting is still based on office blood pressure measurement, and for this reason, all attention must be given to the proper execution of this procedure.La hipertensión arterial (HTA) es uno de los principales factores de riesgo modificables para la morbilidad y mortalidad en todo el mundo, siendo uno de los mayores factores de riesgo para la enfermedad de las arterias coronarias, el accidente cerebrovascular (ACV) y la insuficiencia renal. Además, es altamente prevalente y afecta a más de un tercio de la población mundial. La medición de la presión arterial (PA) es un procedimiento OBLIGATORIO en cualquier atención médica o realizado por diferentes profesionales de la salud. Sin embargo, todavía se realiza comúnmente sin los cuidados técnicos necesarios. Dado que el diagnóstico se basa en la medición de la PA, es claro el cuidado que debe haber con las técnicas, los métodos y los equipos utilizados en su realización. Debemos enfatizar que una vez realizado el diagnóstico, todas las investigaciones y tratamientos a corto, mediano y largo plazo se basan en los resultados de la medición de la PA. Por lo tanto, las técnicas y/o equipos inadecuados pueden llevar a diagnósticos incorrectos, subestimando o sobreestimando valores y resultando en conductas inadecuadas y pérdidas significativas para la salud y la economía de las personas y las naciones. Una vez realizado el diagnóstico correcto, a medida que avanza el conocimiento sobre la importancia del tratamiento adecuado, con la adopción de valores de normalidad más detallados y objetivos de tratamiento más cuidadosos hacia metas de PA más estrictas, también se refuerza la importancia de la precisión en la medición de la PA. La medición de la PA (descrita a continuación) generalmente se realiza mediante el método tradicional, la llamada medición casual o de consultorio. Con el tiempo, se han agregado alternativas a través del uso de dispositivos semiautomáticos o automáticos por parte del propio paciente, en salas de espera o fuera del consultorio, en su propia residencia o en espacios públicos. Se dio un paso más con el uso de dispositivos semiautomáticos equipados con memoria que permiten mediciones secuenciales fuera del consultorio (AMPA; o MRPA) y otros automáticos que permiten mediciones programadas durante períodos más largos (MAPA). Algunos aspectos en la medición de la PA pueden interferir en la obtención de resultados confiables y, en consecuencia, causar daños en las decisiones a tomar. Estos incluyen la importancia de usar valores promedio, la variación de la PA durante el día y la variabilidad a corto plazo. Estos aspectos han alentado la realización de un mayor número de mediciones en diversas situaciones, y diferentes pautas han abogado por el uso de equipos que promuevan estas acciones. Los dispositivos que realizan MRPA o MAPA, que además de permitir una mayor precisión, cuando se usan juntos, detectan la hipertensión de bata blanca (HBB), la hipertensión enmascarada (HM), las alteraciones de la PA durante el sueño y la hipertensión resistente (HR) (definida en el Capítulo 2 de esta guía), están ganando cada vez más importancia. Teniendo en cuenta estos detalles, debemos enfatizar que la información relacionada con el diagnóstico, la clasificación y el establecimiento de objetivos todavía se basa en la medición de la presión arterial en el consultorio, y por esta razón, se debe prestar toda la atención a la ejecución adecuada de este procedimiento.A hipertensão arterial (HA) é um dos principais fatores de risco modificáveis para morbidade e mortalidade em todo o mundo, sendo um dos maiores fatores de risco para doença arterial coronária, acidente vascular cerebral (AVC) e insuficiência renal. Além disso, é altamente prevalente e atinge mais de um terço da população mundial. A medida da PA é procedimento OBRIGATÓRIO em qualquer atendimento médico ou realizado por diferentes profissionais de saúde. Contudo, ainda é comumente realizada sem os cuidados técnicos necessários. Como o diagnóstico se baseia na medida da PA, fica claro o cuidado que deve haver com as técnicas, os métodos e os equipamentos utilizados na sua realização. Deve-se reforçar que, feito o diagnóstico, toda a investigação e os tratamentos de curto, médio e longo prazos são feitos com base nos resultados da medida da PA. Assim, técnicas e/ou equipamentos inadequados podem levar a diagnósticos incorretos, tanto subestimando quanto superestimando valores e levando a condutas inadequadas e grandes prejuízos à saúde e à economia das pessoas e das nações. Uma vez feito o diagnóstico correto, na medida em que avança o conhecimento da importância do tratamento adequado, com a adoção de valores de normalidade mais detalhados e com objetivos de tratamento mais cuidadosos no sentido do alcance de metas de PA mais rigorosas, fica também reforçada a importância da precisão na medida da PA. A medida da PA (descrita a seguir) é habitualmente feita pelo método tradicional, a assim chamada medida casual ou de consultório. Ao longo do tempo, foram agregadas alternativas a ela, mediante o uso de equipamentos semiautomáticos ou automáticos pelo próprio paciente, nas salas de espera ou fora do consultório, em sua própria residência ou em espaços públicos. Um passo adiante foi dado com o uso de equipamentos semiautomáticos providos de memória que permitem medidas sequenciais fora do consultório (AMPA; ou MRPA) e outros automáticos que permitem medidas programadas por períodos mais prolongados (MAPA). Alguns aspectos na medida da PA podem interferir na obtenção de resultados fidedignos e, consequentemente, causar prejuízo nas condutas a serem tomadas. Entre eles, estão: a importância de serem utilizados valores médios, a variação da PA durante o dia e a variabilidade a curto prazo. Esses aspectos têm estimulado a realização de maior número de medidas em diversas situações, e as diferentes diretrizes têm preconizado o uso de equipamentos que favoreçam essas ações. Ganham cada vez mais espaço os equipamentos que realizam MRPA ou MAPA, que, além de permitirem maior precisão, se empregados em conjunto, detectam a HA do avental branco (HAB), HA mascarada (HM), alterações da PA no sono e HA resistente (HAR) (definidos no Capítulo 2 desta diretriz). Resguardados esses detalhes, devemos ressaltar que as informações relacionadas a diagnóstico, classificação e estabelecimento de metas ainda são baseadas na medida da PA de consultório e, por esse motivo, toda a atenção deve ser dada à realização desse procedimento

Ácido corosólico na oftalmologia: avaliação da atividade antiangiogênica, segurança e toxicidade ocular, desenvolvimento e caracterização de implante biodegradável de liberação prolongada

Exportado OPUSMade available in DSpace on 2019-08-12T13:55:47Z (GMT). No. of bitstreams: 1 disserta__o__cibele_final.pdf: 2892145 bytes, checksum: 0394af6530e6cec5b1ddd9f8033f95c3 (MD5) Previous issue date: 23O processo de angiogênese ocorre em situações patológicas como uma tentativa de reparo de danos teciduais, por meio da formação local de vasos sanguíneos. No entanto, em retinopatias proliferativas, a neovascularização traz efeitos que comprometem a função visual. No controle do processo de neovascularização ocular, a administração intravítrea de fármacos com propriedades antiangiogênicas ainda é preferível dentre os esquemas terapêuticos disponíveis, porém são necessárias injeções frequentes. Portanto, a busca por novas substâncias que possam ser empregadas no tratamento dessas doenças, bem como o desenvolvimento de sistemas de liberação prolongada, tem sido alvo de grande interesse. Dentro desse panorama, o objetivo deste trabalho foi avaliar a atividade antiangiogênica e a segurança da administração intravítrea do ácido corosólico (AC), bem como desenvolver sistemas de liberação prolongada visando ao tratamento de doenças causadoras de neovascularização da retina. A citotoxicidade do AC em linhagem celular do epitélio pigmentado da retina (ARPE-19) foi determinada para um período de 48 horas pelo método colorimétrico da sulforrodamina B, sendo observada ausência de toxicidade em concentrações inferiores a 35,5 µmol/L. A atividade antiangiogênica do AC foi avaliada em um modelo in vivo da membrana corioalantoica de embrião de galinha (CAM) e observou-se que concentrações entre 5 e 25 µmol/L foram capazes de inibir a neovascularização, revelando o AC como uma opção terapêutica promissora para tratamento da angiogênese patológica. Também foi realizada a administração intravítrea de AC em olhos de ratos Wistar e não foram verificados, por avaliação eletrorretinográfica e histológica, sinais de toxicidade da retina por um período de 15 dias. Dessa maneira, o AC em concentrações inferiores a 25 µmol/L foi considerado seguro para uso oftálmico. Para contornar os inconvenientes das administrações intravítreas frequentes, foi desenvolvido um sistema de liberação prolongada biodegradável para carrear o AC. Utilizando-se o método de moldagem a quente, foram preparados implantes de PLGA 50:50 contendo 11% de AC. Foi desenvolvido e validado um método analítico por cromatografia líquida de alta eficiência para a quantificação de AC nos sistemas. Os dispositivos foram caracterizados por técnicas de espectroscopia no infravermelho, análise térmica e microscopia eletrônica de varredura e verificou-se a ausência de incompatibilidades físico-químicas e/ou interações químicas entre o polímero PLGA 50:50 e o AC. Foram conduzidos estudos de liberação in vitro e determinou-se a porcentagem de liberação do AC durante 8 semanas, sendo demonstrada a adequabilidade do sistema para uma liberação continuada de AC por um período de 60 dias. A biocompatibilidade preliminar dos implantes foi demonstrada pelo ensaio biológico da CAM. Portanto, a partir dos resultados obtidos, os implantes biodegradáveis contendo AC mostraramse como uma alternativa promissora para o tratamento de doenças causadoras de neovascularização da retina.Angiogenesis occurs in pathological conditions as an attempt to repair tissue damage through the local formation of blood vessels. However, in proliferative retinopathies, neovascularization brings effects that impair visual function. In the control of the ocular neovascularization process, the intravitreal administration of drugs with antiangiogenic properties is still preferred among the available therapeutic schemes, although frequent injections are necessary. Therefore, the search for new substances that can be used in the treatment of these diseases, as well as the development of sustained release systems, has been of great interest. Within this scenario, the objective of this study was to evaluate the antiangiogenic activity and the safety of intravitreal administration of corosolic acid (AC), and to develop sustained release systems aiming at the treatment of diseases causing retinal neovascularization. The cytotoxicity of AC in the retinal-pigmented epithelium cell line (ARPE-19) was determined for a period of 48 hours by the colorimetric method of sulforhodamine B, and no toxicity was observed at concentrations below 35,5 mol/L. The antiangiogenic activity of AC was evaluated in an in vivo model of the chicken embryo chorioallantoic membrane (CAM) and it was observed that concentrations between 5 and 25 mol/L were able to inhibit neovascularization, revealing AC as a promising therapeutic option for the treatment of pathological angiogenesis. Intravitreal administration of AC was also performed in eyes of Wistar rats, and retinal toxicity signs for a period of 15 days were not checked by electroretinography and histological evaluation. Thus, AC at concentrations below 25 mol/L was considered safe for ophthalmic use. To overcome the drawbacks of frequent intravitreal administration, a biodegradable sustained release system has been developed for carrying AC. Using the hot molding technique, 50:50 PLGA implants containing 11% AC were prepared. An analytical method by high performance liquid chromatography was developed and validated for quantification of AC in the systems. The devices were characterized by infrared spectroscopy, thermal analysis and scanning electron microscopy, and it was not verified any incompatibilities and/or interactions between the PLGA 50:50 polymer and AC. In vitro release studies were conducted and the percentage of released AC was determined over 8 weeks, demonstrating the suitability of the system for a continued release of AC over a period of 60 days. The biocompatibility of the implants was confirmed by the CAM biological assay. Therefore, from the obtained results, biodegradable implants containing AC have been shown as a promising alternative for the treatment of diseases causing retinal neovascularization

Development and validation of alternative methods by non-aqueous acid-base titration and derivative ultraviolet spectrophotometry for quantification of sildenafil in raw material and tablets

Sildenafil citrate (SILC) is a potent phosphodiesterase-5 inhibitor used for erectile dysfunction and pulmonary hypertension. This study shows two simple, fast and alternative analytical methods for SILC determination by non-aqueous titration and by derivative ultraviolet spectrophotometry (DUS) in active pharmaceutical ingredient and/or dosage forms. The quantitation method of SILC active pharmaceutical ingredient by non-aqueous acid-base titration was developed using methanol as solvent and 0.1 mol/L of perchloric acid in acetic acid as titrant. The endpoint was potentiometrically detected. The non-aqueous titration method shows satisfactory repeatability and intermediate precision (RSD 0.70-1.09%). The neutralization reaction occurred in the stoichiometric ratio 1:1 in methanol. The determination of SILC active pharmaceutical ingredient or dosage forms by DUS was developed in the linear range from 10 to 40 µg/mL, in 0.01 mol/L HCl, using the first order zero-peak method at λ 256 nm. The DUS method shows selectivity toward tablets excipients, appropriate linearity (R2 0.9996), trueness (recovery range 98.86-99.30%), repeatability and intermediate precision in three concentration levels (RSD 1.17-1.28%; 1.29-1.71%, respectively). Therefore, the methods developed are excellent alternatives to sophisticated instrumental methods and can be easily applied in any pharmaceutical laboratory routine due to simple and fast executions

Interleukin-10 haplotypes are not associated with acute cerebral ischemia or high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia

ABSTRACT Background: The etiology of stroke, a severe complication of sickle cell anemia, involves inflammatory processes. However, the pathogenetic mechanisms are unknown. The aim of this study was to evaluate the influence of interleukin-10 polymorphisms and haplotypes on the risk of acute cerebral ischemia and high-risk transcranial Doppler in 395 children with sickle cell anemia from the state of Minas Gerais, Brazil. Methods: Interleukin-10 haplotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and sequencing. The outcomes studied were acute cerebral ischemia and high-risk transcranial Doppler. Clinical data were retrieved from the children's records. Results: There was no statistically significant difference in the frequencies of polymorphisms and haplotypes between children with and without acute cerebral ischemia or children with or without high-risk transcranial Doppler. These data are consistent with a previous report that showed an absence of association between interleukin-10 plasma levels and high-risk transcranial Doppler velocity in children with sickle cell anemia. Conclusion: Interleukin-10 haplotypes were not associated with the risk of acute cerebral ischemia or high-risk transcranial Doppler velocity in children with sickle cell anemia from the state of Minas Gerais, Brazil

Association of alpha-thalassemia, TNF-alpha (-308GNA) and VCAM-1 (c.1238GNC) gene polymorphisms with cerebrovascular disease in a newborn cohort of 411 children with sickle cell anemia.

Cerebrovascular disease (CVD) is a severe complication associatedwith sickle cell anemia. Abnormal transcranial Doppler (TCD) identifies some children at high risk, but other markers would be helpful. This cohort study was aimed at evaluating the effects of genetic biomarkers on the risk of developing CVDin children fromMinasGerais, Brazil. Clinical and hematological data were retrieved from children's records. Outcomes studied were overt ischemic stroke and CVD (overt ischemic stroke, transient ischemic attack, abnormal TCD, or abnormal cerebral angiography). Out of 411 children, 386 (93.9%) had SS genotype, 23 (5.6%) had Sβ0-thal and two had severe Sβ+-thal (0.5%). Frequency of CVD was lower in Sβ-thal group (p= 0.05).NoeffectofVCAM-1polymorphism on stroke or CVD risks was detected. Cumulative incidence of stroke was significantly higher for children with TNF-α A allele (p = 0.02) and lower for children with HBA deletion (p = 0.02). However, no association between CVD and TNF-α -308GNA was found. CVD cumulative incidence was significantly lower for children with HBA deletion (p= 0.004). This study found no association between VCAM1 c.1238GNC and stroke. An association between stroke and TNF-α -308A allele has been suggested. Our results have confirmed the protective role of HBA deletion against stroke and CVD