Cirugía en horario extendido: una visión de los actores involucrados / Extended hours surgery: a vision of the actors involved

Introducción. Las listas de espera para cirugía de alta prevalencia son producto de una limitada oferta ante una elevada demanda de jornadas quirúrgicas. Tienen un impacto sobre las condiciones médicas de los pacientes y la consulta por urgencias. Como respuesta, se han incorporado los espacios quirúrgicos adicionales en horarios no convencionales. Su creciente implementación, aunque controversial, se reconoce cada vez más como una nueva normalidad en cirugía. Hay una limitada documentación de la efectividad de la medida, debido a la complejidad e intereses de los participantes. Métodos. Se analizó desde una posición crítica y reflexiva la perspectiva de los actores involucrados en un programa de cirugía en horario extendido, estableciendo las posibles barreras y los elementos facilitadores de una política enfocada a procedimientos en horario no convencional. Asimismo, se describen posibles oportunidades de investigación en el tema. Discusión. Los programas quirúrgicos en horarios no convencionales implican un análisis de los determinantes de su factibilidad y éxito para establecer la pertinencia de su implementación. La disponibilidad de las salas de cirugía, una estandarización de los procedimientos y una cultura de seguridad institucional implementada por la normativa vigente, favorecen estas acciones operacionales. Los aspectos económicos del prestador y del asegurador inciden en la planeación y ejecución de esta modalidad de trabajo. Conclusión. La realización segura y el éxito de un programa de cirugía en horario no convencional dependen de la posibilidad de alinear los intereses de los actores participantes en el proceso

Introduction. Waiting lists for high-prevalence surgeries are the product of limited supply due to a high demand for surgical days. They have an impact on patients' medical conditions and emergency consultation. In response, additional surgical spaces have been incorporated at unconventional times. Its growing implementation, although controversial, is increasingly recognized as a new normal in surgery. There is limited documentation of the effectiveness of the measure due to the complexity and interests of the participants. Methods. The perspective of the actors involved in an extended hours surgery program was analyzed from a critical and reflective position, establishing the possible barriers, and facilitating elements of a policy focused on procedures during unconventional hours. Possible research opportunities on the topic are also described. Discussion. Surgical programs at unconventional times involve an analysis of the determinants of their feasibility and success to establish the relevance of implementation. The availability of operating rooms, a standardization of procedures and a culture of institutional security implemented by current regulations, favor these operational actions. The economic aspects of the provider and the insurer affect the planning and execution of this type of work. Conclusion. The safe realization and success of a surgical program in unconventional hours depend on the possibility of aligning the interests of the actors involved in the process

Componente curricular projeto de vida: perspectivas de professoras da rede estadual de São Paulo / Curricular component life purpose: perspectives of teachers of the São Paulo state network / Componente curricular proyecto de vida: perspectivas de profesores de la red estadual de São Paulo

O objetivo deste estudo foi conhecer a experiência de alguns professores ao lecionar projeto de vida durante a implementação do componente curricular Projeto de Vida no estado de São Paulo. Realizou-se uma pesquisa qualitativa, de caráter exploratório. Participaram do estudo sete professoras que lecionavam o componente curricular Projeto de Vida em duas escolas públicas, de uma cidade do interior do estado de São Paulo, escolhidas por conveniência. Foram utilizados o Questionário de Dados Sociodemográficos e o Protocolo de Entrevista Semiestruturada para Projeto de Vida de Professores, elaborados para este estudo. As professoras foram entrevistadas individualmente, on-line, e as entrevistas foram gravadas em áudio e vídeo. Os dados foram analisados por meio de análise temática. Os resultados indicaram possibilidades e desafios em relação à implementação do componente curricular Projeto de Vida. Constatou- se que a maioria das docentes afirmou que escolheu esse componente curricular devido à necessidade de atingir a carga horária exigida na rede estadual. As professoras criticaram a proposta, os conteúdos e os materiais desse componente curricular. As críticas apresentadas pelas professoras estão em consonância com aquelas presentes na literatura em relação à reforma do Ensino Médio e ao Inova Educação. Esses resultados sugerem a necessidade de formação tanto nos cursos de licenciatura quanto em ações de formação continuada, para que os professores se sintam mais seguros e preparados para lecionar o componente curricular Projeto de Vida na Educação Básica. Propõe-se uma perspectiva de formação pautada na reflexão e na troca entre os pares para a construção de um projeto coletivo da escola para o componente Projeto de Vida.(AU)

This study aimed to know the experience of some teachers when teaching life purpose during the implementation of the curricular component "Life Purpose" (Projeto de Vida) in the state of São Paulo. A qualitative, exploratory research was carried out. Seven teachers who taught the curricular component "Life Purpose" (Projeto de Vida) in two public schools in a city in the inland state of São Paulo, chosen for convenience, participated in the study. The Sociodemographic Data Questionnaire and the Semi-structured Interview Protocol for Teachers' Life Purposes, developed for this study, were used. The teachers were interviewed individually, online, and the interviews were recorded in audio and video. Data were analyzed using thematic analysis. The results indicated possibilities and challenges regarding the implementation of the Life Purpose curricular component. It was found that most teachers chose this curricular component due to the need to reach the required workload in the state network. The teachers criticized the proposal, the contents and the materials of this curricular component. Teacher's critics are in line with the criticisms present in the literature regarding the reform of High School and Inova Educação. Therefore, training is essential, both in undergraduate courses and in continuing education actions, so that teachers can teach the curricular component Life Purpose in Basic Education. A training perspective based on reflection and exchange between peers is proposed for the construction of a collective school project for the Life Purpose component.(AU)

El objetivo de este estudio fue conocer la experiencia de algunos profesores al enseñar proyecto de vida durante la implementación del componente curricular Proyecto de Vida en el estado de São Paulo. Se realizó una investigación cualitativa, exploratoria. Participaron en el estudio siete profesores que impartían el componente curricular Proyecto de Vida en dos escuelas públicas en un municipio del estado de São Paulo, elegidos por conveniencia. Los instrumentos utilizados fueron el cuestionario de datos sociodemográficos y el protocolo de entrevista semiestructurada para proyectos de vida de profesores, desarrollados para este estudio. Las entrevistas a los profesores fueron en línea, de manera individual, y fueron grabadas en audio y video. Los datos se sometieron a un análisis temático. Los resultados indicaron posibilidades y desafíos en relación a la implementación del componente curricular Proyecto de Vida. La mayoría de los profesores declararon elegir este componente curricular por la necesidad de alcanzar la carga horaria requerida en la red estatal. Los profesionales criticaron la propuesta, los contenidos y los materiales de este componente curricular. Las críticas presentadas están en línea con las críticas presentes en la literatura respecto a la reforma de la educación básica e Inova Educação. Por lo tanto, la formación es fundamental, tanto en los cursos de grado como en las acciones de educación permanente, para que los profesores puedan impartir el componente curricular Proyecto de Vida en la educación básica. Se propone una formación basada en la reflexión y el intercambio entre pares para la construcción de un proyecto escolar colectivo en el componente Proyecto de Vida.(AU)

Process optimization of physicochemical properties of spray-dried Hydrocotyle umbellata L. extract

Abstract Hydrocotyle umbellata L., Araliaceae, is a species that is recommended in Ayurvedic medicine for its effects on the central nervous system, such as anxiolytic and memory-stimulant effects. Despite the medicinal potential of this species, its phytopharmaceutical and technological potential to produce standardized extracts has not been investigated. This study analyzes the influence of spray drying parameters on the contents of the chemical markers (total phenolic, total flavonoid, and hibalactone) and the functional properties of H. umbellata extract. The optimization of drying conditions was performed using a central composite design combined with response surface methodology and desirability function approach. The mathematical models fitted to experimental data indicated that all the evaluated drying parameters significantly influenced the chemical contents. The optimal conditions were: inlet temperature of 120 °C, feed flow rate of 4 mL min-1, and colloidal silicon dioxide:maltodextrin ratio of 16%:4%. Under these conditions, the powder samples had spherical particles and desirable physicochemical and functional properties, such as low water activity and moisture content, good product recovery, reconstitution, and flowability. Thus, spray drying might be a promising technique for processing standardized H. umbellata extracts.

Saúde mental na universidade: atendimento psicológico online na pandemia da covid-19 / Mental health at the university: online psychological care during the covid-19 pandemic / Salud mental en la universidad: atención psicológica en línea en la pandemia de covid-19

Com a pandemia da covid-19, o contexto universitário, que já vinha sendo palco de discussões em relação à saúde mental, tem vivenciado crises mais severas pelos estudantes. Diante deste cenário, foi desenvolvido o projeto Escuta Solidária, voltado à saúde mental dos discentes de graduação e de pós-graduação. Neste artigo, temos como objetivo discutir o atendimento psicológico online com estudantes do curso de psicologia durante o período de isolamento social rígido (maio a junho de 2020). Fizemos, com os psicólogos voluntários, um grupo focal direcionado para a experiência de atendimento psicológico online de curta duração no contexto pandêmico. Trata-se de um estudo qualitativo, realizado com os 11 psicólogos clínicos participantes do referido projeto. A partir de uma análise fenomenológica crítica, os resultados foram divididos em cinco categorias: a) limitações e contribuições do projeto; b) a importância da capacitação e supervisão clínica para a qualidade do projeto; c) atendimento psicológico online; d) ser psicólogo clínico durante a crise da covid-19; e e) demandas emergentes nos atendimentos psicológicos na quarentena. Por fim, discutimos a importância da desmistificação do atendimento psicológico em situações de crise, especialmente na modalidade online, fomentando questionamentos à formação e atuação dos profissionais, no sentido de estarmos atentos às demandas psicológicas que o contexto de crise acarreta na sociedade.(AU)

With the COVID-19 pandemic, the university context, which had already been the stage for discussions regarding mental health, has experienced more severe crises by students. In view of this scenario, the Solidarity Listening project was developed, aimed at the mental health of undergraduate and graduate students. In this article, we aim to discuss online psychological care with psychology students during the period of strict social isolation (May to June 2020). We carried out, with volunteer psychologists, a focus group aimed at the experience of short-termonline psychological care in the pandemic context. This is a qualitative study, carried out with 11 clinical psychologists participating in the aforementioned project. From a critical phenomenological analysis, the results were divided into five categories: a) limitations and contributions of the project; b) the importance of training and clinical supervision for the quality of the project; c) online psychological care; d) being a clinical psychologist during the COVID-19 crisis; and e) emerging demands in psychological care in quarantine. Finally, we discuss the importance of demystifying psychological care in crisis situations, especially in the online modality, promoting questions regarding the training and performance of professionals, to be aware of the psychological demands that the context of crisis entails in society.(AU)

La pandemia del covid-19 provocó que las universidades, que ya habían sido escenario de discusiones sobre la salud mental, experimentaran crisis más severas entre los estudiantes. Ante este escenario, se desarrolló el proyecto Escucha Solidaria, dirigido a la salud mental de estudiantes de grado y posgrado. Este artículo pretende discutir la atención psicológica en línea con estudiantes de Psicología durante el período de aislamiento social más estricto (mayo/junio de 2020). Se conformó un grupo focal con los psicólogos voluntarios orientado a la práctica de la atención psicológica en línea, a corto plazo, en el contexto de una pandemia. Se trata de un estudio cualitativo, realizado con 11 psicólogos clínicos que participaron en el mencionado proyecto. A partir del análisis fenomenológico crítico, los resultados se dividieron en cinco categorías: a) limitaciones y aportes del proyecto; b) importancia de la capacitación y la supervisión clínica para la calidad del proyecto; c) atención psicológica en línea; d) ser psicólogo clínico durante la crisis del covid-19; y e) demandas emergentes en atención psicológica en la cuarentena. Se concluye que es importante desmitificar la atención psicológica en situaciones de crisis, especialmente en la modalidad en línea, al promover principalmente preguntas sobre la formación y el desempeño de los profesionales con el fin de ser conscientes de las demandas psicológicas que el contexto de crisis conlleva la sociedad.(AU)

Optimization of the ellagic acid synthesis process at the bioreactor level using non-conventional yeasts

Abstract Ellagic acid (EA) is a phenolic biomolecule. For its biosynthesis, a source of ellagitannins is required, such as strawberries and yeasts, as precursors of the tannase and ß-glucosidase enzymes responsible for hydrolysis of ellagitannins. Two experimental mixture designs were applied., varying the yeast concentration and the number of ellagitannins in the culture medium, evaluating the enzymatic activity and ellagic acid biosynthesis. Aiming to find the optimal compositions of the non-conventional yeasts assessed in the research to biosynthesize ellagic acid feasibly and efficiently using a response surface performing the statistical analysis in the StatGraphics® program for obtaining a higher yield and optimizing the ellagic acid synthesis process, the results indicate that the strains Candida parapsilosis ITM LB33 and Debaryomyces hansenii ISA 1510 have a positive effect on the synthesis of ellagic acid, since as its concentration increases in the mixture the concentration of ellagic acid in the medium also increases; on the other hand, the addition of Candida utilis ITM LB02 causes a negative effect, resulting in the compositions of 0.516876, 0.483124 and 2.58687E-9 respectively, for a treatment under the same conditions, an optimal value of ellagic acid production would be obtained. With an approximate value of 7.33036 mg/mL

Covid-19: Vacina boa é a aplicada de forma adequada / Covid-19: Vacina boa é a aplicada de forma adequada

Na atualidade, fotografar ou gravar o instante da imunização contra a Covid-19 se tornou rotina compartilhada nas redes sociais. Essa exposição instigou a observação de uma questão relevante: a técnica de aplicação está correta? Com a veiculação de imagens, é possível visualizar as vacinas sendo administradas em diferentes áreas do músculo deltoide, o que pode acarretar efeitos adversos. A otimização da qualificação técnica e pedagógica dos profissionais que elaboram e ministram as capacitações, bem como o envolvimento efetivo dos vacinadores nos treinamentos para injeção intramuscular é uma necessidade constante para evitar mais danos à saúde da população

Currently, photographing or recording the instant of immunization against Covid-19 has become a shared routine on social networks. This exposition prompted the observation of a relevant question: is the application technique correct? With the transmission of images, it is possible to visualize the vaccines being administered in different areas of the deltoid muscle, which can cause adverse effects. The optimization of the technical and pedagogical qualification of the professionals who design and deliver the training, as well as the effective involvement of vaccinators in training for intramuscular injection, is a constant need to avoid further damage to the health of the population

Otimização de método extrativo para raízes de Arctium lappa L / Extractive method optimization for Arctium lappa l. Roots / Optimización de un método de extracción de raíces de Arctium lappa L

Arctium lappa L. é indicada no Formulário de Fitoterápicos da Farmacopeia Brasileira para o tratamento de distúrbios urinários leves. Estudos já demonstraram o potencial antioxidante, anti-inflamatório e antidiabético deste extrato, onde foram identificados fenóis, lignanas, taninos e flavonoides. O objetivo deste trabalho foi otimizar o método extrativo de raízes de A. lappa. Realizou-se o preparo de extratos por diferentes métodos: Ultrassom, Soxhlet, maceração e turbo extração. A otimização foi realizada por turbo extração seguindo um planejamento fatorial 23, empregando como fatores: teor alcoólico, concentração da matéria prima e tempo de extração. Os extratos foram avaliados quanto ao resíduo seco, teores de fenóis e flavonoides, e atividade antioxidante. Com relação ao resíduo seco, e aos teores de fenóis e flavonoides, os métodos de ultrassom e turbo extração demonstraram melhor poder extrativo. Devido ao menor tempo e custo operacional, a otimização foi realizada por turbo extração, e o extrato otimizado foi obtido utilizando álcool 60%, em proporção matéria prima solvente 1:10 e tempo de extração de 15 minutos. Estas análises poderão nortear futuros testes de transposição de método para escala industrial, diminuindo mão de obra, tempo e custos, visando obter produtos fitoterápicos mais eficientes, com valor acessível à população.

Arctium lappa L. is indicated in the Brazilian Pharmacopeia Herbal Medicines Form for the treatment of mild urinary disorders. Studies have already demonstrated the antioxidant, anti-inflammatory and antidiabetic potential of this extract, where phenols, lignans, tannins and flavonoids were identified. The objective of this work was to optimize the extractive method of A. lappa roots. Extracts were prepared by different methods: Ultrasound, Soxhlet, maceration and vortical extraction. The optimization was performed by vortical extraction following a 23 full factorial design, using as factors: alcohol content, drug concentration and extraction time. The extracts were evaluated for dry residue, phenols and flavonoids contents, and antioxidant activity. Regarding the dry residue, and the phenols and flavonoids contents, the ultrasound and vortical extraction methods showed better extractive power. Due to the lower operating time and cost, the optimization was performed by vortical extraction, and the optimized extract was obtained using 60% alcohol, in a 1:10 drug solvent ratio and extraction time of 15 minutes. These assessments guide the future tests of transposition of the method to an industrial scale, reducing manpower, time and costs, aiming to obtain more efficient phytotherapic products, with affordable value for the population.

Arctium lappa L. está indicado en la Formulacao de Fitoterápicos da Farmacopeia Brasileira para el tratamiento de trastornos urinarios leves. Los estudios han demostrado el potencial antioxidante, antiinflamatorio y antidiabético de este extracto, donde se identificaron fenoles, lignanos, taninos y flavonoides. El objetivo de este trabajo fue optimizar el método extractivo de las raíces de A. lappa. Los extractos se prepararon por diferentes métodos: Ultrasonido, Soxhlet, maceración y turboextracción. La optimización se realizó mediante turboextracción siguiendo una planificación factorial de 23, empleando como factores: tenor alcohólico, concentración de materia prima y tiempo de extracción. Se evaluaron los extractos para determinar el residuo seco, el contenido de fenoles y flavonoides y la actividad antioxidante. En cuanto al contenido de residuo seco, fenoles y flavonoides, los métodos de extracción por ultrasonidos y turbo demostraron un mejor poder de extracción. Debido al menor tiempo y coste operativo, la optimización se realizó mediante turboextracción, y el extracto optimizado se obtuvo utilizando alcohol 60%, en proporción disolvente-materia 1:10 y tiempo de extracción de 15 minutos. Estos análisis podrán orientar futuros ensayos de transposición del método para escala industrial, reduciendo mano de obra, tiempo y costes, con el objetivo de obtener productos fitoterapéuticos más eficientes, con valor accesible para la población.

Optimización de las constantes para el cálculo preciso de cinco modelos de lente intraocular / Optimization of constants for accurate calculation of five intraocular lens models

Objetivo: Optimizar las constantes utilizadas por las fórmulas SRK/T, SRK/T2, Holladay 1 y Hoffer Q para cinco modelos de lentes intraoculares (LIO), implantados durante la cirugía de catarata en el Instituto Cubano de Oftalmología (enero/2006-octubre/2019). Método: Se estudiaron retrospectivamente 47341 pacientes. Las constantes se optimizaron ajustando a cero el error de predicción promedio (EPm) y obteniendo el valor que arrojó el máximo número de ojos con error de predicción absoluto -EP- ≤; 0,25, tanto para la biometría ultrasónica como para la óptica. La eficacia de las constantes optimizadas se verificó mediante el análisis de los errores absolutos medio y mediano (EAM/EAMed) más bajos y el porcentaje de ojos en un intervalo determinado de error de predicción en función del valor de las constantes. También se analizaron el índice de rendimiento de la fórmula de Haigis y un nuevo índice introducido. Resultados: Las constantes optimizadas fueron significativamente diferentes de los valores del fabricante. Los valores obtenidos para EPm = 0 fueron diferentes a los mínimos de EAM y EAMed. El porcentaje de ojos con -EP- ≤ 0,25 y 0,50 D difirió cuando los criterios de optimización fueron diferentes. SRK/T y SRK/T2 mostraron los mejores rendimientos, según ambos índices. Conclusiones: Las constantes optimizadas mejoran los resultados postoperatorios para cada combinación LIO-fórmula. Diferentes criterios de optimización conducen a diferentes resultados. El EAM, el EAMed y el porcentaje de ojos con -EP- ≤; 0,50 D son parámetros válidos para comprobar el rendimiento de las fórmulas, hasta disponer de un índice único, fiable y consensuado(AU)

Objective: To optimize the constants used by the SRK/T, SRK/T2, Holladay 1 and Hoffer Q formulas for five intraocular lens (IOL) models implanted during cataract surgery at the Cuban Institute of Ophthalmology (January/2006-October/2019). Methods: 47341 patients were retrospectively studied. The constants were optimized by adjusting the average prediction error (EPm) to zero and obtaining the value that showed the maximum number of eyes with absolute prediction error -EP- ≤ 0.25, for both ultrasonic and optical biometry. The effectiveness of the optimized constants was verified by analyzing the lowest average and median absolute errors (EAM/EAMed) and the percentage of eyes in a given range of prediction error as a function of the value of the constants. The Haigis formula performance index and a newly introduced index were also analyzed. Results: The optimized constants were significantly different from the manufacturer's values. The values obtained for EPm = 0 were different from the EAM and EAMed minima. The percentage of eyes with -EP- ≤ 0.25 and 0.50 D differed when the optimization criteria were different. SRK/T and SRK/T2 showed the best performances, according to both indexes. Conclusions: Optimized constants improve postoperative outcomes for each IOL-formula combination. Different optimization criteria lead to different results. The EAM, the EAMed and the percentage of eyes with -EP- ≤ 0.50 D are valid parameters to check the performance of the formulas, until a single, reliable and consensual index is available(AU)

Optimization of HPLC method using central composite design for estimation of Torsemide and Eplerenone in tablet dosage form

Abstract A simple, precise, accurate and robust high performance liquid chromatographic method has been developed for simultaneous estimation of Torsemide and Eplerenone in tablet dosage form. Design of experiment was applied for multivariate optimization of the experimental conditions of RP-HPLC method. A Central composite design was used to study the response surface methodology and to analyse in detail the effects of these independent factors on responses. Total eleven experiments along with 3 center points were performed. Two factors were selected to design the matrix, one factor is variation in ratio of Acetonitrile and the second factor is flow rate (mL/min). Optimization in chromatographic conditions was achieved by applying Central composite design. The optimized and predicted data from contour diagram comprised mobile phase (acetonitrile, water and methanol in the ratio of 50: 30: 20 v/v/v respectively), at a flow rate of 1.0 ml/min and at ambient column temperature. Using these optimum conditions baseline separation of both drugs with good resolution and run time of less than 5 minutes were achieved. The optimized assay conditions were validated as per the ICH guidelines (2005). Hence, the results showed that the Quality by design approach could successfully optimize RP-HPLC method for simultaneous estimation of Torsemide and Eplerenone.

Development and optimization of cosolvent-based blended Sertraline orodispersible films - A step to personalized medicine

Abstract Personalized medicine is gaining importance in pharmacotherapeutics as it allows tailoring the drug treatment to achieve the best patient response. Orodispersible film (ODF) is easy to formulate in hospitals, produces dose flexibility to suit an individual needs, particularly for patients suffer from swallowing issues or prohibited to take fluids. Sertraline Hydrochloride (SRT) was solubilized in several cosolvents, then different SRT ODFs based on five hydrophilic polymers namely; polyvinyl alcohol (PVA), hydroxylethyl cellulose (HEC), hydroxypropyl methylcellulose E5 LV (HPMC E5 LV), sodium alginate (NaAlg) and gelatin at two concentrations (2% and 4%) were developed and characterized. The outcomes were exposed to response surface analysis to obtain the desirability results to obtain the optimized formulation. Blended ODFs were developed from 4% PVA and 2% HEC in different blends and then potassium chloride (KCl) as a pore-forming agent was added to the best formulation to investigate its dissolution enhancement effect. F14 containing 4% PVA: 2% HEC 2:1 with 5% KCl showed best physicochemical properties of suitable pH (5.6), disintegration time (6 sec), good folding endurance which released 91 % SRT after 15 min. SRT ODF is an encouraging delivery system in the course of personalized medicine for the management of depression.

Moviéndonos hacia la Urología Híbrida / Moving Towards Hybrid Urology

"Cogito ergo sum" la famosa frase de René Descartes tendría que replantearse hoy como "decido, luego existo". La inteligencia natural es esencialmente una batalla de la racionalidad contra el sesgo y el ruido, la vida finalmente se trata de una suma de decisiones. La medicina no es ajena a este conflicto; es una ciencia humana que gravita sobre la incertidumbre y por ello quienes la ejercemos debemos considerar el fallo como un potencial desenlace, pero el fenómeno de la ilusión terapéutica algunas veces produce un efecto cegador que perpetúa nuestro sesgo. La promesa de disminuir este potencial riesgo en las decisiones y la optimización consecuente en los procesos humanos es lo que dio origen al desarrollo al que llamamos "inteligencia artificial".

"Cogito ergo sum" the famous phrase of René Descartes would have to be rephrased today as "I decide, therefore I am". Natural intelligence is essentially a battle of rationality against bias and noise; life is ultimately a sum of decisions. Medicine is no stranger to this conflict; it is a human science that gravitates on uncertainty and therefore those of us who practice it must consider failure as a potential outcome, but the phenomenon of therapeutic illusion sometimes produces a blinding effect that perpetuates our bias. The promise of reducing this potential risk in decisions and the consequent optimization of human processes is what gave rise to the development we call "artificial intelligence".

Novel biopharmaceutical development investigations towards drug and formulation performance optimization

For a drug to excerpt pharmacological action after oral intake, it first needs to be released from the formulation, get into solution (dissolve), be absorbed, and reach the systemic circulation. Since only solubilized drugs can be absorbed, and thus have therapeutic effect, the understanding of the dissolution and drug release processes of a drug product is of primary importance. Such understanding allows a robust formulation development with an ideal in vivo performance. In order to meet set standards, the performance assessment of oral drug products, such as dissolution testing, often applies conditions that are not reflective of the in vivo environment. The use of non-physiologically relevant dissolution method during the drug product development phase can be misleading and give poor mechanistic understanding of the in vivo dissolution process. Hence, we hypothesized that applying physiologically relevant conditions to the dissolution test would result in more accurate in vivo predictability for a robust and precise development process. Since the buffering system in the intestinal lumen operates at low molarity values, phosphate buffer at low buffer capacity was used as a first approach to an in vivo relevant parameter. Furthermore, a biphasic system was used, that is, the low buffer capacity medium was paired with an organic layer (n-octanol) to mimic the concurrent drug absorption that happens with the in vivo dissolution. Both poorly and highly soluble drugs in immediate release formulations (ibuprofen and metronidazole, respectively) were tested in this set-up to assess the dissolution in the aqueous medium and the partitioning to the organic phase. Additionally, enteric coated formulations were tested in bicarbonate buffer at the in vivo reported molarities values to assess the impact of buffer species on drug dissolution. The evaluated parameters were the buffer system (bicarbonate buffer vs. phosphate buffer), buffer capacity and medium pH. In all approaches, dissolution was also carried out in compendial buffer for comparison purposes. Our results demonstrate that the USP-recommended dissolution method greatly lacked discriminatory power, whereas low buffer capacity media discriminated between manufacturing methods. The use of an absorptive phase in the biphasic dissolution test assisted in controlling the medium pH due to the drug removal from the aqueous medium. Hence, the applied noncompendial methods were more discriminative to drug formulation differences and manufacturing methods than conventional dissolution conditions. In this study, it was demonstrated how biphasic dissolution and a low buffer capacity can be used to assess drug product performance differences. This can be a valuable approach during the early stages of drug product development for investigating drug release with improved physiological relevance. Similarly, all the enteric coated formulations displayed a fast release in phosphate buffer and complied with the compendial performance specifications. On the other hand, they all had a much slower drug release in bicarbonate buffer and failed the USP acceptance criteria. Also, the nature of the drug (acid vs base) impacted the dissolution behavior in bicarbonate buffer. This study indicates that compendial dissolution test for enteric coated tablets lacks physiological relevance and it needs to be reevaluated. Thus, an in vivo relevant performance method for EC products is needed. Overall, the findings of this thesis comprehensively demonstrates that meaningful differences in performance and accordance to clinical reports were only obtained when physiological relevant conditions were applied. Hence, our results indicate that the central hypothesis was answered positively

Para que um medicamento exerça a ação farmacológica após a ingestão oral, ele primeiro precisa ser liberado da formulação, dissolver, ser absorvido e atingir a circulação sistêmica. Uma vez que apenas medicamentos solubilizados podem ser absorvidos e, assim, ter efeito terapêutico, a compreensão dos processos de dissolução e liberação de um medicamento é de extrema importância. Tal compreensão permite o desenvolvimento de uma formulação robusta com o desempenho in vivo ideal. Para atender aos padrões regulatórios previamente estabelecidos, a avaliação da performance de formulações orais, como por exemplo, o teste de dissolução, frequentemente aplica condições que não refletem o ambiente fisiológico. O uso de métodos de dissolução não fisiologicamente relevante durante a fase de desenvolvimento do medicamento pode gerar resultados equivocados sem uma compreensão mecanistica do processo de dissolução in vivo. Portanto, a hipótese desse trabalho é que a aplicação de condições fisiologicamente relevantes no teste de dissolução resultaria em uma predição mais precisa da dissolução in vivo para um processo de desenvolvimento robusto e preciso. Uma vez que o sistema tampão no lúmen intestinal possui baixa molaridade, o tampão fosfato com baixa capacidade tamponante foi usado como uma primeira abordagem como um meio de dissolução fisiologicamente relevante. Além disso, foi utilizado um sistema bifásico, ou seja, o meio de baixa capacidade tamponante combinado a uma fase orgânica (n-octanol) para imitar a absorção in vivo. Formulações de liberação imediata contendo fármacos de baixa e de alta solubilidade (ibuprofeno e metronidazol, respectivamente) foram testadas no sistema bifásico para avaliar a dissolução no meio aquoso e a partição para a fase orgânica. Ademais, formulações com revestimento entérico foram testadas em tampão bicarbonato nos valores de molaridades fisiológicos para avaliar o impacto da espécie tamponante na dissolução do fármaco. Os parâmetros avaliados foram o sistema tampão (tampão bicarbonato vs. tampão fosfato), capacidade tamponante e pH médio. Em todas as abordagens, a dissolução também foi realizada em tampão farmacopeico para fins de comparação. Nossos resultados demonstraram que o método de dissolução farmacopeico não foi discriminativo, enquanto o meio com menor capacidade tamponante diferenciou entre as formulações obtidas via granulação úmida ou compressão direta. Ademais, a utilização da fase orgânica no teste de dissolução bifásica auxiliou no controle do pH do meio aquoso. Portanto, os métodos não compendiais aplicados foram mais discriminativos do que as condições de dissolução convencionais. Neste estudo, foi demonstrado como a dissolução bifásica e uma baixa capacidade tamponante podem ser usadas para avaliar as diferenças na performance de formulações. Esta pode ser uma abordagem valiosa durante os estágios iniciais do desenvolvimento de medicamentos para investigar a liberação destes sob condições fisiologicamente relevantes. Da mesma forma, todas as formulações com revestimento entérico exibiram uma liberação rápida em tampão de fosfato e atenderam às especificações farmacopeicas. Entretanto, a liberação do fármaco foi muito mais lenta em tampão de bicarbonato e consequentemente não cumpriram com as especificações farmacopeicas. Além disso, a natureza do fármaco (ácido vs. base) impactou o comportamento de dissolução no tampão de bicarbonato. Este estudo indica que o teste de dissolução convencional para comprimidos de liberação retardada não possui relevância fisiológica e precisa ser reavaliado. Portanto, os resultados desta tese demonstram de forma abrangente que diferenças significativas na performance condizentes com relatórios clínicos foram obtidas apenas quando as condições fisiológicas relevantes foram aplicadas. Esses resultados indicam que a hipótese central foi respondida positivamente

Aplicação da eletroforese capilar - espectrometria de massas para identificação dos produtos de degradação do aripiprazol em medicamentos / Application of capillary electrophoresis - mass spectrometry to identify aripiprazole degradation products in drugs

Diretrizes internacionais e nacionais como a FDA (Food and Drug Administration), ICH (International Council for Harmonisation) e ANVISA (Agência Nacional de Vigilância Sanitária) estabelecem a exigência de testes de estabilidade para entender melhor a qualidade de um medicamento. O estudo de estabilidade deve ser realizado usando métodos indicativos de estabilidade que possam qualificar e quantificar os insumos farmacêuticos do medicamento, bem como as impurezas e produtos de degradação nele contidos. O aripiprazol é um antipsicótico atípico de segunda geração aprovado para o tratamento de esquizofrenia, transtorno bipolar, depressão e transtornos do espectro do autismo. Os métodos oficiais descritos nas farmacopeias para avaliar o aripiprazol e suas impurezas utilizam a cromatografia líquida de alta eficiência (HPLC) como técnica principal. Nesta pesquisa, objetivou-se desenvolver um método indicativo de estabilidade por eletroforese capilar de zona (CZE) para o aripiprazol na forma farmacêutica de comprimidos, e identificação dos produtos de degradação por espectrometria de massas. O estudo de degradação forçada e a optimização do método desenvolvido por CZE foram realizados utilizando o conceito de delineamento de experimentos (DoE). A separação do aripiprazol de seus produtos de degradação foi conseguida usando uma coluna capilar de sílica fundida (30,2 cm x 75 µm ID), eletrólito de formiato de amônio 6 mmol/L (pH 3) com 5% de metanol sob um potencial de 15 kV e detecção em 214 nm. A capacidade indicativa de estabilidade do método foi investigada pela análise do aripiprazol após ser submetido a condições de estresse ácido, alcalino, térmico, fotolítico e oxidativo, de acordo com as diretrizes ICH. A oxidação foi a principal via de degradação entre as condições de estresse avaliadas. O aripiprazol foi separado dos seus produtos de degradação oxidativa em tempo de corrida abaixo de 5 minutos. O método por CZE mostrou ser linear na faixa de 60 - 140 µg/mL, R2 = 0,9980, precisão calculada como desvio padrão relativo (DPR) menor que 2% e exatidão calculada como recuperação média de 100,93 ± 0,77%. Os resultados obtidos demonstram que o método por HPLC-RP em modo gradiente, separou o aripiprazol e seus produtos de degradação em um tempo de corrida de 30 minutos. Quatro produtos de degradação foram detectados pelo método LC-MS e o principal produto de degradação oxidativo foi identificado. O aripiprazol mostrou-se suscetível à oxidação no grupo piperazina, gerando principalmente o composto aripiprazol-1-N-óxido

International and national guidelines such as the FDA (Food and Drug Administration), ICH (International Council for Harmonization) and ANVISA (National Health Surveillance Agency) establish the requirement for stability tests to better understand quality of a medicine. The stability study must be carried out using stability indicating methods that can qualify and quantify the pharmaceutical ingredients of the drug, as well as the impurities and degradation products contained therein. Aripiprazole is a second-generation atypic antipsychotic drug approved for the treatment of schizophrenia, bipolar disorder, depression, and autism spectrum disorders. The official method described in the pharmacopoeias to evaluate aripiprazole and its impurities is high performance liquid chromatography (HPLC) as the main technique. In this research, the objective was to develop an indicative method of stability by capillary zone electrophoresis (CZE) for aripiprazole in the pharmaceutical form of tablets, and identification of degradation products by mass spectrometry. The forced degradation study and the optimization of the method developed by CZE were carried out using the concept of design of experiments (DoE). The separation of aripiprazole from its degradation products was achieved using a fused silica capillary column (30,2 cm x 75 µm ID), 6 mmol/L ammonium formate electrolyte (pH 3) with 5% methanol under a potential of 15 kV and detection at 214 nm. The indicative stability of the method was investigated by analyzing aripiprazole after being subjected to acid, alkali, thermal, photolytic and oxidative stress conditions, according to the ICH guidelines. Oxidation was the main degradation pathway among the stress conditions evaluated. Aripiprazole was separated from its oxidative degradation products at run times below 5 minutes. The CZE method proved to be linear in the range of 60 - 140 µg/mL, R2 = 0,9980, precision calculated as a relative standard deviation (DPR) of less than 2% and accuracy calculated as a mean recovery of 100,93 ± 0,77%. The results obtained demonstrate that the HPLC-RP method in gradient mode separated aripiprazole and its degradation products in a run time of 30 minutes. Four degradation products were detected by the LC-MS method and the main oxidative degradation product was identified. Aripiprazole was shown to be susceptible to oxidation in the piperazine group, generating mainly the compound aripiprazole-1-N-oxide

Renovación y trasformación / Renewal and transformation

Los cambios que se realizan en cualquier aspecto de la vida son necesarios, transforman la imagen y revitalizan. La mayoría de los cambios conllevan a renovación. Todos los animales se renuevan, las aves pierden sus plumas y reaparecen otras, más vivas, sanas, coloridas y de mejor brillo. Los mamíferos recambian solo su pelaje, algunos de manera estival y muchos de ellos acomodando su color al entorno. El más conocido y evidente es el de los reptiles, las serpientes realizan un proceso biológico complejo que implica aumento de secreciones tipo linfa debajo de la piel antigua que le ayuda a cambiar paulatinamente a su nueva piel. Todos estos cambios son necesarios y revitalizan, dan lozanía y mejoran el estado de ánimo. La SCCOT y la RCCOT han decidido hacer algunos cambios.

Formulation, Optimization, in vitro and in-vivo evaluation of levofloxacin hemihydrate Floating Tablets

Abstract The objective of the present investigation was to design, optimize and characterize the gastro retentive floating levofloxacin tablets and perform in-vivo evaluation using radiographic imaging. The floating tablets were prepared by using polymers i.e hydroxy propyl methyl cellulose (HPMC-K4M) and carbopol-940 individually and in combination by nonaquous granulation method. All the Formulations were evaluated for swelling index (S.I), floating behavior and in-vitro drug release kinetics. The compatibility study of levofloxacin with other polymers was investigated by FTIR, DSC, TGA and XRD. Results from FTIR and DSC revealed no chemical interaction amongst the formulation components. The optimized formulation (F11) showed floating lag time (FLT), total floating time (TFT) swelling index (S.I) of 60 sec, >16h and approximately 75 %, respectively. Moreover, F11 showed zero order levofloxacin release in simulated gastric fluid over the period of 6 h. X-ray studies showed that total buoyancy time was able to delay the gastric emptying of levofloxacin floating tablets in rabbits for more than 4 hours. In conclusion the optimized formulation (F11) can be used for the sustained delivery of levofloxacin for the treatment of peptic ulcer.

Bioprocess optimization of interferon ß-1-a in Pichia pastoris and its improved inhibitory effect against hepatocellular carcinoma cells

Interferon-ß-1a (INF-ß-1a) has gained significant attention due to its emerging applications in the treatment of different human diseases. Therefore, many researchers have attempted to produce it in large quantities and also in a biologically active form using different expression systems. In the present study, we aimed to improve the expression level of INF-ß-1a by Pichia pastoris using optimization of culture conditions. The codon-optimized INF-ß- 1a gene was cloned into pPICZαA plasmid under the control of alcohol oxidase I (AOX1) promoter. The protein expression was induced using different concentrations of methanol at different pHs and temperatures. The biological activity of produced protein was evaluated by anti-proliferative assay. The ideal culture conditions for the expression of INF-ß-1a by P. pastoris were found to be induction with 2% methanol at pH 7.0 culture medium at 30 C which yielded a concentration of 15.5 mg/L INF-ß-1a in a shake flask. Our results indicate that differences in glycosylation pattern could result in different biological activities as INF- ß-1a produced by P. pastoris could significantly more reduce the cell viability of HepG-2 cells, a hepatocellular carcinoma cell line, than a commercially available form of this protein produced by CHO

Optimization and Quest of HPMC loaded Stavudine Controlled Release Dosage Development by Central Composite Design utilizing Reduced Factorial Screening Technique

Abstract The current research focused on screening and finding the significant independent variables in stavudine loaded tablet, followed by optimizing the best formulation using central composite design. The objective of the study to develop stavudine loaded controlled release tablet utilizing reduced factorial design, followed by optimization technique as well as characterization of prepared tablets. Preliminary trial batches were prepared using different grades of hydroxypropyl methylcellulose. The resolution-IV reduced factorial design was selected to screen the significant independent variables in the dosage form design. A total number of eight runs were prepared and responses were recorded. The signified factors identified by half-normal and Pareto chart. The prepared tablets are evaluated for various physiochemical characterizations. Three dependent responses such as hardness, dissolution at 6 hour and 12 hours are considered in optimization process. Later on, drug-polymer interaction study was carried out. The principal of the study design based on finding the best formulation with prefixed set parameter values utilizing the concept of screening technique. It observed that HPMC K15M (57.18 %), HPMC K100 (66.32 %) and PVP K30 (7.97 %) as best composition in a formulation batch would fulfill the predetermined parameter with specific values.

Optimization of glycerol-based medium composition for antifungal metabolites production by Bacillus subtilis

Abstract Bacillus species are promising producers of various compounds that have pronounced antimicrobial, antiviral and antitumor activities. Due to its GRAS status, Bacillus subtilis represents an excellent candidate for the usage in plant pathogens biocontrol. In this research, evaluation of antifungal metabolites biosynthesis by Bacillus subtilis ATCC 6633 and optimization of glycerol-based medium composition, using response surface methodology, for the production of compounds effective against Neurospora crassa were investigated. The results of disc-diffusion method indicate that applied Bacillus strain produces compounds with antifungal activity against tested fungus. In order to find optimal cultivation medium composition, the experiments were carried out in accordance with Box-Behnken design, and optimization was performed using the concept of desirability function combined with previously defined mathematical equation, which describes examined bioprocess. The optimization model predicts that maximum inhibition zone diameter against Neurospora crassa of 32.24 mm is achieved when initial content of glycerol, NaNO2 and K2HPO4 were 49.68 g/L, 2.90 g/L and 6.49 g/L, respectively. Additionally, the second optimization set was made to minimize the consumption of medium components and costs of medium preparation. The obtained results are the basis for further research aimed to develop medium appropriate for economically justified production of bioactive compounds at industrial scale.

Formulation and Optimization of Diclofenac Sodium Loaded Ethylcellulose Nanoparticles

Abstract Design of experiment (DoE) is a useful time and cost-effective tool for analyzing the effect of independent variables on the formulation characteristics. The aim of this study is to evaluate the effect of the process variables on the characteristics involved in the preparation of Diclofenac Sodium (DC) loaded ethylcellulose (EC) nanoparticles (NP) using Central Composite Design (CCD). NP were prepared by W/O/W emulsion solvent evaporation method. Three factors were investigated (DC/EC mass ratio, PVA concentration, homogenization speed) in order to optimize the entrapment efficiency (EE) and the particle size of NP. The optimal formulation was characterized by Fourier Transform Infrared (FTIR), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and in vitro release. Optimized formulation showed an EE of 49.09 % and an average particle size of 226.83 nm with a polydispersity index of 0.271. No drug-polymer interaction was observed in FTIR and DSC analysis. SEM images showed that the particles are spherical and uniform. The in vitro release study showed a sustained release nature, 53.98 % of the encapsulated drug has been released over 24hours period. This study demonstrated that statistical experimental design methodology can optimize the formulation and the process variables to achieve favorable responses.

Optimization of expression yield in a stable cell line expressing a novel mutated chimeric tissue plasminogen activator (mt-PA)

Abstract The development of stable cell lines producing recombinant proteins is very time-consuming and laborious. One of the practical approaches successfully performed is Fluorescence-Activated Cell Sorting (FACS). A mutated chimeric tissue plasminogen activator (mt-PA) was developed by removing the first three domains of t-PA, insertion of GHRP sequence and mutation toward resistance to plasminogen activator inhibitor-1 (PAI-1). In the current study, a new stable CHO-DG44 cell line producing mt-PA was developed by two sequential clonal selections: FACS and clonal-selection by limiting dilution. Furthermore, the expression was more evaluated using two different expression media. Finally, the high-producing clones were selected based on the dot blot and amidolytic activity test. The transfection efficiency of CHO-DG44 cells was 38% as measured by flow cytometry on green fluorescent protein (GFP). After performing FACS on stable cell pools, the expression yield was increased to fifty-fold. In terms of growth profile, CD-DG44 showed higher viability and cell density results than ProCHO5 medium. The expression of mt-PA was significantly higher in CD-DG44 than in ProCHO5, 765 and 280 IU/mL, respectively. Our data indicated that selection of an appropriate expression medium played a critical role in the development of potent producing stable cells by FACS.