Mechanism of action of chemotherapy drugs in promoting liver injury / 临床肝胆病杂志

Drugs are an important cause of liver injury, and according to statistics, about 1100 drugs may induce liver injury. Due to the difficulty in differential diagnosis, drug-related liver injury is still misjudged. As different drugs have different mechanisms of action in inducing liver injury and may cause different degrees of liver injury, targeted countermeasures should be adopted. There are fewer systematic reviews of liver injury caused by chemotherapy drugs. This article mainly introduces the hepatotoxic mechanisms of various chemotherapy drugs, elaborates on the degree of hepatotoxicity caused by chemotherapy drugs, summarizes the clinical manifestations of liver injury caused by chemotherapy drugs, and gives recommendations to clinical treatment.

Comparison on therapeutic effect of stent implantation and drug treatment for young cerebral infarction combined with middle cerebral artery stenosis / 中国介入影像与治疗学

Objective: To compare the effect of stent implantation and drug treatment for young cerebral infarction combined with middle cerebral artery stenosis. Methods: A total of 71 young cerebral infarction patients (aged 30-44 years) with severe stenosis of middle cerebral artery (stenosis rate >70%) were enrolled and divided into drug group (n=39, received conventional oral medication) and stent group (n=32, underwent stent implantation). The therapeutic effects and follow-up outcomes during 24 months were compared between 2 groups. Results: The success rate of stent group was 100%, and 32 stents were implanted. Significant differences were found between the scores at enrollment and those at 3, 6, 12 and 24 months of modified Rankin scale (mRS) and National Institutes of Health Stroke Scale (NIHSS) within both the two groups during the follow-up (all P0.05). Within 24 months' follow-up, the incidence of end-point event was 20. 51% (8/39), the stroke recurrence rate was 20.51% (8/39), and the disability rate of recurrence stroke (mRS score ≥ 2 points) was 20. 51% (8/39) in drug group, while in stent group was 6.25% (2/32), 3.13% (1/32) and 3.13% (1/32), respectively. There was no statistically significant difference of the incidence of endpoint events between 2 groups (P=0.17), while the recurrence rate of stroke (P=0.04) and the disability rate of recurrent stroke (P=0.04) in stent group were both lower than those in drug group. Conclusion: Compared with drug therapy, stent implantation can reduce stroke recurrence rate and disability rate of in young cerebral infarction with middle cerebral artery stenosis.

Enucleação associada à solução de Carnoy no tratamento de tumor odontogênico ceratocístico / Enucleation associated to Carnoy's solution on treatment of keratocistic odontogenic tumor

Tumor Odontogênico Ceratocístico (TOC) é classificado como uma lesão intraóssea benigna, de origem odontogênica. Apresenta comportamento biológico agressivo e alta taxa de recidiva. Por sua heterogeneidade clínica e histológica, gera controvérsias em relação ao tipo de tratamento. Técnicas, como marsupialização, descompressão, enucleação, ou mesmo, ressecção cirúrgica, são algumas opções de tratamento, podendo associar com outras formas de terapias. O presente trabalho tem por objetivo relatar o caso de um paciente do gênero masculino que apresentava lesão osteolítica na região posterior direita da mandíbula, diagnosticada como tumor odontogênico ceratocístico. O tratamento proposto foi enucleação associada à aplicação de solução de Carnoy. Após 4 anos de pós-operatório, a técnica cirúrgica associada à terapia química mostrou-se eficaz, apresentando resultados satisfatórios. O paciente segue em acompanhamento, sem referir queixas álgicas e funcionais, além de não apresentar alterações estéticas... (AU)

Keratocystic odontogenic tumor is classified as a benign intraosseous and odontogenic lesion. It presents an aggressive biological behavior and great tendency to relapse. Also, it is a pathology that is noteworthy due to its clinical and histological heterogeneity. This diversity reflects on controversies in defining the adequate treatment for these lesions, opting for surgical techniques such as marsupialization, enucleation or resection, even associate with other conservative treatment. By upgrading the knowledge of cell biology, development of diagnostic tests and the improvement of surgical techniques, the treatment of oral diseases suffered major changes in recent decades, making it safer and leading to more predictable results. This study aims to report the case of a male patient, suffering from osteolytic lesion in the posterior mandible, diagnosed as keratocystic odontogenic tumor, which was treated by enucleation associated to application of Carnoy's solution, which is an alternative treatment already described. After 4 years follow-up, proposed treatment has been shown efficient presenting satisfactory results. Patient remains accompanied with no pain and functional complaints as well as no aesthetics alterations... (AU)

Análise das propriedades físico-químicas da glucosamina sulfato comercial, uma matéria- prima utilizada em formulações farmacêuticas / Physicochemical properties analysis of commercial glucosamine sulfate, a raw material used in pharmaceutical formulations

Introdução: A qualidade dos produtos em farmácias de manipulação é determinada pela Agência Nacional de Vigilância Sanitária (ANVISA), mas os métodos descritos podem não ser adequados para analisar seus aspectos físico-químicos. Objetivo: Comparar aspectos físico-químicos da glucosamina sulfato de dois diferentes fornecedores com análises realizadas na farmácia de manipulação. Métodos: As características organolépticas, pH, solubilidade e densidade da glucosamina (n=50) dos fornecedores foram analisadas conforme descrito na Farmacopeia Brasileira e Compêndio Oficial e comparados aos laudos técnicos dos produtos adquiridos. Usaram-se os testes de Kolmogorov-Smirnov, coeficiente de correlação intraclasse (CCI) e Bland-Altman. Resultados: A análise de CCIevidenciou baixa reprodutibilidade para o teste de pH e densidade, e a análise de Bland-Altman demonstrou que os fornecedores subestimavam ou superestimavam os valores de pH e densidade em relação à farmácia. Conclusão: Os aspectos físico-químicos estão adequados conforme orientações da Anvisa, mas novas técnicas mais sensíveis devem ser utilizadas para garantir a qualidade da glucosamina nas formulações.

Introduction: The raw materials quality in the manipulation pharmacies are determined by Brazilian Health Surveillance Agency (ANVISA), but the protocols described may not be appropriate to analyze their physicochemical properties. Objective: To compare the physicochemical properties of glucosamine sulfate from two different suppliers with results obtained in the manipulation pharmacy. Methods: The organoleptic characteristics, pH, solubility and density of glucosamine samples (n=50) were analyzed according to the Brazilian Pharmacopoeia and Official Compendium and compared the technical reports of the suppliers. The results were analyzed by the Kolmogorov-Smirnov test, intraclass correlation coefficient (CCI) and Bland-Altman. Results: CCI analyses showed low reproducibility for pH and density test in the samples tested. In addition, Bland-Altman analysis indicated pH values and density of suppliers were underestimated or overestimated compared to the pharmacy. Conclusion: Physicochemical properties of glucosamine are appropriate according to Anvisa specifications, but new more sensitive techniques should be employed to ensure the glucosamine quality in the formulations.

Inibição de Ciclooxigenases 1 (COX-1) e 2 (COX-2) por Monoterpenos: um Estudo in Silico / Cyclooxygenase 1 (COX-1) and 2 (COX-2) Inhibition by Monoterpenes: an in Silico Study

Os monoterpenos têm sido reportados na literatura por suas importantes atividades farmacológicas, tais como antitumoral e anti-inflamatória. O processo inflamatório pode ser controlado, por exemplo, pelo uso de substâncias químicas inibidoras de ciclooxigenases. No entanto, apesar de vários trabalhos reportarem sobre a atividade anti-inflamatória de óleos essenciais e/ou monoterpenos isolados, poucos têm estudado se o mecanismo de ação ocorre devido à inibições de enzimas envolvidas no processo inflamatório. Diante do exposto, este trabalho teve como objetivo aplicar abordagens in silico para o entendimento das propriedades anti-inflamatórias apresentadas por óleos essenciais ricos em monoterpenos. Para isto, selecionou-se vinte monoterpenos, comuns em óleos essenciais, e realizou-se um estudo in silico das propriedades físico-químicas, farmacocinéticas e interações com enzimas ciclooxigenases 1 (COX-1) e 2 (COX-2). Os resultados obtidos sugerem que estes produtos naturais possuem características moleculares e propriedades farmacocinéticas (entre elas, absorção no intestino humano, ligação com proteínas plasmáticas e coeficiente de partição sangue-cérebro) adequadas para substâncias bioativas candidatas a fármacos. As propriedades determinadas são condizentes com as atividades que têm sido relatadas para monoterpenos presentes em óleos essenciais e/ou isolados. Além disso, alguns dos monoterpenos avaliados apresentaram interação com as enzimas COX-1 e COX-2, com energia e orientação semelhante ao fármaco ibuprofeno. Entre os monoterpenos avaliados, o geraniol foi o que apresentou maior energia de interação com as enzimas COX-1 e COX-2, estando ancorado na mesma região da enzima que o ibuprofeno. Desta forma, estudos in silico adicionais poderão contribuir para o melhor entendimento do mecanismo de ação de monoterpenos com ação anti-inflamatória.

The monoterpenes have been reported for their important pharmacological activities such as antitumor and anti-inflammatory. The inflammatory process may be controlled, for example, by the use of cyclooxygenase inhibitors. However, despite many studies on the anti-inflammatory activity of essential oils and/or isolated monoterpenes, few studies have investigated the mechanism of action due to inhibition of enzymes involved in the inflammatory process. Given the above, this study aimed to apply in silico approaches to understand the anti-inflammatory properties of the essential oils rich in monoterpenes. For this, we selected twenty monoterpenes, common in essential oils, and performed an in silico study of the physicochemical and pharmacokinetic properties and interactions with cyclooxygenase 1 (COX-1) and 2 (COX-2) enzymes. The results suggest that these natural products have molecular characteristics and pharmacokinetic properties (including the human intestinal absorption, plasma protein binding, and blood-brain coefficient partition) suitable for bioactive substances drug candidates. The determined properties are consistent with the activities reported for monoterpene in essential and/or isolated oils. Moreover, some of the monoterpenes showed interaction with COX-1 and COX-2 enzymes, with energy and orientation similar to ibuprofen. Among the monoterpenes evaluated, the geraniol showed the greatest interaction energy with the COX - 1 and COX - 2 enzymes, being anchored in the same region of the enzyme that ibuprofen. Thus, additional in silico studies can contribute to a better understanding of the mechanism of monoterpenes with anti-inflammatory action.

Avaliação da qualidade de cápsulas de sinvastatina de farmácias magistrais / Evaluación de la calidad de cápsulas de sinvastatina de farmacias magistrales / Assessment of the quality of simvastatin capsules from compounding pharmacies

OBJETIVO: Validar metodologia por cromatografia líquida de alta eficiência para determinação do teor de sinvastatina em cápsulas manipuladas. MÉTODOS: Foram avaliadas 18 amostras de cápsulas de sinvastatina 40 mg de farmácias magistrais de São Paulo, Guarulhos, São Bernardo do Campo e Campinas, SP, prescritas para pacientes fictícios. As análises basearam-se na Farmacopéia Brasileira e no método da cromatografia, otimizado e validado de acordo com as normas nacionais e internacionais, para os ensaios de identificação, e quantificação em cápsulas manipuladas. RESULTADOS: O peso médio das cápsulas variou de 70 mg a 316 mg; quatro amostras apresentaram variação de peso em desacordo com a especificação. O teor de sinvastatina nas cápsulas estava de acordo com a especificação em 11 amostras; em seis, esse teor variou entre 4 por cento e 87 por cento do valor declarado, descumprindo os requisitos de teor do princípio ativo; a determinação do teor e uniformidade de conteúdo de uma amostra não foram realizadas. No teste de uniformidade de conteúdo, 15 amostras apresentaram valores menores que 85 por cento e com os desvios-padrões relativos maiores que 6 por cento; três farmácias atendiam a especificação desse ensaio. No ensaio de dissolução, oito amostras apresentaram resultados insatisfatórios no primeiro estágio do ensaio e as demais apresentaram resultados inconclusivos. CONCLUSÕES: O método utilizado mostrou boa adequação para aplicação em controle de qualidade, revelando a falta de qualidade de cápsulas de sinvastatina produzidas por algumas farmácias de manipulação.

OBJETIVO: Validar metodología por cromatografía líquida de alta eficiencia para determinación del tenor de sinvastatina en cápsulas manipuladas. MÉTODOS: Fueron evaluadas 18 muestras de cápsulas de sinvastatina 40 mg de farmacias magistrales de Sao Paulo, Guarulhos, Sao Bernardo do Campo y Campinas, Sureste de Brasil, prescriptas para pacientes ficticios. Los análisis se basaron en la Farmacopéia Brasileña y en el método de la cromatografia, optimizado y validado de acuerdo con las normas nacionales e internacionales, para los ensayos de identificación, y cuantificación en cápsulas manipuladas. RESULTADOS: El peso promedio de las cápsulas variaron de 70 a 316 mg; cuatro muestras presentaron variación de peso en desacuerdo con la especificación. El tenor de sinvastatina en las cápsulas estaba de acuerdo con la especificación en 11 muestras; en seis, ese tenor varió entre 4% y 87% del valor declarado incumpliendo los requisitos de tenor del principio activo; la determinación del tenor y uniformidad de contenido de una muestra no fue realizada. En la prueba de uniformidad de contenido, 15 muestras presentaron valores menores que 85% y con los desvíos-patrones relativos mayores que 6%; tres farmacias atendían la especificación del ensayo. En el ensayo de disolución, ocho muestras presentaron resultados insatisfactorios en la primera fase del ensayo, y las demás presentaron resultados inconclusitos. CONCLUSIONES: El método utilizado mostró buena adecuación para aplicación en control de calidad, revelando la falta de calidad de cápsulas de sinvastatina producidas por algunas farmacias de manipulación.

Diseño de una formulación antimicótica

Se desarrolló una formulación con nitrato de miconazol al 2 % en una crema hidrosoluble apropiada, la cual cumple con los requerimientos físicos, químicos, microbiológicos y biológicos para este tipo de forma farmacéutica. Se comprobó que el producto debe ser envasado en frascos de vidrio ámbar o en tubos de aluminio laqueado, además de presentar una estabilidad física adecuada durante 3 años. El contenido del principio activo se mantuvo dentro de los límites establecidos hasta los 16 meses. También se demostró la actividad antimicótica de la preparación y su efectividad terapéutica.

A formulation with miconazole nitrate 2 % is developed in an appropiate hydrosoluble cream, which meets all the physical, chemical, microbiologic and biologic requirements for this type of pharmaceutical form. It was proved that the product should be put into amber glass flasks or into lacquered aluminum tubes. besides having an adecuate physical stability during three years. The content of the active principle was kept within the established limits up to the 16 months. The antifungal activity of the preparation as well as its therapeutic effectiveness were also demonstrated.

Diseño y evaluación de la formulación de tabletas de pimozida 1 y 4 mg

Se estudiaron diferentes formulaciones de tabletas de pimozida en dosis de 1 y 4 mg, diseñadas con el objetivo de obtener una formulación que cumpla con los parámetros establecidos en la Farmacopea de los Estados Unidos XXII para el control de la calidad del producto terminado, así como los requerimientos necesarios para su revestimiento. Entre las formulaciones establecidas la denominada PP cumplió con los parámetros de calidad establecidos, antes y posterior al revestimiento. Los resultados obtenidos en el estudio de vida en estante de las tabletas revestidas fabricadas a escala semiindustrial demostraron que hasta 1 año posterior a la fabricación, éstas cumplen con las especificaciones establecidas en la Farmacopea, lo cual soporta la factibilidad para su escalado al nivel industrial.

Different formulations of Pimozide 1 and 4 mg tablets designed to obtain a formulation that meets the parameters established by the United States Pharmacopeia XXII for controlling the quality of the finished product, as well as the necessary requirement for its coating, were studied. Among these formulations, the so-called PP fulfilled the established quality parameters before and after coating. The results obtained in the shelf life study of the coated tablets made at semiindustrial scale showen that even one year after their making they meet the specifications established by the Pharmacopeia, which supports the feasibility for their scale-up at industrial level.

Determinación de la disolución en tabletas de trifluoperazina 1 mg por el método de colorantes ácidos

Se desarrolló un procedimiento espectrofotométrico por un método de colorantes ácidos con tropeolina OO para la determinación de la solución en tabletas de trifluoperazina 1 mg en las condiciones de disolución de la USP 23. El valor del pH seleccionado para la máxima partición del complejo colorante-trifluoperazina en cloroformo fue de 2,5, en el cual el complejo presentó una absorbancia máxima a 408 nm. La linealidad, precisión, exactitud y robustez del método se evaluaron en soluciones modelos de trifluoperazina de concentraciones exactamente conocidas, que permitieron demostrar la fiabilidad del procedimiento analítico desarrollado y determinaron su adopción como método alternativo de control de calidad del producto.

As spectrophotometric procedure was developed by using a methods of acid coloring matters with tropeolin 00 for the determination of the solution in trifluoperazine 1 mg tablets under the conditions of dissolution of the USP 23. The value of the ph selected for the maximun partition of the coloring matter-trifluoperazine complex in chloroform was of 2.5, in which the complex had a maximum absorbency at 408 nm. The lineality, accuracy, exactitude and robustness of the method were evaluated in model solutions of trifluoperazine of exactly known concentrations that allowed to demonstrate the reliability of the analytical process developed, and to determine its adoption as an alternative method to control the quality of the product.

Incompatibilidad química y estabilidad térmica del baclofeno por análisis térmico

Se realizó un estudio de las posibles interacciones químicas entre el baclofeno, principio activo, y los distintos excipientes preseleccionados en la preformulación del baclofeno tableta, y al mismo tiempo un estudio de estabilidad térmica con el empleo de la calorimetría diferencial de barrido como técnica fundamental, la cual fue complementada con la cromatografía de capa fina y la espectroscopia infrarroja. Se obtuvo como resultado la no interacción química entre el principio activo y los excipientes; además se estableció un orden de estabilidad térmica con el propósito de realizar posibles sustituciones de algunos excipientes en la preformulación, con vistas a garantizar una mayor estabilidad del producto final.

A study of the possible chemical interactions between baclofen, active principle, and the different excipients preselected in the preformulation of baclofen tablet was conducted. A study of thermic stability by using the differential scanning calorimetry, which was complemented with thin layer chromatography and infrared spectroscopy, was carried out at the same time. As a result, the non-chemical interaction between the active principle and the excipients was obtained, and an order of thermic stability was established aimed at making possible substitutions of some excipients in the preformulation in order to guarantees a greater stability of the final product.

Preformulación de vitamina A en tabletas

Se realizaron estudios acerca de la posible influencia de algunos excipientes en la degradación de vitamina A acetato. Se escogieron excipientes que pudieran hacer posible el futuro diseño de formulaciones de este producto para su producción por compresión directa, dentro de ellas se encuentran: celulosa microcristalina ph 101, manitol, sacarosa, lactosa, almidón de maíz, fosfato de calcio dihidratado, talco, estearato de magnesio y dióxido de silicio. Se comprobó que algunos excipientes como lactosa y talco aceleran la degradación de la vitamina A al coexistir en la formulación de las tabletas. De acuerdo con los resultados obtenidos se diseñaron 4 formulaciones que cumplieron con todos los parámetros tecnológicos, y se lograron formulaciones que mantenían su valoración entre el 90 y el 110 % que es el rango establecido por la USP XXII, después de un año de elaboradas, lo que coincidió con el.

Several studies were carried out about the possible influence of some components in the degradation of vitamin A acetate. There was a selection of components that could make possible the future design of this product formulations for its production by direct compression; among them there are microcristalline cellulose ph 101, mannitol, sucrose, lactose, cornstarch, dehydrated calcium phosphate, talc, magnesium stearate, and silica. Some components, as lactose and talc, were confirmed as accelerators for vitamin A degradation when coexisting in the tablets formulation. According to the results achieved, 4 formulations designed fulfilled all the technological parameters, and there were formulations obtained that kept their valuation between 90 and 110 % (this is the USP XXII established range) after a year from its manufacturing, which was coincident with the period of life issued by the manufacturer.

Protocolo de validación de métodos analíticos para la cuantificación de fármacos

Se presenta un resumen de las consideraciones generales para la confección del protocolo de validación de métodos analíticos utilizados en la determinación cuantitativa de fármacos en forma de materia prima o en formulaciones y en estudios de estabilidad. Se describe detalladamente el proceso de validación que incluye los requisitos exigidos para la utilización de las materias primas, materiales de referencia, equipamiento, personal y determinación de los parámetros de linealidad, precisión, exactitud y selectividad (con el procesamiento estadístico de los resultados experimentales y criterios de aceptación), así como la presentación de los resultados en el informe final de la validación.

A summary of the general considerations fot the formulation of a validation protocol of the analytical methods used in drug quantitative determination in a raw material form, or in formulations and firmness studies. The validation process is fully described; it includes the necessary requirements for the usage of raw materials, reference materials, supplying, personnel, and determination of linearity, preciseness, exactness, and selectiveness (with the statistical processing of experimental results, and acceptance criteria), as well as the presentation of outcomes in the validation final report.

Mechanism of action of chemotherapy drugs in promoting liver injury / 临床肝胆病杂志

Drugs are an important cause of liver injury, and according to statistics, about 1100 drugs may induce liver injury. Due to the difficulty in differential diagnosis, drug-related liver injury is still misjudged. As different drugs have different mechanisms of action in inducing liver injury and may cause different degrees of liver injury, targeted countermeasures should be adopted. There are fewer systematic reviews of liver injury caused by chemotherapy drugs. This article mainly introduces the hepatotoxic mechanisms of various chemotherapy drugs, elaborates on the degree of hepatotoxicity caused by chemotherapy drugs, summarizes the clinical manifestations of liver injury caused by chemotherapy drugs, and gives recommendations to clinical treatment.