Modern Pharmacological Effect of Zhishi Xiebai Guizhitang： A Review / 中国实验方剂学杂志

Zhishi Xiebai Guizhitang is a classical prescription for the treatment of chest impediment with the method of warming Yang. It is included in the Catalogue of Ancient Classical Prescriptions issued by the National Administration of Traditional Chinese Medicine （First Batch）， with the effect of activating Yang， dissipating mass， moving Qi and resolving phlegm. Its main symptoms include chest fullness and pain， or even chest pain radiating to the back， wheezing， coughing， shortness of breath， and Qi reversal from the hypochondrium. In modern traditional Chinese medicine， Zhishi Xiebai Guizhitang is clinically used in the treatment of cardiovascular system， digestive system， respiratory system and other diseases， among which coronary heart disease， unstable angina pectoris， myocardial infarction， sinus bradycardia and other cardiovascular diseases have particularly significant effects. This paper reviewed the pharmacological studies of Zhishi Xiebai Guizhitang in the past 10 years. The results showed that each single medicine and the whole prescription alleviated the above cardiovascular diseases to a certain extent， with the pharmacological effects of improving intravascular environment， myocardial ischemia， myocardial ischemia-reperfusion injury， and myocardial hypoxia， anti-inflammation， plaque stabilisation， etc.， and the pharmacological mechanism involved the regulation of relevant active substances in vivo as well as related signaling pathways and ion channels， mainly including thromboxane B2 （TXB2）， prostacyclin I2（PGI2） and phosphatidylinositol 3-kinases/protein kinase B/endothelial nitric oxide synthase （PI3K/Akt/eNOS） signaling pathways， and ATP-sensitive potassium channels. In addition， the relationship between the pharmacological effects of some single medicines and transient receptor potential ankyrin 1 （TRPA1） has been reported that TRPA1 is a key to understanding the mechanism of Zhishi Xiebai Guizhitang in treating cardiovascular diseases， which is worth of further study.

Otimização de novos inibidores da di-idrofolato redutase de Mycobaterium tuberculosis (mtDHFR): Docking molecular, sí­ntese, avaliação da inibição enzimática e da atividade antimicobacte / Optimization of new dihydrofolate reductase inhibitors of mycobacterium tuberculosis (mtdhfr): molecular docking, synthesis, evaluation of enzyme inhibition and antimycobacterial activity

A tuberculose (TB) é considerada uma das principais doenças infecciosas e apresenta fatores críticos como a relação com o HIV/AIDS, tratamento longo e a resistência a múltiplos fármacos. A enzima di-hidrofolato redutase das micobactérias (mtDHFR) é um alvo pouco explorado e apresenta grande potencial para o desenvolvimento de novos fármacos contra TB. Estudos preliminares obtiveram fragmentos com baixa afinidade à mtDHFR, entretanto com potencial para otimização. Com isso, o fragmento foi usado como protótipo para a proposição de 22 análogos. Os compostos foram planejados utilizando informações sobre ligantes e a estrutura tridimensional de mtDHFR, além do biososterismo como estratégia norteadora. Os ensaios de docking molecular com a mtDHFR revelaram que os análogos propostos tiveram escores interessantes e, além disso, a inserção de substituintes demonstrou favorecer a ligação à enzima, o que corroborou o planejamento. Com isso, sintetizou-se 22 análogos planejados e o protótipo MB872, por meio de protocolos de alquilação, hidrólise e cicloadição 1,3 dipolar para os compostos com anéis triazol e tetrazol. Os compostos foram obtidos com rendimentos de bom a ótimo (60 ~ 90%) e suas estruturas foram elucidadas por RMN 1H e 13C. Os resultados do ensaio de inibição enzimática corroboraram com os dados de docking, uma vez que a presença do grupo carboxílico revelou ser importante para a atividade. Além disso, alguns dos compostos revelaram atividades interessantes, entre 8 a 40 µM, sendo que o mais ativo apresentou IC50 de 7 µM. Ensaios de cinética enzimática com o análogo mais ativo indicou uma inibição não competitiva com o substrato natural da enzima, uma vez que os valores de Km se mantiveram constantes, enquanto Vmax decaiu (0,22 µM e 0,43 - 0,34 ΔFU/min, respectivamente). Os análogos sintetizados foram mandados para ensaio in vitro para avaliar a atividade frente a micobactéria

Tuberculosis (TB) is an important infectious disease and presents critical factors such as the relationship with HIV / AIDS, long treatment and resistance to multiple drugs. The enzyme dihydrofolate reductase from mycobacteria (mtDHFR) is a poorly explored and presents great potential to be a target for new drugs against TB. Preliminary studies have obtained fragments with low affinity to mtDHFR, but with potential to become lead compounds. Therefore, the fragment was used as a prototype for 22 analogues proposed in this work. The compounds were designed using bioisosterism, information about ligands and the three-dimensional structure of mtDHFR. Molecular docking assays with mtDHFR revealed satisfactory scores for anlogues. Furthermore, the insertion of substituents seemed to increase the affinity with the enzyme. Thereby, twenty two analogues and prototype were synthesized using alkylation, hydrolysiss and 1,3-dipolar cycloaddition methods. The compounds were obtained in good yields (60 ~ 90%) and their structures were elucidated with 1H and 13C NMR spectroscopy. The enzymatic affinity assay corroborates docking results, because the presence of carboxyl group showed to be important for the activity. Furthermore, some of the compounds revealead interesting activities, ranging 8 to 40 µM. The most active showed IC50 of 7 µM and enzyme kinetics assays indicated noncompetitive inhibition with natural enzyme substrate. The synthesized analogs were sent for in vitro assay to assess mycobacteria activity

In vitro cytotoxicity of chemical preservatives on human fibroblast cells

Preservatives are widely used substances that are commonly added to various cosmetic and pharmaceutical products to prevent or inhibit microbial growth. In this study, we compared the in vitro cytotoxicity of different types of currently used preservatives, including methylparaben, imidazolidinyl urea (IMU), and sodium benzoate, using the human newborn fibroblast cell line CCD1072Sk. Of the tested preservatives, only IMU induced a reduction in cell viability, as shown using the MTT assay and propidium iodide staining (IMU>methylparaben>sodium benzoate). IMU was shown to promote homeostatic alterations potentially related to the initiation of programed cell death, such as decreased mitochondrial membrane potential and caspase-3 activation, in the treated cells. Methylparaben and sodium benzoate were shown to have a very low cytotoxic activity. Taken together, our results suggest that IMU induces programed cell death in human fibroblasts by a canonical intrinsic pathway via mitochondrial perturbation and subsequent release of proapoptotic factors

Synthesis of isavuconazonium sulfate: Research advances / 国际药学研究杂志

Isavuconazole is a broad-spectrum triazole antifungal agent, which is administered as a water-soluble prodrug-isavuconazonium sulfate. Recently, its oral and intravenous formulations are available. Isavuconazole inhibits fungal cytochrome P45014DM, thus interferes with the biological function of cell wall formation and plays the antifungal role. In this paper, we summarize the synthetic methods of isavuconazole, water-soluble segments of side chain and isavuconazonium sulfate and evaluate their advantages and disadvantages, which lays a foundation for isavuconazonium sulfate technology development.

Synthesis of isavuconazonium sulfate:research advances / 国际药学研究杂志

Isavuconazole is a broad-spectrum triazole antifungal agent,which is administered as a water-soluble prodrug-isa?vuconazonium sulfate. Recently,its oral and intravenous formulations are available. Isavuconazole inhibits fungal cytochrome P45014DM,thus interferes with the biological function of cell wall formation and plays the antifungal role. In this paper ,we summa?rize the synthetic methods of isavuconazole ,water-soluble segments of side chain and isavuconazonium sulfate and evaluate their advantages and disadvantages,which lays a foundation for isavuconazonium sulfate technology development.

Estructuración y formulación de la política pública farmacéutica regional y territorial en Colombia / Structuring and Development of Regional and Territorial Pharmaceutical Public Policy in Colombia / Estruturação e formulação da política pública farmacêutica regional e territorial na Colômbia

Problema: radica en la estructuración y formulación de la política pública farmacéutica regional y territorial en Colombia. Justificación: el documento Conpes 155 exige la definición del marco de política pública farmacéutica en Colombia, y por ende a escala departamental y territorial. Método: la fundamentación analítica de dicho Conpes, al igual que el uso de la metodología de marco lógico, fungen como herramientas metódicas para la postulación del trabajo. Marco de referencia: revisión en materia de definición u observancia de políticas públicas farmacéuticas internacionales. Principales resultados: el planteamiento de la respectiva política pública farmacéutica en el departamento de Antioquia y la postulación de dicho escenario en la ciudad capital de Medellín. Conclusiones: la construcción de la política pública farmacéutica nacional aún está en ciernes, obstáculo que impide registrarla en la política pública territorial.

The problem lies on the structuring and development of regional and territorial public drug policy in Colombia. Justification: The document Conpes 155 requires the definition of the public pharmaceutical policy framework in Colombia, and therefore defining it at the departmental and local level. Method: the analytical foundation of the Conpes like the use of the logical framework methodology, serve as methodical tools for the application of the project. Framework: review of the definition or compliance of international drug policies. Main results: the approach of the public pharmaceutical policy in the department of Antioquia and the application of such a scenario in the capital city of Medellin. Conclusions: the construction of a public national drug policy is still in its infancy, fact that hinders the establishment of a territorial public policy.

Problema: reside na estruturação e formulação da política pública farmacêutica regional e territorial na Colômbia. Justificação: o documento Conpes 155 exige a definição do quadro de política pública farmacêutica na Colômbia, e, portanto, na escala departamental e territorial. Método: a fundamentação analítica de tal Conpes, mesmo que o uso da metodologia de quadro lógico, agem como ferramentas metódicas para a execução do trabalho. Quadro de referência: revisão em matéria de definição ou observância de políticas públicas farmacêuticas internacionais. Principais resultados: a colocação da respetiva política pública farmacêutica no departamento de Antioquia e a proposição de tal cenário na cidade capital de Medellín. Conclusões: a construção da política pública farmacêutica nacional ainda está na infância, obstáculo que impede cadastrá-la na política pública territorial.

Investigation of formulation, preparation and stability of rosuvastatin calcium tablets / 第二军医大学学报

Objective To explore the formulation and preparation technique of rosuvastatin calcium tablets with satisfactory stability and reproducibility. Methods Using suitable formulations, we prepared the rosuvastatin calcium granulates by high shear mixer and fluid bed separately, and compared their influences on the granulate properties, tablet characteristics and dissolution. The reproducibility of formulation and preparation technique was investigated. Furthermore, the factors affecting the formulation were also investigated. Results Compared with the fluid bed, granulation using high sheer mixer was more suitable for preparing rosuvastatin calcium granulates. The selected formulation and preparation technique yielded 3 batches of rosuvastatin calcium tablets which met the quality requirement. The tablets had a comparable dissolution profiles to "Crestor " of AstraZeneca. The stability of rosuvastatin calcium was largely affected by the strong light, high humidity and high temperature. Conclusion The optimized formulation and preparation technique have good reproducibility for preparing rosuvastatin calcium tablets, which have good stability.

Influencia del marco regulatorio de los productos farmacéuticos en la salud pública² Análisis a partir de la ratificación por Colombia del Convenio ADPIC y de los Tratados de Libre Comercio con los Estados Unidos y la Unión Europea / Influence of the Regulatory Framework for Pharmaceuticals in Public Health Analysis from Colombia's ratification of the Agreement on Intellectual Property Rights Trade-Related (TRIPS) and the Free Trade Agreements with the United States and the European Union / Influência do marco regulatório dos produtos farmacêuticos na saúde pública Análise a partir da ratificação pela Colômbia do Convênio ADPIC e dos Tratados de Livre Comércio com os Estados Unidos e a União Europeia

Este artículo tiene por objetivo estudiar la relación entre la disponibilidad, los precios de los medicamentos y los intereses de salud pública. Para ello hemos utilizado una metodología de análisis de los intereses económicos implicados y también un método sistemático de tratamiento de la legislación nacional, comunitaria andina e internacional vigente. Igualmente hemos acudido a metodologías de derecho comparado entre nuestro ordenamiento jurídico nacional con los de otros países de mundo occidental. Existe un estrecho vínculo entre la disponibilidad y los precios de los medicamentos y los intereses de salud pública. Nuestro actual sistema legal reconoce a los inventores de nuevos medicamentos como un "monopolio" para negociar en el mercado farmacéutico. Para proteger los intereses públicos nuestra regulación establece algunos límites a los derechos de los inventores. Los derechos de propiedad se limitan en el tiempo y bajo algunas circunstancias es obligatorio autorizar a otros a usar la patente bajo un contrato de licenciamiento. La Organización Mundial del Comercio ha establecido (Decisión del Consejo de la OMC, Ronda Doha 2003) otros límites a estos derechos en caso de condiciones excepcionales. Nuestra Constitución Nacional otorga prevalencia a los intereses públicos sobre los privados. Es un deber de los gobiernos establecer un sistema justo en el cual los inventores puedan obtener una recompensa económica por sus creaciones y la sociedad pueda satisfacer sus necesidades de salud.

This article aims to study the relationship between availability, prices of medicines and public health interests. We have used an analysis methodology of the economic interests involved and a systematic method of treatment of national, international, community and Andean current legislation. Also we have relied on comparative law methodologies between our domestic law and the ones of other countries in the Western World. There is a close link between the availability and prices of medicines and public health interests. Our current legal system recognizes to the inventors of new medicines as a "monopoly" to negotiate in the pharmaceutical market. To protect public interests, our regulation establishes some limits to the rights of inventors. Property rights are limited in time and under some circumstances it is mandatory to authorize others to use the patent under a licensing agreement. The World Trade Organization (WTO) has established (Decision of the Council of the WTO Doha Round, 2003.) other limits to these rights in case of exceptional conditions. Our Constitution gives prevalence to public interests over private ones. It is the duty of governments to establish a fair system in which inventors can obtain a financial reward for their creations and society can satisfy its health needs.

Este artigo tem por objetivo estudar a relação entre a disponibilidade, os preços dos medicamentos e os interesses de saúde pública. Para isso, utilizamos uma metodologia de análise dos interesses econômicos implicados e também um método sistemático de tratamento da legislação nacional, comunitária andina e internacional vigente. Da mesma maneira, recorremos a metodologias de direito comparado entre nosso ordenamento jurídico nacional com os de outros países de mundo ocidental. Existe um estreito vínculo entre a disponibilidade e os preços dos medicamentos e os interesses de saúde pública. Nosso atual sistema legal reconhece aos inventores de novos medicamentos como um "monopólio" para negociar no mercado farmacêutico. Para proteger os interesses públicos, nossa regulação estabelece alguns limites aos direitos dos inventores. Os direitos de propriedade se limitam no tempo e, sob algumas circunstâncias, é obrigatório autorizar outros a usarem a patente sob um contrato de licenciamento. A Organização Mundial do Comércio estabeleceu (Decisão do Conselho da OMC, Ronda Doha 2003) outros limites a esses direitos em caso de condições excepcionais. Nossa Constituição Nacional outorga prevalência aos interesses públicos sobre os privados. É um dever dos governos estabelecer um sistema justo no qual os inventores possam obter uma recompensa econômica por suas criações e a sociedade possa satisfazer suas necessidades de saúde.

Biotransformation of 4 ent-labdane diterpenoid lactones of Andrographis paniculata: Recent progress / 第二军医大学学报

Ent-labdane diterpenoid lactones, the principal constituents of Andrographis paniculata, have a wide range of pharmacological effects, such as antibacterial, anti-viral, anti-inflammatory, antipyretic, andanti-cancer effect, etc. In this review the biotransformations of four principal ent-labdane diterpenoid lactones of A. paniculata are discussed from the following aspects: substrates and types of reaction, transformation systems, and structure activity relationships. Moreover, the currently-existing problems and the prospects are also described to provide reference for further studying the biotransformation of ent-labdane diterpenoid lactones of A. paniculata.

Quebra de normas de segurança na formulação de medicamentos e mortes por intoxicação pela colchicina em adultos / Non-compliance to safety rules regarding medication prescription, leads to two adults' death due to colchicine intoxication

São apresentados dados de dois casos de uma mesma família atendidos em pronto-socorro, com intervalo de uma semana, que evoluíram para morte com diagnósticos de septicemia e de enterite aguda hemorrágica. A investigação realizada pela vigilância epidemiológica e sanitária concluiu que a causa dos óbitos foi intoxicação acidental por colchicina, preparada em farmácia de manipulação e propiciada por quebra de duas normas de segurança que levaram à ingestão de doses 100 vezes maiores que a dose habitual. O relato tem por objetivo alertar os médicos que prestam assistência em serviços de pronto atendimento sobre a necessidade de se incluir na anamnese, com o paciente ou acompanhante, a questão específica a respeito da utilização ou não de medicamentos manipulados, uma vez que o uso de substâncias preparadas em farmácias vem aumentando e acidentes como o relatado poderão ocorrer com maior freqüência, inclusive com outros medicamentos.

We present data from two cases seen at an emergency facility, occurring within a one-week period with two members of the same family, who died of septicemia and acute hemorrhagic enteritis. The investigation, conducted by the sanitary and epidemiological surveillance department, concluded that these deaths were due to accidental intoxication with colchicines. The drug was prepared in a compounding pharmacy, and there were breaches of safety norms leading to the ingestion of doses 100 times higher than the recommended dosage. The present report intends to alert physicians who provide emergency care as to the need to include, during the anamnesis of patients, specific questions to them or to their companion regarding the use of compounded drugs, given that the use of medication prepared in compounding pharmacies is increasing and accidents, as the one reported, may become more frequent and may occur with other drugs as well.