Políticas públicas de medicamentos e a relação de medicamentos essenciais / Public policies on medicines and the list of essential medicines / Las políticas públicas sobre medicamentos y la lista de medicamentos esenciales

Através da edição da Norma Operacional de Assistência à Saúde realizada em 2001 e da publicação do Pacto pela Saúde realizado em 2006 o processo de acesso à saúde, ganhou maior ênfase no quesito de inovações e melhorias do sistema de saúde. A assistência farmacêutica sobreveio como parte fundamental nos serviços e programas de saúde. Neste sentido, o objetivo do presente estudo foi de expor as principais políticas públicas acerca da temática de medicamentos essenciais. Para tanto, foi realizada uma revisão integrativa de literatura, tendo como base de dados o Ministério da Saúde, as Resoluções da Agência Nacional de Vigilância Sanitária, artigos científicos e as publicações da Relação Nacional de Medicamentos (RENAME). No ano de 1998 através da portaria nº 3.916, de 30 de outubro 1998, apresenta-se a população a terminologia de Políticas públicas e, como resposta às diretrizes resultantes desta política, no presente artigo teremos ênfase na RENAME, criada através da portaria nº 3.047, de 28 de novembro de 2019, a qual atende aos princípios básicos e fundamentais do Sistema Único de Saúde: universalidade, equidade e a integralidade, para atender aos tratamentos das diversas doenças e agravos que acometem a população brasileira. Sendo assim, conclui- se que não se trata apenas de políticas públicas, e sim de manter o direito do cidadão estabelecidos pela Constituição da República Federativa do Brasil, para que o paciente consiga adquirir a medicação adequada e na quantidade necessária, permitindo aos profissionais alcançar mais aproveitamento no gerenciamento do ciclo da assistência farmacêutica.

Through the edition of the Operational Norm for Health Care carried out in 2001 and the publication of the Pact for Health carried out in 2006, the process of access to health gained greater emphasis on the issue of innovations and improvements in the health system. Pharmaceutical assistance emerged as a fundamental part of health services and programs. In this sense, the objective of the present study was to expose the main public policies on the subject of essential medicines. Therefore, an integrative literature review was carried out, using the Ministry of Health, the National Health Surveillance Agency's Resolutions, scientific articles and the publications of the National Medicines List (RENAME) as a database. In 1998, through ordinance nº 3.916, of October 30, 1998, the public policy terminology is presented to the population and, in response to the guidelines resulting from this policy, in this article we will emphasize RENAME, created through ordinance nº 3.047 , of November 28, 2019, which meets the basic and fundamental principles of the Unified Health System: universality, equity and integrality, to meet the treatments of the various diseases and conditions that affect the Brazilian population. Therefore, it is concluded that it is not just about public policies, but about maintaining the right of the citizen established by the Constitution of the Federative Republic of Brazil, so that the patient can acquire the appropriate medication and in the necessary quantity, allowing professionals to achieve more use in the management of the pharmaceutical care cycle.

A través de la edición de la Norma Operativa de Atención a la Salud realizada en 2001 y de la publicación del Pacto por la Salud realizada en 2006, el proceso de acceso a la salud ganó mayor énfasis en el tema de innovaciones y mejoras en el sistema de salud. La asistencia farmacéutica surgió como parte fundamental de los servicios y programas de salud. En este sentido, el objetivo del presente estudio fue exponer las principales políticas públicas sobre el tema de los medicamentos esenciales. Para ello, se realizó una revisión bibliográfica integradora, utilizando como base de datos el Ministerio de Salud, las Resoluciones de la Agencia Nacional de Vigilancia Sanitaria, artículos científicos y las publicaciones de la Lista Nacional de Medicamentos (RENAME). En 1998, a través de la ordenanza nº 3.916, de 30 de octubre de 1998, se presenta a la población la política pública de terminología y, en respuesta a las directrices resultantes de esta política, en este artículo haremos hincapié en el RENAME, creado a través de la ordenanza nº 3.047, de 28 de noviembre de 2019, que cumple con los principios básicos y fundamentales del Sistema Único de Salud: universalidad, equidad e integralidad, para atender los tratamientos de las diversas enfermedades y afecciones que afectan a la población brasileña. Por lo tanto, se concluye que no se trata sólo de políticas públicas, sino de mantener el derecho del ciudadano establecido por la Constitución de la República Federativa de Brasil, para que el paciente pueda adquirir el medicamento adecuado y en la cantidad necesaria, permitiendo que los profesionales logren un mayor aprovechamiento en la gestión del ciclo de atención farmacéutica.

3D-QSARpy: Combining variable selection strategies and machine learning techniques to build QSAR models

Abstract Quantitative Structure-Activity Relationship (QSAR) is a computer-aided technology in the field of medicinal chemistry that seeks to clarify the relationships between molecular structures and their biological activities. Such technologies allow for the acceleration of the development of new compounds by reducing the costs of drug design. This work presents 3D-QSARpy, a flexible, user-friendly and robust tool, freely available without registration, to support the generation of QSAR 3D models in an automated way. The user only needs to provide aligned molecular structures and the respective dependent variable. The current version was developed using Python with packages such as scikit-learn and includes various techniques of machine learning for regression. The diverse techniques employed by the tool is a differential compared to known methodologies, such as CoMFA and CoMSIA, because it expands the search space of possible solutions, and in this way increases the chances of obtaining relevant models. Additionally, approaches for select variables (dimension reduction) were implemented in the tool. To evaluate its potentials, experiments were carried out to compare results obtained from the proposed 3D-QSARpy tool with the results from already published works. The results demonstrated that 3D-QSARpy is extremely useful in the field due to its expressive results.

Desenvolvimento de novos medicamentos para doenças negligenciadas: uma análise bibliométrica / New drug development for neglected diseases: a bibliometric analysis / Desarrollo de nuevos fármacos para enfermedades desatendidas: un análisis bibliométrico

Doenças negligenciadas impõem um fardo humano, social e econômico devastador a mais de um bilhão de pessoas em todo o mundo. Embora existam ferramentas para controlar e até mesmo eliminar muitas dessas doenças, novos produtos terapêuticos precisam urgentemente ser desenvolvidos. Este artigo se baseia em um estudo que buscou quantificar e caracterizar a produção científica global sobre desenvolvimento de novos medicamentos para doenças negligenciadas, por meio de uma análise bibliométrica. De modo a investigar a pesquisa relacionada ao desenvolvimento de novos medicamentos para as doenças negligenciadas em âmbito global na última década, foi utilizada a base de dados Scopus. Observou-se aumento da produção de conhecimento sobre o tema, com relevante participação de autores, instituições e financiamento brasileiros, sobretudo de instituições públicas. Contudo, os esforços realizados têm sido insuficientes, sendo necessária a implementação de estratégias futuras de pesquisa e de financiamento que propiciem maior produção científica e uma tradução da pesquisa básica para a prática clínica.

Neglected diseases impose a devastating human, social, and economic burden on more than one billion people worldwide. While tools exist to control and even eliminate many of these diseases, new therapeutic products urgently need to be developed. This article is based on a study that sought to quantify and characterize the global scientific production on new drug development for neglected diseases through a bibliometric analysis. The Scopus database was used to investigate the research related to the development of new drugs for neglected diseases globally in the last decade. An increase in the production of knowledge about the theme and the relevant participation of Brazilian authors, institutions and funding, especially from public institutions were observed. However, their efforts have been insufficient, and the implementation of future research and funding strategies that provide greater scientific production and a translation of basic research into clinical practice is necessary.

Las enfermedades desatendidas imponen una carga humana, social y económica devastadora a más de mil millones de personas en todo el mundo. A pesar de haber herramientas para controlar y incluso eliminar muchas de estas enfermedades, es necesario desarrollar con urgencia nuevos productos terapéuticos. Este artículo se basa en un estudio lo cual ha buscado cuantificar y caracterizar la producción científica global sobre el desarrollo de nuevos fármacos para enfermedades desatendidas, a través de un análisis bibliométrico. Para inspeccionar investigaciones relacionadas con el desarrollo de nuevos medicamentos para enfermedades desatendidas en ámbito mundial durante la última década se utilizó la base de datos Scopus. Hubo un aumento de la producción de conocimiento sobre el tema, con una participación relevante de autores, instituciones y financiamiento brasileños, especialmente de instituciones públicas. Sin embargo, los esfuerzos realizados siguen siendo insuficientes, requiriendo la implementación de futuras estrategias de investigación y financiamiento que propicien una mayor producción científica y una traducción de la investigación básica a la práctica clínica.

Antinociceptive effect of N-(9,13b-dihydro-1H-dibenzo[c, f]imidazo[1,5-a]azepin-3-yl)-2-hydroxybenzamide on different pain models in mice

Abstract N-(9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-yl)-2-hydroxybenzamide (DDIAHB) is a new drug developed through molecular modelling and rational drug design by the molecular association of epinastine and salicylic acid. The present study was designed to assess the possible antinociceptive effects of DDIAHB on different pain models in male ICR mice. DDIAHB exerted the reductions of writhing numbers and pain behavior observed during the second phase in the formalin test in a dose-dependent manner. Moreover, DDIAHB increased the latency in the hot-plate test in a dose-dependent manner. Furthermore, intragastric administration DDIAHB caused reversals of decreased pain threshold observed in both streptozotocin-induced diabetic neuropathy and vincristine-induced peripheral neuropathy models. Additionally, intragastric pretreatment with DDIAHB also caused reversal of decreased pain threshold observed in monosodium urate-induced pain model. We also characterized the possible signaling molecular mechanism of the antinociceptive effect-induced by DDIAHB in the formalin model. DDIAHB caused reductions of spinal iNOS, p-STAT3, p-ERK and p-P38 levels induced by formalin injection. Our results suggest that DDIAHB shows an antinociceptive property in various pain models. Moreover, the antinociceptive effect of DDIAHB appear to be mediated by the reductions of the expression of iNOS, p-STAT3, p-ERK and p-P38 levels in the spinal cord in the formalin-induced pain model.

Planejamento, síntese e avaliação biológica de candidatos a fármacos: busca de inibidores epigenéticos da Sirtuína 2 Sir2 / Design, synthesis and biological evaluation of drug candidates: search for Sirtuin 2 (Sir 2) epigenetic inhibitors

As doenças negligenciadas são causadas por agentes infecciosos e parasitários, como vírus, bactérias, protozoários e helmintos. Essas doenças são prevalentes em populações de baixa renda que vivem em países em desenvolvimento e são responsáveis por incapacitar e levar milhares de pessoas à morte. Este nome se dá pois, apesar de sua grande relevância médica, recebem pouca atenção dos governos e indústrias farmacêuticas. Dentre essas doenças podemos destacar a Doença de Chagas, doença infecciosa causada pelo parasita hemoflagelado Trypanosoma cruzi. Endêmica em 21 países, com 6 a 7 milhões de pessoas infectadas resultando em 7500 mortes por ano. A quimioterapia disponível contra essa parasitose é baseada em apenas dois medicamentos, o benznidazol e o nifurtimox, ativos principalmente na fase aguda da doença e com efeitos adversos graves que comprometem a adesão ao tratamento e, além disso, apesar dos enormes esforços na pesquisa de novos agentes antichagásicos em nível nacional e internacional, na maioria realizada academicamente, ainda não foram encontradas alternativas terapêuticas para a doença, persistindo, assim, a necessidade de descoberta e desenvolvimento de novos fármacos. O início de um planejamento de um novo fármaco se dá pela definição de um alvo bioquímico a ser utilizado na busca de moléculas que possam exercer a função de inibidores ou moduladores, conforme a atividade biológica desejada. Neste sentido, as sirtuínas 2 (Sir2) são enzimas que se mostraram essenciais para o crescimento in vitro do T. cruzi em suas formas amastigota e epimastigota. No caso de tripanossomatídeos, em geral, a superexpressão de Sir2 está relacionada à sobrevivência de formas amastigotas. Assim, essas evidências indicam que a Sir2 de tripanosomatídeos tem grande potencial como alvo biológico na busca e desenvolvimento de novos fármacos antichagásicos. O objetivo principal deste projeto foi identificar moléculas que apresentaram atividade inibitória para a sirtuína 2 de T. cruzi por meio da utilização da estratégia de Planejamento de Fármacos Baseada no Ligante - Ligand Based Drug Design (LBDD) e o desenvolvimento de análogos dos inibidores da Sir2. A modificação molecular está entre algumas das técnicas tradicionais usadas no desenvolvimento racional de um fármaco, e é usada principalmente no desenvolvimento de análogos, e busca melhorar as propriedades farmacocinéticas e/ou farmacodinâmicas de um protótipo, obter propriedades de interação semelhantes ao alvo e, em alguns casos, revelar uma atividade biológica. Com este intuito, análogos do sirtinol e da salermida foram sintetizados e uma nova rota sintética utilizando o microrreator em fluxo contínuo foi desenvolvida e apresentou rendimento superior quando comparado à síntese em bancada. A partir desta metodologia foram obtidos 20 compostos. Os ensaios in vitro contra formas amastigotas do T. cruzi indicaram que 8 compostos inibiram a atividade parasitária em mais de 50%, na dose de 10 µM, sendo que alguns destes apresentaram maior inibição parasitária quando comparados ao benznidazol, o fármaco de referência e único disponível no Brasil. Com estes resultados preliminares, novos ensaios estão sendo realizados para identificar potência e mecanismo de ação destes candidatos a agentes tripanomicidas

Neglected diseases are caused by infectious and parasitic agents such as viruses, bacteria, protozoa and helminths. These diseases are prevalent in low-income populations living in developing countries and are responsible for disabling and killing thousands of people. They get this name because, despite their great medical relevance, they end up receiving little attention from governments and pharmaceutical industries. Among these diseases, we can highlight Chagas disease, an infectious endemic disease caused by the hemoflagellate parasite Trypanosoma cruzi. This disease is endemic in 21 countries, with 6 to 7 million people infected resulting in 7,500 deaths per year. Chemotherapy is based on just two drugs, benznidazole and nifurtimox, which are mainly active in the acute phase of the disease. These drugs have adverse effects that compromise adherence, even more, considering that they are not effective from the point of view of the chronic phase of the disease. Despite the enormous efforts in researching new anti-chagasic agents at the national and international level, and mostly carried out academically, therapeutic alternatives for the disease have not yet been found, thus, the need for the discovery and development of new drugs persists. Sirtuins 2 (Sir2) are enzymes that have been shown to be essential for the in vitro growth of T. cruzi in its amastigote and epimastigote forms. In the case of trypanosomatids in general, Sir2 overexpression is related to the survival of amastigote forms. Sir2 inhibitors, such as sirtinol, have shown efficacy in leishmanicides. Thus, these evidences indicate that Sir2 from trypanosomatids can be considered as a biological target in the search and development of new anti-chagasic drugs. The beginning of a new drug planning study is the definition of a biochemical target to be used in the search for molecules that can play the role of inhibitors or modulators, according to the desired biological activity. The main objective of this project was to identify molecules that presented inhibitory activity to sirtuin 2 of T. cruzi using the Ligand Based Drug Design (LBDD) strategy of planning and the development of analogues of Sir2 inhibitors. Molecular modification is a traditional technique used in the rational development of a drug, as well as the use of natural products, combinatorial chemistry, high-throughput screening (HTS), among others. Mainly used in the development of analogues, molecular modification is applied for different purposes, among them, it seeks to improve the pharmacokinetic and/or pharmacodynamic properties of a prototype, obtain target-like interaction properties and, in some cases, reveal an activity biological. For this purpose, analogues of sirtinol and salermide were synthesized and a new synthetic route using the microreactor in continuous flow was developed and presented superior yield when compared to benchtop synthesis. From this methodology, 20 compounds were obtained. in vitro assays against amastigote forms of T. cruzi indicated that 8 compounds inhibited parasitic activity by more than 50% at a dose of 10 µM, and some of these showed greater parasitic inhibition when compared to benznidazole, the reference drug, and only available in Brazil. With these preliminary results, new assays are being carried out to identify the potency and mechanism of action of these candidate trypanocidal agents

Cristalogénesis biológica y cristalografía en la elucidación de la estructura tridimensional de las proteínas. Revisión narrativa / Protein tridimensional structure by biological crystallogenesis and crystallography. Narrative review

La obtención de información estructural tridimensional de una proteína es de suma importancia en campos tan variados como la bioquímica funcional, las ciencias de materiales o biomédicas. Siendo actualmente la difracción de rayos X de monocristal el estándar de oro para la consecución de este objetivo, la obtención de dicho monocristal sigue siendo un cuello de botella desde el punto de vista práctico, y poco entendido desde el punto de vista teórico. En este artículo se revisa desde la perspectiva estructural de la proteína la forma en que los rayos X permiten obtener la información estructural y las condiciones fisicoquímicas que permiten la formación de un cristal adecuado para estos experimentos.

Obtaining three-dimensional structural information of a protein is of utmost importance in various fields such as functional biochemistry, materials science, or biomedical sciences. Even though single crystal X-ray diffraction is currently the gold standard for this purpose, growing said single crystal is still a bottleneck from a practical viewpoint, and not fully understood from a theoretical point of view. In this article, we review, from a protein structure perspective, the way X-rays provide structural information, and the physicochemical conditions that promote the formation of an adequate crystal for these experiments.

Quantitative Characterization of the Chemical Space Governed by Human Carbonic Anhydrases and selenium-containing derivatives of solfonamides

Abstract Due to the fact that different isoforms of carbonic anhydrase play distinct physiological roles, their diseases/disorders involvement are different as well. Involvement in major disorders such as glaucoma, epilepsy, Alzheimer's disease, obesity and cancers, have turned carbonic anhydrase into a popular case study in the field of rational drug design. Since carbonic anhydrases are highly similar with regard to their structures, selective inhibition of different isoforms has been a significant challenge. By applying a proteochemometrics approach, herein the chemical interaction space governed by acyl selenoureido benzensulfonamides and human carbonic anhydrases is explored. To assess the validity, robustness and predictivity power of the proteochemometrics model, a diverse set of validation methods was used. The final model is shown to provide valuable structural information that can be considered for new selective inhibitors design. Using the supplied information and to show the applicability of the constructed model, new compounds were designed. Monitoring of selectivity ratios of new designs shows very promising results with regard to their selectivity for a specific isoform of carbonic anhydrase.

La acelerada búsqueda de candidatos terapéuticos contra SARS-CoV-2, métodos in silico: Revisión / The accelerated search for drug candidates against SARS-CoV-2, in silico methods: Review

El reposicionamiento de fármacos como la derivatización química, que se han aplicado en los estudios de descubrimiento y diseño de fármacos contra el SARS-CoV-2, dependen del ciclo de vida del virus, las dianas moleculares identificadas y un diseño basado en su estructura e interacciones moleculares. Se realizó una revisión extensa en las bases de datos públicas e institucionales RSCB-Protein Data Bank, ZINC, NCBI (PubMed, PMC), PubChem, Science Direct e instituciones como CDC, NIH y revistas científicas especializadas sobre los avances en la búsqueda de nuevas moléculas contra el nuevo coronavirus basadas en estudios in silico, detectándose más de 40,000 publicaciones sobre SARS-CoV-2 y cerca de 200 relacionadas a dichos estudios, las consideradas más relevantes fueron analizadas e incluidas en este artículo. Su análisis evidencia el avance acelerado de las herramientas computacionales y fortaleza del diseño de fármacos asistido por computadora (in silico approach) para la generación de nuevas moléculas con posibilidad de ser activas contra COVID-19 y presenta las principales dianas moleculares sobre la que actúan estos agentes con potencial antiviral.

The search of new applications for approved drugs by the regulatory authorities around the world, as well as their chemical derivatization in the search for new and effective drugs against SARS-CoV-2 depends of the viral life cycle, action of the drug and a receptor-based design. We performed a deep bibliographic research in peer reviewed scientific journals, data bases RSCB-Protein Data Bank, ZINC, NCBI (PubMed, PMC), PubChem, Science Direct and institutions (CDC, NIH) in the search of new molecules tested in silico against the novel coronavirus. As a result, we found more than 40,000 research papers related to SARS-CoV-2 and nearby 200 look on in silico studies, taking into consideration for this work all the more relevant for us, evidenced the accelerated advance and strength of the drug design assisted by computer (in silico approach) to develop new molecules that can be effective against COVID-19 and, at the same time, it exposes the main molecular targets.

Perspectives on long-acting growth hormone therapy in children and adults

ABSTRACT Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world. Arch Endocrinol Metab. 2019;63(6):601-7

Diseño y evaluación de una proteína multiepitópica como candidata para vacuna contra la enfermedad de carrión / Design and evaluation of a multiepitopic protein as a candidate for a carrion disease vaccine

RESUMEN Objetivos. Diseñar y evaluar una proteína multiepítope como candidato a vacuna contra la enfermedad de Carrión. Materiales y métodos. Mediante herramientas bioinformáticas se seleccionó epítopes de proteínas de membrana externa y se diseñó una proteína multiepítope. El gen de la proteína multiepítope fue subclonado en el plásmido de expresión pET28b y transformado en E. coli BL21 pLys. La proteína multiepítope fue expresada usando isopropil-β-D-1-tiogalactopiranósido y purificada usando resina. Esta proteína purificada fue utilizada para inmunizar ratones BALB/c y se obtuvo anticuerpos policlonales. Se realizaron ensayos de invasión in vitro usando una cepa de Bartonella bacilliformis (B. bacilliformis) a eritrocitos humanos. Resultados. La proteína multiepítope M1 presenta epítopes conservados entre aislamientos de B. bacilliformis, no tóxicos, no homólogos a proteínas humanas y superficiales. Los ratones inmunizados presentaron niveles de anticuerpos IgG capaces de reducir in vitro la tasa de invasión de B. bacilliformis a eritrocitos humanos. Conclusiones. La proteína multiepítope M1 podría servir como candidato a vacuna contra la enfermedad de Carrión; sin embargo, se requiere de más estudios para caracterizar el uso de este antígeno como vacuna.

ABSTRACT Objectives. To design and assess a multiepitopic protein as a candidate for a vaccine against Carrion disease. Materials and Methods. Using bioinformatics tools, epitopes of external membrane proteins were selected and a multiepitopic protein was designed. The multiepitopic protein gene was subcloned into the expression plasmid pET28b and transformed into E. coli BL21 pLys. The multiepitopic protein was expressed using isopropyl-β-D-1-thiogalactopyranoside and purified using resin. This purified protein was used to immunize BALB/c mice obtaining polyclonal antibodies. In vitro invasion assays were conducted using a strain of Bartonella bacilliformis (B. bacilliformis) in human red blood cells. Results. The multiepitopic protein M1 presents preserved epitopes between isolates of B. bacilliformis with are non-toxic, and not homologous to human and surface proteins. Immunized mice presented IgG antibody levels capable of reducing in vitro the rate of invasion of B. bacilliformis into human red blood cells. Conclusions. Multiepitopic protein M1 may serve as a candidate for a Carrion disease vaccine; however, more studies are needed to characterize the use of this antigen as a vaccine.

Avaliação computacional de compostos naturais como potenciais inibidores para PEPCK-M humana: uma alternativa para terapia contra o câncer de pulmão / Computational evaluation of natural compounds as potential inhibitors for human PEPCK-M: an alternative for lung cancer therapy

O câncer de pulmão é a principal causa de morte relacionada ao câncer no mundo. Entre os seus subtipos, o câncer de pulmão de células não-pequenas (CPCNP) é o mais frequente. Apesar dos tratamentos disponíveis, a taxa de sobrevida ainda é baixa para este subtipo, enfatizando a necessidade de novas alternativas terapêuticas. Recentemente, a isoforma mitocondrial da enzima fosfoenolpiruvato carboxiquinase (HsPEPCK-M) foi apontada como responsável pela adaptação metabólica no CPCNP capaz de permitir o crescimento tumoral mesmo em condições de deficiência de glicose. Esta adaptação é possível devido a função da HsPEPCK-M na gliconeogênese, convertendo o oxaloacetato em fosfoenolpiruvato na presença de GTP, o que representa um papel importante no suporte energético desses tumores. Neste contexto, foi demonstrado que a inibição ou knockdown desta enzima foi capaz de induzir a apoptose em CPCNP em condições de baixa glicose. Estes dados realçam a importância de identificar inibidores eficazes para HsPEPCK-M que possam, potencialmente, se tornar uma alternativa para o tratamento do CPCNP

Neste estudo, novos inibidores putativos foram propostos para a PEPCK-M humana (HsPEPCK-M) com base em uma abordagem guiada por computador, incluindo a modelagem de farmacóforo baseada em estrutura e triagem por atracamento molecular. As hipóteses de farmacóforo geradas foram utilizadas para a triagem virtual do conjunto de compostos naturais do banco ZINC, produzindo 7.124 compostos candidatos. Estes foram submetidos à estudos de atracamento molecular utilizando três conformações de HsPEPCK-M geradas por modelagem comparativa. O objetivo foi selecionar compostos com alta afinidade de ligação predita em relação a pelo menos uma das conformações de HsPEPCK-M. Após o atracamento molecular, 612 moléculas foram selecionadas como potenciais inibidores de HsPEPCK-M. Estes compostos foram então agrupados de acordo com sua similaridade estrutural. A análise do perfil químico e as análises do modo de ligação destes compostos permitiram a proposta de quatro compostos promissores: ZINC01656421, ZINC895296, ZINC00895535 e ZINC02571340. Estes compostos podem ser considerados potenciais candidatos a inibidores de HsPEPCK-M e também podem ser utilizados como compostos líderes para o desenvolvimento de novos inibidores de HsPEPCK-M. (AU)

Brazilian malaria molecular targets (BraMMT): selected receptors for virtual high-throughput screening experiments

BACKGROUND Owing to increased spending on pharmaceuticals since 2010, discussions about rising costs for the development of new medical technologies have been focused on the pharmaceutical industry. Computational techniques have been developed to reduce costs associated with new drug development. Among these techniques, virtual high-throughput screening (vHTS) can contribute to the drug discovery process by providing tools to search for new drugs with the ability to bind a specific molecular target. OBJECTIVES In this context, Brazilian malaria molecular targets (BraMMT) was generated to execute vHTS experiments on selected molecular targets of Plasmodium falciparum. METHODS In this study, 35 molecular targets of P. falciparum were built and evaluated against known antimalarial compounds. FINDINGS As a result, it could predict the correct molecular target of market drugs, such as artemisinin. In addition, our findings suggested a new pharmacological mechanism for quinine, which includes inhibition of falcipain-II and a potential new antimalarial candidate, clioquinol. MAIN CONCLUSIONS The BraMMT is available to perform vHTS experiments using OCTOPUS or Raccoon software to improve the search for new antimalarial compounds. It can be retrieved from www.drugdiscovery.com.br or download of Supplementary data.

Surgery-first approach with 3D customized passive self-ligating brackets and 3D surgical planning: Case report

ABSTRACT It is possible to unify three-dimensional customized orthodontic techniques and three-dimensional surgical technology. In this case report, it is introduced a treatment scheme consisting of passive self-ligation customized brackets and virtual surgical planning combined with the orthognathic surgery-first approach in a Class III malocclusion patient. Excellent facial and occlusal outcomes were obtained in a reduced treatment time of five months.

RESUMO É possível unificar técnicas ortodônticas personalizadas e tecnologia de planejamento cirúrgico 3D. No presente relato de caso, apresenta-se um plano de tratamento envolvendo o uso de braquetes autoligáveis passivos personalizados e planejamento cirúrgico virtual, combinado com cirurgia ortognática de benefício antecipado, em um paciente com má oclusão de Classe III. Foram obtidos excelentes resultados faciais e oclusais em um tempo reduzido de tratamento, de 5 meses.

Drug discovery and computational strategies in the multitarget drugs era

The pharmaceutical industry is increasingly joining chemoinformatics in the search for the development of new drugs to be used in the treatment of diseases. These computational studies have the advantage of being less expensive and optimize the study time, and thus the interest in this area is increasing. Among the techniques used is the development of multitarget directed ligands (MTDLs), which has become an ascending technique, mainly due to the improvement in the quality of treatment involving several drugs. Multitarget therapy is more effective than traditional drug therapy that emphasizes maximum selectivity for a single target. In this review a multitarget drug survey was carried out as a promising strategy in several important diseases: neglected diseases, neurodegenerative diseases, AIDS, and cancer. In addition, we discuss Computer-Aided Drug Design (CADD) techniques as a tool in the projection of multitarget compounds against these diseases.

Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[34-d]-pyrimidinodiones as new antiplasmodial compounds

BACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years. METHODS Thirty compounds were synthesised employing the Biginelli multicomponent reaction and subsequent one-pot substitution/cyclisation protocol; the compounds were then evaluated in vitro against chloroquine-resistant Plasmodium falciparum parasites (W2 strain). Drug cytotoxicity in baseline kidney African Green Monkey cells (BGM) was also evaluated. The most active in vitro compounds were evaluated against P. berghei parasites in mice. Additionally, we performed an in silico target fishing approach with the most active compounds, aiming to shed some light into the mechanism at a molecular level. RESULTS The synthetic route chosen was effective, leading to products with high purity and yields ranging from 10-84%. Three out of the 30 compounds tested were identified as active against the parasite and presented low toxicity. The in silico study suggested that among all the molecular targets identified by our target fishing approach, Protein Kinase 3 (PK5) and Glycogen Synthase Kinase 3β (GSK-3β) are the most likely molecular targets for the synthesised compounds. CONCLUSIONS We were able to easily obtain a collection of heterocyclic compounds with in vitro anti-P. falciparum activity that can be used as scaffolds for the design and development of new antiplasmodial drugs.

A indústria de fitoterápicos brasileira: desafios e oportunidades / The Brazilian phytotherapics industry: challenges and opportunities

Resumo O objetivo deste artigo é discutir e analisar os desafios do desenvolvimento da indústria de plantas medicinais e de fitoterápicos no Brasil. Esta indústria representa uma excelente alternativa para responder ao paradoxo da abundância na área de saúde. A metodologia adotada foi uma pesquisa de campo, utilizando-se questionários semiestruturados, com empresas, pesquisadores e gestores públicos para avaliar seu desenvolvimento entre 2009 e 2015 e apontar seus principais problemas. Os resultados observados indicam que os principais desafios são, na pesquisa, a regulamentação da lei de acesso ao patrimônio genético e, na produção, a harmonização da regulamentação em toda a cadeia produtiva da indústria de plantas medicinais e fitoterápicos. A morosidade da implantação das políticas públicas voltadas para a indústria mostra um retrocesso tanto das atividades produtivas com fitoterápicos, quanto das atividades de pesquisa com plantas medicinais no período.

Abstract The purpose of this article is to discuss and analyze the development challenges of the medicinal plants and phytotherapics industry in Brazil. This industry represents an excellent alternative to face the paradox of abundance that exists in the health area. The methodology adopted was a field research, using semi-structured questionnaires with companies, researchers and public managers to evaluate their development between 2009 and 2015 and to point out the most serious problems faced. The results observed indicate that the main challenges found were the regulation of law on the access to the genetic patrimony in the research area, and to bring into harmony the rules in the entire chain of medicinal plants and phytotherapics production area. The slow implementation pace of public policies for the industry shows a setback regarding both productive and research activities with medicinal plants and phytotherapics in the period.

Aplicaciones de la informática en el estudio de productos naturales / Applications of informatics to the study of natural products

En los últimos tiempos, las técnicas computacionales se han constituido en valiosas herramientas para la investigación de sistemas biológicos. Ellas pueden guiar proyectos y complementar métodos experimentales en diversas áreas de aplicación, como la medicina, alimentación y agricultura. En este artículo resumimos y actualizamos los principales conocimientos acerca de los métodos utilizados por la bioinformática y brindamos algunos ejemplos de sus contribuciones en distintos campos. Enfatizamos en el diseño y descubrimiento de nuevas drogas de origen natural, principalmente antimicrobianas. En este sentido, la búsqueda de nuevos medicamentos y estrategias farmacológicas está plenamente justificada por distintas razones, que incluyen la emergencia de resistencia e interacciones farmacológicas, particularmente en pacientes inmunocomprometidos.

In the last times, computational techniques have become valuable tools for research of biological systems. They can lead and complementexperimental methods in different fields of application such as medicine, bromatology and agriculture.In this review we summarize the main knowledge on bioinformatic tools and give some examples of their contributions in diverseknowledge areas. We make emphasis in the design and discovery of new potential drugs, mainly antimicrobial agents of natural origin.In this sense, the search for new medicaments or pharmacological strategies is fully justified because of different reasons, includingemergence of resistance and pharmacological interactions, in particular in immunocompromised patients.

Absorção e metabolização dos hormônios sexuais e sua transformação em tecnologias contraceptivas: percursos do pensamento médico no Brasil / Absorption and metabolization of sex hormones and their transformation into contraceptive technologies: the paths taken by medical thought in Brazil

Resumo O artigo analisa a assimilação de conhecimentos e o desenvolvimento de práticas clínicas e de pesquisa, concernentes aos hormônios sexuais, entre ginecologistas brasileiros. Discute o percurso do pensamento médico da recepção dos hormônios à sua transformação em contraceptivos. O objetivo é compreender estilos de introdução e difusão de tecnologias médicas na área da saúde reprodutiva no Brasil. Utiliza métodos de análise histórica e tem como fonte os Anais Brasileiros de Ginecologia, revista publicada entre 1936 e 1970. O acompanhamento das novidades cientificas sobre hormônios sexuais e seu uso para tratamento de diversas mazelas femininas, desde os primórdios, foi de grande importância para a rápida aceitação médica da contracepção hormonal. Questões científicas e técnicas (efeitos colaterais, dosagens) e a questão populacional compuseram a maior parte dos debates. Objeções da Igreja Católica foram consideradas, mas não pautaram o pensamento médico sobre os contraceptivos. A busca de consolidar a ginecologia como especialidade científica, moderna e cosmopolita e razões sanitárias e demográficas que possibilitavam enquadrar contraceptivos como drogas éticas, são processos subjacentes à assimilação e à metabolização dos hormônios sexuais como contraceptivos hormonais.

Abstract The article analyses knowledge assimilation and the development of clinical and research practices relating to sex hormones among Brazilian gynaecologists. It discusses the paths taken by medical thought from the reception of the hormones to their transformation into contraceptives. Our objective is to comprehend styles of introducing and disseminating medical technologies in the area of reproductive health in Brazil. It uses methods of historical analysis and takes as its source the Anais Brasileiros de Ginecologia, a journal published between 1936 and 1970. From the outset, the accompaniment of scientific breakthroughs in relation to sex hormones and their use to treat diverse female illnesses played a key role in the rapid medical acceptance of hormonal contraception. Scientific and technical questions (side effects, dosages) and the demographic issue formed part of the majority of the debates. Objections from the Catholic Church were considered but did not set the agenda of medical thought on contraceptives. The quest to consolidate gynaecology as a scientific, modern and cosmopolitan area of expertise, along with sanitary and demographic motives that allowed contraceptives to be classed as ethical drugs, are identified as processes underlying the assimilation and metabolization of sex hormones as hormonal contraceptives.

Efecto citotóxico de los compuestos de inclusión de paladio (II) en la beta-ciclodextrina / Cytotoxic effect of palladium (II) inclusion compounds in beta-cyclodextrin

Resumen Introducción. Las tiosemicarbazonas y sus complejos de paladio (II) poseen actividad antineoplásica con pocos efectos secundarios, por lo cual se las considera como una nueva alternativa terapéutica. Sin embargo, existen diferencias en los rangos de la concentración inhibitoria media (CI50) asociada a la divergencia estructural y la solubilidad de los complejos, así como a la sensibilidad de los blancos celulares. La inclusión de fármacos en la beta-ciclodextrina con fines terapéuticos ha mejorado su solubilidad y estabilidad, pero los efectos de su combinación con los complejos de paladio (II) y las tiosemicarbazonas no se han comprobado aún. Objetivo. Estudiar el efecto citotóxico de los complejos de paladio en la beta-ciclodextrina. Materiales y métodos. La actividad citotóxica de los complejos de paladio en la beta-ciclodextrina se evaluó en la línea celular de cáncer de mama (MCF-7), empleando el método de la sulforodamina B. Resultados. Los ligandos MePhPzTSC y Ph2PzTSC, sus complejos de paladio (II) libres e incluidos en la beta-ciclodextrina y el cisplatino mostraron actividad citotóxica en la línea celular MCF-7; sin embargo, la citotoxicidad fue mayor con la inclusión en la beta-ciclodextrina ([Pd(MePhPzTSC)2]•ß-CD y [Pd(Ph2PzTSC)2]•ß-CD). La concentración inhibitoria media (CI50) para estos complejos se obtuvo en concentraciones de 0,14 y 0,49 μM, y con dosis hasta cinco veces inferiores comparadas con las concentraciones de los ligandos libres (1,4 y 2,9 μM), de los complejos de paladio (II) libres (0,57 y 1,24 μM) y del cisplatino (6,87 μM). Conclusiones. El uso de la beta-ciclodextrina mejoró significativamente la actividad citotóxica de las tiosemicarbazonas y sus complejos de paladio (II), lo cual probablemente está asociado al incremento de la solubilidad y biodisponibilidad del compuesto, estrategia que se puede sugerir para el diseño de futuros fármacos antineoplásicos.

Abstract Introduction: Thiosemicarbazones and palladium (II) complexes have antineoplastic activities with mild side effects, for which they are considered new alternative antineoplastic drugs. However, the IC50 ranges of these complexes vary due to differences in their structure and solubility and their sensitivities for various cellular targets. Beta-cyclodextrin is an additive used to improve the solubility and stability of various drugs for therapeutic use, but the combination of beta-cyclodextrin with palladium (II) complexes and thiosemicarbazones has not been tested yet. Objective: To study the cytotoxic effect of palladium (II) inclusion complexes in beta-cyclodextrin. Materials and methods: We tested the cytotoxic activity of palladium complexes combined with betacyclodextrin in the breast cancer cell line MCF-7 using a sulforhodamine B assay. Results: We tested the antiproliferative activity of palladium (II) complexes with and without the ligands MePhPzTSC and Ph2PzTSC and with and without beta-cyclodextrin in MCF-7 cells and compared them to that of cisplatin. All combinations showed antiproliferative activity; however, the activity was greater for the combinations that included beta-cyclodextrin: ([Pd (MePhPzTSC) 2] • ß-CD and [Pd (Ph2PzTSC) 2] • ß-CD), at concentrations of 0.14 and 0.49 μM, respectively. The IC50 for this complex was 5-fold lower than that of the ligand-free combinations (1.4 and 2.9 μM, respectively). The IC50 for free palladium (II) complex was 0.571.24 μM and that for cisplatin was 6.87 μM. Conclusions: Beta-cyclodextrin significantly enhanced the cytotoxic activities of palladium (II) complexes and thiosemicarbazones probably by improving their solubility and bioavailability. The addition of betacyclodextrin is a possible strategy for designing new anticancer drugs.