RESUMEN
Use of litigation to ensure and guarantee access to medical inputs constitutes one of the most effective strategies to ensure observance (or remedy the violation) of the right to health, often in relation to other fundamental human rights such as the right to life or to bodily integrity.More frequently, and in multiple national contexts, judges and courts support lawsuits filed by individuals who need immediate access to health technologies. On many occasions, the rulings that force the State and its institutions to guarantee the supply of a given product do not take into account the reasons the State gives for not providing it, which can range from cost-effectiveness calculations and evaluation, to public policy planning and implementation.Use and abuse of legal proceedings by interested third parties threaten the legitimacy of an instrument that has contributed, without a doubt, to strengthening public engagement in the defense of people's rights, including the right to health.This document is an attempt to provide a context for the evolution of this phenomenon with regard to the instruments, mechanisms, and procedures commonly used by health authorities to efficiently organize access to health technologies. In addition, steps to follow are suggested for both national and regional settings.
A utilização da via judicial para assegurar e garantir o acesso a insumos médicos é uma das estratégias mais efetivas para o cumprimento (ou remediar o descumprimento) do direito à saúde, frequentemente relacionado a outros direitos humanos fundamentais como o direito à vida ou direito à integridade física.Com frequência e em diversos contextos nacionais, juízes e tribunais dão respaldo aos recursos apresentados por indivíduos particulares que precisam ter acesso imediato a tecnologias em saúde. Em várias ocasiões, as sentenças que obrigam o Estado e suas instituições a garantir a provisão de determinado produto não levam em consideração as razões alegadas para a não provisão, de cálculos de custo-efetividade a processos de avaliação, planejamento e execução de políticas públicas.O uso e o abuso de recursos judiciais por terceiros interessados ameaçam a legitimidade de um instrumento que vem indubitavelmente contribuindo para fortalecer a participação dos cidadãos na defesa dos próprios direitos, inclusive o direito à saúde.O presente documento tem o intuito de contextualizar a evolução do fenômeno da judicialização quanto aos instrumentos, mecanismos e procedimentos normalmente usados pelas autoridades sanitárias para racionalizar o acesso a tecnologias em saúde. É feita recomendação sobre os passos a serem seguidos ao nível nacional e regional.
RESUMEN
Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
Asunto(s)
Antimaláricos/análisis , Antimaláricos/farmacología , Descubrimiento de Drogas , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antimaláricos/química , Antimaláricos/toxicidad , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Humanos , Malaria Falciparum/parasitología , Modelos Biológicos , Filogenia , Plasmodium falciparum/enzimología , Plasmodium falciparum/genética , Plasmodium falciparum/crecimiento & desarrollo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/toxicidadRESUMEN
Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , Animales , Antimaláricos/síntesis química , Química Física , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Concentración de Iones de Hidrógeno , Ratones , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Piridonas/síntesis química , Solubilidad , EstereoisomerismoRESUMEN
BACKGROUND: In vitro cultivation of Plasmodium falciparum is usually carried out through the continuous preservation of infected erythrocytes deposited in static thin layers of settled haematocrit. This technique, called the candle-jar method, was first achieved by Trager and Jensen in 1976 and has undergone slight modifications since then. However, no systematic studies concerning the geometry of the haematocrit layer have been carried out. In this work, a thorough investigation of the effects of the geometric culturing conditions on the parasite's development is presented. METHODS: Several experimental trials exploring different settings have been carried out, covering haematocrit layer depths that ranged from 6 mm to 3 mm and separation between the walls of the culturing device that ranged from 7.5 mm to 9 mm. The obtained results have been analysed and compared to different system-level models and to an Individual-Based Model. CONCLUSION: In line with the results, a mechanism governing the propagation of the infection which limits it to the vicinity of the interface between the haematocrit layer and the culture medium is deduced, and the most appropriate configurations are proposed for further experimental assays.
Asunto(s)
Técnicas de Cultivo de Célula , Eritrocitos/parasitología , Plasmodium falciparum/crecimiento & desarrollo , AnimalesRESUMEN
Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.
Asunto(s)
2,2'-Dipiridil/análogos & derivados , Antimaláricos/farmacología , Oxadiazoles/farmacología , 2,2'-Dipiridil/administración & dosificación , 2,2'-Dipiridil/síntesis química , 2,2'-Dipiridil/farmacología , 2,2'-Dipiridil/toxicidad , Animales , Antimaláricos/administración & dosificación , Antimaláricos/síntesis química , Antimaláricos/toxicidad , Atovacuona/farmacología , Cloroquina/farmacología , Diseño de Fármacos , Femenino , Humanos , Hidrazinas/metabolismo , Ratones , Pruebas de Mutagenicidad , Mutágenos/metabolismo , Oxadiazoles/administración & dosificación , Oxadiazoles/síntesis química , Oxadiazoles/toxicidad , Parasitemia/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Pirimetamina/farmacología , Relación Estructura-ActividadRESUMEN
Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4-0.5 µM are able to show in vivo activity.
RESUMEN
RESUMEN La utilización de la vía judicial para asegurar y garantizar el acceso a insumos médicos constituye una de las estrategias más efectivas para asegurar el cumplimiento (o remediar la violación) del derecho a la salud, a menudo en relación con otros derechos humanos fundamentales como el derecho a la vida o a la integridad física. De manera más frecuente y en múltiples contextos nacionales, jueces y cortes respaldan las demandas inter-puestas por particulares que necesitan acceso inmediato a tecnologías sanitarias. En muchas ocasiones, las sentencias que obligan al Estado y a sus instituciones a garantizar el suministro de un producto determinado no toman en consideración las razones aducidas por el Estado para no suministrarlo que pueden variar desde cálculos de costeefectividad a procesos de evaluación, planificación y ejecución de políticas públicas. La utilización y abuso de procedimientos judiciales por terceras partes interesadas amenaza la legitimidad de un instrumento que ha contribuido, sin lugar a dudas, a fortalecer la participación de la ciudadanía en la defensa de sus derechos, incluido el derecho a la salud. El presente documento pretende contextualizar la evolución del fenómeno en relación con aquellos instrumentos, mecanismos y procedimientos que suelen utilizar las autoridades sanitarias para racionalizar el acceso a tecnologías sanitarias. Además, se sugieren pasos a seguir tanto en el ámbito nacional como regional.
ABSTRACT Use of litigation to ensure and guarantee access to medical inputs constitutes one of the most effective strategies to ensure observance (or remedy the violation) of the right to health, often in relation to other fundamental human rights such as the right to life or to bodily integrity. More frequently, and in multiple national contexts, judges and courts support lawsuits filed by individuals who need immediate access to health technologies. On many occasions, the rulings that force the State and its institutions to guarantee the supply of a given product do not take into account the reasons the State gives for not providing it, which can range from cost-effectiveness calculations and evaluation, to public policy planning and implementation. Use and abuse of legal proceedings by interested third parties threaten the legitimacy of an instrument that has contributed, without a doubt, to strengthening public engagement in the defense of people's rights, including the right to health. This document is an attempt to provide a context for the evolution of this phenomenon with regard to the instruments, mechanisms, and procedures commonly used by health authorities to efficiently organize access to health technologies. In addition, steps to follow are suggested for both national and regional settings.
RESUMO A utilização da via judicial para assegurar e garantir o acesso a insumos médicos é uma das estratégias mais efetivas para o cumprimento (ou remediar o descumprimento) do direito à saúde, frequentemente relacionado a outros direitos humanos fundamentais como o direito à vida ou direito à integridade física. Com frequência e em diversos contextos nacionais, juízes e tribunais dão respaldo aos recursos apresentados por indivíduos particulares que precisam ter acesso imediato a tecnologias em saúde. Em várias ocasiões, as sentenças que obrigam o Estado e suas instituições a garantir a provisão de determinado produto não levam em consideração as razões alegadas para a não provisão, de cálculos de custo-efetividade a processos de avaliação, planejamento e execução de políticas públicas. O uso e o abuso de recursos judiciais por terceiros interessados ameaçam a legitimidade de um instrumento que vem indubitavelmente contribuindo para fortalecer a participação dos cidadãos na defesa dos próprios direitos, inclusive o direito à saúde. O presente documento tem o intuito de contextualizar a evolução do fenômeno da judicialização quanto aos instrumentos, mecanismos e procedimentos normalmente usados pelas autoridades sanitárias para racionalizar o acesso a tecnologias em saúde. É feita recomendação sobre os passos a serem seguidos ao nível nacional e regional.
Asunto(s)
Judicialización de la Salud/políticas , Acceso a Medicamentos Esenciales y Tecnologías Sanitarias , Sistemas de Información en Salud/organización & administraciónRESUMEN
Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.
Asunto(s)
Antimaláricos/síntesis química , Compuestos Aza/síntesis química , Eritromicina/análogos & derivados , Eritromicina/síntesis química , Plasmodium falciparum/efectos de los fármacos , Quinolinas/síntesis química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Antimaláricos/farmacología , Compuestos Aza/farmacología , Línea Celular Tumoral , Cloroquina/farmacología , Resistencia a Medicamentos , Eritromicina/farmacología , Bacterias Grampositivas/efectos de los fármacos , Humanos , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Malaria is still one of the most fatal diseases in the world. Development of an effective treatment or vaccine requires the cultivation of the parasite that causes it: Plasmodium falciparum. Several methods for in vitro cultivation of P. falciparum infected erythrocytes have been successfully developed and described in the last 30 years. Some problems arising from the current harvests are the low parasitaemia and daily human supervision requirements. The lack of a suitable model for global culture behavior makes the assay of new methodologies a costly and tenuous task. In this paper we present a model and simulation tool for these systems. We use the INDividual DIScrete SIMulation protocol (INDISIM) to qualitatively reproduce the temporal evolution of the erythrocyte and merozoite populations. Whole system dynamics are inferred by setting the rules of behavior for each individual red blood cell, such as the nutrient uptake, metabolism and infection processes, as well as the properties and rules for the culture medium: composition, diffusion and external manipulation. We set the individual description parameters according to the values in published data, and allow population heterogeneity. Cells are arranged in a three-dimensional grid and the study is focused on the geometric constraints and physical design of experimental sets. Several published experimental cultures have been reproduced with computer simulations of this model, showing that the observed experimental behavior can be explained by means of individual interactions and statistical laws.