Identification of Orthosteric and Allosteric Pharmacological Chaperones for Mucopolysaccharidosis Type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal inherited disease caused by mutations in gene encoding the lysosomal enzyme N-acetyl-alpha-glucosaminidase (NAGLU). These mutations result in reduced NAGLU activity, preventing it from catalyzing the hydrolysis of the glycosaminoglycan heparan sulfate (HS). There are currently no approved treatments for MPS IIIB. A novel approach in the treatment of lysosomal storage diseases is the use of pharmacological chaperones (PC). In this study, we used a drug repurposing approach to identify and characterize novel potential PCs for NAGLU enzyme. We modeled the interaction of natural and artificial substrates within the active cavity of NAGLU (orthosteric site) and predicted potential allosteric sites. We performed a virtual screening for both the orthosteric and the predicted allosteric site against a curated database of human tested molecules. Considering the binding affinity and predicted blood-brain barrier permeability and gastrointestinal absorption, we selected atovaquone and piperaquine as orthosteric and allosteric PCs. The PCs were evaluated by their capacity to bind NAGLU and the ability to restore the enzymatic activity in human MPS IIIB fibroblasts These results represent novel PCs described for MPS IIIB and demonstrate the potential to develop novel therapeutic alternatives for this and other protein deficiency diseases.

[Proposed model for managing drugs used for unregistered indications in Colombia]. / Propuesta de un modelo de gestión de medicamentos en indicaciones no registradas en Colombia.

The use of drugs for unregistered indications, known as "off-label" use, is a practice that creates problems of rational use and access when other options are not available. Health systems should address this situation, particularly in connection with decisions concerning coverage, while trying to minimize health risks and clearly define the roles and responsibilities of the parties involved. Colombia's Ministry of Health and Social Protection (MinSalud), together with the National University of Colombia and national experts, developed a proposal for a model for managing drugs being used for unregistered indications (off-label) and their potential reimbursement with public resources, taking into account international practices and country characteristics. The management model is non-punitive and is geared toward promoting the rational use of these drugs so that barriers to access are reduced whenever their use is supported by solid scientific evidence. The model addresses patient safeguards in the bioethical domain and the roles and responsibilities of the prescriber and government entities.

Medicine Shortages: Gaps Between Countries and Global Perspectives.

Introduction: Over the last decade, global health policies and different research areas have focused on the relevance and impact of medicine shortages. Published studies suggest there have been difficulties with access to medicines since the beginning of the 20th century, and there have been advances in our understanding and management of the problem since then. However, in view of global and regional health care concerns with shortages, we believe this phenomenon needs to be characterized and described more fully regarding the types of medicines affected, possible causes, and potential strategies to address these. The aim of this scoping review was to identify, compare if possible, and characterize the recent literature regarding the situation of medicines shortages between countries, and provide different perspectives, including a global context and national approaches. Methodology: A scoping study presented as a narrative review of the situation and findings principally based on published articles. Results: Based on the reported cases in the literature, a typology of medicines shortage and supply interruption episodes and their causes were proposed; national approaches to notify and manage the medicines shortages cases were described and classified by update frequency; principal differences between market and supply chain management perspectives of the situation were identified and global and countries' perspectives were described. Conclusion: Policy makers require solutions that prevent those cases in which the population's health is affected by episodes of medicine shortages and/or interruption in the supply chain. There is also a need to generate a glossary related to logistics management and the availability of medicines which will be useful to understand and overcome shortages. In addition, recognize that potential solutions are not only related with actions linked to research, development and innovation, but much wider. Overall, we believe this article can act as a basis for future discussions in this important area.

Propuesta de un modelo de gestión de medicamentos en indicaciones no registradas en Colombia / Proposed model for managing drugs used for unregistered indications in Colombia

El uso de medicamentos en indicaciones no registradas (INR), conocido como uso “off-label”, es una práctica que genera problemas de uso racional y de acceso cuando no existen alternativas disponibles. Los sistemas de salud deben gestionar esta realidad, sobre todo cuando se trata de decisiones de cobertura, buscando minimizar los riesgos para la salud y estableciendo de forma clara los papeles y las responsabilidades de los agentes involucrados. El Ministerio de Salud y Protección Social de Colombia (MinSalud), junto con con la Universidad Nacional de Colombia y expertos nacionales, diseñaron una propuesta de modelo de gestión del uso de medicamentos en indicaciones no registradas (off-label) y su potencial reembolso con recursos públicos, teniendo en cuenta prácticas internacionales y la realidad nacional. El modelo de gestión es no punitivo y está orientado a la promoción del uso racional de estos medicamentos, de forma que se reduzcan las barreras al acceso cuando su uso está respaldado por pruebas cientificas de calidad. El modelo incorpora elementos de garantías bioéticas del paciente, los papeles y las responsabilidades del prescriptor y de las entidades de gobierno.

The use of drugs for unregistered indications, known as “off-label” use, is a practice that creates problems of rational use and access when other options are not available. Health systems should address this situation, particularly in connection with decisions concerning coverage, while trying to minimize health risks and clearly define the roles and responsibilities of the parties involved. Colombia's Ministry of Health and Social Protection (MinSalud), together with the National University of Colombia and national experts, developed a proposal for a model for managing drugs being used for unregistered indications (off-label) and their potential reimbursement with public resources, taking into account international practices and country characteristics. The management model is non-punitive and is geared toward promoting the rational use of these drugs so that barriers to access are reduced whenever their use is supported by solid scientific evidence. The model addresses patient safeguards in the bioethical domain and the roles and responsibilities of the prescriber and government entities.

Efectividad y seguridad de atosiban en mujeres embarazadas con trabajo de parto pretérmino / Dexrazoxane to Prevent Cardiac Damage in Patients Under 18 with Hodgkin's Lymphoma or Acute Lymphoid Leukemia on Chemotherapy with Anthracyclines

Introducción: el parto pretérmino es definido como el parto producido antes de la semana 37 de edad gestacional. En Colombia es la principal causa de la morbilidad y mortalidad en el período neonatal. La incidencia del parto prematuro es cercana al 12%, con tasas estables en las últimas décadas, que se pueden deber a la complejidad de fisiopatología o a la falta de conocimientos de la condición. Es responsable a nivel mundial de la muerte en menores de 1 año. Objetivo: evaluar la efectividad y seguridad del atosiban en mujeres gestantes con trabajo de parto pretérmino. Metodología: la evaluación fue realizada de acuerdo con un protocolo definido a priori. Se realizó una búsqueda sistemática hasta noviembre de 2014 en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, sin restricciones de idioma ni fecha de publicación. Se identificaron las RSL y ECA que cumplieran los criterios de elegibilidad. La calidad de los estudios fue valorada con la herramienta AMSTAR. Las características de los estudios fueron extraídas a partir de las publicaciones originales. Los resultados se presentan de acuerdo al reporte de la RSL. Resultados: el atosiban no disminuye la proporción de parto antes de las 48 horas de inicio del tratamiento comparado contra placebo con un RR=1.05 (IC 95% 0,15-7,43), ni comparado contra betamiméticos RR=0,89 (IC 95% 0,66-1,22), ni comparado contra nifedipino RR=1,09 (IC 95% 0,44-2,73). Tampoco disminuye el parto antes de la semana 37 con un RR=1,17 (IC 95% 0,99-1,37) al compararlo contra el placebo y de 1,56 (IC 95% 1,13-2,14) al compararlo contra la nifedipina. Aumentó la probabilidad de parto antes de la semana 28 al compararse contra el placebo RR=3,11 (IC 95% 1,02-9,51). Mostró un mejor perfil de seguridad para eventos adversos maternos al compararlo contra betamiméticos RR=0,47 (IC 95% 0,35-0,62) y contra nifedipino RR=0,38 (IC 95% 0,21-0,68), pero no contra placebo. Conclusiones: no existe evidencia a favor del uso de atosiban en vez de placebo, betamiméticos o nifedipino para la disminución del parto pretérmino antes de la semana 37 ni 28 de edad gestacional. Tampoco disminuye la proporción de partos pretérminos antes de las 48 horas de inicio del tratamiento. El atosiban no fue superior a los comparadores para disminuir los eventos adversos neonatales. Mostró beneficio para la disminución de los efectos adversos maternos cuando se comparó contra betamiméticos o nifedipino. Los ECA incluidos en la RSL identificada tienen alta probabilidad de sesgos por lo cual los resultados se deben evaluar con precaución.(AU)