ABSTRACT
Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.
Subject(s)
Fabry Disease/metabolism , Galactose/analogs & derivatives , Leukocytes, Mononuclear/drug effects , Mutation , alpha-Galactosidase/pharmacology , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/pharmacology , Drug Stability , Enzyme Replacement Therapy , Fabry Disease/genetics , Fabry Disease/therapy , Galactose/chemistry , HEK293 Cells , Humans , Hydrogen-Ion Concentration , Leukocytes, Mononuclear/metabolism , Models, Biological , Models, Molecular , Protein Conformation , alpha-Galactosidase/chemistry , alpha-Galactosidase/geneticsABSTRACT
INTRODUCCIÓN: La limitación del esfuerzo terapéutico debería incluir la limitación de la realización de pruebas diagnósticas que no mejoran los síntomas del paciente. El objetivo de este estudio fue analizar el uso de pruebas diagnósticas en pacientes oncológicos hospitalizados en sus últimos días de vida. MÉTODOS: Se realizó un estudio descriptivo retrospectivo incluyendo todos los pacientes oncológicos estadio IV que fallecieron en el Servicio de Medicina Interna durante un periodo de dos años. Las variables analizadas fueron edad, sexo, número de pruebas de laboratorio (contabilizadas como una sola prueba por cada extracción), número de pruebas radiológicas (radiología simple, ecografía, tomografía computerizada [TC], resonancia magnética [RM]) y si se realizó extracción de analítica de sangre en las últimas 48 horas de vida. RESULTADOS: Fueron incluidos 51 pacientes (15 mujeres, 29,4 %), con una edad media de 71,94 años (desviación estándar 11,06). Se realizaron pruebas de laboratorio a 45 pacientes (88,4 %), con una mediana de 3 pruebas por paciente (rango intercuartílico 1,5). En 41 casos (80,4 %) se realizaron estudios radiológicos, con una mediana de 1 (rango intercuartílico 1,3) estudio por paciente. Las pruebas radiológicas realizadas fueron: radiografía simple (37 pacientes, 72,5 %), ecografía (17 pacientes, 33,3 %), TC (12 pacientes, 23,6 %), RM (1 paciente, 2 %). A 23 pacientes (45,1 %) se les realizó una extracción de sangre en las últimas 48 horas de vida. CONCLUSIONES: Se realiza un número elevado de pruebas diagnósticas en los últimos días de vida de pacientes oncológicos en situación terminal. Aunque las pruebas realizadas no se consideran invasivas, producen molestias innecesarias a los pacientes que no contribuyen al control de síntomas
INTRODUCTION: Any limitation of therapeutic effort should include a limitation of diagnostic tests not contributing to patient comfort. The aim of the present study was to assess the use of diagnostic tests among hospitalized cancer patients during their last days of life. METHODS: A retrospective observational study was performed on all stage-IV cancer patients who died during hospitalization in the Internal Medicine Unit over a period of two years. Analyzed variables included: age, gender, number of laboratory tests, and number of imaging tests (plain X-rays, ultrasound, computed tomography [CT], magnetic resonance imaging [MRI]), and whether a blood test had been performed wIthin the last 48 hours of life. RESULTS: A total of 51 patients were included (women, 15; 29.4 %) with an average age of 71.94 years (standard deviation, 11.06). Of these, 45 patients (88.4 %) underwent laboratory tests with a median of 3 tests per patient (interquartile range, 1.5), 41 patients (80.4 %) underwent imaging tests with a median of 1 test per patient (interquartile range, 1.3). The frequencies of imaging tests were: plain X-rays, 37 patients (72.5 %); ultrasounds, 17 patients (33.3 %); CT, 12 patients (23.6 %); MRI, 1 patient (2 %). Twenty-three patients (45.1 %) underwent at least one blood test within their last 48 hours of life. CONCLUSIONS: A large number of laboratory and imaging tests are performed during the last days of terminally ill, hospitalized cancer patients. While these tests are not considered to be invasive, they cause unnecessary discomfort to patients, and do not contribute to symptom relief
