Long term differential consequences of miglustat therapy on intestinal disaccharidases

Abstract

Miglustat is an oral medication for treatment of lysosomal storage diseases such as Gaucher disease type I and Niemann Pick disease type C. In many cases application of Miglustat is associated with symptoms similar to those observed in intestinal carbohydrate malabsorption. Previously, we have demonstrated that intestinal disaccharidases are inhibited immediately by Miglustat in the intestinal lumen. Nevertheless, the multiple functions of Miglustat hypothesize long term effects of Miglustat on intracellular mechanisms, including glycosylation, maturation and trafficking of the intestinal disaccharidases. Our data show that a major long term effect of Miglustat is its interference with N-glycosylation of the proteins in the ER leading to a delay in the trafficking of sucrase-isomaltase. Also association with lipid rafts and plausibly apical targeting of this protein is partly affected in the presence of Miglustat. More drastic is the effect of Miglustat on lactase-phlorizin hydrolase which is partially blocked intracellularly. The de novo synthesized SI and LPH in the presence of Miglustat show reduced functional efficiencies according to altered posttranslational processing of these proteins. However, at physiological concentrations of Miglustat (≤50 μM) a major part of the activity of these disaccharidases is found to be still preserved, which puts the charge of the observed carbohydrate maldigestion mostly on the direct inhibition of disaccharidases in the intestinal lumen by Miglustat as the immediate side effect.

Case study on the pathophysiology of Fabry disease: abnormalities of cellular membranes can be reversed by substrate reduction in vitro

“…For LRs isolation, cells were solubilized with 1% Triton X-100 and then subjected to sucrose density gradient fractionation as described before [13]. After ultracentrifugation, ten fractions were collected at 4°C from top to bottom.…”

Guía para diagnóstico y tratamiento de la Enfermedad de Gaucher

“…Fue aprobado por la agencia europea para la evaluación de productos medicinales (EMEA) en 2002 y posteriormente por la USA FDA (2003) (50). Es un derivado sintético de la familia de alcaloides polihidroxilados o imino azúcares extraídos de plantas y microorganismos.…”

“…La diarrea puede deberse a la inhibición de la actividad de la disacaridasa intestinal que resulta en diarrea osmótica (50). Estos síntomas pueden disminuir con una dieta libre de lactosa.…”

Estado nutricional de los pacientes con diagnóstico de Niemann-Pick tipo C en Colombia

“…Por su parte, el tratamiento usual de los pacientes con NP-C es la terapia de inhibición de sustrato Miglustat® (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) la cual está aprobada por la Food and Drug Administration (FDA) desde el año 2003 (33,34) y en Colombia desde 2009 (35) . Sin embargo, esta terapia trae consigo complicaciones gastrointestinales, debido a la inhibición de las disacaridasas intestinales, lo cual ocasiona una inadecuada hidrólisis de carbohidratos y la subsecuente diarrea osmótica con alteración en la fermentación colónica, que posteriormente producen pérdida de peso (25,(36)(37)(38) . Debido a las complicaciones gastrointestinales ocasionadas por la terapia de inhibición de sustrato y como parte de un tratamiento integral, el mantener un adecuado manejo nutricional puede minimizar las complicaciones, evitando la pérdida de peso que pueda ocasionar desnutrición, mejorando la calidad de vida del paciente y su familia (36,39) .…”