ABSTRACT
Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is hematopoietic stem cell transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor, or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19-67 years of age) either not eligible to HSCT (n= 8) or awaiting HSCT (n= 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient rapidly died from Covid19. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT.
ABSTRACT
Leriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that crosses the blood-brain barrier in humans and clinical trials have shown evidence of efficacy in neurodegenerative diseases. At clinical doses which are well-tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engagement and efficacy; PPARγ engagement is also supported by clinical and anti-inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy volunteers comprising a single ascending dose (SAD) and a multiple ascending dose (MAD) at oral doses of 30, 90, and 270 mg and 135 and 270 mg, respectively. Leriglitazone was rapidly absorbed with no food effect on overall exposure and showed a linear PK profile with dose-exposure correlation. A physiologically based pharmacokinetic (PBPK) model was developed for leriglitazone based on phase 1 data (SAD part) and incorporated CYP3A4 (fmCYP3A4 = 24%) and CYP2C8-mediated (fmCYP2C8 = 45%) metabolism, as well as biliary clearance (feBIL = 19.5%) derived from in vitro data, and was verified by comparing the observed versus predicted concentration-time profiles from the MAD part. The PBPK model was prospectively applied to predict the starting pediatric doses and was preliminarily verified with data from five pediatric patients.
Subject(s)
Dose-Response Relationship, Drug , Models, Biological , Thiazolidinediones , Humans , Male , Child , Thiazolidinediones/pharmacokinetics , Thiazolidinediones/administration & dosage , Thiazolidinediones/blood , Adult , Young Adult , PPAR gamma/agonists , Adolescent , Administration, Oral , Healthy VolunteersABSTRACT
En esta nota mostramos la elevada prevalencia de silicosis encontrada en una marmolería tras una exposición a una novedosa presentación de sílice.Se trata de un estudio observacional, prospectivo, en el que se han estudiado 11 trabajadores que se exponen desde 1995 a diversas presentaciones de superficies de cuarzo. Los puestos de trabajo se dividen en dos grupos: por una parte 4 sujetos desarrollan trabajos de corte en el taller; el resto de los trabajadores trabaja en el montaje. Hasta la fecha no han utilizado sistemas de protección respiratoria específicos.Se han diagnosticado 6 casos de silicosis, lo que supone una prevalencia de enfermedad para este ámbito del 54,5%. De los 6 afectados, 5 (83,33%) son montadores.Destacamos el elevado riesgo de desarrollo de silicosis en el manejo de los diversos productos que conforman la gama de superficies de cuarzo(AU)
In this note we present the increased prevalence of silicosis found in a marble factory after exposure to a new presentation of silica.A prospective, observational study was conducted on 11 workers who were exposed to different presentations of quartz surfaces since 1995. The jobs were divided into two groups: 4 subjects worked in the cutting workshop; the rest of the workers worked in assembly. Up to that date they had not used any specific respiratory protection apparatus.Six cases of silicosis have been diagnosed, which assumes a disease prevalence in this environment of 54.5%. Of the 6 affected, 5 (83.3% are assemblers.We highlight the high risk of developing silicosis in the handling of different products which make up the range of quartz surfaces(AU)