RESUMEN
UNLABELLED: Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. ß2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles. PURPOSE: To test the hypothesis that a ß-blocker might reduce the efficacy of ERT, because the action of ß-blockers opposes those of ß2-agonists. METHODS: Mice with Pompe disease were treated with propranolol (a ß-blocker) or clenbuterol in combination with ERT, or with ERT alone. RESULTS: Propranolol-treated mice had decreased weight gain (p<0.01), in comparison with clenbuterol-treated mice. Left ventricular mass was decreased (and comparable to wild-type) in ERT only and clenbuterol-treated groups of mice, and unchanged in propranolol-treated mice. GAA activity increased following either clenbuterol or propranolol in skeletal muscles. However, muscle glycogen was reduced only in clenbuterol-treated mice, not in propranolol-treated mice. Cell-based experiments confirmed that propranolol reduces uptake of rhGAA into Pompe fibroblasts and also demonstrated that the drug induces intracellular accumulation of glycoproteins at higher doses. CONCLUSION: Propranolol, a commonly prescribed ß-blocker, reduced weight, increased left ventricular mass and decreased glycogen clearance in skeletal muscle following ERT. ß-Blockers might therefore decrease the efficacy from ERT in patients with Pompe disease.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Propranolol/farmacología , alfa-Glucosidasas/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Células Cultivadas , Antagonismo de Drogas , Evaluación Preclínica de Medicamentos , Fibroblastos/metabolismo , Glucógeno/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Humanos , Ratones Noqueados , Propranolol/uso terapéutico , alfa-Glucosidasas/farmacologíaAsunto(s)
Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/cirugía , Trasplante de Corazón , Enfermedades Mitocondriales/complicaciones , Adulto , Suplementos Dietéticos , Ejercicio Físico , Femenino , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Resultado del TratamientoRESUMEN
Benefits of enzyme replacement therapy with Myozyme (alglucosidase alfa), anecdotally reported in late-onset Pompe disease, range from motor and pulmonary improvement in less severely affected patients, to stabilization with minimal improvement in those with advanced disease. We report a case of a 63-year-old patient with significant morbidity who made notable motor and pulmonary function gains after two years on therapy. Thus, improvements in those with advanced disease may be possible after long-term treatment.