Assessment of drug therapy in Parkinson’s disease

Abstract

The pharmacological management of motor and non-motor symptoms of Parkinson’s disease (PD) is the central theme of this thesis. In a literature study, we revealed that relatively few efforts have been made to investigate the role of pharmacogenetics in the response to anti-PD drugs and that only few replication studies have been performed. Some interesting associations between genetic variants and anti-PD drug response have been found, but these were conflicting. We concluded that pharmacogenetic polymorphisms should not be assessed routinely or exceptionally during the clinical management of PD. We compared patient characteristics and the incidence of discontinuation of two non-ergoline DA, ropinirole and pramipexole, between a retrospective clinical practice cohort with PD and data from randomized clinical trials (RCTs). We concluded that the overall incidence of discontinuation of ropinirole and pramipexole between the patients in our clinical-practice cohort and patients in the RCTs was comparable for the short term. In a retrospective cohort study we identified non-genetic and genetic determinants for the discontinuation of non-ergoline DA treatment in patients with PD. Apomorphine use and levodopa dosages between 500 and 1000 mg were positively associated with discontinuation. The absence of a 15x CA repeat allele in the dopamine receptor 2 gene was significantly associated with a decreased discontinuation of non-ergoline treatment. We concluded that more research is needed to replicate these findings. In a case-control study we investigated the association between the use of DA and hospitalization due to ischemic events in patients with PD. We concluded that DA use one year prior to the index date was not associated with a higher risk of ischemic events requiring hospitalization. In a case-control study we studied the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures. Current use of dopaminergic drugs was associated with a nearly two-fold increased risk of hip/femur fractures compared to never use, but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1 year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures. We concluded that fracture risk assessment may be warranted in elderly users of dopaminergic drugs. In a retrospective cohort study we assessed whether there is an association between initial use of serotonergic antidepressants and changes in anti-PD drug treatment. We concluded that there is no evidence to be more cautious using SSRIs or serotonergic antidepressants compared to other antidepressants in patients with PD. We determined the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD during a 4-week, randomized, double-blind, placebo-controlled, crossover trial. Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% versus 1 patient (4.3%) with placebo (p=0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. We concluded that oral glycopyrrolate 1 mg three times daily is an effective and safe therapy for sialorrhea PD