Maurits E. L. Arbouw

Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial.

Background: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug with a quaternary ammonium structure not able to cross the blood-brain barrier in considerable amounts. Therefore, glycopyrrolate exhibits minimal central side effects, which may be an advantage in patients with PD, of whom a significant portion already experience cognitive deficits. Objective: To determine the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD. Methods: We conducted a 4-week, randomized, double-blind, placebo-controlled, crossover trial with oral glycopyrrolate 1 mg 3 times daily in 23 patients with PD. The severity of the sialorrhea was scored on a daily basis by the patients or a caregiver with a sialorrhea scoring scale ranging from 1 (no sialorrhea) to 9 (profuse sialorrhea). Results: The mean (SD) sialorrhea score improved from 4.6 (1.7) with placebo to 3.8 (1.6) with glycopyrrolate (p = 0.011). Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% vs 1 patient (4.3%) with placebo (p = 0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. Conclusions: Oral glycopyrrolate 1 mg 3 times daily is an effective and safe therapy for sialorrhea in Parkinson disease. Classification of evidence: This study provides Class I evidence that glycopyrrolate 1 mg 3 times daily is more effective than placebo in reducing sialorrhea in patients with Parkinson disease during a 4-week study.

Pharmacogenetics of antiparkinsonian drug treatment: a systematic review

Pharmacotherapy is the mainstay in the treatment of Parkinsons disease and the armamentarium of drugs available for the therapy of this disease is still expanding. Anti-Parkinsons disease drugs are effective in reducing the physical symptoms, such as hypokinesia, bradykinesia, rigidity and tremor. However, there is a large interindividual variability in response to anti-Parkinsons disease drugs with respect to both drug efficacy and toxicity. It is thought that genetic variability in genes encoding drug-metabolizing enzymes, drug receptors and proteins involved in pathway signaling is an important factor in determining interindividual variability in drug response. Pharmacogenetics aims at identifying genetic markers associated with drug response. Ideally, knowledge of these genetic markers will enable us to predict an individuals drug response in terms of both efficacy and toxicity. The role of pharmacogenetics in the treatment of Parkinsons disease is relatively unexplored. Therefore, we aim to present a systematic review of the published pharmacogenetic studies in Parkinsons disease and to describe polymorphic genes of interest for future research.

Novel insights in pharmacogenetics of drug response in Parkinson’s disease

receptor DRD2 gene, the dopamine transporter (DAT ) gene and μ1 opioid receptor (OPRM1) gene. Motor fluctuations have been associated with a DRD2 gene polymorphism [6], although other studies could not replicate this finding. Conflicting results have been reported concerning the relationship between the occurrence of drug-induced hallucinations in PD and genetic polymorphisms. While some studies demonstrated significant associations between hallucinations and polymorphisms in the DAT gene, the cholecystokinin (CCK ) gene and the apolipoprotein E (APOE) gene, others failed to replicate these results. Associations were found between sleep attacks without warning signs and a polymorphism in the DRD4 gene, the preprohypocretin (HCRT ) gene, the DRD2 gene and the catechol-O-methyl transferase (COMT ) gene. In addition, similar findings were found in recent studies investigating polymorphisms in genes encoding dopamine D 2 and D 3 receptors [7–9] and COMT [10]. Lin and colleagues investigated the role of angiotensin I-converting enzyme in levodopa response [11]. They demonstrated that patients with a homozygote (ins/ins) genotype of the ACE gene had a 2.5-times higher risk of levodopa-induced psychosis, a disabling complication, particularly in the later stage of the disease. The role of angiotensin I-converting enzyme in the development of levodopa-induced psychosis is relatively unexplored. It is necessary to reproduce this study in independent cohorts. We concluded that, in comparison with other subject areas such as psychiatry [12], relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. The focus of pharmacogenetic studies in patients with PD was mainly on genes coding for drug receptors, drug transporters and synaptic drug-metabolizing enzymes (pharmacodynamics). The pharmacogenetic studies in both PD and psychiatry did not, for the most part, Parkinson’s disease (PD) is characterized by brady kinesia, rigidity and tremor, and is the result of degeneration of dopaminergic neurones in the substantia nigra pars compacta. PD has a prevalence of approximately 0.5–1% in persons of 65–69 years, rising to 1–3% among persons of 80 years and older [1]. Twin studies suggest a limited role for genetic factors in the etiology of PD, perhaps most prominently in early-onset forms [2]. The etiology of the common late-onset forms of PD remains largely to be elucidated. Anti-PD drugs, such as levodopa and the direct-acting dopamine agonists, are effective in reducing the motor symptoms of PD. However, these drugs are also associated with the development of motor complications, such as levodopainduced dyskinesia (LID), response fluctuations and side effects, such as hallucinations and excessive daytime sleepiness. In clinical practice, a large interindividual variability in drug response has been noticed. For example, up to 45% of levodopa users develop LID within 5 years, while others remain free of LID for many years [3]. Up to 25% of users of dopaminergic drugs develop hallucinations, whereas others do not [4].

Dopamine agonists and ischemic complications in Parkinson’s disease: a nested case–control study

BackgroundIt has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson’s disease (PD) has not been studied.ObjectiveOur aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD.MethodsWe performed a nested case–control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified.ResultsThe study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95–1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists.ConclusionsThis study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization.