Bladder dysfunction is a major clinical issue in patients with Parkinson’s disease (PD). The prevalence of lower urinary tract symptoms (LUTS) characterized by urinary urgency, frequency, and incontinence was previously reported. LUTS often appear once treatments for PD have been initiated. Anti-Parkinson treatments may influence bladder control in an unpredictable manner. These symptoms have a severe impact on the QOL of PD patients. The adenosine receptor A2A is strongly expressed in the striatum, interacts with dopamine D2 receptors, and modulates dopamine transmission. Istradefylline, a novel non-dopaminergic selective adenosine A2A receptor antagonist. We previously reported that istradefylline improved not only motor symptoms, but also lower urinary tract symptoms (LUTS) in patients with PD in one-year period (ref 1). However, it currently remains unclear whether istradefylline is useful for the treatment of PD patients with LUTS in the over 1 year real-world clinical settings. There is no previous study regarding the effect of anti-Parkinson treatment to LUTS sustainable in the long term.
Therefore, the main purpose of this study was to survey the effects of 3 year istradefylline treatment in PD patients.

In this prospective study, patients were invited consecutively from the Department of Neurology to participate between March 2015 and July 2015, regardless of the presence of LUTS. We enrolled male 12 male PD patients. The mean of age of patients was 69 (63-83) years old, the Hoehn-Yahr stage was 2 (2-3), and disease duration was 11 (7-29) years. During first 1 year, no changes to the type of rehabilitation or PD medication were required. After 1 year treatment, neurologist and urologist can change both anti-Parkinson drug and LUTS treatment drugs without any limitation. The current study is mainly focused on the treatment changes of PD patients during 3 years, after 1 year administration of adenosine A2A receptor antagonist istradefylline (20 mg/day).

One patient was discontinued istradefylline and changed to another anti-Parkinson drug because of the clinical condition. No adverse urological effects were observed in any patient. Two patients were increased the dose of istradefylline (40mg/day: maximum dose) for the control of PD symptoms during 3 years, and these two patients were not changed LUTS and no additional urological therapy. And 6 patients were not changed urological therapy (only changed anti-Parkinson drugs). Storage symptoms in three patients were deteriorated and added on anti-cholinergic agents or beta-3 agonist. Voiding symptoms in one patient were deteriorated and added on alpha-blocker (therapeutic process of all patients were shown in Figure).

This study revealed that 91.7% male patients with PD continued istradefylline 3 years without any adverse effects, of which 72.7% patients were maintained LUTS without any urological therapy. The prevalence of LUTS/BPH increases with age and it deteriorated quality of life. LUTS are more likely to occur at more advanced stages of PD, and progressively deteriorate with the disease duration. However, natural course of LUTS in the patients of PD is not fully understand. One-fourth patients need additional urological treatment despite an appropriate neurological treatment. There is no real-world data of adenosine A2A receptor antagonist for the treatment of PD. We think this is a very informative study for physicians and patients. Previous data reported that not only storage symptoms, but also voiding symptoms were improved by the treatment with istradefylline during one year. However, the current study was prospective study, we could not decide the long-term effect of istradefylline for LUTS.
The limitations of this study include the small number of patients treated and the absence of a placebo control, randomized larger research will be required to solve this problem in future.

Istradefylline is a very tolerable drug, and could effectively improve not only motor symptoms, but also LUTS in patients with PD in a long-term period.

Clinical Neuropharmacology, 2018, in press