Efficacy of Adenosine A2A Receptor Antagonist Istradefylline as Augmentation for Parkinson’s Disease: A Meta-analysis of Randomized Controlled Trials

Abstract

Adenosine A2A receptor antagonist istradefylline has been approved this year for manufacturing and marketing in Japan. We, therefore, did this meta-analysis to systematically assess the efficacy and safety of istradefylline as augmentation to levodopa in patients with Parkinson's disease (PD). We systematically review the relative randomized controlled trials (RCTs) up to March 2014, which compared istradefylline to placebo for the short course of treatment for PD in adults. The primary outcome was daily OFF time and secondary outcome was UPDRS Part III score (on state). Data were obtained from seven RCTs, including 2205 patients. Compared to placebo on primary and secondary outcome, istradefylline group both showed significant reductions (WMD -0.60, p = 0.0001; WMD -1.07, p = 0.002). Subgroup analysis suggested that istradefylline 20, 40, and 60 mg/day in both group showed significant reductions on the two outcomes. Based on these results, Istradefylline could be an efficacy and safety augmentation drug added on to levodopa or other existing anti-Parkinsonian therapies. Limited by the number of studies, future large-scale studies are needed to verify these results, assess the long-term effect of istradefylline and the effect of istradefylline as monotherapy, and find the most effective dose of istradefylline.

Purinergic Signalling: Therapeutic Developments

“…K ATP ( Dragicevic et al, 2015 ) and P2X1R ( Gan et al, 2015 ; Navarro et al, 2016 ; Yang Z. et al, 2016 ) in PD have also been reported, perhaps indicating new therapeutic targets. Clinical trials istradefylline, an A 2A R antagonist, have taken place and it may have a beneficial effect in conjunction with commonly used anti-Parkinson’s therapies ( Tao and Liang, 2015 ; Uchida et al, 2015 ; Vorovenci and Antonini, 2015 ), although in a later study, istradefylline was shown to enhance amyloid-β generation and γ-secretase activity ( Lu et al, 2016 ). Oligomerisation kinetics of A 2A and dopamine D 2 R have important implications for PD ( Casadó-Anguera et al, 2016 ; Ferré et al, 2016 ; Guixà-González et al, 2016 ).…”

Purinergic Signalling and Neurological Diseases: An Update

“…antagonist, have been undertaken and it was suggested that it could be an efficacy and safety augmentation drug added on to levodopa or other existing anti-Parkinson's therapies [35]. Later studies have supported this strategy [36,37].…”

Potential Therapeutic Applications of Adenosine A2A Receptor Ligands and Opportunities for A2A Receptor Imaging

“…The A 2A R antagonist istradefylline (KW‐6002, Fig. ) has been approved in Japan as an adjuvant in treatment of PD patients with L‐DOPA (where DOPA is dihydroxyphenylalanine) . It can reduce motor fluctuations (off‐time) during dopamine replacement therapy.…”