Objective: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A 2A receptor antagonist, istradefylline, shows promise for the treatment of PD. Methods: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (Ϯ standard deviation) of Ϫ10.8 Ϯ 16.6% (95% confidence interval, Ϫ13.46 to Ϫ7.52) and for placebo, Ϫ4.0 Ϯ 15.7% (95% confidence interval, Ϫ7.73-0.31; p ϭ 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of Ϫ1.8 Ϯ 2.8 hours for istradefylline and Ϫ0.6 Ϯ 2.7 hours for placebo ( p ϭ 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. Interpretation: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia. Neurol 2008;63:295-302 Although Parkinson's disease (PD) has several treatment options that initially can provide excellent symptomatic relief, 1 control of its disabilities typically declines over time. Because PD is characterized by loss of dopaminergic neurons projecting from substantia nigra to striatal nuclei, the most rational and effective therapy for restoring dopaminergic neurotransmission has been the dopamine precursor L-dopa. Ann2 Two years after starting L-dopa therapy, however, many patients start to experience fluctuations that interrupt control of parkinsonism, sometimes for up to several hours per day. 3,4 Adjusting the effects of L-dopa (by dosing changes or extenders such as catechol-Omethyltransferase or monoamine oxidase B inhibitors) or adding other dopaminergic drugs can improve "off" (undermedicated) states. Despite these options, inadequate control of motor fluctuations is a major source of disability for chronically treated PD.Beyond restoring dopaminergic input to striatal neurons, other pharmacological interventions can influence From the

Adenosine A2A receptor antagonists have antiparkinsonian effects of their own with a reduced propensity to elicit dyskinesias. They might therefore be useful agents in the treatment of PD.

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The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.

Istradefylline demonstrated a significant reduction in the percentage of awake time per day spent in the OFF state, which resulted in a clinically meaningful reduction in OFF time, without an increase in ON time with troublesome dyskinesia, and was well tolerated as adjunctive treatment to levodopa in Parkinson disease.

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The selective localization of adenosine A2A receptors to the striatopallidal system suggested a new therapeutic approach to the management of Parkinson's disease (PD). The results of behavioral studies using A2A receptor-specific agents in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys highlight the therapeutic potential of A2A antagonists as a novel treatment for PD. However, little is known about the role of A2A receptors in basal ganglia function or their pathophysiologic role in PD. Recently, the authors found that presynaptic A2A receptors modulate GABAergic synaptic transmission in the striatum and globus pallidus (GP), suggesting an A2A receptor-mediated dual modulation of the striatopallidal system. Striatal A2A receptors may increase the excitability of medium spiny neurons (MSNs) by modulating an intrastriatal GABAergic network. In addition, pallidal modulation occurs at striatopallidal MSN terminals located at the GP, enhancing GABA release onto GP projection neurons and directly suppressing their activity. Blockade of these modulatory functions by A2A antagonists could counteract excessive striatopallidal neuronal activity provoked by striatal dopamine depletion in patients with PD, leading to a reversal of parkinsonian motor deficits.