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From the Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Address correspondence and reprint requests to Dr. Thomas N. Chase, Building 10, Room 5C103, National Institutes of Health, Bethesda, MD 20892; e-mail: chaset{at}ninds.nih.gov
Background: Observations in animal models suggest that A2A antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A2A receptor–mediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications.
Methods: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A2A antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design (40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale.
Results: KW-6002 alone or in combination with a steady-state IV infusion of each patient’s optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p < 0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone (p < 0.05). All cardinal parkinsonian signs improved, especially resting tremor. In addition, KW-6002 prolonged the efficacy half-time of levodopa by an average of 47 minutes (76%; p < 0.05). No medically important drug toxicity occurred.
Conclusions: The results support the hypothesis that A2A receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.
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