Istradefylline

Istradefylline [KW-6002; (E)-1,3-diethyl-8-(3,4-dimethoxystryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione; Kyowa Pharmaceuticals] is a novel adenosine A2A antagonist. It has been shown that istradefylline can directly stimulate dopamine release in the rat nucleus accumbens (28) and beneficial motor effects have been consistently shown in 6-hydroxydopamine (6-OHDA) rodents and MPTP primates (29,30). A single dose typically improved locomotion for about 10 hours and motor hyperactivity (dyskine-sia) did not develop with long-term administration. When used in combination with dopaminergic drugs in these models, istradefylline potentiated the duration of benefit and also allowed for dose reduction and improved dyskinesia, while maintaining improved locomotion.

Hauser et al. (31) reported a 12-week, double-blind, randomized, placebo-controlled, exploratory study in which PD subjects with both motor fluctuations and peak-dose dyskinesia were randomized to treatment with placebo (n = 29), istradefylline up to 20 mg/day (n = 26), or istradefylline up to 40 mg/day (n = 28). As assessed by home diaries, subjects assigned to istradefylline experienced a mean reduction in the proportion of awake time spent in the off state of 7.1% compared with an increase of 2.2% in the placebo group (P = 0.008). Dyskinesia severity was unchanged, but on time with dyskinesia increased in the istradefylline group compared with the placebo group. No differences were observed in change in UPDRS scores or Clinical Global Impression. Adverse events were minimal and additional studies are ongoing.

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