Adenosine A2A receptor antagonists for Parkinson's disease: rationale, therapeutic potential and clinical experience.
Long-term disability in Parkinson's disease (PD) is related to progression of the underlying disease and the emergence of complications of chronic levodopa therapy. There is a need for new medications that can slow the underlying progression of degeneration, improve PD symptoms in early disease without inducing dyskinesia, and improve motor fluctuations and 'off' time in advanced disease without worsening dyskinesia. Much interest has focused on the development of nondopaminergic therapies, with antagonists of the adenosine A2A receptor emerging as leading candidates. A2A receptors are selectively expressed in the basal ganglia and specific A2A antagonists reverse motor deficits without causing dyskinesia in animal models of PD. The antiparkinsonian potential of A2A receptor blockade has been expanded further by convergent epidemiological and laboratory findings suggesting a possible neuroprotective effect of A2A receptor antagonists in PD. Istradefylline (KW-6002) is the first of several adenosine A2A receptor antagonists in development for PD to advance to phase III clinical trials. Initial studies indicate that in patients with motor fluctuations on levodopa, addition of istradefylline reduces 'off' time. Additional studies are necessary to evaluate the benefit of istradefylline as monotherapy in early disease, its effect on the development of dyskinesia, and its effect on disease progression.
Department of Neurology, University of South Florida and Tampa General Healthcare, Tampa, Florida 33606, USA. rhauser@hsc.usf.edu
Robert A
RA
Hauser
Michael A
MA
Schwarzschild
D058917:Adenosine A2 Receptor Antagonists; D000368:Aged; D006801:Humans; D008954:Models, Biological; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D011687:Purines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D043705:Receptor, Adenosine A2A / Q000502:physiology; D016896:Treatment Outcome
D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline