title: Adenosine A(2A) receptor antagonist treatment of Parkinson's disease.
abstract: BACKGROUND
  Observations in animal models suggest that A(2A) 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 A(2A) 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 A(2A) 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 A(2A) 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.
authors.affiliation: Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: W
authors.initials: W
authors.lastname: Bara-Jimenez
authors.forename: A
authors.initials: A
authors.lastname: Sherzai
authors.forename: T
authors.initials: T
authors.lastname: Dimitrova
authors.forename: A
authors.initials: A
authors.lastname: Favit
authors.forename: F
authors.initials: F
authors.lastname: Bibbiani
authors.forename: M
authors.initials: M
authors.lastname: Gillespie
authors.forename: M J
authors.initials: MJ
authors.lastname: Morris
authors.forename: M M
authors.initials: MM
authors.lastname: Mouradian
authors.forename: T N
authors.initials: TN
authors.lastname: Chase
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002230:Carbidopa / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012449:Safety; D016896:Treatment Outcome
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011687:Purines; C111599:istradefylline; D007980:Levodopa; D002230:Carbidopa