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.
RCT Entities:
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: K Fuxe; D Marcellino; D O Borroto-Escuela; M Guescini; V Fernández-Dueñas; S Tanganelli; A Rivera; F Ciruela; L F Agnati Journal: CNS Neurosci Ther Date: 2010-03-16 Impact factor: 5.243
Authors: Kjell Fuxe; Sergi Ferré; Meritxell Canals; Maria Torvinen; Anton Terasmaa; Daniel Marcellino; Steven R Goldberg; William Staines; Kirsten X Jacobsen; Carmen Lluis; Amina S Woods; Luigi F Agnati; Rafael Franco Journal: J Mol Neurosci Date: 2005 Impact factor: 3.444
Authors: K Fuxe; M Canals; M Torvinen; D Marcellino; A Terasmaa; S Genedani; G Leo; D Guidolin; Z Diaz-Cabiale; A Rivera; L Lundstrom; U Langel; J Narvaez; S Tanganelli; C Lluis; S Ferré; A Woods; R Franco; L F Agnati Journal: J Neural Transm (Vienna) Date: 2006-10-27 Impact factor: 3.575
Authors: S Ferré; I Diamond; S R Goldberg; L Yao; S M O Hourani; Z L Huang; Y Urade; I Kitchen Journal: Prog Neurobiol Date: 2007-05-01 Impact factor: 11.685
Authors: Kjell Fuxe; Dasiel O Borroto-Escuela; Wilber Romero-Fernandez; Miklós Palkovits; Alexander O Tarakanov; Francisco Ciruela; Luigi F Agnati Journal: Neuropsychopharmacology Date: 2013-09-06 Impact factor: 7.853