The adenosine A receptor antagonist/inverse agonist, KW-6356 enhances the anti-parkinsonian activity of L-DOPA with a low risk of dyskinesia in MPTP-treated common marmosets.

The adenosine A receptor antagonist/inverse agonist, KW-6356 has been shown to be effective in Parkinson's disease (PD) patients as monotherapy and as an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor. However, the effects of KW-6356 combined with L-DOPA on anti-parkinsonian activity and established dyskinesia has not been investigated in preclinical experiments. We examined the effects of combination of KW-6356 with L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets.

Anti-parkinsonian activity of the adenosine A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets.

KW-6356 is a novel adenosine A receptor antagonist/inverse agonist that not only blocks binding of adenosine to adenosine A receptor but also inhibits the constitutive activity of adenosine A receptor. The efficacy of KW-6356 as both monotherapy and an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor in Parkinson's disease (PD) patients has been reported. However, the first-generation A antagonist istradefylline, which is approved for use as an adjunct treatment to L-DOPA/decarboxylase inhibitor in adult PD patients experiencing OFF episodes, has not shown statistically significant efficacy as monotherapy.

The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets.

The adenosine A2A receptor antagonist, istradefylline improves motor function in patients with advanced Parkinson's disease (PD) optimally treated with a combination of L-DOPA and a dopamine agonist without increasing the risk of troublesome dyskinesia. However, the effects of istradefylline on motor function when administered in combination with low dose of L-DOPA and dopamine agonists as occurs in early PD are unknown. We investigated whether istradefylline enhances the combined anti-parkinsonian effects of a suboptimal dose of L-DOPA and a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset.

The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets.

The adenosine A2A receptor antagonist, istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson׳s disease (PD) already treated with combinations of L-DOPA and dopamine agonist drugs but who are still exhibiting prolonged 'OFF' periods. In contrast, the effects of istradefylline on motor function when administered in combination with low dose dopamine agonist therapy in early PD are unknown. We now investigate whether istradefylline administered with a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide enhances anti-parkinsonian activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset.

Adenosine A₂A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets.

The adenosine A₂A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson's disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A₂A antagonists are most effective in potentiating motor function when combined with sub-maximal doses of L-DOPA. However, the effects of combining istradefylline with sub-optimal L-DOPA treatment on established dyskinesia have not been studied.