Dyskinesia is a frequent and disabling side effect in patients with Parkinson's disease treated with chronic dopa-therapy. Preclinical data in the 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) monkey suggest that alpha-2 antagonists may reduce dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. We assessed, in a pilot randomised placebo-controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha-2 antagonist, on motor parkinsonian disability and L-DOPA-induced dyskinesia following an acute oral challenge of L-DOPA in 18 patients with Parkinson's disease. The severity of L-DOPA-induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L-DOPA. These results suggest that blocking alpha-2 receptors in patients with Parkinson's disease might improve L-DOPA-induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long-term management of dyskinetic patients with Parkinson's disease.

Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT‐431 is the prodrug of A‐86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa‐responsive Parkinson's disease received five doses of ABT‐431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12‐hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT‐431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT‐431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT‐431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well‐tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease. Ann Neurol 1999;45:736–741

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A single morning dose of dual-release formulation was compared with a slow-release formulation of L-dopa plus benserazide in a randomized, double-blind, cross-over study in 16 fluctuating patients with PD. The mean time to "on" was shorter with the dual-release formulation (43 +/- 31 minutes) than with the slow-release formulation (81 +/- 39 minutes) (p < 0.001), whereas the mean time to relapse to "off" was similar for both formulations. The dual-release formulation had a significantly shorter time to reach peak concentration (t(max)) and greater maximum concentration (C(max)) and area under the plasma concentration time curve (AUC(0--5 h)) than the slow-release formulation, whereas apparent elimination half-life (t(1/2)) was similar for both formulations.