Optimizing levodopa pharmacokinetics in Parkinson's disease: the role of COMT inhibitor.

Abstract

After more than 30 years of clinical use, levodopa therapy still offers the best symptomatic control of Parkinson’s disease (PD), and all patients will require it during the course of their disease [1, 2]. However, with each year of levodopa treatment, about 10% of patients will develop motor complications [3, 4]. There is considerable evidence that abnormal intermittent or pulsatile activation of brain dopamine receptors leads to the development of motor complications in PD, through the induction of plastic changes in striatal neurons and altered neuronal firing patterns [5, 6]. These observations suggest that long-acting dopaminergic agents that provide more-continuous stimulation of dopamine receptors might be associated with a reduced risk of inducing motor complications [7, 8]. For example, long-acting dopaminergic agents are associated with a reduced frequency and severity of motor complications in MPTP monkeys [9, 10]. The same short-acting dopamine agonist also induces gene changes in striatal neurons and dyskinesia when it is administered intermittently, but not when it is infused in a continuous manner [11, 12]. Prospective double-blind clinical trials in PD patients similarly demonstrate that the risk of inducing motor complications is markedly reduced if therapy is initiated with a long-acting dopamine agonist compared with a short-acting formulation of levodopa [13, 14]. It is less clear if motor complications can be reversed with long-acting or continuous dopaminergic therapies. We recently demonstrated in a prospective, randomized trial, that patients randomized to receive treatment with continuous subcutaneous daytime infusions of the dopamine agonist lisuride experienced significant improvement in both “off” time and dyskinesias compared with patients randomized to receive oral levodopa treatment with or without other medical therapies [15]. Continuous infusions of levodopa, apomorphine, or lisuride have been shown to consistently reduce “off” time and the severity of motor fluctuations [16–19]. In some patients, this improvement in “off” time was associated with a marked reduction in the severity and duration of dyskinesia [18].