Strategies for continuous dopaminergic stimulation. A continuous stimulation of dopamine receptors can be achieved by prolonging the activity of levodopa by modifying the release or the delivery of this short-acting dopaminergic agent. For this purpose oral sustained release formulations of levodopa Madopar HBS® and Sinemet CR®, were developed. These long-acting controlled release formulations showed improvement in activities of daily living of the patient, however not in controlling motor fluctuations [47, 50-51]. In addition the intake of small doses of a liquid formulation of levodopa/carbidopa improved the ’on’-time without worsening the dyskinesia, but did not affect the pulsatile levodopa plasma concentration or the motor response fluctuations [52]. In contrast clinical trials showed an improvement in motor dysfunction after chronic IV infusion of levodopa [53]. A more recent small open-label clinical trial, in which continuous intravenous levodopa [54] was compared to oral administration, also shows a reduced risk of motor complications in the infusion group [55]. Besides IV infusion, duodenal infusion via a portable pump of low doses of levodopa ameliorates plasma fluctuations and dyskinesia with a satisfactory therapeutic window in advanced Pd patients [51, 56]. Dopamine agonists in general have significant longer half-lives compared to levodopa [57]. Several studies in patients have discovered that DA are less likely to induce motor fluctuations after chronic treatment. In addition some studies have suggested a neuroprotective effect of DA [50, 58-59]. Therefore this class of drugs has gained more popularity over the recent years as alternative to or in combination with levodopa. In accordance to the levodopa treatment, the current strategy is to achieve continuous stimulation of the dopamine receptors to reduce development of motor fluctuations. This led to the development of long-acting therapeutic formulations of DA. For instance the slow-release formulation of a dopamine agonist, bromocriptine, showed promising efficacy but has not been widely used in Xxxxxxxxx’x disease [51]. Furthermore ropinirole, formulated as extended release tablets, requires only one dose intake per day. The incidence of motor complications is reduced, while the adverse effects are comparable to other dopamine agonists [50, 60]. Although promising results were obtained with oral modified release formulations, other delivery routes were explored to achieve continuous drug delivery. Various routes of administration of apo...
