Continuous drug delivery in early- and late-stage Parkinson's disease as a strategy for avoiding dyskinesia induction and expression.

The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of L: -dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by L: -dopa than by dopamine agonist drugs. This has been associated with the short duration of L: -dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of L: -dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD.

Transcriptional alterations under continuous or pulsatile dopaminergic treatment in dyskinetic rats.

Continuous dopaminergic treatment is considered to prevent or delay the occurrence of dyskinesia in patients with Parkinson's disease (PD). Rotigotine is a non-ergolinic D(3) > D(2) > D(1) dopamine-receptor agonist for the treatment of PD using a transdermal delivery system providing stable plasma levels. We aimed to investigate the differential influence on gene expression of pulsatile L: -DOPA or rotigotine versus a continuous rotigotine treatment. The gene expression profile within the nigro-striatal system of unilateral 6-hydroxydopamine-lesioned rats was assessed in order to differentiate potential changes in gene expression following the various treatment using Affymetrix microarrays and quantitative RT-PCR. The expression of 15 genes in the substantia nigra and of 11 genes in the striatum was altered under pulsatile treatments inducing dyskinetic motor response, but was unchanged under continuous rotigotine treatment that did not cause dyskinetic motor response. The route of administration of a dopaminergic drug is important for the induction or prevention of motor abnormalities and adaptive gene expressions. The decline of neurotrophin-3 expression under pulsatile administration was considered of particular importance.

Rotigotine transdermal patch for the treatment of Parkinson's disease and restless legs syndrome.

The nonergoline dopamine agonist rotigotine, is delivered transdermally using a silicone-based patch (Neupro(R); UCB Pharma GmbH), which promotes unidirectional drug flow from the transdermal system to the skin. Pharmacokinetic data show stable steady-state plasma concentrations over 24 h, maintained with once-daily patch administration. Stable plasma concentrations are reflected by stable concentrations in the brain, as has been shown in animal studies. This suggests a continuous stimulation of dopaminergic receptors, which may result in a reduction in or prevention of abnormal involuntary movements in Parkinson's disease (PD) after prolonged treatment. Clinical trials have demonstrated that rotigotine is efficacious as monotherapy for PD and restless legs syndrome (RLS), and open-label extension studies have shown its long-term efficacy. Furthermore, rotigotine can be used effectively in coadministration with levodopa, enabling a reduction of the levodopa treatment doses in PD. Transdermal application also yields favorable pharmacokinetics for rotigotine: rapid metabolism and lack of skin accumulation allow for good control of chronic administration or withdrawal by patch removal, and the transdermal application approach circumvents problems of gastrointestinal absorption and enables administration prior to, during or following surgery. In addition, no dose adaptation is required regarding gender or ethnicity, or for patients with impaired liver or kidney function or on hemodialysis. The safety profile of rotigotine transdermal patch is favorable; common side effects attributed to transdermal delivery or dopaminergic stimulation are generally mild to moderate in intensity. Importantly, augmentation of RLS is uncommon under long-term rotigotine treatment and dyskinesia in PD patients mostly developed only after levodopa initiation. Overall, rotigotine transdermal patch has demonstrated favorable clinical efficacy and tolerability in the treatment of PD and RLS.

Continuous rotigotine administration reduces dyskinesia resulting from pulsatile treatment with rotigotine or L-DOPA in MPTP-treated common marmosets.

We previously showed that continuous infusion of rotigotine resulted in less dyskinesia than repeated pulsatile rotigotine administration or repeated oral administration of L-DOPA in MPTP-treated marmosets. Now we investigate whether continuous rotigotine delivery modifies established dyskinesia induced by prior exposure to repeated pulsatile administration of L-DOPA or rotigotine in MPTP-treated common marmosets. Repeated oral administration of L-DOPA or subcutaneous bolus administration of rotigotine over 28 days improved motor deficits but resulted in the onset of dyskinesia of moderate intensity. When these animals were switched to a 28-day continuous infusion of rotigotine, the reversal of motor disability was maintained. In those animals initially treated with L-DOPA, there was a small reduction in dyskinesia intensity but a significant reduction in the duration of dyskinesia. However, in animals initially treated with repeated bolus administration of rotigotine, dyskinesia intensity was significantly reduced. Initial treatment with a continuous infusion of rotigotine for 28 days reversed motor disability and resulted in a low incidence of dyskinesia. On switching to repeated oral administration of L-DOPA, the improvement in motor disability was maintained but the propensity of L-DOPA to provoke dyskinesia was not affected. In addition, while the continuous delivery of rotigotine prevented the expression of dyskinesia, the previously demonstrated ability of dopamine agonists to prime for dyskinesia could not be avoided. These data suggest that dyskinesia induced by pulsatile drug treatment may be improved by switching to continuous rotigotine delivery. In addition, while continuous delivery of rotigotine may prime for dyskinesia, it does not lead to its expression.

Continuous delivery of rotigotine decreases extracellular dopamine suggesting continuous receptor stimulation.

Rotigotine, a non-ergolinic dopamine receptor agonist for treatment of Parkinson's disease was continuously administered over 48 h (0.5 mg/kg s.c., slow release formulation) to conscious rats striatally implanted with a microdialysis probe. Subsequently, the levels of rotigotine increased to a maximum of 3.42 + 2.1 nmol/l and remained at a level of 2.81 +/- 0.82 nmol/l for 48 h. Concomitantly, the dopamine levels consistently decreased to 20% of the control level. This suggests that the sustained administration of rotigotine provides stable extracellular drug levels in the striatum resulting in continuous stimulation of dopamine receptors.