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Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the pros and cons of initiating treatment with levodopa-sparing strategies. The current drive toward early levodopa monotherapy is primarily driven by safety and tolerability concerns with dopamine agonists and only mild efficacy of other available approaches. Recently, P2B001, a novel once-daily combination of low-dose, extended-release formulations of pramipexole and rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this drug evaluation, we review the preclinical and current clinical data for P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.Parkinson’s disease is the fastest growing neurologic disorder across the globe. Once diagnosed, it is now generally agreed that there is no clinical rationale to postpone symptomatic treatment in people who develop Parkinson’s-related disability. There are three main treatment options available for use in early Parkinson’s disease: levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Of these, there is a current push toward using levodopa as the main first-line therapy. This is primarily because of the significant safety and tolerability concerns with dopamine agonists and only mild efficacy of MAO-B inhibitors. Recently, P2B001, a novel drug formulation combining once-daily, extended-release, low dosages of the dopamine agonist pramipexole and the MAO-B inhibitor rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this article, the authors review the preclinical and current clinical data on P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

L-DOPA-induced dyskinesia (LID) is a major complication of the treatment of Parkinson's disease (PD). LID comprises two major components, the priming process responsible for its onset and the expression of involuntary movements that underlies its clinical manifestation. The mechanisms responsible for these components are partially understood and their biochemical basis is being unraveled but avoidance and treatment remain an issue. In this chapter, we review what is known about the involvement of dopaminergic systems in LID and the way in which dopaminergic therapy can be used to avoid the onset of LID or to reverse or suppress involuntary movements once these have been established. The involvement of specific dopamine receptor subtypes, continuous dopaminergic stimulation (CDS) and continuous drug delivery (CDD) is reviewed. However, a major role is emerging in the avoidance and suppression of LID through the use of nondopaminergic mechanisms and we consider the present and future use of glutamatergic drugs, serotoninergic agents, adenosine antagonists and others as a means of improving therapy. There is compelling basic science supporting a role for nondopaminergic approaches to LID but at the moment the translational benefit to PD is not being achieved as predicted. There needs to be further consideration of why this is the case and how in future, both experimental models of dyskinesia and clinical trial design can be optimized to ensure success.

Parkinson's disease (PD) is a degenerative movement disorder resulting from the loss of dopaminergic neurons in the substantia nigra pars compacta. The most widely used treatment for PD is administration of the dopamine precursor L-DOPA, although this eventually results in uncontrolled involuntary movements (dyskinesia) that can be more debilitating than the underlying disease itself. The causes of L-DOPA-induced dyskinesia are unclear, but probably involve non-physiological pulsatile stimulation of dopamine receptors or non-physiological dopamine release (eg, from serotonergic nerve terminals) in the striatum. In any case, this signaling leads to an imbalance in the activity of two basal ganglia pathways, the 'direct' and 'indirect' striatal output pathways, that are characterized by distinct neurochemical architectures. The wide range of neurotransmitter and neuromodulatory receptors present on these two striatal output pathways offers a huge range of potential therapeutic targets. Two main strategies for the treatment of dyskinesia exist: the use of drugs that can be given as an adjunct to L-DOPA, reducing the occurrence of dyskinesia without impairing its antiparkinsonian effect, or therapies with equal antiparkinsonian action as L-DOPA that do not elicit dyskinesia. Novel treatments for dyskinesia in clinical/preclinical development include A(2alpha) receptor antagonists, alpha(2) adrenoceptor antagonists, mu-opioid receptor antagonists and subtype-selective NMDA antagonists. Future research strategies are likely to focus on the molecular mechanisms underlying the emergence of dyskinesia and may lead to the development of agents that can prevent or reverse the cellular changes underlying this phenomenon.