Oral and infusion levodopa therapy in the management of Parkinson's disease

Abstract

Introduction: The clinical diagnosis of Parkinson’s disease (PD) is based on the identification of bradykinesia and at least one additional feature among rigidity, resting tremor and postural instability. These clinical features have been estimated to appear when at least 50% of the nigral dopamine neurons and 70% of putaminal dopamine tissue contents are lost [1]. Dopaminergic imaging suggests that at least 30% of the dopamine storage capacity (measured by 18 F-DOPA uptake) and 50% of putamen dopamine transporters have been lost by the onset of contralateral limb bradykinesia and rigidity [2]. In addition to the above motor symptoms, a number of nonmotor symptoms are associated with PD. These include gastrointestinal, cardiovascular, urological and psychiatric symptoms, as well as problems with vision, pain and sleep [3]. There is general agreement that the typical motor features of PD depend on putaminal dopamine depletion. Indeed, these features respond well to dopaminergic treatments, the most effective being levodopa (l-DOPA), a dopamine precursor that can cross the blood-brain barrier. Treatment with levodopa contributes significantly to improvements in the quality of life of people with PD and increases their expected life length (reviewed in [4]). Moreover, treatment with peroral levodopa is relatively well tolerated and inexpensive [5]. Many of nonmotor symptoms may also respond to levodopa treatment [3]. Because of the above reasons, levodopa is currently considered the “gold standard” for the symptomatic treatment of PD [4, 5]. However, the response to levodopa changes with disease progression, becoming complicated by motor fluctuations and dyskinesias in a majority of patients within a few years. As will be discussed below, these motor complications can become disabling, calling for a reduction in oral levodopa dosage and/or for its replacement with advanced invasive treatments. Moreover, levodopa is poorly effective against clinical features that mainly depend on the degeneration of nondopaminergic systems. These include some nonmotor symptoms as well as motor features that occur in advanced disease stages, such as freezing of gait and falls [6]. In this chapter, we will review the history of levodopa pharmacotherapy in PD, the complications of this therapy, the options currently available to optimize oral treatment with levodopa, and recent advances in developing methods for a more continuous levodopa delivery. (Less)