ABSTRACT
Parkinson’s disease (PD) is a chronic, neurodegenerative disease associated with a progressive loss of nigrostriatal dopamine neurons and resultant reduced striatal dopamine concentration.1 The cardinal motor features of PD are tremor, bradykinesia, and rigidity. Levodopa, the chemical precursor of dopamine, remains the cornerstone of antiparkinsonian therapy, although its long-term use is hampered by the induction of motor complications including end-of-dose wearing off and dyskinesia.2,3 Although levodopa has a short serum half-life, patients initially experience a sustained clinical response through the day, presumably due to the ability of remaining nigrostriatal neurons to take up levodopa, convert it to dopamine, and then store and release dopamine into the synaptic cleft over time.4,5 As more and more dopamine neurons are lost, this storage and release capacity is diminished, and patients nd that they improve for a few hours after taking levodopa and then the clinical benet wears off. Ultimately, patients become dependent on a constant inŸux of levodopa into the brain, and clinical response Ÿuctuates in concert with serum levodopa. Many patients also develop choreiform, twisting-turning movements, called dyskinesia, that occur during dopamine peaks. The development of dyskinesia is related to both disease progression and exposure to medications, particularly levodopa.6-8 It is thought that exposing postsynaptic dopamine receptors to Ÿuctuating dopamine stimulation is a key factor in the development of dyskinesia.9,10
Levodopa has a serum half-life (t1/2) of approximately 60 min.11,12 It is predominantly metabolized by the enzymes dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT).13 When orally administered by itself, only 1% of levodopa passes into the brain, and there is a high incidence of nausea and vomiting due to the peripheral formation of dopamine.14,15 When levodopa is combined with a DDC inhibitor such as carbidopa, the half-life of levodopa is extended to approximately 90 min, and the incidence of nausea and vomiting is greatly reduced.16-18 Approximately 5%–10% of orally administered levodopa reaches the brain when it is administered with a DDC inhibitor.19
