Peter A. LeWitt, M.D.

In 1957, Arvid Carlsson reported on experiments in an animal model of Parkinsonism that eventually led to the use of levodopa as a symptomatic treatment for Parkinson's disease (PD). This amino acid precursor of levodopa is taken up in the gut by a facilitated transport mechanism that also operates through the blood-brain barrier. Once levodopa has gained entry into the brain, it undergoes rapid transformation to dopamine in striatal nerve terminals. Restoration of this deficient neurotransmitter in the Parkinsonian brain has constituted the major therapeutic option for treating PD for almost four decades. For some patients, all symptomatology of PD can be reversed temporarily from this drug. Although still the mainstay of PD therapeutics, levodopa presents many challenges for long-term use because of various adverse effects that can develop. These include the eventual loss of symptomatic improvements lasting longer than the rise and fall of blood concentrations of the drug (the long-duration effect). Other problems that can arise include the induction of involuntary movements (dyskinesias) that, once initiated, never remit. Patients chronically receiving levodopa can experience prominent wearing-off of benefits between doses, vivid dreams and hallucinations and, rarely, impulse control disorders.

Adjunctive medications that can extend upon the benefits of levodopa (such as inhibitors of monoamine oxidase-B and catechol-O-methyl transferase) have improved its utility for patients with wearing-off responses, the most common problem associated with chronic levodopa therapy. Currently under development are novel means for enhancing its pharmacokinetic profile, including parenteral and transdermal levodopa delivery, and improved sustained-release preparations. Levodopa prod-rugs have also been investigated. A novel therapy currently undergoing a clinical trial was designed for intrastriatal generation of levodopa by means of implanted human retinal cells (Spheramine). Co-administration of a dopaminergic agonist with levodopa have been shown in several clinical trials to lessen the risk for developing involuntary movements and motor fluctuations, though how this is accomplished remains to be learned. Another puzzling aspect of levodopa's neuropharmacology is whether it acts as a neuromodulator independently of its role as a dopamine precursor.

Despite suspicions to the contrary for many years, the current consensus is that levodopa lacks neurotoxicity. A dose-response study investigating for neuroprotective effects against progression of PD (the ELLDOPA study, carried out in North America) provided evidence for this possibil-ity. Based on its potency as a symptomatic action against Parkinsonism, levodopa belongs in the therapeutic armamentarium for treating all stages of this disorder.