ABSTRACT
Even though oral levodopa (combined with a peripheral dopa decarboxylase inhibitor) remains the most efficacious symptomatic drug treatment for Parkinson’s disease (PD), it is not devoid of problems. The emergence of motor-response complications in levodopatreated PD patients has puzzled and fascinated neurologists for over 30 years. Sooner or later, most patients eventually experience a predictable (so-called “wearing-off” effect) and less often unpredictable return in parkinsonian disability during the day, associated with nonmotor symptoms (neuropsychiatric, cognitive, or dysautonomic) and various dyskinesias, for reasons that remain elusive. The very short plasma half-life, poor bioavailability, and erratic absorption of oral levodopa are consistently present throughout the illness, and unequivocal changes in the peripheral pharmacokinetic handling of levodopa have never been demonstrated. Thus, attention shifted toward acquired changes in central pharmacokinetic properties (so-called “buffering capacity”) and additional pharmacodynamic factors to explain and eventually correct the fluctuations of the levodopa motor response. Experimental attempts have tried to match the fairly good correlation between stable plasma levels of levodopa and sustained motor response with ways to continuously supply the dopamine precursor by bypassing the oral route.
