Pathogenetic studies of motor fluctuations in Parkinson's disease

Pharmacokinetic and pharmacodynamic mechanisms for levodopa have been studied in relation to the pathogenesis of the motor fluctuations which complicate advanced Parkinson's disease. Since levodopa clearance from the general circulation was found to be similar in patients with wearing-off or on-off phenomena and those with a stable response to levodopa, peripheral pharmacokinetic factors are unlikely to be involved. Efficacy half-time for levodopa, on the other hand, was significantly reduced in patients with mainly wearing-off fluctuations in comparison to those manifesting a stable response to oral levodopa; individuals with predominantly on-off phenomenon had an even more extreme reduction in the duration of the antiparkinsonian action of levodopa. Conversion from oral to intravenous levodopa treatment immediately stabilized plasma levodopa levels in both the wearing-off and on-off groups; motor variability also decreased, especially in those with wearing-off phenomenon. During 11 days of continuous intravenous levodopa therapy, additional reductions in motor fluctuations occurred in both groups, but at a significantly faster rate in patients with wearing-off than in those with on-off responses. These results suggest that wearing-off phenomenon may arise as a consequence of the degeneration of dopamine terminals due to natural disease progression with a resultant inability to buffer variations in levodopa availability; on-off phenomenon, may reflect additional postsynaptic dopamine receptor dysregulation, possibly in response to the resultant, nonphysiologic fluctuations in synaptic dopamine.