Clinical implications of sustained dopaminergic stimulation

Fluctuations in motor performance are the major problems in chronic management of Parkinson's disease. Most of these fluctuations reflect the decline of levodopa availability. As a consequence, levodopa dosage might be increased and the interdose interval progressively shortened. The postsynaptic dopamine receptors at this point are exposed to a nonphysiologic shift in dopamine level, which may induce changes at the receptor site and contribute to the appearance of 'on-off' phenomena and dyskinesias. We compared a group of 18 patients treated for 60 consecutive months with continuous subcutaneous lisuride infusion with a group of 20 patients treated with conventional oral levodopa treatment. The clinical evaluations performed during the study showed in the lisuride group only a worsening of dyskinesias, whereas the other symptoms remained unchanged. In the other group the evaluation scores showed a significant worsening of all long-term treatment complications. The slow-release preparations of levodopa may ensure a more continuous dopaminergic stimulation than standard formulations. However, the use of these compounds is difficult in severely fluctuating patients because the lack of a plasma peak level usually leads to a very long delay before patients turn 'on.' We studied the pharmacokinetic and clinical effects of the two slow-release preparations of levodopa [Madopar HBS and Sinemet controlled-release (CR)] and a combination of Sinemet CR plus standard Sinemet in 13 fluctuating parkinsonian patients. The results of this study show that the combination of standard Sinemet and Sinemet CR ensures a more prolonged clinical effect with a very short latency to the 'on' phase.