July 2006
Olanow
CW, Obeso JA, Stocchi F
Continuous dopaminergic stimulation is a therapeutic strategy for the
management of Parkinson's disease, which proposes that dopaminergic
agents that provide continuous stimulation of striatal dopamine
receptors will delay or prevent the onset of levodopa-related motor
complications.
Dopaminergic neurons in the basal ganglia normally fire
in a random but continuous manner, so that striatal dopamine
concentrations are maintained at a relatively constant level. In the
dopamine-depleted state, however, intermittent oral doses of levodopa
induce discontinuous stimulation of striatal dopamine receptors. This
pulsatile stimulation leads to molecular and physiologic changes in
basal ganglia neurons and the development of motor complications.
These
effects are reduced or avoided when dopaminergic therapies are delivered
in a more continuous and physiologic manner. Studies in primate models
and patients with Parkinson's disease have shown that continuous or
long-acting dopaminergic agents are associated with a decreased risk of
motor complications compared with short-acting dopamine agonists or
levodopa formulations.
Continuous dopaminergic stimulation can be
achieved with a continuous infusion, but infusion therapies are
cumbersome and not likely to be acceptable to patients with early
disease. The current challenge is to develop a long-acting oral
formulation of levodopa that provides comparable anti-parkinsonian
benefits without motor complications.
