Disease progression, drug action and Parkinson’s disease: Why time cannot be ignored

Abstract

A clinician administers medications both seeking immediate benefits but also calculating the long-term effects of the medications on the course of the disease. It is this attempt to anticipate the effects of the drugs on the course of the disease that has created the most uncertainty and controversy in the field of Parkinson’s disease (PD) therapeutics. The challenge has been to disentangle symptomatic drug effects, long-term adverse effects and disease progression. We have previously described a pharmacological interpretation of the effects of levodopa in PD [1]. That review focussed on the time course of motor effects within a dosing interval of minutes to hours and identified the pharmacological features of effects of levodopa that might distinguish the clinical patterns of stable and fluctuating response. In particular, we pointed out that the shorter equilibration half-life of levodopa in fluctuating patients was the most influential single parameter explaining the differing time course of response in these patient groups. In the decade that has passed we have taken a longer term view of the response to levodopa and studied its evolution in cohorts of patients over several years [2–6]. This long-term approach has enabled us to identify and describe new features of the clinical pharmacology of levodopa in which we have relied heavily on appreciating the role of the passage of time on a longer time scale than the dosing interval. Our approach involves examining changes in the response to antiparkinsonian medications as well as progression of the disease as measured by clinical function over years. Our aim here is to summarize these findings and propose a further level of integration of a model for levodopa pharmacodynamics in PD and discuss its implications for long-term treatment strategies and the evaluation of new treatments.