Disease Progression in Parkinsonís Disease Ė Evidence for Protective Effects of Drug Treatment
N.Holford (1), P.Chan (1), J.Nutt (2)
(1) Department of Pharmacology & Clinical Pharmacology, University of Auckland, New Zealand; (2)Department of Neurology, Oregon Health Sciences University, USA
Objectives: The effects of drug treatment on the progression of Parkinsonís disease have been studied in large clinical trials but no conclusion has been reached about their protective effects. This study investigated the time course of the Unified Parkinsonís Disease Response Scale (UPDRS) in a large cohort of patients over 8 years to describe disease progression and drug effects.
Methods: 800 patients enrolled in the DATATOP study were followed for up to†8 years. Time and drug treatments were used to model the progression of 15,236 UPDRS observations†with NONMEM using the first order conditional method.
Results: The progression of UPDRS was adequately described by a linear model. An improvement in objective function was obtained with a Gompertz function which predicted an asymptotic Ďburn-outí state. Levodopa, deprenyl, bromocriptine and pergolide had both symptomatic and protective effects. The symptomatic effects of levodopa were greater than the other drugs but protective effects were similar. The efficacy (Emax) of levodopa increased with time reaching its peak about†2 years after initial entry. The combination of levodopa and deprenyl had a greater protective effect than predicted from their separate effects.
Conclusions: Modelling disease progression has revealed both expected and unexpected features of drug action in Parkinsonís disease. The model has been used successfully to predict the outcome of a trial designed to detect a protective effect of levodopa .
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