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Induction by Dopamine D1 Receptor Agonist ABT-431 of Dyskinesia Similar to Levodopa in Patients With Parkinson Disease
O. Rascol, MD, PhD;
J. G. Nutt, MD;
O. Blin, MD, PhD;
C. G. Goetz, MD;
J. M. Trugman, MD;
C. Soubrouillard, MD;
J. H. Carter, MD, ANP;
L. J. Currie, MD;
N. Fabre, MD;
C. Thalamas, MD;
W. J. Giardina, PhD;
S. Wright, MD, PhD
Arch Neurol. 2001;58:249-254.
Background Dyskinesias are a frequent adverse effect of long-term levodopa therapy.
The relative contribution of dopamine D1 and D2 receptor
function to the pathophysiology of levodopa-induced dyskinesias remains a
matter of controversy.
Objective To establish whether a selective D1 dopamine agonist induces
more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson
disease.
Methods We studied ABT-431, the prodrug of a fully selective D1 agonist,
in 20 subjects with advanced Parkinson disease and a fluctuating response
to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind,
randomized design (French centers); 12, in an open, randomized design (US
centers). We assessed and compared the antiparkinsonian (Unified Parkinson's
Disease Rating Scale) and dyskinetic (response induced by an acute challenge
of a suprathreshold dose of levodopa and by 4 different ascending doses (5,
10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge.
Results The separate analysis of the double-blind and open data led to the same
findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431
were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited
similar antiparkinsonian benefit and produced similar dyskinesias as levodopa.
Conclusion Dopamine D1 agonists can induce a full antiparkinsonian response
but do not support previous hypotheses suggesting that D1 agonists
are more or less likely to produce dyskinesias than levodopa.
From the Clinical Investigation Centre, Departments of Neurology and
Pharmacology, Institut National de la Santé et de la Recherce Médicale
U 455, Toulouse University Hospital, Toulouse, France (Drs Rascol, Fabre,
and Thalamas); the Department of Neurology, Oregon Health Sciences University,
Portland (Drs Nutt and Carter); the Centre of Clinical Pharmacology and Experimental
Therapeutics, Marseille University Hospital, Marseille, France (Drs Blin and
Soubrouillard); the Section of Movement Disorders, Department of Neurological
Sciences, Rush–Presbyterian–St Luke's Hospital, Chicago, Ill (Dr
Goetz); the Department of Neurology, University of Virginia Health Sciences
Center, Charlottesville (Drs Trugman and Currie); and Neurological and Urological
Diseases Research, Abbott Laboratories, Abbott Park, Ill (Drs Giardina and
Wright). Drs Rascol and Blin received a consultancy honorarium from Abbott
Laboratories to conduct this trial.
Corresponding author and reprints: O. Rascol, MD, PhD, Laboratoire
de Pharmacologie Médicale et Clinique, Faculté de Médecine,
37 Allées Jules Guesde, 31073 Toulouse Cedex, France (e-mail: rascol{at}cict.fr).
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