Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease.
BACKGROUND
Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy.


OBJECTIVE
To establish whether a selective D(1) 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 D(1) 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.


CONCLUSIONS
Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.
Rascol
O
O
Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 37 Allées Jules Guesde, 31073 Toulouse Cedex, France. rascol@cict.fr
Nutt
J G
JG
Blin
O
O
Goetz
C G
CG
Trugman
J M
JM
Soubrouillard
C
C
Carter
J H
JH
Currie
L J
LJ
Fabre
N
N
Thalamas
C
C
Giardina
W W
WW
Wright
S
S
D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D018491:Dopamine Agonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004409:Dyskinesia, Drug-Induced; D005260:Female; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000009:adverse effects
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D011355:Prodrugs; D011725:Pyridines; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; D007980:Levodopa; C095428:adrogolide hydrochloride