Combination treatment of the partial D2 agonist terguride with the D1 agonist SKF 82958 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian cynomolgus monkeys.
The optimal combination of a dopamine D2 agonist and a D1 agonist was evaluated for symptomatic treatment of Parkinson's disease. Behavioral effects of combination treatment of the full D2 agonist quinpirole or the partial D2 agonist terguride with the full D1 agonist SKF 82958 [(I) 6-Chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2, 3, 4, 5-tetra-hydro-1H-3-benzazepine] were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity such as irritability, excitability and aggressiveness and of dyskinesias such as licking of paws, chewing and biting. Both quinpirole and SKF 82958 alone improved the parkinsonism with a slight induction of the hyperactivity and dyskinesias. Terguride also improved the parkinsonism but did not induce the hyperactivity and dyskinesias. Combination treatment of quinpirole with SKF 82958 not only showed a tendency to augment the antiparkinsonian effects but also induced the marked hyperactivity and dyskinesias. On the other hand, combination treatment of terguride with SKF 82958 also augmented the antiparkinsonian effects but did not induce any hyperactivity and dyskinesias. These findings suggest that combination therapy with a partial D2 agonist and a full D1 agonist or monotherapy with a dopamine agonist that has both partial D2 and full D1 agonist properties might be beneficial for treating motor dysfunction in Parkinson's disease without inducing dopaminergic side effects.
Akai
T
T
Research Department, Institute of Pharma Research, Development and Medical Science, Osaka, Japan.
Ozawa
M
M
Yamaguchi
M
M
Mizuta
E
E
Kuno
S
S
D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage*; D018491:Dopamine Agonists / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D008090:Lisuride / Q000008:administration & dosage / Q000031:analogs & derivatives*; D020267:MPTP Poisoning; D008252:Macaca fascicularis; D010300:Parkinson Disease / Q000188:drug therapy*; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000819:agonists*
D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C006208:dironyl; C071262:SK&F 82958; D008090:Lisuride