Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naive primates.
Long-acting dopamine agonist drugs induce a lower incidence of dyskinesia in MPTP-treated primates and patients with Parkinson's disease compared to pulsatile treatment with levodopa, supporting the concept of continuous dopaminergic stimulation as a means of dyskinesia avoidance. We examined the effects of L-dopa administered with or without the COMT inhibitor entacapone on dyskinesia induction in previously untreated MPTP-treated common marmosets. Administration of L-dopa (12.5 mg/kg p.o.) plus carbidopa twice daily produced fluctuating improvement in motor behavior coupled with dyskinesia. Coadministration with entacapone produced similar patterns of motor improvement and dyskinesia that were not different from that produced by L-dopa alone. Treatment with L-dopa (6.25 mg/kg p.o.) plus carbidopa four times daily reversed motor disability and induced dyskinesia in a manner that was not different from the twice-daily treatment regimens. However, coadministration with entacapone produced more continuous improvement in locomotor activity with less dyskinesia than animals treated with L-dopa four times daily alone. These data support the notion that pulsatile stimulation contributes to the development of dyskinesia and suggests that more frequent dosing of L-dopa plus entacapone may be a useful treatment strategy for patients in the early stages of Parkinson's disease.
Smith
Lance A
LA
Neurodegenerative Diseases Research Centre, GKT School of Biomedical Sciences, King's College, London, United Kingdom.
Jackson
Michael J
MJ
Al-Barghouthy
Ghassan
G
Rose
Sarah
S
Kuoppamaki
Mikko
M
Olanow
Warren
W
Jenner
Peter
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002144:Callithrix; D002230:Carbidopa / Q000008:administration & dosage / Q000627:therapeutic use*; D002396:Catechols / Q000008:administration & dosage / Q000627:therapeutic use*; D015259:Dopamine Agents / Q000009:adverse effects*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000175:diagnosis / Q000209:etiology* / Q000517:prevention & control*; D005260:Female; D007279:Injections, Subcutaneous; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use*; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D009570:Nitriles; D012720:Severity of Illness Index; D013378:Substantia Nigra / Q000187:drug effects; D013997:Time Factors
D000978:Antiparkinson Agents; D002396:Catechols; D015259:Dopamine Agents; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002230:Carbidopa