The α₂ adrenergic antagonist fipamezole improves quality of levodopa action in Parkinsonian primates.
Reduction in the antiparkinsonian benefit of levodopa is a major complication of long-term levodopa treatment in advanced Parkinson's disease (PD). Such loss of benefit arises because of reduced duration of action and appearance of disabling dyskinesia. We assess the potential of the α(2) adrenergic antagonist fipamezole to reduce motor complications in parkinsonian macaques. MPTP-lesioned macaques were treated acutely with fipamezole (10 mg/kg) alone and in combination with two doses of levodopa. Fipamezole extended both duration and quality of antiparkinsonian action of levodopa. Duration of antiparkinsonian action, on time, was increased by up to 75% while "good-quality" on time, i.e., that not associated with disabling dyskinesia, was increased by up to 98%. Combination of fipamezole with the lower dose of levodopa provided antiparkinsonian benefit at least equivalent to that provided by the higher dose levodopa alone. However, with the combination, antiparkinsonian benefit was of much better quality. The proportion of on time without disabling dyskinesia (79%) was significantly greater than that with high dose levodopa alone (45%). Increased duration and quality of levodopa action may represent therapeutically valuable actions of α(2) adrenergic antagonists.
Johnston
Tom H
TH
Division of Brain, Imaging, and Behaviour-Systems Neuroscience, Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Canada.
Fox
Susan H
SH
Piggott
Matthew J
MJ
Savola
Juha-Matti
JM
Brotchie
Jonathan M
JM
D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D004185:Disability Evaluation; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination / Q000379:methods; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D013997:Time Factors
D058669:Adrenergic alpha-2 Receptor Antagonists; D015259:Dopamine Agents; D007093:Imidazoles; D007189:Indans; D007980:Levodopa; C480818:fipamezole