Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys.
Dyskinesia is an important complication of treatment in Parkinson's disease (PD). Sarizotan, a 5-HT(1A) agonist with high affinity for D3 and D4 receptors was investigated on L-Dopa-induced dyskinesia (LID) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. Five MPTP female cynomolgus monkeys (Macaca fascicularis) with a moderate to severe parkinsonian syndrome and LID were used. Sarizotan 0.2, 1, and 2 mg/kg administered alone did not worsen parkinsonian symptoms; there were no effect on locomotor counts or on normal behavior of the monkeys. Sarizotan 0.2, 1, and 2 mg/kg administered 30 min before a fixed dose of L-Dopa (25-30 mg/kg s.c.) + benserazide (50 mg) did not affect the antiparkinsonian response to L-Dopa. However, mean dyskinetic scores were significantly reduced with sarizotan 1 and 2 mg/kg but not at 0.2 mg/kg. Higher doses of sarizotan (4 and 8 mg/kg, administered immediately before L-Dopa) reduced L-Dopa-induced locomotor response in all monkeys. A pharmacokinetic investigation in these monkeys showed a dose-dependent increase in mean plasma sarizotan concentrations with similar mean plasma concentrations for sarizotan 1 mg/kg alone or with L-Dopa, indicating a lack of sarizotan/L-Dopa interaction. The time course of plasma sarizotan concentrations was associated with time of maximal reduction of dyskinesias. When administered daily for two weeks in combination with L-Dopa in the same MPTP monkeys, sarizotan 1 mg/kg had a sustained antidyskinetic effect while maintaining the antiparkinsonian and locomotor effect of L-Dopa. This detailed sarizotan investigation in MPTP monkeys supports the antidyskinetic activity of this drug and for 5-HT(1A) agonists.
Grégoire
Laurent
L
Molecular Endocrinology and Oncology Research Center, CHUQ, CHUL Pavillon and Faculty of Pharmacy, Laval University 2705 Laurier Blvd, Québec, PQ, Canada.
Samadi
Pershia
P
Graham
Julie
J
Bédard
Paul J
PJ
Bartoszyk
Gerd D
GD
Di Paolo
Thérèse
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology*; D005260:Female; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D009930:Organic Chemicals / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D010052:Ovariectomy / Q000379:methods; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000978:Antiparkinson Agents; D009930:Organic Chemicals; D017366:Serotonin Receptor Agonists; D007980:Levodopa; C443959:sarizotan; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine