Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys.

Abstract

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.

• Authors: Laurent Grégoire, Pershia Samadi, Julie Graham, Paul J Bédard, Gerd D Bartoszyk, Thérèse Di Paolo
• Journal: Parkinsonism & related disorders (Parkinsonism Relat Disord) Vol. 15 Issue 6 Pg. 445-52 (Jul 2009) ISSN: 1873-5126 [Electronic] England
• PMID: 19196540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Organic Chemicals
• Serotonin Receptor Agonists
• Levodopa
• sarizotan
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Animals
• Antiparkinson Agents (adverse effects)
• Behavior, Animal (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Dyskinesia, Drug-Induced (drug therapy, etiology)
• Female
• Levodopa (adverse effects)
• Macaca fascicularis
• Organic Chemicals (metabolism, pharmacokinetics, therapeutic use)
• Ovariectomy (methods)
• Parkinsonian Disorders (chemically induced, drug therapy)
• Serotonin Receptor Agonists (metabolism, pharmacokinetics, therapeutic use)