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Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys.
Parkinsonism Relat Disord. 2009 Jul; 15(6):445-52.PR

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+Show Affiliations

Molecular Endocrinology and Oncology Research Center, CHUQ, CHUL Pavillon and Faculty of Pharmacy, Laval University 2705 Laurier Blvd, Québec, PQ, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19196540

Citation

Grégoire, Laurent, et al. "Low Doses of Sarizotan Reduce Dyskinesias and Maintain Antiparkinsonian Efficacy of L-Dopa in Parkinsonian Monkeys." Parkinsonism & Related Disorders, vol. 15, no. 6, 2009, pp. 445-52.
Grégoire L, Samadi P, Graham J, et al. Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys. Parkinsonism Relat Disord. 2009;15(6):445-52.
Grégoire, L., Samadi, P., Graham, J., Bédard, P. J., Bartoszyk, G. D., & Di Paolo, T. (2009). Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys. Parkinsonism & Related Disorders, 15(6), 445-52. https://doi.org/10.1016/j.parkreldis.2008.11.001
Grégoire L, et al. Low Doses of Sarizotan Reduce Dyskinesias and Maintain Antiparkinsonian Efficacy of L-Dopa in Parkinsonian Monkeys. Parkinsonism Relat Disord. 2009;15(6):445-52. PubMed PMID: 19196540.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys. AU - Grégoire,Laurent, AU - Samadi,Pershia, AU - Graham,Julie, AU - Bédard,Paul J, AU - Bartoszyk,Gerd D, AU - Di Paolo,Thérèse, Y1 - 2009/02/03/ PY - 2008/09/04/received PY - 2008/10/27/revised PY - 2008/11/01/accepted PY - 2009/2/7/entrez PY - 2009/2/7/pubmed PY - 2009/9/18/medline SP - 445 EP - 52 JF - Parkinsonism & related disorders JO - Parkinsonism Relat Disord VL - 15 IS - 6 N2 - 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. SN - 1873-5126 UR - https://www.unboundmedicine.com/medline/citation/19196540/Low_doses_of_sarizotan_reduce_dyskinesias_and_maintain_antiparkinsonian_efficacy_of_L_Dopa_in_parkinsonian_monkeys_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1353-8020(08)00310-6 DB - PRIME DP - Unbound Medicine ER -