Cargando…

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study

In advanced stages of Parkinson’s disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskine...

Descripción completa

Detalles Bibliográficos
Autores principales: Svenningsson, Per, Rosenblad, Carl, af Edholm Arvidsson, Karolina, Wictorin, Klas, Keywood, Charlotte, Shankar, Bavani, Lowe, David A., Björklund, Anders, Widner, Håkan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014080/
https://www.ncbi.nlm.nih.gov/pubmed/25669730
http://dx.doi.org/10.1093/brain/awu409
_version_ 1782452246158508032
author Svenningsson, Per
Rosenblad, Carl
af Edholm Arvidsson, Karolina
Wictorin, Klas
Keywood, Charlotte
Shankar, Bavani
Lowe, David A.
Björklund, Anders
Widner, Håkan
author_facet Svenningsson, Per
Rosenblad, Carl
af Edholm Arvidsson, Karolina
Wictorin, Klas
Keywood, Charlotte
Shankar, Bavani
Lowe, David A.
Björklund, Anders
Widner, Håkan
author_sort Svenningsson, Per
collection PubMed
description In advanced stages of Parkinson’s disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson’s disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson’s disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson’s Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [–1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [–0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [–1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson’s Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson’s disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias.
format Online
Article
Text
id pubmed-5014080
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-50140802016-09-12 Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study Svenningsson, Per Rosenblad, Carl af Edholm Arvidsson, Karolina Wictorin, Klas Keywood, Charlotte Shankar, Bavani Lowe, David A. Björklund, Anders Widner, Håkan Brain Original Articles In advanced stages of Parkinson’s disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson’s disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson’s disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson’s Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [–1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [–0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [–1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson’s Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson’s disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias. Oxford University Press 2015-04 2015-02-05 /pmc/articles/PMC5014080/ /pubmed/25669730 http://dx.doi.org/10.1093/brain/awu409 Text en © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Svenningsson, Per
Rosenblad, Carl
af Edholm Arvidsson, Karolina
Wictorin, Klas
Keywood, Charlotte
Shankar, Bavani
Lowe, David A.
Björklund, Anders
Widner, Håkan
Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study
title Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study
title_full Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study
title_fullStr Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study
title_full_unstemmed Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study
title_short Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study
title_sort eltoprazine counteracts l-dopa-induced dyskinesias in parkinson’s disease: a dose-finding study
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014080/
https://www.ncbi.nlm.nih.gov/pubmed/25669730
http://dx.doi.org/10.1093/brain/awu409
work_keys_str_mv AT svenningssonper eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT rosenbladcarl eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT afedholmarvidssonkarolina eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT wictorinklas eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT keywoodcharlotte eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT shankarbavani eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT lowedavida eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT bjorklundanders eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy
AT widnerhakan eltoprazinecounteractsldopainduceddyskinesiasinparkinsonsdiseaseadosefindingstudy