title: Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease: a dose-finding study.
abstract: 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.
authors: 1 Department of Clinical Neuroscience and Neurology, Karolinska Institutet, 17177 Stockholm, Sweden per.svenningsson@ki.se.
authors: Per
authors: P
authors: Svenningsson
authors: 2 Division of Neurology, Department of Clinical Sciences, Lund University, Skane University Hospital, 221 84 Lund, Sweden.
authors: Carl
authors: C
authors: Rosenblad
authors: 1 Department of Clinical Neuroscience and Neurology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors: Karolina
authors: K
authors: Af Edholm Arvidsson
authors: 2 Division of Neurology, Department of Clinical Sciences, Lund University, Skane University Hospital, 221 84 Lund, Sweden.
authors: Klas
authors: K
authors: Wictorin
authors: 3 Amarantus BioScience Holdings, Inc., San Francisco, CA 94111, USA.
authors: Charlotte
authors: C
authors: Keywood
authors: 4 Psychogenics, Inc., Tarrytown, NY 10591, USA.
authors: Bavani
authors: B
authors: Shankar
authors: 4 Psychogenics, Inc., Tarrytown, NY 10591, USA.
authors: David A
authors: DA
authors: Lowe
authors: 5 Neurobiology Unit, Wallenberg Neuroscience Centre, Lund University, 221 84 Lund, Sweden.
authors: Anders
authors: A
authors: Björklund
authors: 2 Division of Neurology, Department of Clinical Sciences, Lund University, Skane University Hospital, 221 84 Lund, Sweden.
authors: Håkan
authors: H
authors: Widner
mesh_terms: D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004409:Dyskinesia, Drug-Induced / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy*; D010879:Piperazines / Q000097:blood / Q000627:therapeutic use*
chemical_list: D010879:Piperazines; D007980:Levodopa; C063828:eltoprazine
keywords: Parkinson’s disease; dyskinesias; eltoprazine; l-DOPA; serotonin