Objective/Rationale:
Researchers have identified a new potential drug target — receptors located on the serotonin neurons in the brain — for alleviation of involuntary movements, dyskinesias, in Parkinson's disease (PD) patients, who can experience dyskinesia as a side effect of their levodopa medication.
Project Description:
Based on results obtained in pre-clinical studies, this team will now conduct a exploratory clinical trial in a group of 24 Parkinson's patients. Researchers have shown that the abnormal dyskinesia-inducing dopamine release can be effectively blocked by drugs that act on the 5-HT1A and 5-HT1B receptors, located on the serotonin neurons, and that this blocking effect is particularly prominent when the two receptors are activated simultaneously. Eltoprazine, the drug chosen for this trial, possesses such combined receptor activity and has shown very promising results in pre-clinical trials.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
Levodopa is the most commonly used medication by PD patients, but, as the disease progresses, it can be the cause of debilitating dyskinesias. The effects of levodopa, both positive and negative, are caused by its conversion to dopamine in the brain. In patients with moderately advanced disease the conversion to dopamine takes place mainly in the remaining dopamine neurons and their axon terminals in the striatum. As the disease progresses, and fewer and fewer dopamine terminals survive, another neuron system kicks in: the serotonin neurons. The serotonin neurons are capable of converting levodopa to dopamine, and store and release the newly synthesized dopamine as a “false transmitter,” but in a non-physiological manner. Studies in multiple pre-clinical models of the disease have shown that that the dyskinetic movements induced by repetitive, low doses of levodopa are triggered by such “dysregulated” dopamine release from the spared serotonin neurons.
Anticipated Outcome:
The purpose of this study is, first, to clarify whether similar positive effects on levodopa-induced dyskinesias can be obtained also in patients, and second, to establish the optimal dose of the drug to be used in further trials where the drug is given over extended periods of time.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
Final Outcome
The study included 18 patients with idiopathic Parkinson´s disease who expressed dyskinesia in response to their regular levodopa medication. In each of five test sessions the patients received, in randomized order, either placebo or Eltoprazine at one of three doses, 2.5, 5.0 or 7.5 mg, administered together with levodopa. The severity of dyskinesia induced by the single levodopa dose, and the effect on the underlying parkinsonian symptoms, were assessed by blind scoring from video recordings by two independent assessors. The results show that Eltoprazine at the two highest doses, 5.0 and 7.5 mg, induced a significant reduction of levodopa-induced dyskinesia, on average by approximately 10-15 percent. At none of the doses did Eltoprazine interfere with the anti-parkinsonian effect of the treatment. No serious side effects were recorded. The results provide preliminary evidence that Eltoprazine can have beneficial effects on the dyskinetic side effects of levodopa medication when administered concomitantly with levodopa.
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