Objective/Rationale:
The primary objective of this proposal is to determine if a prodrug of acamprosate could inhibit L-DOPA induced dyskinesias (LID). Functional interactions between the dopamine and glutamate neurotransmission pathways are thought to play a role in the induction and maintenance of LID. Acamprosate calcium has been shown to inhibit glutamate release and is used clinically for the treatment of alcohol relapse. XenoPort-sponsored studies have previously shown that acamprosate has the ability to block LID in a pre-clinical model of Parkinson’s disease.
Project Description:
Acamprosate has low oral bioavailability and can cause gastrointestinal (GI) disturbances (emesis and nausea) following administration as Campral® tablets. To address these limitations XenoPort has designed a novel prodrug of acamprosate that is more readily absorbed after oral administration. This allows a similar or higher exposure to acamprosate to be achieved with a lower dose. The main goal of this project will be to demonstrate that after oral administration a prodrug of acamprosate effectively and safely reduces LID in a pre-clinical model of this condition. The study will also ensure that the anti-LID efficacy of acamprosate does not interfere with the anti-parkinsonian effect of L-DOPA treatment.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Levodopa/carbidopa (LD/CD) is currently the most effective treatment for the motor symptoms of Parkinson’s disease. Unfortunately, this therapy is complicated by inducing potentially disabling involuntary movements or LID. While not specifically approved for the treatment of LID, amantadine has been shown to decrease LID and is frequently prescribed off-label for this indication. However side effects may limit its use and given this limitation there is a clear need for improved therapy for the treatment of LID. This project will provide validation of a new potential treatment strategy that hopefully will provide better efficacy and tolerability for patients with LID.
Anticipated Outcome:
A positive outcome in this study would validate the approach of using an acamprosate prodrug for the treatment of LID and provide further rationale for additional development activities.
Progress Report
The main goal of this project was to determine if after oral administration a prodrug of acamprosate effectively and safely reduced levodopa induced dyskinesias (LID) in animal pre-clinical model of this condition without interfering with the anti-Parkinsonian efficacy of levodopa (LD). The acamprosate prodrug, XP23741, was administered in a repeated escalating dose manner. Efficacy was observed against LID, and no reduction in the anti-parkinsonian efficacy of LD was observed at the highest dose tested. However, the efficacy for the acamprosate prodrug was less than was observed with an active comparator, the mGluR5 antagonist fenobam. Fenobam has been studied in a number of clinical trials for conditions other than LID. Efforts are currently underway at the Parkinson’s Institute to further characterize the effects of fenobam in the pre-clinical model of LID and to determine if the drug is efficacious at doses that do not cause unwanted side effects.