The role of istradefylline in the Parkinson’s disease armamentarium

ABSTRACT

Introduction

Adenosine antagonism, i.e. of the A_2A receptor, improves dopamine-sensitive motor behavior in patients with Parkinson’s disease with oral levodopa-associated motor complications. Only the xanthine derivative istradefylline is currently approved in Japan and in the US. This compound easily crosses the blood–brain barrier and shows high affinity to A_2A receptors.

Areas covered

This narrative review discusses the place of istradefylline in the current available drug portfolio for Parkinson’s disease following a literature research in PubMed.

Expert opinion

Istradefylline is safe and well tolerated. Its efficacy was pronounced, when patients were on a lower chronic oral levodopa regimen. Levodopa causes a homocysteine elevation, which reflects an impaired methylation potential. As a result, an upregulation of A_2A receptor occurs and weakens the efficacy of istradefylline as modulator of dopamine effects on motor behavior in Parkinson’s disease. This is the hypothetical reason why clinical trials failed, when patients were on a higher chronic levodopa regimen.

A way out of this dilemma is to enable higher dosing of istradefylline and substitution of L-dopa with compounds, which do not influence the methylation capacity. Long-term trials may show these levodopa sparing and thus motor complications delaying effects of istradefylline.

Plain Language Summary

Stimulation of adenosine receptors antagonizes the beneficial effects of dopamine on movement. Accordingly, the adenosine receptor antagonist istradefylline was approved for the treatment of advanced patients with Parkinson’s disease, who were treated with levodopa, the blood–brain barrier trespassing precursor of dopamine. Patients have to suffer from so-called levodopa-associated motor complications, which are characterized by intervals with good and bad motor behavior. Clinical trials showed that istradefylline co-administration improved these fluctuations of movement. This review aims to define a broader role and potential of istradefylline for the treatment armamentarium of Parkinson’s disease. Increasing dosing of levodopa weakens the methylation potential in the brain as a result of the methyl group consuming conversion of levodopa to 3-O-methyldopa in glial cells. Impaired methylation causes an upregulation of adenosine receptors. This augmented availability of adenosine receptors weakens the effects of istradefylline. Therefore, clinical trials in patients with a higher levodopa dosage failed in contrast to studies with patients on a lower levodopa dose. This review suggests long-term investigations, which aim to demonstrate that istradefylline has the potential to delay the need for levodopa in the treatment of patients with Parkinson’s disease.

KEYWORDS:

• L-dopa
• adenosine
• istradefylline
• Parkinson’s disease
• dopamine substitution

Article highlights

• A_2A receptor antagonism with istradefylline [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione] ameliorates motor behavior and oral levodopa-associated motor complications in patients with Parkinson’s disease.

• Orally administered istradefylline is approved in Japan and in the US.

• An upregulation of A_2A receptors occurs as a consequence of an impaired methylation potential, triggered by higher central levodopa availability and its methyl group consuming conversion to 3-O-methyldopa in glial cells.

• The higher A_2A receptor availability weakens the istradefylline efficacy.

• Higher dosing of istradefylline and sparing of levodopa with compounds, which do not weaken the central methylation potential, will hypothetically contribute to a lower increase of dopamine substitution in patients with Parkinson’s disease in the long term.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.