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Investigational Drug May Reduce “Off” Time in Parkinson’s

A study conducted in Japan adds new evidence that istradefylline, a drug that has been investigated but not approved in the US, can reduce "off" time in people with Parkinson's disease (PD) who are taking levodopa therapy. The results appear in the March 11 online edition of Movement Disorders

The gold-standard Parkinson's medication, levodopa, works by boosting levels of dopamine, a key chemical messenger, in the brain. But for many people, PD symptoms return in between doses, when levodopa's effects wear off. This fluctuation in the drug's effectiveness is known as "off" time. The experimental drug istradefylline acts on a different molecular pathway involved in controlling movement, and is called an adenosine receptor antagonist.  Several clinical trials have tested whether adding istradefylline to dopamine therapy can even out motor fluctuations and lessen "off" time.

For the new study, researchers led by Yoshikuni Mizuno, M.D., at the Kitasato University School of Medicine, recruited 373 people in Japan with PD movement symptoms ranging from mild to severe. Participants were on average 66 years old and experienced about six hours a day of  "off" time. A little more than half were women. To investigate the effects of two different doses of istradefylline, and compare these with a placebo, the scientists divided the volunteers into three groups. Participants in each group received one of the three treatments in the form of a pill.  


  • Daily "off" time was reduced by about an hour in participants who received either 20 mg/day or 40 mg/day of istradefylline; the higher dose did not have a stronger effect.
  • Among those taking doses of istradefylline, the most common side effect was dyskinesia (involuntary movements); however, at either dose, taking the drug did not increase dyskinesia to an extent considered troublesome.
  • Istradefylline was safe and generally well-tolerated.

What Does It Mean? 

Levodopa treatment is the mainstay treatment for PD. Unfortunately, as the disease progresses, people affected by PD require higher more frequent doses of the medication to stay in the "on" state. This new study supports earlier research about istradefylline. It finds that the drug may provide a modest benefit for people with Parkinson's who take levodopa by reducing wearing-off fluctuations.

Istradefylline is one of several similar drugs currently in clinical trials for Parkinson's disease. These new drugs are broadly called A2A-antagonists and work like caffeine but in a specific way, by targeting the part of the brain affected by PD.  Unlike other PD drugs, A2A antagonists do not affect the dopamine system. Thus they may have great potential at improving PD symptoms.

The fact that the medication was able to reduce off time by an average of roughly an hour a day is encouraging. The fact that this reduction was associated with increased dyskinesia is discouraging. Also, the report that 40mg a day had a similar effect to 20mg a day is disappointing. This suggests that the modest effect observed in this study cannot be enhanced by increasing the studied dose.

Istradefylline has been investigated in clinical trials for about a decade and was recently approved for use in Japan. Although studies in the US have found it to be safe, results on its effectiveness have been mixed. In 2008, the US Food and Drug Administration issued a "not approvable" letter to the drug's Japanese developer.  These latest results may help put istradefylline back on track to becoming a treatment option for people with PD in the US.  

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What medications are available for Parkinson's? What's on the horizon? Contact PDF's HelpLine at (800) 457-6676 or, or use our free resources below.

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Reference: Mizuno Y, Kondo T and the Japanese Istradefylline Study Group (2013) Adenosine A2A receptor antagonist istradefylline reduces daily off time in Parkinson's disease. Mov Disord. Early View Ahead of Print. DOI: 10.1002/mds.25418


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Source Date: Apr 12 2013