PHILADELPHIA— After Parkinson's disease patients use the drug levodopa or L-dopa for several years as a treatment for restoring the cellular communication that controls muscle movement by replacing lost dopamine, they begin to experience motor complications that include a shortened response to each dose of L-dopa.
"As time goes on and the disease progresses, the off periods, that is, time during which the medicine is not working at its best, come more frequently as on periods, or times during which patients experience their best response to the drug, last for shorter periods of time," explained Jay S. Schneider, PhD, who heads the Parkinson's Disease Research Unit at Thomas Jefferson University Hospital.
Parkinson's disease gradually destroys brain cells that produce dopamine. As dopamine levels drop, symptoms increase: tremors in the arms, legs and face; periodically stiff or frozen limbs; slow movement, particularly a shuffling gait; and impaired balance and coordination.
Dr. Schneider, Professor of Pathology, Anatomy and Cell Biology and Neurology at Jefferson Medical College of Thomas Jefferson University, and movement disorder specialists Tsao-Wei Liang, M.D., Assistant Professor of Neurology, Jefferson, and Daniel Erik Kremens, M.D., J.D., Assistant Professor of Neurology, Jefferson, are spearheading a new clinical trial to test a new anti-Parkinson's drug in an attempt to decrease such off-time experiences and extend L-dopa's effectiveness.
The study will evaluate whether a drug, E2007, can significantly lengthen the time that a patient's L-dopa medication is effective, reducing both the amount of off time during the day, as well as other unwanted side effects of L-dopa treatment. E2007 is non-dopaminergic drug that acts on a subclass of receptors called the AMPA receptors, which mediate fast synaptic transmission in the central nervous system.
Standard treatments for Parkinson's disease focus on restoring the cellular communication that controls muscle movement by replacing lost dopamine with L-dopa. While this therapy works well for a while, it can't stop the disease's inevitable march - and the patient's decline. While one current strategy is to focus on neuroprotective agents to modify disease progression, another is to use so-called "adjuncts" that can have modest effects on patients' off-times, when L-dopa can be ineffective for brief periods.
"The hope is that by altering dopamine transmission through the modulating the activity of AMPA receptors, there will be measurable effects on the dopamine system," said Dr. Liang.
The study is designed for patients with more advanced Parkinson's who have been taking L-dopa for some time and are now experiencing fluctuations in its effectiveness.
Individuals must have at least two hours of off time a day. Groups of patients will receive either one of two dosages of the drug or a placebo. The trial is also aimed at evaluating E2007's safety, as well as how patients tolerate it. The study will involve approximately 700 patients at about 150 centers across the U.S., Canada, Australia, New Zealand and South America. Jefferson hopes to recruit at least 12 patients.
"It's an interesting approach and an exciting trial because it is exploring a drug in a new therapeutic category," said Dr. Kremens."L-dopa is still the gold standard and we haven't come up with a better dopamine agonist as yet."