[Stitcher]

Jefferson participating in global study to extend effectiveness of drug for Parkinson's

Thomas Jefferson University
Public release date: 18-Apr-2007
http://www.eurekalert.org/pub_releas...-jpi041807.php

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."

[ZucchiniFlower]

It might also help with dyskinesias:

Neurology 2000;54:1589-1595

AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys
S. Konitsiotis, MD, P. J. Blanchet, MD, PhD, L. Verhagen, MD, E. Lamers, MD and T. N. Chase, MD

From the Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.



OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias.

BACKGROUND: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined.

METHODS: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa.

RESULTS: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05).

LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05).

CONCLUSIONS: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

[kk13]

Sorry to burst your balloon, but I've been in the E2007 clinical trial for 6 months + and have noticed NO inprovement at all... In fact, My symptoms have gotten much worse!!! Maybe, I'll be the "oddball" and most everyone else in the study will benefit, who knows? The few other people in the study that I've spoken to have either minimal or no benefit, as well.

I think the rotigotine patch holds a lot more promise...I'm keeping my fingers crossed. Good luck to us all, whatever the meds may be.

[aftermathman]

Regards,
Neil.

[kk13]

Neil -
It's possible that I WAS on the placebo for the first several months. I don't know when they'll even tell us which we were originally on. But the placebo group was eliminated several weeks ago, at which time I was guaranteed to be on the "real thing."
At the lower dose for the first 2 weeks I noticed -surprisingly enough - a reduction in "on" time, more severe "off" time (i.e. unable to walk at all!) and more violent dyskinesias!!! Great, huh?
Then, admittedly only several days ago, the dose was doubled (2mg - 4mg) and my symptoms/side effects mentioned above got even WORSE. So bad that I'm considering dropping out of the trial. I know it's only been days on the max. dose, but I'm going through hell and find it hard to believe that I'm still "adjusting" to this new med.
Any thoughts? I appreciate the input.
Keith

[ashleyk]

Hi Keith, sorry to see that you are not doing so well in the E2007 drug trial. If it doesn't work out for you, since you must be the adventurous type to become involved in it, please look into the "dextromethorphan" thread here. I take LDN (see below) to hopefully stop PD progression, one or two others who recently began DM have seen symptom improvement while another, who has been on DM for maybe a year or two, has not seen much progression if any. Some others may have stopped DM. Experimenting on your own is a risk but the dose levels for DM and LDN are fairly low and some of us think we see good results.
Regards, Ashley

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
http://www.lowdosenaltrexone.org/index.htm

[kk13]

Ashley-
Thanks for the info. on DM. I have noticed in recent years that whenever I get a cold and take coiugh medicine (coincidentally, DM), I seem to have a "better-than-average" day as far as PD sypmtoms go. Less "down" time, less severe dydkinesia, etc.
And I agree with you, after reading the recommended info on the subject, that long-term use is probably not too dangerous at such low doses. I will try it (when study is over).
By the way, I spoke with my MDS yesterday about my reaction to the E2007. I am going to take a break for a few days and see what happens. Last night was my first missed dose ever and today I feel better than I have in months! That might not last, or it may just be the placebo effect, but whatever it is, I am very grateful for a day with a little less suffering.
Thanks again for your concern and I'll keep you posted on any DM results.
Keith