Journal of Neurosurgery [2007] 106 (4) : 614-20
(Slevin JT, Gash DM, Smith CD, Gerhardt GA, Kryscio R, Chebrolu H, Walton A, Wagner R, Young AB.)

Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal.

OBJECT: Glial cell line-derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months has been previously shown to improve significantly motor functions and quality of life measures in 10 patients with Parkinson disease (PD) in a Phase I trial. In the present study the authors report the safety and efficacy of continuous treatment for a minimum of 1 year. After the trial was halted by the drug sponsor, the patients were monitored for an additional 1 year during which the effects of drug withdrawal were evaluated.

METHODS: During the extended study period, patients received a 30-microg/day unilateral intraputamenal infusion of GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 microl/hour.

RESULTS : The Unified Parkinson's Disease Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38% in the off- and on-medication states; the motor UPDRS scores were also improved 45 and 39%, respectively. Benefits from treatment were lost by 9 to 12 months after the cessation of GDNF infusion. The UPDRS scores returned to their baseline and the patients required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of risk of infection. Seven patients developed antibodies to GDNF but without evident clinical sequelae. There was no evidence for GDNF-induced cerebellar toxicity, as evaluated by magnetic resonance imaging and clinical testing.

CONCLUSIONS: The unilateral administration of GDNF results in significant, sustained bilateral benefits in patients with PD. These improvements are lost within 9 months of drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.

THANKYOU!
Dear ******* -
I know that dear Dr. Greg has spent most of his life trying to cure us!

Why when drugs that knowingly damage and kill people line the shelves of our Pharmacy shoppes, tell me why in the HELL, can't they let us live,

for example:

They have let us have a Coke and a addicted smile since 1886 !?

May 8, 1886: Looking for Pain Relief, and Finding Coca-Cola Instead
By Tony Long 05.08.07 | 2:00 AM
1886: Trying to come up with a headache cure and general pain reliever, pharmacist John Pemberton invents the beverage that will become known to the world as Coca-Cola in a backyard kettle.

Pemberton received a medical degree at 19 and worked as a druggist in Columbus, Georgia, before joining the Confederate army during the Civil War. He rose to the rank of lieutenant colonel with the Third Georgia Cavalry and was severely wounded in battle.

Trying to control the pain resulting from those wounds, Pemberton became addicted to morphine.

After the war, Pemberton settled in Atlanta, where he began work on a beverage combining coca leaves and cola nuts. His objective was to create a pain reliever but when his lab assistant accidentally mixed the concoction with carbonated water on May 8, 1886, the two men tasted it, liked it, and decided it might make a profitable alternative to ginger ale and root beer.

Pemberton sold the rights to Coca-Cola (twice, actually, but that’s another story) as his behavior became more erratic. He died only two years after his accidental invention and only a few months after the Coca Cola Corporation was incorporated.

It's no urban myth: Coca leaves do indeed contain traces of cocaine, which was then believed to help control one's dependence on opiates, including the morphine that helped end Pemberton’s life at 57.

(Source: Wikipedia)

Isn't the whole GDNF issue about drug companies fear of litigation?
In this case isn't the real enemy litigation rather than drug companies.

Cabergoline (Dostinex in the US) was fully approved for PD use in the UK and widely prescribed, now as a result of the recent link to heart valve disease the following article has just appeared on "lawyersandsettlements.com"

The last bit under "Dostinex Legal Help" says it all!!


[I]New York, NY: If you live in the United States and you are taking Dostinex for Parkinson's disease... You shouldn't be.

The drug, approved in 1996 by the U.S. Food and Drug Administration (FDA) for the treatment of the hormone deficiency known as hyperprolactinaemia, is commonly used to treat Parkinson's in other parts of the world, and has been known to creep onto prescription pads for Parkinson's in the United States.

However this is off-label territory - a slippery slope - and the concern over Dostinex in higher dosages more commonly associated with Parkinson's, remains the link to potential heart issues, and specifically valvular heart disease.

In Parkinson's patients, Dostinex targets the areas of the brain that have become deficient due to the onset of the disease - namely the depletion of dopamine, which results from the degeneration of neurons in the brain that control movement. Dostinex, in layman's terms, has the capacity to mimic the effects of dopamine in the brain, and positively impacts areas such as muscle control and motor skills, and helps with the stiffness and tremors often associated with Parkinson's.

While effective, the dosage required for Parkinson's patients is upwards of 40 times higher than levels required for the approved application with hyperprolactinaemia hormone disorder.

It is within the context of these higher dosages that studies have uncovered the link between Dostinex and heart valve problems. In two recent clinical trials conducted outside of the United States, Dostinex was found to contribute a higher risk for heart valve disease, compared to patients taking some other form of medication to control Parkinson's. An Italian study in Milan found that 29 per cent of trial participants taking Dostinex were seen to have heart valve damage in the moderate to severe range. Meanwhile, in Germany, respondents were found to be seven times at risk for leaking heart valves, than those not taking Dostinex.

Other side effects identified range from nausea, to dry mouth, to vertigo. However, the concern over the potential for heart disorders remains uppermost in people's minds.

For its part, the FDA remains satisfied that despite the risks for unapproved, off-label use, the potential for heart valve damage in Americans is minimized so long as the drug is used for which it was originally intended, and approved. Recommended dosage levels for the treatment of hyperprolactinaemia are well below a threshold that has any negative impact on the heart.

Dostinex is manufactured, and marketed in The United States and Canada by Pfizer. U.S. sales of the drug exceed U.S $80 million a year. It is known generically as cabergoline, and is considered completely safe in the lower dosages associated with hormonal therapy.

There remains, however, a serious risk to the heart in patients taking higher dosages required for the treatment of Parkinson's. Patients with a history of, or currently taking Dostinex for Parkinson's should consult their doctor - especially if any of the more serious risk factors, including leaky valve syndrome, are known to be present or suspected.

A leaking heart valve does not close tightly, which allows blood to run, or 'leak' backwards across the valve. This makes the heart work harder, and can often restrict blood flow to other parts of the body. Leaky valve disease almost always requires surgery to correct.

The two studies linking high dosages of Dostinex with valve disease appeared in the New England Journal of Medicine, in January of this year.

By Gordon Gibb

Dostinex Legal Help
If you or a loved one have experienced heart problems after taking Dostinex, please send your story to a [Dostinex Lawyer] who will review your claim at no cost or obligation.


Every drug has side effects and for drug companies the worse side effect is litigation!

Chris

Isn't the whole GDNF thing about Amgen's bottom line? i remember a member here (Paula, was it you? I have forgotten who sent it to me, and where I stored it!)) who unearthed a video showing the vice president of Amgen speaking at a gathering about GDNF during the early days of the trials. If I remember correctly he spoke about the cumbersome, involved delivery system--and that there were not enough surgery suites and neurosurgeons to install the delivery system into all the parkinson's patients in the US (and the world). he emphasized the need to find a new delivery system--expect that is exactly what they are working on right now....I for one will be unsurprised if the same GDNF formulation with a new delivery system is brought to trial by Amgen in the not too distant future (one can only hope, since they are unwilling to allow any academic institution or another pharmaceutical entity to use amgen's formulation of the factor). with the participants willing to sign any waiver the amgen lawyers could devise, worry about litigation from this small number of victimized individuals seemed moot.
and as my husband can readily attest--the worst side effect of drugs is not litigation----

Olsen you are right about the tape, except it wasn't made for what it sounds like. Jaye found it online and we sent it to 60 Minutes. (Amgen)was actually promoting GDNF development at that time and saying that in spite of the fact that it wouldn't be a money maker and would tie up surgical rooms, etc. - they were going to pursue it anyway and showed imaging proving it promoted cell growth.

Chris, I don't believe that litigation was the primary reason for the halt, although I certainly am not in support of all the lawsuits that occur by greedy people. This drug wasn't on the market yet and would not have been given to the public for quite some time. The FDA approved continued use for the trial participants only. No side effects, other than antibodies, which is not uncommon, ever surfaced in humans, who were on it in the UK for over 3 years. No one had anything to sue about. Here's a big unanswered question about concern over lawsuits. If they were so concerned, why did follow up after the halt take 6 months to even begin at the Oregon trial center?

Amgen wouldn't think twice about tying a case up in court for many many years, rather than license the property out. Whatever the reason, it isn't for patients like us, who need a treatment now.

I'm going to start a thread today sometime about the Bio conference.

paula