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Drug limits uptake of calcium into brain cells to treat PD

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Unread 02-21-2013, 08:13 PM   #1
olsen
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Default Drug limits uptake of calcium into brain cells to treat PD

"... currently no such test for Parkinson's, but at Northwestern University, researchers think they might have found a way to slow its progression.

"We looked at the cells in the brain that were most vulnerable to the disease. What we saw was they allowed lots and lots of calcium into their cell bodies," said Jim Surmeier, Physiologist who spoke to VOA by Skype.

The calcium eventually killed dopamine-producing cells and triggered Parkinson's symptoms. But the Northwestern University scientists found a drug that limits the brain cells' uptake of calcium..."

http://www.voanews.com/content/new-t...e/1607833.html
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Unread 02-22-2013, 09:23 AM   #2
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Default The mysterious "drug" is isradipine and is available now

Calcium Channels as a Potential Target for Neuroprotection in Parkinson’s Disease
Tanya Simuni, D James Surmeier
US Neurology, 2011;7(2):109-12
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1 % of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Recent studies demonstrate that dopaminergic (DA) neurons in the SNc, as well as many neurons in other regions affected by PD, have a distinctive physiologic phenotype. They are autonomous L-type Cav1.3 Ca2+ channels pacemakers. Continuous Ca2+ influx results in increased oxidative stress that may explain the selective vulnerability of these neurons. More importantly for PD, blocking these channels with isradipine, the most potent of the dihydropyridine (DHP) channel antagonists at L-type Ca2+ channels with the Cav1.3 subunit, protects these neurons in in vitro and in vivo models of parkinsonism. Neuroprotective effect is achieved at the serum concentrations that can be achieved with the doses approved for human use. Recent epidemiologic data also points to a reduced risk of PD with chronic use of specifically centrally acting DHP Ca2+ channel antagonists. Isradipine is an approved agent for the treatment of hypertension. Our pilot data demonstrate acceptable dose-dependent tolerability of isradipine in early PD. A pilot Phase II multicenter, double-blind, placebo-controlled, safety, tolerability, and dosage finding study of isradipine in early PD has completed recruitment, with the results of the study to be available in the near future. Results of that study will inform the design of the planned Phase III pivotal efficacy trial of isradipine, as a disease modifying agent in early PD.
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Unread 02-22-2013, 01:37 PM   #3
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Default

Quote:
Originally Posted by reverett123 View Post
Calcium Channels as a Potential Target for Neuroprotection in Parkinson’s Disease
Tanya Simuni, D James Surmeier
US Neurology, 2011;7(2):109-12
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1 % of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Recent studies demonstrate that dopaminergic (DA) neurons in the SNc, as well as many neurons in other regions affected by PD, have a distinctive physiologic phenotype. They are autonomous L-type Cav1.3 Ca2+ channels pacemakers. Continuous Ca2+ influx results in increased oxidative stress that may explain the selective vulnerability of these neurons. More importantly for PD, blocking these channels with isradipine, the most potent of the dihydropyridine (DHP) channel antagonists at L-type Ca2+ channels with the Cav1.3 subunit, protects these neurons in in vitro and in vivo models of parkinsonism. Neuroprotective effect is achieved at the serum concentrations that can be achieved with the doses approved for human use. Recent epidemiologic data also points to a reduced risk of PD with chronic use of specifically centrally acting DHP Ca2+ channel antagonists. Isradipine is an approved agent for the treatment of hypertension. Our pilot data demonstrate acceptable dose-dependent tolerability of isradipine in early PD. A pilot Phase II multicenter, double-blind, placebo-controlled, safety, tolerability, and dosage finding study of isradipine in early PD has completed recruitment, with the results of the study to be available in the near future. Results of that study will inform the design of the planned Phase III pivotal efficacy trial of isradipine, as a disease modifying agent in early PD.
I tried isradipine for a while but it is unique among calcium channel blockers in having a strong diuretic effect so it grounded me. I am now interested in apoaequorin (Prevagen.) The manufacturer says they are not testing it against PD but since it stops age related calcium pathologies in the brain, it might be worth a try. It has been criticized for supposedly not being able to cross the BBB but Quincy Bioscience says tests on dogs refute this.
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Unread 02-23-2013, 03:40 AM   #4
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Default I take isradipine ...

I was put on isradipine when I was dxd with PD. Still taking it now. It has "changed" my PD from mostly rigid to mostly tremors. My MDS says the NW drug is a more specific calcium channel blocker and can be taken in higher doses without affecting blood pressure.

Isradipine used to be available as a controlled release formulation but was taken off the market a while ago. The standard release formulation is available as a generic.
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Unread 02-23-2013, 12:54 PM   #5
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Lab Rat, trading rigidity for tremors doesn't sound like a good deal to me. I had been thinking of taking it to see if it would help my tremor dominant parkinsonism. What degree of tremor did you have before taking isradipine (dynacirc)--did you have no tremors before or just a little bit that didn't interfere with adl's or what? MJFF website announced back in July 2012 results of clinical trial of isradipine insofar as dosage safety is concerned with a plan to move ahead with a stage III trial which would focus on efficacy. I was encouraged by this because elsewhere I think I had read that it could help w/tremors. That's why I'm taken with your account of it inciting tremors that you may not have had otherwise....
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Unread 02-23-2013, 06:01 PM   #6
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Default been there, done that

Sorry, but this is old news and when it first came out, we went on it and took it for awhile. No difference that we could tell, we took it for quite a while before giving up on it.

I really wish they would not re-release things like this, making it sound new and promising. Maybe there really is something here, but to me, it seems more like hype so that funding into this research is continued. Nothing in this "new" press release is any different from what I remember reading before.
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Unread 02-23-2013, 10:44 PM   #7
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Default Furthermore...

\[quote=Arsippe;959899That's why I'm taken with your account of it inciting tremors that you may not have had otherwise....[/QUOTE]

Ask lots of questions before trying this class of drug. While Isradapine was deemed safe in clinical trial safe for PWP, it was only tested for effect on blood pressure. However, two older calcium channel blockers that are in the same class as Isradapine have actually induced Parkinsonism. In most cases, PD like symptoms went away once drug is stopped, but not all were reversible; interestingly, tremor persisted in many people. Results of CCB Induced Parkinsonism studies in the 90's:

Despite a global improvement, cognitive and mood disturbances subsided slowly, and tremor persisted in most patients. After 18 months of CCB withdrawal, 44% of patients had depression, 88% had tremor, and 33% still had criteria for diagnosis of parkinsonism. During the survey, only three patients were found to be fully recovered (3 0f 32). 1992
http://www.ncbi.nlm.nih.gov/pubmed/1349506


Most patients with CCBIP improved spontaneously. Twenty-four months after CCB withdrawal, only 14% exhibited akinetic rigid syndrome, but 92% of patients still had tremor. 1998
http://www.ncbi.nlm.nih.gov/pubmed/18591113/

I would be very reluctant to try anything in this class without having some questions answered first. The first question is obvious; how can
drugs in the same class be at odds like this? This theory on calcium influx is interesting, but how can an inhibitor be neuroprotective in some and cause parkinsonism in others? I also think it is far too specific a target specific for a disorder with such a wide variety of causes.

My other question is how does this theory account for loss of norepinephrine? It has been established that we lose more of that neurotransmitter than we do dopamine, so I am highly skeptical of any study that only looks at treating loss of dopamine. Also, there is far more evidence that alpha-syn plays a main part in PD, so how does the calcium theory leave any room for protein misfolding?

Looking at Lab Rat's experience in light of the tremor readings in the above studies is enough to scare me off and the holes in the theory just substantiate it. I am probably wrong to be so skeptical but that association with PD is scary. I don't meant to upset anyone who has benefit from it , and maybe I know squat and drugs in this class are like apples and oranges. If they would simply explain that I would feel much more at ease, but I have yet to see it.

Lastly, alluding to LFAC's costly four year experiment, there is very little evidence it is even effective in humans. According to MJFF, Phase II trial established that doses up to 10 mg (20 mg was max) were deemed the max tolerable for PWP, yet there was not a hint of efficacy. If the efficacy tipping point is 12 mg then what? I would be very surprised if this sees Phase III. Trial researchers admitted the following on Phase II results. If the drug showed no real efficacy at 10 mg vs. placebo what is the point of going forward?


And by and large, there was little to no efficacy signal shown, although we believe that there was a hint of difference between the active drug and placebo, and in a positive way.


https://www.michaeljfox.org/foundati...289&category=3

I agree with LFAC, given full-disclosure this seems a dead end so I wonder too...why all the hype?!?

Last edited by Conductor71; 02-23-2013 at 10:46 PM. Reason: grammar
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Unread 02-24-2013, 02:16 AM   #8
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Default Isradipine -- Part II -- more details

Here is how I understand the isradipine "story"

1)If it works at all -- it is a mild disease modifier -- not neuro protective -- absolutely not a cure.

2)Only PWP's that already have high blood pressure that is treated with medication should give any thought to switching to isradipine at an effective dosage to manage their blood pressure -- the PD benefit would just be a bonus. (according to my MDS)

3)The clinical trials to find a "safe dosage" for PWPs were designed to use isradipine even in PWPs with normal or low orthostatic blood pressure readings -- thus the very low 10mg / day finding.
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