http://www.urmc.rochester.edu/news/s...ex.cfm?id=4042

There's two ways of looking at the regulatory process:

Black and white: a drug is never to be used until it is approved by the regulator to treat named illnesses.

Shades of grey: the regulatory process produces information, which added to personal data suggest that the drug should or should not be used by a particular person.

The article pointed to in post 1 states:

"Isradipine is a Food and Drug Administration-approved drug to treat high blood pressure. Researchers suspect that the drug may also be effective in treating Parkinson’s for a couple reasons. First, population scale studies have shown that people taking the drug for high blood pressure have a lower incidence of Parkinson’s disease. Additionally, isradipine is in a category of drugs called calcium channel blockers, meaning they inhibit certain cellular functions. Researchers speculate that overactive calcium channels may play a role in the death of the dopamine producing cells in the brain that is one of the hallmarks of Parkinson’s."

Those people who see things in shades of grey and are using other drugs to treat high blood pressure may wish to discuss with their doctors moving to isradipine. It can be argued both ways whether this is an off-label use.

Many PwP have low blood pressure. Does this preclude using isradipine? Or, can a second drug be added to raise BP enough to off-set the decrease caused by isradipine? This sounds perverse, and may, indeed, be perverse. It is contingent on your assessment of the risks of PD against those linked to high blood pressure.

John

The news about Isradipine is in no way new. The relationship between the drug and lower incidence of PD has been around for over a decade. There has now been pre-clinical mouse data that supports they hypothesis of neuroprotection. In addition, conceptually, it makes sense. The announcement is for the start of the first human studies to actually test the drug for neuroprotection.

I think your suggestion about discussing it with your doctor for possible off label use is a good one. I had that conversation with my doctors (both MDS and Cardio) last year. I would suggest, however, that you keep the following in mind:

1. To date, there has only been a correlational relationship between use of the drug and lower incidence of PD (similar to tobacco and coffee). This in no way means the drug can slow or stop progression.
2. You do not know what the dosing schedule of the study will be. My understanding is that they used a much stronger dosage in the pre-clincal study than would normally be prescribed for high BP. I highly doubt any doc would recommend going over the prescribed dosage off label.
3. If it actually does work, you may not even realize if for years. Keep in mind this is not for symptom control, its supposed to be neuroprotective. So, you wouldn't normally expect immediate or short term symptom relief. What you might expect is gradual improvement or longer term stabilization. I think the study goes on for three years.

That all being said, it is certainly worth having the conversation with your doctors. Or, since this is going to be a large multi-centered trial, people should consider joining the study and getting the proper dosage (if your not a placebo) along with ongoing, continuous monitoring.

As you stated, John, PwP do not want to be playing around with their BP without proper monitoring. This may be a reason to join the study rather than try it on your own. There will be some unique approaches to offsite patient monitoring. Carematix will support clinical trial operations including data management and real time uploading of blood pressure readings from patients at home. Verizon Enterprise Solutions will provide the communications technology that enables the exchange of data so that patient information can be securely transmitted to researchers for analysis and interpretation.

Gary

I've been on 10mg of isradipine for 2 years. As Tupelo3 points out, this is not a new finding. You can find several PD blogs with personal experiences using isradipine.... not many report a noticeable change in progression.

I think you will find that 10mg is a small dose.

Up until 2012, isradipine was available in continuous release form (DynaCirc CR) and, in my opinion, was more effective in PD.

I do think stadard isradipine has a very mild positive effect in PD. And, no, I have no proof.

I do have slightly high blood pressure, which isradipine fixes... if it slows my PD, that's a bonus.

We tried isradipine several years ago and it did nothing for us, I hate to report. We did not have any issues with blood pressure before, so we were worried it might cause some issues in that area, but felt the risk was worth it if it helped with the PD. We could not tell any difference after a year+ on it, so stopped using it.

I think since this drug has been out for so long and the news is not new, there are many white ratters who would have been heralding its praises if it really helped in the PD dept.

I'm glad if some PWp report relief from PD symptoms from this drug, but to me it just seems like it's another shady case of grasping at straws to increase revenues.

lurking, it's an old generic so i assume not a lot of money for anyone, not even researchers.
it does bring up how difficult it is to provide neuroprotection after PD is visually detected, might be too late. that's why detecting pd or genes that increase your chances of pd as early as possible is so critical. i've read everyone would get pd if you lived long enough since we lose 1-2% of dopamine producing neurons naturally, so if you had one event that damaged a lot of neurons or somehow have a damaged system for repairing neurons you'll get pd "sooner".

lots of things have been tested to try to stop progression, CO-Q10, vitamin C, vitamin E, selegeline, i remember reading how when mirapex came on the market it was tested for neuroprotection - sinemet was thought to slow progression. TEVA is certainly making a fortune on the neuroprotection hope.

Keeping in mind that this was primarily a safety study and only looked at efficacy as a secondary outcome, here is a summary of the Phase II trials:


FINAL OUTCOME

STEADY-PD successfully completed enrollment of 99 subjects at 21 sites over 13 months. The tolerability of isradipine was dose-dependent. Isradipine 10 mg daily dose was the maximally tolerable dosage. The most common adverse events were dosage-dependent peripheral edema and dizziness. While there was no difference in efficacy between treatment arms, the effect size compared to placebo did not rule out possible meaningful clinical benefit. Isradipine had no PD symptomatic effect based on the wash-in or washout analyses. The data supports the use of 10 mg dosage for the future efficacy trial.

There was no symptomatic benefit. However, as I previously posted, you wouldn't necessarily expect anything different if the drug does have neuroprotective potential.

Thank you all for your replies. Taken in isolation I agree with most of the points made. But, I'm unsure as to the extent to which we agree on the general issue: do you and your doctors wait for regulatory approval before acting, or do you act on incomplete theoretical reasoning, epidemiological data and animal studies?

Especially lacking, in my opinion, is a discussion of the opportunity cost of not moving early.

This is a general issue. But the issue of isradipine is a good one to discuss, because the issues are so clear. NICE (National Institute for Clinical Excellence) in the UK publish clinical guidelines. The one for hypertension recommends:
- Offer people aged under 55 years an ACE inhibitor or a low-cost ARB. If an ACE inhibitor is prescribed and is not tolerated (for example, because of cough), offer a low-cost ARB.
- Offer people aged over 55 years and black people of African or Caribbean family origin of any age a calcium-channel blocker (CCB). If a CCB is not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic.
http://www.nice.org.uk/nicemedia/liv...6015/56015.pdf
This advice is given without taking into account PD. People presenting aged over 55 will get a calcium-channel blocker. People under 55 will normally not. But, in my opinion what is known about isradipine should be enough to lower this threshold age for PwP.

Measuring progression precisely is, indeed, difficult. And may be impossible if there are different subtypes of PD. But, great precision is not required in order to act. An estimate of progression can be made using a proxy measure. For PD this could be finger tapping rate or distance covered on foot in 10 minutes etc.. Do these give an exact measure of PD? No, of course, not. But, that is the wrong question. The right question is: Does using these measures give better results than not using them? Using proxy measures to act on is wrong only if they led to goal incongruent activity. In other words, for harm to be done, a potential therapy would have to show a decrease in the rate of decline of the proxy measure, walking speed say, but increase the true rate of progression. This is certainly possible, but in my opinion it is unlikely.

Finally, someone made the point that using isradipine in the hope that it decelerates the progression of PD is like clutching at straws. To some extent it is: but if you've nothing better to hold on to it makes sense. More positively, I stress that, properly engineered, and in just a few days, clothes, bridges and ocean-going boats can be made out of straw.

John

You offered two choices, wait or start the drug off label with no monitoring, no control for other variables, no method of truly knowing if it works. It's interesting that you didn't suggest the third alternative, which is to enroll in the trial and help get the proper research done so that all of us in the community will know if the drug actually has any neuroprotective benefit.

I believe your constant touting of self research is very admirable. I certainly believe in the importance of anecdotal evidence. With those stories come hypotheses that can then be validated or tossed aside (e.g. CoQ10). However, in this case, we've already moved beyond that. The drug will be properly tested. All that is needed now are PwP to volunteer to participate in the trials.

So yes, you can do it on your own, and hopefully it works. Unfortunately, neither you, or anyone else, will ever know for sure that it worked. Even if you appear to have slowed your progression three years from now, how will you know that it was the isradipine that was responsible rather than one of the other multitude of meds and supplements we all take (e.g. curcumin, coconut oil, green tea, blueberries, or whatever the story of the day is)? Furthermore, will you now forego any additional new drugs or supplements over these years or just keep on adding to the confusion?

I can understand when we take the supplements that most of us know probably don't work, but say anyway, what the heck.... However, isradipine is a very strong med which can easily cause hypotension in a PD patient. Trust me, I know from experience. Under the direct supervision of both my MDS and Cardiologist I started Propranolol to see if I could get any benefit in tremor control. Well, within one week my wife had to rush me to the emergency room as a result of a significant overnight drop in BP and heart rate. I was there for two days before they got it back under control.

So, my long winded answer to your question is that yes, there are certainly times when we should take research under our own control. This is particularly true when it concerns supplements, procedures, etc that have had good anecdotal evidence. In this specific case, with isradipine, I guess if your cardiologist recommends that you take a BP med, then it is certainly worth the discussion of taking this instead of one of the others if you will get equal BP control. However, I personally don't think the evidence is compelling enough that I would ever consider using this drug now off-label just for the hope of getting PD neuroprotection.

Tupelo3,

I have never proposed that anyone not suffering from hypertension should use isradipine in the hope that it slows the progression of their PD. Rather, I've suggested that PwP with hypertension should discuss with their doctors using this rather than other hypertensive drugs.

My own position is that hypertension was diagnosed at the same time as PD. I was put on an ACE inhibitor. This controlled the hypertension. But when I went on levodopa my blood pressure dropped further taking me into hypotensive levels. One day, on a long walk, I fainted. I stopped the ramipril and now have a nice BP of 110/75. I don't see isradipine as being of any use to me.

Regarding supplements, I barely use them, sometimes turmeric, but only at normal cooking levels. I sometimes use music therapy, strobe lighting, TENS machine, forced exercise of the arms. I get mixed results from these. The two "alternative" approaches that I do rely on is walking, I walk everywhere, and socialising.

You appear to think that the trial will find THE answer as to whether isradipine is efficacious for PwP. You may be right. I'm skeptical, however, I suspect that PD is a collection of diseases - some of which may respond positively to a treatment, while others respond negatively. This makes it difficult to do better overall than the placebo effect.

It seems to me better if trials are based on the individual - properly monitored, properly measured - but with the aim of finding what works for that person, rather than hoping to find a treatment that fits all.

I find it difficult to understand why a trial should take 3 years. What extra information will the last two years give? I've posted previously on high frequency testing - measuring 24/7 rather than every 3 months, say.

My position is clearly influenced by the fact that I'm 9 years post diagnosis. Even if a wonder drug that stops all progression is discovered, tested, given regulatory approval and gets into pharmacies, at an affordable price, tomorrow, I will still be affected badly by PD.

It's this sense of urgency that I wish to get across.

John