Off label medication - how to choose

[WinnieThePoo]

Ian Frizzels recent vlog about his MP's intervention regarding the prescription for Exanatide inspired this post. I hope he contributes. It's unashamedly selfish. Having tried to establish DIP on first diagnosis, I switched to research for disease modifying "new hopes" after the DATscan.

My dilemma. Do I try for 1,2,3 or none of the "target" drugs. These are Exanatide, Isradipin, and Simvastatin. Ian has clearly concluded that Exanatide is the golden bullet, and it is my favourite by a short head. It's possible indicated benefit would appear to be neuroprotection in early stage PD - although Ian's neurologist (at the trial centre) apparently agrees it would potentially benefit his further progressed condition.

Exanatide, and repurposed drugs were the most promising immediate option, although further research revealed new developments in the microbiome to be interesting (and possibly the most readily accessible)

I mentioned to my French neuroligist I had read about Exanatide and could he prescribe it (we may have had a language issue). His response to my decision to decline Sinemet and look to new disease modifying options was to suggest Rasagiline and refer me to Christine Brefel at Purpan Toulouse. As a result of that I am waiting to join a trial for a monoclonal Asyn antibody. It's France. I'm still waiting. I wrote a letter a week ago. Trial was due to start "by the new year"

I asked my UK GP if he could prescribe drugs I was interested in. He didn't know what the DATscan showed, hadn't heard of Isradipine, and referred me to a neurologist appointment (back in June - appointment January 23rd. I just tried to change it, and next available is June 2019. We have some problems in the NHS)

Exanatide is struggling to get a phase 3 trial going and it will take 5 years for a conclusion.

Isradipin is in phase 3 (completed November 2018) results due 1st quarter 2019. This looks the most likely to actually establish a neuroprotective effect and be the first to get licenced (I hope I haven't jinxed it with commentators curse). Just making it to the end of the trial suggests some positive outcomes. There is recent research, since the trial began, (on mice), which suggests a mechanism for how and why it is working. If its working.

Simvastatin is in phase 3 concluding early 2020. My least favourite - there is confusing research around statins, and I have taken them before and felt sh1t. (although a condition like PD changes my willingness to tolerate side effects)

I have blood pressure between 140/90 and 150/100 depending on how and when you measure. Cholesterol of around 7.5 last blood test.

My French GP will prescribe Isradipine for BP. (and probably Simvastatin if I asked). My UK GP has (gleefully) prescribed Simvastatin (10mg) which I haven't taken yet. He has been trying to get me on statins for years, and I didn't enjoy the experience. The phase 3 trial dose for PD is 80mg which is off the scale for normal cholesterol control

The trial dose of Isradipine is 10mg which again is at the top of the range for BP control

Exanatide I am probably a good candidate for since I have pretty good bowel function, and am a little overweight (88kg 180cm).

Any drug has side effects. A combination of drugs a multitude of interactions. With each other, general physiology, and ... the microbiome. (Interestingly Dr Athuda speculated that it was possible that Exanatides action in PD was effected via microbiome changes, at least in part)

So - mostly I am planning to wait till the January appointment, and see if I can leverage Ian's off-label recommendation for one of my own. I can also probably wait for the Isradipine trial outcome - but maybe take it for BP anyway if side effects are tolerable

I share Ian's view that with a progressive neurodegenerative condition tomorrow is a day too late to start a medication which WILL slow or stop progress.

But when its not clear if any one medication does, several appear to work via different mechanisms, how do you back the right horse? Or know whether to call off the race and back all of them?

[MBAnderson]

I'll leave it to others to give you advice on pharmaceuticals and instead say what I would do if I were in your situation -- which is really just to say I am. Many are.

I've been taking Isradapine for 2 or 3 years. It's an old, weak drug that's so old and weak the VA took off its formulary. It takes 6 weeks for your blood serum to reach a therapeutic level. I haven't and don't expect to notice anything from it by itself.

Essentially, I'm in a perpetual state of examining every credible option and will probably try all of them and likewise, I'm doing a continuous contraindication/reading search of everything (food, supplements, whatever.)

I'll probably try Exenatide. Not Simvastatin. Not ready for an antibody trial, but would not be surprised if it helps.

I'm about to start Vinpocetine, then probably won't make any changes for many months while I do the microbiome thing. I expect it to help.

I believe in the feedback loop thing and I figure that if I do 8 or 10 of the most probable options, that might produce an accelerating improvement in overall health.

I try to stay away from the exotic stuff, although I have to admit to taking a couple. None of the stuff you're considering is very exotic.

I've said it before, but I believe there is a sweet spot out there for many of us.

[MBAnderson in reply to MBAnderson]

Speaking of multiple modalities.

"Preclinical studies

Extensive preclinical studies from numerous laboratories have identified multiple pathogenetic targets for potential intervention. These include, in addition to amyloid-β (Aβ) oligomers and tau, inflammatory mediators, apolipoproteins and lipid metabolism factors, hormonal mediators, trophic factors and their receptors, calcium regulatory pathways, axoplasmic transport machinery, neurotransmitters and their receptors, prion protein, and a host of other potential targets. However, one of the drawbacks of these preclinical studies is that many have implicated single pathways, and shown large effects of targeting one pathway, whereas in human studies, such approaches have not been borne out. There are several possible inferences from such discrepant results: first, it is possible that it will be necessary to target multiple pathways simultaneously in order to effect an improvement in symptoms and pathophysiology. Second, it is possible that targeting a single pathway will be sufficient, but that earlier intervention will be required. Third, it is possible that all of these seemingly disparate pathways will converge on a single critical pathway, so that either a single targeted therapy or a multi-component, multi-targeted approach may be effective. And fourth, of course it is possible that neither of these two types of approaches will be sufficient. It is worth noting, however, that it is possible that addressing multiple targets within the network underlying AD pathophysiology may be successful even when each target is affected in a relatively modest way; in other words, the effects of the various targets may be additive, multiplicative, or otherwise synergistic."

ncbi.nlm.nih.gov/pmc/articl...

[Islandhappy in reply to MBAnderson]

I have been using vinpocetine for about a month. Getting a result. It’s all experimental isn’t it?

[Hidden in reply to Islandhappy]

What benefit have you gotten from vinpocetine? You say you have been taking it for a month. How soon after starting vinpocetine did you notice the result? Thank you!

Art

[Islandhappy in reply to Hidden]

It helped with foot neuropathy that made my feet and ankles feel like they were buzzing, it made me more energetic and more ambitious. I wasn’t sure it was a placebo affect. I take 30 mg. Per day in 3 doses. It is supposed to increase circulation in brain and extremities.

[Hidden in reply to Islandhappy]

How soon did you notice those results?

Art

[Islandhappy in reply to Hidden]

Within a week.

[Hidden in reply to Islandhappy]

That is a fast response to vinpocetine! Thank you for the reply!

[Islandhappy in reply to Hidden]

The feelings in the feet were easy to evaluate

[Hidden in reply to Islandhappy]

Could I just verify your dose? It looks like you are taking a total of 90 mg/ day? That is higher than I have seen in any studies so far. Thank you!

Art

[Islandhappy in reply to Hidden]

OMG.. good thing you picked up on that!!!! its 30 mg per day, taken in 3- 10 mg doses. understand that I also take vit D, mannitol, ginger, tumeric, vit c, fish oil, B1, b complex, green tea plus NAD and some other supplements, hoping I have all bases covered. i also take 1/2 CD/LD am and pm and mucuna. so far so good..

[Hidden in reply to Islandhappy]

It certainly seems like you have your bases covered!

[Islandhappy in reply to Hidden]

I’m a walking experiment🙂

[Ruffinglgo]

I started PD research after year of denial was over and following a NYT article which included Isradipine and Inosin. Inosin keeps uric acid levels down before conditions like Gout set in which I have now -pain and swelling of finger joints. Started immediately as soon as my primary said OK 5 mg Isradipine once every am. In the afternoon 5mg Lisinipril taken to prevent legs feet swelling. No problems and remained steady Until this year's physical and primary checks out the old ticker and yes, you probably guessed this already, sent me to cardiologist to confirm afibb diagnosis wrote prescription 50 mg daily Metoprolol ER daily. Seems I am spiraling downhill faster than before. Sharp debilitating pain causes Gout? in joints especially...so I have 2 thoughts go looking for a new primary (he receives payment from BIG PHARMA). AND A 3RD NEUROLOGIST. Oh I do like her but at last appointment she seemed reluctant to suggest new therapies or even my suggestion that Ropinirole was causing afibb episodes to flare up and that I had documentation to back up this claim. She wasn't upbeat . And then she dropped a bombshell Get a DBS. OK I started to protest you know my problem is related to balance and rigidity DBS doesn't helpthose. My brother hadoDBS Less than than year ago. Lost his voice. DBS pacemaker has been turned off by surveillance cameras.Requires lots of adjustments. University Hospital not near by and requires at least a dozen visits to determine eligibility. Does this mean I am excess baggage. Or perhaps her supervisor is demanding that she MOVE ON TO someone else. s

[park_bear in reply to Ruffinglgo]

Are you taking inosine? It raises uric acid levels. It does not keep them down. If you are taking it that is the cause of your gout.

In my opinion taking inosine in order to raise uric acid levels is a really bad idea - high levels of uric acid are associated with all kinds of bad outcomes.

[WinnieThePoo]

Thanks for the replies MBA and Ruff. Life gets complicated, don't it? What I maybe hadn't made clear was that one reason for delaying ANYTHING, other than basic microbiome good practice (and exercise / stress-management), was to avoid muddying the waters. My aim is to stop/slow progress - not (primarily) manage symptoms. I have the great privilige that at the moment I don't need to manage symptoms. I appreciate many on this forum are not so fortunate - but I am making the most of it.

My only available measure of disease progress is the symptoms - so if I mask them, I lose my monitoring ability.

I would note both of you use medications referenced but not at PD trial dosages. The early trials determined the maximum dosage tolerable, which generally corresponded with maximum therapeutic effect. 10mg Isradipine. 80mg Simvastatin.

Like Marc, I used to be indecisive, but now I'm not so sure. I change my mind a lot. But my current thinking is still try to fix the microbiome first before muddling anything else. In particular, if fix the microbiome means poo transplant, there is some evidence that may address the high cholesterol and borderline hypertension. If it doesn't, it probably makes sense to try to get up to 10mg per day Isradipine for the hypertension control regardless of whether it helps PD

For the minute, I am not absolutely sure the progress hasn't slowed or stopped. I am a superstitious bugger, so wish I hadn't said that, but it's far from clear (also early days)

Thanks again for the responses.

[park_bear in reply to WinnieThePoo]

You are right to avoid the simvastatin. Not good for the brain: scientificamerican.com/arti...

See also my writing here:

When Good Doctors Prescribe Bad Medicine

tinyurl.com/zvgcu79

[WinnieThePoo in reply to park_bear]

And the case for the defence

ncbi.nlm.nih.gov/pmc/articl...

SImvastatin is definitely my last choice, and only something I would consider if the results of the phase 3 are very positive. "The FDA approved dose" of 80mg is the maximum permitted dose, and plenty of people get bad side effects on 1/4 of that. I need some cholesterol lowering bugs to come along for the ride in a poo transplant. If I have one.

[park_bear in reply to WinnieThePoo]

I agree – if they achieve a robust phase 3 result that merits consideration.

As to the usual blood lipid panel HDL and LDL, these results are pretty much irrelevant to cardiovascular risk. In the US we have suffered 50 years of bad dietary advice. Cholesterol has been given a bum rap. These books are by medical doctors and carefully referenced to the literature:

The Great Cholesterol Myth

amazon.com/gp/product/15923...

This is a relatively quick read .

Eat Fat, Get Thin

amazon.com/gp/product/03163...

This is a very thorough discussion of dietary factors affecting health.

[MBAnderson in reply to WinnieThePoo]

Poo,

I agree, in your early-stage, I would do the microbiome adjusting 1st and in isolation of other things.

I think getting a poop transplant is not unlike adopting a baby, i.e., you want to know who the parents are. I understand unrelated characteristics come along for the ride.

Marc

[WinnieThePoo in reply to MBAnderson]

I'm looking at the Taymount clinic. They have comprehensive screening. And charge for it. Still interested to see what bug sets I have and how much I can change those without a transplant. Also watching progress with poo pills.

[MBAnderson in reply to WinnieThePoo]

Keep us posted.

If you can't play golf now, but can play after your fecal transplant, that'll be fun.

[MBAnderson in reply to WinnieThePoo]

Re: your concern about HDL, here is a discussion about IV trehalose and atherosclerosis. You may find it an interesting site.

longecity.org/forum/topic/9...

[WinnieThePoo]

Oh boy. The 22 pages close format text (in French) consent form for the trial has arrived. The French medical service is first class, but they have no bedside manner. I don't have bicycle clips strong enough. Will try to knuckle down and read it. Trial screening is 12 January, MRI and DATscans 21 January, first injection 8 February. At least Gin isn't contra-indicated!

[Ianfrizell]

I didn't decide that exenatide was the drug for me via any scientific process. At the time the clinical trial results were announced there were also promising results for nilotinib. I didn't fancy taking a chemotherapy drug, so that ruled nilotinib out. The exenatide trial was carried out by the same team that did my DBS, and I had a good chat to Professor Limousin, who was very enthusiastic about me trying it. The only reservation that I have is that it could possibly provoke pancreatitis, but nothing ventured nothing gained. Still waiting to see if Norman Lamb's letters have had any effect...

Ian

[WinnieThePoo in reply to Ianfrizell]

Exanatide looks very promising. Frustrating that the phase 3 isn't under way yet. Since your vlog I have established I could get exanatide off label and probably get my GPs to pay for it. But I will probably go for the prx002 trial. Its 2 years starting February and I probably can cope with that. I'd like to do my bit for the parkinsons community while I can and it looks a promising drug, so if I'm not in the placebo group I might just benefit from it. Trial protocol I have to sign is pretty scary but I have a full bottle of tanquaray in the cupboard so I'll try to find the Dutch courage

[MBAnderson in reply to WinnieThePoo]

They'd get more volunteers if the terms weren't so scary.

What happens to your access to the drug after the two-year trial is over?

[WinnieThePoo in reply to MBAnderson]

I've asked the question. One of 27 I am waiting for a reply to. They are going to respond when they have all the answers. I think they are just waiting on trial clearance for the dexamthasone eye drops I have to use daily to stop a corneal graft rejecting. Hopefully today.

From the chat I had with the research assistant, unless the drug has safety issues and is withdrawn, I can continue but it is no longer free. I'm not clear whether the French health care will pick up the tab if it's not authorised.