Vit D3>125nmol/L min in blood. FIRST SMALL STEP for pwMS

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby Squeakycat » Wed Jan 02, 2013 12:59 am

MarkW wrote:Refined Target for D3 is 125nmol/L (50ng/ml) as that put pwMS on the plateau for reducing relapses. Before anyone says there is no proven link between relapses and MS progression, I know but are relapses an enjoyable experience or best avoided ?
MarkW

Mark, I should really read through this whole thread and look at your logic and calculations for a target level, but I'm going to shoot from the lip on this one since it caught my eye and will return with citations later.

The body allows you to produce 20,000 IU a day, more if you have special needs. People with full sun exposure plateau at 25(OH)D levels above 220 nmol/L (88 ng/ml). Perhaps not coincidentally, this is the approximate normal level for our evolutionary cousins, the ape.

These are levels absent special needs! There is a special need in pwMS which I think points to a need for even higher levels to have effect.

I would contend this is the starting point and that daily equivalents (pulsed weekly) above 10,000 IU are likely necessary to have real effect in MS.

This raises the second question which you point to, what effect should we expect?

What stands out in the pivotal study of vitamin D in EAE mice is that it stopped active encephalitis cold. 100% of the treated mice did not develop encephalitis and 100% of those treated after encephalitis had developed were able to stop it. And they showed that stopping vitamin D supplementation reversed these positive effects.

What this tells me is that the most immediate and dramatic effect of gaining vitamin D sufficiency is that it allows vitamin D to find a way to maintain the integrity of the blood brain barrier.

One of the main functions of regulatory hormone VitD is to manage the cell replacement cycle when a cell is damaged, whatever the cause, turbulent blood flow, hypoxia, EBV, Dr. Wheldon's c. pneumonia.

It almost doesn't matter what causes the breech in the blood brain barrier, it is Vitamin D's job to restore its integrity.

It does this by managing cell replication and apoptosis as well as by marshaling the immune system to clean up the mess and attempt to deal with any pathogens that are attacking the endothelium.

As such, the principle benefit of vitamin D supplementation should be to quickly repair any injury to the bbb and set off the process to dispose of the injured cells by apoptosis and ward off any pathogens threatening the bbb.

I suspect that in the EAE mice, it was vitamin D's role in protecting the bbb that made it so effective.

In humanMS, where I would expect to see the most immediate effect would be in stopping active lesions (gadolinium enhanced lesions) which are an indication of a breech in the bbb.

The second end point would be to reduce the number of relapses, especially to the extent that these are caused by injury to the endothelium. By maintaining vitamin D sufficiency appropriate for pwMS, the blood brain barrier integrity should be protected.

Were I designing clinical trials of vitamin D, I would do several things:

1. Limit enrollment to those with gadolinium-enhanced lesions (or have a group large enough to have significance).
2. Set my primary endpoint as the reduction in gadolinium-enhanced lesions and the secondary endpoint as a reduction in the number of relapses.
3. Set a target 25(OH)D level of 220 nmol/L (88 ng/ml) and achieve that quickly with a loading dose that would attain this level quick time.
(Loading Dose = 40 x (Target 25(OH)D level/nmol/L - Serum 25(OH)D level nmol/L) x BodyWeight(Kg))
4. Set a maintenance dose that is escalated until the 25(OH)D level reaches an equilibrium and does not rise further. I think that dose is likely to be above 10,000 IU per day, pulsed weekly to avoid hypercalcemia.

I don't know if Vitamin D plays a role in remyelination. I do know that there is a very promising drug, LKE, that stimulates remyelination apparently through CRMP-2 and has shown remarkable progress in halting and reversing several neurodegenerative diseases such as MS, ALS, and Alzheimers in animal models.

I would not expect to see any short term change in EDSS which is linked to the demyelination. But once the bbb integrity is attained, there are likely natural processes, or new drugs, that can trigger remyelination.

I think the simple fact of all this is that MS would not exist if the bbb integrity were maintained and once it has been injured, adequate levels of Vitamin D should restore its integrity and minimize damage as it did in the EAE mice. What is central is the BBB. All the immune reaction to that is secondary. Put a thumb in that leak and you can manage MS.

Should note that I don't think Vitamin D is a panacea. It acts on many things which have to be fully functioning for it to have effect. There are many co-factors involved from adequate calcium levels to the integrity of the innate immune system. Constant pounding on the endothelium from turbulent blood flows, associated hypoxia and local hypertension, have to be fixed.

The immune system grew up in a very hostile environment and may well be over-reacting to some things. There is some basis in evolutionary biology to consider that neuroinflammation is a type of "disposable soma" consequence to evolving in a pathogen-rich world.

That may mean that there is still a role for some limited interventions with immune suppresives while you try to attain an equilibrium by restoring the integrity of the BBB.

Sorry for the length. I have a very serious genetic disorder: An Irish heritage where the quantity of words is highly prized, even when they don't add much.
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Re: Vitamin D Abstracts ECTRIMS 2012

Postby Squeakycat » Wed Jan 02, 2013 2:54 am

MarkW wrote:Lots of research (I mean lots) and useful evidence but no patient focussed recommendation from ECTRIMS, so sad.
MarkW

Mark, one fascinating study at ECTRIMS which was a poster listed under a very cryptic title showed that grandchildren of vitamin D deficient mice develop induced, but not inherited, defects in critical Vitamin D processing genes. I have that from the author, not the abstract which doesn't mention mice.
From physico-chemical agents exposure to MS
S. Ramagopalan (London/Oxford, GB)

Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near MS associated genes identified from genome-wide association (GWA) studies. VDR-binding regions overlapped with active regulatory regions much more than expected by chance. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS associated genomic regions.

This seems to indicate that the children of pwMS, to the extent that what happens in mice, happens in humans, will likely have Vitamin D processing deficiency which could become manifest in a number of diseases where Vitamin-D insufficiency is implicated.

It also raises a question in my mind whether the gene polymorphisms associated with MS are inherited, ie, the mother or father had these deficiencies, or if they were induced as a result of maternal vitamin D insufficiency.
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby MarkW » Wed Jan 02, 2013 5:45 am

Hello Ed (Sweakycat),
Thanks for your input. I have update my advice to be:
===============================================================
First step is to take Vitamin D3. My advice (edited 02 Jan 13):
- Take 5 to 10,000 IU a day of D3. It is very cheap and safe for adults.
- Target level (minimum for pwMS) is 125 nmol/L of 25-hydroxyvitamin D
in blood (50ng/ml).

================================================================
When I read about the levels in the UK population (30-50 nmol/L) this is a massive increase. I agree with you that high levels of D3 are better. I am trying to get pwMS to protect themselves and their families from MS by using a very cheap medicine.
Best wishes for 2013,
MarkW
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Neuros dose too low for Vitamin D3

Postby MarkW » Wed Jan 02, 2013 6:08 am

Rocky Mountain MS Center posted the article below, based on one piece of research?
MS Neuros are behind on CCSVI and Vit D3, shame on these 'MS experts'.
MarkW
-------------------------------------------------
Vitamin D: Do You Need it and How Much?
Breaking News (Dec 2012)
A new study out of Sweden on Vitamin D and multiple sclerosis (MS) adds to the growing body of evidence that suggests that the sunshine vitamin may help prevent MS. Furthermore, data from the study may help us understand what levels of vitamin D are most protective.
During this study, published in the November 20, 2012 issue of Neurology, researchers accessed two population-based biobanks, which were cross referenced with a national birth registry. These biobanks contained 291,500 samples from 164,000 persons collected since 1975 in the northern half of Sweden. From these samples researchers identified and analyzed the vitamin D levels of 192 people who had MS and 37 gestational samples from pregnant mothers whose offspring later developed MS.
This study suggests that people who maintain blood levels above 30 ng/ml of the circulating form of vitamin D are less likely to develop MS compared to people with vitamin D levels below 30 ng/ml. Furthermore, this study suggests that maintaining levels of vitamin D above 30 ng/ml from the third trimester until 26 years of age decreases the risk of developing multiple sclerosis.
Tom Stewart, PAC and co-author of a book about dietary supplements and MS, explains that, when considered in context with other studies, this study raises the possibility that at least some cases of MS may be prevented by maintaining modest blood levels of vitamin D. “For starters, children and siblings of people with MS should have their vitamin D levels checked and vitamin D deficiencies should be treated. Blood levels should probably be increased to 30 ng/ml through supplementation. If testing isn't practical, adult children or siblings of people with MS might simply supplement with approximately 2000 IU of vitamin D per day. For most people, this dose of vitamin D will raise blood levels to above 30 ng/ml.”
This study suggests that children benefit from optimum levels of vitamin D as well. Dr. Teri Schreiner, Pediatric Neurologist at the Rocky Mountain MS Center at Anschutz Medical Campus, recommends that all of her MS patients have their children’s vitamin D levels tested every year or every other year. “If their children’s vitamin D levels are low, I recommend they supplement. Children who haven’t started puberty yet should be given a dose that corresponds to their level of vitamin deficiency. Children who have already started puberty can safely be given 1,000 IU of Vitamin D,” adds Schreiner.
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby Squeakycat » Wed Jan 02, 2013 3:21 pm

MarkW wrote:Hello Ed (Sweakycat),
Thanks for your input. I have update my advice to be:
===============================================================
First step is to take Vitamin D3. My advice (edited 02 Jan 13):
- Take 5 to 10,000 IU a day of D3. It is very cheap and safe for adults.
- Target level (minimum for pwMS) is 125 nmol/L of 25-hydroxyvitamin D
in blood (50ng/ml).

================================================================
When I read about the levels in the UK population (30-50 nmol/L) this is a massive increase. I agree with you that high levels of D3 are better. I am trying to get pwMS to protect themselves and their families from MS by using a very cheap medicine.
Best wishes for 2013,
MarkW

Mark, I think we need to review all the results of the trials to come up with a number. There is one that did a dose escalation series that tells us something about what the right level is.

I think this can be worked out by seeing when the body stops increasing 25(OH)D as you increase the dose. If you add more and 25(OH)D goes up, then you probably still don't have enough. If it flattens out and doesn't increase, then the body is saying I have enough and am now degrading any additional input.

The other way to look at this is to see what levels were in trials where there was an effect and see if we can figure out what levels work and which don't. There are now quite a few trials reports.

And, one thing that stands out in the original EAE mouse study was that they had no effect without calcium. One of the Kimaball/Veith studies says that you need 1,200 mg/day calcium. Together, they tell us that calcium is a co-factor that is important. Maybe magnesium is too. And zinc. We need to look at what the various studies, outside of MS, say about this. There are currently 516 studies of cholecalciferol. Some have been completed and some have papers already.

We should be able to see from all of this what is showing effect and what doesn't.

All the best to everyone in 2013!

Ed
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby EJC » Wed Jan 02, 2013 4:13 pm

MarkW wrote:Hello Ed (Sweakycat),
Thanks for your input. I have update my advice to be:
===============================================================
First step is to take Vitamin D3. My advice (edited 02 Jan 13):
- Take 5 to 10,000 IU a day of D3. It is very cheap and safe for adults.
- Target level (minimum for pwMS) is 125 nmol/L of 25-hydroxyvitamin D
in blood (50ng/ml).

================================================================
When I read about the levels in the UK population (30-50 nmol/L) this is a massive increase. I agree with you that high levels of D3 are better. I am trying to get pwMS to protect themselves and their families from MS by using a very cheap medicine.
Best wishes for 2013,
MarkW


These seem to be very large numbers compared to RDA.

Emma currently takes supplements each day:-

Vit D3 = 1000 IU
Magnesium = 250mg

If I'm reading this right you're suggesting pwMS should be taking 5 to 10 times RDA of D3? That seems an awful lot.

Is there any downside of "overdosing" on D3 or does the body simply eject naturally any amount it finds unusable?
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby Squeakycat » Wed Jan 02, 2013 4:42 pm

EJC wrote:These seem to be very large numbers compared to RDA.

Emma currently takes supplements each day:-

Vit D3 = 1000 IU
Magnesium = 250mg

If I'm reading this right you're suggesting pwMS should be taking 5 to 10 times RDA of D3? That seems an awful lot.

Is there any downside of "overdosing" on D3 or does the body simply eject naturally any amount it finds unusable?

EJC,

The problem is that the RDA is set to basically prevent rickets, not to an optimum level for other things like MS.

We don't yet know what the right level is for people with MS. There are a number of clinical trials and I think reviewing these will tell us something. From what I have seen so far and I've only just started this, you start to see some effects at levels around 8,000 IU a day. Trials that used less don't show any effect.

There are real dangers in taking too much Vitamin D, but what is too much depends on a number of factors.

Anyone taking really high levels should do this in consultation with a physician. You need to know that your liver and kidneys are functioning properly. You have to know what your calcium and phosphorus levels are. You need to know what your Parathyroid Hormone (PTH) levels are.

If you take too much, you run the risk of calcifying your kidneys, heart and other soft tissue organs. That is a real danger.

In addition, too much will cause the body to hollow out your bones, stealing calcium from them. That also has the effect of releasing too much phosphorus which becomes toxic at high levels.

So very high levels, well above those Mark is suggesting, can be very dangerous.

The standard way to avoid problems is pulse dosing. Instead of taking 1,000 IU a day, you take 7,000 one day a week. It is not uncommon for doctors to ask you to take 50,000 IU or even 100,000 IU all at once. Even higher levels are possible.

What this does is suppress PTH. When PTH is high, it signals the kidneys to gather up as much calcium as possible and increases the absorption of calcium as well as resorption from bones.

A single high dose pushes PTH down and by doing that, lowers the signals to the kidneys to start accumulating calcium.

Hope that helps clarify this.
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby Squeakycat » Wed Jan 02, 2013 4:46 pm

EJC,

I should have added an important point. The effect of VitD on PTH depends on what the body's level is when you take the Vitamin D. If you are at a low level, then a large dose will push PTH down. But as your level increases, the large dose has less effect on PTH.

The answer to almost every question about the body is that "it is complex" and as an integrated system with many feedback loops, the answer always "depends" on what else is going on!
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby NZer1 » Wed Jan 02, 2013 5:00 pm

I sent a link to George Jelinek and I think that Terry Wahl and Ashton Embry have followed the Vit D connection closely as well, I will link them to this as well.

:)
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby EJC » Wed Jan 02, 2013 5:05 pm

So 5,000 to 10,000 IU a day is not considered a very large dose?

That would be considered within safe limits for the average adult?
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby Squeakycat » Wed Jan 02, 2013 5:08 pm

ECJ

The US Endocrine Society, folks who know a little bit about hormones created a task force to look at Vitamin D for the population as a whole.

They are very critical of the US-Canadian Institute of Medicine (IOM)Guidelines and recommend much higher levels and note that they may not be enough!

Their report is here. Their recommendations along with those of the IOM are on page 12.

Recommendations vary based on sex and things like whether you are pregnant.

For a women, 31-50 years old, their recommendation is as follows:
Estimated Endocrine Society
AGE Requirement RDA Upper Limit Recommended Upper Limit
31–50 400 IU 600 IU 4,000 IU 1,500–2,000 IU 10,000 IU

The above data is all nicely formatted here, but doesn't display that way. Sorry.

The Endocrine Society is essentially recommending a level almost 4X as high as the national standard, 400 versus a lower level of 1,500 and a range that is 3X the RDA, 600 versus 2,000. Their Upper Limit is more 2.5 times greater.

And these are recommendations for everyone, not for someone who has a special requirement for more as is almost certainly the case for people with MS.
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby EJC » Wed Jan 02, 2013 5:10 pm

So what do you guys take and how long have you been at that dosage?
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby Squeakycat » Wed Jan 02, 2013 5:48 pm

EJC wrote:So 5,000 to 10,000 IU a day is not considered a very large dose?

That would be considered within safe limits for the average adult?

EJC, just happened on the following in the Endocrine Society review. It shows that you can safely take high doses as they are recommending in certain situations. These are doses designed to raise low levels, not daily maintenance doses:
Alternative strategies for nursing home residents include 50,000 IU of vitamin D 2 three times per week for 1 month (134) or 100,000 IU of vitamin D every 4 months (61).

That works out to a daily equivalent of 21,428 IU every day for a month.

They do suggest an upper limit under normal circumstances of 10,000 IU a day, but clearly see a need for more in certain situations.
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby jimmylegs » Wed Jan 02, 2013 6:20 pm

also i have not yet seen studies that look at d3 dose response in varying states of zinc repletion or depletion. i personally respond hugely differently to d3 doses, depending on my zinc status. went to 271 one time, after correcting zinc deficiency and then taking a d3 dose that i intended to get me to 150 or so based on prior experience.
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Re: FIRST STEP-Take Vitamin D3 Before & After De-Stenosis.

Postby EJC » Wed Jan 02, 2013 6:22 pm

I've just read this entire thread from start to finish and many of the linked articles.

What level of zinc intake would you recommend to balance a daily intake of 5K to 10K in D3?
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