This Is MS Multiple Sclerosis Knowledge & Support Community

Anonymoose wrote:Squeaky...are you going to keep squeaking or try it??!! So far, it's next on my list if rituxan fails. I need to research it more though. It'd be nice if some guinea cat went before me. errrr. Do you have ms?

I don't have MS, but I have offered to try up to 3X the dose to test safety.

I have used calcitriol for 13 years to treat cats with kidney problems and feel very comfortable with my understanding of the risks and see them as minimal and manageable.

I am talking with several medical professionals with MS who are going to try it the next time they have a relapse since that will provide the maximum opportunity to see if it changes things. And there is serious discussion about getting funding to support a proper safety clinical trial.

A friend who is on Rituxan is considering taking calcitriol just before his next two month dose of Rituxan so that the effect of Rituxan is at its nadir. And I have a friend who is a professor of oncology who is looking into whether there would be any contraindication with taking a single, high dose of calcitriol while being treated with Rituxan.

I know you didn't ask for my opinion, but Rituxan will not work. It will kill off your good and bad B-cells, but as they regenerate, the T-cells will again direct them at your myelin. Plus, the standard protocol calls for methylpred and that simply temporarily dampens your immune system without changing anything. Hayes directly tested calcitriol against methylpred and found calcitriol to be far superior on all measures.

Rituxan is suppressing part of your immune system, B-cells. Calcitriol is your immune system controller so by taking a high dose, you are supporting the immune system, not suppressing it.

PM me with your email addy and I will send you the relevant papers on using calcitriol plus D3.

jimmylegs wrote:Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419671/
"The synthesis of bioactive vitamin D requires hydroxylation at the 1α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1α-hydroxylation in the kidney ..."

This might be of potential interest. Several supplements, such as CoQ10 and curcumin, are sold with piperine which is an extract of black pepper. It increases the absorption of these supplements. However, it does this by inhibiting the cytochrome p family of enzymes. Taking supplements with piperine may be reducing the efficacy of vitamin D3 supplementation.

http://www.thisisms.com/forum/natural-a ... ml#p181912

NHE

Squeakycat wrote:

Anonymoose wrote:Squeaky...are you going to keep squeaking or try it??!! So far, it's next on my list if rituxan fails. I need to research it more though. It'd be nice if some guinea cat went before me. errrr. Do you have ms?

I don't have MS, but I have offered to try up to 3X the dose to test safety.

I have used calcitriol for 13 years to treat cats with kidney problems and feel very comfortable with my understanding of the risks and see them as minimal and manageable.

I am talking with several medical professionals with MS who are going to try it the next time they have a relapse since that will provide the maximum opportunity to see if it changes things. And there is serious discussion about getting funding to support a proper safety clinical trial.

A friend who is on Rituxan is considering taking calcitriol just before his next two month dose of Rituxan so that the effect of Rituxan is at its nadir. And I have a friend who is a professor of oncology who is looking into whether there would be any contraindication with taking a single, high dose of calcitriol while being treated with Rituxan.

I know you didn't ask for my opinion, but Rituxan will not work. It will kill off your good and bad B-cells, but as they regenerate, the T-cells will again direct them at your myelin. Plus, the standard protocol calls for methylpred and that simply temporarily dampens your immune system without changing anything. Hayes directly tested calcitriol against methylpred and found calcitriol to be far superior on all measures.

Rituxan is suppressing part of your immune system, B-cells. Calcitriol is your immune system controller so by taking a high dose, you are supporting the immune system, not suppressing it.

PM me with your email addy and I will send you the relevant papers on using calcitriol plus D3.

Thanks squeaky. I appreciate any and all info/opinions I can get. I didn't do the standard rituxan protocol. I did 4 weekly doses iv and it with solucortef (12-24 hr half life I think) and I'll be starting valtrex Tuesday. My war on ebv. Still have hope something different will happen.

The calcitriol phenomena is very intriguing. Although eae isn't ms...you can't discount that an immune system is an immune system and there is a chance humans may respond in a similar way to calcitriol. If they cure ms in the next 25 years, it will be a lucky, not completely understood happenstance. Why not calcitriol?

I'd love to read the papers you've got. I'll pm you my email. Thanks!

1. When Hayes gives her mice sufficient calcitriol to raise CSF levels, pro-inflammatory cytokines undergo programmed cell death, without zinc.

2. Studies, including several by Hayes in EAE show that vitamin D3 has little effect in MS, but calcitriol stops EAE in 100% of her mice without zinc being added.

3. A number of recent studies show what is blocking the conversion of D3 to bioactive calcitriol is the action of pro-inflammatory cytokines, TNF-alpha and IL-6. These studies are in Alzheimers, IBD and two cancer, not MS, but there is no reason to think this is not the same thing that is happening in MS, and again, no involvement of zinc.
What Hayes has shown is that the reason the immune system is out of control in EAE and likely in MS is that conversion of D3 to calcitriol is being blocked. These other studies show that is because of TNF-alpha and IL-6. Nothing about zinc there and the solution is not more zinc, but providing calcitriol directly. This bypasses the conversion problem by making calcitriol directly available to cells.

i'm not arguing the importance of calcitriol and I am not talking about zinc interactions with calcitriol. the studies I posted are about zinc's capacity to facilitate proper conversion of 25(OH)D3 *to* calcitriol via various mechanisms including for example the activity of the critical enzyme 25-hydroxyvitaminD-1α-hydroxylase, and the structure of the VDR receptor.

regarding pro-inflammatory cytokines:
Zinc in Human Health: Effect of Zinc on Immune Cells
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277319/
"We have reported recently that in both young adults and elderly subjects, zinc supplementation decreased oxidative stress markers and generation of inflammatory cytokines."

given that ms patients are low in zinc it seems most prudent to correct that problem first before worrying about downstream issues..

Jimmylegs,
Thought I would separate out the question of vitamin D3 metabolism from zinc.
There are two ways D3 is converted to calcitriol:
1. Through hydroxylation in the liver and kidneys. This provides serum calcitriol.
2. Directly in every cell through the action of CYP27B1 as long as there is sufficient D3, or more precisely 25(OH)D3.

bringing it back. re your item 1 for starters. the hydroxylation in the liver gets you to 25(OH)D3. The hydroxylation in the kidney (via the critical enzyme 25-hydroxyvitamin D 1α-hydroxylase) gets you to calcitriol.
Genetic Disorders and Defects in Vitamin D Action
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879401/
"The critical enzyme to synthesize calcitriol from 25(OH)D, the circulating hormone precursor, is 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase)."

zinc status is linked to calcitriol status, possibly via interactions with 25(OH)D 1-α-hydroxylase synthesis in the kidneys:
1,25(OH)2D response to combined zinc and phosphorus depletion in rats.
"...Zn depletion limits the increase in plasma 1,25(OH)2D concentration associated with P depletion. The mechanism is unknown but may involve an effect of Zn on renal 25(OH)D 1-α-hydroxylase synthetic activity."

Jimmylegs,

Peace. I didn't mean to come across as challenging you or showing a disdain for zinc. Really.

The problem that Hayes protocol addresses is that cells are unable to convert 25(OH)D3 to calcitriol and calcitriol is the master, regulatory hormone of the adaptive immune system.

What I was trying to communicate was that Hayes's treatment works by bypassing the conversion problem and making calcitriol directly available to cells. That results in the dying off through programmed cell death of pro-inflammatory cytokines and the proliferation of anti-inflammatory cytokines.

At that point, conversion works, likely because there is a reduction in TNF-alpha and IL-6 which seems to be what blocks conversion in other diseases where this has been studied. They may well do that by manipulating zinc. I don't know.

The process works because by administering calcitriol directly, no zinc-dependent conversion process is needed.

D3 then maintains remission which is a sign (among some others) that conversion is then working. Perhaps EAE mice are inherently sufficient in zinc and that may not be true in humans.

The only point I was trying to make at that calcitriol + D3 worked without zinc supplementation. Maybe it would have worked even better with it. Maybe that will be an issue in humans even though it doesn't appear to be one in EAE.

It is not that zinc is unimportant in vitD metabolism, but that the treatment with calcitriol works without zinc supplementation.

It could be an issue in humans, but not in EAE so it would certainly seem sensible that any trial of this in humans, look for deficiencies in any of the vitD co-factors such as zinc, magnesium and copper and correct them before treatment to avoid having a failure because of a deficiency.

I haven't seen any trials of vitamin D in MS that have done this, but when we are King and Queen of MS Clinical Trials, we shall simply order that it be done or off with their heads!

Again, did not mean to come across as argumentative, but was just making the point that zinc was not a factor in Hayes' experiments and they worked well without looking at zinc.

Ed

no drama, just clarifying and making distinctions between the context of the studies you're talking about, compared to the studies i'm talking about.

The problem that Hayes protocol addresses is that cells are unable to convert 25(OH)D3 to calcitriol and calcitriol is the master, regulatory hormone of the adaptive immune system.

i'm talking about the potential for zinc to correct that cellular failing. I don't go for approaches that bypass broken systems. I prefer to fix them wherever feasible. when a nutritional deficit common to ms patients is potentially involved, I personally feel it is irresponsible to ignore it in favour of a downstream supplemental substitute for endogenous calcitriol.

Perhaps EAE mice are inherently sufficient in zinc and that may not be true in humans.

I have never heard of EAE mice being matched to the nutritional deficit status typical of ms patients. I can, however, think of at least one published case where researchers used murine nutrient deficiency as a model of human illness (depression), in order to test pharmaceutical solutions. <laughing ruefully while shaking head>

The only point I was trying to make at that calcitriol + D3 worked without zinc supplementation.

understood - at this stage i am hopeful that you see my point as well.

It could be an issue in humans, but not in EAE so it would certainly seem sensible that any trial of this in humans, look for deficiencies in any of the vitD co-factors such as zinc, magnesium and copper and correct them before treatment to avoid having a failure because of a deficiency.

i agree 1000%.

I haven't seen any trials of vitamin D in MS that have done this, but when we are King and Queen of MS Clinical Trials, we shall simply order that it be done or off with their heads!

neither have i. it's a gap that continues to get on my nerves.

jimmylegs wrote:no drama, just clarifying and making distinctions between the context of the studies you're talking about, compared to the studies i'm talking about.

i'm talking about the potential for zinc to correct that cellular failing. I don't go for approaches that bypass broken systems. I prefer to fix them wherever feasible. when a nutritional deficit common to ms patients is potentially involved, I personally feel it is irresponsible to ignore it in favour of a downstream supplemental substitute for endogenous calcitriol.

Laudable goal and fair enough contention, but . . .

If zinc would have the same effect as calcitriol + D3 in EAE and possibly MS, then people with adequate zinc levels shouldn't have MS. Is everyone deficient? Are people who are not deficient free of the disease?

The other question is that studies in other diseases in which CYP27B1 is being blocked are all pointing to TNF-alpha and IL-6 as the culprits.

Will adequate zinc levels deal with them? And if so, is there anything to suggest that this is true in EAE or MS? I don't know the answer to that question. It is a question.

SqueakyCat wrote:Perhaps EAE mice are inherently sufficient in zinc and that may not be true in humans.

jimmylegs wrote:I have never heard of EAE mice being matched to the nutritional deficit status typical of ms patients. I can, however, think of at least one published case where researchers used murine nutrient deficiency as a model of human illness (depression), in order to test pharmaceutical solutions. <laughing ruefully while shaking head>

I now see you are coming at this from a slightly different perspective than I originally thought was the case, but my point that bypassing the problem of conversion to get the immune system back on track worked with calcitriol + D3 and didn't require zinc supplementation still stands.

I see now that you weren't so much questioning that as suggesting that it would be better to deal with a nutritional deficiency than to bypass the problem, even if bypassing it initially fixes the problem indicating to me since there was no zinc involved, that the root of the problem is not likely to be a zinc deficiency.

jimmylegs wrote:understood - at this stage i am hopeful that you see my point as well.

I think I do in terms of your view that you should try to address the problem at the root level of a nutritional deficiency, but I'm not convinced that this is the problem, nor that ensuring adequate zinc levels would fix it.

Squeakycat wrote:I haven't seen any trials of vitamin D in MS that have done this, but when we are King and Queen of MS Clinical Trials, we shall simply order that it be done or off with their heads!

jimmylegs wrote:neither have i. it's a gap that continues to get on my nerves.

It just makes complete sense to do this. It makes sense to investigate CCSVI. To check for and deal with potential stealth bacterial infections. To address possibly active EBV.

The calcitriol + D3 does not directly fix any of those things, although restoring the immune system to a healthy state may make it possible for the immune system to deal with them, except of course ,things like venous malformations.

I monkeyed around with a lot of quotes here. Hope I have all that right!

If zinc would have the same effect as calcitriol + D3 in EAE and possibly MS, then people with adequate zinc levels shouldn't have MS. Is everyone deficient? Are people who are not deficient free of the disease?

short answer: yes and yes, imo. zinc deficiency is poorly defined. also imho. what we can say with scientific backup is the following: technically in ms zinc is 'low normal'. this is the case for many chronic diseases. if you focus on 'healthy' status, you typically find high-normal serum zinc levels.

optimizing zinc can have marked effects on vitamin d3 status. i *can't wait* for the studies on this type of interaction to come out.
'unpublished case study': my vitamin d3 dose-response *tripled* after i identified and corrected my underlying (outright, documented, no question) zinc deficiency. (update: probably the work i had done on magnesium status was a more important factor in my much improved dose response to vit d3)

The other question is that studies in other diseases in which CYP27B1 is being blocked are all pointing to TNF-alpha and IL-6 as the culprits.
Will adequate zinc levels deal with them? And if so, is there anything to suggest that this is true in EAE or MS? I don't know the answer to that question. It is a question.

yep looks like it will:

Zinc in Human Health: Effect of Zinc on Immune Cells (2008)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277319/
"In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the up-regulation of A20 mRNA, which, via TRAF pathway, decreases NF-κB activation, leading to decreased gene expression and generation of tumor necrosis factor-α (TNF-α), IL-1β, and IL-8." "A few investigators have reported that inflammatory cytokines such as TNF-α (tumor necrosis factor-α) and IL-1β, generated by activated monocytes-macrophages, also are known to produce increased amounts of ROS (23,24). Increases in these cytokines are associated with decreased zinc status in patients.

Zinc-suppressed inflammatory cytokines by induction of A20-mediated inhibition of nuclear factor-κB (2011)
http://www.sciencedirect.com/science/ar ... 071000287X
"We confirmed that zinc-induced A20 contributes to downregulation of TNF-α and IL-1β by antisense and short interfering RNA A20 studies."

Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent (2010)
http://ajcn.nutrition.org/content/91/6/1634.short
"After 6 mo of supplementation, the intake of zinc, compared with intake of placebo, increased the concentrations of plasma zinc and decreased the concentrations of plasma high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, macrophage chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), secretory phospholipase A2, and malondialdehyde and hydroxyalkenals (MDA+HAE) in elderly subjects. "

I haven't dug deep enough to see if any studies to date have examined these interactions in ms or eae. but as you can see from the dates we are looking at quite recent academic developments. for the time being i like occam's razor, given that the relatively poor zinc status of ms patients has been established.

Good stuff. Zinc it is!

Along with calcitriol +D3.

Nothing here says that zinc alone will change status in MS, or do you read it that way?

I read it as: optimize zinc first, then test to determine if additional d3 or calcitriol are needed.

since zinc corrects overexpression of TNF-alpha and IL-6 as above, AND zinc fosters proper renal hydroxylation of D3 to calcitriol as per the studies above, AND IF vit d3 status is positively correlated with or even dependent on zinc status (a nice specific study would help here), then zinc alone may result in higher levels of endogenous d3 and calcitriol.

I think it is more likely that additional 25(OH)D3 would potentially be needed.. not so much additional supplemental 1,25(OH)2D3.

anyway, I have a deadline at midnight so better pitter patter.

jimmylegs wrote:I read it as: optimize zinc first, then test to determine if additional d3 or calcitriol are needed.

since zinc corrects overexpression of TNF-alpha and IL-6 as above, AND zinc fosters proper renal hydroxylation of D3 to calcitriol as per the studies above, AND IF vit d3 status is positively correlated with or even dependent on zinc status (a nice specific study would help here), then zinc alone may result in higher levels of endogenous d3 and calcitriol.

I think it more likely that if anything, additional 25(OH)D3 could potentially be needed.. not so much additional supplemental 1,25(OH)2D3.

Legs,

No! No! NO ! ! !

Not one of these studies suggests that you can halt MS by maintaining adequate levels of zinc. Not a single one.

Or even any of the other diseases where the problem is that 25(OH)D3 is not being converted to 1,25(OH)2D3.

And I think if it were this simple, someone would have stumbled on this besides you, no offense intended.

The problem that is overcome by a single high dose of calctiriol + D3 is that 25(OH)D3 is not being converted to calcitriol in the CNS. You can have perfectly acceptable levels of both 25(OH)D3 and calcitriol in the blood, and adequate levels of 25(OH)D3 in CSF, but still have a problem if the problem is that CYP27B1 conversion is not working.

It is only EAE and mice, but Hayes' series of studies demonstrate that D3 alone will not effect the course of EAE, but calcitriol + D3 will both stop it and keep it in remission. The calcitriol is key to this happening because it makes it directly available to cells bypassing the conversion problem.

I personally would not waste time on zinc since this works in EAE. If it didn't work, zinc might be something to look at.

I've been discussing this offline in the context of active EBV and it will not completely work there because EBV hides in B-cells and blocks the Vitamin D Receptors so making calcitriol available will not have any effect as far as B-cells where there is an active EBV infection.

If calcitriol +D3 doesn't work in MS, then I can see a reason to test zinc in EAE to see if that alone has the same effect as calcitriol + D3.

Again, I'm not disputing that it would make perfect sense to ensure adequate nutritional status before testing calcitriol + D3 in pwMS to eliminate that as a confounding factor in whether it works.

The studies you cite do suggest that it alone could have an effect in MS, but if that is so, why has this not been investigated in MS or at least EAE?

Is there any evidence that people who attain adequate zinc levels after being dx with MS go into remission? Any?

Here is one study of zinc in EAE. It does conclude that there was a reduction in severity, but compare that to a complete remission which was sustained for the duration of the study in 100% of the mice treated with calcitriol +D3:

Source URL: http://www.ncbi.nlm.nih.gov/pubmed/22350510
PMID: 22350510
DOI: http://dx.doi.org/10.1007/s10534-012-9532-z
Journal Title: Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine
Journal Date: Jun 2012
Journal Issue: 3
Journal Volume: 25
Journal First Page: 529-39
Abstract URL: http://www.ncbi.nlm.nih.gov/pubmed/2235 ... t=abstract
Article Title: Zinc aspartate suppresses T cell activation in vitro and relapsing experimental autoimmune encephalomyelitis in SJL/J mice.
Article Authors: Diana Stoye,Claudia Schubert,Alexander Goihl,Karina Guttek,Annegret Reinhold,Stefan Brocke,Kurt Grüngreiff,Dirk Reinhold

Importantly, administration of a medium range dose of 30 μg/day zinc aspartate [1.5 mg/kg body weight (BW)] in a therapeutic manner led to a significant reduction of the clinical severity of the EAE during the first relapse of the disease. A lower zinc aspartate dose (6 μg/day, 0.3 mg/kg BW) had no significant therapeutic effect on the severity of the EAE, while administration of higher zinc aspartate amounts (120 μg/day, 6 mg/kg BW) led to more severe disease. Taken together, our data suggest that zinc aspartate can modulate activation, proliferation and cytokine production of effector T cells in vitro and in vivo and that activated autoreactive T cells may be potential therapeutic targets of tightly controlled zinc supplementation in autoimmune diseases like MS.

There were four studies in 2001-2003 about Zn-MT-II in EAE that showed effect, but apparently not enough for anyone to follow up on this.

I think you are suggesting that adequate zinc plus a little D3 will have the same effect as calcitriol + D3 in EAE or maybe MS.

I just don't see support for that suggestion. It might work in MS. It might work in EAE. The studies of zinc in EAE suggest that it is helpful, but not a 100% remission and sustained remission in 100% of the the treated mice so I think what we know based on these studies is that it would not be as effective as calcitriol + D3 in EAE. We still, of course, don't know if calcitriol + D3 will work in pwMS.

I have to believe that there would at least be some anecdotal evidence that the combination of zinc and D3 adequacy would stop progression in MS if this were true. I don't see even that evidence and surely, there must be some pwMS who have tried this?

not sure where the outburst came from, and I don't have time to bother

Squeakycat wrote:Here is one study of zinc in EAE. It does conclude that there was a reduction in severity, but compare that to a complete remission which was sustained for the duration of the study in 100% of the mice treated with calcitriol +D3:

The zinc/MS question seems convoluted at best (at least in my mind at this time).

Here's an EAE study that found improvements with zinc & copper chelation...

Copper/zinc chelation by clioquinol reduces spinal cord white matter damage and behavioral deficits in a murine MOG-induced multiple sclerosis model.
Neurobiol Dis. 2013 Jun;54:382-91. doi: 10.1016/j.nbd.2013.01.012. Epub 2013 Jan 27.

• The present study aimed to evaluate the therapeutic potential of clioquinol (CQ), a metal chelator, on multiple sclerosis pathogenesis. Experimental autoimmune encephalomyelitis was induced by immunization with myelin oligodendrocyte glycoprotein (MOG(35-55)) in female mice. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were analyzed. CQ (30mg/kg) was given by gavage once per day for the entire experimental course. CQ profoundly reduced the daily clinical score and incidence rate of EAE mice. The CQ-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and reduced infiltration by encephalitogenic immune cells including CD4, CD8, CD20 and F4/80 positive cells. CQ also remarkably inhibited EAE-associated BBB disruption and MMP-9 activation. Autophagy contributes to clearance of aggregated proteins in astrocytes and neurons. The present study found that EAE increased the induction of autophagy and CQ further increased this expression. Furthermore, the present study found that post-treatment with CQ also reduced the clinical score of EAE and spinal cord demyelination. These results demonstrate that CQ inhibits the clinical features and neuropathological changes associated with EAE. The present study suggests that transition metals may be involved in several steps of multiple sclerosis pathogenesis.

So, has there been a clinical trial of zinc in actual MS patients? I would like to see that paper even if it was just a small phase Ia.

NHE wrote:The zinc/MS question seems convoluted at best (at least in my mind at this time).

NHE,
Indeed! Getting rid of metal seems to help in a number of neurodegenerative diseases.

There appears to be a very narrow Goldilocks range for most. Too little is bad. Too much is bad. But just right is therapeutic.