all things vitamin D

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Re: all things vitamin D

Postby NHE » Wed Oct 30, 2013 1:55 am

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.
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Re: all things vitamin D

Postby Squeakycat » Wed Oct 30, 2013 7:09 am

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.
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Re: all things vitamin D

Postby jimmylegs » Wed Oct 30, 2013 7:29 pm

on outright zinc deficiency in ms patients:

Serum level of iron, zinc and copper in patients with multiple sclerosis (2013)
http://jmj.jums.ac.ir/~jumsjmj/files/si ... 0187b3.pdf
Mean serum iron levels were significantly elevated in MS patients (127.04 ± 34.67) compared to these levels in the control group (103.95 ± 33.81). Mean serum zinc levels were significantly decreased in MS patients (10.92 ± 2.114) as compared to these levels in the control group (14.05 ± 3.2). Also, mean serum copper levels were significantly decreased in MS patients (88.58 ± 19.56) compared to the levels in the control group (110.37 ± 37.1).

adding zinc would work to bring the iron levels back into line.

ooo, minerals hitting the mainstream (not sure why vit d3 would not be listed here):

Consensus guidelines for the diagnosis and treatment of multiple sclerosis (2013)
http://informahealthcare.com/doi/abs/10 ... 013.787979
"Nutritional deficiency/toxicity: Vitamin B12, copper, zinc, ceruloplasmin, folate, heavy metal screen."

there is no question whatsoever in my mind that addressing deficiency would be beneficial, and that not doing so would be negligent.

the single study I can think of off hand where ms zinc levels were higher than controls, looked at erythrocytes. the altered distribution of zinc in that situation actually is another indication of underlying deficiency.

since we can anticipate correction of 25(OH)D3/1,25(OH)2D3 endogenous synthesis in the mix, so much the better to correct any zinc depletion issues that are found in patients. even leaving aside the 25(OH)D3/1,25(OH)2D3 side of things, there are always the other 300+ enzymes and 1000+ processes that require zinc.
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Re: all things vitamin D

Postby Squeakycat » Wed Oct 30, 2013 7:39 pm

jimmylegs wrote:there is no question whatsoever in my mind that addressing deficiency would be beneficial, and that not doing so would be negligent.
Jimmylegs,

Agree COMPLETELY.

When we win the lottery, we can fund the ultimate study that looks directly at counts for all the different immune cells implicated in MS and see what happens to them when you increase zinc levels.
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Re: all things vitamin D

Postby jimmylegs » Wed Oct 30, 2013 7:44 pm

had a look at the full text of the EAE chelation study. from the title the researchers appear to be manipulating nutrient levels via clioquinol, but they do not appear to have measured serum zinc or serum copper before or after. at the start of their study they have not matched the nutritional status of a typical ms patient.
for the clioquinol study results to be meaningful applied to ms patients (which is assuming a lot considering it is a murine EAE study), researchers should have started with measurably zinc deficient mice. (the mice should have been low in copper to start too, for that matter).
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Re: all things vitamin D

Postby ribeye » Thu Nov 07, 2013 1:34 pm

Hello,
Wondering how the human male dose for calcitriol and d3 regimen can be calculated. 400ng for a mouse would be how much for 100kg man. My GP is interested in this study and is willing to let me try it. He just wants a figure before dosing me.

Having a bit of a flare now and not a huge fan of prednisone.

Thanking all of you for this wonderful forum. Peace to all.
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Re: all things vitamin D

Postby THX1138 » Thu Nov 07, 2013 1:59 pm

Just remember to supplement sufficiently with magnesium also, as vitamin D uses up magnesium. There are several posts about this on this website.

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Re: all things vitamin D

Postby Squeakycat » Thu Nov 07, 2013 2:18 pm

ribeye wrote:Hello,
Wondering how the human male dose for calcitriol and d3 regimen can be calculated. 400ng for a mouse would be how much for 100kg man. My GP is interested in this study and is willing to let me try it. He just wants a figure before dosing me.

Having a bit of a flare now and not a huge fan of prednisone.

Thanking all of you for this wonderful forum. Peace to all.


A rough figure for the weight of a mouse is 25 grams so the ratio to the weight of a 100 kg human is 100x1000/25 = 4000.

4000 x 400 ng = 1,600,000 ng = 1,600 mcg. Maximum Tolerated Dose for calcitriol is between 74 mcg and 120 mcg.

120 mcg was the lowest effective dose in female mice so may be sufficient to have an effect.

Calcitriol will have to be compounded since the maximum shipping dose is 0.5 mcg. It is available from most scientific chemical suppliers such as Caymen Chemicals who I know manufacturers in the US as opposed to Chinese white powder suppliers.
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Re: all things vitamin D

Postby Squeakycat » Thu Nov 07, 2013 2:23 pm

ribeye wrote:Hello,
Wondering how the human male dose for calcitriol and d3 regimen can be calculated. 400ng for a mouse would be how much for 100kg man. My GP is interested in this study and is willing to let me try it. He just wants a figure before dosing me.

Having a bit of a flare now and not a huge fan of prednisone.

Thanking all of you for this wonderful forum. Peace to all.


The equivalent human dose of D3 is 4,240 IU/day.

Also, the mice were given a loading dose of D3 aimed at raising their levels to 120 nmol/L (50 ng/ml). The formula for the loading dose is based on your current 25(OH)D3 level.

Loading dose in IU = 40 x (120 nmol - Current 25(OH)D3 level in nmol) x weight in kg

In addition to ascertaining your 25(OH)D3 level, it is important to ensure that kidneys are functioning properly based on BUN and Creatinine levels and that both calcium and phosphorous levels are within normal limits.

The body clears excess calcitriol within 6-8 hours.
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Re: all things vitamin D

Postby ribeye » Sat Nov 16, 2013 11:41 am

Has anyone tried a megadose of calcitriol yet? If I am able to get the go ahead, I will do it. A controlled study would be great but none on my radar so far. Also, what can someone expect to feel when dosed so highly. Is the MTD the absolute limit? Thanks for all of the great info.
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Re: all things vitamin D

Postby Squeakycat » Sat Nov 16, 2013 3:13 pm

ribeye wrote:Has anyone tried a megadose of calcitriol yet? If I am able to get the go ahead, I will do it. A controlled study would be great but none on my radar so far. Also, what can someone expect to feel when dosed so highly. Is the MTD the absolute limit? Thanks for all of the great info.

No one yet, that I know of, but a lot of eager volunteers.

The MTD is far from the absolute limit and it was tested in the context of a weekly dose at this level. In the study, the highest IV dose was 96 mcg, and some testing was done at 168 mcg orally. I'm still looking, but I know that in at least one cancer study, a dose over 300 mcg was tested and that study may have gone as high as 500 mcg.

In the dosing study, as far as I can tell from the study itself, the hypercalcemia was based on lab values, not clinical signs.

The effects of hypercalcemia are generally, nausea, vomiting, diarrhea (and constipation), muscle weakness, excessive thirst, frequent urination, fatigue and lethargy and mental confusion.

Calcitriol should clear the body within 6-8 hours and the standard treatment for hypercalcemia is to withdraw further doses. Since the protocol is a single dose, that is already done. Other treatment for hypercalcemia, usually induced by problems with the parathyroid glands include methylprednisolone, IV fluids, and loop diuretics such as furosemide.

Hoping to have some news on a formal trial soon. The main question is funding.
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Re: all things vitamin D

Postby Andrey » Sun Dec 15, 2013 4:10 pm

Is there any significant risk in trying the one dose of calcitriol and d3 regimen afterwards?

I have been taking d3 for almost a year daily (5.000-10.000 iu in the form of vit. d3 water based drops) having my blood checked for d3 and calcium/creatinin levels every 2-3 months. The d3 levels varied from 80 to 150 nmol... Currently yet I see no reasons change this regimen. So why not try to add one dose of calcitriol?

Theoretically, could I face significant risks if I have a dose of calcitriol and continue my "standard" d3 regimen? Maybe this single calcitriol dose will so much "enchance" current d3 regimen?! (who knows, maybe those mice are not the only lucky ones :) ) Or just don't do anything... Or?

Please share what do you think. What could be this "one dose" of calcitriol for a male of 80 kg? Calcitriol is avaliable here in the form of tablets (0.25 and 0.5 microgramms (one of those tablets come from the copaxone producer Teva :) )

If I understand correctly the worst scenario - is to see signs of hypercalciemia (to check for it I could have a bloodtest every 2 weeks for couple of months) and to quickly react accordingly (stopping d3 and lowering calcium intake), possibly having some positive outcome (like mice?? :) ) So WHY NOT?

Ideas and thoughts would be very helpful!!!

Andrey



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I perfectly realize that all this (if done) is under my own risk and I would not advise anyone to follow these ideas without a doctor's (at least a GP) instruction as there could be unpredictable adverse effects. These are all just hypothetical ideas.
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Re: all things vitamin D

Postby Squeakycat » Sun Dec 15, 2013 5:26 pm

Andrey wrote:Is there any significant risk in trying the one dose of calcitriol and d3 regimen afterwards?

I have been taking d3 for almost a year daily (5.000-10.000 iu in the form of vit. d3 water based drops) having my blood checked for d3 and calcium/creatinin levels every 2-3 months. The d3 levels varied from 80 to 150 nmol... Currently yet I see no reasons change this regimen. So why not try to add one dose of calcitriol?

Theoretically, could I face significant risks if I have a dose of calcitriol and continue my "standard" d3 regimen? Maybe this single calcitriol dose will so much "enchance" current d3 regimen?! (who knows, maybe those mice are not the only lucky ones :) ) Or just don't do anything... Or?

Please share what do you think. What could be this "one dose" of calcitriol for a male of 80 kg? Calcitriol is avaliable here in the form of tablets (0.25 and 0.5 microgramms (one of those tablets come from the copaxone producer Teva :) )

If I understand correctly the worst scenario - is to see signs of hypercalciemia (to check for it I could have a bloodtest every 2 weeks for couple of months) and to quickly react accordingly (stopping d3 and lowering calcium intake), possibly having some positive outcome (like mice?? :) ) So WHY NOT?

Ideas and thoughts would be very helpful!!!

Andrey



P.S.
I perfectly realize that all this (if done) is under my own risk and I would not advise anyone to follow these ideas without a doctor's (at least a GP) instruction as there could be unpredictable adverse effects. These are all just hypothetical ideas.
The risks associated with calcitriol are minimal and well known, but the issue at the moment is to figure out what dose is needed in humans to have the same effect that it had in mice and then be sure there are no adverse effects of that dose in people with MS.

Calcitriol has a very short half life. It is used or degraded within 6-8 hours so any effect should be transient. But because the goal is to raise CNS levels, a high dose is required, though it may turn out that it isn't all that high compared with some doses that have been tested in people with cancer.

The target 25(OH)D3 level is 125 nmol/L.

Before taking a high dose of calcitriol, it would be important to ascertain that Calcium and Phosphorous levels are normal was well as kidney function (BUN and creatinine).

The risk of raising your 25(OH)D3 levels to one that has "significant" risk of hypercalcemia is minimal.

Without dose escalation testing, there really is no way to know what dose will have the same effect in humans as it did in the EAE mice. Calculations based on weight and surface area for the lowest dose to have effect in mice range from 10 mcg to 120 mcg, but there is simply no way of knowing whether either dose will have the same effect short of testing.

The good news is that because it is possible to measure the effect on immune cells, there is a quite objective way to directly measure the effectiveness within hours of the calcitriol dosing so a small, short dose escalation trial should quickly give us an answer to what dose is needed for effect. That can then be followed up with a larger trial to test the safety of that dose in pwMS. Again, the results will be known in days, not weeks or years.

These trials are currently being planned. As soon as the details are known, a budget will be put together and then we are going to have to raise money to get this testing done. Preliminary estimates are that it could easily be done for less than the cost of three people taking Gilenya, Tecfidera, or Tysabri for a year.
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Re: all things vitamin D

Postby Andrey » Sun Dec 15, 2013 7:07 pm

Maybe we need to ask some MS organization to make and fund such trial as soon as possible (or I hope they are doing that already) ! There should be some possibilites to accelerate this process not to wait years for the results... Doest need FDA approval :)

Even ccsvi was investigated a lot in the past couple of years and that was way more complicated and expensive...

Do you know what calciteiol+d3 regimen trials exist and where do they happen?
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Re: all things vitamin D

Postby Squeakycat » Sun Dec 15, 2013 7:19 pm

Andrey wrote:Maybe we need to ask some MS organization to make and fund such trial as soon as possible (or I hope they are doing that already) ! There should be some possibilites to accelerate this process not to wait years for the results... Doest need FDA approval :)

Even ccsvi was investigated a lot in the past couple of years and that was way more complicated and expensive...

Do you know what calciteiol+d3 regimen trials exist and where do they happen?
A small group of us have committed to fundraising through three existing organizations as soon as the design of a trial is finalized.

This should get us the fastest results. Applying to MS organizations will take a long time and there is no guarantee of getting funding for a trial like this.
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