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DIRECT-MS sponsors a vitamin D trial

Postby Nick » Fri Sep 22, 2006 3:28 pm

A Dose/Safety Study of Vitamin D for Persons with Multiple Sclerosis

Introduction – Beginning in 2000, Direct-MS has strongly advocated the use of adequate vitamin D supplementation for the prevention and treatment of multiple sclerosis. Since that time we have also actively promoted the need for clinical research to test the effectiveness of vitamin D for preventing and treating MS. Before clinical trials to test the efficacy of vitamin D for MS can be done, it is necessary to determine the optimal dosage of vitamin D to use in such a trial. Direct-MS chose to fund this preliminary “Dose/Safety” study for vitamin D to ensure that the necessary clinical research on the efficacy of vitamin D for MS happens as soon as possible.

Leaders – The chief investigator of the clinical research is Dr Paul O’Connor, Clinical and Research Neurologist, Chief, Division of Neurology and Director of the MS Centre at St Michael’s Hospital in Toronto. Dr O’Connor has assembled a large and impressive team of researchers for this trial. They include Dr Jodie Burton, Co-investigator, MS Clinical Fellow, St. Michael’s Hospital, University of Toronto; Dr Melanie Ursell, Co-investigator, Staff, Division of Neurology, St. Michael’s Hospital; Dr Reinhold Vieth, Co-investigator. Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto; Samantha Kimball, Co-investigator. Master of Science Student, Department of
Nutritional Sciences, University of Toronto; Dr. Louise Thibault Professor, School of Dietetics and Human Nutrition, McGill University, Montreal; Sally Kilborn, Master of Science Student, School of Dietetics and Human Nutrition, McGill University; Dr. H. Michael Dosch, Co-investigator. Professor of Immunology, University of Toronto and the Hospital for Sick Children, Toronto; Dr Amit Bar-Or, Co-investigator. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal; Dr Cheryl D’Souza, Centre for Research in Neurodegenerative Diseases, University of Toronto. .


Ethics – The study has been approved by the Ethics Boards of St Michael’s Hospital and McGill University.

Goals
– The main goal of the study is to determine the optimal dose of vitamin D to use in a subsequent clinical trial which will test the efficacy of vitamin D for affecting disease activity in MS. Such an optimal dose will be the maximum dose which is well tolerated without any adverse side effects and which also has a significant effect on immune activity.
A second objective is to determine if there are any positive effects of higher doses of vitamin D3 on bone health in people with MS.
A third objective is to examine the relationship between diet and MS especially vitamin D intake from food sources.
A fourth objective is to examine the effect of vitamin D on mood and feelings of well-being of the participants.

Methods – The study will involve 30 participants, all of whom have MS (RRMS, SPMS or PPMS) and will last one year. Each participant will be given an increasing dose of vitamin D3 starting at 28,000 IU per week (4000 IU/d). The dose of vitamin D3 will be gradually increased every 2 to 6 weeks to the highest dose of 280,000 IU per week (40,000 IU per day). After the highest dose is taken for 6 weeks, the dose of vitamin D3 will be lowered to a maintenance dose of 70,000 IU per week (10,000 IU per day) that will be taken for 12 weeks. The dose of vitamin D3 will then be lowered again to 28,000 IU per week (4000 IU per day) taken for another 8 weeks. 1200 mg of calcium will be taken daily during the entire study.
Blood and urine samples will be obtained every month and analyzed to determine if any anomalous calcium or creatinine/calcium ratios are present in any of the participants. The blood samples will also be analyzed for immunological markers of inflammation and blood brain barrier integrity (cytokine profiles, lymphocyte response measures and matrix metalloproteinases) and the proportion of change in bone turnover markers. Measures of well being will be assessed using the Hospital Anxiety and Depression Scale questionnaire.

To examine dietary habits and amounts of nutrients participants get in the diet, particularly vitamin D, they will be asked to complete a “Food Frequency Questionnaire”. In addition, a “24-hour recall” food questionnaire will be given.

Results – The blood tests will determine if high doses of vitamin D3 have any adverse effects on calcium levels in the body. Such adverse effects include the elevation of serum calcium levels above normalized ranges (range 2.1-2.6 millimoles per liter) or urinary calcium:creatinine ratios above 1.0. The measurement of immunological markers will allow the determination of the effects of the various doses of vitamin D3 on immune activity. These two data sets will allow an optimal dose of vitamin D to be determined. Such a dose will be used in subsequent clinical trials for MS and possibly other diseases related to vitamin D deficiency (e.g. prostate cancer).
The other studies mentioned above will provide insight into the value of higher doses of vitamin D for preventing and treating osteoporosis and for treating depression.

Discussion – This clinical trial is basically a “Phase I” trial meaning it is designed to determine the metabolism and pharmacologic action of vitamin D3 in humans, the side effects associated with increasing doses, and evidence of effectiveness for treating immune reactions related to MS disease activity.

Such a trial must be done before any proper clinical trial on the effectiveness of optimal doses of vitamin D for treating MS can be initiated.

Cheers
Nick
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Seeking more details

Postby lyndacarol » Fri Sep 22, 2006 5:16 pm

Nick, I thought someone here had already posted an abstract about such a completed study (done over 7 months, I think).

This sounds as if it is proposed for the future. When is it scheduled tentatively to begin? Has this study completed the enrollment of participants? Do you (Direct-MS) have any input on this project since you have "strongly promoted the need for clinical research...."? Could you suggest that, among objectives, researchers determine if there are any effects of high doses of vitamin D3 (positive or otherwise) on insulin levels?
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Re: Seeking more details

Postby Nick » Wed Sep 27, 2006 2:57 pm

Hi Lynda

lyndacarol wrote:Nick, I thought someone here had already posted an abstract about such a completed study (done over 7 months, I think).?


You are partially correct. Part 1 of this trial has been completed but over a shorter duration than 7 months. We are funding the second segment for a longer duration which should provide evidence of a significant effect on immune activity.


lyndacarol wrote:This sounds as if it is proposed for the future. When is it scheduled tentatively to begin?


It is already underway to my knowledge.


lyndacarol wrote: Could you suggest that, among objectives, researchers determine if there are any effects of high doses of vitamin D3 (positive or otherwise) on insulin levels?


These are the items to be tested for:

Physical and neurological exam
(including EDSS and AI scores)
Routine blood work:
-calcium, albumin
-creatinine, urea, liver enzymes
-parathyroid hormone, vitamin D3
Urine samples:
-calcium, creatinine, +/- blood
Urine kit home collection of 2 urine samples for you to bring to next visit
Matrix Metalloproteinases
Lymphocyte response assay
Cytokine profiling
Bone marker testing:
Bone Alkaline Phosphatase (in blood)
N-Telopeptide (in urine)
Hospital Anxiety and Depression Questionnaire
Electrocardiogram (ECG)
Renal (kidney) ultrasound
Food Frequency Questionnaire
24-Hour Food Recall Questionnaire

I don't have influence over what is being measured. you would have to contact the researchers directly to test your theory. I suspect though you would be too late.

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Nick
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Vitamin D and latitude

Postby dignan » Tue Dec 05, 2006 9:30 am

Interesting study on vit D and latitude in the U.S.



Location and Vitamin D synthesis: Is the hypothesis validated by geophysical data?

J Photochem Photobiol B. 2006 Dec 1;
Kimlin MG, Olds WJ, Moore MR.
Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Kelvin Grove, Qld, 4059 Brisbane, Australia.

The literature reports strong correlations between UV exposure and latitude gradients of diseases. Evidence is emerging about the protective effects of UV exposure for cancer (breast, colo-rectal, prostate), autoimmune diseases (multiple sclerosis, type II diabetes) and even mental disorders, such as schizophrenia. For the first time, the available levels of vitamin D producing UV or "vitamin D UV" (determined from the previtamin D action spectrum) and erythemal (sunburning) UV from throughout the USA are measured and compared, using measurements from seven locations in the USA are measured and compared, using measurements from seven locations in the US EPA's high accuracy Brewer Spectrophotometer network.

The data contest longstanding beliefs on the location-dependence and latitude gradients of vitamin D UV. During eight months of the year centered around summer (March-October), for all sites (from 18 degrees N to 44 degrees N latitude) the level of vitamin D UV relative to erythemal UV was equal (within the 95% confidence interval of the mean level). Therefore, there was no measured latitude gradient of vitamin D UV during the majority of the year across the USA. During the four cooler months (November-February), latitude strongly determines vitamin D UV. As latitude increases, the amount of vitamin D UV decreases dramatically, which may inhibit vitamin D synthesis in humans. Therefore, a larger dose of UV relative to erythemal UV is required to produce the same amount of vitamin D in a high latitude location. However, the data shows that at lower latitude locations (<25 degrees N), wintertime vitamin D UV levels are equal to summertime levels, and the message of increasing UV exposure during winter is irrelevant and may lead to excessive exposure.

All results were confirmed by computer modeling, which was also used to generalize the conclusions for latitudes from 0 degrees to 70 degrees N. The results of this paper will impact on research into latitudinal gradients of diseases. In particular, it may no longer be correct to assume vitamin D levels in populations follow significant latitude gradients for a large proportion of the year.

Pubmed reference
Last edited by dignan on Tue Dec 05, 2006 9:19 pm, edited 1 time in total.
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Postby LisaBee » Tue Dec 05, 2006 7:49 pm

I saw this one too, and it was interesting. I couldn't figure out a couple of things from the abstract though, that is, when they talked about vitamin D UV (I presume this is UVB) and erythemal UV (I presume this is UVA). I don't know if this presumption is correct without seeing the whole paper, but I'll use it as shorthand. They state that the ratio of UVB and UVA are the same over a gradient of latitude during all but winter months. I doubt though that the even if the ratios of the two wavelengths are equal, that the absolute UV radiation strength is equal across all latitudes. It can't be. I burn very easily, and the farther south I go in the US, the less time it takes me to burn in the sun. Even within the state of Florida, I can tell a difference between the northern and central/southern sections of the state. Conversely, I visited St. Petersburg, Russia, in the summer and was able to walk around in sunlight 2-3 hours with no sunscreen on and not burn. Admittedly, I was much further north than the continental US, but the same is true in San Francisco vs. Florida - I could spend maybe 30-45 minutes in the sun in San Francisco (if there is sun in the summer!) - that length of time would literally cook me in south Florida sunlight in the summer.

The abstract seems to suggest that people stay out in the sun, wherever they are, as long as they can without burning, so that overall, their UV dose would be equal. But this isn't true, because it presumes people would stay outside longer up in Vermont than Florida. If my UVA dose to start to burn in Miami is five minutes, I can also get an appreciable UVB dose in five minutes but just walking across a parking lot. If I am in Vermont, it might take me, say 30-45 minutes to get the same dose. If the only time I am outside in Vermont is walking to and from my car, I'll only get a fraction of the Miami dose of both UVA and UVB.

The real measure of vitamin D synthesis from sunlight would be to collect both blood levels in people in different latitudes and measure their UV dose while they wear some kind of personal monitor or badge. This has actually been done in some studies. There would still have to be some sort of adjustment for the amount of skin actually exposed to sunlight and skin pigmentation (dark skin less efficient) and age (elders less efficient).

Or maybe someone could get the whole paper and read it for me - I just can't figure it all out from the abstract.....
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UVA vs. UVB

Postby lyndacarol » Tue Dec 05, 2006 9:02 pm

LisaBee, you know I am no scientist. And I can't claim to understand the posted abstract concerning Vitamin D, but I will hope to understand more after going over it a few more times.

From other sources I have read that UVB is responsible for sunburn as well as the source for Vitamin D manufactured in the skin. UVA is the culprit in aging and wrinkles.

It seems to me there must be distinct subcategories within UVB (or the researchers are trying to link the two effects of UVB, since one is obvious and indicates the level of the other, not-obvious-without-testing).
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Postby dignan » Tue Dec 05, 2006 9:24 pm

See if this helps...I haven't read it yet...

http://www.niwascience.co.nz/rc/atmos/u ... 6/Olds.pdf
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Postby LisaBee » Thu Dec 07, 2006 5:43 pm

Thanks, lyndacarol and dignan! You both cleared up some confusion for me. lyndacarol, I actually am a scientist of sorts, but that doesn't mean I'm right :wink:

lyndacarol, you are right that UVB radiation, the kind associated with vitamin D production in the skin, is also primarily the wavelength of UV that promotes skin burning. Some burning capability though, extends into the UVA range. UVA is less effective than at causing sunburn, but it can still happen with a long enough exposure. I used the terms incorrectly and when I have more time I'll try to correct my initial posted response. What the Olds and Kimlin paper that dignan showed is that the vitamin D production, even within the UVB range of 280-320 nm, falls off more quickly than the erythemal response as the wavelength of UV increases. It is easier to see on Figure 1 of the paper dignan linked to than it is to describe.

Given the clarification in Olds and Kimlin paper, I think I understand the Olds et al. 2006 abstract a little better now, but stil not completely. They are saying, I think, that there may be circumstances where the dose of erythemal UV may be high, but still not trigger significant vitamin D production, and therefore a standard "UV index" may not be good enough for indicating the potential for Vitamin D production.

I agree with them on that. I still don't think their findings argues against a gradient. I suspect, if you took two populations, one at high latitude, one at low, with similar diet and skin coloration, and similar time spent in sunlight, the group at the lower latitude (closet to equator) will have, on average, higher serum vitamin D levels than those further from the equator. If you were able to control for amount of skin exposed (hard to do in cold weather!) between the two groups that would elminate another confounder, at least as far as correlating strength of vitamin D producing UV with latitude.

However, people at lower latitudes in the US don't necessarily have a lot of sun exposure and may be vitamin D deficient due to their clothing and lifestyle. In the Olds and Kimlin conference paper, the authors note that 8% of Queensland Australia residents were deficient in vitamin D, yet that area of Australia has the highest incidence of skin cancer. The question I have is whether the 8% Queensland residents that were deficient in Vitamin D have evidence of concurrent significant sun exposure. I sort of doubt that would occur, but if it did it would be interesting (and puzzling).

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Vitamin D protects against MS, large study suggests

Postby Nick » Tue Dec 19, 2006 8:24 pm

Vitamin D protects against MS, large study suggests

An abundance of vitamin D seems to help prevent multiple sclerosis, according to a study in more than seven million people that offers some of the strongest evidence yet of the power of the "sunshine vitamin" against MS. The research found that white members of the U.S. military with the highest blood levels of vitamin D were 62 per cent less likely to develop multiple sclerosis than people with low levels.

There was no such connection in blacks or Hispanics, possibly because there were so few in the group studied. Also, the body makes vitamin D from sunlight, and the pigmented skin of blacks and other dark-skinned ethnic groups doesn't absorb sunlight as easily as pale skin.
The new research echoes findings in smaller studies that examined why the nerve-damaging disease historically has been more common in people who live in regions farther from the equator where there is less intense year-round sunlight.

"This is the first large prospective study where blood levels are measured in young adults and compared to their future risk. It's definitely different and much stronger evidence," said Dr. Alberto Ascherio, the senior author and an associate professor of nutrition at Harvard's School of Public Health.The study appears in Wednesday's Journal of the American Medical Association.

"If confirmed, this finding suggests that many cases of MS could be prevented by increasing vitamin D levels," Ascherio said. Still, he said the findings don't prove that a lack of vitamin D can cause MS, so it's too preliminary to recommend that people take vitamin D pills to avoid the disease.

Vitamin D is also found in fortified milk and oily fish, but it's hard to get enough just from diet. Sunlight is the biggest source of vitamin D, which is needed for strong bones. Other studies have linked high levels of vitamin D in the blood to lower risks of a variety of cancers. The MS researchers worked with the U.S. army and navy in analyzing blood samples of military personnel stored by the Department of Defence.

Vitamin deficiency in young people

Military databases showed that 257 service men and women were diagnosed with MS between 1992 and 2004. The increased MS risk was especially strong in people who were younger than 20 when they entered the study. The researchers said that finding suggests that vitamin D exposure before adulthood could be particularly important.
Using blood samples to measure vitamin D levels "tends to nail it down in a much more reliable way" than studies that have relied on people's memories of vitamin D exposure, said Dr. Nicholas LaRocca of the National Multiple Sclerosis Society.

MS is among the most common nerve disorders affecting young adults, mostly women. Canada has the highest incidence in the world at 240 cases among every 100,000 people, according to a study by a University of Calgary team published in the journal Multiple Sclerosis in 2005.
Around two million people worldwide have MS, a chronic autoimmune disease in which the body attacks the fatty insulation that surrounds nerve fibres.

Ascherio said there's some evidence that its incidence is increasing in sunny regions including the South and West, possibly because people are avoiding the sun or using sunscreen to protect against skin cancer. Some doctors think those practices also have contributed to vitamin D deficiencies in adolescents and young adults.

"There's no question that vitamin D deficiency is an epidemic in the United States," said Dr. William Finn, a vitamin D expert at the University of North Carolina at Chapel Hill. The MS study "is just one more reason to pay attention to it."

MS symptoms vary but can be disabling and can include tingling pain in the arms and legs, fatigue and vision problems. Doctors believe it is genetic and perhaps triggered in susceptible people by environmental causes, including possibly some viruses. Vitamin D deficiency could be another trigger.

It's unclear how lack of vitamin D might contribute. In mouse experiments, the vitamin stimulated production of chemicals that fight an MS-like disease.

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Nick
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links

Postby notasperfectasyou » Thu Dec 21, 2006 3:02 pm

I thought I’d start a list of links to Vitamin D articles that might help folks assimilate this information faster. It’s not a new topic. You can tell from the dates on some of these articles that it’s been around a while.

The Role of Vitamin D in Multiple Sclerosis

Vitamin D intake and incidence of multiple sclerosis

Vitamin D and multiple sclerosis

Genetic analysis of vitamin D related genes in Canadian multiple sclerosis patients

Vitamin D and Autoimmunity: Is Vitamin D Status an Environmental Factor Affecting Autoimmune Disease Prevalence?

A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing–remitting multiple sclerosis

Mounting Evidence for Vitamin D as an Environmental Factor Affecting Autoimmune Disease Prevalence

That’s just a few. There are a lot more. Infact in some of these pages you can get cites of other artciles that cited that article. If you want me to post more links like this I will.

My gut tells me that Vitamin D is more so linked to prevention and likely does a lot less once you have MS. But, we’re still taking 4000 IU’s of D3 daily. D3 is one of the cheaper supplements that’s on the MS list. napay
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good one

Postby jimmylegs » Fri Dec 22, 2006 6:57 am

great start napay :D

d
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Re: good one

Postby notasperfectasyou » Fri Dec 22, 2006 11:41 am

jimmylegs wrote:great start napay :D

d


Thanks Jimmy. I'm hoping that by providing links others might read the basic research and post conclusions here. It honestly takes me too long to do posts the way I have in the past. I need the folks here to help synthesis the info.

My search on Vitamin D Multiple Sclerosis came up with over 2000 hits on Journal articles. I spent an hour typing out the above post.........

napay
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Postby jimmylegs » Fri Dec 22, 2006 1:55 pm

ya it is sure a ton of work. your time spent is well worth it and just having the links available are a great big help
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New recommendations for vitamin D intake

Postby Nick » Tue Jan 09, 2007 4:06 pm

Risk assessment for vitamin D

John N Hathcock, Andrew Shao, Reinhold Vieth, and Robert Heaney

ABSTRACT

The objective of this review was to apply the risk assessment methodology
used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D.

New data continue to emerge regarding the health benefits of vitamin Dbeyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitaminD intakes. The UL established by the FNB for vitaminD(50 microg, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL.

We present a risk assessment based on relevant, well-designed human
clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose gt/=250 microg/d (10,000 IU vitamin D3) supports the confident selection of this value as the UL.

Am J Clin Nutr 2007;85:6 –18.

This article is available for reading here.

Cheers
Nick
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Postby JFH » Wed Jan 10, 2007 2:57 am

Glad you posted that Nick, thankyou.
John
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