Friday, 10 April 2015

Biotin Time

This time in a fortnight it will be Biotin day....Why because on friday 24th you may have the closest thing to the clinic with MD1003. There is a plenary session talk at the American Academy of Neurology.....would this happen for a negative trial?......Maybe. There have been questions about what is biotin

Biotin, also known as vitamin H or coenzyme R,is a water-soluble B-vitamin (vitamin B7).It is composed of a ureido (tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring. A valeric acidsubstituent is attached to one of the carbon atoms of the tetrahydrothiophene ring. Biotin is a coenzyme forcarboxylase enzymes, involved in the synthesis of fatty acids, isoleucine, and valine, and in gluconeogenesis.

The only human health condition for which there is strong evidence of biotin's potential benefit as a treatment is biotin deficiency.This week we will hear whether it is useful in MS

Biotin is necessary for cell growth, the production of fatty acids, and the metabolism of fats and amino acids. Biotin assists in various metabolic reactions involving the transfer of carbon dioxide. It may also be helpful in maintaining a steady blood sugar level. Biotin is often used as a dietary supplement for strengthening hair and nails, though scientific data supporting this outcome are weak. Nevertheless, biotin is found in many cosmetics and health products for the hair and skin.

Biotin deficiency is rare because, in general, intestinal bacteria produce biotin in excess of the body's daily requirements. For that reason, statutory agencies in many countries, for example the USA and Australia, do not prescribe a recommended daily intake of biotin. (There you go a use for microbiota hurray). However, a number of metabolic disorders exist in which an individual's metabolism of biotin is abnormal, such as deficiency in the holocarboxylase synthetase enzyme which covalently links biotin onto the carboxylase, where the biotin acts as a cofactor.

Biotin is consumed from a wide range of food sources in the diet, but few are particularly rich sources. Foods with a relatively high biotin content include peanuts, Swiss chard and other leafy green vegetables, raw egg yolk (however, the consumption of avidin (which binds to biotin)-containing egg whites with egg yolks minimizes the effectiveness of egg yolk's biotin in one's body), liver, and Saskatoon berries. The dietary biotin intake in Western populations has been estimated to be 35 to 70 μg/d (143–287 nmol/d). Biotin is also available in supplement form and can be found in most pharmacies.

Animal studies have indicated few, if any, effects due to high level doses of biotin and the half lethal dose in rodents is about 5-6g/kg, so a 100mg tablet is about 1mg/kg. In the study it will be three times a day.

Energy is essential to cellular function and we can get this energy by metabolizing carbohydrates, proteins, and fats. The Kreb's Cycle is a critical component for macronutrient metabolism and energy conversion. The complete metabolism for each of them must, at some point, go through the Kreb's Cycle. 

 (Read on or go to ******)

The Kreb's cycle takes place in the mitochondria of the cell. This cycle is a series of chemical intermediates that are transformed to another intermediate by enzymes specific to that step in the cycle. Each step is catalyzed by a specific enzyme. The cycle starts with oxaloacetate and ends with oxaloacetate. The cycle produces 1 ATP, 3 NADH, and 1 FADH2 per turn. If you recall from glycolysis, two pyruvates are produced per molecule of glucose. Pyruvate is converted to acetyl CoA which enters the Kreb's cycle. Therefore, one molecule of glucose eventually creates 2 turns of the krebs cycle.

Kreb's Cycle EnergyThe 2-carbon acetyl portion of acetyl CoA is oxidized to 2 CO2 molecules during the cycle.

Some amino acids can enter at different steps in the Kreb's cycle. During the metabolism of odd chain fatty acids, one three carbon molecule remains at the end. It enters the Kreb's cycle at the Succinyl CoA step. Thus, the Kreb's cycle is very important for energy production from all food supplies.

The first step in the Krebs Cycle is the formation of citrate from the combination of oxaloacetate and Acetyl CoA. The acetyl group from acetyl CoA is added to oxaloacetate forming citrate via the enzymecitrate synthase. The CoA from acetyl CoA leaves as CoASH. Not much else occurs at this step. Citrate inhibits citrate synthase (product inhibition). So does succinyl CoA by competitive inhibition.

Citrate is converted to isocitrate by the action of aconitase. Again, not much occurs here.

Isocitrate DH acts on isocitrate, converting it to α-ketoglutarate, producing an NADH and CO2 (carbon dioxide) in the process. The carbon that forms CO2 comes from the acetyl group that enters the cycle. This is our first yield from the Kreb's cycle. The removal of carbon dioxide is termed oxidative decarboxylation

NADH inhibits isocitrate DH (product inhibition). NADH product inhibition provides control over three steps in the Kreb's cycle. Since there are only 4 controlled steps in Kreb's, NADH is an important control mechanism. This step is also controlled (enhanced) by increased ADP and calcium.

This is a pretty big and important step. The α-ketoglutarate DH complex acts upon α-ketoglutarate ultimately forming Succinyl CoA. This enzyme complex is described in fair detail in the pyruvate to acetyl CoA step. However, it should be noted that the α-ketoglutarate DH complex is just one of a family of enzymes that oxidatively decarboxylate these a-keto acids. There is an oxidative decarboxylation occuring here (the 2nd carbon from the acetyl entering the Kreb's). In other words, CO2 is released. CoASH is needed and NADH is also produced. Some amino acids (BCAA's) and the 3-carbon molecule remaining after beta oxidation of odd chain fatty acids enter the Kreb's Cycle at this step by being acted upon by this enzyme complex.

NADH inhibits this enzyme complex (as described previously). As NADH concentrations increase, the Kreb's cycle slows down.

All of the remaining intermediates in the Kreb's cycle are four carbon molecules.

This step produces NADH and allows other energy sources (such as AA's and fatty acids) to enter here.

The CoASH that went into step 4 comes off here. Succinate thiokinase acts upon succinyl CoA removing the CoASH and forming succinate. The energy from its release fuels the formation of GTP. Some would say that the GTP fuels the conversion of ADP to ATP (that's where we get the ATP discussed in the overview).

Two pairs of electrons from the acetyl group of acetyl CoA remain even though the carbons have been removed as carbon dioxide. The remaining steps in the Kreb's cycle are transferred to NAD+ and FAD and ultimately reforming oxaloacetate.

In this step, succinate DH acts upon succinate forming fumarate and converting FAD to FADH2. The FAD accepts one of the pairs of electrons that remain. Now only one pair of electrons from the original acetyl group remain in fumarate.

Succinate DH resides within the inner mitochondrial membrane. It binds FAD fairly tightly. All of the other enzymes involved in the Kreb's cycle are located in the mitochondrial matrix.

The only thing that happens in this step is that water is added to fumarate. The enzyme fumarase adds a hydroxyl group and a proton (from the water) to fumarate converting it to malate.

This is the final step of the Kreb's cycle. It is the final step because the intermediate that we added acetyl CoA to, oxaloacetate, is reformed. The final pair of electrons from the original acetyl group are donated to NAD+ forming NADH. The enzyme that catalyzes the reaction is malate DH.

NADH inhibits this step.

In case I haven't mentioned it earlier, there are five co-enzymes needed for the Kreb's cycle to function properly. They have been mentioned in the steps but I didn't specifically point them out (as I will do now). They are: NAD+, FAD, thiamine pyrophosphate, lipoate (lipoic acid), and CoA.

As mentioned earlier, other molecules (such as fats and amino acids) can enter the Kreb's cycle at different locations to produce energy. For example, during periods of long-duration, low to moderate-intensity exercise (aerobic), beta-oxidation of odd-chain fatty acids may enter the Kreb's at the alpha-ketoglutarate DH step. However, when these products must be synthesized, these intermediates have to be pulled out of the cycle. Citrate and malate may be pulled out of the cycle for product synthesis. This would result in a deficiency of the 4-carbon intermediates. Fortunately, there are reactions that re-supply these intermediates. They are called anaplerotic reactions. An example of one of these reactions is the conversion of pyruvate and carbon dioxide to form oxaloacetate. 
The enzyme that catalyzes this reaction is pyruvate carboxylase. This enzyme must have biotin in order for it to function properly.
***********************************************
Biotin is a water-soluble vitamin that serves as an essential coenzyme for carboxylases catalyzing the transfer of a carboxyl (COOH) group to targeted substrates . The five biotin-dependent carboxylases are: pyruvate carboxylase (PC), propionly-CoA carboxylase (PCC), β-methylcrotonyl-CoA caboxylase (MCC), and acetyl-CoA carboxylase (ACC), with the latter enzyme existing in two distinct isoforms one of which is in the cytosol (ACC1) and the other is attached to the outer mitochondrial membrane (ACC2). PC, PCC and MCC are expressed in astrocytes and neurons and are involved in the production of oxaloacetate, succinyl- CoA and acetyl CoA CoA that are key intermediates for the tricarboxylic acid (Krebs) cycle which plays a central role in neuronal energy production . Activation of the Krebs cycle by very high doses of biotin may therefore increase the energy production in axons, thus avoiding the “virtual hypoxia phenomenon”. On the other hand, ACC1 (and ACC2) is involved in the synthesis of malonyl CoA from acetyl CoA and citrate. The synthesis of Malonyl CoA represents the rate-limiting and committed step of long-chain fatty acid biosynthesis. In the nervous system, ACC immunoreactivity is high in oligodendrocytes , and its activity is detected in purified myelin, suggesting that ACC (either ACC1 or ACC2) might be a key regulator for myelin synthesis. Furthermore, studies in cell cultures have shown that lactate, the main energetic substrate in the central nervous system, is oxidized in the Krebs cycle to produce ATP in neurons, whereas oligodendrocytes use lactate in part to produce membrane lipids presumably for myelin . Overall, high doses of biotin, could target the main metabolic processes related to progressive MS by:

(1) activating the Krebs cycle in demyelinated axons to increase energy production;

(2) activating the Krebs cycle in oligodendrocytes to increase the production of citrate required for lipids synthesis and; 

(3) activating ACC1 and ACC2, the rate-limiting enzymes in the synthesis of long chain fatty acids required for myelin synthesis

So why MS, it happened that someone is a study for something else who appeared to respond to high dose biotin had secondary progressive MS, they did a study in a few more MSers and they got better. However they could have "regressed to the mean" The went down in dose in a couple of people to 100mg and it didn't seem to work and up to 600mg and it was no better to plucked 300mg/day as the dose at 100mg/three times a day.

Let's hope this is all good luck as it clearly was not planned or understood.

The clinical trials only look at one dose...the regulators will not like this. 

However, I wonder if we are under starters orders for 30 10mg tablets a day (£2.50/day). My advice is to wait and see how the results of the trials play out and get the real drug and don't scoff the nutriceuticals.

The placebo vs Drug is a 9-12 months study, the placebo switched to active drug after year one of a two year study...Which is remarkably short.....and I suspect too short for the regulators. In the CUPID trial there was little change in 3years in the placebo arm.

A DMT study has to be 2 years they were talking 3 at one point so are we looking at a symptom control effect, like Fampridine which helps people walk quicker or something that really affects progression? Alternatively is this a repair agent because the endpoint is looking for improvement.

NCT02220933 (n=150) The purpose of this study is to demonstrate the superiority of MD1003 over placebo in the disability of patients suffering from progressive multiple sclerosis and especially those with gait impairment.

The placebo vs Drug is a 6 month study

NCT02220244 (n=105) The purpose of this study is to demonstrate the superiority of MD1003 over placebo in the visual improvement of patients suffering from chronic visual loss resulting from multiple sclerosis related optic neuritis.

PLEASE REMEMBER The trial may also be a DODO and fail Miserably. So don't get your hopes up. Also we don't know what the side effects are in an earlier study some people had the runs and they lost a few people in the trial was that chance or drug related?

Let's wait and see what the results have to say.

125 comments:

  1. What is the expected timeframe to treatment if these results are successful?
    Also if they are succesful what is the issue with supplementing Biotin?
    And where did you get the data that this was an accidental find that helped spms?

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    1. The second trial reads out at the end of the year. I suspect they will need more studies to satisfy the regulators but maybe not. The patent was only filed in 2013 so they have been off the mark pretty quickly.

      The accidental finding and serendipity was reported in the MSARDS paper published in March 2015 that I posted.
      Do you want to know the story?

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  2. A lot of these new treatments seem to coincide with their original sources being from sources suggested in the numerous Ms diets? Coincidence?

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    1. It is not rocket science to make an idea that the brain needs energy and then thing of foods that may do this or that but the current biotin study is using 10,000 times the recommended biotin limit

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    2. The current Recommended Daily Intake is around 35mcg. As with a lot of neutraceuticals there is no Recommended Upper Limit - "computer says insufficient data"

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    3. Sorry MD - Recommended Daily Allowance/Intake and recommended Upper Limits ain't the same thing. Just look at the RDAs for Vit D - virtually all of them are way below the Vit D Council (and the Barts Bunch) recommendation of 5,000 IU per day. And isn't part of the point of initial trials to help establish safe Upper Limits?

      The Vit D Council notes that:
      "Very high levels of 25(OH)D can develop if you:
      - take more than 10,000 IU/day (but not equal to) everyday for 3 months or more. However, vitamin D toxicity is more likely to develop if you take 40,000 IU/day everyday for 3 months or more.
      - take more than 300,000 IU in a 24 hour period."

      These amounts are much greater than the Council's recommended RDA.

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    4. Anon at 7.54am - some of the foods that contain biotin are excluded in some of the MS diets and recommended inclusions in others - it depends which one you choose to subscribe to (if any). In any case, it would be impossible to obtain the "therapeutic" dose of biotin used in the first study from any diet - if you ate enough to get that much biotin you'd end up the size of a double decker bus - with all of the accompanying health problems that go with morbid obesity!

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    5. Biotin tablets i've seen for fifteen pounds for 100 x 1000ug tablets.
      Additional information states take one to two tablets a day. 1000ug 2000% RDA. Don't exceed dose.
      1ug equals 1mcg.

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  3. Yes I suppose it's not rocket science but if it works it's the equivalent of one of the biggest findings since they put rockets in space if it helps progressive Ms
    This isn't the big not big announcement were waiting for is it?
    Surely you expect a lot to start taking high dose biotin if the trials report success, it's interesting how it works on the spinal cases too!

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    1. maybe isnt this potentially big.
      I suspect you will be correct access to treatment without the need for a neuro.
      It has the hallmarks how much will be charged for a £2.50 dose.
      We have got do it yourself tecfidera so I would not e pext anything different

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  4. This is potentially huge yes but straight answer is this the big announcement?
    Or are you mouses keeping something up your sleeves

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  5. So looking at the treatment triangle, has biotin (if it works) the potential to be neuroprotective or is it regenerative? Would it be a possible add on to say alemtuzumab treatment to prevent progression? (I know this is full of ifs and buts and maybes)

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    1. Lexie, Biotin may be effective in the short-term, as anything which boosts the Krebs cycle will give extra energy. There is no preclinical work to support a role for neuroprotection with Biotin. To avoid side effects from high dose use its probably safer to go further down the chain to the electron transport chain! with Coenzyme Q10 - the NIH currently have a clinical trial with a drug called Idebenone which is similar in PPMS (IPPoMS)

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    2. Neuro Doc
      Re "Biotin may be effective in the short-term, as anything which boosts the Krebs cycle will give extra energy"
      Are you saying that it may help with fatigue overall, or just "neurological fatigue" such as when your legs stop working if you walk too far, and that any such benefits may only be temporary?
      Also - as the Krebs explanation was way over my head - are you saying that it may help boost re-myelination? Would this help in areas which are already scarred or only in nerves which are not yet too badly damaged?
      I realise it is very early days yet for any clear answers one way or the other on Biotin, but an explanation in simple English for non-scientist MSers would be handy.

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    3. It's early days, all clinical trials are obliged to collect patient reported outcome measures as part of their assessments which will include fatigue and this will be available to the public when the data is published. Mouse Doc's comments on boosting lipid synthesis needs to be tested in a remyelination model in the lab. Some of the preliminary data in the literature is pointing to biotin being anti-inflammatory (a feature shared by all vitamins by the way, including vitamin D)

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    4. Neuro Doc - I've got a question re Q10.

      Which form should one buy - there are two kinds: ubiquinone and ubiquinol - both are available. I'd like to try it out at 100mg but don't know if:

      - they both cross the BBB

      - which form is more beneficial and thus neuroprotective (presumably)

      Thanks.

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    5. Sorry but NeuroDoc is unlikely to answer as we cannot give medical advice on the blog and Q10 is not approved for use in MS.

      It has not been definatively shown to have neuroprotective effects. There have been some trials in MS using higher doses,without conclusive results published as yet.

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    6. i see.

      can you at least answer if both kinds of Q10 cross the BBB?

      I should get it cos it's recommended for seniors for a couple of things (heart muscle) and my Mum thinks about taking a lower dosis as well as an anti-aging precaution.

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  6. Are you suggesting that coq10 and biotin do the same thing? Also what about MitoQ which is essentially coq10 that they claim crosses the bbb easier

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  7. Also what's better in your opinion MitoQ or idebenone?

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  8. Re "we don't know what the side effects are in an earlier study some people had the runs"
    Ha Ha - even if biotin doesn't work maybe it will prove useful to help with MS related constipation when functioning of the lower end of the digestive tract has been affected by MS damage and lesions..........

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    1. I am far from a legitimate understanding of this complex disease, but I have read that LDN seems to help some progressive types. In addition, there is apparently some effect from LDN on hair and nails. Is it just a coincidence that Biotin also has some effect on hair and nails? Could both of these drugs be working in similar fashion in MS?

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    2. "Ha Ha - even if biotin doesn't work maybe it will prove useful to help with MS related constipation when functioning of the lower end of the digestive tract has been affected by MS damage and lesions." Hilarious! Ha ha! Even more funny when you think about the multitude of laxatives already available.

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    3. LDN & Biotion I would bet coincidence but I don't reaaly know

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    4. In all my quite extensive investigations into LDN before I decided to try it, I have not found any claims by LDN users that it helps with hair and nails. If you disregard the possibly/probably exaggerated claims of "mobility miracles" made by some (e.g. after two weeks on LDN I threw away my crutches etc), LDN's main benefits for MS seem to be in halting progression, improving mobility, and reducing bladder problems.
      I think it would be quite ironic if LDN and biotin turned out to be an answer for progressive MS (even if only a partial answer). At least LDN does not have the nasty side effects of DMTs, and we'll just have to hope that (a) the biotin trial results are positive, and (b) the big biotin doses involved don't turn out down the track to have negative impacts (at least with biotin being water soluble you just excrete any excess)
      Unfortunately, unless a Big Pharma Alternative does some proper trials with LDN, it will remain one of those unproven grass roots "patient based evidence" options, despite increasing numbers of neuros being quite happy for their patients to take it, as it does no harm.

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    5. There seems little appettite with the neuros based on comments at the research day

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  9. Biotin forms famously strong adducts with avidin or streptavidin. Are there human proteins with similarly high binding affinity for biotin? Obvisously, biotin cofactor binds to the enzymes it activates. It's tempting to also think about protein targets, or perhaps even "titrating out" some autoreactive antibodies. Are these thoughts compeltely off the mark?

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    1. Very interesting thoughts - I'd like to know the answer to your question too.

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    2. We biotinylate antibodies in science alot but not sure if this is a plausible mechanisms but who knows you may be right..thanks for the thought

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    3. Not sure if failed Gilenya trial gets one

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  10. At last we are getting some answers :)

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  11. Thanks for the info mouseDocter

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  12. Plenury session it's gotta be big! They don't reserve these for the lil boys. would you agree?

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    1. Agree... a plenary session would suggest something intersting,,,but it may not be

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  13. I've read a little more about the trial and it's 150 plus people in the trial followed for twelve months with the primary endpoint reduction on edss by 1 point? Or improved timed walk?

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    1. MD1003 in the treatment of primary and secondary progressive MS. MS-SPI is a randomized, double-blind, multicentre, placebo-controlled (2:1) trial of MD1003, 300 mg/day, in 154 patients with progressive MS who have demonstrated progression in the 2 years prior to enrolment. Patients were enroled with a baseline EDSS (Expanded Disability Status Scale) score of between 4.5 and 7 and were treated for one year. The primary endpoint was the proportion of pts who improved at nine months (M9), with confirmation at 12 months (M12). Improvement was defined as either a decrease in EDSS (by at least 1 point for baseline EDSS =5.5 and 0.5 points for EDSS =6) or an improvement in TW25 (a timed 25-foot walk) of at least 20%. The comparison for each outcome was the best EDSS and TW25 scores obtained at the screening and randomisation visits

      So primary endpoint is improved walking OR change in EDSS and the result is a positive result at 9 MONTHS in drug verses the placebo of 50 placebo and it was reported that expected launch is 2017 (http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=6454..Thanks to L for sending this info)

      However would famprydine succeed with this endpoint. I suspect so as improves walking.

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    2. Fampridine only works for 35% of patients who try it, and questions have been raised on this blog about whether it actually could contribute to increasing the rate of progression. If you are going to get a positive result with Fampridine you will find out within 2 to about 12 weeks.
      While the numbers for this Biotin study were very tiny, 16 out f 18 patients (89%) with spinal cord involvement showed improvement, although it took from 2 to 8 months to be apparent. Somewhat of a longer wait to find out, but much better numbers, even though the number of trial participants is minute, and the biotin produced improvements in other symptoms, which Fampridine does not do.
      Roll on 24th April, and here's keeping the fingers crossed for some good news for progressive MSers.

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    3. Not everybody responds to fampridine; and the side effects include seizures. So, any improvement for fampridine non-responders is certainly welcome, and diarrhea wins over seizures any day.
      More interestingly: let's assume the biotin trial is positive. Can the improvements on biotin and on fampridine be additive (or better yet, synergistic)? One can hope...

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    4. If it is a repair agent it is good for all MSers and likewise any treatments for progression will benefit all MSers

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    5. I would hope that if biotin works as a remyelenation treatment there would be no need for Fampridine - then there would not be the same risk of seizures

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  14. Ps gotta love the French if they pull
    This off!!!!

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    1. I didn't realize it was a French trial.....oh well, will have to keep waiting:-)

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    2. Good things come out of France and French Science....Mr Pasteur springs instantly to mind...and Mr Charcot

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    3. Luc Montagnier (HIV researcher) hard to believe any work can be done with all the fine wine and food in France. It would be much easier in the UK :-)

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    4. Let's not forget Inspector Clouseau.

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    5. Re Food and Wine

      For non-Brits....I'ld just like to say the days of meat and two seasonal veg have gone...we have more Michellin Starred Restaurants than you can shake a stick at. I should know as ProfG has been to most of them:-0 and we drink more Champagne than the French.

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  15. What an entirely weird discovery if this does turn out to be something.

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  16. Thanks Mouse Doctor :) I love an educated opinion. I just hope Md1003 holds progression at bay. Because of the way Md1003 improved vision I'm h opting it's more effective than famprydine.

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  17. God bless Md1003 to treat ms. This looks hopeful

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  18. There are powders available online for $169 per 100 grams (nearly a year supply).

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    1. You can buy lots of chemicals very cheaply but remember chemicals fit for humans need quality control as chemicals can contain lots of impurities that may not be good for you. We are currently spending thousands getting rid of some in our clinical material.

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    2. Just like the dubious green tea extracts - stick with the tea, I say. /Naomi

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  19. 'It is not to be imagined that he should know the remedies of disease who knows not their original causes' Celsus 25BC-AD50.

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  20. Mouse are you saying this is a symptom treatment rather than disease modifier?

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    1. This is speculation but if we look at the endpoints it is IMPROVEMENT at 9 months not stabilization and no worsening.

      Most DMT trials wait for the placebo to get worse and hope that the drug slows the rate of decline.This is a 9 month study and so the placebo group is not going to decline that quickly, I would think. So what would we expect with a neuroprotective agent...probably stabilisation maybe some improvement if the natural repair mechanisms can kick in.

      However one wonders whether this is a symptom control thing. Have more energy and you can walk more but how about a wild speculation and the reason that they are looking for improvement is because it is a REPAIR agent.
      There is no basic science behind this yet and s it cold anything, remember it could be nothing as this speculation.
      Remyelination can occur quickly and certainly within 9 months. Is this why there are visual effects.

      Maybe they have stumbled on a remyelination agent.....

      So in 2 weeks time when it is all a bust do not come back and complain I was raising hopes:-) However food for thought.

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  21. Anyone else scared incase this turns out to not be succesful?

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    1. Just wait and see what happens it may be a bust, we have been here before and been disappointed.

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  22. can I ask how could of the md1003 possibly improved vision if there wasn't something substantial going on? In as layman's terms as posiible please thanks MDoctor

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    1. Many MSers have optic neuritis neuros do nothing except abit of steroid and vision usually recovers. However I will need to read paper or patent o know more about the people in the study. Maybe it is repair.

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  23. Would this help with spasticity etc? You would think so if it could help remyelination or issues with spinal cord?
    Also how common is spasticity early in disease?

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    1. We have to wait for the results if there is remyelination all sorts of things can happen. Spasticity is a product of damage and can occur early but will be more common as disease progresses. remember we have no idea whether this does anything yet...we have to sit back for a couple of weeks and see what the talks really say.

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  24. Thanks MDoctor, I agree in early rrms but apparently these patients were high edss late progressive am I right you would be able to interpret the study better than me so I'll wait until you Check that thanks again.

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    1. The people in this study were progressive MSers up to EDSS 7 so advanced. http://multiple-sclerosis-research.blogspot.com/2015/03/biotin-for-progressive-ms.html.

      http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=20140130&CC=CA&NR=2879434A1&KC=A1

      The improvement was 2 months after start so I am leaning more to remyelination or a load of bumcum

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  25. Please please be remyelination

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  26. Am I right in thinking they've used biotinylated products before for remyelination in mouse models and other spinal injuries in humans?

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    1. I dont think so we use biotinylated antibodies for staining as each biotin molecule can bind to four avidin molecules you link a stain to the avidin and it amplifies the signal of the staining

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    2. I think the stoichiometry is 4 biotins per one avidin (this does not change your answer, though)

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  27. I've seen some of the indivisl case reports, and it looks like the visual improvements are quite small, one of the participants had a relapse whilst on biotin so it looks like more of a remyelination product possibly?

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    1. so this supports our point that to get optimum response you need to do these treatments on top of control of inflammation,but until there is a cheap option available, it is not considered cost effective by NICE, then SPMS/PPMSer will not get optimum treatment

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  28. possibly
    That's really burst my bubble though

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    1. These are around so dont be too dispondent

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  29. Surely though it will help repair whatever damage the relapse does or any other inflammation if it works as a remyelination agent?

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  30. Reading about biotin, I ran across the following info (Wikipedia - Biotin Deficiency):
    "Prolonged use of certain drugs, especially phenytoin, primidone, and carbamazepine, may lead to biotin deficiency... Evidence suggests that these anticonvulsants accelerate biotin catabolism. Therefore, supplemental biotin, in addition to the usual minimum daily requirements, has been suggested for patients who are treated with anticonvulsants that have been linked to biotin deficiency."
    Is it just a coincidence that phenytoin and carbamazepine are potentially neuroprotective/remyelinating agents? Is there a common pathway linking them somehow?

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    1. I dont think so drugs notably carbamazepine induce enzymes in the liver called cytochrome P450 and these cause the degradation of drugs e.g. biotin if wiki is right inducing degrading carbamazepine itself. This is one of the reasons it was not used inoptic neuritis study.

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  31. Mouse
    How long until this is available as a treatment if it shows success? I've had high hopes for it until I read the issues of relapses whilst on it yesterday, we need another miracle looking treatment! Where's the charcot project when you need it

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    Replies
    1. A far as relapses go - there are plenty of DMTs out there for relapsing MS, so this issue is totally unimportant and irrelevant for those who don't have relapsing MS. It's long overdue for there to be something which might help progressive MSers, so here's hoping......

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    2. My thoughts exactly. /Naomi

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  32. First thing if the results are negative it goes nowhere except the bin. If the results are positive then they will wait until the next trial finishes. I have seen that it is hoped to be inmarket in 2017. However if the regulators are not happy they will want more trials. I think this could be a possibility. GWpharma thought they would be in market by 2004 it was 2010 in europe and we are 2015 and still waiting in usa.

    As to relapse that would not disturb me. If drug is remyelination symptom control or neuroprotective then they probably will not stop the peripheral immune response
    We rely on this to find neuroprotective drugs more quickly in our experimental models. However we have a number of drugs to stop relapse already so you just mix the two drugs...simples.

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  33. If successful md1003 and aemzumutab a killer combo

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  34. Good stuff
    Bit of a kicker about the timeframe though, I thought being as they've been so quick this far they might be quick to market, otherwise there'll be a lot of people if it's succesful taking biotin supplements

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    Replies
    1. A year from last trial to regulators is not slow.

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  35. Please good god remylation

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  36. Are you going to AAN - will you live tweet the results of this trial. I am working with the PPMS community and we want to hear results right away.

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    Replies
    1. I'm assuming Prof G will be attending, maybe he will Tweet. In any case it will be on the blog very quickly as soon as the results are announced.

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    2. Agreed. I'll be on pins and needles! (and my spouse is the one with MS) If Prof G isn't there, is there a hashtag that other conference attenders will use? #AAN2015 or some such?

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  37. That would be good
    Get it on here asap it'll be blogged by others there anyway I would imagine

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    Replies
    1. Oh yes, the press will be full of cure of the year articles - it's really important that accurate information (rather than hype) is posted

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    2. Rest assured you will be getting an accurate interpretation of the results here. No hype, no tripe.

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    3. Thanks for that MD2 - I can't stand the hype in the media every week anymore - it gets on my nerves after 5 years of constant miracles!

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    4. if you read it in the media the chances are it is exaggerated or just plain wrong. I started blogggng as the press said I was working on a trial ofaborted foetuses

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  38. Hopefully md1003 is a real miracle!

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    Replies
    1. soundz like you could be cruising for a bruising it may be part of a jigsaw

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  39. I know what your saying Mouse Dr but as someone above said with effective date such as alemtuzumab and neuro protective agents assuming md1003 is remylation this is a god send surely.

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  40. Sorry if this has been answered above, given this was trialed / studied on advanced MSers amongst others , would you have expected loss of neurons rather than just myelin at this stage and so nothing to re-coat ?

    Regards as alwyas

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    Replies
    1. I may think that loss of nerves would result in deteriroation but these guys are not looking at slowing deteriroation but for recovery of function so i doubt you are regrowing nerves this is why i was thinking remyelination. Even in advanced MSers there is always demyelination present so there are nerves that could be remyelinated.

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    2. Thanks, I'd sort of come to the conclusion it may repair what can be repaired and so some function regained. To be honest if it stopped progression I'd take it, a chance to breathe and take stock would be welcomed.

      Regards as always.

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  41. I was thinking that too

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  42. Thank god the results are soon ! Please god let the results be really positive with no side effects! !

    ReplyDelete
    Replies
    1. The result will be incremental based on what was published. However there is a chance the results will be negative. The AAN starts this weekend and ProfG can hopefully send me the abstract but we will have to wait until friday before we post.

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  43. So even if it is a success in guessing it's a very amall success and not really a major help?

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  44. There was a 1942 study of biotin in mice with vision issues and spasticity
    All improved when treated with biotin! Only 70 years then !

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  45. What do yo make of today's news md1003 meets primary endpoints phase 3. A scientific view of what this could mean please Mouse Doctor

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    Replies
    1. Sounds promising but releasing this a week before they report at the AAN is a bit naughty, though par for the course for pharma. We'll have to pick over the data before we make firm conclusions. You'll be hearing more soon.
      http://www.businesswire.com/news/home/20150417005032/en/MedDay-announces-pivotal-Phase-III-study-MD1003#.VTEXdPAso3g

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    2. THE AAN starts this weeekend so i suspect the press embargo went today.
      Good news

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  46. Does this also mean the secondary point was not met, i.e., progression slowing??

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    Replies
    1. I'd like to know this as well. Stability is the most important thing to me.

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  47. if they improved thats better then halting progression md1003 regression of the disease in a sense :)

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  48. So mouse surely does this mean a treatment for progressive Ms?!

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  49. Wow time to pop out the champagne

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  50. POSITIVE DATA!!!!!!

    http://www.businesswire.com/news/home/20150417005032/en/MedDay-announces-pivotal-Phase-III-study-MD1003#.VTF8duktGP8

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  51. Get your skates on with EBV and charcot then gents I'm convinced you've got the real cure

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  52. md1003 and genbac1 or raltegravir coul do it

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  53. The primary endpoint is a reduction in edss by 1 point for 4.5-5.5. And 0.5 for above am I corresct?
    If that's the case and it does show majority and Id like to think nearly all improved then this is huge!

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  54. The ON trial with md1003 is presenting in September too I think

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  55. It'll be 2017 before this is a treatment that is the big issue! This needs to be fast tracked

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  56. Biotin time part deux

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