In PD, the inflammatory mediator IL-17 is active and is at elevated levels. In a previous post, I discussed how IL-8 is at elevated levels in the cerebrospinal fluid (CSF) of PwP and draws other inflammatory mediators such as IL-6, IL-1b and TNF-alpha into action as part of the inflammatory cascade. Inhibition of IL-8 reduces IL-6, IL-1b and TNF-alpha. Here is a link to that post :
IL-17 is higher up than IL-8 in the inflammatory cascade and it activates more inflammatory mediators and pathways. There are multiple newer drugs that specifically target IL-17 because it is active in multiple disease states and makes a good target given its position in the inflammatory cascade. Here is a link describing the role of IL-17 in PD.
with the already FDA-approved drug secukinumab could potentially be used to
slow disease progression in PD patients. ' >> ' IL-17 concentrations were below the level of detection in the HV group but were elevated in the DC group (Figure 1A). An approximate four-fold decrease was observed in the IL-17 concentration levels (0.09 pg/ml to 0.023 pg/ml) with a treatment dose of 200 mg thiamine daily (Estimated AUC = 204 nmol/L x hour approximately in the 10-h window) by the end of week 3. ' >> ' No patients reported any kind of drug related adverse events; therefore, the safety profile of thiamine administration was excellent at 200 mg daily in this small pilot group. ' <<<
So although we still do not know the exact mechanisms by which B1 helps relieve PD symptoms, inhibition of IL-17 is apparently one contributing factor and will ultimately make B1 very useful in treatment of other diseases where inflammatory IL-17 is active and at elevated levels. In the study above, B1 caused that four fold reduction in IL-17 in just 3 weeks with no reported side effects in the study participants! On this forum, members are already aware of how safe B1 is at just 200 mg/day. Not so much for Secukinumab though with a monthly cost of approximately $6,000 and plenty of potential side effects.
My take away from this is that even if you see no apparent benefit from HDT, taking at least 200 mg/day seems worth at least considering for the sole purpose of lowering the inflammatory cytokine IL-17 closer to healthy control levels which should be undetectable, but are elevated in PwP and contributes significantly to the chronic and damaging inflammation associated with PD.
Art
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If that fails, just go to PubMed and search for these two titles :
>>> IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease <<<
>>> Repurposing Treatment of Wernicke–Korsakoff Syndrome for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-Vitro Evidence and Pharmacokinetic Profile <<<
My husband is at 100mg B1. If he takes more, he experiences knee pain, however, he is willing to try 200mg (trial dose). Hope this dose will help him even more.
It's trial and error. It's not leg pain, it's knee pain. He noticed after a long time that the higher B1 dose the more knee pain. So we tried lower doses and once he reached 100mg, knee pain didn't bother him anymore. I wish and pray that he can take 200mg now to meet the criteria of this trial.
I went through the same dance with hip pain. Odd that B1 can cause this. I'd love to understand why. I get 100mg in my B complex. I'll try splitting dose and going up to 200, see what happens...
I believe you and my husband are not the only ones who have experienced pain caused by most likely a higher or lower dose of B1. Hope 200mg will work for you and my husband!
Is it by chance if Thiamine overdosing causes the same sorts of pain as its TTFD derivative ? "After about a month with this dose, I was getting into bed one evening and was suddenly afflicted with the worst pain in my left leg that I had ever experienced."
Read the following by Dr Londsdale, an indefatigable Thiamine advocate:
"Back Pain and B Vitamins: Notes from Personal Experience"
That was a very interesting writing by Dr. Lonsdale and anyone who takes B1 should be sure to read it!
On a related note, Dr. Costantini said he saw similar pain issues in his patients when their B1 intake was a little high. Here is a link to the B1 FAQ page and Dr. C addressed this issue in Q&A number 55.
If he tries it and it worsens the knee pain, he can always go back down to 100 mg/day, but it would be nice if he could maintain 200 mg/day to potentially obtain the benefit described in the study!
That's what we are hoping for, Art. Starting with injections twice, even three times a week per Dr. C., down to 100mg with his morning 1/2 t Sinemet and two MP capsules.
It seems it did it gradually in 3-4 months. Before that I saw a rheumatology doctor who gave me some anti-inflammatory medicine which I did not take. I had the pain for a while and just went away after starting B1. Except B1 and C/L I do not take any other medication.
This really is interesting and it makes sense as joint inflammation generally involves increased IL-17 and your estimated time frame of 3 to 4 months may give an idea of how quickly it takes thiamine to effectively control IL-17. Given that the study was only 3 weeks in length, we don't know if continued use at that dose would have eventually lowered IL-17 even further.
Also interesting, the earliest people on Cosentyx / Secukinumab (IL-17 inhibitor/binder) was 3 weeks while others took up to 16 weeks to see benefit. Again, this suggests that B1 will be useful for other health conditions.
If you don't mind saying, how much B1 are you taking per day and are you taking it everyday? Thank you.
I started at 2g/day in March 2018 and then lowered to 1g / day after one year. Usually I take it daily but sometimes I skip it for 2-3 days (not on a regular basis). Except the tremor in RH all the other symptoms are gone starting 3 months after I took B1. The knee pain disappeared about the same time with the PD symptoms.
High levels of IL-8 in the cerebrospinal fluid of PwP may be explained by their corollary: low levels of free thiamine there (Jimenez-Jimenez et al., 1999).
Thank you - very interesting is the thinking still the more B1 HCL the better - given some are on 1g to 4g a day? I guess it depends on symptom relief?
Yes, I just wanted to point out one possible way that B1 may be useful in PD and other diseases since we essentially do not know how it works in PD. One thing to keep in mind about the dosing model they created and used to arrive at this dose of 200/mg per day is that it does not guarantee that a higher dose will not do more toward lowering IL-17 further or having other beneficial effects.
It is unknown as there have been no studies to confirm that idea, but the anecdotal evidence would suggest that that is a possibility as some forum members have reported benefit at higher dose up to 4 grams while some members have reported benefit at dosing as low as 25 mg/day, but these extremes in dosing effectiveness are in the minority as many report benefit at the 1500 mg to 2500 mg range, but finding that sweet spot is not always easy. The study in the original post merely showed the efficacy of 200 mg/day at very significantly lowering the inflammatory cytokine, IL-17.
Yes, it's not been easy to find my husband's dose. Still adjusting it after more than a year. We'd settled on 1500mg these past months, but recently he reported increased sleep time drooling. And I noticed more speech difficulty. We adjusted his dose to 2000mg.
Two or three days of that dose and I noticed he was speaking clearly. We'll see how it goes.
Hello Art ~ Thank you for the new information. My husband is on 25 mg B1 4 days a week and 12.5 mg sublingual 2 days, taking Sundays off. We have tried higher doses which increases his anxiety levels and tremor so we have settled on this. He did have the best outcome on 100 mg of B1 Mononitrate which I had accidentally purchased. I have wondered about going back to that type but it is the wrong one. He does get 110 mg B1 HCL in his B complex. So I guess he’s kind of close to the 200 mg/ day. I wonder if I could VERY slowly increase his B1, kind of sneak it in so maybe his body wouldn’t realize what was happening and then not get so wound up about it?Any thoughts? After reading this information I would really like to get him up to the 200 mg dose.
Somebody on the forum mentioned that B1 mononitrate should work also as the previous thought on the forum was that it was fat soluble and might get stored to levels that may be too high, but apparently that was not correct as outlined on this NIH page regarding thiamine.
>>> ' The most commonly used forms of thiamin in supplements are thiamin mononitrate and thiamin hydrochloride, which are stable and water soluble [1,12]. '<<<
One thing to keep in mind is that Dr. Costantini had to choose the form of thiamine that he thought the majority of his patients would be able to get, since he had patients around the world , without too much problem and Thiamine HCI/HCL seems like the easiest to get.
This is FABULOUS news!!! And the article says it is one of the most common B1’s along with the hydrochloride!! I cannot thank you enough. I will get him back on the B1 Mononitrate, then!!
Sorry for my late, but unfortunately I can not speak English well, so it's Dr Erika Trevi who is writing these emails to you.
We don't use benfothiamine because previous trials report it does not enter in the neural cells, that's why it is not used for the diseases which don't affect the Central Nervous System (Bettendorff L.).We administer thiamine cloridrate. For your situation 1 intramuscular injection twice a week (or an oral dose of 4 grams each day, two tablets in the morning and two at lunch time) should bring to the complete regression of the symptoms in 1 or 2 months. As an attached link, you'll find a paper with the possible thiamine side effects.
In another email, I'll send you all my published studies.
Yes, that is the same information on the B1 FAQ page. Dr. C was always clear on why he didn't use Benfotiamine, but were you bringing that point up for a specific reason, Roy? Lizzy was enquiring about B1 mononitrate and it is not the same as Benfotiamine which is generally considered to be useful in the case of diabetes type 2.
Hello Art ~ You had a "conversation" with me 2-3 weeks ago and helped me tremendously and also asked that I update you on our progress. (I have no idea where that "thread" is.)
Here is the update on our B1 journey ~ Started B1 Mononitrate 25 mg 2 times a day, 11 days ago ~
As of yesterday ~
My husband is laughing more and joking around more like he used to.
He talks more.
Anxiety is extremely minimal to non existent.
Tremor has decreased but not totally resolved.
He doesn't complain of "feeling like something isn't right in his head".
He can drive for a couple of hours without anxiety and the "terrible" feeling in his tremor foot, the foot still will tremor but he but he doesn't need his wooden "foot roller" to be able to tolerate the driving.
He isn't needing me to massage his tremor foot as often as he did pre-B1 Mononitrate.
Two days ago we drove 2 hours to purchase e-bikes to help with our exercise routine and the drive went well even though he was driving our manual transmission pickup in stop and go traffic of the larger city.
All in all I am so thankful for your help!!! There are no words, really to thank you enough.
Also, I took your advice and we added Melatonin to his stack of supplements. His current dose is 46 mg with no ill effects. My question is ~ How do I know when we have reached a good dose for him?
Again thank you for your help and time and have a fabulous day ~
He was miserable on the HCL ~ I am thankful for another option and the help of finding that option!! I agree ~ if it helps that's what matters. Thank you!
It is so wonderful to hear how much your husband improved after switching to Thiamine Mononitrate from Thiamine HCI!!! You just never know how such a small change can make such a significant difference!
Thank you very much for coming back and updating the forum as there are likely others who are currently using Thiamine HCI who may also see such extra improvement in symptoms by switching to Thiamine Mononitrate. We are all different, so of course it is not likely to be the same for everybody, but because you and your husband were willing to "test the waters", we now have another option to Thiamine HCI! Thank you again, Gail!
if this may interest you, know that I started my hdt protocol on the basis of two 100 mg capsules of b1 solgar... almost immediately my leg pain disappeared... swallowing improved, More energy my voice became clearer...
I overdosed. I went from 200 mg to 400 mg but this overdose was due to Solgar's b complex high potency, vitamin B6 peaked... once everything was back to normal I resumed my hdt protocol at 300 mg
as I am very cautious, I waited six months before switching to a dose of five hundred milligrams...
today I'm going to 750mg...I think my sweet spot is between 500mg and 1 gram, because I slightly overdosed at 1 gram...
Magnesium Taurate does also and the taurine component also offers positive effects in the brain. The compromise which really isn't a compromise at all because it contains all three in one product, is this :
Hi there. I am a 76 yr old woman with PD and 4 years since diagnosis. I very quickly deteriorated into the mask like facial problem and speech problems. No tremor to speak of and sleep patterns are stable and refreshing. I have had very promising results for the B1 treatment and was very excited. However, as soon as I go above 250 mgs a day I get the most excruciating back pain, to the extent that I have to stop it. Whilst on the B1 I can smile and talk and in general have a good quality of life albeit I do tire easily. What can you suggest?
One remedy is to take a B-vitamin multi such as B-50 alongside your B1 capsule, but you say you did well on B1 up until you went above 250 mg. If you were doing well below 250 mg, you likely need to go no higher. Keep in mind that some forum members have reported that their optimal dose is as low as 25 mg per day. Not everybody has needed to go to very high dosing. If you are responding below 250 mg, your optimal dose is likely down in that area.
Another important way that Thiamine/B1 works against PD is because Thiamine and its derivatives are scavengers of Peroxynitrite. You may be thinking, that's nice, but what is Peroxynitrite? It is a highly potent oxidant that is formed when the free radical nitric oxide and the free radical superoxide react with each other resulting in Peroxynitrite.
In PwP, Peroxynitrite is at significantly elevated levels and very damaging as it contributes to neurodegeneration as it is damaging to many many molecules in cells. Bottom line is that elevated peroxynitrite = elevated UPDRS scores = worse symptomatology in PwP as suggested by the following study!
europeanreview.org/article/...
The above study draws this conclusion :
>>> ' Higher levels of NO and peroxynitrite leads to higher UPDRS scores. It seems since current PD treatments do not affect the pathology of the disease, using drugs that exert neuroprotective properties should be considered for the treatment of PD in order to prevent further neuronal cell loss. ' <<<
Thiamine and its metabolites on the other hand are Peroxynitrite scavengers as outlined in this link.
researchgate.net/publicatio...
Since I am writing this, I would like to add that Melatonin is also a potent scavenger of Peroxynitrite. This adds further confirmation to the use of the combination of Melatonin and Thiamine in the pro-health repetitive cycle discussed here :
Another vitamin that reduces Nitric oxide is Hydroxycobalmin (a form of B12). Nitric oxide like Art said is high in PwPs. Nitric oxide reduces blood pressure. So people with high blood pressure needs to be aware of taking agents that reduces nitric oxide.
You bring up a very interesting point, Kia! Many on this forum have reported orthostatic hypotension. Can NO inhibition/reduction be a potential remedy and are we talking NO in the form of ENOS, INOS or....?
Maybe a reason for orthostatic hypothension in PD is high level of NO . Hydroxycobalmin scavanges the NO in a way that it is used to treat migraine (Prophylactic treatment).
Since genetic tendencies also involved , predicting the outcome is hard.
What about Levodopa itself, a real mess indeed ?"In fact, some autonomic problems, such as orthostatic hypotension, can be exacerbated by dopaminergic therapy." (Lim & Tan 2016).Why ? Because it causes a(n unusual) rise of noradrenaline in noradrenergic alpha2 receptors. Patients are prescribed drugs such as Gutron to counter this effect.
Here is an important quote from a review I am currently reading that I want to share with the forum because it helps to define exactly why inhibition of IL-17 is so important in stopping neuroinflammation in PD and other diseases involving neuroinflammation.
>>> ' The most potent immune response induced by gut bacteria involving in neuroinflammation is Interleukin 17 (IL-17) forming T-Helper type 17 (TH 17) cells [7], [39], [40]. ' <<<
If you believe that neuroinflammation speeds the brain damage and disease progression of PD, and I am such a believer, then you realize the importance of returning IL-17 to undetectable levels as seen in healthy controls in order to suppress neuroinflammation and disease progression.
HDT is a highly potent inhibitor of IL-17. HDT = High Dose Thiamine.
Melatonin is an inhibitor of TH-17 differentiation resulting in suppression of IL-17. Melatonin is produced in the gut in the presence of sufficient SCFAs. PwP have elevated levels of activated IL-17 and are lacking in these SCFAs as well as the bacteria that produce them.
Here is another important quote from the review :
Growing documents demonstrate SCFAs (along with the colon's role in energy supply and trophic factors, and the management of Treg cell colonies), also have pivotal physiological influences on some organs such as the brain and is supported by evaluations performed in vivo, which showing that dysbiosis of gut microbiota has been involved in neurologic behavioral and pathologies like Parkinson, Alzheimer, depression as well as an autism spectrum disorder (ASD) [29], [63], [70], [71], [72], [73], [74], [75]. Additionally, microbiota-derived manipulation and administration of SCFA have been proposed as treatment targets for such diseases [76].
This new study (September 2021) suggests another possible way that thiamine may be useful for neurodegenerative disorders by protecting against glutamate cytotoxicity via suppression of Endoplasmic Reticulum Stress and Oxidative Stress as seen as reduced MDA levels. Thiamine also increased the levels of the antioxidants, Superoxide Dismutase (SOD) and Catalase (CAT).
>>> ' Recently, several studies have suggested a pivotal role for the interleukin-17A (IL-17A) cytokine family in human inflammatory or autoimmune diseases and neurodegenerative diseases, including psoriasis, rheumatoid arthritis (RA), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and glaucoma. ' <<<
For all of you who are taking B1/HDT or considering taking it, I just received a reminder notification from forum member Gigi reminding us that Biotin may be needed in order to optimize the positive effects that thiamine has shown in many forum members. Here is a link discussing this idea which she thoughtfully included with the reminder !
In the following study link below, it is suggested that certain butyrate producing bacteria may not be able to produce butyrate in the absence of Thiamine. This gives another relevant reason of why people find benefit with the use of thiamine. It also gives another reason why some people get more benefit from thiamine than others, if their natural B1 production in the gut is still sufficient to aid in the production of B1 or too low to assist in that production and various degrees in between those two extremes.
B1 is naturally produced in a healthy gut microbiome, but not as much in the perturbed gut microbiome that is frequently seen to varying degrees in PwP.
Dr. Costantini never got the studies he wanted for HDT, but ongoing thiamine studies continue to uncover the truths of why B1 is beneficial for so many PwP through multiple methods of action. This study shows one more of those methods of action as thiamine's ability to help facilitate the production of short chain fatty acids (SCFAs) by interacting with the relevant SCFA producing bacteria.
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A few questions about how the B1 Therapy is currently administered, and an idea on how to improve results.
Controlling systemic inflammation - through skin cream?!
