#422

I posted it in the comments of the blog (sorry I’m on my phone).

Where did you buy the L form?

Yes I agree that if tanganil caused dementia it might have been caught. Even more so as it’s mostly used by people 60+ in France. However most French users use a rather low dose of one pill daily for a few weeks and then nothing, way less than in the RBD trial (check my comment on the blog post for the detailed numbers).

If you have GBA then Ambroxol theoretically makes the most sense for you. Have you tried it?

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#423

Yes, actually, I’ve been taking ambroxol since 2021. I bought the powder from India and have been making my own capsules, because the dose for PD (like Tanganil for vertigo vs N-Acetyl-L-Leucine for whatever) is MUCH higher than what you can buy OTC.

I pretty much will try anything that sounds promising, especially if there is a mechanism attached that makes any kind of sense.

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#424

I agree that makes sense.

Where do you buy your acetyl-l-leucine from? I bought some tanganil but I’d love to find a serious source of the L form (I don’t trust Chinese suppliers that much, chemical suppliers can be better but they don’t sell to retail, and I don’t live in the US so can’t buy the FDA approved one that easily).

#425

Heh–I found it on amazon (brand: Aksunder) of all places, and of course when it arrived it OBVIOUSLY came from China. So I’m a little worried.

It’s a 1000g bag of very sour, quite insoluble (in water) powder that makes me suspicious, though when we asked they told us it would be sour and insoluble. It only cost $135, and I say only because the prescription price for the exact same thing is $13,000.00 per month! So no, I pretty much don’t have access to the FDA approved one either!

There is another source and brand I found: N-Acetyl-L-Leucine, Ac-Leu-OH: AJI92 Standard & Derivative Benefits I’m tempted to buy it, just to compare taste and solubility. It’s basically $50 for 500g. If you can access that one, tell me. We can compare!

I’m also a little concerned eventually someone is going to put the cabosh on our ability to get it…I doubt the drug companies here want cheap versions of their drugs floating around. :o(

#426

Yes, I saw the Mark Nature one, but I’m not convinced of its quality either.

I think these chemical suppliers are considered reputable and serious:

Other chemical suppliers might not be as good but are 10x cheaper:

“Good” suppliers offer third-party certificates of analysis and quality. You could ask that to Aksunder. You might also pay ~$200 for a company to analyze your products.

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#427

Hypoxia therapy seems interesting in PD. We have a long discussion about hypoxia and longevity here, with some posts relevant to PD:

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#428

What is N-Acetyl-L-Leucine’s mode of action?

#429

Also, a life update on my side: I’ve just been diagnosed with Parkinson’s disease (yes, at 32yo it sucks :smiley: ). I diagnosed myself 3 years ago, so that diagnosis was an “official” confirmation. It took a long time to convince doctors, but that’s the usual journey for people with complex diseases… (Thanks a lot to @DrFraser and @dradambat for their help and support in this journey!). At least I was able to learn about the disease and start lifestyle + pharmaceutical interventions to improve my condition.

I’m looking for this Holy Grail of interventions:

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The level of evidence is often weak, and one has to make some bets on risk/benefits.

So besides lifestyle interventions (most of what Dr Laurie K Mischley recommends: MIND diet, exercise, yoga, meditation, stress management, sleep hygiene, avoiding pesticides, eating organic, a bit of black coffee and green tea, etc. + getting vaccinated for pretty much everything), I’m taking the following Rx drugs and supplements:

Intervention Biomarker(s) Neuroprotection Safety
Dapagliflozin 10 mg eGFR, HbA1C, HOMA-IR, time in range with CGM Potentially for AD & PD (association studies & animal models) Safe + might extend lifespan in rodents
Telmisartan 80 mg SBP Potentially for AD & PD (ongoing RCTs) Safe
Amlodipine 5 mg SBP Potentially for AD & PD (other DHP CCBs might be more potent though) Safe, DHP CCBs extend lifespan in worms
Ezetimibe 10 mg apoB Very weak evidence for AD & PD Safe and probably safer than statins for PD
Selegiline 1.25 mg None (mood + PD symptoms) Might be neuroprotective in PD (controversial) Safe at low dose but many drug interactions, might extend lifespan in rodents (ITP in progress)
Lithium orotate 1 mg None (mood) Ongoing trials in AD & PD Very safe at low dose, extends lifespan in worms
Methylcobalamin (1 mg/week) Serum B12 Might be neuroprotective in AD & PD Safe if serum B12 kept in normal range
Theracurmin 30 mg None Weak evidence for neuroprotection in PD Looks safe, curcumin didn’t extend lifespan in the ITP but Protandim that contains curcumin did

Dapagliflozin, telmisartan, lithium, and selegiline are the interventions where I “saw”/“felt” a direct and significant positive effect. Others (amlodipine, ezetimibe, B12, and Theracurmin) are more like “safe bets,” but I’m not sure I saw improvements (maybe for B12 and Theracurmin, but hard to tell). I’m considering switching from amlodipine to isradipine (new RCT might start soon) or nilvadipine (Australian RCT results due this year) and maybe ezetimibe to obicetrapib if it gets approved.

I’m also interested in:

  • Probiotics: I saw positive effects with Symprove, but it might only be symptomatic. It was trialed in PD at King’s College London and the first results are encouraging. Waiting for the full results to be published.
  • GLP-1RAs: exenatide phase 3 failed. I tried oral semaglutide and saw some tiny cognitive & motor improvements but offset by some mood deterioration and excessive sympathetic activation. There are ongoing trials of oral semaglutide in AD & PD: I’ll wait for the results. Or I might try microdosing tirzepatide.
  • Terazosin: pre-clinical data is very good, RCT about to start in the UK. I tried 1 mg a few times: great sleep and energy the day after. But it gave me mild orthostatic hypotension and tachycardia. It might be worth trying one month to see if the body adapts and the effects disappear. Or try 0.5 mg? Or wait for the RCT results…
  • Coenzyme Q10: RCTs at high doses failed in PD. But 60 mg/day ubiquinone is probably very safe and might be a good bet.
  • Acetyl-leucine: as discussed above. I’ll probably wait a bit before doing a test.
  • K2 MK-7 (menaquinone-7): one interesting paper + ongoing German RCT. It gives me mild insomnia, though (which is evidence of its potency on mitochondrial function per @John_Hemming )
  • TUDCA (taurursodiol): ongoing RCT of UDCA. TUDCA is probably more potent (and more easily accessible). I tried 500 mg and didn’t see any positive effects so I stopped. I’ll wait…
  • High-dose NR (Nicotinamide riboside): I think there are potential risks. RCT results due this year. I’ll wait.
  • Urolithin A: potentially more potent and safer than NR. I didn’t see positive effects when trying it though. I might give it another try.
  • Ambroxol: I took it at a low dose (60–80 mg) for 9 months and saw great improvements but then I think it gave me some benign arrhythmias so I stopped. This article (Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review 2024) suggests: “As in previous reports, our patient was treated with ERT and ambroxol, and her improvement in blood data and neurological symptoms could be attributed to the combination of these agents. On the other hand, the clinical course of our patient suggests that ambroxol does not necessarily improve brainstem dysfunction leading to laryngospasm and dysphagia. Based on these findings, we speculate that the brainstem might be more vulnerable to lysosomal dysfunctions than neurons in the cerebral cortex. Thus, respiratory failure, cardiac arrhythmia and other signs of dysautonomia must be observed carefully during the follow-up period.” Ambroxol also recently failed in the PDD trial in Canada: not good. I happily take it whenever I have some cough, though :slight_smile:
  • Ibuprofen: interesting data but long-term use doesn’t seem safe. I happily take it whenever I have a viral infection, though :slight_smile:
  • Everolimus: rapamycin/sirolimus doesn’t seem to cross the BBB and to help in PD. But everolimus might. But I’m not convinced by the safety profile…

I’m also very interested in intermittent hypoxia and I’ll probably do 3 sessions next week (protocol TBD…).

If anyone has recommendations or ideas of things to try let me know :slight_smile: Prediction markets see a first disease-modifying treatment approved around 2030 (see here and there and also there) so it’s all about staying alive and in good shape until then + hope for AGI to come earlier and accelerate that timeline :sweat_smile:

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Challenge my drug stack, be ruthless but honest
Lewy Body / Parkinsons
Lewy Body / Parkinsons
#430

Whether it’s the DL form (approved for vertigo in France) or the L form (approved for Niemann–Pick disease type C in the US), I don’t think anyone knows the mechanism of action!

One assumption is that it improves lysosomal function: A bit of ADLL for RBD – The Science of Parkinson's

It might also balance the brain’s pH, get rid of lactate, and make the brain less acidic. And it might inhibit mTORC1 and improve brain glucose usage: Drug Repurposing Update #2 – Tanganil ® (Acetyl-Leucine) – Potential Mechanisms of Drug Action  – Syngap Research Fund

This paper suggests it might rebalance the gut: https://www.sciencedirect.com/science/article/pii/S0361923023001545

So… no one knows!

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#431

I think reducing acidity generally is useful. Randox do pH measurements of urine.

#432

So sorry to hear about your diagnosis at such a young age. You are a brilliant young man and you are taking positive steps to slow or halt the progression of the disease. I wish you the best in your battle. If anyone can find a way to halt or overcome it, I believe that you can!

You have my heartfelt best wishes.

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#433

Thanks :pray: Even though I’m doing a lot and I believe that these interventions work (some of my symptoms are better today than 3y ago), I’m slowly coming to accept that, unless a magical cure comes, it’s a battle that one cannot win… That being said, I think a magical cure is possible:

  • Bemdaneprocel stem cells are entering phase 3. Results in 2 years. If positive it would mean stem cell therapy available in 2027. I’m not sure it would stop the decline but it could “reset” the brain cells to their pre-disease state and gain a few years (or decades?) while waiting for a treatment that stops the neurodegenerative process.
  • Multi-arm multi-stage trials are starting in France, the UK, Australia and the US so they’ll more compounds quicker. I’m sure they’ll find something that can slow down by at least 10% per year the decline. 10% less decline isn’t much but if it compounds over time and if you combine it with stem cell therapy you’re sorted I think.
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#434

Yeah, Antoine, this sucks. I read your diagnosis announcement and it was a gut punch. I really wasn’t expecting it, you are a good researcher and I believe if anyone, you can pull off a victory here. I’ll try to focus more on PD in the course of my habitual PubMed reading. And yes, hypoxia looks good, we’ve had hints of this since the original smoking connection - I think this is productive directionally, if we also explore the possible mechanism; why does hypoxia work in PD - if we can start to understand that, we might be able to address the same cascade through other means than oxygen deprivation.

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#435

By coincidence, I was looking into riboflavin for brain health, so I may as well throw this one out (caveat, Saudi Arabia):

Riboflavin Has Neuroprotective Potential: Focus on Parkinson’s Disease and Migraine

It’s not some great revelation, just a generalized review, but perhaps worth giving riboflavin a look.

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#436

Thanks a lot.

Yes, if we understand why hypoxia works, then we might create “hypoxia-in-a-pill” as this Harvard team did last month: JCI - Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α

I looked at riboflavin (see this thread: Riboflavin and Neurocognitive Decline ). I tried it a bit and saw no improvements (I actually felt a bit unwell). I then tested my serum riboflavin: perfectly normal. So I gave up on riboflavin until there’s more evidence…

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#437

Sorry, I didn’t see that thread, thanks. If ribo doesn’t work for you, no sense in hammering it. But before I let go of ribo, I thought I’d throw in this red meat factor (I don’t know your diet!):

High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson’s disease patients

OK, no more about riboflavin!

#438

Yes but the evidence is a bit weak looking at other papers:

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#439

I think PD and Aging are both driven by aspects of mitochondrial deterioration.

Chronic Hypoxia I think reduces the rate at which mitochondria deteriorate. The body has systems to improve mitochondria hence if you can hold back the deterioration then the body can improve mitochondria.

Varying pO2 by a reduction stimulates HIF 1 alpha which acts to improve mitochondria.

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#440

@adssx That’s bad luck for sure. You might have PD but it doesn’t have you.

I know you are not a fan of blood donation but look into iron and PD. Here’s review paper.

I look forward to learning what you find helpful.

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#441

Thanks, yes iron metabolism is dysfunctional in PD. I looked at it and it’s very complex:

:exploding_head:

So people are looking at more subtle ways to fix that. The most promising interventions are:

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