Interesting. You should look at what Cure Parkinson’s UK is doing: they only fund disease-modifying trials using repurposed drugs or supplements. Easy to replicate:
Their trial of the anty-hypertensive drug isradipine (taken orally) failed in the past but they’re now exploring intranasal isradipine as they think it’ll increase the delivery to the brain and work this time.
Regarding GLP1 agonists, in the 2017 Phase 2 exenatide study, the stablization of the motor features was only observed in the off-medication state. I understand from the preliminary Phase 2 lixisenatide study results that the stablization of the motor features was observed in both the on and off medication states. Still, exenatide seems best at brain uptake (if I understand the graph correctly…): https://twitter.com/foltynie/status/1735700379491307973
I’m pretty convinced that one of the aforementioned repurposed compounds will prove slow the progression in a phase 3 trial in the next few years. The exenatide phase 3 trial ends next month and we’ll get results soon hopefully.
Other interesting compounds that are under study or may be worth studying: taurine, photobiomodulation (red/infrared light similar to SYMBYX PDCare), rapamycin (although it failed for MSA), low dose CoQ10 (~150mg/d, higher doses failed), low dose lithium (there’s an ongoing trial), glycine, and astaxanthin.
Inhibition of mammalian target of rapamycin complex 1 mTORC1 normalized protein synthesis, decreased loss of dopaminergic neurons, and ameliorated behavioral deficits in fly and mouse models.
Treating the genetically engineered mice with rapamycin, a drug that targets mTOR, not only prevented excessive protein production in mice with a condition like Parkinson’s disease, but also eased some of the slow, halting movements and weak grip strength that are hallmarks of Parkinson’s disease in people. […] Researchers may, for example, develop drugs that act like rapamycin — currently used as an anti-rejection and anti-cancer medication — but work specifically in the brain to save dopaminergic neurons, sparing patients unnecessary body-wide side effects."
Could intranasal rapamycin do the job? Does anyone have the article to check the dose they used?
When I am looking for a paper that has been published recently (the ones pre-2021 are on Sci-Hub.ee) I go to twitter and try to find the author (or one of the authors) to see if they have posted a link with the code to read the full article. Many of them do this I’ve found (or I contact them on twitter to ask them to if they haven’t).
Yes, 20mg/kg is pretty high for rodents but I’ve seen studies of up to 100mg/kg (short term obviously). Kaeberlein/Bitto did the transient rapamycin lifespan study with 3 months at 8mg/kg (injection). Seemed to go well for the male mice, but a plateau for female mice.
Thanks. “intraperitonially with rapamycin (6 mg/Kg; #R-5000, LC laboratories) or vehicle (10% PEG400, 10% Tween 80 in water) on the day of the intrastriatal α-syn PFF injection and every two days thereafter following the intrastriatal α-syn PFF injection for 30 days.”
How does rapamycin absorption differs from intraperitonially VS orally?
We initially used a treatment regimen consisting of intraperitoneal (i.p.) injections of 8 mg/kg rapamycin daily for 90 days. This dose was selected because we have previously found that it increases survival and alleviates disease phenotypes in short-lived mouse models of dilated cardiomyopathy, muscular dystrophy, and the severe mitochondrial disease Leigh Syndrome (Ramos et al., 2012; Johnson et al., 2013). Based on efficacy in the Leigh Syndrome mouse model and serum drug levels in wild type mice, we estimate that this treatment regimen is comparable to dietary delivery of eRapa at approximately 378 ppm (Johnson et al., 2015), or 27-fold higher levels than initially shown to extend lifespan in mice when continuous treatment is initiated at either 9 months or 20 months of age (Harrison et al., 2009; Miller et al., 2011)
I’ve done a bit of i.p dosing in the past. It’s a bit of a half-way route of drug administration (between oral and i.v)
Intraperitoneal injection bypasses first-pass metabolism from the gut, but is still subject to first-pass metabolism by the liver, since absorption is via visceral peritoneum which drains into the hepatic portal vein.
I get worried that the interactions might be too much.
I pulse the rapa 10mg weekly and pulse off the quercitin (and wish I knew whether to take the quercitin WITH the rapa or not). Besides ambroxol I take once-a-week exenatide, and B12 shots and until someone tells me otherwise that’s enough needles thank-you-very-much :o)
I do take a multi-B (with all the fancy forms like methylcobalamin) and lithium and meloxicam (an anti-inflammatory) and have read (I think Peter Attia?) that NR doesn’t cross the BBB very well.
I wonder about Nilotinib (is it similar in action to quercitin?) and I also wonder about an SGLT2 inhibitor. I haven’t gotten there yet. As I said, I would give a lot for advice. I’m kind of flying blind.
I haven’t read everything yet, but: “Their re-examination points towards some results suggesting positive effects, but these findings will require further investigation. A parallel clinical trial of nilotinib (supported by Cure Parkinson’s and Van Andel Institute) did not find the same results and indicated that the drug was insufficiently accessing the brain. […] It is important to understand that these studies involve re-analysing data in a biased fashion – searching results for any interesting correlations or effects, and as such, these investigations should be considered as ‘hypothesis generating’ exercises. Researchers use these sorts of analyses to find new ideas for experiments that can then be tested, and further research will be required before isradipine or nilotinib can be re-examined in people with Parkinson’s.” ( Post-hoc analyses of the isradipine and nilotinib trial results - Cure Parkinson's ).
What’s the relationship between quercetin and nilotinib/dasatinib btw?
What’s your current lithium dose? This trial suggests 30-45mg/day, “slowly titrated in each patient up to the maximum tolerated dosage in this range”: CTG Labs - NCBI
Regarding Nilotinib, I guess we’ll soon get the results of this trial, which may help you to make a decision: CTG Labs - NCBI
Quercitin and nilotinib (plus like a million other things I guess) are senolytics, and somewhere I read about “synergistic cytotoxicity” which maybe was meant to be good but sounded a bit scary to me. I’m a little protective of my brain cells. But really, I don’t know. These articles quickly soar over my head.
I DO take lithium, although my doctor for some reason is terrified of it (actually, he is convinced it causes tremor) so I only take 5mg a day. I wouldn’t mind titrating up–think I’ll look up signs of maxing out. Thx!
Yes, I eagerly follow all the trials, particularly the repurposed drug trials. Wish results came faster!
Parkies tend to run low blood pressure, and I am no exception, generally running like 110/65 or so. Maybe it’s one bright spot in an otherwise grim landscape :o)
Your doctor is right, but as far as I can determine it’s only at prescribed therapeutic levels.
Does your doctor know that the doses of lithium we are taking in the form of lithium orotate are much much lower than commonly prescribed?
I have been taking lithium orotate for over two decades at doses from 5 - 15 mg of elemental lithium.
As I reported previously, I had started to develop what I believed were age-related "essential tremors. I did not associate the tremors with the lithium supplement. But, who knows?
A few weeks after I started rapamycin my tremors went away and I have been free of them since. I was not aware that lithium was a probable cause as I developed tremors when I was about 78 yrs. old.
“The available evidence suggests higher lithium doses and plasma levels are associated with an increased risk of developing lithium tremor, implying a dose-response relationship”
“Tremor was related to higher doses, to higher concentrations, and to higher gradients of lithium in plasma”
I take 1 mg of lithium orotate daily. It seems to be a good microdose. Lithium is also synergistic with Rapamycin. Supposedly it cancels Rapa’s lipid effects. Maybe I need to dose higher?
Yes it’s frustrating how slow trial results come out. You can often get them faster by contacting the authors. For instance the results of this trial are not yet out ( Risk Reduction for Alzheimer's Disease - Full Text View - ClinicalTrials.gov ) but the author told me that it failed: 2y of intensive BP control with losartan and amlodipine + physical exercise did not improve cognitive performance.
Yes I’m aware of the hypotension risk in PD but I’d still look at BP, especially continuously over a day or week (for instance with a device like Aktiia) because:
Some antihypertensive drugs are considered as potential repurposed treatments for PD (namely CCBs like isradipine and ARBs like candesartan/telmisartan)
If LPS contributes to PD, then a number of possible therapeutic strategies could be considered for further evaluation in clinical trials as outlined below. However, if LPS is elevated in only a subset of PD, patient stratification would be essential for targeting the most appropriate patients. Monitoring of blood LPS levels in such trials would provide important validation of the mechanistic principle, alongside clinical efficacy measures. […] (4) Blocking LPS receptors. Candesartan, an existing drug licensed for the treatment of hypertension, has been shown to reduce TLR4 expression and activity, is expected to cross the BBB, and has a good safety profile, making it an attractive candidate for repurposing in Parkinson’s disease.
Does anyone know how to test for serum LPS?
I’m also curious:
Are there things that you tried but stopped because they did not seem to work or had bad side effects?
Among all your interventions, if you had to keep only one, which one would it be?
ldl picks up the LPS which is then cleared from the body when the ldl is picked up by the liver. Statins make the liver produce more ldl receptors to remove ldl from the bloodstream. This is why ldl measurements decrease and how the lps gets taken out. So, statins help with removal of lps, according to Krause.
I don’t know if the above is correct but the use of cholesterol-lowering drugs is associated with decreased risk for PD:
News in Context: Cholesterol Medication and Parkinson’s 2022: “In the meantime, if you need a cholesterol medication, it may be worth discussing whether a statin might be beneficial, particularly if you live with Parkinson’s or with a risk for the disease, such as having a family member with PD, carrying a genetic link, or acting out your dreams.” (MJ Fox Foundation)
Lovastatin 80 mg/day or placebo with 1:1 randomization was administered for 48 weeks. […] Lovastatin treatment in patients with early-stage PD was associated with a trend of less motor symptom worsening and was well tolerated.
1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period […] In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial.
So maybe statins are only symptomatic and not DMT.
Even for mice that’s a lot, no?
