Terazosin / doxazosin / alfuzosin may protect against dementia with Lewy bodies

We find an association in men who are taking Tz/Dz/Az and a lower hazard of DLB compared with similar men taking other medications. When combined with the literature of Tz/Dz/Az on Parkinson disease, our findings suggest that glycolysis-enhancing drugs may be broadly protective in neurodegenerative synucleinopathies. A future randomized trial is required to assess these associations for causality.

The UI researchers think that a specific side effect of the drugs targets a biological flaw shared by DLB and Parkinson’s disease, as well as other neurodegenerative diseases, raising the possibility that they may have broad potential for treating a wide range of neurodegenerative conditions.
For the new study, the UI researchers used a large database of patient information to identify more than 643,000 men with no history of DLB who were newly starting one of six drugs used to treat benign prostatic hyperplasia (enlarged prostate).
Three of the drugs, terazosin, doxazosin, and alfuzosin (Tz/Dz/Az), have an unexpected side effect; they can boost energy production in brain cells. Preclinical studies suggest that this ability may help slow or prevent neurodegenerative diseases like PD and DLB.
The other drugs, tamsulosin and two 5-alpha-reductase inhibitors (5ARIs) called finasteride and dutasteride, do not enhance energy production in the brain and therefore provide a good comparison to test the effect of the Tz/Dz/Az drugs.

In addition to BPH (benign prostatic hyperplasia), alpha-1 blockers like terazosin are also used in resistant hypertension (after ARB + DHP CCB + Thiazide-like at max dose failed to reach BP goals).

Could low-dose terazosin be interesting for neuroprotection in men with elevated BP @DrFraser?

Half of males above 50 suffer from BPH, so should they all take terazosin rather than finasteride?

Terazosin 1 mg also potentially useful for hyperhidrosis: Effect of terazosin on sweating in patients with major depressive disorder receiving sertraline: a randomized controlled trial 2012

Five ongoing trials, results expected between 2024 and 2026:

  • Terazosin Effect on Cardiac Changes in Early Parkinson’s Disease
  • Terazosin for Dementia With Lewy Bodies
  • Motor Function Efficacy of Pharmacological Treatments Targeting Energy Metabolism, in Parkinson’s Patients
  • Terazosin and Parkinson’s Disease Extension Study
  • A Randomized Controlled Trial of Doxazosin for Nightmares, Sleep Disturbance, and Non-Nightmare Clinical Symptoms in PTSD

I sponsored terazosin in Ora Biomedical MMC and it failed btw:

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The alpha blockers, like terazosin have a few side effects, and I wonder how much of this is dose dependent, as dosing is 1-10 mg. Postural hypotension, hypotension, tachycardia, somnolence, nervousness are among the common ones. If it was good at 1 mg … probably low rate of side effects … at 10 mg … might find a few with head injuries from passing out with standing.

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The terazosin DDD for BPH is 5 mg, so we can assume it was the dose used by men in the above study. So 5 mg might already be neuroprotective. Can we go even lower? The trials are using 2 to 10 mg (as the target dose), so we’ll soon know. Also: what about low-dose but long-term accumulation? Could 1 mg per day for 10 years be as good as (if not better than) 10 mg per day for one year in terms of neuroprotection?

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Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review ; PMC11206543.

Both theoretical about pathways involved and about possible therapeutical strategies for Alzheimer, Parkinson and other “tauopathies”. Summarizes in text numerous substances researched sofar or still in research and results sofar.

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Super interesting: Biological Age Prediction From Wearable Device Movement Data Identifies Nutritional and Pharmacological Interventions for Healthy Aging 2021

We additionally identified one FDA-approved drug associated with decelerated biological aging: the alpha-blocker doxazosin. We show that doxazosin extends healthspan and lifespan in C. elegans.
While no drug of the 500 + FDA approved drugs we assessed passed significance following a correction for multiple hypothesis testing (Benjamini and Hochberg), one compound—doxazosin—passed significance using a stringent unadjusted p-value cutoff (p < 0.01) (Figure 4E). Users of doxazosin were more likely to have negative deltaAges, representing a possible age-deceleration due to the drug, when compared to all others in the same demographic population.
As stated above, the association between doxazosin and decelerated age does not necessarily mean it causally benefits healthy aging. We therefore turned to C. elegans to test if doxazosin was causally geroprotective.
We then used a microfluidics platform totest lifespan and healthspan. Here we used multiple doses of doxazosin (3.3 and 33 ÎĽM) as previous observations show that microfluidics devices provide more direct drug contact than agar plates, and therefore a lower dose is needed (Hewitt et al., 2018). Indeed, we saw the greatest beneficial effects at 3.3 ÎĽM.
We confirmed that doxazosin extended worm lifespan (p < 0.0001) (Figure 4H; Supplementary Table 4) and simultaneously studied worm motility so as to measure healthspan via locomotion. With automated locomotion measurements, we calculated what percentage of worms remained highly active (defined as moving a distance greater than their body length in a 30 s window). Upon doxazosin treatment, we observed a higher percentage of highly active animals throughout life, particularly in the later ages tested, confirming their improved healthspan (Figure 4E; Supplementary Table 5). Altogether, we conclude that doxazosin extends both lifespan and healthspan in C. elegans.

The paper and its authors look good (although the journal is not great). So potentially lower doses are better for longevity (in worms at least…) @DrFraser!

I’ve just emailed Ora Biomedical to reproduce the above paper. Wait and see…

And also published this month: Risk of Parkinson’s disease among users of alpha-adrenergic receptor antagonists: a systematic review and meta-analysis 2024

This study was based on a total of 678 433 BPH patients, out of which 287 080 patients belonged to the TZ/AZ/DZ cohort and 391 353 patients belonged to the tamsulosin cohort. The pooled incidence of PD was higher in tamsulosin users (1.28%, 95% CI: 1.04–1.55%) than in TZ/AZ/DZ drug users (1.11%, 95% CI: 0.83–1.42%). The risk of occurrence of PD was significantly lower in patients taking TZ/AZ/DZ than tamsulosin (n= 610,363, HR = 0.82, 95% CI = 0.71–0.94, P = 0.01; I2 = 87.4%).

(Note: A 3-month supply of doxazosin 1 mg costs 2 USD on IndiaMart…)

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Their answer:

That doxazosin result looks like a pretty classic case of p-hunting. They tested something like 450 animals in each condition and found an 8% increase in lifespan. While statistically significant, I would be disinclined to believe it is biologically relevant. The survival curve presented and the data in the table are pretty unimpressive, although they worked very hard to show it (and get it published).
We can test it, but I bet the effect isn’t robust enough for us to statistically resolve it. We aim with our system to find large-effect size interventions (>25% increase).

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This may be the impetus for the ongoing trials in dementia and parkinsons with respect to GLP1-R peptides.

And one of the reasons I’ll probably take this for the duration :slight_smile:

What’s the relation here with alpha-1 or alpha-1-a blockers?

Not sure there is a relation in that respect. Just another drug candidate with a similar end result, reduced neuro inflammation.

Glucagon-like peptide-1 suppresses neuroinflammation and improves neural structure

https://www.sciencedirect.com/science/article/abs/pii/S1043661819317505

There’s zero relation as far as I know. But yes, GLP1-RAs might also be repurposed for NDDs.

The same team (Iowa U) published this pre-print in May: A pilot dose-finding study of Terazosin in humans 2024

Eighteen healthy men and women (60 – 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics.
Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response.
Third, what is the dose-response relationship for TZ’s impact on energy metabolism in people? This point is relevant because TZ showed a biphasic effect on energy metabolism in mice, suggesting higher doses might counteract the potential energetic benefits.
This study provides insight into the relationship between the dose/concentration of TZ and its metabolic effects. For both ATP/Hb levels in whole blood and brain FDG uptake, a dose of 1 mg/day TZ did not significantly alter values, while 5 mg/day yielded significant differences and 10 mg/day did not generate further changes. These results are consistent with findings that the relationship between TZ concentration/dose and the activity of PGK1 as an isolated protein, in cells and in animals, is biphasic; low TZ concentrations increase activity and high concentrations inhibit PGK1. The biphasic response is an inherent property of the TZ:PGK1 interaction and we recently provided a molecular explanation for this unusual behavior.

Another signal for low-dose neuroprotective use of alpha blockers @DrFraser? (not too low though…)

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As adssx mentioned an article of the same research group in the previous post this not be about Lewy body dementia because per wikipedia that starts most often at age around 50 with death within 4 years on average. So the study on TZ must be judged in its own right and may be of greater interest for may of us.

I’m not really familiar with these drugs, so checked on Wikipedia:

One thing caught my attention… probably a low risk, but definitely something I’d want to avoid “Severe side effects may include priapism”

Sources I found say it is “very rare”. A 2020 paper mentions 18 cases reported: Priapism – A rare side effect of alpha blockers: Report of 2 cases and literature review | Revista Internacional de Andrología

Alpha 1 blockers have been used for more than 30 years and they’re in the top 200 most prescribed drugs in the US. So if that’s 18 cases in history that’s very very very low. But good to know for someone with a personal or family history of priapism.

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https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.934

This paper found 122 cases with tamsulosin:

In several patients, priapism resolved following discontinuation of tamsulosin and recurred after its reintroduction. Both in the published and unpublished data, for majority of the cases, the time to onset of priapism was within few days following the first intake of tamsulosin.
So far, there are no studies that explored the dose–response relationship of tamsulosin and priapism. Besides, in all of the cases including both the retrieved and published ones, where dose of tamsulosin was reported, there was no issues of overdose except in one case. Thus, more information is required to conclude on this criterion.

Tamsulosin is more selective so it’s supposed to have fewer side effects and it’s way more commonly used (top 24 drug in the US, considering that it’s almost only used by men it’s huge): The Top 300 of 2021

So maybe the risk is higher for terazosin / doxazosin. But it’s hard to find data.