#50

Repurposing FDA-approved drugs targeting FZD10 in nasopharyngeal carcinoma: insights from molecular dynamics simulations and experimental validation 2024

Doxazosin can induce apoptosis in various cancer cell types, including prostate cancer cells, neuroblastoma cells, breast cancer cell through EGFR and NF-κB pathway. It also sensitizes cancer cells to Osimertinib, an anticancer drug.

1 Like
#51

Target the Heart: a new axis of Alzheimer’s disease prevention 2025

:warning: Preprint :warning:

Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer’s disease. Utilizing a neural network model, Z-LaP Tracker, we previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved drugs using Z-LaP Tracker revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. 14 of these drugs were heart medications, including angiotensin receptor blockers, beta-blockers, alpha-adrenergic receptor antagonists, and a statin. This suggests some heart medications may be effective in preventing or ameliorating Alzheimer’s disease pathology. Other studies have shown that many of these 14 drugs directly or indirectly inhibit the calcineurin-NFAT pathway, alike cyclosporine A. Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. This indicates that co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for Alzheimer’s disease and cardiovascular dysfunction, while mitigating side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer’s disease in many patients, physicians may be able to create a treatment regimen that simultaneously addresses both conditions. Our results suggest that cyclosporine A combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol are the most promising candidates for future exploration.

The usual suspects:

Upon comparison with two small-molecule libraries, Tocriscreen FDA-approved Drugs Library and Cayman Chemical FDA-Approved Drugs Screening Library , we identified 14 FDA-approved heart therapeutics that prompted CsA-like behavioral profiles: irbesartan, losartan, eprosartan, telmisartan, doxazosin, prazosin, nebivolol, carvedilol, simvastatin, droperidol, trifluoperazine, mirtazapine, calcifediol, and cilostazol .

3 Likes
#52

I am highly curious about the various zozins now. It is claimed that they increase ATP availability. ATP is mitochondria fuel–well, it is just plain cell fuel for everything. I am using Flomax at present, but perhaps I should consider one of the zozins instead. More ATP for the muscles would be great for workouts, and my brain needs all the help it can get. I wonder what the downsides of the zozins might be?

#53

Do you have a reference to this?

#54

Perhaps I am misunderstanding the paper bigly as the president might say.

“α-1 adrenergic receptor antagonists that also bind to and activate a key adenosine triphosphate (ATP)–producing enzyme in glycolysis. It is hypothesized that the increase in energy availability in the brain may slow or prevent neurodegeneration,”

Is this saying that available ATP is improved for all cells and tissues? That seems way too easy.

#55

A pilot dose-finding study of Terazosin in humans

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.

I tried terazosin 1 mg twice for a couple of days. I took it at bedtime. The first day I literally woke up and started to do push-ups right after. Never done that in my life. I had a lot of energy. The energy boost was less intense the following days but still there. Unfortunately, terazosin gave me a bit of orthostatic hypotension so I stopped. I think it might be worth trying again as trials seem to show that the hypotension can disappear after some time.

@Ray1: based on all the papers, tamsulosin (Flomax) might not be ideal for the brain.

2 Likes
#56

Homeostasis is an issue that has effects. If the cells find there is what they determine as too much energy then they wind things back by possibly fusing mitochondria.

The complex area is that the cells ordinarily cannot actually make the mitochondria more efficient (other than through mitophagy) hence although they can increase ATP availability and reduce it they cannot change the ratio between ATP and acetyl-CoA other than by increasing mitochondrial efficiency.

Hence an intervention that increases ATP availability without increasing mitochondrial efficiency is likely to be knocked back. I will read the link.

1 Like
#57

It seems that terazosin, in addition to increasing ATP, also improve mitochondrial function (see the various papers I posted in this thread).

1 Like
#58

Scanning that paper, however, its primary affect is on glycolysis and hence it would not increase the Mitochondrial membrane potential.

Hence although it would increase the efficiency by which glucose is converted to acetyl-CoA it depends whether you see that as part of the mitochondrial function (it occurs in the cytosol).

1 Like
#59

Simultaneous terazosin intervention led to an increased ratio of red fluorescence aggregates to green fluorescence monomers, effectively restoring the membrane potential (Figure 5A, B).
Terazosin reversed the decline in mitochondrial membrane potential caused by PA. (A)

1 Like
#60

This paper also looked at MMP but I don’t have access to the full text.

#61

This paper is open access

https://onlinelibrary.wiley.com/doi/10.1111/cpr.13764

They were using Palmitic Acid to reduce the MMP and terazosin restored it. I am not sure that this can be carried forward to fixing a flawed mtDNA or the effects of it.

1 Like
#62

Yes that’s the one I cited here: Terazosin / doxazosin / alfuzosin may protect against dementia with Lewy bodies - #59 by adssx

But the one I don’t have access to and that looked at MMP is this one: Terazosin / doxazosin / alfuzosin may protect against dementia with Lewy bodies - #49 by adssx

And yes you’re right, we don’t know if that’s transferable to damage from say aging.

2 Likes
#63

If it were really so simple to just increase ATP to prevent dementia, then good old creatine monohydrate might be beneficial.

I looked for information on exercise and Terrazosin, and I was surprised to find that Terrazosin is thought to have a negative effect on performance in spite of the enhanced glycolysis.

#64

Bad news? Network Analysis and Machine Learning for Signal Detection and Prioritization Using Electronic Healthcare Records and Administrative Databases: A Proof of Concept in Drug-Induced Acute Myocardial Infarction 2025

Among the remaining signals, 80 were prioritized, and five emerged as the highest priority: terazosin, tamsulosin, allopurinol, esomeprazole, and omeprazole.
Terazosin and tamsulosin, both alpha-1 adrenergic antagonists primarily used for treating benign prostatic hyperplasia and hypertension, have been associated with adverse cardiovascular effects. These drugs lower blood pressure by causing vasodilation; however, they can also lead to postural hypotension and reflex tachycardia. The cardiovascular stress induced by these side effects may increase the risk of AMI, particularly in older patients or those with pre-existing cardiovascular conditions.

1 Like
#65

Cross-posting:

1 Like
#66

I didn’t know there was a trial of terazosin for ALS in Oxford. “Participants will take up to 10mg oral terazosin daily for up to 6 months.”

“Overall study end date 31/03/2025”
“Intention to publish date 31/03/2026”

One year to publish the results… Academia is a disgrace.

2 Likes
#67

Modulation of neuronal α1-adrenergic receptor reduces tauopathy and neuroinflammation by inhibiting the STING/NF-κB/NLRP3 signaling pathway in Alzheimer’s disease mice 2025

:warning: Preprint + China + Mice :warning:

ADRA1 critically mediates tauopathy and neuroinflammation through STING/NF-κB/NLRP3 signaling. These results identify ADRA1 as a promising therapeutic target for AD prevention and treatment.

Consistently, pretreatment with Terazosin or AMD3100 suppressed Aβ42-mediated elevations in p-Taus396, p-Tau202/205, p-Tau231 and total Tau5 levels, along with reduced activation of the NF-κB pathway (p-NF-κB p65/NF-κB p65) and NLRP3 inflammasome components (NLRP3, caspase-1, cleaved caspase-1, IL-1β, and IL-18)
Notably, Terazosin and AMD3100 also suppressed Aβ42-induced ROS elevation in SH-SY5Y cells.
The progression of AD is marked by two synergistic pathological drivers—reactive gliosis and maladaptive cytokine release—which collectively establish neuroinflammatory suppression as a non-negotiable therapeutic priority. Preclinical studies demonstrate that ADRA1 antagonist Terazosin reduces hippocampal and cortical GFAP/CD68 expression in APP/PS1 mice, whereas ADRA1 agonist phenylephrine enhances astrocytic IL-6 production. Our findings align with this paradigm, showing that neuronal ADRA1 overexpression in WT mice elevates hippocampal GFAP, Iba-1, and inflammatory cytokine levels. Notably, IL-6—a key mediator amplified in this process—activates the STAT3/cGAS/STING signaling pathway in glial cells to propagate neuroinflammation. This suggests that IL-6 upregulation induced by neuronal ADRA1 dysregulation may initiate a self-perpetuating cycle of glial activation and neuroinflammatory exacerbation via STAT3/cGAS/STING signaling.

2 Likes
#68

Antihypertensive Drug Use and COVID-19 Disease Severity in Hospitalized US Veterans: A Retrospective Cohort Study 2025

After adjusting for the aforementioned potential confounding variates, CCBs (HR: 1.09, 95% CI (1.03–1.16), p = 0.002) were independently associated with an increased risk of mechanical ventilation. In contrast, ACEI (HR: 0.90, 95% CI (0.85–0.95), p < 0.001), alpha blockers (HR: 0.92, 95% CI (0.87–0.97), p = 0.001), and CCB (HR: 0.93, 95% CI (0.88–0.98), p = 0.006) were independently associated with a decreased risk for mortality (Table 2).
Interestingly, alpha blockers were associated with a protective function against death. According to the JNC-8 recommendations, alpha blockers are a 3rd-line antihypertensive treatment prescribed when hypertension is unable to be controlled by first or second-line treatments [27]. A possible mechanism for the protective effect of alpha blockers may result from their ability to reduce left ventricular hypertrophy, an independent risk factor for cardiovascular mortality and morbidity, and improve glomerular filtration rate, reducing kidney damage [35]. Given the diversity, complexity, and frequency of confounding comorbidities in hypertensive patients, prospective randomized control or propensity-matched studies are needed to study the effects of alpha blockers on COVID-19 severity.

#69

The massive issue with alpha-1 blockers is their potential cardiotoxicity…

α1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload 2006

These results suggest that the adverse cardiac effects of α1-antagonists in clinical trials are due to loss of α1-signaling in myocytes, emphasizing concern about clinical use of α1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.
One arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in hypertension tested the α1-antagonist doxazosin versus the diuretic chlorthalidone in 24,335 men and women with cardiac risk factors (5). This arm of the trial was stopped prematurely, because doxazosin doubled the incidence of heart failure, and further detailed analyses indicated a doxazosin effect to increase heart failure that was not seen with other antihypertensive medications (5–8). Similarly, in the Vasodilator–Heart Failure Trials (V-HeFT), the α1-antagonist prazosin did not improve survival as did other vasodilators and even tended to increase mortality (9). Doxazosin and prazosin are piperazinyl quinazolines, which at high doses can cause apoptosis in heart and other tissues independent of α1-ARs (10, 11), and also have relatively high affinity for α2-AR subtypes B and C (12, 13).

On the other hand: Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure 2023

Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74–0.93, P = 0.001) and 0.95 (95% CI 0.93–0.97, P = 8 × 10−6).
This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.
There are contradictory data on the role of α1 blockers in HF. Doxazosin and prazosin were associated with an increased risk of HF in several studies, including the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) and another trial comparing doxazosin to chlorthalidone (3, 5, 42). However, no direct comparison between α1 blockers and placebo in a large trial is available. On the contrary, non-specific α1 blockers were recently associated with an improvement in death and rehospitalization for HF, and specific α1A blockers with a neutral effect in a large HF cohort (6).

:man_shrugging:

2 Likes