Repurposing Duloxetine as a Potent Butyrylcholinesterase Inhibitor: Potential Cholinergic Enhancing Benefits for Elderly... 2024 Darreh-Shori et al

Full title: Repurposing Duloxetine as a Potent Butyrylcholinesterase Inhibitor: Potential Cholinergic Enhancing Benefits for Elderly Individuals with Depression and Cognitive Impairment

Abstract

Despite the advent of new treatment strategies, cholinesterase inhibitors (ChEIs) are still the go-to treatment for dementia disorders. ChEIs act by inhibiting the main acetylcholine-degrading enzyme, acetylcholinesterase (AChE). Nonetheless, accumulating evidence indicates that the impact of inhibition of the sister enzyme, butyrylcholinesterase (BChE), could be even broader in older adults due to the multifaceted role of BChE in several biological functional pathways.

Therefore, we employed an in silico modeling-based drug repurposing strategy to identify novel potent BChE inhibitors from the FDA drug database. This was followed by in vitro screening and ex vivo enzyme kinetic validation using human plasma samples as the source of BChE. The analysis revealed that the antidepressant drug, duloxetine, inhibited BChE with high selectivity in comparison to AChE. In contrast, two other antidepressants, namely, citalopram and escitalopram exhibited a weak to moderate activity.

Ex vivo enzyme inhibition kinetic analyses indicated that duloxetine acted as a competitive inhibitor of BChE with an inhibition constant (Ki) of 210 nM. This Ki value is comparable with 100–400 nM concentration of duloxetine following normal dosages in humans, thereby indicating that duloxetine should be able to induce a pharmacologically and biologically relevant in vivo inhibition of BChE. Additionally, we performed the enzyme inhibition kinetic assessment in parallel for ethopropazine, a known potent selective BChE inhibitor, and physostigmine, a dual inhibitor of AChE and BChE. These analyses indicated that duloxetine should be considered a potent BChE inhibitor since its Ki was comparable with ethopropazine (Ki = 150 nM) but was 4 times smaller than that of physostigmine (Ki = 840 nM).

In conclusion, this study reports the discovery of duloxetine being a highly potent selective competitive BChE inhibitor. This, in turn, indicates that duloxetine could be the choice of antidepressive treatment in older adults with both depressive and dementia symptoms since it may offer additional clinically beneficial effects via this secondary mode of cholinergic enhancing action.

Open access, https://pubs.acs.org/doi/10.1021/acsomega.4c05089

 

Sightly off topic perhaps...

On Duloxetine:

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases

 

Not an effective drug for FM, prescribed often in the USA, but patients taper off when it stops working for pain, if it ever did, and because of big side effect profile.

Repurposing the drug---hope it helps those with dementia.

 

Of all the drugs that could be repurposed for dementia patients they had to choose Duloxetine aka Cymbalta, an SNRI, not an SSRI. It stops people feeling emotion ( anhedonia ) and pleasure, reduces motivation (which is in short supply in those with dementia anyway), increases the risk of suicide, isn't a pain reliever, and has severe withdrawal symptoms. Is the idea just to decide "He/she is demented, let's silence them for our convenience by taking away their emotions."?

https://en.wikipedia.org/wiki/Duloxetine#Adverse_effects

 

The abstract tells you why they selected this particular drug.

 

That may be so, but my biochemical knowledge isn't up to the task. I'm writing from the point of view of knowing people who've suffered dementia and died, and from the point of view of someone who was prescribed several SSRIs and an SNRI (Duloxetine) over the years for a problem that turned out to be caused by low iron.

 

I need no biochemical knowledge to understand from the abstract that;

here the authors explain that butyrylcholinesterase is worthy of investigation. It is also something that could be of interest to pwME, which is why the paper came to my attention.

and that

here they explain that they went looking for drugs that worked on butyrylcholinesterase, and that they found duloxetine did, and therefore why it is of interest to them.

and finally

this answers your question, "Is the idea just to decide "He/she is demented, let's silence them for our convenience by taking away their emotions."?", by explaining that there may be additional clinical benefit from it.

 

I was sick as a dog on it, it caused hideous intolerable migraines when I am not remotely prone to them. Never again. This is a very problematic med and afforded no benefit to me when ldn and lda are. My dad had dementia but didn't tolerate it either. I wouldn't wish this drug on my worst enemy.

 

I emailed a renown FM nurse researcher last week and she told me that big pharma has shrunk back massively from FM research. Their big push is dementia drugs.

The huge cohort of baby boomers and the substantial rate of dementia in the elderly = potential for massive profits.

Duloxetin, the FDA-approved but ineffective drug for FM* has declining sales, no doubt.

Therefore the research march for repurposing begins...stay tuned for more of that.


* It was amazing to watch the rollout of the major clinical trials on the later FDA approved drugs for FM (duloxetine, pregabalin, milnacipram). Then after the huge sales and the widespread adoption of these drugs in the USA for FM, which is still in place and touted by GP practices, new research found that only 12-13% of FM patients stayed on any of the drugs (ineffective or the big side effect profile).

Therefore I tend to look at the big pharma economics underlying any research.