here the link to the new study of Professor Melcangi :
https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02039
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Worthless crap.
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your comment brings a lot of value to the community, thank you.
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So what is the result of the study?
At no point does this seem to focus on PFS specifically, rather than Finasteride, when administered may have off-target effects.
Give him a break folksâŠI really think its smart to take a look at other targets that might explain why we get PFS at the first placeâŠThinking outside the box is not a bad idea in my opinion, even if this âstudyâ which i wouldnât necessarily call, doesnât prove anythingâŠ
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This is much more significant than you guys are giving it credit for.
Melcangi found a new MOA for finasteride that was never before seen.
It also safely explains why Khera found that 75% of PFS patients had arterial insufficiency and/or venous leak causing ED ( I have 2 failed penile doppler ultrasounds showing VL). Also easily explains energy and cognition symptoms.
â
Jotting down potential targets to increase
Carbachol, which activates both nicotinic and muscarinic receptors, produces 12â19-fold increases in PNMT mRNA and a 22-fold increase in epinephrine release.
Muscarine alone produces a dose-dependent increase (mean sixfold) in steady state PNMT mRNA levels and stimulates the rate of transcription fivefold.
Nicotine also induces a dose-dependent increase (mean of 8.5-fold) in PNMT mRNA levels.
Likely, what is needed though, would be something that increases the actual levels of the enzyme.
Perhaps an explanation why dexamthasone made so many guys feel recovered or improved: "Low, but detectable, [phenylethanolamine N-methyltransferase] (PNMT) activity was observed in [PC12 cells], and [dexamethasone] increased its activity 5.6-fold at 72 h [[21]]l).
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At no point does Melgangi describe any persistent effect of Finasteride on this mechanism even after its no longer taken.
Worthless crap??
Melcangi is light years ahead of anyone else looking into this
One hundred percent in line with neurotransmitters and everything I have been trying to look into lately. As well as a small handful of others on this forum narrowing in on neurotransmitters
https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02039#
âAs reported above, PNMT enzyme is responsible for epinephrine production and the adrenal gland represents the main source of this hormoneâ
âIn conclusion, data presented here indicate that the 5α-R inhibitor FIN is also able to interact with PNMT. This concept is supported by 3D proteome wide-scale screening, by docking and MD simulations, by an in vitro biochemical assay, and in vivo analysisâ
âWe believe that the present findings may help in explaining the various side effects reported by FIN users, in particular those related to sexual function and gut-microbiota alterationâ
âAs reported in Figure 5, norepinephrine levels significantly increased after drug treatment (Figure 5A), while those of epinephrine decreased in a statistically significant way (Figure 5B). The data obtained are in line with the hypothesis of a reduced enzymatic activity due to FIN inhibitionâ
âOverall, the data obtained after in vivo FIN treatment indicate a decreased conversion of norepinephrine into epinephrine in the adrenal glands of drug-treated rats, reasonably due to a reduced enzymatic activityâ
âIn summary, the balance of epinephrine and norepinephrine is crucial for achieving an erection.(76,77) Thus, based on the results we obtained, it is possible that FIN administration, by affecting PNMT enzymatic activity, is involved in the sexual problems reported by FIN usersâ
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so it could be that while taking fina the circulation of adrenaline decreases a lot, then when the suspension, when it comes back into circulation, causes anxiety and all that would cause an uncontrolled increase in adrenaline
Could evaluating an adrenaline inhibitor to relieve insomnia, anxiety and brainfog be an idea?
even this fact of the inhibition of adrenaline i do not see how it can explain the stop of the hair loss after the suspension of finas âŠ
The fact that heâs looking at off-target proteins says to me PFS could literally be anything.
An unknown drug interaction.
Off-Target Protein Definition,
Off - target activity is biological activity of a drug that is different from and not at that of its intended biological target. It most commonly contributes to side effects.
Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidisciplinary approach has been used to identify potential finasteride off-target proteins.
Overall, considering the side effects described, the blockade of the conversion of peripheral testosterone may not be the only factor responsible for the symptomatology reported after the 1 mg/day dose.
The large number of proteins found in the human body implies that a drug may interact with many proteins, called off-target proteins, besides its intended target.
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Yes . But the study is still looking at a specific one and confirming finâs impact on the
PNMT enzyme and epinephrine production
Looking at a specific thing and confirming that fin impacts that specific thing is a big find. I wonder though if this finding is specific to Fin or if Dut and Saw P also impacts the PNMT enzyme and Epinephrine production. If this is something that happenedâs in result of taking dut and saw P then in my mind this has a bigger chance of explaining the sexual sides
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My epinephrine is very high, obviously stuck in flight of fight mode.
Has anyone tried beta blockers before? These directly lower epinephrine.
The comments routinely posted on anything here are even worse and more worthless than random youtube comments would be.
Did you get it tested ?
If so urine, blood or saliva?
My overall epinephrine and norepinephrine production appears to be on the lowish end per my urine results. So based off urine testing anyway iâm not seeing my norepinephrine high suggesting that itâs accumulating in result of not enough of it being able to convert to epinephrine due to decreased PNMT enzymatic activity. However I had these values tested years into PFS. So right after getting PFS maybe my norepinephrine would have been high due to it accumulating like this study is suggesting.
My opinion on this is as follows:
It shows how important it is for us to have neurotransmitter testing done so that we are looking at as many things as possibly beyond hormones.
I donât think fin permanently inhibited the PNMT enzyme in the adrenal glands or anywhere else in the body. I think that for those of us who are sensitive to 5AR inhibitors one of the things that happens is that our bodies lower the PNMT enzyme purposely in order to limit norepinephrine to epinephrine production because it thinks that thatâs what needs to happen in order to maintain homeostasis.
âAs reported in Figure 5, norepinephrine levels significantly increased after drug treatment (Figure 5A), while those of epinephrine decreased in a statistically significant way (Figure 5B). The data obtained are in line with the hypothesis of a reduced enzymatic activity due to FIN inhibitionâ
âOverall, the data obtained after in vivo FIN treatment indicate a decreased conversion of norepinephrine into epinephrine in the adrenal glands of drug-treated rats, reasonably due to a reduced enzymatic activityâ
âIn summary, the balance of epinephrine and norepinephrine is crucial for achieving an erection.(76,77) Thus, based on the results we obtained, it is possible that FIN administration, by affecting PNMT enzymatic activity, is involved in the sexual problems reported by FIN usersâ
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I totally agree with you.
I donât get it, there is such less exitement about these findings. These findings are huge and if further analysed probably the base for a cure for some of the symptons (insomnia, erecticle dysfunction).
But in stead of a lot of talk and further Investigation from the Foundation there is only silence.
We finally are a few steps away from a cure for Insomnia, anxiety, erecticle dysfunction and nobody acts.
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You could be right
So my theory is that when the inhibitory neurotransmitter Allopregnanolone is lowered the neurotransmitters that in a sense counter and do the opposite of the inhibitory neurotransmitters such as dopamine,
norepinephrine and epinephrine are adjusted to âmatchâ the sudden change in the lowered inhibitory neurotransmitter state. Notice how Melchangi finds in this study that norepinephrine accumulates and stops converting to epinephrine. Almost like the body knows to specifically stop epinephrine production because with lowered Allopregnanolone maybe the body needs to lower epinephrine. And for some reason in us the neurotransmitter receptors become permanently unbalanced. I think Melchangi is seeing evidence of this in this latest study but itâs not simply because fin inhibits norepinephrine to epinephrine production. I think itâs more of a general imbalance in neurotransmitters. If people got tested in the urine neurotransmitters and saliva pregnenolone sulfate we could see if my imbalance could be replicated
Iâm low in pregnenolone sulfate. Read what it does to GABA receptors and NMDA receptors
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Does anyone have information on any of these points:
- What is Melcangi studying next?
- What is frequency of his publications?
- How does he obtain funding? Does this appear set to continue?
- Does he think we are permanently affected?
- Has anyone had direct correspondence with him and what was the result of this?
Just curious. I know some people âlikeâ or âdonât likeâ his work. Personally I am just curious on above points.
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I donât mean to be a bum but the short answer is âNoâ
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Iâm sure he has some idea what he wants to investigate next.
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There is no consistent pace in this sort of thing and depending on the specific study it might take years for a new one to come out.
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I believe he works at a university and Iâm sure he has access to various donation pools and a bit of government funding through the uni. Most of his studies are rather small anyway and are probably done with the resources and assistants available to him.
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There is far too little known about PFS to even make a wild guess. Being a researcher only means that he puts time and effort in tests related to the topic. It doesnât mean he has answers about the condition that other people donât have. His most recent study wasnât even about PFS at all, and more about finasteride in general. As finasteride doesnât cause problems in the vast majority of the people who take it, you could understandably argue that such information isnât huge for us.
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Researchers like him are being hounded by PFS patients with high expectations way too often. This achieves nothing except waste both correspondentsâ time. It would only satisfy a rather selfish desire to âknow what the man is up toâ. He doesnât have the answers either. Itâs better for all of us if we let the man be. If he needs anything from any of us, Iâm sure we would be informed.
My advice:
I wouldnât put much hope in this one researcher or put yourself in a position where you are âwaiting for his next study to come outâ because youâre only setting yourself up for high expectations and very likely disappointment. These things go in small steps and process is slow. Heâs probably doing what he can and what he thinks may be interesting and relevant contributions. If anything significant ever comes from that, it would be great but that isnât a given. A lot of people here are adding spice with their own theorymongering to make these studies seem more significant than they are. Iâm all for optimism but letâs not twist the actual narrative.
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