Merck's own patent document (US Patent 5962442) makes it clear that it's unreversible?

[Timebot]

This discussion may belong in the “Finasteride Studies” section; but I wanted to have this read by as many people on this forum as possible. I’m reaching the end of my emotional and physical rope after having read US Patent 5962442. Basically, it’s Merck’s own documentation of Finasteride, written by the inventors and is titled ominously as “Irreversible Inhibition of Human 5a-Reductase”. Emphasis on “irreversible”.

The link for the document has already been posted on this site, but I think it’s good to let those who are still considering the drug, or who think it’s something they can “try” it - to read this and then DON’T!

google.com/patents?id=x_MXAA … ng#PPA7,M1

In it, the creators proudly outline the process through which they devised a drug which is “slow-binding” (which in drugs normally allows for reversible effects) but in the case of Finasteride, turned out to “form an essentially irreversile enzyme-inhibitor” (page 3) that binds to the enzyme as a “Michael acceptor”. The company seems to have been unaware of how powerful it was until it was put on clinical trials, at which point they must have realized that the drug was less a reversible, temporary therapeutic type but more a “novel mechanism-based irreversible inhibitor of 5a-reductase” in the body. Now considering that 5a-reductase is not just an evil enzyme that kills hair, but also regulates our hormones, gives us our sex-drive, our muscles, our mental acuity and general health as well - purposely making a drug irreversible with the goal of suppressing 5a-reductase permanently is TOTALLY INSANE. Irreversible would mean that nothing that anyone of us do will accomplish anything more than alleviate symptoms. Please correct me if I’m wrong as I’m currently in a very down state after reading this article through; but it’s pretty clear that nothing short of the death of this enzyme (meaning the death of the host) will change the situation. From the article, which is not advertising or marketing, but a cold clinical study of an in-house product - it seems pretty clear that Finasteride destroys the body’s ability to produce the enzyme from the prostate ever again. The thought of loosing the ability to have sexually powerful feelings in the brain and then the body, of having good health and mental thought impaired permanently is making me feel slightly suicidal.

Currently, I’m in a very depressed state with absolutely no libido (I don’t even respond to porn, which for men is usually the most potent visual stimulant for sexual response). It’s frightening, in a very primal and basic way - like watching the sun rise and feeling absolutely no warmth from it.

I have no idea at this point. I’ve lost faith in a solution. It seems like we’ve all taken a mild form of cyanide and have to deal with it.

I apologize for the negativity of this post; but I’m angry at myself and at Merck. I’m angry for why I said “yes” to a doctor’s suggestion that I try a drug I had not even asked for or considered. I’m just not feeling very hopeful right now, after spending most of my life living healthy, taking care of myself and trying to do the right thing.

TB

[ScaredMale30]

I have to be quick, but in brief this is a bit of a misunderstanding.

When Merck says fin is an irreversible 5AR enzyme inhibitor, they mean that when it binds to some 5AR enzyme, that enzyme becomes inhibited and remains inhibited.

But the body is always producing new 5AR.

Say you take just one finasteride pill. The 5AR in your body is inhibited. But slowly that (now inhibited) 5AR is replaced by newly produced 5AR. After a couple of weeks, all the inhibited 5AR in your body is gone, and has been replaced by new 5AR. Of course, if you continue to take finasteride, the newly produced 5AR will also be inhibited.

But Merck are not saying that if you take finasteride, 5AR will never work in your body ever again. They clearly would not want to claim that. And this clearly is not the case, given that most men take finasteride without problem and return to normal hormonally when they stop taking it.

[Mew]

purposely making a drug irreversible with the goal of suppressing 5a-reductase permanently is TOTALLY INSANE. Irreversible would mean that nothing that anyone of us do will accomplish anything more than alleviate symptoms. Please correct me if I’m wrong as I’m currently in a very down state after reading this article through

As ScaredMale30 mentions, only those 5AR2 enzymes bound by Finasteride are “irreversibly” inhibited (due to extremely tight binding of Finasteride to the enzyme, and such slow dissacociation that the inhibition is in fact, “irreversible”).

5AR2 which has not been bound to the drug is not irreversibly inhibited. Once the patient synthesizes new 5AR2 enzyme which is not bound by the drug, activity would be restored. I recommend you read through this entire thread: propeciahelp.com/forum/viewtopic.php?t=1053

Some quotes from the above:

“Mechanism (or time) -based enzyme inhibition is associated with irreversible or quasi-irreversible loss of enzyme function, requiring synthesis of new enzyme before activity is restored”

"The method of the present invention provides for sustained inhibition of 5α-reductase even when the dose regimen is interrupted and the levels of the 3-oxo-4-azasteroid drug having a 1,2-double bond drop, as when the patient misses a dose. In this situation of interrupted dosing, 5α-reductase that had been inhibited cannot recover from the inhibition and additional drug is required to inhibit only the 5α-reductase that has been newly synthesized by the patient."

---

it seems pretty clear that Finasteride destroys the body’s ability to produce the enzyme from the prostate ever again. The thought of loosing the ability to have sexually powerful feelings in the brain and then the body, of having good health and mental thought impaired permanently is making me feel slightly suicidal.

Again, the drug basically works as an “irreversible inhibitor” only for those enzymes bound to it, and only for as long as you take it. Once you stop taking it, new 5AR2 enzyme should be produced and activity restored.

Now here is where the problem lies: new 5AR2 enzymes and activity SHOULD be restored in those tissues where it was irreversibly inhibited by Finasteride.

In our cases, did it?

Nobody knows because nobody has specificially tested for “Adiol-G” or 5AR2 activity post-Fin in genital skin fibroblast cultures (where 5AR2 is rife):

propeciahelp.com/forum/viewtopic.php?t=761
propeciahelp.com/forum/viewtopic.php?t=1453
propeciahelp.com/forum/viewtopic.php?t=2376

books.google.com/books?hl=en&lr= … #PPA122,M1

On the other hand, there are guys here who have normal or elevated DHT levels post-Fin… so what does that mean? Is 5AR2 working correctly, or is the DHT being put out by 5AR1 to compensate?

Theories…

propeciahelp.com/forum/viewtopic.php?t=2262
propeciahelp.com/forum/viewtopic.php?t=2216
propeciahelp.com/forum/viewtopic.php?t=1400

I have no idea at this point. I’ve lost faith in a solution

The solution is to get RESEARCH done on us. Finding a doc or geneticist or androgen metabolism specialist WILLING to do the tests for syndromes od 5AR2 deficiency, 3a-hydroxysteroid dehydrogenase/3b-hydroxysteroid dehydrogenase deficiency, 17b-HSD III deficiency, and androgen insensitivity/mutation at the receptor level.

5AR2 deficiency can be diagnosed via genital skin fibroblast culture, the rest via genetic labs.

This is the stage many are at here – we’ve gotten bloodwork which is either really out of whack, or pretty normal… but nobody has been able to get beyond this to REALLY look at where the problem might lie. If you can find a doc or researcher (a Professor at a university, for instance) willing to help, we might be able to get more answers.

The user “Awor”, per the thread above, is furthest along in his quest to get such answers thanks to testing of Androgen Receptor function/binding.

[ScaredMale30]

Mew are you having any luck in your quest to get researchers interested?

I know that Awor and his researcher are considering a genetic study of the androgen receptor: maybe we should focus our efforts on making that happen.

[Mew]

No luck yet with the docs I’ve seen.

[ScaredMale30]

Do you think we should get some kind of organised campaign together to see if we can interest anyone? Write to university departments, endocrinology societies, etc?

[Mew]

Of course, people are free to do as they wish and contact who they wish.

Actually convincing medical professionals to take an interest in our cases is a whole different matter, however. It’s one thing to talk about it, another to actually make the effort through action and make things happen.

I encourage everyone to make an effort to reach out, tell their story, and try to generate awareness of our problems thanks to this drug. All the materials you need to provide to docs are in the Finasteride Studies section.

The general theories surrounding 5AR2 deficiency and androgen insensitivity certainly warrant further investigation.

[ScaredMale30]

I realise that I’m free to contact whoever I choose, but I was thinking of something more along the lines of a whole-forum approach, which may be more powerful.

I’m six months off, and so far I have only seen a couple of doctors about my case. Now things have settled down a bit, I’ll set about contacting other potentially interested parties by letter. I think I’ll give my old university a shot, for a start.

Have you tried writing to endocrinology departments at universities in Canada and the States? A letter to the Canadian Society of Endocrinology and Metabolism? Or the Canadian Medical Association Journal?

[Mew]

I was thinking of something more along the lines of a whole-forum approach, which may be more powerful.

Sure, but actually getting people to do that is impossible since this is going strictly on Internet-only communication. People would have to do such things out of their own personal will, we cannot force someone to make a phone call.

Also, we already have a doctor who has come to this website and requested written case studies of members from this forum. He had to post twice since he didn’t get enough the first time around. So it seems despite people posting on this forum, a certain percentage do not take the next step and make a sustained effort in the real world to take action and get the word out.

So what can you do?

Have you tried writing to endocrinology departments at universities in Canada and the States? A letter to the Canadian Society of Endocrinology and Metabolism? Or the Canadian Medical Association Journal?

Having what I said above, no I have not – YET.

That’s because I am slowly working on another Finasteride-related project to help our cause in such cases… but really, the onus should not be all on me to do all the legwork. I can only do so much, and only have so much time in a day. Not to mention this is all very mentally exhausting.

Please, do contact those organizations and see what kind of response you get. If you need further assistance, PM me and we can discuss privately.

Cheers.

[gcac]

That’s because I am slowly working on another Finasteride-related project to help our cause in such cases

Are you able to say what that might be?

[Mew]

A comprehensive website about the post-Finasteride syndrome, with the research from Finasteride Studies section of this forum laid out in a more easy-to-read format.

Basically a 1-stop-shop for researchers to get the big picture, and help provide them with starting points for investigation.

Launch date: when it’s done.

[ScaredMale30]

The website sounds like a great idea.

Prompted by this discussion, I yesterday sent approach emails to two research scientists over here in the UK who are specialists in the androgen receptor.

I’ll continue to search out new names and make contact. And I’ll also try the UK endocrinology society, the British Medical Journal, etc. I’ll keep you posted.

[gcac]

I agree. Good Idea. I’m sure it will also help “would be finasteride users”.