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Darolutamide (odm-201), A Better Topical Than Enzalutamide?

Discussion in 'Antiandrogens - Propecia, Dutasteride, etc.' started by DavidsDome, May 4, 2017.

  1. IdealForehead

    IdealForehead Senior Member My Regimen

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    Well for what it's worth I haven't told people to use it. To the contrary I've told people NOT to use it. So if it's a conspiracy it's not a very interesting one.

    I will never post pictures of my face or hair on any website. That's a personal rule for my own privacy and I don't care to violate it. I have posted the information I have for peoples' interest. Take it or ignore it.

    I don't know what could be "fishy" about a powerful androgen receptor antagonist besides the stuff I've already said myself two or three posts up. It's a drug that's going to make hundreds of millions of dollars a year for Bayer in treatment of prostate cancer within the next 5 years. It's should revolutionize the treatment of prostate cancer given its greater potency than any other androgen receptor antagonist and the fact that it doesn't cross the blood brain barrier, so side effects are expected to be much lower (and have been in the studies so far) compared with more conventional anti-androgenic agents.
     
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  2. Ollie

    Ollie Senior Member My Regimen

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    I don't see it as fishy at all. We've had Ru58841 being used in the hairless community for a long time now and its about time we found a better alternative treatment like darolutamide. Its exciting knowing its soon to be used in the treatment of prostate cancer which brings piece of mind to its safety status, and its nice to have something which gram for gram is much stronger than RU and therefore more effective - at least until the cell based treatments come out.
     
  3. IdealForehead

    IdealForehead Senior Member My Regimen

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    I'll try to delve into this a bit briefly then I'm going to try to take a break from here if I can compel myself to do so.

    The main issue that we must be careful here is of realizing that dose-response curves for medications are not linear. That is to say, 5 mg finasteride is not 5x stronger than 1 mg finasteride. In fact, 5 mg finasteride is only slightly more effective, because both doses nearly max out this medication's potential effect.

    The same applies when we are trying to compare RU with darolutamide. It becomes very difficult to create direct comparisons for a number of reasons.

    For reference, most dose response curves look like this:

    paraquat.jpg



    I posted the math I used to try to compare RU and daro here. It was difficult as we don't have any studies that directly compare the two, but there was enough data to reconstruct what a direct comparison might look like. This data is based on the IC50 concentrations of various anti-androgens. IC50 concentrations are the amounts required for 50% inhibition of a given number of androgen receptors. So any comparison has to be very specific to that hypothetical condition.

    To extend the math there, this is what I think we can reasonably state:
    • In a hypothetical condition where a certain volume of 5% RU58841 inhibits half the androgen receptors on a scalp, equal inhibition could likely be provided by an equal volume of darolutamide at a concentration of 0.028% to 0.087%.
    • In a hypothetical condition where a certain volume of 7.5% RU58841 inhibits half the androgen receptors on a scalp, equal inhibition could be provided by an equal volume of darolutamide at a concentration of 0.042% to 0.13%.
    • In a hypothetical condition where a certain volume of 10% RU58841 inhibits half the androgen receptors on a scalp, equal inhibition could be provided by an equal volume of darolutamide at a concentration of 0.056% to 0.17%.
    I know those sentences sound ridiculous and tortured, but they have to be.

    The data we have is only regarding the IC50 concentrations (concentrations for 50% androgen receptor inhibition), and there is a curved response above and below that. Daro and RU will "curve" to different extents based on their individual properties.

    So I don't actually know how much stronger 0.5% daro would be than 5% RU58841. I am sure it would probably be much stronger. But we can't really quantify that. The above bulleted statements are as far as I am aware we can state with any degree of confidence, and even that's reaching.

    I know it's a bit confusing. I've rattled it through my head many times and that's the best I can do though.

    Given these limitations, I think a better and more useful guideline for the practical topical dosing of darolutamide would be to adjust the dose to the maximum tolerated amount and compare to the oral castration dose.

    Ie. 0.5% 2 mL twice a day is only 10 mg twice a day. The oral castration dose is 600 mg twice a day (a high dose is needed for oral castration due to daro's low half life when in the blood). So this topical application of 10 mg twice a day is only 1.6% of the castration dose. This is a tiny amount and likely to be tolerable for most people, even if it all absorbs into the blood. A 2% solution would be 6.7% of the castration dose, which might cause side effects or might not.

    We would need major studies on the topical administration of darolutamide with real men to figure out what the maximum dose most guys could get away with before side effects kick in or where the maximum ceiling effect is reached. If any well financed hair researchers or PhD candidates are by any chance reading this and looking for a new project, I think this would be a good one! One can hope. I'd love to read that study. In particular, a study of 1 mg oral finasteride vs. various topical daro doses would be fascinating.
     
    #83 IdealForehead, Nov 16, 2017
    Last edited: May 11, 2018
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  4. Ollie

    Ollie Senior Member My Regimen

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    @IdealForehead because of its strength what do you think about daro's systemic build up (topical use) and its impact on systemic DHT and Test ? Potential for nasty side effects as well ?
     
  5. IdealForehead

    IdealForehead Senior Member My Regimen

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    The half life of darolutamide in the blood is only 15.8 hours, and it breaks down into an equally powerful metabolite ORM-15341 which has a 10 hour half life.

    This is not quite as good as RU58841. RU has a half like of 1 hour, which breaks down into 93% a weak antiandrogen, and 1% cyanonilutamide, an antiandrogen similar in potency to RU with another 20 hour half life.

    Overall then in principle, the antiandrogenic effect from darolutamide will likely linger systemically to a slightly greater effect in the blood than RU. However, as posted earlier in this thread (flip back a page or two), since darolutamide does not significantly cross the blood-brain barrier, it should be less likely to mess up brain signalling pathways that control hormonal levels.

    This is partly why daro is going to be huge for its intended market and partly also why it makes a theoretically good agent for topical hair loss treatment.

    If you haven't read the posts on darolutamide side effect rates in the studies done already, go back to the prior pages and read them as I don't want to repeat all that again. Point is, it did very well with very few side effects. It seems to be a very clean drug.

    Bayer has chosen darolutamide to develop because the fact that it breaks down into an equally powerful metabolite (ORM-15341) helps extend its functional half life. They want the longest half life possible for less frequent dosing. But for hair, we want the opposite. We want anything that gets into the blood to break down very quickly.

    So in theory, an even cleaner but likely equally effective agent for topical hair loss vs. darolutamide would be to use ORM-15341 directly instead. Using ORM-15341, would cut out the initial 15.8 hour half life for darolutamide to break down into ORM-15341. So the total half life would only be ORM's 10 hour half life.

    However, I think this is unnecessary and would just complicate matters at this point. It's hard enough to find any sources for daro, let alone "ORM-15341". Additionally, personally, I don't think a bit of systemic anti-androgenic effect is really such a bad thing. We know that men with balding are at higher risk of prostate cancer and prostate enlargement. If a tiny daily microdose of darolutamide enters my blood stream over the next 30 years, and it may reduce my chances of developing those problems, I'll take it as a positive. My dad is struggling with enlarged prostate now. It's not fun. As long as my mood and energy are good, and my dick seems to basically work, I'll call that a win and be happy.

    I don't think I have much else to say about daro or anything else unless some news comes out or I have new developments as listed above. I'm all out, and as said I want to get back to some other things. So that's it for me for now. Be back soon guys.
     
    #85 IdealForehead, Nov 16, 2017
    Last edited: May 11, 2018
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  6. SeanFUE

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    Ideal, lots of quality information. Very very helpful. Thank you for breaking it down so articulately.
     
  7. Jonnyyy

    Jonnyyy Senior Member My Regimen

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    You should what Hellouser did with RU.
     
  8. whatevr

    whatevr Senior Member My Regimen

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    My theory as to why enzalutamide and darolutamide thus far seem to have a rather benevolent safety profile when used topically is their high affinity. Because they are so effective at binding to the androgen receptor, most of the molecules that enter through the scalp will immediately bind to the first androgen receptor they find (in the hair follicles), and will not continue on into the bloodstream.

    RU on the other hand, being low affinity garbage, will easily get outcompeted and boxed out by DHT, leaving a good deal of it go for "another round" throughout the entire body via the bloodstream, binding to androgen receptors in god knows which places. RU also crosses the blood-brain barrier based on my subjective experience.

    This is why I believe that despite the long half life, most enzalutamide users so far do not report any side effects, and I'm very convinced darolutamide users will experience even fewer. If there is anything close to being a super-high power AA with very few side effects, darolutamide is the closest we're likely to get in the near future.

    To sum it up, it's entirely possible that MDV and ODM (due to their high affinity) will likely have fewer, or a lot fewer side effects than RU, despite having drastically longer half-lives.
     
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  9. Recon_s

    Recon_s Established Member My Regimen

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    So not so long ago everyone was jumping on Enza after "xandros" or what ever his name was made some bold claims about only applying a few times a month and jumping up a norwood or 2. I just Feel Daro is going the same direction great theory lots of hype just lacking credibility. I stand corrected if people have had success with Enza... and I mean regrowth not "I'm gone from shedding 98.5 hairs a day to 95.25 per day" lol
     
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  10. whatevr

    whatevr Senior Member My Regimen

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    I'm starting enzalutamide next week. We have another member starting darolutamide soon as well. More data is coming, until then, the jury is still out.
     
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  11. Jonnyyy

    Jonnyyy Senior Member My Regimen

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    If there was a way to get it cheaper I'd definitely buy darolutamide
     
  12. whatevr

    whatevr Senior Member My Regimen

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    Keep your eyes out for group buys in the next few months, there will definitely be some.
     
  13. sunchyme1

    sunchyme1 Senior Member My Regimen

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    on which forums?
     
  14. whatevr

    whatevr Senior Member My Regimen

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    SAGA, probably.
     
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  15. Recon_s

    Recon_s Established Member My Regimen

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    I didn't see anyone reporting success on Enza? how come you are deciding to go that route?
     
  16. peewee

    peewee Established Member

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    I'm glad you're going to sick around and congrats on your success.

    What would be your opinion to add daro to an ru mix of everclear and pg? would it dissolve and would it absorb?
     
  17. whatevr

    whatevr Senior Member My Regimen

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    What OTHER route, after failing on Propecia and RU58841, do I even have left?

    Aside from spinning the cylinder and letting luck decide my fate...

    Going bald is not an option, darolutamide is still too expensive. I have aggressive hair loss on both sides of the family, started balding at 19, I'm NW2.5 diffuse at 25 now, and it still keeps going. I've exhausted my options.

    This is my 'all in' move.
     
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  18. IdealForehead

    IdealForehead Senior Member My Regimen

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    Thanks. I won't be posting as much anymore but i will try to check the forum periodically to see if there's anything useful i can add to discussions.

    Solubility of daro is only known in DMSO at 80 mg/ml. I don't know if it would dissolve in ethanol or pg alone. Enza is also primarily soluble in dmso so that is probably something they share in common.

    DMSO is dirt cheap and freely available on Amazon and ebay. It's not hard to get some and add to a solution. It is also supposed to help penetration of active ingredients so i can't see any downside to its use.

    Regarding dissolution of daro in gneral, the daro i have has come in little tiny 2-3 mm cracked chunks. It has not been a very fine powder. This is not a major problem really but a minor inconvenience. The compound is chemically correct by NMR and mass spec which is all that matters. However it is a bit stubborn to dissolve in general due to the 2-3 mm "chunks" taking time to break up in solution.

    Ways i have gotten around this are to mix the daro directly into the 2 ml of dmso i am using in a glass dish and use a small mixing spoon to "smoosh" and break up the chunks so they can dissolve more rapidly. Or i have just dumped it all in together and shaken it for around an hour or two which works too. Both are a bit tedious to do every 5-10 days for the rest of my life though.

    I'm gonna ask Luo if he can try to process the next batch into a finer powder. Current batch i think he has 300 grams of so he probably won't be making another batch very soon. Also this may be due to the inherent nature of daro or daro synthesis, so there is no guarantee he or anyone can make a smoother powder. Some compounds just like "clumping" a bit when you dry them out. Perhaps he can just run what he has through a shaker or blender to break it down into finer granules which would make it easier. I will ask.

    Probably the best solution long term for me will be to order a small hobby paint shaker for $40-50 on ebay and use that to shake my vials. Minoxidil (despite being a very fine powder) also tends to takes a long time and a lot of shaking to maximally dissolve so that would help that as well. That just may be the nature of daro.

    I'm occupied with other things right now but I'm gonna order one of these in the next week and I'll post back how well it works.

    Search ebay for hobby paint shaker if you want to check one for yourself. I am all about maximum efficiency so if this works it will be very worthwhile as an extra tool to have around long term. This is just a time saving measure and not necessary in any way.

    s-l400.jpg
    Example Ebay Link
     
    #98 IdealForehead, Nov 18, 2017
    Last edited: Nov 18, 2017
  19. ALightInTheDark

    ALightInTheDark Established Member My Regimen

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    I appreciate what you're doing there it looks very promising.
    Have you thought of liposomal carrier/vehicle ? Or doing a Darolutamide GB for people interested here ? It could be great.
     
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  20. Jonnyyy

    Jonnyyy Senior Member My Regimen

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    Interested in a Darolutamide buy if you hear anything about one.
     
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