Cb's Metabolism Needs To Be Examined

[Gone]

One of the main selling points of cortexolone 17-a propionate, aka CB-03-01, aka Winlevi, aka Breezula, is its safety profile.

Winlevi phase 1: "showed no measurable side effects"

Winlevi phase 2: "No clinically relevant safety issues were noted with any of the concentrations of Winlevi™ tested and no clinically relevant signs of the typical LSR generally associated with corticosteroids use were appreciated. In the HPA/PK study only 3 out of 42 subjects resulted borderline in the lab test relevant to HP axis, with no sign of clinical corticosteroid specific adverse events."

http://www.cassiopea.com/activities/product-pipeline/winlevi.aspx

Breezula: "Breezula™ does not interfere with the hormonal and, in particular, androgenic profile of patients; libido and sexual behavior are unaffected in clinical trials to date. Because the API of Breezula™ is the same as that of Winlevi™, both product candidates have the same safety profile. Although Breezula™ has a higher concentration of this API, because the scalp is less permeable than facial skin, the systemic penetration of the two product candidates is substantially the same."

http://www.cassiopea.com/activities/product-pipeline/breezula.aspx

There are two proposed reasons for why CB has few side effects. The first: "CB-03-01 might poorly penetrate the blood brain barrier, thus failing to achieve adequate concentration in CNS."

https://www.researchgate.net/public...nd_Peripherally_Selective_Androgen_Antagonist

The second, and more popular, is that CB is "rapidly" hydrolyzed to cortexolone, which does not have an anti-androgenic effect. This is the idea that Cosmo/Cassiopeia has run with since the study cited above, one of the first about CB.

However, what is extremely important, the point of this thread, is to understand the significance of how quickly this hydrolysis occurs. The metabolism of CB. In every single article about CB, for acne or alopecia (found all of them on JAAD), they all claim that CB is "rapidly metabolized" but don't mention how rapidly. So I purchased the "biological profile" study cited from researchgate, because it was the first to use these terms, and lay out the alternative hypothesis that they have now neglected. But even that text, in full, does not explain how/how quickly CB is metabolized.

According to the Merck Manual, on the topic of drugs in the circulatory system: "After a drug is absorbed into the bloodstream, it rapidly circulates through the body. The average circulation time of blood is 1 minute. As the blood recirculates, the drug moves from the bloodstream into the body’s tissues."

http://www.merckmanuals.com/home/drugs/administration-and-kinetics-of-drugs/drug-distribution

So, if a drug can take 1 minute to spread around the entire body, it will probably only take a fraction of a second to move from your scalp to your face. If you have thinning side hair/side burns and apply CB to treat Androgenetic Alopecia, CB could reach your facial hair in less than a second. It might take only a few seconds to move from your scalp to your chest tissue.

Now, it does seem that the clinical trials have supported that this doesn't happen. Gynecomastia and facial hair loss haven't been reported as far as I have read. But I think we should still be cautious. CB is a powerful anti-androgen. There is nothing about the drug that would inhibit it from inducing classic AA side effects IF the unmetabolized drug made it to those tissues.

So if the clinical trials haven't shown these side effects, what does this mean? Is CB metabolized within a microsecond? Is this even possible? How could this be tested?

If this information had been pursued/released already, I'd probably already be taking this drug. But it's still an anti-androgen, and I'd like to know more about it. Any way we could test this? I'd appreciate your guys' input.

 

[WMQ]

The in vitro study showed it took SIX HOUR for cb to be 90 percent metabolized in human blood.

That combined with your post just showed every single reason why people do get sides from cb(and they did. At least a fraction of them trialing from black market sources).

lol at the company's report. Clinically irrelevant? How do you determine that? It took Merck twenty years to admit that finasteride does mess with your brain and give you mental sides.

 

[Gone]

Thanks. Could you send me the link to the in vitro study?

 

[WMQ]

Thanks. Could you send me the link to the in vitro study?

I think it's this one:

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0031-1297043

Might got it wrong though. You can also search through the posts of hilbert, I saw him posting that study too.

 

[Gone]

"Biological Profile of Cortexolone 17a-Propionate (CB-03-01), a New Topical and Peripherally Selective Androgen Antagonist"

This is the study you linked me, and also one of the studies I referenced in the OP. I couldn't find anything about an in vitro examination of CB-03-01's metabolism. That study merely postulates that that process might be responsible for its "antisystemic" action.

I'll look through Hilbert's posts or ask
him, and I'd appreciate it if you did the same.

 

[Gone]

http://pubs.rsc.org/en/content/articlehtml/2014/md/c4md00049h

I think this is it.

 

[Gone]

 

[Gone]

So what you were saying is correct, CB is about 89% intact when left in human plasma in vitro. As Hilbert said in the thread I got this from, human blood in vivo will likely cause the drug to metabolize quicker.

But how does this explain their repeated claims that it has no systemic anti-androgenic activity? I don't understand how the claim and the data are compatible.

 

[hilbert]

[QUOTE="Gone, post: 1417542, member: 12854 what you were saying is correct, CB is about 89% intact when left in human plasma in vitro. As Hilbert said in the thread I got this from, human blood in vivo will likely cause the drug to metabolize quicker.

But how does this explain their repeated claims that it has no systemic anti-androgenic activity? I don't understand how the claim and the data are compatible.[/QUOTE]
i was also scared by that study, but then talked to competent persons who said that in vivo is totally different.
@Gone you should also consider the penetration through the skin and derma. it takes some time, and cb is metabolized rapidly into 21-ap. there, it's safe.

winlevi is in ph3, so we will know. and facial skin is 1/5 of scalp skin.
using it since feb, and had no sex sides.

 

[WMQ]

The way I see it, the fact that cb gets metabolized quickly simply means there is a much smaller possibility of getting AA sides from it. It is mucher safer, but is it completely safe? Might not wanna be so absolute, especially after we saw that in vitro study.

Think about how there are also people doing completely fine on RU and finasteride.

 

[Gone]

"

i was also scared by that study, but then talked to competent persons who said that in vivo is totally different.
@Gone you should also consider the penetration through the skin and derma. it takes some time, and cb is metabolized rapidly into 21-ap. there, it's safe.

winlevi is in ph3, so we will know. and facial skin is 1/5 of scalp skin.
using it since feb, and had no sex sides.

It would have to be A LOT different though. Some people will want to apply this on the sides of their heads where hair is thinning. It would literally have to be converted to its other drug form in less than a second before it started affecting surrounding tissues.

Also, like Cosmo did in one of their studies, I would want to use it with iontophoresis, which can potentially exclusively target the pilosebacious unit if you set it up right. But from what you're saying, it might be safer to just apply it directly to your head so as to give it a chance to metabolize.

If anything, I think we have learned that an in-vivo study on its metabolism is warranted. I am waiting for Winlevi's phase 3 as well to see what side effects are reported. It honestly astounds me that it couldn't cause facial hair loss or gyno. Maybe not those side effects in particular, but any side effects.

In regards to facial vs scalp thickness, Cassiopeia has claimed that the 1% on the face and the 5% concentration on the scalp will have roughly the same absorption. More of the drug is needed for a deeper penetration. So I think Breezula's side effects are just as useful as Winlevi's.

I wish we could get an in-vivo test of CB's metabolism. And if it turns out worse than we thought (basically anything over 1 second [yes, that's what I would consider "rapid," lol]), then we will have to work together to find a better drug targeting solution.

 

[hilbert]

"
It would have to be A LOT different though. Some people will want to apply this on the sides of their heads where hair is thinning. It would literally have to be converted to its other drug form in less than a second before it started affecting surrounding tissues.

does it take just a second for a liquid on the skin to be absorbed and reach the blood vessels under the derma?
it's nearly 1 cm of flesh... I'm not an expert, but I don't think so.
e.g. when we apply a topical, all the derms recommend not to wash our head for at least 1 hr.

and a lot of the CB "corruption" happens in this transit.

 

[hilbert]

The way I see it, the fact that cb gets metabolized quickly simply means there is a much smaller possibility of getting AA sides from it. It is mucher safer, but is it completely safe? Might not wanna be so absolute, especially after we saw that in vitro study.

Think about how there are also people doing completely fine on RU and finasteride.

You're right. I've seen people on RU and finasteride doing fine with 0 sides (except for watery semen and loss of morning erections on finasteride, afaik), and people on topical lard having systemic sides.
The truth is that our samples are always too small, and we (or, at least, I) have no expertise in biochem to evaluate what I observe.

We have to consider a number of factors: some of the CB on the scalp will bind to the ARs (hopefully, most of it); so dose ranging is fundamental. Part of it will go through the skin and derma, and transform. Part of it will make it to the blood vessels, and transform more. How much, and how fast?
Of course no idea; with my poor knowledge, I would be either stupid or arrogant if I would take a position here.

So: I'm sure letting my hair go would destroy my hormonal balance (thanks to my brain and hypothalamus) probably more than CB.
This drug is in phase 3 for a topical for a thinner skin area, and no relevant adverse event have emerged (this is not an approved drug with B$ invested: Cosmo is still in time to bail out and save a lot of money, if this had an unsafe profile).
In 3 weeks I've been using it for 1 year, and I seem to maintain on it (and other stuff)... so, I'll go ahead.

 

[Gone]

does it take just a second for a liquid on the skin to be absorbed and reach the blood vessels under the derma?

No, it takes longer than that. What does allegedly take a second however is for a drug to move from the blood vessels near your scalp follicles to the blood vessels near your beard follicles and other tissues.

(I have read before that capillaries and veins connected to small structures do not process blood as quickly as the "primary" circulatory system. This could be a useful calculation for understanding how much leeway the drug needs as it metabolizes).

This problem is that the dermal papilla, which exerts some control over the hair's characteristics, and is a huge storehouse of excessive androgen receptors in Androgenetic Alopecia, is directly connected to the body's circulatory system. In every diagram of the dermal papilla I've seen, the blood vessels go up into the dermal papilla itself, and form this little loop. The blood goes into the papilla, loops around and then out again. The design of hair follicles being literally intertwined with the rest of our body makes it notoriously difficult to use topicals without side effects.

So it's not that you want the CB to be degraded in the skin before it reaches the dermal papilla, because then the drug is useless and won't antagonize AR. But if the drug does reach the dermal papilla successfully, and you have even one molecule of CB that doesn't attach to an AR, or you overdosed that specific hair follicle, it's now in the bloodstream. The ideal hair loss drug would be one that can strongly inhibit AR in the dermal papilla and other hair compartments (as CB does very well), but expresses through some means a complete aversion to systemic circulation (which CB is
claimed to do). That's why I was excited about CB and am still intrigued by it, it's a step closer to an ideal maintenance treatment. But until we have in vivo evidence, which probably won't impress me with my high standards, there's no sure way to tell.

I demand a drug that f*****g disintegrates with blood on contact lol. That's basically what we all need.

 

[kuba197]

You're right. I've seen people on RU and finasteride doing fine with 0 sides (except for watery semen and loss of morning erections on finasteride, afaik), and people on topical lard having systemic sides.
The truth is that our samples are always too small, and we (or, at least, I) have no expertise in biochem to evaluate what I observe.

We have to consider a number of factors: some of the CB on the scalp will bind to the ARs (hopefully, most of it); so dose ranging is fundamental. Part of it will go through the skin and derma, and transform. Part of it will make it to the blood vessels, and transform more. How much, and how fast?
Of course no idea; with my poor knowledge, I would be either stupid or arrogant if I would take a position here.

So: I'm sure letting my hair go would destroy my hormonal balance (thanks to my brain and hypothalamus) probably more than CB.
This drug is in phase 3 for a topical for a thinner skin area, and no relevant adverse event have emerged (this is not an approved drug with B$ invested: Cosmo is still in time to bail out and save a lot of money, if this had an unsafe profile).
In 3 weeks I've been using it for 1 year, and I seem to maintain on it (and other stuff)... so, I'll go ahead.

Do we finally know which vehicle should be used?

 

[Gone]

Hilbert, the more I read about serum, plasma, and blood, the less reason I have to think that the blood's metabolism in vivo will be vastly different from what tests have already indicated in blood plasma.

Plasma is just blood without large particles and cells. It lacks red blood cells and white blood cells (basophils, neutrophils, macrophages, monocytes, lymphocytes, and eosonophils), but contains all the same liquid components, including hormones and enzymes.

Plasma would in most cases be taken after a short fast, so chemicals and enzymes from food (which contain enzymes and can, depending on the food, affect systemic drug metabolism) should also be absent from drug plasma.

So plasma lacks chemicals from food and solid particles. Yet despite this, and this is an uninformed belief, I don't think either of these would significantly reduce the time of a 6 hour steroid metabolism, not to the extent we'd need it to. Cassiopeia's claims of a rapid metabolism are unfounded by their plasma data, the only thing that supports this is their safety results, which could serve as evidence to the claim regardless of plasma tests. If anyone has an explanation for this topic, please chime in.

 

[Breyfogle]

I'm gonna be the dummy newb for a second:

You brainiacs think we can go off-label and double the Winlevi dose for hair purposes when it comes out?

 

[WMQ]

Hilbert, the more I read about serum, plasma, and blood, the less reason I have to think that the blood's metabolism in vivo will be vastly different from what tests have already indicated in blood plasma.

Plasma is just blood without large particles and cells. It lacks red blood cells and white blood cells (basophils, neutrophils, macrophages, monocytes, lymphocytes, and eosonophils), but contains all the same liquid components, including hormones and enzymes.

Plasma would in most cases be taken after a short fast, so chemicals and enzymes from food (which contain enzymes and can, depending on the food, affect systemic drug metabolism) should also be absent from drug plasma.

So plasma lacks chemicals from food and solid particles. Yet despite this, and this is an uninformed belief, I don't think either of these would significantly reduce the time of a 6 hour steroid metabolism, not to the extent we'd need it to. Cassiopeia's claims of a rapid metabolism are unfounded by their plasma data, the only thing that supports this is their safety results, which could serve as evidence to the claim regardless of plasma tests. If anyone has an explanation for this topic, please chime in.

I think his point is that human blood stream is a much more dynamic environment that's constantly metabolizing and renewing, in other word more resilient. You might as well say blood stream is a river while in vivo environment is like "dead water".

 

[WMQ]

I'm gonna be the dummy newb for a second:

You brainiacs think we can go off-label and double the Winlevi dose for hair purposes when it comes out?

Theoretically yes but no one knows in reality.

 

[orkun]

You can not lose sight of losing bad beard. Cb hope we were back again.