Cb's Metabolism Needs To Be Examined

[Gone]

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".

I'll try to address all of this point. But if you're also implying somewhere that the movement of blood in the bloodstream (a river, so to speak) will be more effective at drug metabolizing than "dead water," (which you may not be) all you'd have to do is stir the blood plasma for a minute or so. I understand this wasn't part of their measurements, but you could theoretically simulate the motion of the bloodstream by stirring the sample. I do not believe, disjointed from any specific evidence, that kinetics of the drug in the bloodstream alone could reduce the metabolism time from 6 hours to < 1 minute (rapid metabolism).

The blood plasma is also "constantly metabolizing" the drug. In regards to the blood renewing itself, I've read that the body produces 2-2.4 million red blood cells per second. Clearly this is a lot of regeneration going on, which would not take place in plasma. But the only reason I can think of that renewal in plasma would be relevant, is if there wasn't enough plasma to metabolise the drug, if there weren't enough enzymes present to aid its breakdown, and I don't think this was the case. It's not that there wasn't enough plasma, the drug metabolized slowly for some other reason.

It does turn out, however, that both white blood cells and red blood cells are important in drug metabolism, and make up about half of the blood volume. I found one source that simply states this...

"The organs and cells most involved in drug metabolism are the liver, kidneys, lungs, and white blood cells."

https://books.google.com/books?id=A... white blood cells on drug metabolism&f=false

... and another that specifically describes the relationship between red blood cells and steroid metabolism (CB is a steroid). This may not apply to all steroids however and I'm sure there are variations in the effects of different steroids. Have a look. (RBC = red blood cell)

http://onlinelibrary.wiley.com/stor...tr&s=4b250434df364f73c26e9773d265c534261b668b

This source actually describes numerous different effects that red blood cells have on drug metabolism.

So, it's true that the solid components of blood do have an effect on metabolizing the drug, but I do not believe that the motion of the bloodstream or the blood's renewal would be especially pertinent to metabolizing the drug "rapidly." I want Cassiopeia to be right about this, but they have to show it in the data.

 

[hilbert]

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.

@Gone, I was also concerned when I first read this paper last year. I was few weeks on CB, and trying to understand what I was doing.
(At the time, I was also totally unsure about what I was actually using; later I had all the tests repeatedly done, and proven it was proper CB).

In particular, I could not understand why the authors, in front of those table 3, were still concluding that "The absence of systemic activity can be explained by a rapid hydrolysis of the 17a-ester affording the inactive cortexolone (3).".

I remember I asked someone more knowledged than me, who told me that CB, once applied on the skin, goes through these steps:
- a part of it works as a topical AA, binding to the ARs in the DP (hopefully most of it, if we're not playing with high doses -- btw, I'm still using max 50 mg per day in 2,5 ml)
- the rest has to make its way through the skin and upper derma, to reach the main blood vessels; probably a high amount of it is metabolized in this process, since the skin and derma are quite active (with local blood vessels, etc.)
- what's left, then, enters the bloodstream, and is metabolized according to those timescales in table 3 (or hopefully faster)

So, do we have any proof? Well, no. Winlevi should be safe enough in a cream, on a skin thickness 1/5 of the scalp...
I've just passed the 1-year mark on CB. I've had periods with libido, and periods with low libido. But I'm also using other meds (minoxidil + progesterone and 17-alpha-estradiol), and I'm not in the best period of my life (to be soft). Usually low libido comes on my worst sub-periods.
Night erections are almost always there (none of them when i was on finasteride), and I apply CB right before bedtime. Daytime ones as well, when I'm in the mood.
Still, this is not a proof at all, of course.

 

[Gone]

Hilbert I really appreciate the detail in your responses. One part of your reply I keyed on was this:

@Gone, I was also concerned when I first read this paper last year. I was few weeks on CB, and trying to understand what I
- a part of it works as a topical AA, binding to the ARs in the DP (hopefully most of it, if we're not playing with high doses -- btw, I'm still using max 50 mg per day in 2,5 ml)
- the rest has to make its way through the skin and upper derma, to reach the main blood vessels; probably a high amount of it is metabolized in this process, since the skin and derma are quite active (with local blood vessels, etc.)
- what's left, then, enters the bloodstream, and is metabolized according to those timescales in table 3 (or hopefully faster

The thing is, every anatomical diagram I've seen shows that the dermal papilla is at the very bottom of the dermis, and rests directly on subcutaneous fat. It is already through the skin.

Furthermore, I'm not sure how relevant it is that a dermal papilla capillary is not a "main" blood vessel; the circulatory system is all connected, and just like oral finasteride makes its way to the hair follicle, so can an applied topical make its way into the circulatory system. There is really no bias against smaller blood vessels as far as I can tell. If there was a bias, every topical, including minoxidil, would work perfectly locally. I think the problem as I've complained before is that the target for hair loss drugs is directly intertwined with blood vessels.

Clearly CB is not like like oral estrogen in terms of side effects, you seem to be doing just fine and that's great. The thing is, even if Cassiopeia can't explain why it doesn't have side effects, I'd still take it if its safety is good enough. I'm frustrated with my indecisiveness though because I don't know if I should wait for the further phase data to come out.

I checked the website, phase 3 data for winlevi is scheduled for first half of 2018, and phase 2 data for breezula is scheduled for the second half of 2018. As Cassiopeia explains on their website, due to the thickness of the area of application and appropriately adjusted dose, the safety should theoretically be identical.

I don't know, I'm still thinking about this.

 

[hilbert]

Hilbert I really appreciate the detail in your responses. One part of your reply I keyed on was this:


The thing is, every anatomical diagram I've seen shows that the dermal papilla is at the very bottom of the dermis, and rests directly on subcutaneous fat. It is already through the skin.

Furthermore, I'm not sure how relevant it is that a dermal papilla capillary is not a "main" blood vessel; the circulatory system is all connected, and just like oral finasteride makes its way to the hair follicle, so can an applied topical make its way into the circulatory system. There is really no bias against smaller blood vessels as far as I can tell. If there was a bias, every topical, including minoxidil, would work perfectly locally. I think the problem as I've complained before is that the target for hair loss drugs is directly intertwined with blood vessels.

Clearly CB is not like like oral estrogen in terms of side effects, you seem to be doing just fine and that's great. The thing is, even if Cassiopeia can't explain why it doesn't have side effects, I'd still take it if its safety is good enough. I'm frustrated with my indecisiveness though because I don't know if I should wait for the further phase data to come out.

I checked the website, phase 3 data for winlevi is scheduled for first half of 2018, and phase 2 data for breezula is scheduled for the second half of 2018. As Cassiopeia explains on their website, due to the thickness of the area of application and appropriately adjusted dose, the safety should theoretically be identical.

I don't know, I'm still thinking about this.

yes, indeed it seems all very difficult to understand.
what I can tell you is:
1- once I asked a surgeon (Feriduni) if local capillaries can improve the systemic absorption of topicals (because I have an area of my scalp with hyper-capillarization, probably due to transplants). He said no, it's 2 different parts of the system.
2- I've read a paper on ways to deliver topicals, and for the scalp skin there are 3 routes: intracellular and transcellurar (typical) + directly through the hair duct. It seems that this route is the most effective (and indeed we know that absorption of topicals is greatly reduced in cases of SD, scales, sebum clogs, etc.). So, I hope that CB is effective for the part that makes is way to the DP through the hair canal, and the part that goes through the skin becomes progressively inactivated by skin biological processes.

no idea though. I have no gyno, ball aches, erection problems, anxiety, etc. But I have very low libido in the last 4 months. Though, I had good libido on CB, even after many months.

 

[Gone]

I believe you mean intercellular, not intracellular, because I transcellular and intracellular mean the same thing according to my checking of this topic. I read about those pathways a few months back as well.

For this whole thread I was looking at and concerning over the metabolism of the drug that makes it through the shunt pathway (hair follicles) while you were also looking at its metabolism in the skin. I guess I didn't make this clear. So from here on what I'm referring to is the CB that travels in the follicular route. If we assume that traveling through the skin around the follicles (scalp skin) disables the drug, then the only other aspect of this we have to consider is the drug that travels through the hair follicles.

One of the most obvious factors that would affect that amount of CB that makes it to dermal papilla blood vessels, is dosage, and this is the most easily controlled. If we could pick exactly how much CB would go into every hair follicle according to how much it needed, down to the molecule, we could theoretically, (and if we theoretically used the drug purely through the shunt pathway route) have a perfect topical delivery. But since the dose is approximated, there is the problem that we don't know if CB prefers to enter the DP cells vs. the blood vessels. As we know, the better you can dose it the better, but there are still numerous possibilities where the drug just bypassed this in favor of some
other target.

You seem good on side effects, have you thickened at all?

 

[hilbert]

I believe you mean intercellular, not intracellular, because I transcellular and intracellular mean the same thing according to my checking of this topic. I read about those pathways a few months back as well.

For this whole thread I was looking at and concerning over the metabolism of the drug that makes it through the shunt pathway (hair follicles) while you were also looking at its metabolism in the skin. I guess I didn't make this clear. So from here on what I'm referring to is the CB that travels in the follicular route. If we assume that traveling through the skin around the follicles (scalp skin) disables the drug, then the only other aspect of this we have to consider is the drug that travels through the hair follicles.

One of the most obvious factors that would affect that amount of CB that makes it to dermal papilla blood vessels, is dosage, and this is the most easily controlled. If we could pick exactly how much CB would go into every hair follicle according to how much it needed, down to the molecule, we could theoretically, (and if we theoretically used the drug purely through the shunt pathway route) have a perfect topical delivery. But since the dose is approximated, there is the problem that we don't know if CB prefers to enter the DP cells vs. the blood vessels. As we know, the better you can dose it the better, but there are still numerous possibilities where the drug just bypassed this in favor of some
other target.

You seem good on side effects, have you thickened at all?

of course, intercellular. sorry for the typo.

I fully agree with your analysis. Actually, if we want to concern, we should also ask about that CB that gets "inactivated". Into cortexolone... which is a precursor to cortisol. which can do good or harm.
if cortisol gets to high, afaik TSH should also increase. In the blood tests I did (2, 4 and 9 months on CB), both cortisol and TSH were ok. anyway...

About thickening... well, it's a complex subject. I'm not only on CB. What I can say is that, since I dropped finasteride (oral then topical) 1 year ago, switching to CB 2% and seti 400mg per day, I'm maintaining. In some periods, I even saw some improvements. And it seems I've survived effluvia better than on finasteride.

 

[Gone]

You've probably looked at this before, but here's what they had to say about that:

They considered even the 3/42 cases to be unrelated to the drug, if I'm interpreting this right.

Thanks for the update.

 

[hilbert]

You've probably looked at this before, but here's what they had to say about that:View attachment 49305
They considered even the 3/42 cases to be unrelated to the drug, if I'm interpreting this right.

Thanks for the update.

yes i knew. and i'm hoping so much they are right.

 

[hilbert]

btw, why worrying on cb?
https://mobile.nytimes.com/2016/09/07/well/live/why-your-toothpaste-has-triclosan.html

mine has it, since years. f*ck.

 

[hilbert]

btw, i did blood tests with a complete panel yesterday. still incomplete results, but it seems that it's all ok (tsh, cortisol, lh, fsh, T, etc.). will update this when i get all the parameters.

 

[CONOR1863]

My understanding is that CB doesn't cause facial hair loss because it's not going systemic (enough). Anyone have an idea on how it might affect a hair transplant that included beard hair grafts?

 

[tgfbeta]

I used 50mg daily and at the end of my second week I've experienced sexual side effects. It seems like I'm a rare case as most people experience cortisol-related sides (insomnia) or dry eyes. I stopped dosing yesterday because I'm having pretty significant ball ache and shriveling/numbness of my shaft. One thing to note however, is that it seems to work fairly quickly. It reduced my shedding/itch after about 1 week, and I have tiny vellus growth along my hairline, but it's not enough for someone besides myself to notice.