Newly Discovered Factor in Androgenetic Alopecia. The Cure is Near?

HairShocka

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COX-inhibiting nitric oxide donator

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COX-inhibiting nitric oxide donators (CINODs), also known as NO-NSAIDs, are a new class of non-steroidal anti-inflammatory drug (NSAID) developed with the intention of providing greater safety than existing NSAIDs.
These compounds were first described by John Wallace[SUP][1][/SUP] and colleagues. CINODs are compounds generated by the fusion of an existing NSAID with a nitric oxide (NO)-donating moiety by chemical means, usually by ester linkage. CINODs retain the anti-inflammatory efficacy of NSAIDs via inhibition of cyclooxygenase (COX) while arguably improving upon gastric and vascular safety, most likely via vasorelaxation, inhibition of leukocyte adhesion and inhibition of caspases, all known effects of NO.
The first CINODs were developed in the 1990s, and as yet none have been approved for use by the general public. The importance of developing such drugs was increased when COX-2-specific NSAIDs rofecoxib (Vioxx) and lumiracoxib (Prexige) were removed from major pharmaceutical markets in the mid-2000s due to vascular safety concerns. In addition, traditional NSAIDs increase blood pressure and interfere with the actions of antihypertensive drugs. Several CINODs are currently being tested in clinical trials, the most advanced of which are being conducted by the French pharmaceutical company NicOx, whose flagship compound naproxcinod (NO-naproxen, nitronaproxen) is in phase III trials for the treatment of osteoarthritis.[SUP][2][/SUP] Naproxcinod is a fusion of naproxen and a NO-donating group. Other CINODs are also being tested by NicOx for the treatment of diseases in which inflammation plays a role.[SUP][3][/SUP]


Pretty cool but the FDA said no to it.. Cox inhibitor + Nitric oxide!

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We need to reduce Cox-2 in the skin so PGD2 goes back as per normal without reducing Cox-1 by preserving or boosting it.. Cox-1 is needed for the production of PGE1.. by using Minoxidil, Miconazole Nitrate...

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Can COX-2 inhibitor-induced increase in cardiovascular disease risk be modified by essential fatty acids?

Das UN.
Source

UND Life Sciences, #205, 2477 Overlook Road, Cleveland Heights, OH 44106, USA.

Abstract

Selective COX-2 inhibitors increase the risk of myocardial infarction and stroke. This has been attributed to their ability to inhibit endothelial COX-2 derived prostacyclin (PGI2) but not platelet COX-1 derived thromboxane A2 (TXA2). On the other hand, aspirin blocks both COX-1 and COX-2 enzymes without decreasing PGI2 but blocks TXA2 synthesis that explains its beneficial action in the prevention of coronary heart disease (CHD). The inhibitory action of aspirin on COX-1 and COX-2 enzymes enhances the tissue concentrations of dihomo-gamma-linolenic acid (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). These fatty acids form precursors to PGE1, PGI2, PGI3, lipoxins (LXs), and resolvins that have anti-inflammatory actions. In contrast, increase in the concentrations of DGLA, AA, EPA, and DHA is much less with specific COX-2 inhibitors since they do not block the formation of eicosanoids through COX-1 pathway. COX-2 inhibitors interfere with the formation of LXs and resolvins that have neuroprotective and cardioprotective actions. EPA and PGI2 have anti-arrhythmic action. EPA, DHA, and AA augment eNO formation that prevents atherosclerosis. This suggests that COX-2 inhibitors increase cardiovascular and stroke risk by interfering with the formation of eNO, PGI2, LXs, and resolvins and implies that combining EFAs with COX-2 inhibitors could prevent these complications.

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Straight from Wikipedia.... Sprecher's shunt chart... yep... western diet is highly inflammatory... too much omega 6!!


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Hello Squeegee.

I've been reading your posts to articles and I'm confused on a few points you made. Hope you can give me some insight.

You mentioned on page 75 of this thread that:

"Minoxidil, Miconazole Nitrate or Nitroglycerin cream all upregulates PGE1. PGE1 is the major hair growth booster from the prostaglandins family. DGLA is the immediate precursor of PGE1. (Prostaglandin E1). PGE1 counteracts PGE2 as well."

1. Why is counteracting PGE2 good? Isn't there a lot of evidence pointing to block PGD2 and increase PGE2 to combat hairloss? I'm confused about this since minoxidil increases PGE1 but also PGE2, but PGE2 also causes inflammation. My guess is it's not the up regulation of PGE2 from minoxidil that is beneficial for hair at all, in fact it's what makes minoxidil sort of a double edged sword: allows dead hairs to grow back, but in the meantime it's also causing inflammation and causing more hairloss underneath.

2. DGLA or Dihomo-γ-linolenic acid, I think is a pretty rare form of omega 6 fatty acid. "They" say that the omega 3 to omega 6 balance is important and the western diet is too rich in omega 6, but if we are able to get just DGLA, would taking it do you think would cause inflammation? since it is omega-6. I'm trying to figure out how I can increase PGE1 without increasing PGE2.

Thanks! :)
 

Bogopad

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I was put on a daily oral NSAID in 2013 (don't remember which one, think it was valdecoxib) which caused my scalp hair to thicken and my lower eyelashes to thin out. It was an obvious change. It took me a while to put 2 and 2 together. It affected prostaglandin by inhibiting production of arachidonic acid. PGs act locally but can be suppressed systemically or locally. I am taking topical ibuprofen (200 mg gel) in 5 mL moisturizer now (1 week) and so far it seems to be cutting down the sebum I normally pick off my scalp. There should be a correlation with reduced inhibition of hair growth.

Finasteride used to work great for me but side effects were awful. It would also reduce acne thru reduction in PG and therefore sebum, which was nice.
 

drgs_not_hugs

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Just went through the last 50 pages, some notes on supplements I made for myself:

Cetirizine likely inhibits the wrong type of pgd2, but boosts pge2 a little
Beta Carotene as cox-2 inhibitor w/o inhibiting PGE2
Nitric Oxide inhibits COX-2, increases COX-1 (arginine, citrulline etc)
Carvacrol and a list of other COX-2 inhibitors http://www.longecity.org/forum/topic/68250-list-of-random-cox-2-inhibitors/
NAC (N-Acetyl Cysteine) and cold showers as glutathione boosters
Something to do with pgd2 as body's responce to blood clotting (?) (minoxidil, vit d, aspirin, curcumin are all blood thinners)

A selective H-PGDS inhibitor would be ideal

Aspirin, NSAIDs, curcumin, quercetin, luteolin, etc all inhibit PGD2, but also PGE2 to some extent
Not sure about paracetamol
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847847/
http://www.ncbi.nlm.nih.gov/pubmed/17175104
 

Dench57

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Bump. This really is an excellent and informative thread, I'm still reading through most of it.

Since trying Propecia for 3 months between November-February I have the most inflamed, itchy/oily burning scalp and accelerated hairloss. I can only theorise that this is caused by intensely upregulated androgen receptors and the subsequent hypersensitivity to DHT. I'm trying to address this inflammation "downstream" from where DHT attaches to the receptor in the dermal papilla (since DHT inhibition seems to just result in upregulation for me, I can't stop the process at source).

I've tried so many different approaches including keto shampoo, every vitamin/supplement under the sun, topicals including spironolactone cream, topical cetirizine, ramatroban and things like Fluridil and Revivogen. Nothing has helped the inflammation.

I am considering something like Sulfasalazine. Not a safe drug by any stretch but I am desperate now after 8 months of 24/7 scalp inflammation. I haven't found a doctor willing to prescribe it, but its mechanism looks promising in the treatment of chronic inflammation. I've read anecdotal reports of it killing people's scalp itch/oiliness. There's a rather famous thread from hairlosshelp where a guy claims to have experienced full frontal regrowth from Sulfa and nothing else. I'm not expecting anything like that. I don't expect it to help massively with my male pattern baldness; I've given up treating my accelerated hairloss, but anything that can calm down the scalp inflammation can only be good for my hair.

I'm kind of working on the following theory:

My experience with Finasteride

· Significantly and permanently(?) upregulated androgen receptor in the scalp/hair follicles, making them more sensitive to DHT.
· Elevated DHT activity -> NF Kappa B over-expression -> COX2 over-expression -> increased PGD2 (body’s response to chronic inflammation) -> manifests itself as itching, tingling, burning, pain and subsequent destruction of hair follicle. This is a chronic state of inflammation, constantly stimulated by DHT.


Sulfasalazine

Inhibits:

· TNF alpha from binding to its receptor, NF Kappa B, COX-2 (and subsequent prostaglandins) TGF beta and caspase activity. All of these are implicated in hairloss and the inflammatory component of male pattern baldness. I've also read a study which showed Sulfasalazine almost doubles PGE2 output, which stimulates hair growth as far as I know.

Would anyone else like to chime in on whether they think this could work to reduce the inflammatory component of male pattern baldness? Or am I completely screwed without a DHT inhibitor? This is of course assuming I can tolerate the side effects or even get my hands on the drug in the first place.
 

Armando Jose

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I'm kind of working on the following theory:

My experience with Finasteride

· Significantly and permanently(?) upregulated androgen receptor in the scalp/hair follicles, making them more sensitive to DHT.

How is it possible that finasteride acts upregulating AR's? is it a quick or a slow process?....
 

Dench57

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How is it possible that finasteride acts upregulating AR's? is it a quick or a slow process?....

I honestly don't know. In my experience it was a very quick process, happening within a few weeks of my first dose. Most cases of reflex-hyperandrogenicity happen quickly I understand. I believe my body responded to the drop in DHT by simply creating many more, increasingly sensitive androgen receptors, "balancing" out the lack of DHT by making me much more sensitive to the 20-30% that remained. Of course when I stopped taking finasteride, I now had 100% DHT and massively increased sensitivity to it. As far as I know, once ARs have been upregulated, they can't be downregulated back to normal.

Bear in mind this is mostly theory based on the fact finasteride can upregulate ARs, other people's experiences, and my own experience with increased sebum production, libido, accelerated hairloss (all symptoms of sensitivity to DHT). I'd love for it to be something else but I can't think what else it could be.
 

FiveMore

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I honestly don't know. In my experience it was a very quick process, happening within a few weeks of my first dose. Most cases of reflex-hyperandrogenicity happen quickly I understand. I believe my body responded to the drop in DHT by simply creating many more, increasingly sensitive androgen receptors, "balancing" out the lack of DHT by making me much more sensitive to the 20-30% that remained. Of course when I stopped taking finasteride, I now had 100% DHT and massively increased sensitivity to it. As far as I know, once ARs have been upregulated, they can't be downregulated back to normal.

Bear in mind this is mostly theory based on the fact finasteride can upregulate ARs, other people's experiences, and my own experience with increased sebum production, libido, accelerated hairloss (all symptoms of sensitivity to DHT). I'd love for it to be something else but I can't think what else it could be.

I have trouble believing that the receptors cannot down-regulate. The body is constantly adjusting and returning to its natural state. I enjoy your posts Dench and am not doubting your story at all, I just cannot imagine how your condition could be permanent (assuming, of course, that the problem is that your receptors have up-regulated). You would have to produce somehow more DHT than pre-finasteride in order for the receptors to not return eventually back to normal. Take it with a grain of salt as I have not done my own research in androgen receptors, but I do know that is generally how dopamine/serotonin receptors work.
 

Koga

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I have trouble believing that the receptors cannot down-regulate. The body is constantly adjusting and returning to its natural state. I enjoy your posts Dench and am not doubting your story at all, I just cannot imagine how your condition could be permanent (assuming, of course, that the problem is that your receptors have up-regulated). You would have to produce somehow more DHT than pre-finasteride in order for the receptors to not return eventually back to normal. Take it with a grain of salt as I have not done my own research in androgen receptors, but I do know that is generally how dopamine/serotonin receptors work.

I agree 100%. Although I seriously doubt whether it's just the finasteride that upregulated the receptors and made your inflammation so much worse. There's really not a whole lot of scientific valuable information on this specific problem.
 

Dench57

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Yeah I'm really not sure about the whole upregulation thing anymore. You'd think it would have been proven in studies - all we have is Dr. Sawaya saying at an old hair congress saying there was an "intense upregulation" of AR in scalp biopsies of post-Finasteride using patients. Whatever happened to me, it's obviously extremely rare and my body reacted in a fairly unique way - it does not apply to the vast majority of finasteride users. But I was slowly balding for 3 years before finasteride without the slightest itch, nothing, then within 3 weeks of Propecia I got the itch which has gradually developed into burning and scalp pain too. I've spoken to many people who said they went through a few months of this when starting finasteride/dutasteride and it eventually went away. Perhaps I should've rode it out, but it's impossible to know. It's been 9 months now since I quit and it just progressively gets worse.
 

FiveMore

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I used to work for University of PA. There doing this to get grant money, trust me. Also to publish books about balding. There not going to have a cure with 10 years, I guarantee you.

They want grant money to do what with if not pursue their hypothesis? What was your role at the university? They just want to publish some books for fun? An actual cure is a race to a gold mine, you think these guys are just messing around?
 

hellouser

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prostaglandin d2 antagonist:

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A novel DP(2) receptor antagonist (AM-461): a patent evaluation of WO2011085033.
WO2011085033
http://www.bioportfolio.com/resources/p ... on-Of.html
http://www.ncbi.nlm.nih.gov/pubmed/22082220
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AM211
http://www.ncbi.nlm.nih.gov/pubmed/22110163
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MK-7246
http://www.ncbi.nlm.nih.gov/pubmed/20943773
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Ramatroban
http://www.ncbi.nlm.nih.gov/pubmed/15179446

I'm going to order this one very soon!
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http://en.wikipedia.org/wiki/Cromoglicic_acid
Guys, Please stop waisting your time on this one. I have not even 1 clear study that show its spupresses or block the PGD2, GPR44 receptor, You guys cant confuse prostanglandins with Histamine! If someone can prove I'm worng with a study, please do!
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We cant use cox2 blockers, because we will also reduce the pgE2 and pgF2... and we dont want that.


So Lets find a good PGD2, GPR44 antagonist!


Just found this intersting patent!:

http://www.google.com/patents/US2011002 ... &q&f=false



I'm Also very intersted in the CRTH2 antagonist OC000459
http://www.oxagen.co.uk/crth2-1.htm
http://www.chemspider.com/Chemical-Stru ... 37014.html

ITs one of the most selective and effective out there (from my findings)

I will arrange custom synthesises These weeks..


I think this is better then ramatroban!

AM211 should be very effective against PGD2. There was a talk about it at the Hair Congress in Miami. Here's the poster:

uaiHbd1.jpg


And the presentation:
http://www.hairlosstalk.com/interac...ntagonists-Reverse-the-Hair-Growth-Inhibition
 

Roberto_72

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Interesting that in this UPENN study they mention that there would be markers to predict if the treatment would be suitable for you.
Which is something that is missing now with finasteride/min, two drugs you have to take for 6 months / a year before understanding if they work for you or not.
 

BTW

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They want grant money to do what with if not pursue their hypothesis? What was your role at the university? They just want to publish some books for fun? An actual cure is a race to a gold mine, you think these guys are just messing around?

You really have no idea how academia works. Most of the time people don't give a **** and just want something, ANYTHING to get grant money. They will research the most irrelevant protein if that means they can get a study about it. To make it clear, people care more about getting the grant money and the ISI publication than the actual content of the study
 

Afro_Vacancy

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I'm an academic.

IMO, BTW's post correctly describes the majority of the people working within this system.
 
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