Topical Flutamide v. Topical Spiroactalone

[CCS]

jel as scientist suggested

Re: Flutamide Solution 1% Check it out Please.
From: maneless
Date: 25 Nov 2000
Time: 06:01:49
Remote Name: 64.12.105.156

Comments
I'm not really not trying to be rude to you but what you are doing is ridiculous. You need the exact same gel and formulation that the Israeli doctor used - it has to be the exact same.

If it's not the exact same then the flutamide molecule may not permeate the skin of the scalp and get to the follicle or it may get to the follicle but also deeper into the body and cause side affects. .

You are not making this gel as the Israeli doctor did and yet you are expecting the same results. Your logic is surreal. Think about what you're doing.

You want to make this stuff the exact same as the Israeli doctor made it if you want the same results. Why can't you understand that? You have no chance of getting this stuff into the right part of the hair follicle in the right concentration and doing what it's supposed to do without getting into the rest of the body unless you make this stuff the exact same way that the Israeli doctor did.





The Formula Again
From: The formula of Dr. Sintov`s flutamide-gel again:
Date: 25 Nov 2000
Time: 16:30:23
Remote Name: 62.227.30.184

Comments
James Bond has posted the formula of the gel. I think every proffessional chemist or pharmacist can make exact the same gel.

http://l2.espacenet.com/dips/bnsviewer?CY=
wo&LG=en&DB=EPD&PN=9962464&ID=WO+++9962464A1+I+

Here it is in its most basic form. All numbers are percentage by weight.

Flutamide = 1% (I would put this as a minimum starting dose).

Ethanol = 30%

Propylene Glycol = 24%

Glycerine = 3%

Arlacel 186 = 1% (glyceryl mono and di-oleate)

Methocel E15-LV = 4% (Hydroxypropyl methylcellulose)

Distilled Water = q.s.

(All ingredients are medical grade)



The Formula Again

From: maneless
Date: 25 Nov 2000
Time: 18:27:55
Remote Name: 205.188.199.38

Comments
I've been advised that there is some question as to whether or not this is the exact same formulation that he used in the study that worked. Just to answer all these questions I suggest that we get ahold of all of this drs. journal articles and see if there is any helpful information inside. The very article that was first brought to this forum may have not been a complete article but rather may have only been a condensed version of an article/study. The complete version may include the details/ingredients of how to make this gel in exact accordance with how the good Israeli doctor made it.







From the full-text of Sintov paper- making the gel
From: MJ
Date: 28 Nov 2000
Time: 16:15:05
Remote Name: 192.11.226.104

Comments
In the Materials & Methods section of Sintov's paper, he briefly describes how to formulate his gel. Here's how it goes:

-The gel will consist of (by weight) 1% flutamide, 1% glyceryl oleate, 4% hydroxypropyl methylcellulose, 30% ethyl alcohol, and the rest distilled water, so measure out the appropriate amount of each depending on how much gel you want.

-Dissolve the flutamide in the ethyl alcohol. There is no mention of heating the solution at all, which I take to mean that the drug readily dissolves in the alcohol at room temp.

-While mixing the solution, gradually add the glyceryl oleate and distilled water. Mix until solution is uniform.

-Finally, add hydroxypropyl methylcellulose to gel the solution.

-Believe it or not, you're done.

Frankly, I see no need to pay anyone to compound this solution for us- this is about as straightforward a synthesis as you're ever likely to see, and so there's no reason not to just go ahead and whip it up in the kitchen. All of these substances are non-toxic, so there's very little risk involved.

I'd advise everyone to experiment with the amount of methycellulose in the gel so as to get the desired consistency, which will likely vary from person to person. The methylcellulose is only included to gel the solution, so there's some room for variation there. The key ingredient is the glyceryl oleate, which allows similar percutaneous penetration to a 50% water, 50% alcohol solution, yet increases the "holding time" for the flutamide in the skin. Neat trick, I think. I'd also suggest adding a bit of BHT to the solution to reduce potential oxidation. -MJ

 

[CCS]

topical flutamide compounded professionally

these guys sent the directions to dr lee and a community drug maker, had it made, and bought it. end of thread

 

[CCS]

someone named Bryan comments on topical flutamide

>Ah, Bryan, ever so obstinate- you know damn well that the degree of systemic absorption in humans is much smaller than in hamsters. (snip)<

MJ, what you posted has absolutely no relevance whatever to what I've been saying!

I'm fully aware now (I've studied the article you mention, and others besides) of the degree to which topical flutamide is absorbed in humans. However, I'm amazed that you don't see that that's a separate issue from what I've been talking about! I'm trying to get across to everyone that there's no particular reason to put flutamide in your topical minoxidil, because (for the umpteenth time) there are little or no local effects from this drug. I can see by your response that I was wise to reinforce this by posting about the other study that found the same results.

Once again: yes, less than 50% of topically applied flutamide is actually absorbed systemically in humans. Furthermore (and this is the biggie), there are little or no purely local effects from topical flutamide.

Bryan

 

[Bryan]

the thread says that pubmed has many studies on flutamide and hair growth...

The only one I've ever seen is the Sintov study.

Bryan

 

[Old Baldy]

Here's one looking at hirsutism:

Cusan L, Dupont A, Gomez JL, Tremblay RR, Labrie F.
Medical Research Council Group in Molecular Endocrinology, Centre Hospitalier, Universite Laval Research Center, Quebec, Canada.

OBJECTIVE: To compare the clinical efficacy and safety of the pure antiandrogen flutamide and the steroidal derivative spironolactone in the treatment of hirsutism in women. DESIGN: Fifty-three premenopausal women suffering from moderate to severe hirsutism were randomized into two groups and received either flutamide or spironolactone in association with a triphasic oral contraceptive (OC) pill. Hirsutism, acne, seborrhea, alopecia, and side effects were monitored monthly for a treatment period of 9 months and a follow-up after treatment period of 6 months. Blood samples were taken at each visit for assessment of endocrine, biochemical, and hematologic parameters. RESULTS: After only 6 months of therapy, flutamide caused a maximal reduction in the hirsutism score to a value within almost normal range; during the same period, spironolactone caused only a 30% reduction of the hirsutism score. Whereas flutamide caused a dramatic (80%) decrease in total acne, seborrhea, and hair loss score after only 3 months of therapy, spironolactone caused only a 50% reduction in acne and seborrhea, with no significant effect on the hair loss score. Four patients in the spironolactone group but only one in the flutamide group stopped the medication because of adverse side effects. CONCLUSION: The present data obtained in a randomized prospective study clearly demonstrate that the pure antiandrogen flutamide is superior to spironolactone in the treatment of female hirsutism and its related androgen-dependent symptoms and signs in women.

PMID: 8299783 [PubMed - indexed for MEDLINE]

 

[CCS]

a study bryan found, quoted

Here's that study which measured the systemic absorption of topical flutamide in humans. Some of you may not have seen it:


J Invest Dermatol. 1976 Jun;66(6):379-82.

"Percutaneous penetration and metabolism of topical (14C)flutamide in men"

Katchen B, Dancik S, Millington G.

This study was designed to determine the fate of the nonsteroid antiandrogen flutamide in men following a single 6-hr topical application of 5 mg 14C-labeled drug dissolved in 50% ethanol/50% propylene glycol. Analysis of 0-120 hr urine shows at least 16% of the applied flutamide is absorbed. Fifty-six percent of the dose is recovered from the site of application with cotton swabs moistened with 50% ethanol/50% propylene glycol. Flutamide plasma levels peak in 4 to 6 hr at about 1.3 ng/ml and then decline rapidly to about 0.08 ng/ml 24 hr after application. Only 13% of plasma 14C is associated with flutamide 6 hr after drug application. There are at least 10 plasma metabolites, of which 6 have been tentatively identified. These are alpha, alpha, alpha-trifluoro-4'-amino-m-acetotoluidide (A); alpha, alpha, alpha-trifluoro-4'-amino-2-methyl-m-lactotoluidide (B); alpha, alpha, alpha-trifluoro-4'-nitro-m-acetotoluidide (C); alpha, alpha, alpha-trifluoro-2-methyl-4'-nitro-m-lactotoluidide (D); alpha, alpha, alpha-trifluoro-4'-amino-2-methyl-m-propionotoluidide (E); and alpha, alpha, alpha-trifluoro-6-nitro-m-toluidine (F). (D) is the major plasma metabolite, and its concentration exceeds flutamide's between 8 and 24 hr after drug. All the plasma metabolites are found in 0-24 hr urine in minor amounts. An additional metabolite, alpha, alpha, alpha-trifluoro-amino-5-nitro-p-cresol (G), accounts for 27% of urine 14C.

 

[CCS]

"Hydroxyflutmide is the active metabolite, and is MUCH more potent than flutamide. However, that human study of topical flutamide which I've posted about a few times over the years tested BOTH of them, and found minimal difference in effectiveness between the two; so the apparent explanation for that is that there are sufficient levels of the appropriate enzyme activity in human skin to do that conversion.

Bryan
hairlosshelp"

another explanation is that both pass through the skin so quickly that there is not time for any effects, and then the conversion happens in the body.

 

[CCS]

Thanks Old Baldy.

quoting brian:
I know of only four studies that deal with topical flutamide, and I have all of them right here: the two animal studies (rats, mice, and hamsters) that showed that it works by systemic absorption; the one measuring the amount of systemic absorption in humans; and the one showing a difference in human sebaceous gland response between males and females (I've posted extensively about that one in the past). I'm unaware of any other topical flutamide studies.

Do any of this talk about hirsutism?

 

[CCS]

I've been reading Brian's old posts at hairlosshelp, trying to piece together the studies. And i just looked at that pubmed study. it is not a topical, which is probably why bryan did not list it. he would probably say that the flutamide is stronger systemically but has a weaker local effect.

"Ethanol = 30%, Propylene Glycol = 24%, Glycerine = 3%,
Arlacel 186 = 1% (glyceryl mono and di-oleate),
Methocel E15-LV = 4% (Hydroxypropyl methylcellulose),
Distilled Water = balance"
The glyceryl mono and di-oleate is supposed to keep flutamide in the skin longer, but I don't know if it slows it from getting to the androgen receptor as well.
The studies Bryan has sighted probably used different vehicles.

After 120 hours, 16% was found in the urine as various metabolites, and serum levels dropped to 5% in 24 hours, and peaked at 4-6 hours. 56% was wiped off the skin at 6 hours. This was in 50% ethanol, 50% propylene glycol, with 5mg flutamide over an unspecified area of scalp. What happened to the extra 28%? Did it get absorbed in the fat or other areas? Was some stuck to receptors for a while?

We know the hydroxyflutamide is more potent, yet applying both topically gives the same effect. So flutamide is converted to hydroxyflutamide fast in the skin or the hydroxy flutamide passes through the skin fast enough not to take effect then, and then comes back systemically to the skin later.

The lack of skin conversion of flutamide to hydroxyflutamide would explain spironolactone have stronger local effects. So if we can make a good topical, it would need hydroxyflutamide, not flutamide, assuming the skin can't make the conversion. I'm sure a college chemist might be able to convert one to the other.

Next, there is the question of "if it is such a strong anti-androgen, then why does it not grab a receptor on its way through the scalp?" Well assuming non-transformed flutamide is strong enough to bind to the receptors in a short period of time, it is possible that all the receptors get filled up, and that excess flutamide is entering the system. At sufficient over load, it would seem like 100% just passes through. I would advocate smaller doses for this reason. How small? Well if 750mg is prescribed orally, and lets assume 1500mg blocks every receptor in the body, and the scalp, particularly the hair line or problem area, is 100cm2 and 1cm deep, that is 100g of flesh out of 75kg of person, or about 1/750 the total mass. So 1500mg/750 = 2mg. Since about 50% was absorbed in 2 hours, we would need 4mg in the cream. But 5mg was used in this study, and 16% exited the urine in 120 hours. My estimate looks pretty dead on unless it built up in the fat or somewhere else.

 

[CCS]

i must point out to anyone considering applying spironolactone and flutamide at the same time that the spironolactone will compete with flutamide for androgen receptors and cause more flutamide to enter the blood sooner. They should have done that in the human absorption experiment to determine which had a stronger local effect in vivo.

then there was the animal flank were both sides were affected equally even though it was applide to both. This implies a nearly 100% absorption in animals, unless flutamide bonded to the receptors locally while excess went systemic, and then the hydroxyflutamide can back and competed with the flutamide at the topical sight and replaced it soon afterwards. That would give the equal results even if flutamide does have a local effect. that brings the question of whether the dose in this experiment was higher than it had to be.

also, people keep asking for a low dose that won't go systemic. i must point out that this is probably not possible, unless enzymes that make the non-androgenic metabolites are in the skin. Our goal should be to use a low enough dose to not oversaturate the androgen receptors, so that the flutamide sits there for a while before going systemic. this way, even though all the topical dose goes systemic, we can have the amount per day much lower, and just high enough to maintain the follicles near saturation. think of it like a traffic jam on a small section of freeway. Past the jam, cars are spread out. yet the number of cars slowing down for the job is equal to the numbers leaving it, and the jam stays the same size, like a compression wave.

unless the skin can convert flutamide to hydroxyflutamide before it passes into the blood, achieving this will be inefficient, unless we can apply topical hydroxyflutamide.

the serum concentration reaches a maximum when the rate of flutamide leaving the scalp is equal to the rate that the body is metabolizing the flutamide. it approaches this max when the filling rate is faster than metabolism, and it leaves this max when the filling rate is slower than the metabolism. i would assume the metabolism rate is probably faster when the blood level is higher, and the filling rate is highest when the non-receptor bonded scalp flutamide levels are at a peak. The serum levels reached a max at 4-6 hours, and at 6 hours the scalp was wiped of excess flutamide. The amount of excess flutamide in the scalp is determined by the rate entering the skin, which gets faster once momentum is established, and increases fastest once the receptors are filled more. i don't think there is enough information here to know if scalp excess flutamide max comes before or during serum max.

 

[CCS]

those scientists wasted research money

those scientists who did the spironolactone/flutamide study on women wasted money. they should have just applied the flutamide to one cheak and checked to see how the other cheak did. if both responded the same, that would mean that systemic absorption was almost 100%. they then should have cut the doses in half (or had two dose groups at a time) and kept this up until only one cheak was affected. If only one was affected, that would mean a truly local dose and little systemic absorption. If such a dose did not exist, and both cheaks just got less and less benifits, that would mean Bryan is right that only spironolactone has local effects.

Bryan, in the study, did they apply it to both cheaks?

If spironolactone reduced hair growth by 50%, then topical spironolactone should do pretty good on men when combined with oral finasteride.

 

[CCS]

old baldy, are there any other flutamide studies where they applied it to just one cheak on women and checked for effects on the other check?

 

[CCS]

http://images.google.com/imgres?imgurl= ... n%26sa%3DN
scroll almost halfway down for picture

http://images.google.com/imgres?imgurl= ... n%26sa%3DN
picture near top

http://images.google.com/images?sourcei ... a=N&tab=wi
hydroxyflutamide just has an extra oxygen, as a OH substituted for a hydrogen in the methyl group.

Notice how hydroxyflutamide looks very much like the bigger metabolite of fluridil. I wonder why the fluridil metabolite is not anti-androgenic.

I think I can find a way to react flutamide to make hydroxyflutamide. i just need to figure out what other by products there would be. I need to review organic chemistry anyway, and need to figure out how to determine if the flutamide actually is flutamide. I'm not sure if a single benzene ring would show upon UV or not.

I think our goal is 0.5 or 1% hydroxyflutamide using that vehicle I copy pasted. but how much does it cost.

 

[Bryan]

Here's one looking at hirsutism:

You're right. I forgot that one on hirsutism. I guess I had male pattern baldness on the brain!

Bryan

 

[Bryan]

Thanks Old Baldy.

quoting brian:
I know of only four studies that deal with topical flutamide, and I have all of them right here: the two animal studies (rats, mice, and hamsters) that showed that it works by systemic absorption; the one measuring the amount of systemic absorption in humans; and the one showing a difference in human sebaceous gland response between males and females (I've posted extensively about that one in the past). I'm unaware of any other topical flutamide studies.

Do any of this talk about hirsutism?

No. They had nothing to do with hair follicles in any way. The ones measuring a biological response (including the animal studies) all had to do with sebaceous glands, not hair.

Bryan

 

[Bryan]

Re: those scientists wasted research money

those scientists who did the spironolactone/flutamide study on women wasted money. they should have just applied the flutamide to one cheak and checked to see how the other cheak did. if both responded the same, that would mean that systemic absorption was almost 100%. they then should have cut the doses in half (or had two dose groups at a time) and kept this up until only one cheak was affected. If only one was affected, that would mean a truly local dose and little systemic absorption. If such a dose did not exist, and both cheaks just got less and less benifits, that would mean Bryan is right that only spironolactone has local effects.

Bryan, in the study, did they apply it to both cheaks?

That spironolactone/flutamide study used ORAL doses of the drugs. They weren't applied topically.

Like I said in that previous post, I was only aware of four studies that applied flutamide topically, in man or beast. However, I suppose one minor omission at the time I originally wrote that was the Sintov study; so now I'll say that there are exactly FIVE studies that tested topical flutamide in man or beast! :wink:

Bryan

 

[Bryan]

then there was the animal flank were both sides were affected equally even though it was applide to both. This implies a nearly 100% absorption in animals, unless flutamide bonded to the receptors locally while excess went systemic, and then the hydroxyflutamide can back and competed with the flutamide at the topical sight and replaced it soon afterwards. That would give the equal results even if flutamide does have a local effect. that brings the question of whether the dose in this experiment was higher than it had to be.

I hate to tell you this, but one of the topical flutamide experiments (probably the most interesting one of all) seems to refute that theory. I'm talking about this one: "Local and Systemic Reduction by Topical Finasteride or Flutamide of Hamster Flank Organ Size and Enzyme Activity", Chen et al, J Invest Dermatol 105: 678--682, 1995.

They applied the following doses of flutamide topically to only ONE flank organ of different groups of hamsters: 30, 100, and 300 micrograms. But BOTH flank organs were equally affected, and in a dose-dependent manner: the 30 ug dose had no significant affect on either side; the 100 ug dose caused about a 30% decrease on both sides (I'm estimating this from the graph they provide); and the 300 ug dose caused a 52% decrease on both sides. So it appears unlikely that simply carefully choosing just the right dose of topical flutamide is going to let you minimize the systemic effect, while keeping a "local" effect intact.

Bryan

 

[CCS]

topical flutamide can't work.

thank you bryan, for repeating the dose dependence details I either forgot or had not seen.

That proves without any doubt that flutamide as ZERO local effect in hampsters. The only way if could possibly have any effect in humans is if our skin were different enough from hampsters that we not only transform it to hydroxyflutamide.

Are hampster androgen receptors the same as human androgen receptors? What type of receptor did Dr Proctor use when measureing the competitive ability of various anti-androges?

 

[CCS]

hey guys, i figured out something really interesting last night and almost forgot it. just because you don't get side effects from flutamide does not mean it is not having extremely strong effects on your body.

anti-androgens blocking androgen receptors should give similar side effects to DHT inhibition (in addition to other side effect from the anti-androgens reacting elsewhere). Dutasteride inhibits 93% of serum DHT and like 98+% of the type II enzyme, which includes the prostate, yet most people don't get side effects from it and most of the 2.5mg/day participants in the phaseII trails tolerated the dose. This means that flutamide could be having profound affects on your body and you might not know about it because you are not getting side effects, just like you don't from dutasteride. Flutamide blocks ALL androgens everywhere, whereas dutasteride just inhibits DHT made primarily in cells with type 2.

definitely check that flutamide is growing your hair and that spironolactone did not.

I think hydroxyflutamide is much stronger than spironolactone, which is much stronger than flutamide, locally.

i think the reason hydroxyflutamide applied topically had the same effects as flutamide applied topically is either too much was applied or humans can convert flutamide to hydroxyflutamide in the skin or flutamide passed through the skin quickly, get converted quickly and come back and influence the skin and all the body. I still think we need some dose dependence experiments in humans with hydroxyflutamide and flutamide. hairy women are out best subjects.

 

[CCS]

I just re-read that study on hurituism. oral spironolactone affects acne but not hair loss. why? is it because over active hairs have more receptors than most cells, and therefore need more anti-androgen for an effect? are androgen receptors different in different parts of the body? or do hair receptors need more complete blockage to affect hair loss, whereas sebum androgen receptors have effects that are more proportional to dose? This last idea could be explained by hyroxyflutamides strength.