Pathophysiology and some treatment agents
More questions and answers
Emerging Model for Pattern Balding (after Kligman, others )
Hormones do something to hair follicle which causes it to be read as "foreign body" by your immune system, which then mounts an attack. The main damage in balding is probably immunologically-mediated. Damage to lining of blood vessels, which produces hair growth-stimulatory factors, makes this worse.
Organ rejection drugs ( e.g., cyclosporin ) reverse balding better than
antiandrogens. This gives a rough indication of the relative importance
of hormonal verses immunological factors in maintaining the balding state.
Conversely, cyclosporin and similar agents may also have a "phenytoin-like"
action on follicles, separate from their immunosuppressive properties.
Antibodies to hair follicles are also present in blood
Medical Treatment of Hair Loss
Aside: Forget looking in the medical literature for new hair loss treatment agents. Because of the commercial potential, everyone (including me) goes after patents. Most drug companies want to keep things secret as long as possible and so often don't publish on a new drug until it's ready for commercial release.
BTW, when developing any drug, the first place a PhD pharmacologist ( the guys who really develop drugs ) looks is in the patent literature. Most physicians and nonpharmacologists biomedical researchers do not know about about looking at patents, so you will rarely see them quoted. Most media. writers don't know about patents either, so they get surprised by new products all the time.
Even if a researcher is just interested in basic mechanisms, this is a bad mistake. For example, several patents indicate that superoxide dismutases or "SODases" stimulate hair growth. Still another patent from the Procter and Gamble company indicates that an SODase inhibitor blocks hair growth.
The important implication is that superoxide radical ( an important messenger in many other systems ) is also a messenger modulating hair growth. Similarly, another patent claims that inhibitors of the systhesis of nitric oxide ( the "natural minoxidil" ) inhibit hair growth. There is not a hint of this in the "open" biomedical literature.
Besides, at last count, over forty US and several hundred foreign patents are issued in this area. Probably most work at least some--few if any have been published.
Antiandrogens: E.g.: Proscar, Cyoctal, spironolactone.
Poorly-effective alone. Mainly useful as adjuvants to other therapy where they 1) make it work better 2) Help prevent tolerance. Every few years, a new antiandrogen will be presented as the ultimate "solution for balding". This has yet to work out. E.g., clinical trials with cyoctal, arguably the most potent topical antiandrogen, were terminated because of lack of effectiveness.
We'll see about Proscar. aka finesteride, the weakest one.Reports suggest it works about as well as topical spironolactone, about a 50% response rate. Merck sent the protocols into the FDA in December, 1996, so it may be FDA approved soon.
BTW, I have prime patents in this area ( for growth stimulators plus antiandrogens ). In fact, because of the publication of our patents, the combination of a hair growth stimulator plus and antiandrogen is now " obvious " and thus unpatentable. I sure wish antiandrogens worked better.
Possible explaination: Male hormones only initiate balding. Further, whatever hormones do seems to be mostly irreversible. The main damage to the hair follicle seems to be done by other factors, especially immunological. But I reserve the right to change my mind about this
These are blood vessel dialating hair-growth stimulators. OTOH, most dialating agents don't stimulate hair growth. So, vessel dilatation is not directly related to hair growth stimulation.
Possible explaination: Nitrovasodialators mimic some natural messenger substance mediating both dialation and hair growth. Currently, the best candidate is nitric oxide ( aka, EDRF or NO ). For a paper summarizing the evidence that minoxidil is an artificial form of nitric oxide, go here. NO is a ubiquitous transmitter which has identical effects to minoxidil on blood vessels. The action of both these agents and nitric oxide seems to be secondary to opening "K-channels", important for regulating a variety of cellular processes.
Whenever you see NO ( as in miNOxidil or naNO ) in the name of a drug, it probably has the nitric oxide chemical group in it. Similarly, as you might expect if nitric oxide is an important stimulator of hair growth, inhibitors of NO production reduce hair growth. See: "Reduction of Hair Growth", US pat# 5,463,478.
e.g.-- Prazotide copper (Procyte corporation) and Copper-Binding Peptide
(Procter and Gamble). Also, a peptone-derived copper binding peptide was
recently patented by Loren Pickart, who did the work with prazotide. It
is marketed as "Folligen". A form of Prazotide copper, Graftcyte,
recently received FDA approval for preventing hair loss in hair transplant
In the late 70's, we found that SODase prevents stress loss in experimental animals. This was an incidental observation while we were trying to prevent diabetic cataract in rodents with the copper/zinc peptide antiinflammatory agent Orgotein, a purified SODase...Such diabetic animals undergo massive shedding of hair.
Orgotein didn't provent diabetic cataract. But, quite unexpectedly,
it did prevent the hair loss.
Go here to see a picture.
From evidence like the antiinflammatory activity of Orgotein, we know that
superoxide is a messenger for inflammation, among other things.. So, this
suggested that superoxide might also be a natural messenger regulating
TEMPOL is another SODase. Researchers at the National Cancer Institute report that TEMPOL increases the regrowth rate of hair in experimental hair loss following radiation. I own the patent for TEMPOL and other similar nitroxide spin labels and spin traps. These may have uses in many other degenerative diseases such as age-related neurological disorders like Parkinsons disease and Altzheimers. The may also be useful in the amelioration of sepsis, tissue ischemia, and reperfusion injury.
Because of our early discoveries, recently, the US patent office issued me the dominant patent on using SODases and other metal-binding peptides for hair loss. This covers all the others. Other radical scavengers are also effective. So are Pyridine-N-oxides such as NANO and its esters, for which there are patents to both a Japanese drug company and ourselves.
In fact, this technology is so mature that the Procter and Gamble corporation has a US patent on a well-known SODase inhibitor ( DDTC ) to prevent hair growth.
SODases destroy superoxide free radical: Superoxide reacts with nitric oxide ( the putative "natural" minoxidil ) to produce other toxic products, so these agents may work by increasing nitric oxide levels or by destroying these reactive componds.
The most important of these is peroxynitrite. From work with Parkinson's
Disease, Altzheimers, as well as many other human diseases, a picture is
emerging concerning how SODases protect against peroxynitrite production.
For example superoxide and nitric oxide may interact in heart attack to
produce peroxynitrite, which may actualy cause much of the damage.
Alternately, such agents may interfere with the immunological component in hair growth. Active oxygen species are the most important mediators of cell-mediated immunity. BTW, a mild infiltrate of immune cells develops around the normal follicle as the hair cycle progresses. This may be the source of the superoxide that tells hair to stop growing.
Significantly, nitric oxide and superoxide have opposing "yin-yang"
effects on a number of bodily systems. Examples include blood-vessel dialatation
( nitric oxide dialates, superoxide constricts ), blood clotting, etc.
Also, nitric oxide and superoxide react with each other to form toxic nitroperoxynitrite.
Most likely, the apparent superior effectiveness of the SODase growth-stimulators over the nitric oxide-like growth stimulators is due to such multiple actions.
These paired agents may be the most ubiquitous transmitter substances around. You can explain a lot by assuming that nitric oxide is the transmitter that initiates and maintains hair growth, while superoxide both inhibits hair growth and causes hair to transition from the growth phase to the loss phase. Also, superoxide reacts with nitric oxide to form toxic products. These may be important in mediating the immune attack.
Interestingly, such processes may play a role in other disorders such
as Altzheimer's disease. Here, the pathogenic mechanisms are worked out
in some detail. For a recent review of this, see:
"Altzheimer's Disease, A Radical Vascular Connection", J. S. Stamler, in Nature, vol 380, p108 ( March 14, 1996 ).
A Superoxide / nitric oxide interaction may also figure in high blood
Tschudi, et al. Direct in situ measurement of nitric oxide in mesenteric resistence arteries. Increased decomposition by superoxide in hypertension. Hypertension, vol 27, p.32, (Jan. 1996 ).
The mechanism is probably rather similar to what happens in balding, as well as other degenerative diseases. E.g., the first article even suggests treating Altzheimers with SODases, as well as Nitric Oxide-like drugs. As noted, these are also effective in the treatment of hair loss.
BTW, there are so many patents involving SODases and hair loss because
the SODases are such promising drugs for inflammation and degenerative
diseases in general that scientists are always trying them in new animal
disease models. In the course of these studies, they rediscover that SODases
are also hair growth stimulators.
To head off questions: no, Altzheimer's disease is not associated with balding. The production of beta-amyloid, the probable culprit, is confined to the brain. On the other hand, systemic amyloidosis is associated with hair loss.
In essence, there are two defined classes of hair-growth stimulators other than the antiandrogens (which work indirectly ). These are:
Agents such as NANO and TEMPOL may fit both groups.
Finally, I am always getting questions about some new substance touted as the ultimate cure for balding.
To avoid unnecessary questions, I'll give my standard answer: There
are so many things that grow some hair on some persons that a company would
have to try pretty hard to get something that did not work at all. E.g.,
the Rogaine vehicle is responsible for about half of what you get from
Rogaine. So, you can assume just about everything that is claimed to grow
hair works at least a little.
Similarly, as is common in dermatology, no single agent works all that well, so questions about " what is best " are hard to answer. I am always changing my mind about such things, but, the SODases are arguably the best single agents. While there is a lot of good science behind the individual agents, the real secret to treating hair loss is rather crude. You use a lot of different agents which work in different ways and you use lots of them.
Peter H. Proctor, PhD, MD
Key words: regrowth alopecia hair loss
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