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Hairlosssucks.com

Novel Agents for the Treatment of Alopecia
Marty E. Sawaya
Recent approval in the United States of two new
THERE ARE VARIOUS forms of alopecia, the products, Propecia (Merck Co, Rahway, NJ) and
most common being androgenetic alopecia (AGA), Rogaine Extra Strength 5% (Pharmacia & UpJohn Co,
which affects millions of men and women. The Kalamazoo, MI), indicated In men to promote scalp
severity of hair loss in women is usually much less hair growth, have added a new dimension to
treatment options offered by physicians In treating

than in men. Hair loss for both men and women androgenetic alopecia (AGA). The search for new and
may begin as early as the teen years, but can even effective agents to treat many different hair loss
start in later decades of life. In men with AGA, one problems has been intensified by the increase in hair
of the earliest findings is an increase in the biology research taking place worldwide, from
percentage of hairs in a telogen phase of the hair university-academic institutions to the phar-
cycle, so that initial hair loss may appear maceutical companies. All have a desire to profit from
marketing such drugs that have been termed,

indistinguishable from a telogen effluvium. Similar "cosmeceuticals.” Millions of men and women of
every race suffer from various forms of alopecia, the
psychologically devastating to accept, giving less most common being AGA where the target tissue
overall body-image satisfaction and making it active androgen, 5 alpha-dihydrotestosterone (DHT)
difficult to cope and retain integrity of personality aggravates genetically programmed scalp hair
functioning. AGA has been reported to be an follicles that results in short, fine, miniaturized hairs.
Currently available to treat alopecia are drugs

autosomal dominant trait with partial or variable indicated for other disease processes because no
other agents are accessible; some have severe
side-effects and many are minimally effective. These
prescription drugs were not originally indicated for

BIOCHEMICAL ADVANCES FOR MEN
alopecia and have not been adequately tested in
AND WOMEN WITH AGA
controlled clinical trials to assess for efficacy, safety,
and toxicity. These agents continue to be used

Although for many years it had been assumed clinically to treat patients with various forms of
that the hormonal basis for AGA in women was the alopecia. As a result, a variety of new agents are
same as for men, no studies have confirmed this. emerging in the patient application process to gain
Recent work has shown that on the scalp there are protection and approval specifically for various forms
local differences in the amounts of steroid of alopecia. This report reviews the most recently
metabolizing enzymes that convert weak androgens approved products, some of the more promising
compounds in clinical trial development, as well as

to more potent androgens (Fig 1). This is important those in the over the counter (OTC) "natural"
because the skin is an endocrine target tissue for treatments category.
androgen hormone action, similar to ovary, testes, and the adrenal gland. Studies have shown that persons using anabolic-androgenic steroids show hypertrophy of sebaceous glands, with systemic hirsutism, and AGA. In Figure 1, the hormone pathway describes the potential of weak and abundant precursor hormones such as DHEA (dehydroepiandrosterone) to be metabolized to more potent androgens such as testosterone (T) and dihydrotestosterone (DHT). The enzymes have been localized in sebaceous glands and hair follicles of scalp skin. Therefore, the skin has the potential to mediate TREATMENTS FOR ALOPECIA (HAIR LOSS)
Fig 1. Androgen meta-
bolic pathway in skin, where
conversion of the weak cir-
culating precursor, dehydro-
epiandrosterone (DHEA) to
4-androstenedione and tes-
tosterone takes place via 3B
and 17B-hydroxysteroid de-
hydrogenase (HSD) en-
zymes, respectively. Testos-
terone is converted to 5
alpha-dihydrotestosterone
(DHT) via 5 alpha-reductase
(5aR). Estrogens are synthe-
sized from precursors, 4-an-
drostenedione and testos-
terone to estrone and es-
tradiol, respectively.

androgen action without relying on elevated sys- follicle structure, finding aromatase to be specifi- cally located in outer root sheath of hair follicles An important enzyme in the Figure 1 pathway is adds to the importance of studying the entire hair 5 alpha-reductase (5aR), which mediates reduction follicle and not just the dermal papilla cells. of T to DHT, via the reduced pyridine cofactor, Aromatase has been shown to convert androgens nicotinamide adenine dinucleotide phosphate such as T, and androstenedione to the estrogens, (NADPH). There are two forms of 5aR, type 1, estradiol and estrone, respectively. It was also which is thought to be primarily in the skin, found that in women, there may be two- to five-fold especially sebaceous glands, as well as the kidney greater levels of aromatase in female scalp versus and liver; type 11 isoenzyme is predominant in male, perhaps explaining why women may have a gonadal tissues, ie, prostate, seminal vesicles, and sparing of the frontal hairline in AGA and may others, but in recent years, it was also found in hair have a less severe pattern of hair loss than men. It follicles on the scalp where miniaturization takes is uncertain if the estrogens formed from aromatase place. This finding explains how finasteride has are playing a role in suppressing the severity of hair hair growth-promoting properties, indicating loss, or whether aromatase is primarily reducing the efficacy for these specific androgen inhibitors overall load of androgens formed locally in the hair against the type 1 or 11 isoenzyme form for treating The next very important step to understanding Overall, the importance of 5aR and the two androgen action in skin is the binding of the target specific isoenzyme forms are apparent because the tissue active androgens, T and DHT, to the tissue distribution in the body differs, as well as androgen receptor (Fig 2). The androgen receptor biochemical characteristics of the enzymes. The (AR) has been purified and located in specific skin isolation of these two 5aR forms raises interesting questions concerning regulation and their specific structures, such as hair follicles and sebaceous roles in androgen physiology because new glands. Although the mechanism described in compounds will be designed to target one specific Figure 2 depicts T binding to the AR, we are now enzyme or both enzyme forms, depending on the realizing that very complex enzyme mechanisms such as phosphorylation and sulfhydryl reduction Another important enzyme that has come to of this receptor are important in forming an recent attention is the cytochrome P-450 aromatase activated hormone-AR complex that has the ability enzyme (Fig 1). Because it is known that androgen to bind to specific hormone response elements at MARTY E. SAWAYA
stimulate or alter cellular processes mediating hair some therapies may even target cofactors that mediate these reactions, such as reduced NADPH, which is necessary in mediating 5aR of testosterone CLINICAL OBSERVATIONS OF AGA
to DHT. Therefore, these "secondary" mechanisms In genetically predisposed men, the balding must be considered because novel therapeutics may process is triggered by exposure to androgens at target this direction as well (see Zinc). puberty. In women, the relationship between Previous publications provide a more detailed systemic elevated androgen levels and alopecia is overview of novel agents for alopecia; however, difficult to determine, because approximately 30% this review will cover some of the more pertinent to 40% of women who experience AGA have a agents approaching the marketplace for clinical systemic endocrine problem, leaving the condition in a majority of women to be called idiopathic. We are now finding that many patients who were once 5aR Inhibitors
called "idiopathic" have qualitative differences in In this category there are the structural steroid the N-terminal domain of the androgen receptor competitive inhibitors that chemically resemble the where the number of polyglutatmine repeats can substrate, T and bind to the active site of the render androgen sensitivity. Therefore, quantitative and qualitative factors targeting the androgen Table 1 describes 5aR inhibitors along with their receptor must be recognized before considering structures, trade names (chemical names), and treatment options because not all patients may respond to conventional treatments based on 5aR, Propecia (finasteride; Merck Co, Rahway, NJ) or other nonreceptor-mediated mechanisms. has recently been approved by the Food and Drug Based on these direct mechanisms regarding Administration (FDA) in the US for men with cellular DHT metabolism via quantitative and AGA. Propecia is a specific 5aR type 11 enzyme qualitative aspects to the 5aR isoenzymes and AR inhibitor and does not bind to the AR; therefore, it in AGA, it is important to also keep in mind that is not called an antiandrogen, but an androgen inhibitor. Fig 2. Cellular mechanism for androgens in skin. Steroids can enter the hair follicle cells from systemic
sources that circulate via blood vessels. Once steroids passively diffuse through cell membrane, enzyme
conversion to DHT can take place via 5aR and cofactor, nicotinamide adenine dinucleofide phosphate (NADPH).
DHT has high affinity to the androgen receptor. The DHT-androgen receptor (AR) complex is sulfhydryl reduced
and undergoes phosphorylation, enabling it to bind to specific gene sites and alter RNA polymerase activity of
cellular factors that affect hair growth.

TREATMENTS FOR ALOPECIA (HAIR LOSS)
Table 1. Androgen Inhibitors
Nonproprietary
Name/Trade Name
Chemical Structure
Dosage/Indications
Finasteride/PROSCAR, Propecia
5 mg/d of Proscar tablets for benign prostatic hyperplasia
Propecia indicated for men with AGA, current trials for
women with AGA, 1 mg/d of Propecia tablet
Off label indications: for women with AGA, hirsutism,
acne

GI 198745/Dutasteride
Not currently available; in clinical trial studies for AGA at
GlaxoWellcome (Research Triangle Park, NC); future
acne studies being developed
Not currently available; undergoing patent review at
Pharmacia & Upjohn Co (Kalamazoo, MI), but indicated
W09704002
for AGA as well as other dermatologic indications.
Note similarity in structure to above compounds.
The pharmokinetics of finasteride show that after 876; patients who took the drug had an average of 107 more hairs than those who took the placebo. decreases by 65% in 24 hours. Serum concentra- Hair counts were maintained for up to 24 months in tions of testosterone and estradiol increase about the men who continued to take the drug. A third 15%, but remain within normal limits. Prostate study of 326 men with mild to moderate frontal hair concentrations of testosterone increase about six- loss found that after 1 year, finasteride treated men fold. Finasteride is well absorbed in the gastroin- had statistically significantly higher hair counts on testinal tract, metabolized in the liver, and excreted the frontal scalp. Approximately 50% of treated in urine and feces, with a half-life of 5 to 6 hours. men and 30% of those who took placebo thought Small nanogram levels of the drug are detectable in the appearance of their hair had improved. Hair human semen; this is not thought, however, to have regrowth was not reported in older men taking 5 mg any consequence in women who are exposed by finasteride (Proscar; Merck Co, Rahway, NJ), perhaps because it was not indicated in those trials Three double-blind multicenter trials were con- ducted in men ages 18 to 41 years and the results of Adverse events described with 5 mg finasteride these trials have been presented as abstracts. In (Proscar) in a small percent of older men were loss combined results from two of the trials, 1,553 men of libido, erection, ejaculatory dysfunction, hyper- with mild to moderate male AGA of the vertex took sensitivity reactions, gynecomastia, and severe finasteride 1 mg/day or placebo orally for 1 year. myopathy. Finasteride causes a 30% to 50% After 3 months of treatment, the men who took decrease in prostate specific antigen (PSA) in finasteride were more satisfied with the appearance clinical trials with 1 mg tablets in men 18 to 41 of their hair. At the end of 1 year, in a circle on the years old. A decreased libido, erectile dysfunction, vertex scalp, a 1 inch diameter-mean baseline hair or a decreased volume of ejaculate have been reported in less than 2% of patients, which in counter (OTC) in the US. Most recently, Extra reality is between 0.5% to 1% when compared with Strength 5% Rogaine (Pharmacia & Upjohn Co) placebo. Finasteride had teratogenic effects in has hit the OTC shelves in the US, with approval animals on high doses, causing genitourinary on November 1997. Pharmacia & Upjohn has sole abnormalities in male offspring. The concentration rights to being the only manufacturer for the next 3 of the drug in semen of men who took 1 mg/day years for this new version of minoxidil, which is was much lower than the concentration associated with teratogenic effects in monkeys. The Merck Despite lack of understanding of the distinct manufacturers warn that women who are or may be mechanism of action, in women it has been shown pregnant should not have exposure to finasteride to increase the nonvellus hairs when using it for 32 orally or handle crushed or broken tablets. weeks or more. One potential drawback to Thirty tablets of Propecia 1 mg/day cost the minoxidil therapy is that spontaneous reversal to pharmacist less than $47, according to wholesale the pretreatment state can be expected 1 to 3 price (AV*/P) listings, whereas 30 tablets of Pros- months after cessation of therapy, indicating min- oxidil has a direct effect on the hair follicle, G1198745 (GlaxoWellcome, Research Triangle sensitizing it and making it dependent on the drug Park, NC) investigational compound is currently in for future growth. In the US, various generic clinical trial studies around the US for men with brands are now available OTC, which have brought AGA. Structurally, as shown in Table 1, it is down the price of minoxidil therapy from similar to the parent structure of finasteride, $50/bottle when it was Rogaine, a prescription maintaining the 4-aza structure of the steroid product, to now approximately $10 to $15 dollars nucleus; however, on the 21-carbon position is a per generic bottle, which lasts about 1 month. tri-fluorophenyl group that renders the molecule to Rogaine Extra Strength costs the pharmacist be electronegative and perhaps gives greater approximately $28.32 for 60 mL, who can raise the affinity for both the type 1 and 11 isoenzyme forms price to the consumer; therefore, good advice to of 5aR. Therefore, this drug is similar to finaste- patients would be to shop around before buying the ride, in that both competitively inhibit 5aR; however, finasteride is specific for inhibiting type The mechanism of action although still unclear, 11, whereas G1198745 inhibits both isoenzymes. seems to open potassium channels and increases This compound is known to inhibit >90% serum proliferation and differentiation of epithelial cells DHT levels in 24 hours after oral administration, and because of this greater ability to inhibit DHT, it Serum concentrations after topical application of may be more effective in promoting hair growth on 2% minoxidil, used twice a day, (about 5% of those the scalp of men, as well as treating acne, with with oral minoxidil), and of the 5% solution (about 10% of those with the oral drug), have been reported in some patients using 2% solution. patent review for Pharmacia & Upjohn Co Minoxidil is metabolized in the liver and excreted (Kalamazoo, MI). It has great structural similarity to the above two compounds, with activity against As far as effectiveness, four unpublished 32 to 5aR inhibition similar to G1198745. This 48 week studies presented to the FDA compared compound is not available, and it is not known if the effects of placebo, 2% minoxidil, and 5% there are plans for clinical trial development at this minoxidil by counting the net gain in hairs in 1 cm time, but has been indicated for AGA and other 2 areas of the scalp. As described, two studies in dermatologic hormone-related conditions. women did not find statistically significant differences between 2% and 5% minoxidil. A Vascular/Angiogenic-Related
32-week study in men found that the mean increase Compounds
from baseline in hairs/cm2 was 5 with placebo, 30 Regaine/Rogaine (minoxidil; Pharmacia & Up- with 2% minoxidil, and 39 with 5% minoxidil. A john Co, Kalamazoo, MI) 2% has been used 48-week study in men found a mean increase in worldwide for over 10 years, and is now over the with 2% minoxidil, and 18.5 with 5% minoxidil. are needed to verify this because the only previous Previous studies have shown that when the drug is study was performed in the macaque monkey stopped, all of the newly regrown hair falls out. model, which did show benefit when used together. Despite these reports, the new advertisements Although other vasodilatory/angiogenic related claim 45% more effective hair growth than regular compounds are progressing through the develop- strength 2%, with regrowth occurring as early as 2 ment pipeline, it is difficult to ascertain their months, with five times more hair regrowth overall effectiveness at this time until human clinical trials than placebo and with no major safety concerns. are performed. Many compounds that mimic Most physicians and lay people who have been minoxidil in vasodilatory properties fail to show using minoxidil for many years are not concerned the same results, hence there may still be a unique about safety aspects because most feel it to be a mode of action about this compound that is yet to very safe product. Concerns are more focused on be fully uncovered. Unpublished investigations the effectiveness of the product in promoting and have suggested minoxidil to have oxidative- maintaining hair growth. The 5% Extra Strength reductive potential to facilitate cofactor reactions necessary in side chain steps for hair follicle improved hair growth for individuals that may not growth, as well as other suggestions of stimulating some of the keratin genes of hair matrix cells for Adverse effects noted with oral minoxidil in- synthesis of hair shaft keratins, producing thin, fine, clude tachycardia, angina pectoris, and fluid reten- indeterminate hairs often seen with continued use tion. When taken orally during pregnancy, minoxi- dil has been associated with hypertrichosis of the fetus and congenital anomalies. One double-blind study in 35 balding men found that topical use of Other New Compounds in Development
2% minoxidil caused small but statistically signifi- lamin (prezatide copper). lamin (Procyte Co,
cant increases in left ventricular end-diastolic Seattle, WA) is a new drug that was just FDA volume, cardiac output, and left ventricular mass. approved in 1996, which is one of the superoxide Infrequently, dizziness and tachycardia have been dismutases (copper binding peptide). It was FDA reported with 2% solution, and patients are advised approved as an antimflammatory wound healing to reduce frequency of application, which helps to gel. Procyte, the company that makes lamin, is eliminate these side effects. Local irritation, working on getting approval for one of its other itching, dryness, and erythema may occur with use superoxide dismutases, Tricomin, for use in hair of topical minoxidil, most likely caused by the loss treatment. lamin hit the shelves in early July vehicle formulation of alcohol and propylene 1996, with results thus far indicating that it may help some people with hair loss. Some people have The conclusion on minoxidil 5% and 2% solu- reported hair growth related to lamin, with most tions are that they can produce a modest increase reporting a "strengthening of existing hair.
in hair growth on scalps of young men with mild to ProCyte have also announced release of another moderate hair loss, with continuous application for product, GrafCyte, which is basically lamin in a years to maintain the effect. Questions as to the use few different forms. It has been approved by the of 5% Extra Strength in women are being posed, FDA for use after transplants to prevent newly with some clinicians already giving this to young transplanted hairs from going into a resting phase. women with early hair loss, even though it is only indicated by the manufacturer, Pharmacia & immediately after transplants and results may be seen sooner than the typical 6 to 8 months. The Combinations. Many patients may be asking
product will be released in moist press applications their physicians now and in the future about using to be applied for an hour, 4 times per day for 4 both topical Extra Strength 5% Rogaine along with days after a hair transplant. A mist spray and oral Propecia 1 mg/day, which many believe may shampoo have also been announced, with hopes be beneficial working together synergistically; that it will be used by those suffering from hair loss in general; however the moist presses will only grow. Nutritionally speaking, biotin and folic acid be available to the transplant surgeons. are required for hair growth and are usually Polysorbate 80. Polysorbate 80, an OTC
supplied in a normal diet; therefore, unless there is product, has been around since the early 1980s as it a deficiency in these because of poor nutrition or was first used in the Helsinki Formula sold on wasting diseases, increased doses may not help hair television until the FDA banned such advertise- grow. In fact, excess megadoses of these may cause ments. There were claims that it grew hair in some hair loss, so if an adequate balanced diet is being people, but it was not effective in most individuals maintained, a general vitamin supplement should who used it. Perhaps those who did see a hair do as well in providing nutritional needs for hair growth response were noting hair that was growing through successive miniaturization cycles, which Zinc. A lot has been claimed about zinc for use
often happens in double-blind studies where in various diseases, including topical use for acne, another androgen related problem. Specific forms Folligen (copper chloride). Folligen is a new
of zinc, ie, zinc acetate, zinc sulfate, and others, treatment similar to lamin Gel, but in cream form have various properties that promote wound contains not only a copper complex, but Saw healing, help treat acne, and promote hair growth. Palmetto (see later) for use as an androgen inhibitor The last few years spouted a new formulation of of 5aR. Again, another product that has not been zinc in a skin cap to treat scalp psoriasis, and thoroughly tested for positive results in scaley, erythematous conditions of the skin, with findings that the main ingredient was actually Saw Palmetto (serenoa repens). Serenoa
clobetasol, a corticosteroid that was found to be the repens berries grow naturally, with the extract active ingredient that caused the great improvement claiming to be an androgen inhibitor of 5aR to when used for various conditions. In any case, it is inhibit DHT production, mainly claimed for use in cautioned that zinc may be an important factor prostate problems. There have not been extensive topically or for oral use depending on the studies performed, but implications in promoting formulation of the zinc. Zinc sulfate was found to hair growth on the scalp have been indicated. Side be an inhibitor of DHT production, not that it effects noted have been breast growth in men, which may indicate that it does not act on DHT inhibits 5aR, but that it limits reduced cofactor, alone. To be effective, the extract of the berries NADPH, which is necessary for the 5aR of must be taken, not the berries themselves. Another active ingredient, pygeurn. africanum compound, is A criticism to many of these herbal or OTC added to this extract and is thought to influence remedies is that they are not governed by strict testosterone metabolism, although it is not clear on FDA criteria, and that the purity, consistency, and how at this point. The product comes in capsule concentration of these agents can vary from batch form (60 capsules for $11.80) with two to four to batch, whether they are in liquid, pill, or topical capsules as the recommended dose per day in In conclusion, there are various new novel Amino acids. Arginine/L-arginine and/or
treatments for use in alopecia. Some of these have cysteine/L-cysteine have been proposed as playing gone through rigorous double-blind clinical trial a strong role in hair growth and offered in nutrition testing with FDA approval as to their proven health food stores to "make nails stronger and help claims, whereas others have yet to do so. Although the hair follicle to make more hair." These amino acids can be taken alone or together in oral liquid approaching the marketplace, it is wise to guide form with doses recommended at 500 to 1000 mg a patients and advise them of how these agents work and if they have been adequately tested before Biotin and folic acid. These too have been
spending their money and raising their hopes. around for a long time with claims to help hair Realistic expectations should continue to be the main guideline when offering any treatment for alopecia.

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Residente de tercer año de Pediatría, HIGA San José de Pergamino Lactante de sexo masculino de dos meses de edad, que ingresa a nuestra sala de Pediatría con diagnóstico de atelectasia masiva. Refiere cuadro de 72 hs de evolución caracterizado por dificultad respiratoria e hiporexia. Antecedentes personales: fruto de un embarazo controlado, G1 P1, parto eutócico, RNT de 40 semanas de ge

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