Fluridil
for hair loss
Product Details
A NOVEL DERMO-COSMETIC AGENT FOR TOPICAL APPLICATION IN ANDROGENIC
HAIR LOSS, i.e. EFFLUVIUM AND ALOPECIA
I. INTRODUCTION
The pathophysiology of both male and female alopecia
(hair loss) is not yet fully understood and its therapy is
unsatisfactory.
Factors ranging from low scalp blood flow, deficiency
of nutrients and hair-related vitamins, neurogenic effects,
microbially-driven inflammatory changes, etc., have been considered.
There are several alopecias known, but the prevalent type, both in men
and women, is androgenic, i.e. caused by the androgenic hormones (AH)
affecting the scalp hair follicles. AH are important in the physiology
of skin; they promote the growth of the beard and of the body hair
throughout life.
The growth of the scalp hair also depends on AH, but
only in early life. It is not yet explained why AH, with increasing
age, switch from promoting growth of the scalp hair to its loss,
inducing conditions known as an androgenic effluvium (AE) and alopecia
(AGA). In hirsutism and acne vulgaris, excess of cutaneous AH was
shown to be the major factor in those complex syndromes.
The AH can affect the hair only via the androgenic
receptor (AR), a cellular protein transcription factor which interacts
with a specific region of DNA. Thus, both testosterone and its more
potent analog, 5-alpha-dihydrotestosterone (DHT), must bind to the AR
in the hair follicles in order to affect hair.
Antiandrogens (AA) are systemically administered drugs
which block the AH binding to AR. Originally developed for the
treatment of prostate cancer, these compounds, since they block AR
systemically, have considerable side effects, including loss of libido
and of male sexual functions.
These drugs cannot be used in males for
the AE or AGA treatment at all, not even topically, since they are
well resorbed from the skin and are stable in vivo. Topical steroidal
AA such as cyproterone acetate, chlormadinone acetate and
spironolactone were not successful, supposedly because of poor
absorption into the skin; some also have a skin irritation potential.
AA administered systemically were proposed for
treatment of women suffering with AE and AGA (Ref. #1), but concerns
for side effects call for clinical studies.
It is generally known, at
least in males, that extended AR blockade leads to AR mutation, and
that the mutated receptor attains the capability to be activated by
other substances such as various steroidal metabolites and even
progestins and estrogens, insulin-like growth factor, epidermal growth
factor and keratinocyte growth factor and neuroendocrine transmitters
such as serotonin.
It has also been shown that the AR blockade
amplifies the AR gene. It is therefore apparent that treatment of hair
loss in women by blocking AR with systemic AA is not ideal and that in
men it would not be acceptable at all.
Currently available for treatment of AE and AGA are
the topical Minoxidil and its analogs, such as Aminexil, and the oral
finasteride (Ref. #2). Minoxidil, an antihypertensive drug,
incidentally prevents hair loss, and to an extent, promotes regrowth,
but only in the vertex scalp; the activity is tentatively explained,
among others, by activation of the prostaglandin endoperoxide
synthase-1, increase of the local blood flow, suppression of bacterial
infection and/or by a modification of the AH metabolism in the dermal
papilla. (Refs. 3,4,5).
Finasteride taken orally and daily suppresses
conversion of testosterone into dihydrotestosterone (DHT), thus
lowering AH activity in the scalp.
The studies indicate about half of
the men achieve slight to moderate improvement in the anterior mid
scalp and in approximately one-half, the effluvium is arrested. Side
effects include decreased libido and erectile function, which
disappear after drug withdrawal. (Ref. #6)
No studies are yet
available to prove whether such a long-term systemic manipulation of
hormonal balance is harmless.
Clearly, a topically active antiandrogen suppressing
rather than blocking the cutaneous AR, while not irritating and not
absorbable from skin into the body, would be useful in the therapy of
AH dependent cutaneous afflictions.
We designed and synthesized a number of novel
antiandrogens and found that some, rather than blocking, suppressed
the AR in a concentration and time-dependent fashion. (Ref. #7) Some
of these compounds showed extremely low or no systemic bioavailability
upon oral and/or topical application.
The compound with the best
overall properties for topically active suppression of cutaneous
androgen receptors proved to be BP-766 (Fluridil), since it is rapidly
biodegradable into two components of high systemic and local tolerance
devoid of antiandrogenic activity.
It therefore offers a novel and
sound concept in handling cosmetically androgenic effluvium and
incipient alopecia, as well as other skin conditions such as hirsutism
which depend on the excess of the skin male hormones, both in males
and females.
FLURIDIL:
Products of hydrolytic decomposition:
Fluridil's physicochemical properties, stability,
the GMP manufacturing process of the bulk and of the final product
offered in 2 ml ampoules of 2% solution in isopropanol, were
established. Further, Fluridil's environmental fate and effects,
mutagenicity, acute and subacute toxicity in rodents, cutaneous
absorption, skin irritation and sensitization potential in animals and
humans, and the mechanism of the activity, in vitro, were assessed.
In a study in human volunteers, Fluridil, even at
trace levels, was not detected in the serum, therefore, it cannot be
expected to have systemic effects.
This was confirmed by a clinical
study conducted presently at a Medical School Dermatology department
(Chairman: J. Bucek, M.D., Palacky University, Olomouc, Czech
Republic).
In most subjects, increase in anagens (growing hair) and
decrease in telogens (dying hair) after 3 months of daily application
of 2 ml 2%Fluridil was substantial; there were no changes in the
hematological and hormonal profiles and there were no adverse effects.
Fluridil, as a topical cosmetic agent, has received a marketing
approval in the Czech Republic and approvals in other countries are
pending.
- Diamanti-Kandarakis, E. Current aspects of
antiandrogen therapy in women. Current Pharm Des, 1999 Sep, 5(9):
707-23.
- Scow, DT; Nolte, RS; Shaughnessy, AF.Medical
treatments for balding men American Family Physician, 1999 Apr 15,
59(8): 2189-94, 2196.
- Michelet, JF; Commo, S; Billoni, N; Mah, YF;
Bernard, BA. Activation of cyto-protective prostaglandin
synthase-1 by minoxidil as a possible explanation for its hair
growth-stimulating effect. Journal of Investigative Dermatology,
1997, Feb, 108(2) : 205-9.
- Pirard-Franchimont, C; DeDoncker, P;
Cauwenbergh, G; Pirard, GE: Ketoconazole shampoo: effect of
long-term use in androgenic alopecia. Dermatology, 1998; 196 (4):
474-7.
- Sato, T: Tadokoro, T; Sonoda, T; Asada, Y;
Itami, S; Takayasu, S. Minoxidil increases 17 beta-hyroxysteroid
dehydrogenase and 5 alpha-reductase activity of cultured human
dermal papilla cells from balding scalp. Journal of Dermatological
Science, 1999 Feb 19(2): 123-5.
- Kaufman, K D; Olsen, EA; Whiting, D; Roberts,
J L; Hordinsky, M; Shapiro, J; Binkowitz, B; Gormley, G J.
Finasteride in the Treatment of Men with Androgenic Alopecia.
Finasteride Male Pattern Hair Loss Study Group. Journal of the
American Academy of Dermatology. 1998 Oct, 39 (4 Pt. 1): 578-89.
- Sovak, MS; Bressi, JC; Douglas, J; Campion,
B; Wrasidlo, W. Androgenic Directed Compositions, U.S. Patent
Application #09/215,351, 1998.
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