Hair loss abstract
A method of treating inflammatory skin diseases and/or hair loss,
comprising administering to a patient in need of such treatment
a therapeutically effective amount of a leukotriene receptor anatagonist,
an antihistamine, or other anti-inflammatory drug, preferably at
least twice a day, preferably for at least two months.
Hair loss claims
What is claimed is:
1. A method of treating hair loss disorders, comprising administering
to a subject in need of such treatment a therapeutically effective
amount of a leukotriene receptor antagonist wherein said leukotriene
D4 receptor antagonist is selected from the group consisting of
zafirlukast and montelukast.
2. The method of claim 1, wherein said leukotriene receptor antagonist
competitively inhibits the binding of leukotriene D4 at the leukotriene
D4 receptor site.
3. The method of claim 1, wherein said leukotriene receptor antagonist
4. The method of claim 1, wherein the administration occurs at
least twice per day.
5. The method of claim 1, wherein the treatment lasts at least
6. The method of claim 1, wherein there is substantially no interruption
7. The method of claim 1, wherein said hair loss disorders is selected
from the group consisting of androgenic alopecia and hereditary
8. The method of treating hair loss disorders of claim 1, wherein
the leukotriene receptor antagonist is a CysLT.sub.1 -antagonist.
Hair loss description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to acne and other inflammatory skin
diseases. More particularly, the present invention relates to methods
of treating acne and other inflammatory skin diseases including,
but are not limited to, acne vulgaris, acne rosacea, acne conglobata,
sebaceous cysts and hidrandenitis suppurativa through the oral administration
of at least one drug selected from the group consisting of anti-leukotriene
agents, and anti-histamine agents. These include, but not limited
to, leukotriene antagonists, blockers, and inhibitors as well as
histamine antagonists, blockers, and inhibitors.
2. General Background of the Invention
Acne vulgaris is a dermatological disorder that affects 17 million
Americans with a prevalence rate exceeding 85% in teenagers, declining
to about 8% in 25 to 34 year olds, and to 3% in 35 to 44 year olds.sup.8.
It is multifactorial and its course varies with cause and age. "There
is no disease that produces more psychic trauma, maladjustment,
insecurity, and feelings of inferiority than does acne.".sup.13
For many family physicians acne vulgaris is a very complex and
challenging illness due to its inconsistent and often mutable response
to treatment. All too many physicians are aware of the insidious
nature of this disease and the intense emotional or physical disturbance
resulting from acne. No other malady has as its consequence such
intense feelings of inferiority, maladjustment and insecurity. The
majority of cases seen in the outpatient clinical arena are those
that have either been previous treatment failures or those that
are presenting for re-treatment because of ongoing medical noncompliance.
Often patients are disinclined to continue a chronic, multidrug
treatment regimen because of the potential for developing undesirable
side effects, notwithstanding, the assumption of burdensome medical
risks; Avoidance of treatment measures usually results in predictable
exacerbations of acne lesions and a depreciative outcome, whereas
treatment tolerance and potential adversity is rewarded with success.
Recently several authors have reviewed and summarized the treatment
options for acne vulgaris..sup.8, 10 Although effective treatment
is available for both short and long term management of acne vulgaris,
a strategy for oversight and individualization is essential as relapse
is not uncommon; nonetheless, satisfactory results are not guaranteed
with the use of any one of the currently available drugs alone.
Although the medical causes of acne vulgaris are not known, most
patients can be managed with a variety of drugs that have been developed
recently. However, results vary based on one's particular choice
of chemotherapy or method of medical management Although many effective
pharmaceutical preparations, both prescription and nonprescription,
are currently available for use in the treatment of acne vulgaris,
no one drug appears effective against all distinctive types of acne
and most preparations are laden with significant side effects. Comedolytic
agents, for example, in their attempt to promote comedonal drainage
cause significant skin irritation. Topical antibiotics decrease
the number of mild to moderate inflammatory lesions by inhibiting
the growth of p. acnes and are also associated with skin irritation,
dryness, and potential antibiotic resistance. Oral antibiotics are
the standard for treating moderate to severe acne lesions, however,
superinfection may occur and long-term use requires routine laboratory
monitoring. Hormones in their attempt to decrease sebum production
are not without side effects and are usually reserved for females.
Oral Vitamin A acid derivatives, although very effective, are only
approved for severe nodular acne and commonly exhibit serious adverse
Anti-infectious agents, have also been used as a treatment for
acne and other inflammatory skin diseases. Although used quite often
in family practice and other medical settings, anti-infectious agents
at doses effective for other diseases do not completely eradicate
acne within a reasonable period of time. Even at the higher doses
of anti-infectious chemotherapy used for more aggressive diseaes,
these anti-infectious agents do not completely clear acne.
I note here Mat acne appears to be more inflammatory than infectious,
inflaming the face surround the pilosebaceous unit and only "infecting"
a single pilosebaceous unit Acne is not characterized by a classic
cellulitis that would assume to be migrating from the microabscess
region Rather, it develops a perilesional inflammatory reaction
that persists and remains insidious until medical intervention occurs.
If acne were indeed an "infectious" disease, left untreated
we would expect it to spread to contiguous tissue creating a substantial
problem. However, it never appears to do so.
In addition, the currently available treatments and management
of acne and other inflammatory skin diseases using antibiotics appears
to violate basic medical principles. Acne is a characterized as
a microabscess. An abscess is typically treated by incision and
drainage, not by antibiotics. Propionibacterium acnes (p. acnes)
is an anaerobic diptheroid organism that does not appear to cause
disease in any other areas of the human body. Thus, P. acnes should
not be perceived as a primary pathogen but rather as an opportunist
that becomes entrapped in the pilosebaceous unit. When entrapped,
an anaerobic environment is created. This allows the bacteria to
multiply, and pustie to form which eventually causes an inflammatory
response in the individual. Certainly, when this occurs antibiotic
treatment is useful to remove the growing bacteria and accounts
for some of the limited success seen in patients treated with antibiotics.
What is needed is a treatment that is effective against all distinctive
types of acne and a variety of other inflammatory skin diseaes and
is not laden with significant side effects.
Since the mid 1970's medical research has emphasized and shown
substantial evidence that a temporary excessive dihydrotestosterone
production is implicated in the pathogenesis of acne vulgaris, androgenetic
alopecia, idiopathic hirsutism and benign prostatic hypertrophy.sub.7.
The studies by Sansoni and Mauvais-Jarvis clearly associate a local
increase in dihydrotestosterone formation with the development of
acne,.sub.7 and skin functions such as sebum secretions (Strauss
and Pochi, 1963) and body hair growth are well known to be under
androgen control.sub.4. The special article by Price in 1975 suggests
that with the proper antiandrogen the highly desirable effect of
reducing excessive dihydrotestosterone formation by blocking or
selectively inhibiting testosterone 5 alpha reduction should have
little systemic effect and the psychological and other important
roles of testosterone itself should not be affected.sup.7. Nonetheless,
current therapy utilizing pharmacological agents that exhibit antiandrogenic
activity have failed to live up to earlier expectations in the management
of these diseases. For instance, the Type II 5 alpha reductase specific
inhibitor Finasteride (Propecia), indicated for the treatment of
androgenetic alopecia in men, is contraindicated in women and children
and is associated with considerable precautions and adverse reactions
such as two fold elevations in serum prostatic specific antigen
and decreased labido, erectile dysfunction and ejaculatory dysfunction
The following U.S. Patents are incorporated herein by reference:
U.S. Pat. No. 6,034,228 Human signal transduction serine/threonine
kinase, U.S. Pat. No. 6,034,057 Peptide inhibitors of fibronectin,
U.S. Pat. No. 6,034,056 Fibronectin adhesion inhibitors, U.S. Pat.
No. 6,008,223 Therapeutic compounds, U.S. Pat. No. 5,998,444 Piperidinyl
compounds as NK1 or NK2 antagonists, U.S. Pat. No. 5,993,859 Pharmaceutical
agents, U.S. Pat. No. 5,990,130. Therapeutic heterocycles, U.S.
Pat. No. 5,977,135 Bicyclic heterocycles, U.S. Pat. No. 5,965,576
Cyclic amide derivatives for treating asthma, U.S. Pat. No. 5,965,396
Human lymph node derived GTPase, U.S. Pat. No. 5,962,265 Human signal
transduction serine/threonine kinase, U.S. Pat. No. 5,900,432 Therapeutic
des, U.S. Pat. No. 5,889,024 Substituted heterocycles, U.S. Pat.
No. 5,866,568 Heterocyclic compounds, U.S. Pat. No. 5,861,401 N-heterocyclyl
sulphonamide derivatives and their use as endothelin antagonists,
U.S. Pat. No. 5,861,392 Therapeutic heterocycles, U.S. Pat. No.
5,739,149 Substituted piperidinobutyl nitrogen-containing hetercyclic
compounds and analogues thereof as neurokinin antagonists, U.S.
Pat. No. 5,731,309 Substituted heteroalkyleneamine neurokinin antagonists,
U.S. Pat. No. 5,710,169 Therapeutic heterocycles, U.S. Pat. No.
5,705,505 Cyclic amide derivatives for treating asthma, U.S. Pat.
No. 5,700,798 Methods for using benzoxazines for treating asthma,
U.S. Pat. No. 5,693,639 Therapeutic heterocyclyl amionosulfonyl
phenyl compounds, U.S. Pat. No. 5,677,317 Lactam compounds which
are useful in the treatment of asthma, U.S. Pat. No. 5,668,137 N-heterocyclic
sulfonamides having endothelin receptor activity, U.S. Pat. No.
5,654,299 Aryl substituted heterocycles, U.S. Pat. No. 5,641,793
Pyridine compounds which have useful pharmaceutical activity, U.S.
Pat. No. 5,635,509 Piperidine derivatives useful as neurokinin antagonists,
U.S. Pat. No. 5,622,964 Heterocyclic derivatives, U.S. Pat. No.
5,612,367 Method of enhancing bioavailability of pharmaceutical
agents, U.S. Pat. No. 5,602,138 NKA affecting piperidyl heterobicyclic
compounds, U.S. Pat. No. 5,589,489 Cyclic amide derivatives for
treating asthma, U.S. Patent No. 5,583,152 Method for treating vasospastic
cardiovascular diseases heterocyclic amide derivatives, U.S. Pat.
No. 5,576,333 Carboxamide derivatives, U.S. Pat. No. 5,567,700 Therapeutic
heterocycles which antagonize neurokinin receptors, U.S. Pat. No.
5,559,132 Carboxamide derivatives for treating asthma, U.S. Pat.
No. 5,559,131 Carboxamide derivatives for treating asthma, U.S.
Pat. No. 5,534,525 Lactam derivatives; U.S. Pat. No. 5,521,199 Piperidinyl
compounds as neurokinin receptor antagonists, U.S. Pat. No. 5,512,594
Ether derivatives having 5-lipoxygenase inhibitory activity, U.S.
Pat. No. 5,510,386 Aminosulfonylphenyl compounds for treating urinary
incontinence, U.S. Patent No. 5,504,216 Method for repairing an
amorphous sulfonamide, U.S. Pat. No. 5,504,089 2-hydroxyalkyl-benzimidazoles,
-quinazolines and -benzothiawles as potassium channel agonists,
U.S. Pat. No. 5,486,515 2-fluoroalkyl-1,4-benzoxaxines as potassium
channel mediators, U.S. Pat. No. 5,482,969 Certain N(4-benzoyl-2-phenyl)-3-trifluoro-2-hydroxy-propananude
derivatives, U.S. Pat. No. 5,482,966 Oxime derivatives, U.S. Pat.
No. 5,482,963 Phanmaceutical agents useful as leukotriene antagonists,
U.S. Pat. No. 5,478,843 Thiazole derivatives, U.S. Pat. No. 5,478,842
Ether derivatives having 5-lipoxygenase inhibitory activity, U.S.
Pat. No. 5,457,125 Oxime derivatives, U.S. Patent No. 5,455,253
Heterocyclic derivatives. U.S. Pat. No. 5,453,439 Hydroxylamine
derivatives, U.S. Pat. No. 5,440,035 Heterocyclic amide derivatives,
U.S. Pat. No. 5,420,298 Pyrrolidine derivatives, U.S. Pat. No. 5,411,973
Therapeutic alcohols, U.S. Patent No. 5,401,751 Isoquinoline derivatives
suitable for use in leukotriene mediated disease, U.S. Pat. No.5,391,758
Heterocyclic amide derivatives, U.S. Pat. No. 5,376,680 Oxime derivatives,
U.S. Pat. No. 5,373,007 Pyridooxazinyl or pyridothiazinyl as inhibitors
of leukotrienes, U.S. Pat. No. 5,367,079 Cycloalkane derivatives,
U.S. Pat. No. 5,350,754 Heterocyclic cycloalkanes, U.S. Pat. No.
5,338,734 Heterocyclic amide derivatives and pharmaceutical use
thereof, U.S. Pat. No. 5,334,614 Hydroxylamine derivatives, U.S.
Pat. No. 5,332,757 Oxime derivatives.
BRIEF SUMMARY OF THE INVENTION
A method of treating acne and other inflammatory skin diseases
is provided which comprises administering to a patient in need of
treatment an anti-leukotriene or antihistamine agent, or other anti-inflammatory
agent alone or in combination, preferably twice a day, preferably
for at least two months.
DETAILED DESCRIPTION OF THE INVENTION
Current treatment outcomes in patients with acne vulgaris are not
consistent nor fully explained with present day therapy. Immunological
factors appear to play a more important role than previously recognized.
Because acne is an inflammatory skin disease, we investigated the
use of anti-inflammatory agents on the treatment of acne. The anti-inflammatory
agent we investigated most fully included the anti-leukotriene,
With the onset of puberty and under the direction of androgenic
hormones sebaceous glands enlarge secondary to increased triglyceride
formation. Triglycerides are then hydrolyzed to free fatty acids
by the enzyme hyaluronidase from p. acnes. With the release of hyaluronidase
by p. acnes, hyaluronic acid present in cell coats breaks down.
Free fatty acids are not truly immunogenic by themselves but become
so by virtue of their chemical reactivity with self skin proteins
thereby creating larger conjugates..sup.4 Increasing complexity
as well as host genetic factors contribute to a molecules immunogenicity.
In the presence of this free fatty acid moiety, or immunogen, cell
surface antibodies or immune system cells become reactive, triggering
the release of leukotrienes, histamines, and other vasoactive substances.
Tissue congestion occurs compromising the orifice of the pilosebaceous
complex ultimately creating an impaction at the follicle. The microcomedo,
or acne precursor lesion, is the resultant product of this process.
Extravasation of the contents of the pilosebaceous unit into the
surrounding dermis results in the inflammatory acne lesion. Eventually,
follicle walls rupture and acne nodules develop. Supportation of
the acne nodule results in the acne cyst.
Because the inflammatory response of the acne lesion is mediated
by the release of leukotrienes, and histamines, then the introduction
of anti-leukotrienes and/or antihistamines will effectively prevent
the formation of new acne lesions and exert a significant impact
on the resolution of old lesions.
Anti-leukotrienes are a topic of great interest at the present
time. Leukotriene (LT) synthesis begins with phospholipase A.sub.2
mediated conversion of phosphatidyl choline from the nuclear membrane
to arachidonic acid. Arachidonic acid binds to 5-lipoxygenase (5-LO)
activating protein (FLAP) effectively increasing its concentration
in the vicinity of the 5-LO enzyme. Arachidonic acid is then converted
to leukotriene A.sub.4 (LTA.sub.4). LTA.sub.4 may then be converted
to the chemotaxin LTB.sub.4, or, in sequential steps to LTC.sub.4,
LTD.sub.4, and LTE.sub.4. LTC.sub.4, LTD.sub.4, and LTE.sub.4 are
the cysteinyl leukotrienes.
There are two types of anti-leukotriene agents, LT synthesis inhibitors
and LT receptor antagonists. Zafirlukast is an anti-leukotriene
that competitively inhibits the binding of leukotriene D4 at its
receptor site. Currently, the medical applications of zafirlukast
is in the prophylactic treatment of patients with mild to moderate
asthma..sup.5 Zafirlukast alone has already become established as
the standard of care in long term asthma management in both adolescence
and adults, and is now indicated for use in the pediatric population
aged seven and above. Results of other studies suggest efficacy
in the treatment of leprosy reaction,.sup.14 migraine prophylaxis.sup.11,
atopic dermatitis.sup.2 and chronic urticaria..sup.12
It is important to note that zafirlukast (such as Accolate.RTM.)
is a selective and competitive receptor antagonist of leukotriene
D.sub.4 and E.sub.4 components of slow reactive substances of anaphylaxis.
Zafirlukast is a member of a class of drugs initially called the
LTD.sub.4 -receptor-antagonists. These drugs are now named the CysLT.sub.1
-antagonists to "recognize that each of LTC.sub.4, LTD.sub.4
or LTE.sub.4 is a potential natural agonist at their common receptor
in human airways".sup.9. Zafirlukast inhibits leukotriene formation
by competitively inhibiting the binding of leukotriene D.sub.4 at
its receptor site; it does not inhibit the formation of leukotriene
B.sub.4 Because leukotriene B.sub.4 is relatively high up in the
cascade of events leading to the synthesis of the cysteinyl leukotrienes
(LTC.sub.4, LTD.sub.4, and LTE,.sub.4), blocking leukotriene B.sub.4
formation can cause more general and significant deleterious side
effects not seen by more specific targeting of the downstream leukotrienes
LTC.sub.4, LTD.sub.4, and LTE.sub.4 as is the case with zafirlukast
This study was designed to evaluate the effectiveness in treating
acne vulgaris with the drug zafirlukast After having established
a mechanism by which zafirlukast would be effective in the treatment
of acne vulgaris, and subsequently treating a single case of acne
conglobata successfully during the summer and fall of 1999, this
study was purposely designed to evaluate the treatment of acne vulgaris
with the drug zafirlukast
Objective: To determine if the anti-leukotriene zafirlukast is
effective in the treatment of acne vulgaris/acne rosacea.
Design: Inception cohort investigational study conducted from October
1999 to January 2000.
Setting: Rural Family Practice clinic in Waldheim, La.
Participants: A total of 7 male and 8 female patients aged 12-45
years diagnosed with mild, moderate, or severe acne vulgaris including
one case of acne conglobata and 2 cases of acne rosacea were given
20 mg. of zafirlukast (ACCOLATE.RTM. brand from AstraZeneca) twice
daily from week 1 through week 4. The dose was increased to 30 mg.
twice daily at week 4 and continued through week 8. At week 8 the
dose of zafirlukast was decreased to 20 mg twice daily and continued
until the termination of the study at 10 weeks.
Between the months of October and November 1999 both adolescent
and adult patients were recruited consecutively at a family practice
clinic in rural Louisiana to participate in an investigational study
to determine the effectiveness of zafirlukast in the treatment of
acne vulgarism Those patients who provided informed consent and
who have reported a prior medical diagnosis of acne vulgaris were
enlisted into the study. This cohort was composed of a total of
seven male and eight female Caucasian patients, age twelve to forty
five years, diagnosed with mild, moderate or severe acne vulgaris.
Pre-study recruitment assessment data was consistent with the following:
one of fifteen patients was diagnosed with acne conglobata; two
of fifteen patients were diffused with acne rosacea, one of which
had acne scars who had previously been treated with oral isotretinoin
for nodular-cystic acne; eleven of fifteen patients with moderate
to severe inflammatory/nodular-cystic acne; all patients had self
medicated with topical comedolytic over-the-counter agents; three
of fifteen patients had never been treated with prescription (topical
or systemic) medications; twelve of fifteen patients were prescribed
a range of three to five medical prescriptions (both topical and
systemic) with varying degrees of success and failure; three of
fifteen patients had previously taken oral isotretinoin; two of
fifteen patients had been offered oral isotretinoin but refused
Inclusion criteria for study enlistment encompassed any patient
who was requesting medical treatment of a chief complaint of acne
dermatitis, coincident with a clinical diagnosis of acne vulgaris
confirmed by physical examination. These patients voluntarily agreed
to be treated with zafirlukast knowing that alternative treatment
(both topical and systemic) were available. At the initial visit
all patients were instructed on the use of zafirlukast This was
to be administered by mouth twice daily. The potential side effects,
potential adverse reactions, and other risks were all explained.
Patients all agreed to avoid any over-the-counter acne preparations
and were to use any household soft-soap product to wash the facial
skin twice daily. Zafirlukast was to be administered at the dose
of 20 mg. twice daily from week one through week four and then to
be increased to 30 mg. twice daily at week four and continued through
week eight. At week eight the dose of zafirlukast was to be decreased
to 20 mg. taken twice daily and continued until the completion of
the study at ten weeks.
Main Outcome Measures: Subjective and objective medical examination
and qualitative photographic analysis were employed at each patients
initial visit to establish baseline. Thereafter, each patient was
consecutively examined and photographed at two to three week intervals.
At each respective visit, treatment benefits were assessed, compliance
was questioned, and side effects, if any, noted. Patient satisfaction
was measured by having all participants complete a post study survey.
This questionnaire allowed patients to document adversities or side
effects, self-esteem improvement, diminution of facial pain and
discomfort, and overall satisfaction with the course of treatment.
Data was utilized from primary care visits at the Waldheim Family
Results: All fifteen patients finished the study and completed
the post study survey. Significantly, all participants attained
periods of acne remission during the study. Subjective and objective
clinical improvement was observed as early as two weeks, but routinely
occurred within 3-4 weeks of initiating zafirlukast therapy. All
cases of mild, moderate, or severe acne vulgaris studied including
acne rosacea, acne conglobata, and nodulocystic acne responded similarly
in their observed periods of remissions or exacerbations. The data
were correlated with qualitative photographic analysis. Satisfaction
ratings in the post study survey were high and most patients preferred
to continue zafirlukast alone or as combination therapy with other
comedolytic or anti-infective agents.
In so much as there was a continual decline in both inflammatory
and non-inflammatory acne lesions during this study, patient self-esteem
progressed and appeared to improve by week four, and matured by
week eight, only falling off slightly during periods of acne recurrence.
Remission of acne vulgaris, characterized by the absence of new
lesion formation, old lesion regression and the observed decline
in perilesional erythema and facial discomfort, were all factors
contributing to the amelioration of patient self-esteem.
Only one patient was compliant in taking zafirlukast throughout
the entire study. He was able to maintain complete remission and
accomplish total regression of any inflammatory acne lesion. He
experienced only a mild facial erythema for two days following the
dosage drop from 30 mg to 20 mg.
However, it was not uncommon for patients to miss anywhere from
two to three consecutive doses in any one week and six patients
had significant dosage discontinuation each at nine, seven, six,
five, and two at three consecutive days, respectively. One patient
who missed three consecutive days also missed every weekend throughout
the entire study. Only one person requested referral to dermatology
at the termination of the study. Data analysis revealed that he
was one of two participants consistently non-compliant throughout
the entire study. It should be noted, however, that medical noncompliance
is not a quite uncommon finding during the management of a chronic
medical condition during any study and does not reflect the success
of the treatment. For example, in this study, factors that contributed
to non-compliance include the twice daily dosing requirements, a
false sense of well being once remission was realized, the mere
fact that most patients whom were non compliant were in the study
group compromising those in the teenage years and usually took weekend
a retreat from their homes and the guidance of their parents whom
were directing their therapy to some degree. There were also those
who were content with the remission of new lesions and less inclined
to be concerned with the regression of old acne lesions.
Those who were consistently non-compliant had acne reoccurrence
within 2-3 days after more than 2-3 doses missed. Discontinuation
of zafirlukast therapy over a 5-7 day period was associated with
reoccurrence of acne form lesions equal to baseline levels. However,
reinstitution of zafirlukast therapy was associated with old lesion
regression and new lesion remission, commonly occurring within a
period of time resembling the duration of zafirlukast deprivation.
There appeared to be no added benefit observed in taking 30 mg.
twice daily from week 4 thru week 8.
Although perilesional erythema appeared to resolve only by approximately
10-15% by week two, significant reductions of 40-50% and 80-90%
were achieved by weeks four and eight respectively. Remarkably,
there was little if any perilesional erythema accompanying the development
of any new inflammatory acne lesion that developed while any patient
was taking zafirlukast.
One participant who suffered with acne rosacea felt a sense of
asthenia in taking zafirlukast on an empty stomach, thereafter she
continued the study from week two through, week ten at 10 mg. dosage
levels twice daily with no further side effects observed. She was
the only participant whom ever realized any potential side effects
while being treated with zafirlukast.
Conclusion: This study substantiates efficacy in modifying the
inflammatory reaction of acne vulgaris Zafirlukast exerts a potent
therapeutic effect on the acne process and plays a pivotal role
in the prophylactic management of acne vulgaris. The recommended
dosage of zafirlukast for adults (.gtoreq.12 years) is 20 mg twice
daily; for pediatrics (7-11 years) the recommended dosage is 10
mg twice daily. The preferred daily dosage range of zafirlukast
for adults (>12 years) is about 20 mg twice daily; for pediatrics
(7-11 years) the recommended dosage is about 10 mg twice daily.
It is preferably taken twice daily or administered in a form that
it is released into the bloodstream twice daily. It is preferably
taken consistently for at least 4 weeks, more preferably at least
8 weeks, and even more preferably at least 12 weeks. Most preferably,
it is taken every day without stopping. The method of the present
invention is most effective if zafirlukast is taken as prescribed
every day. Additional controlled studies, such as double blind placebo
studies, increasing drug dosage at the onset and throughout entire
length of study, prolonged study periods and study protocols that
would include anti-leukotriene therapy side by side with comedolytic
anti-infective, anti-histamine and anti-androgen therapies will
demonstrate the significant value of zafirlukast in patients who
suffer from this dreadful disease.
Other Effective Treatments Encompassed by the Present Invention
In addition to zafirlukast, the following drugs will also be effective
in treating acne and other inflammatory skin diseases.
Montelukast (such as Singulair.RTM.) is another leukotriene blocker.
Singulair was tested and shown to be effective. It is a selective
and orally active leukotriene receptor antagonist that inhibits
the cysteinyl leukotriene receptor. The recommended dosage for adults
(.gtoreq.15 years) is 10 mg in the evening; for pediatrics (6-14
years) the recommended dosage is 5 mg in the evening.
Leukotriene inhibitors (such as cromolyn sodium) will also work,
but may be less desirable as they may have harmful side effects.
Cromolyn sodium acts by inhibiting the release of histamine and
leukotrienes from the mast cell. In vitro and in vivo animal studies
show that cromolyn sodium inhibits synthesized mast cell degranulation
that occurs after exposure to specific antigens. Cromolyn sodium
acts by inhibiting the release of mediators from mast cells. Studies
show that cromolyn sodium directly blocks calcium ions from entering
the mast cell thereby preventing mediator release. Cromolyn sodium
inhibits both the immediate and non-immediate bronchoconstrictor
reactions to inhaled antigens. Cromolyn sodiun also attenuates bronchospasm
caused by exercise, aspirin, cold air, sulfur dioxide and environmental
pollutants (see Physicians' Desk Reference page 987, 50th edition
Examples of commercially available cromolyn sodium are Gastrocrom.RTM.,
Intal inhaler.RTM., Intal nebulizer solution, Opticrom Ophthalmic
solution and cromolyn sodium inhalation solution USP. The recommended
dosage of Gastrocrom.RTM. for adults (13+) is two 100 mg ampoules
taken orally 4 times per day (800 mg daily total), 1/2 hour before
meals and at bedtime, and for children 2-12, one 100 mg ampoule
taken orally 4 times per day (400 mg daily total), 1/2 hour before
meals and at bedtime.
Zileuton (such as Zyflo.RTM.) is an oral active inhibitor of 5-lipoxygenase,
the enzyme that catalyzes the formation of leukotriene from arachidonic
acid. The recommended dosage for adults (.gtoreq.18 years) is 600
mg four times per day (2400 mg daily total).
Histamines play some role in acne formation, and antihistamines
administered daily will help reduce acne formation. Preferred antihistamines
include loratadine (e.g. Claritin.RTM.), ranitidine (e.g. Zantac.RTM.),
cimetidine (e.g. Tagamet.RTM.), famotidine (e.g. Pepsid.RTM.), nizatidine
(e.g. Axid.RTM.), and fexofenadine (e.g. Allegra.RTM.), hydroxyzine
HCl (e.g. Atarax), cyprohepadine (e.g Periactin), promethazine HCl
(e.g. Phenegan), cetrizine (e.g. Zyrtec), and hydroxyzine pamoate
(e.g. Vistaril) because they do not sedate. However, other antihistamines
would work as well. It is believed that antihistamines administered
daily may help reduce acne formation if taken for 2 months or longer.
Loratadine is especially preferred due to its dual action of acting
as an antihistamine and as a leukotriene C4 antagonist
Examples of Antihistamines Useful in the Present Invention:
A. Histamine H.sub.1 -receptor antagonist compounds that can be
used in the method of the present invention include those listed
in the Physicians Desk Reference (2000 ed.) under the following
product categories in the blue pages on page 204, etc.: 1) antihistamines
and combinations; 2) also see under nasal preparations--antihistamines;
and 3) ophthalmic preparations--antihistamines and combinations.
B. Histamine H.sub.1 -receptor antagonist compounds that can be
used in the method of the present invention include those corresponding
to the ones listed in A above which are listed in the nonprescription
P.D.R. (2000 ed.).
C. Histamine H.sub.2 -receptor antagonist compounds that can be
used in the method of the present invention include those listed
in the Physicians Desk Reference (2000 ed.) on page 210.
D. Histamine H.sub.2 -receptor antagonist compounds that can be
used in the method of the present invention include those corresponding
to the ones listed in C above which are listed in the nonprescription
Physicians Desk Reference (2000 ed.).
The method of the present invention will also work for sebaceous
cysts as well as acne.
If no dosages are listed herein for a particular drug, the dosage
recommended for treatment of asthma can be used.
Hair Loss Treatment Method
The significance of inflammation in acne pathogenesis is well described
in the literature over the past several decades. In as much as it
has been clinically proven that the inflammatory reaction associated
with acne vulgaris, and rosacea resolves in patients taking zafirlukast,
which competitively antagonizes the cellular receptor for cysteinyl
leukotrienes, the cyst LT 1 receptor.sup.7., there is still no adequate
explanation as to why patients suffering from these dreaded diseases
develop a state of remission while taking this drug. Having considered
the research data presented thus far, several questions still remain.
Considering the fact that acne vulgaris is androgen mediated, does
zafirlukast exhibit antiandrogen activity, and if so, would this
drug have any benefit in treating other diseases know to be mediated
by antrogens? In an attempt to answers these questions, further
study was undertaken to determine whether or not a biological marker
exists that would explain our findings and if so would current and
past scientific investigation support our conclusion.
During the summer of 2000 an investigative study was initiated
to determine the efficacy of zafirlukast in the treatment of androgenetic
alopecia A middle aged 40 year old blond haired caucasian male whom
was actively undergoing genetically influenced alopecia was recruited
and voluntarily enlisted into the study under informed consent.
Prior to taking zafirlukast this patient had never received treatment
for androgenetic alopecia and physical examination showed no evidence
of pathological hair loss. Zafirlukast was initiated at a dose of
20 mg taken twice daily and within the first 6 weeks of zafirlukast
treatment both the patient and his wife witnessed less occurrence
of hair loss and by the fourth month of treatment regrowth of hair
in the area of temporat and vertex balding was observed. Serum ancillary
studies obtained at the completion of his fourth month of zafirlukast
therapy revealed a dihydrotestosterone level of 32 NG/DL (normal
25 to 75 NG/DL). Just two months earlier serum luteinizing hormone,
total testosterone, androstenedione and dehydroepiandrosterone sulfate
levels were determined to be normal. Having considered that dihydrotestosterone
levels may have been suppressed to a low normal range, as pre treatment
dihydrotestosterone serum determination had not been performed,
the dose of zafirlukast was increased to 40 mg taken by mouth twice
daily. Continuing this dose for a one month period of time, serum
dihydrotestosterone levels were reanalized and determined to be
21 NG/DL (normal 25 to 75 NG/DL). Additionally, serum 3-alpha androstanediol
glucuronide, estrone, androstenedione, total testosterone, prostate
specific antigen, and progesterone levels were within normal limits
at this time. The patient was then withdrawn, from zafirlukast therapy
and there were no specific complications or side effects during
a one month abstinence from zafirlukast and serum dihydrotestosterone
levels were redetermined and found to be 15 NG/DL (normal 25 to
75 NG/DL). This patient was then given the option to continue treatment
with zafirlukast at a dose of 40 mg taken by mouth twice daily for
the treatment of androgenic alopecia and decided to do so as he
had witnessed the continued regrowth of hair and remission of hair
loss while taking zafirlukast. There were never any side effects
observed while he was taking zafirlukast In an attempt to verify
and cross reference these significant findings with a male patient
undergoing treatment with zafirlukast for acne vulgaris and a female
patient whom enlisted into a study to determine the effects of zafirlukast
on hereditary balding and whom had previous treatment failures with
finasteride, blood serum analysis was performed to determine whether
or not dihydrotestosterone suppression was also occurring in these
individuals as well. The results are as follows:
In a 19 year white male undergoing treatment for Grade IV cystic
acne vulgaris with zafirlukast at 40 mg po bid (by mouth twice a
day) for 4 weeks, preceded by 2 weeks of zafirlukast treatment at
30 mg bid, his serum dihydrotestosterone level was determined to
be 16 NG/DL (normal was 25 to 75 NG/DL).
In a 53 year old white female undergoing treatment with zafirlukast
at 40 mg po bid for hereditary balding, her pretreatment dihydrotestosterone
level was 5 NG/DL (normal 5 to 30 NG/DL); after 4 weeks of continuous
treatment her dihydrotestosterone serum concentration was 4 NG/DL
(normal 5 to 30 NG/DL) and at 6 weeks of continued treatment her
serum dihydrotestosterone level was determined to be less than 3
In both of these individuals not only was dihydrotestosterone suppression
realized but a significant improvement in acne lesion remission
and clearing in the male individual and regrowth of frontal hair
in the female individual was documented. Both individuals continued
medical treatment and management of their respective illnesses under
informed consent never witnessing any side effects or adversities
and are pleased with their outcomes thus far.
For many years medical researchers have studied the pathways of
androgen metabolism and have recognized its undesirable consequences
i.e., acne vulgaris, androgenetic alopecia, idiopathic hirsutism
and benign prostatic hypertrophy, besides others. There now appears
to be significant evidence to suggest that in some individuals the
drug zafirlukast not only blocks the potent inflammatory reaction
mediated by leukotrienes, but also possess antiandrogen activity
In this study a dose and time dependent effect has been identified
with the treatment of both acne vulgaris and common baldness in
genetically susceptible men and women without physical or psychological
compromise, or forfeit of quality of life. The use of zafirlukast
in treating these dreaded diseases appears to be safe and effective
at doses above those recommended for the treatment of asthma as
shown in this study. Serum liver function studies monitored during
this study remained in the normal range of value except in one patient
with known Hepatitis C and abnormal pretreatment liver function
studies; however, in all patients including the one patient with
Hepatitis C, serum liver function studies improved with zafirlukast
treatment possibly indicating a role in treating liver diseases
in the future.
There are several biological mechanisms that could be implicated
in explaining the results of this study including the following:
A) By inhibiting the action of 5-alpha reductase or 17 beta-hydroxysteroid
dehydrogenase, the two principal pathways of testosterone metabolism
in all growing hairs and skin cells.sup.7.
B) By inhibiting the formation or action of the metabolite of testosterone
or androstenedione i.e. dihydrotestosterone, 5-alpha androstanediol,
5-alpha androstanedione, 5-alpha androsterone or estrone.sup.7.
C) By inhibiting the peripheral conversion of androstenedione to
testosterone in the skin.sup.7.
D) By inhibiting adenyl cyclase due in fact to high dihydrotestosterone
levels in the hair follicle(high dihydrotestosterone levels in genetically
marked hair follicles initiate baldness by inhibiting adenyl cyclase).sup.7.
E) By alteration of the androgen receptor protein in the peripheral
target cells allowing them to concentrate androgens at the presumed
site of action in the cell nucleus i.e., interception, antagonism,
or inhibition of the highly specific antrogen receptor protein that
binds with dihydrotestosterone and transports it to the cell nucleus.sup.7.
F) By blocking dihydrotestosterone at a given target site.sup.7.
G) By promoting the formation of progesterone.sup.7.
H) By promoting the formation of steroids all having structural
resemblance to testosterone and thus competing with testosterone
for the binding site on the enzyme 5-alpha reductase i.e., 4 androsten-3-one-17
beta-carboxylic acid, androstenedione and deoxycorticosterone.sup.7.