Note: Descriptions are shown in the official language in which they were submitted.
r~ ~ ~) 1 3 6 1 7 ~
- W093~2306~ - PCT/US93/04763
THERAPEUTIC USES OF PUNGENT
BOTA~ICAL5 AND T~EIR RELATED COMPOUNDS
Technical Field
The invention relates to a new class of general
antiinfective compounds obtainable from plant species
of the pepper, and ginger families, and chemically
related species that are also useful in the treatment
of tissue injury, and skin disorders.
Back~round ~rt
There is a wide array of microorganisms that are
patho~enic to man, and other organisms. Pathogenic
bacteria, viruses,~rickettsia, and fungi may cause disease
in:their host organism whether plant, animal, or man.
Fungal diseases~of man and animals,:often referred
; to~ :as mycoses, may be classlfied into two b~oad
categories~ Deep tissue, or~systemic mycoses involves
the ::wide dissemination of pathogenic fungi growing in
internal~organs, ~and tissue, and superficial mycoses,
whi~h generally:repr sent different types of pat~ogenic
fu~g:i than those that infect the skin, hair, nails and
S mucosa.
Deep ~issue : mycoses including aspergillosis,
actinomycosis, ~: :blastomycosis,: coc idioidomycosis,
:cryptococcosis, histoplasmosis, nocardiosis,
paracoccidioidomycosis, entomcphthoromycosis and
occasionally candida, may infect~the lungs, brain, ~ones,
spinal fluid, liver, heart, kidneys, and other internal
organs/ as well as the skin. Depending on severity,
~: deep tissue mycoses may cause illness that ranges from
~: ~ :asymptomatic to life threatenlng.
Superficial mycoses, also called dermatophytosis,
describe disorders such as ringworm, ~thlete's foot,
wo 93r23061 ~ 1 3 6 ~ 7 ~ PCTJUS93/04763
favus and candida, which infect the skin, hair, nails
and mucosal linings. There are perhaps three dozen or
so known species of pathogenic fungi, and yeasts
responsible fox causing these diseases.
The National Health Survey of 1971-1974 projected
from its sampling that about one out of every twelve
people in the United States had some form of
dermatophytosis, with men being four' times more likely
than women to contract infections. ~'
Surveys of other nations reveal '`'a much higher
incidence of superficial mycotic dis'èiases, among the
poor, and underdeveloped countries of Africa, Asia, South
America,~ and those areas of the world having tropical
climates.
; Tinea is another term used to describe ringworm.
It is usually followed by another term which describes
the particular locati~on of the;infection. Hence, ath~etes
foot is~ often referred to as "tinea pedis'~. Scalp
ringworm is also~known as "tinea capitis"; body ringworm
as~-"tinea corporis",~ jock itch as l'tinea cruris" etc.
;Though~ not considered to be life threatening, as some
deep tissues~mycose~s can be, superficial mycoses assuredly
take~ a ~ falr ~toll~of ~ man~ and~ animals in misery,
inconvenience, and~expense.
Though not~alassified as a serlous illness by the
medical ~profession;,~ this does not necessarily reflect
the~;view~ point of~those sufferers~ of superficial fungal
infections. On~a personal level, an athlete whose
performance on the playing field is diminished because
of painful cuts on the feet due to an athlete's foot
nfection~, may ~consider ~it to~ be a serious illness.
A~young woman ~who develops ba~ld patches on her scalp
due to ringworm may feel that~she has a serious illness.
It is also likely that she may ieel the same about a
ringworm infect}on of the fingernails~, where the nails
assume a ho~rible, unsightly appearance as a result of
thickening, brittleness and discoloration typical
:
213~174
WO93/23061 3 PCT/US93/04763
of the disease. Add to this a year and a half of
systemic treatment to see results, and she may feel that
she indeed has a very serious illness.
Do people who are unemployed, low income, or without
medical coverage consider an illness, that in addition
to causing discomfort, can cost them several hundred
dollars a year in treatments, and still not be cured?
Do ranchers think of ringworm as a serious disease, when
the feed lots, who are paying high prices for livestock,
refuse their herd because of ringworm? I think the answer
is a resounding "yes'."
Antlbiotic drugs such as penicillin, tetracycline,
and sulfa ect., though often effective in the treatment
of bacterial in~ectlons, are useless against infections
caused by viruses, rickettsia, and f ungi. Fungal
disorders, for example requir~ treatment with a separate
group of antimlcrobial drugs, known as antifungals,
or antimycotics. ~ ~
Antimycotic~drugs (fig. 14 - 1;6) were first
introduced~ ~ln ; the~ 195~0's with nystatin (1954),
amphotericin ~B (~1958~)~, and griseofulvin (1959). These
; drugs ~ were~ Qriginally adm1nlstered systemically.
Tolnaftat~e~ fig.~17~ was introduced in 1965 as the first
effective~topical~ant~ifungal treatment. Since the 1970's,
a ; number of~ azole~' derivative antifungals such as
clotimazole~ (~fig.~ 20~), miconazole~ lfig. 21), econazole
flg~ 22)~, ketoc~onazole, and others h~ave made their
appearance~as~-~an;timycotics for ~both~systemic, and topical
administration ~ The~more current trend has been toward
the developement of a~"triazole" (fig. 23) class of
antifungals, 1nc~ludl~g such derivativ~s as fluconazole
fig. 24), terconazole ;~fig. 25), and itraconazole ect .
Prior art treatments for superficial mycosesr in
additlon to ~eing expens1ve, require repeated application
before 1mprovement can~ be seen in the patient. Currently
;available over the counter treatments, containing
clotrimazole, miconazole, tolnaftate, or undecylenic
:
WO93/23061 2 1 3 6 1 7 4 PCT/US93/04763 ~v
acid, recommend up to sixty applications of the product
in order to provide full benefit. More treatments are
often required.
Regardless of economic impact, even wealthy
individuals, with the best health care available suffer
with all the others when it comes to the discomfort,
and bother of repeated application of medication that
is slow acting, and often ineffectiv~`~t producing cure
or relief of symptoms.
Even prescription topical antifùngals, administered
by a dermatologist, may require as many as two hundred
applications over a~period of three months to cure some
cases of athlete's foot alone. Nail infections may
require eighteen months of multiple, daily treatment
to provide cure. In addition to being very expensive
and time ~consuming~, applying the medicine repeatedly
each day is ~both~ersome. Coupled with the discomfort
of the~ fungal ~lsorder, the; expense, and inconvenience
assooiated with the treatment adds ;further to the misery
of the~condition.
The current cost of treating ringworm and other
superficial mycoses~ excludes the economically
dlsadvantaqed,~who~;~suffer most from the conditlon, from
receiving~ tréa~tment. Poor sanitation, a lower standard
of~general health,;~along with the fact that it is rarely
treated~, adds~;to the~ greater prevalence of ringworm,
and~ other~ superfic~ial mycoses ~among lower income
ndividuals. To a low income fam1ly in the United States,
an extra fi~e dollars a week expense to buy the cheaper
~topical over the counter fungal tr~atments can cause
real hardshlp ~on the household budget. For the
disadvantaged of many developing countries, fiv~ dollars
a week looks more~like a good wage for a healthy workin~
man supporting a family, than what one can afford to
pay to treat a skin condition that takes weeks to cure,
if it can be cured at all. For these reasons, superficial
mycoses among the poor usually go untreated, being
~ ~ ,
213~174
~ W~93/2~61 PCT/US93/04763
prohibitive because of the cost of treatment.
In this respect, the current array of prior art
antifungal treatments have failed to significantly heal
superficial mycoses throughout the world, being
inaccessible to most of the world because of cost. In
addition to the misfortune of not having viable treatment
for tens of millions of sufferers of fungal infection,
no markets are created, and no products sold, to the
advantage of no one. Prior art antifungal treatments
keep the price of treatment high, the market volume small,
and undiverse, and ~only bring marginal relief to a
relative few of the many suffers.
The bad ~economics of currently available topical
antifungals prohibits their use in the livestock industry,
; as well. The~ cost~of the medicine, coupled with the
labor required for repeated application~ to livestock,
forbids the creatlon ;of a significant market for these
medicines~ withi~n~ the~ industry. ~As stated earlier,
livestock inf~ected~wi~th ringworm are refused by feed
lots~. T~he rancher~holding them ba~ck, in turn, raises
bls~prlces~ to~ cover this~ llablllty; effecting all
prooessors~and~consumers of meat~produ~Gts.
Ringworm,~being~highly contaglous, can spread through
a~ h~erd~within~a~ few~ short weeks, ~not a}lowing enough
tlme ~for~ treatment~- ànd recovery ~l~n the weeks prlor to
going~ to~market~ even~ if they are treated. With the
;current wày~o~ topical~ antifungals~,~treating food animals
for ri~gworm~ is~an absurd notlon.~ The cost involved
in applying a mediclne, perhaps fifty times, to a single
head of livestock could never be justified. For this
~f~ reas~on, treatment~ ls~wlthhel~d, to~ the dlsadvantage of
both the~ rancher ~and the an~lmal, which in addition to
suffering -discomfort, spreads the disease to other
animals, perpetuat~ing the cycle ~urther. In addition
to~ money lost, ~-no viable solution is offered by
pharmaceutical manufacturers which would otherwise enjoy
a new,~ very large potential market.
~13617~
W O 93/23061 - PC~r/US93/04763
Whether or not one feels the economic impact of
superficial mycoses, all suffers experience the
inconvenience of having to make repeated application
of currently available prior art topica~s. The necessity
of making repeated applications is an indication of weak
drug action, and that is another great flaw of prior
art antifungal treatments.
Systemic antifungal drugs are also used to treat
superficial mycoses, in addition to the deep tissue
diseases. Drugs ~like amphoteri~in B, clotrimazole,
enconazole, griseofluvin, ketoconazole, miconazole, and
~ ` :
nystatin, are administered internally, usually orally,
or by~lnjectlon. Like~the topical antifungals described
~earlier, most of the systemics treatments require multiple
doses ~in order to ~be effective. Systemic treatments
are the~most costly ~of all, re~ulring the supervision
of~a~physlcian. They are most dangerous to the patient,
with~undesirable~ sidè~effects that can further endanger
th~e~health of~the~patient. :The risk~of damage to internal
organs~, and adverse~ reactions to other medications, are
factors that~must be carefully weighed by physicians
; adminlst;ering;~systemlc~ antifungals;. With this, other
less~severe,~ yet~unpleasant side effects, include nausea,
vomiti~ng,~headache,;~dizziness,~fever, di~arrhea, and many
ot~her~ adverse effect~s~that contr~lbute to the misery and
health~of~the~patient.
Amphoter~ic~l~D~ B~(flg. 14),~gi~ven by injection in
the~treatment~of~s~ys~temic fungal infection, carries with
it the risk of liver and kidney damage, and can also
result ln blood dlsorders. It~lnteracts negatively with
many~cardiac~medl~cations, and dl~uretLcs, as well as other
antibiotics. ~
Griseofulvin ~(fig. 16~, usually taken orally, for
fungal lnfections of the skln, hair, and nails, has a
risk of liYer damage. Reduced bone marrow function,
with lowered white cell levels is another possible adverse
effect of ~ treatment. Drug~ ~ interactions with
,
WO93/23061 ~13 fi 1 7 4 PCT/USg3/047
anticoagulants, and barbiturates reduce effectiveness,
and the risk to pregnancy often forbids treatment.
Ketoconazole, taken orally for systemic fungal
infec~ior,s, also carries the risk of liver damage as
a result of treatment. The effectiveness of ketoconazole
is di~inished by interaction with various antacids, and
other gastric medications. Ketoconazole increases the
potency of other drugs, and is reduced in potency by
some antibiotics.
Miconazole (fig.~ 21), taken by injection for fungal
infection of the lungs, brain, kidney, and lymph nod~s,
can aIter blood chemistry resulting in anemia. Miconazole
also interacts negati~vely with med cations for diabetes,
epilepsy and ant~coagulants. The effectiveness of
amphot~ericin B ~s~reduced by miconazole.
Nystatin (f1~g.~ 5), taken orally for candida
disorders;, is of~little use in the treatment of systemic
fungal infections.~ Thoug~h~having far fewer adverse side
effects~than the~other~antifungal drugs, it is ineffective
against ;most ~fungal~ nfections~ except candida, and
aspergillus, making~it~of~limited usage.
Treatment~ wi~th~these systemic antifungals often
produces~ many~other~ very~unpleasant side effects, in
addition~ to ;the~ aduerse effects upon blood romposition,
nte~rnal~organs and other~medlcatlons being taken by
the~ pat~lent~ Taken ;~lnternally,~ amphotericin B,
riseofulvin~, ~ketoconazole, miconazole and nystatin,
may~caus~e~ nausea, vomiting, diarrhea~, dizziness, headache,
fever and other disorders during the coarse of treatment.
These symptoms, though~unpleasant enough for the patient,
can also lead; to-~more serlous mplications, further
advancing the ~ health of the -ient. Beside these
known adverse ~effects, others y-_~ unknown, will be
discovered with further research. The full effect of
internal treatment ;with antibiotics on the body is a
very complex matter, and warranting much caution.
Topical treatment of superficial mycoses is much
:
;~l36~
WO93/23061 PCT/US93/04763
safer than internal treatments. The prior art, however,
has failed to produce topical antifungal medications
effective enou~h to deal with more serious infections.
Thls necessitates the use of systemic treatments, which
are more dangerous, costly, time consuming, and associated
with many other~ unpleasant illnesjses to treat even
super~icial mycoses.
The adverse effects of prior art systemic antifungal
treatments is a more ~serious complication of treatment
for deep tissue~ mycoses than superficial mycoses.
Patlents suffering ~from~deep tissue disorders, such as
cryptococcosis, ~ histoplasmosis, blastomycosis,
coccidioidomycosis,~ paracoccidioidomycoses, and others,
are generally in a much poorer state of health than
patlents~ being trea~ted for dermatophytosis. For this
rea~on~, the adverse ~effects~ of~ systemic treatment have
greater~impact ~on ~the overall health of patients being
t~reated~for~deep;~t~lssue~mycoses. Thls is; of particular
signi~ficance in ~ the~ treatment of immunocomprimised
patients.~
Deep~ tissue~ myco~ses flnd their greatest opportunity
in ~lmmunocomprlmlsed~ patlents.~ ~These lnclude cancer,
organ transplant patients, and others~on immunosuppressant
mediGatiQn~ and~ particularly~ with ~patients suffering
from`~lmmune ~dlsorders~such~ as ~acquîred lmmune deficiency
syndrome,~otherwlsé~k~nown as ~AIDS~ These patients, who
are~very~ ndeed~, ~a~re highl~y susceptibl~e to infection
;from~these~ dlseases,~as thelr natural ~defenses against
the path~genic microbes is greatly reduced.
~ , . . . .
The adverse~effects~ of treatment with currently available
prlor ~art ~ sys~temlc;~ antlfungàls,~are devastating to
immunocomprimi-sed~ ~patients, to t~he p~int of being
themselves~ life ~threatenlng to the; patient. To ~hose
patients in greatest~ neéd of traatment for deep tissue
mycoses, the medl~cat1on is most dangerous to administer.
;With the ~ steady rise in treatment with
immunosuppressan~t~ drugs, and~the much more dramatic rise
~ 2136174
"~ WO93~23~61 ~ PCT/US93/04763
q
in the number of cancer, and AIDS cases reported, and
anticipated for the future, the demand for safe,
effective, and low cost treatments for both deep tissue,
and superficial mycoses, is more urgent than ever. The
prior art has largely failed to meet this criteria as
a result of high cost, low ineffectiveness, and the high
toxicity of their antifungal medications.
The focus of the prior art upon the development
of azole derivatives, is perhaps largely responsible
for keeping the cost high, and the effectiveness of
antifungal treatments so low. The newer generation
trlazole (fig. 23) derivatives, including fluconazole
(fig. 24), terconazole ~fig. 25), itraconazole, and
others, cost many millions of dollars to develop, and
apparently are not that much more effective than the
prior generation imidiazole (fig. 19) derivatives, and
certainly are doing nothing to make treatment more
a~ff~ordab~e, or~convenient. Beside this, they have much
narrower~application~ ~than the imidiazoles, and are
considered auxiliary, a~nd not mainline treatments.
It~ seems doubtful at this point, that either of
the azole groups~;~will produce derivatives of significantly
,, :
greater effectiveness in the treatment of fungal
disordèrs,~ than what `lS currently available with prior
art~reatments~
Disclosure of Invention
Accordingly,~ several objects and advantages of my
invention include a method for treating fungal infections,
otherwise known as mycoses, in which cure is complete
wlth~as few as one slngle application of my medication.
Rather than making scores of applications, usually
required by prior art antifungal medications, my
medication usually requires just one treatment to affect
full cure. The effectiveness of my medication is nothing
short of astounding, and is truly generations ahead of
currently available antifungals.
'
WO~3~23061 ~336174 PCT/US93/0476~
/~
I have discovered that plants of the pepper family,
and plant species with similar chemistry contain active
agents that provide complete cure when applied to areas
infected with mycotic diseases. These agents may be
administered in the wide range of~ commonly used drug
vehicles and carriers, with resu~t~s that are absolutely
unprecedented when compared to ~ior art treatments.
Tinea, in its various forms, otherwise known as
athlete's foot, jock itch, favus, and ringworm, along
with other types of dermatomycoses such as candida, may
be completely healed after a single treatment with my
medication. ~opical treatment of these diseases, in the
form of an lnfusion, ~ bath, douche, shampoo, lotion,
drops, tincture, plaster, powder, aerosol, or other
carriers, all~provide outstanding results.
; Currently ava~ilable prior art over the counter
topica~l treatments for ringworm containing clotrimazole,
mic~nazole, tolnaftate,~ or undecylenic acid, usually
requi~re several ;weeks~of daily multiple treatments before
mprovemen~t can be observed~ln the conditlon. In addition
to the~;considerable;;~expense of having to buy several
co~tainers of the ~medication, the tlme, and inconvenience
i;nvolved~in maklng~repeated applications with meager
results~ ~adds~ further to~ the mlsery and discomf~rt of
the~ disease~ Even ~mlld to moderate cases of tinea can
easily requLre~ more than~ sixty ~;applications of these
products~ before ~ the~ condition improves. The weak
therapeutic actlon ~of~these prior~ art, over the counter
treatments is often insufficient to produce adequate
results, and ~must be treated ~by a physician, using
prescription toplcal, and systemic antifungals taken
internally. ~
Prescription treatment with;~antifungal medications
is~ the most expensive of all ~treatments. Beside the
~: ~
cost of having an attending dermatologist, the medications
themselves are m~re~ expensive than the over the counter
varieties. This~ type of treatment, being the best the
~ ~ ;? ~ ~ 3 ~ 1 7 4
W~93/23061 PCT/US93/04763
ll
prior art has to offer, still may require several ~onths
of multiple daily doses of the antifungal medication
to cure some kinds of ringworm. Treatment for athlete's
foot may require up to three months of multiple daily
doses of the medicine before the condition can be cured.
Ringworm infections of the toe nails can take up to
eighteen months to heal! So adding the expense of
visits to a dermatologist, time lost from work or leisure,
the time and inconvenience of applying the medicine,
the cost of the medicine, and the ongoing discomfort
of the disorder, all have an economic impact that is
quite considerable, in addition to the discomfort of
both the disease and the side effects of
treatment.
Systemic treatment with antifungal druys, such as
amphotericin ~, clotrimazole, griseofulvin, ketoconazole,
miconazole, nystatin and others, in addition to being
expensive and time consuming, have many bad side effects
that can further endanger the health of the patient.
These drugs, taken internally, ~arry the risk of damage
to liver and other~internal organs, and ~dverse effects
up~n blood chemistry. Patients receiving such treatments
must be monitored for changes in blood and organ function,
as a safeguard against serious damage that can result
from treatment. Prior art systemic antifungals also
intaract adversely with a large number of other
medications, another area that requires close attention
by the attending physician. seside this, other adverse
effects include nausea, vomiting, diarrhea, fever,
headache, and other unpleasant symptoms that accompany
the disco~fort of the disease.
With my medication, a single topical application
is~all that is usually required to completely cure most
types of dermatophytosis. Even recalcitrant cases of
athlete's foot are healed in as few as half a dozen doses
of my medicine. Body and scalp ringworm lesions
disappear, usually within the first day after treatment,
~2~36~1 4
WO93/23061 PCT/US93/04763
/c~ .
and require no follow up dosages. With my treatment,
systemic treatment of superficial mycoses is a thing
of the past. Instead of making several visits to a
dermatologist, and taking repeated doses of drugs that
are expensive, dangerous, slow acting, and create other
illnesses as a side effect, one need only make a single,
or few topical applications of my treatment for complete
cure~ In addition to effëctiveness that is truly
astounding, these pepper compounds are completely safe,
being derived from commonly consumed food. Topical
applicatlons of my treatment generally require less active
agents, than what might be commonly consumed in a meal
~; that includes any of the pepper species. In addition
to that, there is no long term, chronic exposure to the
medicine, as is required with prior art topical
antifungals, thàt have only a long term therapeutic
effect, lf any at all!
The prophylactic action ~-of pepper constituents
contlnues~ to~ protect damaged tissue from reinfection,
by ~maintaining its antifungal action for days after
treatment, in additlon to it's di~rect, and immediate
fungicidal action.~This further aids rapid healing, by
allowlng~diseased ~tissue to regenerate, rather than
concentrate energy on combating disease
.:
Pepper also appears to~ act as an immunostimulant,
by preclpltatlng leukocytes, and~other mononuclear cells,
along with~ a variety of antifungal compounds from the
blood, and surrounding~tissue,~to the area of infection.
Though done primarily through inducing inflamation, pain
and dlscomfort are not required in order to receive
the fuIl therapéutic benefit. Pepper compounds are also
believed to aid in~the delivery of these antifungal immune
resposes of ~the bo~dy, and increase their potency in
addition to its own antifungal actions~
Healing, and excelle~ated regeneration of diseased
tissue is another important therapeutic action opepper
compounds. While whole, healthy skin is the bes
2~3~17~
; WO93/23061 - PCr/USg3/04763
/3
protection against infection from dermatophytes, pepper's
a~ility to regenerate diseased skin is equally astounding
to it's antifungal action.
The healing, and tissue regeneration actions are
further demonstrated in the treatment of other forms
of dermatitis such as dandruff, seborrhea, eczema, warts~
corns ect.. These chronic skin disorders, which are not
currently recognized as being of microbial origin, also
respond with complete cure when treated with pepper
compounds, often in the same way as superficial mycoses.
These diseases, for which the prior art believes
incurable, may also be completely cured with my invention,
often as easily as superficial mycoses such as ringworm
are cured.
In a study o~ eight patients, all infected with
various forms of~ dermatophytosis, complete cure is
obtained ~after one topical application of the medication
of the ~urrent invention in five of the eight cases
:,
studied. ~The other three cases studied are cured within
half a dozen treatments or less. None of ~he patients
are takin~ any kind of medication for ringworm, or for
any other disorder~ and no special sterilization measures
of clothing, furniture or bedding axe taken, beyond
otherwise good personal hygiene.
; In the first portion of the study, a family of three~
all afflicted with~ rlngworm, are completely healed after
a single topical treatment with a pepper compound.
The infant ~has developed approximately six ringwo-
~lesions~about the back of the scalp, and back, and ric! :
side of the ne~k~ The first few lesions were noticed
a~month before.
The mother of the~ infant has about six ringworm
lesions on the right arm, most on the outside bicep.
The appearance of the lesions was first noticed
approximately three months before.
The father of the infant has approximately eight
ringworm lesions on the left arm, most on the outside
WO93/23061 ~ ~3 ~ PCT/US93/0476
/~
bicep. The right arm has four lesions, also on the outside
of the bicep. Four other lesions appear on the shoulders,
and lower back. The man first noticed lesions of this
type approximately eight years earlier.
On all three subjects, the rlngworm lesions have
the same general appearance. The Iesions are ring shaped,
with slightly raised outer bor~ders that are sometimes
crusty. The lesions are red, w~th a smooth, and sometimes
scaly interior. A clear, sticky fluid sometimes covers
the lesion. The average diameter of the ring is about
15mm (.6"), with some as large as 20mm (.8"). The lesions
appear, and remain for several weeks, sometimes
disappearing, leaving lighter colored skin at the site
of the prior lesion~
The man is first to be treated with a preparation
of capsicum, wherein a plaster is applied to three lesions
on the left bicep. A very slight, momentary tingling
sensation is reported. The sensation lasts for about
the first five minutes after application, and is not
uncomfortable. The plaster is left on the skin for about
one hour, then rinsed off with water. Afterward, the
lesions~appear redder than they did prior to application
of plaster. After six hours, the }esions appear to be
whiter, ~with the coloration being more similar to the
skin tone of the healthy skin, than prior to treatmentO
At ~wenty hours, all three lesions appear healed, as
it requires very close examination to reveal khe site
of the prior leslon. The characteristi patch of lighter
colored skin that normally accompany lesions that have
healed by themselves is not present.
The other dozen or so ~esions found on the man are
examined, and found to be substantially unchanged from
their last examination the day before. Another
examination on the third day yields the same results,
with no sign of the three lesions that were treated ar.d
healed, and little change in the untreated lesions.
Also, on the third day after initial treatment,
-~, 2 1 '~ 7 ~
- WOg3/23061 PCT/US93/0476~
/~
the other dozen ringworm lesions on the arms and trunk
of the man, are treated with the same capsicum plaster,
with identi~al results. All twelve ~esions, regardless
of location, are healed with the exact location of the
prior lesivn being difficult to determine because of
the advanced degree of healing of the skin in that area.
One week later, the woman is treated with the same
capsicum pIaster as the man, with similar results. At
three days after treatment, all six lesions are completely
` :
healed in similar fashion to those on the man.
One week aftèr the woman is treated, the infant
girl is also treated with the capsicum plaster in the
same manner as both~ her ;parents, and is healed in the
same way, with the dlsappearance of all lesions within
about one day.; I~t is ~also interesting to note that the
infant girl ~displays ~no si~gn~ of discomfort when the
medication is applied, and does not cry, or even appear
to~take notlc~e of~the treatment.
Regular examinations of these three patients, over
a~ period of ~several~months, fail~s~ to identify the
reappearance~of~one~ single rin~worm lesion in any one
of them~ Each l~esion~ of~ the patient is completely healed
of ~ringworm, after ~just one single topical treatment
with~my~medlcine~ 1Q0% cure of twenty-eight ~esions
on~ three;~subjects~ s~ ac~omplished after a single dose
of my medica~t~ion,~wi~thout reappearance of a single lesion.
~This ~ s done w~lthout sterili~zation measures, and aside
from~any other~medication whatever.
In another~ portion of the study, a woman in her
middle thirties is healed of athlete's foot within hours
of a single treatment of my m;edicatlon. The woman works
a ~full time job, ~in ~whlch she is required to be on her
feet most of the time. Approximately one week after
having purchased~a more comfortable pair of shoes for
work,~ the woman develops an inflammatory ~ariety of
athlete's foot. The primary symptoms are intense itching
on top of the toes and foot, felt mostly in bed at night,
~ i3~
WO93/23061 P~/US93/~4763 `
/~
along with a bad~ musty foot odor. The itching is now
interfering with sleep each night.
The woman soaks her feet in a bath, prepared from
infusio~ of capsicum, for fifteen minutes. The woman
reports a warm, tingling sensatio~ that lasts about ten
minutes. This treatment is admin~stered at 8:00 p.m..
The woman retires for the evening at 10:00, and does
not experience any of the itching characteristics of
the previous evenings. ~or three weeks the woman reports
not a single recurrence of the itching on the feet.
She contlnues to wear the same footwear as before, and
does not take any~ kind of sanitary, or other precautions
to avoid reinfection.
After about three weeks, the woman begins to notice
a qradual return of the itching on top of the feet that
she had~ experlenced before. Within another week or two,
the itching~ is ~ as intense as ever, and is again
interfering wlth~sleep.~ ~
The~woman's~ feet~ are~ treated with a lotion of
caps~icum,~ u~si~ng ~raw~ aloe vera gel as the lotion carrier.
Lotion is applied~t~o the feet, and rinsed off with water
at the~end of half an hour. The treatment is ~dministered
at ~8~ 00~in ~the~evenlng, before the woman retires for
the~evening ~at~;~10~00. The woman reports no itching that
evening,;~nor~a~fterwards, ~for many ~months. She disposes
of~ the~ comfortable~ s~hoes,~ she had bought for work, and
h;as no ~further~récurr nce of ~athlete's foot symptoms.
The~;woman~ is ~completely healed of ~athlete's foot after
just one single treatment with my medication!
Thé sixth case involves a five year old girl, who
is completely healed~ of a recalcitrant case of dry
athlete's foot.~ ~Prior to treatment, the childls feet
are peeling ;severe~ly 1n the areas between the toes, and
on the entire ~sole of the foot. Loose skin, in pieces
as larg~ as about 4mm l1/8") square are hanging around
the lower edge of the ball of the foot. The entire sole
oE the foot is calloused, and has a ~rinkled appearance.
213617~
WO93/~3061 PCT/US93~04763
/?' .
Deep cuts occur periodically on the ball of the foot
and around the base of the toes, particularly the great
and small toes. The child often complains that her feet
hurt from the cuts, but otherwise describes no other
discomfort or symptoms. The girl has had these symptoms
for about three years, since age two years
At age two years, the girl develops a particular
affection for a certain pair of shoes, and wears them
constantly, refusing to wear other shoes. Weeks later,
the girl develops a very offensive foot odor. Afterward,
her feet gradually develop the symptoms described above,
becoming chronic over the next three years.
An ethanol tincture of capsicum is applied to the
girl's feet7 The gir~ ~omplains about a stinging
sensation in the cuts around her great and small toes~
The girl cries ~or about five or ten minutes, then repor-s
that the sting is yone. The girl is a~so treated with
the same capsicum ti~cture on days three and five, after
the~ 1nitial treatment. The investigator performs these
second and third treatments because he is not sure if
the first ~reatment is sufficient to penetrate such thick
callouses on t~e soles of the feet, having never treated
such badly damaged skin with this particular treatment.
On day three, just prior to the second treatment, the
: :
feet are examined and appear slightly improved. The
cuts~around the toes have formed scabs, and no discomfort
is reported by the ~irl after application of the tincture.
On day five~ the feet are a~ain examined before
receiving the third treatment, and again appear to be
further improved. The cuts are continuing to scab over
and heal, and the~girl reports no discomfort from the
medicine. This general trend continues for the next
several days, yet treatment is not again administered.
By the fourteenth day, the feet are nearly,
completely healed. There are no cuts or scab~ed cuts,
and no pealing or loose skin. The callouses are nearly,
completely reduced, and the skin has a healthy color
WO93/23061 2 ~361~ 4 PCT/US93/0476~
/~
and texture, and no lonyer has a wrinkled, ragged
appearance. It is not possi~le to determine that the
girl has ever had athlete's foot, as her f~et are healthy
and normal. The child is excit~d that her feet are "like
new again". -
On day twenty one, the gi~;s feet are againexamined. The skin around the bo~tom and sides of the
toes has succumbed to reinfection, as the skin is again
peeling, though not as severely as before the first
treatment.
At six weeks, the girl's feet have returned to the
pretreatment condition. The skin on the sole of the
feet is thickened and calloused. The skin on the soles
and between the toes is peeling and has a ragged
appearance. Cuts appear periodically at the base of
the toes, on the heel and at the ball of the foot. The
~dry athlete's foot is back in full force.
`~The reinfection of the girl's feet is not presumed
to be the result of recontamination, as no sanitary
measures have been taken to prevent r~infection, and
the girl continues to wear the same footwear as before
the treatment. As these pathogenic fungi find opportunity
in~damaged skin tissue such as that described, the skin
must~ be healed~to prevent reinfection. The best protection
from reinfection be1ng healthy, undamaged skin.
This is one reason why the prior art has such
difficulty curing this type of ringworm. The therapeutic
;~action of prior art antifungals is so weak and slow
acting, it arrests the resident fungi only envugh to
allow the healing process of the skin a slight advantage~
~; This is why a case of dry athlete's foot can easily
require twelve weeks of daily, multiple treatments with
prior art medicatlons to provide cure, which is usually
only temporary.
The dramatic improvement of the girl's feet between
the last treatment on day five, and the examination on
day fourteen, suggests accelerated healing over any
"' '' WO93~23061 2 1 3 6 ~ 7 4 PCT/US93/04763
/~ .
activity of fungi during this interval. It also suggests
a prophylactic action by my medicine that may provide
protection for perhaps seven days or more.
Recalling complete cure after a single dose of my
medicine in the first five cases leads to the conclusion
that the fungi are eradicated on initial contact with
my medication. What distinguishes them from this sixth
case is the relatively minor degree of skin damage they
suffered, in relatlon to the present case. This further
supports the notion of the prophylactic action of my
medicine, as seven days or less is ample time to heal
the~minor skin~damage caused by the body ringworm lesions.
In an attempt ~to determine the maximum duration
of capsicum's prophylactic effect, and to compare it's
performance~ wl~th that~ of synthetic capsaicin, the
synthetic ~version~ of the primary irritant found within
natural~capslcum, t~he~ girl's~feet are~again treated.
Prior to treatment,~ the glrl f 5 feet have again
returned to their original, recalcitrant condition that
was~ noted~ prior~to~ the first treatment. The girl's
feet are~ p~eling ~severely on the bottom and sides of
-théi~toes~, ~and on~the ball of~ the ~ foot. The skin in this
area~ 1S~ thlckened~ and~ caIloused,~ with deep cracks
sometimés resultin~g~ in~ painful cuts. The skin-has a
wrinkled,; dry,~-and~ragged ~appearance,~ with intermittent
red~ blotches,~ occupying about half~ the total surface
area.~ Small~ cuts~appear periodically around the base
of~ thè~great~ and~ small ~toes, whlch often cause pain,
especially when walklng.
A loti~n of capsicum, consisting of 4 cm (~
teaspoon~) of ~ground red~ pepper~mixed with 48 cm3 (12
te~aspoons) of ~raw,~ aloe ver;a gel, is ~applied to the
c~hild's left foot. The girl describes a tic~ling
sensation as lotion~ is being applied, and is laughing.
About three minutes afterward, the girl begins crying,
s~aying: that the 'cuts on her toes~ are burning. She
contlnues to~cry~for about ten more minute~s, and afterwar~
WO93J23061 2~3~ 4 PCT/US93/04763
o?~
indicates that the burning has gone.
At the same time, an ointment of capsaicin,
consisting of about .03 percent capsaicin (from oleoresin)
in turpentine oil is applied to the right foot. There
are no cuts on the right foot at this time, and the girl
reports no discomfort from the medication.
The medications described a~ve are applied once
each week for the next two weeksj and observed regularly
over the next three weeks, with little notable change
the first few days.
On day three, the feet are examined, and appear
to be showing signs of improvement. The peeling does
not seem as severe~ and the red blotches look as if they
:
a:re fading. The cuts on the left foot are healing, and
show no sensitivity when firmly squeezed with the fingers.
On day four~ the feet are again examined, and look
much better than the previous day. The peeling is again
, ~
reduced, and the~red blotches have completely disappeared.
The; right foot looks slightly better than the left,
suggesting the;therapeutic effectiveness of the capsaicin
ointment. The cuts on the left foot show further progress
in healing.
pon examination on the sixth day after treatment,
the ch~lld's feet look very much improved. The loose
skin~ has for the~most part worn away, being replaced
by healthy s~ln~ that shows no scaling, or discolor.
The; cuts on the~ left foot have disappeared, and both
feet show reduced~skin thickness, and only faint reminder
of cracks that are mostly healed. sOth feet look about
the same, suggesting equivalent therapeutic performance
between capsicum and capsaicin preparation.
The examination of day seven reveals little change
in the condi~tion of the feet from day six except that
they appeared slightly better on day six. Small cuts
along the base of the small toe on the right ~oot are
not causing discomfort, as the medicine is applied for
the second time.
WO g3~2~K1 2 13 6 1 7 4 PCT/US93/04763
o~/
Subsequent examinations of the next seven days reveal
a similar pattern to that of the prior week. Little
change is observed the first few days after treatment,
with very noticeable improvement being observed between
the fourth and sixth day after treatment. This pattern
is also established on days eleven ~hrough thirteen,
,
yet without substantial advance in the stage of healing
beyond that observed on the sixth day.
;~ ~ It is evident that a single weekly application of
my médicine produces substantial improvement in
recalcitrant cases of athlete's foot. Though this
: : : :
mprovement is sustained, it is not usually sufficient
to~induc~e ~full cure~ at least within a three week span.
Nor does the degree of improvement compare to the results
; of the pri~or~study~ n~which the medlcation was applied
;three~times within~the~fir~st week.~ Depending upon the
case, two; to~four~applications per week should be
sufficient~to~ provide~complete, and~sustained cure for
recalcltrant~cases~of athlete's foot~;
To ~demonstrate~a complete cure for recalcitrant
athlete's~foot,~and;~to~ compare the~ performance of a red
peppe~r (~capsi~cum~ f~rutescens) extr;act with that of one
madé~from~ black~ peppér ~(piper ~nigrum), the~girl's feet
are~àgaln-~trèated.~ The~gi~rl's right~foot is~treated with
`;~àn~ethanol tincturé~of capsicum~made from ground red
pépper,~ while~ the~left foot is~at the same time treated
wi-th~a~similar~ tincture~ prepa~red ~instead with an equal
amount of black~"pepper.~The~girl's feet are treated eleven
times, once every other day, over a period of three weeks.
The pattern of~previous tests is~ also observed in this
trla~ wlth` both the~red, ~and~bl~ack pepper tinctures
performlng ~wl~th~ eq~ual ~effectiveness. As in the other
tes~ts wlth~th~è~girl, ~slgnificant~lmprovement is observed
between the fourth~ and sixth day after ~treatment, with
dramatic improvement ~being noted at two weeks. At three
weeks, very ~little~ sign of the prior disorder remains,
and the condition~ does not return after weeks of
wog3~23061 ~1 3 6 ~ ~ PCT/US93/04763
- c~2
observation. Th~ girl is healed of recalcitrant athlete's
foot, with just eleven topical treatments over a period
of less than three weeks.
In the seventh case study, a woman of sixty is cured
of a dry variety of athlete's foot. Prior to treatment,
the woman's feet have peeling sk1n between the toes,
and thickened soles with cuts on~the underside of the
heal.
The woman's feet are soaked in a capsicum tea for
fifteen minutes at a time, once a day, for five days.
On ~the second day, the woman complains that her feet
are very dry, and that one of the cuts on her heel is
making walking difficult because of the pain. By the
fourth day, she indicates the cessation of those symptoms.
After ~elght weeks, the feet are examined and the skin
appears healthy, with;no sign of peeling or thickening
of~ the~ skin. The woman indicates that after the fourth
day~ of~ treatment,~ she did notice~ the reimmergence of
symptoms at the time ~of the eight week examination, and
felt~cured since.~ ~
In ~th~e ~elghth~case ~study, a boy of thirteen is
comp;letely healed of a severe fungal infection of the
face,~ ~and~nec~ a;fter just two weeks of treatment with
my~ ~medlcation. :; ~
pver~; a perlod~ of nearly five months, the boy has
~h~ ;been suf~ering from~what is desclbed~as an angry, bright
red~rash about th;e~face, from beneath the eyes, down
to ~the ~bottom,~ and~sides of the neck. The boy's father
decribes the disorder as "literally ea$ing his son's
face awa~." The boy, and his family are for some time
qulte~ dlstressed,~as; treament adminlstered by a genexal
practitioner, and~ two dermatologists over more than
four~mon~hs, fails to heal the condition. The expense
of treatment is nearing $1,000 out of pocket. The visits
to the physic~ian, have cost the parents more than twenty
hours away from work, and the boy must be excused from
school the same amount of time. The boy is of coarse
:`: :
` '~13617~
. ~! WO 93t23061 ' PCT/US93/04~63
doubly distressed, as in addition to the discomfort of
the disease, he must bear the humiliation of wearing
this rash on his face that is more horrible in appearance
; than a severe case of acne!
A skin scraping sent to a laboratory reveals the
presents of fungal hyphae, not of the ringworm variety.
;The boy is~ g1ven griseofulvin orally, but must
~' discontinue treatment after one wee~ as a result of severe
nausea.~The boy; ls then ~iven tolnaftate topically, and
has shown no;slgnif1cant improvement in the condit~on
over a~period of sever`al weeks.
The boy is then g1ven lot1on prepared with capsicum,
and~ instruct~d ~to apply the medication ~once every other
~day after bathing until symptoms disappear. All other
treatments are also discontinued.
The~ boy~'~s ~father admin1sters the treatment as
'prescribed,~and~ is~ seeing noticeable improvement by the
thlrd~;~day~ Th~e~condition~ continues~to~i~prove over this
period~ and~by~the tenth day the skin is almost compIetely
healéd, ~with~ bar~e~ly~ a remanent of the prior disease
remaining.~To~ say~the least~ the boy's family and friends
are~amazed~ and~ astounded~at the ra~pldlty of cure of
t~h~is~ horrlbl~y~ uns1ght~ly~ conditi~on,'~that ~h~ad persisted
fo`r~`'so~ many~ month~s~;before ~without ~improvement, often
r f ing~to~t e lclne~as~"a;lltera1~Godsend~
The~;treatment'is discontinued~after only two weeks,
and the~boy~1s'~hea~led~without; relapse~ after many weeks
`of observation~;`even~until~ the time~of this wr:iting.
As~can~ be~seen ~from these several examples, the
effectiveness~ of~ my~toplcal antifungal medlcation is
tru1y~ astoundlng~ Slngl~e~'appl~lcat1on cure of
dermatophytosis~ being unheard of among~ ~prior art
tréatments, is~ th;e~usual result with~ the medication o
my~ invention.~ No~ longer is it necessary for suffers
to~endure~prescr~lpt~lon therapies,~ which are slow acting,
time~ consuming~, ~eXpensive and potenti~ally dangerous with
;many ~other ;~unpl~easant ~adverse effects. With my
. .
~ } 3 ~
WQ93/23061 ~ PCT/~'S93/0476~ `
~?~
medication, embodied in the form of a topical, over the
counter treatment, even recalcitrant cases of athlete's
foot can be cured with a few periodic applications of
my medicine. Instead of months o;f; antibiotic therapy,
administered by a dermatologist~ the sufferer can cure
the condition themselves, with~a safe, inexpensive and
astonishingly power me~icine, such as mine.
The`savings in health care cost that my invention
provides for the treatment of dermatophytosis alone is
astronomical. Prior art treatments, that cost many
hundreds of dollar~s and represent considerable loss of
ime from work and~ ~leisure, are no longer required.
Wlth~ my ~medicatlon,~ these same disorders can be cured
for pennies, with only minutes of time required by the
sufferer, and without~the attention of a physician.
; nith the very considerable cost savings my medicine
provides, the sufferer also gets prompt relief from the
symptoms of ~dermatophytosis. Instead of waiting days,
or~weeks~to gain rellef from ringworm itch, as is the
requirement~of~prlor~ art toplcals, my treatment provides
re~lief in~just~mlnutes~ Instead of enduring weeks, or
;months~ of~sys~temlc~an~tlfungal~treatment to see improvement
in~ ~à~; reca;lcitrant~ case~ of~athlete~'s foot, with ~y
treatment,~dramatlc~ ;improvement is~ seen within hours,
to~a~few ~days~of~thè~ fi;rst treatmen~t. The savings here,
in~ terms ~ of~ haman~ dlscom~or~t and inconvenience is
incalcuable. ~
The ~amazlng~::heal~lng~ ~power :of:~ my~ medicine, coupled
with tremendous economic advantage it provides, opens
the doorway for the;cr~eation of many new, and very large
markets ~fo~r ~top1cal~ treatment~ of~ superficial mycoses.
Rather than exclude the econom1cally; disadvantaged from
a viablé trea~tment,~as prior art antifungals do because
~, " ~ ~ :
of~ their hiqh~ cost, and lack `~of effectiveness, my
;treatment can be produced and~sold at a very low price
relative to prlor art topicals, and still provide a very
large profit~ margin for marketers~. My product will
,~
3 ~
W~93/23061 PCT/USg3/047$3
~ 5
greatly expand the ~arket base for ringworm medicines,
by tens of millions of individ1lals worldwide, and most
important, provide effective m~ical care for those in
greatest need of it. Severe cases of ringworm can be
completely cured for less than a penny in actual cost
of the active agents within my medication. If such a
product is sold for a dollar, it would open the market
up to many ~lllions of people world wide, and provide
a tremendous~ commercial opportunity for drug
manufacturers.
In the United States, a topical ringworm treatment,
such a~ mine, costs less to produce than the current
prior art over the counter brands, yet, is scores times
more effective. If sold at competitive prices to prior
art brands, the superior effec~iveness of my medication
will radically outsell the competitor brands. The high
effec~t~iveness of ~my~ treatment will also attract the
purchase~of low ;income lndividuals, who otherwise are
not ~able to ~afford~ prior art medlcations. Because of
the need~to purchase several containers of prior art
over the counter ~;~opical treatments to cause even
temporary cure,~ ~of~a~ single case, low income people do
not buy the medication because of the cost, and simply
go ~untreated.~ In~ addltion to a~dding more misery to
thelr already ~unfortunate circumstances, it further
contributes to :~ the spread of the disease, thereby
perpetuatlng~this undesireable cycle.
Prior art topical treatments for dermatophytosis,
such as clotrimazole, miconozale, tolnaftate, and
undecylenic acid, are~not effective for dealing with
;the ~problem. ;Their weak drug action, coupled with their
:: :
high prices, preclude their use among the economicall~
d~isadvantaged~and have not been able to establish a market
for them.
The expense and weak action of prior art antifungals
has also occluded creation of a market for treatment
.
~ of ringworm,~ and other superficial mycoses within the
:: :
W~93/~3U61 2 i 3 6 1~ ~ PCT/US93104763
~ 6
livestock industry. The current economics of treating
food animals for ringworm, with available prior art
treatments, forbids the practice. The economic impact
of ringworm within the livestock industry is felt first
by the rancher, whose head are refused by the feed lot
~ecause of it. ~eing highly contagious, and finding
particular opportunity under certain weather conditions,
an outbreak of ringworm can infes~ a herd within a very
short amount ~f time, and pre~;ent them from market.
This economic liability is then added to the cost of
the food product, which eventually impacts everyone.
Ringworm and other superficial mycoses are just another
~usiness liability, for which prior art treatments have
failed to remedy, much less establish a market for.
With the treatment of the current invention, the
combination of ~unprecedented effectiveness, and lower
cost, make it now economically feasible to establish
a~ product for treatment of ringworm, candida, and other
soperflcial mycoses,~ within the liv~stock industry~
My medication is especially appropriate for this
appllcatlon, being~ itself derived from food compounds,
; generally recognlzed as safe ~GRAS) by the U.S. Food
and Drug Administration. With my medicine, an outbreak
of~ ringworm among a herd of llvestock within tXe last
week~ before market,~ need no longer prevent them from
market as beforeO
The aston1shlng effectiveness of my medicine, in
comparison to prior art topical and systemic antifungals,
has crucial bearing in the treatment of deep tissue,
as well as, superficial mycoses. The common
interchangability of currently prescribed prior art
: ~
medications between topical and systemic administration,
suggests the use of my invention for systemic treatment
of deep tissue mycoses as well. As prior art antifungals,
such as amphotericin B, econazole, griseofulvin,
ketoconazole, miconazole, nystatin, and related drugs
are administered as systemics, as well as topicals, my
213617~ `
WO93t23061 PCT~US93/04763
~ 7
treatment shows excellent promise as a systemic
antifungal, as well as a topical.
The active principals found within capsicum, and
piper species, and related families provide an important
research tool in the systemic treatment of deep tissue
mycoses, such as aspergilliosis, actinomycosis,
nocardiosis, cryptococcosis, histoplasmosis,
blastomycosis, coccidioidomycosis, paracoccidioidomycosis,
entomophthoromycosis, candidiasis, and others. Pepper
extracts may be given by injection into the blood, spinal
fluid, or dirPctly into diseased tissue. Analogs of these
active constituents may be developed for oral
adminlstration, however, some modification of the
molecular structure may be required to prevent
decomposition of the actlve agents that occur as a result
of digestive processes.
With the very rapid increase in the incidence of
deep tissue~ fungal disorders, and projections suggesting
even greater increases for the future, the need for more
powerful, safer treatments is more crucial than ever.
Flnding opportunity in immunocomprlmised patients such
as cancer, organ transplant patients, and others on
immunosuppressant drugs~ and those suffering from AIDS:
thes~ diseases are life threatening. Also life
.
threatening to these patients is systemic antifungal
treatment with prior art medicines. Their high toxicity,
and multiple adverse side effects, often have devastating
`~impact on the health of these patients, who are already
very sick. Complications arising from treatment with
prior art antifungals can end their life, in addition
to addlng addit~onal misery to their already tragic
circumstances.
; Even immunocompetent patients can become very ill
as an adverse effect of systemic antifungal treatment.
Serious adverse effects include damage to liver, kidneys,
and other internal organs. Changes in ~lood composition
often lead to enemia. Less serious adverse effects, yet
WO93J23061 21361~ ~ PCT/VS93/04763
Z~
ones that are capable of causing considerable misery
for the patient include nausea, vomiting, diarrhea,
dizziness, headache, fever and other disorders. These
adverse effects are hard enough to bear for an otherwise
healthy patient being treated for athlete's foot, let
alone a patient having just underg~ne an organ transplant,
or in the advanced stages of AIDS, or cancer!
Pepper, on the other hand, being itself a food
compound consumed by man, is good for the body, not
harmful as the prior art antifungals can be. All of
mankind, throughout the world has used these plants
for food, and from long experience of thousands of years,
knows them to be safe and healthful to the body~ Pepper
compounds, being far less toxic than prior art
antifungals, wiIl not induce further illness in the
patient, like prior art treatment, as dosages are usually
less ~han the amounts commonly eaten at one time by those
who enjoy the fruit,~ or spice.
Solanacea~ piperacea, and related species of plants
are widespread throughout the world, and are grown in
virtually every~ country of the world. ` Their active
constit;uents have all~been synthesized, and some can
be~obtained very cheaply from~existing commercial sources.
Pepper extracts~ are versatile, and work very weil in
all ~conventional drug vehicles and~ carriers, allowing
for the maximum amount of product embodiments.
:
Today, moxe than every before, the importance of
having medications that are not only safe, and effective,
but cost effective as well, is becoming critical to the
,
preservation of our very way of life. The escalating
cost of health care in the United States is causing real
hardship on the middle and lower economic classes to
the extent that about 1 in 6 americans cannot even afford
health care insurance~
Health care costs are consuming a greater share
~of the middle class budget with each new year. Money
that would otherwise be spent on better housing, college
~ 213~174
~093/23061 PCT/US93/04763
,2 S
educations, early retirement, entertainment, and many
consumer goods must instead be spent to cover the cost
of health care. In addition to lowering the standard
of living for our citizens, it takes much needed capital
away from many key industries that provide employment
for our citizens and create tax revenues that pay the
national debt, and support our government.
Rising health care costs have excluding our lower
income citizens from adequate medical care, and are the
primary contributor to the national debtO They are moving
th~s country, and others closer, and closer toward
econvmic ruin, while excluding increasingly larger
segments of our society from adequate health care. How
is a society ~enefitted by a system that provides adequate
heàlth care at the cost of economic ruin? At best, that
is merely trading one illness for another, i~e., a
pkysical illness for an economic one.
A medication, such as put forth by the current
invention,- counters this trend of escalating health care
costs being economlcally, as well as medically
therapeutic. It - is very safe, and o~ unprecedented
:: , :
effectiveness. It provides far more complete, and rapid
` cure of dlsease ~than prior art mPdications, and at a
cost of just pennies on the dollar.
The concepts set forth by the invention further
serve as a ~model by which government medicaid, and
medicare programs would save hundreds of millions of
dollars each yea~r in expenditures. Nationallyj the total
savings in Gross National Product for the United States
could exceed 20 billion dollars annually if the treatment
for dermatophyte infections alone were fully implemented.
While providing considerable savings to each nation
~of the world, my medication will greatly expand the size
of the antifungal drug market. The Pconomically
d1sadvantaged throughout the world, who are currently
excluded from this market because of high cost, ~nd weak
performance of the prior art over the counter topical
:
WOg3/23061 2 13 6 17 ~ PCT/US93/0476~ `
- 3~
treatments, will purchase my product because of its
dramatic effectiveness. New veterinary uses, not
currently existing, will also contribute to a larger
consumer market than eYer before. Add to this an overseas
market, aimed at producing a product for developing
countries, and the total consumer base for these products
will expand by hundreds of millions of individuals,
currently excluded from t'~ë market by the high cost,
and ineffectiveness of prior art treatments.
;~ Now, ~nd finally, an antifungal treatment exists
that can save our nation ~alone, billions of dollars each
year in the treatment of dermatophyte infections alone.
A drug that will greatly expand the ~size of the market
for antifungal treatments, bring rapid cure to tens of
millions of suffers in~our country, and around the world,
and~provlde~ an ~important ;weapon in the war against the
more ~serious infectious diseases that will save lives
s well.
Brief~Descrlption of the~Drawings~
Fig. ~ is~a~molecular~dlagram of phenol.
Fig.~ ~2 - 13 show~molecular diagrams of compounds of the
current lnvent~ion.~ ~ ;
Fig.~ 2~i~s~a molecular~dlagram of ortho-methoxyphe~ol.
Fig.~ 3~lS a mo~lecu~lar diagram~of vanillyl~
Pig~ 4~is;~a~mo~iecul~ar~dlagram~of
3-methoxy-4-hy~droxybenzyIam~ine.
Fig~ 5 is a~molecular diagram of~ vani;llylamide.
Fig. 6 is a molecula~r~diagram of the capsaicinoids.
Fig. ~7 is a molecu~lar diagram of piperidine.
Flg~.~; 8 is a mol;ecular diagram of~the~pungent alkaloid
principals~of pepper.
Fig. ~ 9 is a~molecular diagram of eugenol
Fl~g.~ 10 is a molecular diagram of curcumin.
Fig. 11 is a molecular diagram of gingerol.
Fi~. 12 is a molecular diagram of resiniferatoxin.
Fig. 13 is a molecular diagram of tinyatoxin.
~13617~
WO93/23061 PCr/US93/04763
~/ .
Fig. 14 - 25 show molecular diagram of common prior art
antifungal ~rugs.
Fig. 14 is a molecular diagram of amphokericin B.
Fig. 15 is a molecular diagram of nystatin.
Fig. 16 is a molecular diagram of griseofulvin.
Fig. 17 is a molecular diagram of tolnaftate.
Fig. 18 is a molecular diagram of ciclopirox.
~ig. 19 is a molecular diagram of imidazole.
Fig. 20 is a molecular diagram of clotrimazole.
Fig. 21 is a molecular diagram of miconazole nitrate.
Fig. 22 is a molecular diagram of econazole nitrate.
Fig. 23 is a molecular diagram of triazole.
Fig. 24 is a molecular~diagram of fluconazole.
Fig. 25 is a molecular diagram of terconazole.
:
B~st Modes for Carrying out the Invention
A medi~inal preparation of pepper, and its active
constituents~ may ~be administered in a wide range of
conventional drug~ vehicles and carriers. Capsicum~ and
black pepper ~are ~available~ commercially as oleoresin,
in a wide range cf concentrations, and pungencies, and
may be us~ed in~pl~ac~e of the plant product described below.
The~various~; preparations described below are made
from a ~moderate ~pungency commercial grade of ground
cayenne ~pepper ~(capsicum frutescens) t or black pepper
(piper~ nigrum),~ as ~an ~ indicator of approximate
concentration ~ within each~ carrier. Their equivalents
may~be~éstlmated,~and prepared from commercially available
oleoresin, or from any of the pungent principals, some
of which are also available commercially in pure natural,
or synthetic form. ~
The ~erm ~"~pepper", or "pepper compoundsl' are used
somewhat generically to indicate a "pungent botanical".
, ,
Other botanicals such as those of the 2ingiberacea family
ncluding ginger lZinglber officinale), turmeric (Curcuma
longa), cardamon (`Elettaria cardamomum), Melegueta pepper
Aframonum melegueta~, members of the Euphorbia genus
WO93/23061 2 ~ 3 ~17 ~ PCT/~IS93/04763
. ~ .
including Euphorbia resinifera, poinsetta (Euphorbia
pulcherrima), clove (Eugenia aromatica), allspice (Pimenta
officinalis) and others having similar constituents may
be prepared in the same way as pepper by following the
general procedures outlined below in the capsicum pepper
illustration below. Included among this list of botanicals
is of course the other members of the Solanacea pepper
family including members of the capsicum genus with the
annuum, baccatum, and longum specles. Among the Piperacea
family, species of the peperoma, and piper genus which
include the retrofractum, nigrum, and longum species.
Other species of plants having similar chemistry may
also be used in place of the above.
The performance of each preparation will of course
depend on type,~and concentration of botanical, carrier,
and solvent used in~relation to the particular pathogenic
organism involved. The chemical properties, and
solubility of many~ o~ these botanical compounds,
inoluding informatlon on separation, and quantitation
of~ their constituents are also availa~le from similar
sourcès~ in the scientific llte~ature, and and may be
consulted for more detailed investigations.
For purposes~ ;of research, or the treatment of
; disease,~ the ~indlvidual compounds responsible for the
pungent~ quality of red p ppers, and other capsicums may
be~obtalned~directly~from ground red pepper, according
to procedures ~described in the ;article "Separation and
Quantltatlon of Red Pepper Major~ Heat Principals by
Reverse Phase High-Pressure Liquid Chromatography" by
Patrlck Hoffman et. al., in the Journal of Agricultural
Fo d Chemistry 1983,~Vol. 31, pages 1326 - 1330. Though
se~eral related capsaicinoids have been identified in
trace amountsl the ~ajor;capsaicinoids (fig~ 6~ include:
::
Capsaicin. C18H27NO3
(N-[(4-hydroxy-3-methoxyphenyl)methyl]8-methyl-
6-nonenamide).
~ WOg3~23061 ~ 1 3 6 1 7 4 PCT/US93/04763
.~ .
Dihydrocapsaicin. C18H29NO3
(N-1(4-hydroxy-3-methoxyphenyl)methyl]-8-
methylnonanamide).
Norcapsaicin. C17H25NO3
(N- r ~ 4-hydroxy-3-methoxyphenyl)methyl]7-methyl-5-
octenamide).
Nordihydrocapsaicin. C17H27NO3
(N-~(4-hydroxy-3-methoxyphenyl)methyl]-7-methyloctanamide.
Homocapsaicin.ClgH29N03
(N-1(4-hydroxy-3-methoxyphenyl)methyl]-9-methyl-7-
decenamide~.
Homodihydrocapsaicln. C1gH31NO3
(N-[(4-hydroxy~--3-methoxyphenyl)methyl3-9-
methyldecanamide).
N-vanillyl-n-nonamide. C17H27NO3
(N-1(4-hydroxy-3-methoxyphenyl)methyl3-n-nonamide).
; Nonanoic acid~vanillylamide. C17H29NO3
Decanoic acid;vanilly~lam~ide. C18H31NO3
Other capsaicinolds, not Iisted here, are identified
n research litera~tu~re as~tra~e elements within capsicum,
and~may be used~in~medlcinal preparations as well, along
wi~th~ ~other~ analagous compounds.
Capsa~lci~noi~ds may; be generally classified as acid
amide ~deriva~tives~of~phenol (fig. 1). The charactexistic
pungent, irritating~ sensory effects of these compounds
a~re~typlcal of acid~amides, whether derlved from phenol,
~or piperldine~(fig~.7).~
;~Phenol ~fig. 1), though lacking pungent flavor,
:1~ !
is highly corrosive, caustic, and toxicr deriving many
of ~its~ propertles from lts basic benzene structure. While
this gives phenol ~certain antimicrobial properties, it
is yenerally consldered to be unsuitable for therapeutic
use in man, and animals, due to it's high toxicity,
, ~
~and irritating effects on tissue.
-~,
With the addition of a methoxy goup ~OCH ) to
phenol, methoxyphenol is formed. In the ortho position,
:
W093/23061 213 61 1 4 PCT/US93/04763
we have ortho-methoxyphenol (fig. 2), also known as
guaiacol, an extract obtaina~le from trees of the guaiacum
genus~ The effect of this methoxy group in part is an
increase in aromacy, and a decrease in toxicity, and
caustic properties otherwise existing in phenol, yet
without apparent decrease in antimicrobial properties.
The attachment of hydrocarbon ~roups to the ring
structure, to form higher analogu~ apparently increases
the antimicrobial properties of methoxyphenol, and phenol~
It is presumed that ~he meta, or para isomers of
methoxyphenol have similar properties to the ortho, in
like manner to the similarities between the phenol
isomers.
The addition of the methylene group (CH2) in the
para position to ortho-methoxyphenol produces vanillyl
(fig. ~3)~. Like phenol, and methoxyphenol, it is presumed
that changing the position of the methylene ~roup to
orm other ~vanillyl- isomers will produce compounds Qf
similar, although not exact properties to that of
anillylc ~ ;
The vanillyl ~structure sn which the capsaicinoids
are~ constru~ted is also typical of the pungent principals
found~in ginger (zlngiberacea) specles of plants.
ollectively~known as gingerol (fig. 11~: s~ogaoll
~a~adol, zingerone, gingerol and~ other analogs, have
a dif~erent slde~ chain than the capsaicinoids, and lacking
an ammonia (NHn) g;roup, are nelther amines, or amides
like the capsaicinoids or piperidines. Hydrolysis of
gingerols yield vanillyl, and a fatty acid side chain,
both of which demonstrate like therapeutic properties
to~the capsaicinoid hydrolytes.
Also members of the gingerJ or Zingiberacea family,
turmeric (Curcuma longa L.) contains the compound curcumin
.
(fig~ 1n), actually a vanillal derivative differing from
vanillyl by one hydrogen (H) atom having an ~CH)
substituent, rather than a methylene (C~2) in the para
position. This analog differs further with a side chain
, ` : .
~ ~ ~136174
;; WO93/23~61 PCT/US93~047~3
~?~
unique from the othexs. Cardamon, allspice, clove, black
pepper, and many others contain eugenol, another vanillyl
analog with yet another hydrocarbon side chain.
Other botanical sources of vanillyl analogs include
gum euphorbium, and extract of certain species of the
Euphorbia genus, which contain the capsaicin analog
resiniferatoxin (fig~ 12), along with its analog
tinyatoxin ~ f ig . 133 and others.
Replacement of one of the hydrogen (~) atoms of
ammonia ~NH3), with vanillyl, and the replacement of
the other hydrogen (H~ atom with an organic hydrocarbon
group produces vanillylamide (fig. 5). In the case of
the ~capsaicinoids (fig. 6), or capsaicin analogs for
example, this organic hydrocarbon group is a chain acid
tR'), varying from about 8, to 14 carbon atoms, depending
upon the part~icular capsaicinoid. These side chains,
both saturated, ~and ;unsaturated (including add to the
pungency of ~capsicums, and themselves possess
antimicrobial properties of their own, without apparently
:,
cont~ib~ting ~orrosiveness, or toxicity to ~anillyla~ide.
Hydrolysis~ o~ ~capsaicinoids yield actiYe aa.-nts
as~ well. The 5pl1ttiDg off of the side acid chain; and
it'~ replacement~ with a hydrogen ~H) atom yields the
primary ~ ~ amine~ ~ vanill~lamine, or
3-methoxy-4~hydroxybenzylamine (fig. 4) from vanillylamide
fi~.~ 5), in the case of all capsaicinoids. Conversely,
th~ slde acld~chaln, receiving a hydroxy (OH) group,
lS converted to a~ fatty acid, and yields a different
hydrolyte for each individual capsaicinoid. In the case
of capsaicin ~fig. 6), hydrolysis of the side acid chain
R'~ (fig. 6) CO-ICH2~)4-CH=CH-(CH3)2 yields iso-decylenic
acid COOH- ( CH2 ) 4-CH=CH-CH- ( CH3 ) 2 .
~he ~piperidines ~fig. 7 & 8)3, represent a group
.
of analogous alkalold compounds from which most of the
pungent principals found within plants of the piperacea
family, of which black pepper (piper nigrum3 is a member J
are found. Als~o classified as acid amides, the
WO93/23061 2 ~ 3 6 1 ~ 4 PCT/VS93/04763
~G
piperidines, like the capsaicinoids found in capsicum
species, are primarily responsible for the characteristic
sharp~ pungent taste of black pepper.
The piperidine ring (fig. 7) structure is diverse
from that of phenol (fig. 1j. Though also a six membered,
carbocyclic compound, piperidines instead contain one
nitrogen (N) hetero atom within ~he ring Piperidine
is heteroparaffinic, and contains` no double bonds. The
hetero nitrogen atom within the ring is a contributor
to the pungency of these compounds. The attachment of
a hydrogen (H) atom to the hetero nitrogen atom within
the ring forms the amine structure. Attachment of a
hydrocarbon group, in the form of a side acid chain
~R" fig. 8~ attached to a benzene structure establishes
the acid amide structure. These compounds include;
piperine C17H1g 3 (fig. 8), chavicine C17~19N3'
iperettine C19H2lo3Nr piperidine (CH2)5NH, piperyline~
piperolein ~, piperolein B, piperanine, and others.
Hydrolysis of piperidines, like the capsaicinoids,
yield active, pungent compounds. Cha~icine, for example
is hydrolysed to piperidine, which receives an additional
hydrogen (H) atom to form a primary amine, and chavicic
acid, which receives the hydroxy ~OH) group to fvrm the
fatty acid.
Hydrolysis of these capsaicinoid, and piperidine
acid amides, as well as the other listed compounds may
be accomplished wlth chemical catalysts, or by boiling
a liquid preparation of these compounds with water.
Hydrolysis does n~t appear to diminish the pungency of
these compounds, and in some cases actually appears to
enhance both their pungency, and therapeutic action.
The carbonyl group (C=O) side chain substituent,
common to all the above compounds (except eugenol) is
also believed to be a contributor to antimicrobial
activity.
The chemical structure of prior art antifungals
(fig. 14 - 25) use neither the phenolic, or piperidine
~.. ~ ,
i W093/23061 2 1 3 6 1 7 ~ PCT/US93/047~3
~ 7
,
(fig. 7 & 8) amine, or amide structures. The current
trend appearing to favor azole derivatives. These include
the imidazole (fig. 19) derivatives such as clotrimazole
(fig. 20), miconazole (fig. 21), ketoconazole, econazole
(fig. 22), and others. The newer triazole (fig. 23) class
includes fluconazole (fig. 24), terconazole ~fig. 253,
itraconazolel and others.
Other active agents found within capsicum include
cltric acid, vi~amins A, B1, B2, C, and E, iron,
potassium and niacin in significant quantities, along
with other lipids, and carotenoids including capsanthin,
capsorubin, and others. Vitamin C concentrations of 100
milligrams ~per ounce~, are the highest of any natural
food compound. Vi~amin A content is also high, with 6170
I.U. per ounce.
An infusion of pepper may be prepared by soaking
approximately 4 ~cm3 ~ (1/4 teaspoon) of commercially
availab;le;~ground ~red, or black pepper, to one liter
tl quart) of wate~ of sensibly comfortable temperature.
Infusion~ should~be allowed to soak at least ten minutes
befoxe use for ~best~results. According to preference,
usion may,~ o;r may not be strained to remove plant
residue before use. ~
A tea;;~of~is~a more;potent verslon of infusion above,
using ~about~ 16 cm3~ (~1 teaspoon~ of~ground pepper for
eac~h ~liter (quart)~ of sensibly comfortable water. ~ea
may~lso~be~ prepared ~from boiling~water, or itself be
bolled~ in~water~before use. Boiling pepper in water
assures complete hydrolysis of the pungent principals,
which axe also active agènts.
A ~tincture~ may be~ prepared by soakin~ ground red,
or ~black pepper ln a solution containing~approximately
60%~ ethanoI, and 40~ water. Pure ethanol, and other
solvents such as ~acetone, chloroform, vinegar (acetic
:
acid), and others ~may also be used. The ~luid volume
of the solution may be about thre~, or four times that
of the dry volume of the qround pepper. The mixture
WO93/23061 PCT/US93/04763
213617~
should be agitated, at least occass~onally, over a period
of at least two hours, with maximum extraction being
obtained after about six hours. Allowing the mixture
to sit over night produces excellent results. Before
use, the residual ground pepper may be ~strained off,
and liquid tincture saved for use. ~`
A preparation of pepper drops ~mày be obtained by
reducing tincture through heat, or passive evaporation.
Drops made by this method are similax in purity to some
grades of commercially available oleoresin of capsicum,
and black pepper.
A plaster, or poultice may be prepared by mixing
ground pepper with~ water, until it has a paste-like
consistency that will assure good adherence to the skin,
or cloth to which it is applied.
A~lotion, cream, or sha~poo may be obtained by adding
to any~ commercially available shampoo, cream, or lotion,
a~portion~ of ~drops, or tlncture equal to approximately
25% of~the volume of lotion, cream, or shampoo carrier.
A douche~ lS prepared from infusion, or tea that
is~ strained of the ~plant residue material before use.
A suppository ~is~ made from drops in~ cocoa butter,
o~r~gelatin ~in the~ same strength as douche, or lotîon.
An injection;~ S~p~repared from a purified ~ersion
of infusion, tea,~drops,~etc., adminis~ered intravenously,
in~tlssue, or~ mlxed~ wlth, and lnjected into the spinal
A;powder is pepper in ground form, or extracts mixed,
and/or bound within a ~inding powder carrier such as
talc.
Pepper, and ~any ~of its active constituents may be
administered as~a general antiinfective in the treatment
of disorders including fungal, and bacterial infections.
:
Pepper extracts may be administered within
conventional drug~ vehicles, and carriers, and are
recommended for use in four basic concentrations.
:: :
r
WO93/23061 ~ ~ 3 6 1 7 4 PC~/US93/0476~
Recommendations for treatment given below are general,
and may be altered to suit specific conditions. If one
recommended concentration for some reason appears
unsuitable, the next graduation should be used.
Other botanicals such as ginger, turmeric, cardamon,
clove, poinsetta, ect. which have many therapeutic
properties in~ common with pepper, may be used in place
of pepper described below. Though these botanicals share
common properties with pepper, variable results between
:
the two are to be expected according to concentration
of botanical product, the carrier, and solvent used,
and the particular pathogenic organism involved. With
this in mind, modi~ications to the ,ecommendations given
below are sometimes warranted depending on specific
circumstances. If one recommended concentration is not
s~uitable,~a different one may be tried. Factors to
con~idex are the~degree of tissue damage, patien~
sensit~lvity to~the~medlcation,~an~d certainly how anxious
the patient is~to ~be ~rid of the disorder! In most, if
not~all~ cases,~ daily~ treatment need not be continued
beyond the ~first;~ few ~weeks to completely resolve
dermatophyte~lnfeotlons~.;
In ~ the ~l~wer~ concentrations, an infusion may be
used~in~ the~;treatment~of milder~ microbial infections
including dermatophyte~ infections, particularly when
tissue damage is~minimal. Infusion works well as a scalp
rlnse~ -a~bath~ for~-the~feet, and~ skin, and as a douche
in` the~treatment of candida, and other vaginal disorders.
Infusion is also recommended if patient sensitivity
to the higher concentrations becomes significant.
In~ higher~concentrations, a tincture, a powder,
a poultice, and a~preparatlon of drops, are recommended
;in the treatment of severe dermatophytosis. Hiqh
concentrates, ;such ~as these, are preferred where tissue
damage is signif~lcant, and where infect~ion sites are
causing consider-able discomfort for the patient. Drops,
: ~ :
~ for example, work ~well for topical treatment of nail
~, :
WO93/23061 2 ~ 3 ~ 1 7 ~ PCT/US93/0476~ `''"
infections, ringworm lesions, and infected hair. These
high concentrates generally produce cure after the first
dose when treating skin lesions, and have a prophylactic
action of greatest duration, lasting up to about five
days after application. As it is~-usually necessary to
. .,
induce substantial heaIing of ~he skin as a measure
against recontamination, and reinfection of dermatophytes,
the higher concentrates appear to be most effective as
prophylactics as well.
A tea r~present~s a moderate concentration of pepper
compounds. It may be used in the same manner as infusion,
or in the trea~tment of more severe cases of
dermatophytosis. ~Tea ~should be u~ed if infusion fails
to bring immediate relief of secondary symptoms, such
as itching in~ athlete's foot, candida, or jock itch,
wlthin one hour of~ th'e;flrst treatment.
Tea may also ~be~ used in place of the higher
con~c~entration carr1èrs,~such as drops or tincture. It
is often ~equally~effective in curing severe cases of
dermatophytosis, i~n~ whi~ch there is significant tissue
damage, as~ the~ high ~concentrates~ ~ In this case, tea
is~preferred ovex~the~ high concentrates, particularly
f~ the patient sens~ltivlty to~the mèdicat'i'on is causing
s~lgn}f~lcant~discomfort.~
Tea~ ls~ also;suitable~as~ a gargle, or mouth rinse
f~or~thru;sh,~ or othe~r~fungal infect~ions of t~he throat,
and~oral~cavity.
For~an~ injection~ of~pepper compounds in deep tissue,
splnal f luid, or intravenously, milder concentrations,
such as infusion are recommended for initial treatment.
While injection of~pepper extracts such as capsaicin
have been administered safely in animal testing of
: : :
analgesics, it is not known at this writing if data exists
on treating humans with injection of pepper compounds.
,
A lotion, or shampoo may be prepared with any
commonly available lotion, or shampoo, and applied to
infected areas in its intended manner. Other therapeutic
:
L36174
~ WO93/23061 PCT/US93/04763
~/
agents, in addition to pepper extracts, may be added
to shampoo and lotion. If irritation is a concern, a
topical anesthetic, such as lidocaine, or benzocaine
may be added to lotion to reduce severity. If skin is
very dry, emollients may also be added to lotion.
A pepper aerosol may be inhaled in the treatment
of throat, and respiratory infections. In this
administration~ aerosol should be derived from a lower
concentration such as infusion, as pepper is extremely
irritating to the nose, throat, lungs t and eyes,
especially when airborne. This is especially true of
capslcum aerosol~. For this reason, aerosol is somewhat
-
limlt~ed~in it's medicinal application.
The irritating effects of pepper aerosol, and
particularly capsaicum, is greater when distributed
within ~an ether1c~tincture so1ut1on, such as alcohol,
ether, chloroform,~or acetone. Once airborne, even minute
concentrations have~;~a~tear gas, or macelike effect on
the eyes~, and res~irator~ system. A single, half second
spray ~ of ~à~ ~ayenne ~pepper ethanol tincture (60%
ethanol/40~ water works well) aerosol from a hand held
di~spenser~1s~sufflc1ent~to render a fifteen hundred square
foot ~enclosed~ area~uninhabitable to humans, and animals,
as~chokl~ng, cough1ng,~and burning irritation to the eyes
and~ respiratory~ system make habitation of the room
n t o l e r a b l e .
While~ this~may~ mit the use~of~aerosol for medicinal
appllcat~ions;,~it~ `appears to have~ tremendous potential
for military, ~and paramilitary applications, particularly
as a safe and more effective altexnative to tear gas,
and other antipersonnel aerosols. Pepper aerosol also
show great potential in agriculture as a crop
a~ntlinfective/ant1f~ungal, insecticide, and pest repellent.
Pepper powder~is also very irritating when airborne,
and like aerosol,~ has a more limited medical application
than the other ;carriers. If used as a foot powder for
example, it is best to fix the pépper compounds within
: :
WO93~23061 2 13 6 1 7 ~ ~ P~T/US93/0476~
a powder binder such as talc, to prevent, or lessen escape
of airborn particulate.
As to the therapeutic properties of pepper compounds,
and are several actions I believe to ~e at work in the
operation of the medication of the current invention.
While some of the actions described below are factual,
others are theoretical, or hypothetical, and are set
forth as possibilities, and are not intended to be
binding. They represent an attempt to further explain
the operation of the current invention, and to give
direction to areas warranting further research.
The first therapeutic action of pepper extracts
upon administration is that of an irritant, or as I prefer
to call an inflamatory. The irritant constituents of
capsicum, namely the capsaicinoids (fig. 6), their
hydrolytes, and the other acid amide piperidines (fig.
7 & 8), and their hydrolytes found in black pepper,
and ~ related compounds are all instrumental in
precipi~ating a rapid lnflamatory response in the area
of administration. This is observed, for example, when
applied to skin in the treatment of various forms of
tinea. The area of treatment often turns red, or pink,
and~ feels warm or hot. Burning, or warm tingling is
sometimes reported by patients after t~pical
:
~administration of pepper extracts/ usually the result
of ~excessive dosage, or exposure to open cuts in tissue.
Though thls burning sensation can become quite intense,
it does not usually last beyond the first five or ten
minutes after treatment. The burning subsides into a
warm, tingling sensation that is no longer uncomfortable
to patients. The induction OI inflammation to the point
of pain is accidental, and not necessary for cure.
Inflammatory responses associated with even slight warmth
and redness are more than adequate to provide sufficient
therapeutic action.
The ~herapeutic value of inflammation, is the
stimulation of the body's own immune response in the
2136174 ~CT/USg 3 / 0 4 7 6 ~
2 _ 433 Rec'd PC~P.T~ 1 9 AU~ 1994
area of infection. This precipitates a varied array
of _fungistatic serums, including leukocytes, and other
mononuclear cells in the area of infection. These
fungistatic serums inhibit the growth of pathogenic fungi.
Inflamation also increases the rate of skin shedding,
which combats penetration of the fungus, or other organism
into the skin. In thls mode of action, the microbe is
essentially "cast off" with the diseased tissue. Perhaps
or thls reason, those varieties of dermatophytosis that
are accompanied by inflammation often eventually heal
on their own. The noninflammatory varieties such as
dry athlete's foot, however become chronic, and are very
difficul~t to heal. The lack of participation of the immune
responses of the host prevents healing, and cure.
Pepper compounds are believed to act as an adjuvant
to these ~fungist~atl~c ~serums, by facilitating their
pathways through the~blood vessels, and skin of the host,
and through the;~cell~wall~of the fongi, or other pathogen.
Being composed~prlmarily of~lipids,~capsicum for example
is~believed to ~l~ncrease~the permeability of the cellular
membrane ~of~both~the~host, and~fungi. In addition to
aiding~ the~ de~livery ~of~ antlfungal serum, the increase
in c~ell~ membràne~ permeability also facilitates the
del~ivery~of undecy1enic~acLd, another antlfungal compound
found~in~sweat~,~into~thé~fungi.~;With the aid of increased
;permeabllity; provided~ by ~pepper compounds, these
antlfungal compounds~, ;which are normally fungistatic,
become~;funglcidal~
The direct antimicrobial properties of pepper and
another of the ~notably pungent botanicals ginger may
be ~observed! in~vi;tro,~in addition ~to those observed in
vivo~in ~the actual~treatment of dlseaseO
A series~ of~ in~ vitro tests are conducted on 3
tincture samples~prepared~from the~ground spice of cayenne
pepper ~Sample A), black pepper (Sample B), and ginger
(Sample C). Each spice~is measured, and mixed with pure
ethanol in an amount three times ;the measured volume.
ED ~tEET
WO93~23061 l 361~ ~ PC~/US93/04763
2 ~
The mixtures are stored for 18 hours at room temperature
(22C), and agitated on 5 separate occassions over the
period. The mixtures are then strained of residue, and
submitted for testing. Also included is Sample F; a
tincture prepared with commercially pure capsaicin
(8-methyl-N-vanillyl-6-nonenamide~ at a concentration
of 25mg./ml. pure ethanol. -
~
Initial in vitro tests performed by a medicaluniversity laboratory~ report that none of the Samples
A, B, C, or F show;antlmicrobial activity against Candida
albicans, or~Neurospora crassia on a solid medium, carrot
juice agar (pH 6~ screenlng.
A liquid ~as~say in ~itro screen performed by a major
U.S. pharmaceutical company however, reveals activity
agalnst all 11: strains o~ pathogenic fungi tested,
includi~g ~7 s~tral~ns~ of Candida! These pathogenic strains
are~ responsi~ble ~ ~for~ deep~ tissue ~mycotic infection,
although the~ ~andida~ str~ains~ also cause superficial
myco~tic infectlons~of~the~skin,~and mucosa~as well.
;At f~irs~t ~gl~ance~, a~general; hierarchy of activity
relative to the degree``of pungency~ among the botanical
Sa~mples~ A~ B,~&;~C~is~ evident, with~cayenne pepper being
most~pungent,~ followed~ by black pepper, and then ginger.
Though~ exceptlons~ are evident in~ the tests, degree of
pungency~ s;~an~ accurate general; 'lrule~ of thumb" with
regard~ to e~aluating the relative~effectiven~ss of the
botan~i;ca1s.~ This~ observation however, for reasons set
f~orth~ below,~shoul~d~not be lnterpreted~ as~ an indication
that the therapeutic effects of the botanicals are
, , ~
determined soley~by~the degree, and~ quantity of pungent
`principals~pres~ent~in~the Samples, ~though it lS a factor.
Thl~s~will~`be~further~;addressed below.
Perhaps most~ ntriguing of ~the test results below
s~that Samples A,~ B, C, & F of ~the current invention
show greatest activity against those fungal strains most
resistant to ~the~ drug standard ~ Amphotericin B! In
particular, C~. albicans ATCC 38?47~, ~ c. ke~fyr ATCC 28838,
:: . ....
: :
W~93/23061 213 ~1 7 4 PCT/US93/04763
and T. glabrata ATCC 15545 show particular sensitivity
to Samples A, B, C, & F in this screen. These strains,
being most resistant to s~;a~dard drug therapies, pose
th~ greatest potential fo. causing life threatenin~
illnesses. The necessity of prolonged treatment with
high dosages of highly toxic antifungal drugs required
to treat these diseases is often itself life threatening
~o the patient.
Another important feature of these test findings
is evidence of the presence of multiple antimicrobial
compounds within the Samples. In comparing Samples A
& F for example, it is apparent that the antimicrobial
action of cayenne pepper (Sample A) cannot be wholly
attributed to the presence of capsaicin alone in the
ground spice.
A revlew of the aforementioned article "Separat-on
and Quantitation of Red Pepper Major Heat Principals
by Reverse Phase ~ High Pressure Liquid Chromatograph"
indicates by rigorous testing a total "capsaicinoid"
content not exceeding about 1.9 mg./gram in common red
pepper. Sample A ~eing diluted 3 times with ethanol
wouId fix its maximum capsaicinoid content at perhaps
~ ,
.Q63%,~ or about 630 ug.jml.. Capsaicin accounting for
about half of the total capsaicinoid content of ~common
red pepper, would fix the capsaicin content of Sample
A at about .032%, or about 320ug/ml.. This diluted 256
times shows ~Sample A as having activity against C.
albicans ATCC 38247 ~at a capsaicin concentration of less
than 1.25 ug./ml., and total capsaicinoid content of
less than 2.5 ug./ml against which ~mphotericin B
requires a concentration of 25 ug/ml.! Additionally,
capsaicin though the most toxic compound found in any
gnif iGant amount ln capsicum peppers, is much less
toxic than Amphotericin B'
In comparison, Sample F has a concentration of pure
capsaicin at 25 mg./ml. - about 40 times the total
capsaicinoid content of Sample A, yet is still short
WO93/23061 PCT/US93/0476~
2136~
of the Sample A performance accross the board! This can
only mean the presence of another antifungal compound,
and/or a synergistic relationship between the mix o~
capsaicinoids and other compound within the botanical
that account for the total anti~icrobial effect. It may
also suggest that the therapeutic actions of these
botanicals are not generally improved by extensive
isolation of their individual constituents, and that
the total therapeutic mechanisms involved are quite
complex, involving a substantial number of compounds
in addition to the phenols, and piperidines present~
In this respect, high purification of individual
constituents has the undesireable effect of to some degree
dismantling the full therapeutlc action of the compound.
Sample F is the exception containing a purified
isolate (capsalcin) of the primary pungent principal
found in x~d~pepper and other capsicums. Sample F also
has perhaps ~3 t1mes~ the~ capsaiclnoid, and 6 times the
capsalcln~content of~the most pungent species of capsicum
known ~o :exist in nature. Yet accross the board, Sample
F~ all~s ~sh~rt of the~:basic bot nloal extract Sample A
even though lt has:40 times the capsaicinoid concentration
of Sample:~A!
: While the ~above: tests ~provide important ~nsight
:into somè of the therapeutic actions of the current
invention, ~they are of course~only partially indicative
of; the :full:;antlmicrob:ial action present, even as the
e~rlier carrot; julce agar tests: failed to reveal any
activity at all. The fuller antimicrobial activity of
the compounds described above are: of course observed
in vivo: in the actual treatment of disease, wherein the
~ i . : -
bodily immune responses are also mo~ulated. These
compounds repeatidly cure dermatophyte infections in
~: as few: as a single application. ~an this be said of
Amphotericin B, or any of the other currently available
:~ topical treatments? Absolutely not!
JU I ~ ~t
WO93/23~61 PCT/US93/0476
~ .
Organism Minimum Inhibi~ory Concen~
test sample standard
:(number of dilutions) ug/ml
A B C FAmphoter.B
: Candida Albicans 16 ~6 8 8 1.56
: ATCC 10231
Candida Albicans 16 16 8 8 1.56
,
579a :; ~ :
Candida A~bicans - :~ :16 16 16 16 1.56
442
Candida~AIblcans;~:; 256 16 8 25625.00
ATCC 38247
Candida~Alblcans~ 16 16 8 8 1.56
ATCC~62376
Candlda:tropl alls;~ 6 32 16 16~ ?. 56
C~andida kéfyr: ~ 64 ~32~ 16 163.1~
l6~ 32 :16~ ~83:.12
ATCa~ 5545~
;Cryptococcus albidus~ 4~: ::8 ~:: 8~ 16~ 1.56
Sacchàromyces~cer~v~slae;16~: 16 3~ ~1:6~ 1.56
Asper il~lus~ nlgér:~ 16 4~ 4:~;: 4 ~ : 1.56
ATCC~ 6404 ~
Spéc~ Yeast:~extrac~t:~ Nitrate : Br:oth +~ Glucose, water
so~lvent, 48 hour Incubatlon, all Samples precipitate
at 50~ in YNB+:G~
Sample~ A =~:cayenne~;pepper* ~ ~Sample B:~= black pepper*
Sample~C = glnger*~ Sample F = capsaicin
/commerclally~;~pure~8-~ethyl-N-vanlllyl-6-nanenamide)
25mg/ml pure ethanol.~
*tlncture 3:1 ground spice in eth~anol 18 hours @ 22C.
W093~23~61 ~361~4 ~8 PCT/US93/~4763
The irritant acid amides found within both kinds
of pepper~ and their hydrolytes, appear to have direct
fungicidal actions. Isodecylenic acid, one of the
hydrolytes of capsaicin, is b~lie~ed to have antifungal
properties superior to it's~ ~atty acid chain relativel
undecylenic acid, and offërs important clues to the
developement of still other antimicrobials, structured
.
similarily for increased effectiveness. Another hydrolyte
of the capsaicinoids, 3-methoxy-4-hydroxybenzylamine
(fi~. 4), suggests a new class of amine antimicrobial
compounds, derlved from this, and other analogus
structures~. ~
Other possible antimicrobial agents found in pepper
plants, that may play a role in producing curative
results, are known as phytoalexins. Phytoalexins, such
as the ~compound capsid~iol, found in plants of the
sola~nacea~; famlly whlch lncludes capsicums, are a group
of antimcrobial agents, not normally present in the plant,
that~are~produced by~ he plant,;only in response to trama
caused by heat, cold, mechanical injury, or attack by
insects,~ or microbes.~ Capsidiol, and other of the
phytoalexins~ produced~ by ~sol~anàcea~ species, are known
to~have~antifungal ~properties against ~fungi that are
pathogen1c~to;~solanacea specles of plants. While-these
fung~ are~ not; patogenic~ to~ man,~;lt is possible that
;capsidiol, or ~another phytoalexin;~ produced in response
to~ thelr~challenge,~ has antifungal~ action against fungi
that~are~ pathogenic~ to man, as well as~those pathogenic
to plants. It is therefore possible that capsidiol,
or another phytoalexin may play a role in curing fungal
disorders in man~and animals, as well as plants.
Dehydrati~on lS another possible therapeutic action
of pepper compounds. In the treatment of superficial
mycoses, pepper extracts appear to dry the skin to a
degree that may be inhospitable to fungi. Perhaps the
.
result of increased permeability, or the formation of
salts on the skin, ~the skin, though drier, is not
_ ~136174
WO93/230~1 PCT/US93/~4763
~ , .
uncomfortably so, and may have at least a fungistatic
effect as a result of reduced hydration.
The prophylactic action of pepper extracts is another
important therapeutic feature of the current invention.
In addition to having immediate fungicidal action in
the treatment of superficial mycoses, pepper compounds
remain in the skin for perhaps ten days after treatment,
to prevent reinfection. Patients often report the
reoccurrence of the warm, tingling sensation in treated
areas while bathing, days after treatment. Exposure
to water appears to also restimulate its therapeutic
action as well.~ If feet, or skin become moist, and
sweaty, the therapeutic action is intensified, at the
:
same pathogenic fungi would otherwise proliferate. This
provides a shield; against reinfection due to
; recontaminatlon, ;and ~protects the skin while it heals~
Pepper compounds also function as a vulnerary,
aiding,~and accelerating the healing and regeneration
of ~tlssue. ~As ti~ssue damage can be severe in certain
f~orms~of dermatophytosis,~such; as favus, nail infections,
; and~ athlete's foot,~it ~becomes necessary to heal the
damaged~tl~ssue befor~e~;full cure lS possible. Pathogenic
fungi, f~inding opportunity in damaged skin for example,
will~ often continue to reinfect those areas unless the
skln~is healed.~ This~ i~s one~reason~ prior art medicatlons
are~so ineffective towards cure. It becomes ne~essary
to~ heal~the skin to~ safeguard~against repeat infection,
as ~healthy, ~wh~ole~skin -is the best protection against
~reinfection. ~As capsicumfor example, is particularly
i high in vitamlns, and other nutrients, they also appear
to have a~healing;~effe~ct on damaged tissue.
The power~of~pepper compounds~to excellerate healing
of injured ~issue;i~s~also quite dramatically demonstrated
in~the treatment of~lacerations. We commonly have treated
the most stubborn, long lasting laceration infections
with pepper compounds (lotion containing hydrolysed blac~
;pepper drops lS a personal favorite), only to witness
~14
W093~23061 2 ~3 6 1 PCT/US93/04763
5 Z~
within just hours, reductions in redness, swelling,
sensitivity, and exudate that are quite frankly hard
to believe! One is equally astounding upon ~itnessing
the improvement seen in just a day or two after treatment!
A medication~such as;described above is an invaluable
wound healing treatment, ,particularly for the immune
suppressed, and ~should be used to treat cancers, and
other neoplasms.
Pepper compounds are also unbelieveably effective
;in the treatment o;f burns, and abrasions. On several
occassions- I have~treated burns with pepper lotion with
results as~astounding~as~with lacerations~. The improvement
in~he~heallng of~the`skin is quite notable within hours,
with continued improvement in the following days that
S ~nothing ~short ~ of ~astounding.~ This; also is very
; important to burn~patients, and is likely to excellerate
recovery~t~o~a~degree~that ;will~save~the llves of many
that~woul~otherwise die from their injuries.
Peppe~r ~compounds~ could~ be injected iiltO deep tissue
to` excellerate;~the~ heallng ~of buises ~and contusions.
This~ would~:be~ of~;-great~;benefit to athlete~s,`~and accident
hér ~ant1mlcrobial actions ~of pepper; compounds
are~pe~haps~due~to~the~ hi~gh concentration~of~ antioxidant
ompounds~such~ às~vi;tamin E, ~aromatic amines, phenols,
and -amino~phenoi~s~found~ln pepper,~partlcular~ly capsicum.
se~antioxidants~ may~ nterfere~with ~the action of
digestive;~ ~enzyme~s~ secreted by~ the fungi,~ that are
; necessary ~for ingesti~n of nutrition, in effect starving
the~fung~ It is~also~posslble that high ~concentrations
o~citric~acld~ ;or;~v~l~timins found in pepper, are ~directly
toxlc~ to the fungi. ~
onvexsely~,~ the~very high~ concentration of vitamin
C,~ a known~ oxidant, may also interfer with the ability
; of~the~fungl to d~lgest,~and ingest~nutrition, by instead
oxldlzing;it's~food compounds before~they can be absorbed,
also depriving the;fungi of food.~
. ~:::
~ ~3~17~
W~93/23061 PCT/~'S93/~476
S~,
Since capsicum is so high in vitamin A, the B
complex, C, D, and E, it can be used to treat several
nutritional disorders including scurvy, pellagra,
beriberi, rickets, xerophthalmia, and a host of related
diseases. Significant amounts of iron, and potassium,
make it excellent for correcting fluid absorption, and
retention imbalan~es that result from dehydration due
to diarrhea, and vomiting. Infusion, or tea of capsicum
may be given to correct dehydration due to diarrhea.
Soaking the ground powder only briefly in cool water,
to produce a cold tea, or infusion should be sufficient
to release the water soluble C, and B vitamins, and
mineral salts, without releasing as many of the pungent
principals, which may make ingestion difficult.
; Other evidence of the healing, and regenerative
properties of ~pepper is observed in the treatment of
other skin diseases such as psoriasis, dandruff,
seborrhea, and other forms of eczema. Topical treatment
of these dlsorders~ wlth pepper, within the same drug
vehicles and carrlers~ described here in the treatment
of fungal disorders, produces curative results that are
equalIy astounding~ As these diseases are not believed
to be~ of microbial origin, they are none the less
completely healed, usually without relapse, aft~r as
few ~as one single treatment! This is further evident
that peppèr compounds; stimulate the healing process of
:
the skln, and encourage regeneration, growth, and
normallzation of tlssue function.
Pepp~r compounds also appear to possess keratolytic
actlons, which aid heallng of these general forms of
dermatitis, by aiding in the breakdown of keratin in
the skin. This also makes them useful in the treatment
of warts, corns, callouses, acne, wrinkles, and cancers.
Keratolytic action may also have an antimicrobial effect,
by ~perhaps interfering with the ability of pathogenic
microorganisms such as fungi to digest, or ingest the
keratin on which they feed.
WOg3/2~61 PCT/U~93/0476~
36~1 4 ~-~
In one study, a four year old girl, with chronic
seborrhea of the scalp, was completely healed of the
disorder after just three treatments with capsicum drops.
The girl has two lesions, approximately 25mm (1") diameter
on the top portion of her scalp,; that she has had since
infancy. The lesions are ti~tly packed with thick,
yellowish white scales appro~ximately 2mm (1/16") in
diameter. The area above the lesions is covered with
loose scales, that are seen whenever the hair is parted.
The two seborrhea lesions are treated topically,
with capsicum drops, prepared from heat evaporated
tincture. The dosage is once a day for three consecutive
days.
Within the first few weeks, the lesions gradually
~lose their superficial loose scales, leaving only the
tightly pached scales that are th~ lesion itself. At
three weeks, however, even the tightly packed scales
have disappeared, and no lesions can be found; the
patient~ is completely healed! The area of scalp
previously infected with seborrhea is now healthy, and
normal, and completely indistin~uishable f~xom the rest
of the ~scalp, which~ is healthy. It is not possible to
determine if the; girl had ever even had seborrhea, as
no evidence of- the~prior disease can be found o~ very
close examination. ~Subsequent examinations over a period
of several months~ indicate a healthy scalp, with no
recurrence of seborrhea or any other dermatologic
disorder.
Another illustration of the keratolytic properties
of pepper compounds involves a 12 year old boy, afflicted
with a large plantar wart on the heel of his foot, in
which the boy is completely healed after a single
treatment with a pepper extract.
The boy has a large, brownish colored plantar wart
on the upper inside portion of the heel of his right
foot. For more than two years, the wart has caused the
~boy mild, to extreme discomfort, particularly when
. .
WO g3t23061 2 1 3 6 1 7 4 PCr/USg3/04763
s~
walking. On numerous occassions over the course o~ thi~
period, the wart has been treated with several over the
counter, and physician prescribed topical medications
that yield no noticable improvement in the condition.
The boy is accustomed to shaving the wart off at the
skin surface at regular intervals to reduce the size,
and hence the degree of discomfort associated with its
rapid growth. When the upper layers of the wart are
removed in this manner, the remainder of the tumor appears
as a cluster of~ milky-white stones buried below the
translucent layers of skin on the heel. Regardless of
these continued; treatments, the wart continues to grow
back causlng the~usual dlscomfort.
Prior to treatment with pepper drops, the wart is
examined, and appears ~o occupy a brownish, rough area
of the heal approximately~ 25mm. t1") in diameter at the
: ~
base. The central ~porti~on is raised, forming a nodule
approximately~6mm.~ (~1;;t4~") above the skin surface.
The wart is~ treated topically with one (1) drop
of pepper ~drops ~that~were prepared~ from a standard 4:1
red~ pepper acetone ~incture that was reduced 40 times
by~ room~temperature ~evaporation. Upon application, the
boy reports no~notable sensation from the treatment.
Eight~-~weeks~after ~this single treatment, the'boy's
heel~; is again; examined, ~and to the astonishment of the
boy~and~h1s~mother~ the~ wart is completely disappeared!
Close~ examination of~the entire foot shows no evidence
of ~warts~. ~The~ previously lnfected area of skin looks
perfe~tly normal and healed, with no trace of disease,
or abnormality.'
;When asked ~about details of the course of healing
of~ the wart, the boy replied that after treatment with
the~pepper drops,~he~had experienced no further discomfort
;in ~the~ area of the wart. This lack of discomfort caused
him to forget about the wart, a~d he had not looked at
it since treatment. ;
The above Lllustration in addition to demonstrating
:
W093/~3~61 ~ ~ PCT/U593/04763
the keratolytic activity of pepper compounds also suggest
the possibility of antimicrobial activity. Viruses ~eing
a known cause of warts are probably inhi~ited by pepper
compounds. This in combination with the keratolytic,
and perhaps vulnerary action of pepper are responsible
for~such dramatic healing result~. It has been many months
at this writing since the bo~'s treatment. The wart has
not returned, nor have new ones arisen.
From these examples, we see the multiple t~erapeutic
actions of pepper~ its constituents, and related compounds
for stimulating healing, and regeneration of tissue
damaged by both disease, and injury, in addition to its
antiinfective uses, and how pepper appears to interact
with the bodyls own regenerative capabilities to normalize
health, and function of tissue. Many other examples exist
whlch illustrate these same therapeutic actions at work
in the treatment of dis ases that cause abnormal growth,
and proliferation of keratin including eczema, general
dermatitis, and practically all other dermatologic
disorders.
~ :
Industrial Applicabilîty
Thus the reader will see, that the current invention
pro~ides~ an antimicrobial treatment, with a degr~e of
effectiveness in the treatment of fungal diseases that
is many generations ~head of the prior art.
Naturally o~curing compounds, found in pepper plant
species of the solanacea family, which include the
capsicums C. frutescens, C. annuum 7 C. Baccatum, and
the piperacea family which includes the peperoma, and
plper genera, and the well known retrofractum, nigrum,
and longum species among others, and related compounds,
are found to have profound therapeutic actions in the
treatment of fungal disorders. These compounds may be
administered in most commonly used drug delivery vehicles,
and carriers, with outstanding results.
A single topical treatment with my medication is
~ 31~1 74
W~93/23061 PCT/USg3?047~
all that is usually necessary to provide complete cure
for most superficial mycoses including ringworm,
inflamatory athlete's foot9 jock itch and candida. The
onset of effect is immediate, with cessation of symptoms
usually within the first hour of treatment, and complete
: healing within the first few days.
Prior art topical medications, on the other hand,
usually require scores of applications before full results
are seen, and often do not provide adequate cure, much
less relief of symptoms even with long term use.
Even recalcitrant cases of dry athlete's foot, which
: often require months of treatment with prior art
~:: systemics, is completely healed usually within less than
a dozen topical treatments with my medicine. Severe
cases of dermatophytosis such as this, and others, may
now be~treated toplcally by the sufferer, with a relative
~; ~ few applicatlons of an over the counter treatment
containing peppe~ extracts.
: Prior art systemic treatments, which require the
attendance of a dermatologist, and daily multiple doses
of the medication: over a period o~ several months, can
cost hundreds~ of ~dollars to treat, and are often
;unsuccessful~ in providing complete cure. In addition
to this~ considerable~ cost in time, money, and
inconvenience, prior art systemic antifungals have many
adverse~ effects, ~which are not only unpleasant~ but can
: themselves cause seriou:s ;health problems~ The risk of
damage to lnternal organs, blood composition and adverse
interactlons wlth other medications, are factors that
must be carefully weighed by physicians administering
prior art systemic antifungals. With this, other less
sever, :yet unpleasant -side effects include nausea,
vomlting, headache, dlzziness, fever, diarrhea, and many
other disorders that contribute to the misery and ill
: health of the patient.
: : With pepper compounds, systemic treatment with prior
art antifungals, with their high cost, wea~ therapeutic
~:
~,~36~ 4 --
WO93/~3061 PC~/US93/04763
~Z
action, and adverse side effects are no longer necessary
to treat superficial mycoses. Instead of months of
systemic therapy that is very costly, time consuming,
510w to provide results, and an endangerment to health,
the sufferer can cure the ~condition themselves, with
a safe, inexpensive, and astonishingly powerful medicine
such.as mine~
Pepper compounds are safe, being a food, consumed
by man for thousands of years, and do not induce illness
in the patient as prior art antifungals often do. Pepper
is~ widespread throughout the world, and is grown in
v1rtually every country. Its active constituents, most
of which are pungent acid amide compounds, easily
obtainable from the ground product, have all been
synthesized, and many are available from commercial drug
,
and chemical manufacturers.
The amazing healing power of my medicine, coupled
with the tremendous economic advanta~e it provides, paves
the way for the ~creat;ion of many new and very large
mar~ets: for topical treatment of dermatophytosis. Rather
than~ exclude the economically disad~antaged from
treatment, as prior art an~ifungal: do because of their
high cost,~: and meager effectiveness, my treatment can
be ~produced, and ~sold for less than prior art topicals,
and still provide a larger profit margin for marketers
than :lS~ common~ wlthin that industry. My product will
greatly expand the market base~for tinea medicines alone
by tens of:millions of individuals worldwide, and most
importantly, provide effective medical care for those
most in need of it.
Even severe cases of dermatophytosis~ which cost
hundreds of dollars to treat with prior art antifungals,
can be completely cured in less time, and for less than
one cent worth of pepper. A product such as this, sold
for just one dollar, will attract many millions of
consumers to the market, who are curr~ntly excluded
because of the high cost and ineffectiveness of currently
~t3617~
WOg3/23061 PCT~US93/04763
s7
available pxior art topical antifungals.
The high effectiveness, low toxicity, and very low
cost of My medication will greatly broaden the size
of the ~eterinary market for treatment of mycoses. The
high effectiveness, low toxicity, and very low cost
of my medicine also makes feasible the creation of a
significant market for treatment of mycoses within the
livestock industry. Being highly contagious, and finding
opportunity under certain common weather conditions,
dermatophytoses such as ringworm for example, can become
epidemic within a herd, within a very short time,
disqualifying them from sale at the feed lots.
The weak therapeutic action, and high cost of prior
art topical antifungals has prevented the formation of
a market for the treatment of livestock for superficial
mycoses. To treat; foo;d animals such as cattle, with
any of the prlor art topical antifungals before market
is an absurd notion. The cost of medicine, its very
slow action, coupled with the very considerable amount
of labor -required to repeatedly admlnister the medicine,
can never be justified from an ~economic standpoint.
For this reason, no significant market exists within
the livestock industry~for such products.
With~the treatment of the current invention, however,
the~ comb;ination~ of safety, low cost, and astonishing
effectiveness~, ~ make~ it now economically feasible to
establlsh a product for treatment of ringworm, candida,
and other superficial mycoses within ~ the livestock
industry~, as well as for deep tissue microbial infections.
Being derived from food compounds generally recognized
as~safe (GRA5~ by the U~S. ~ood and Drug Administr~tion,
my medication lS especially appropriate for use in the
li~estock industry. With my medication, an outbreak
of ringworm within a herd, in the last week before market,
need no longer prevent them from market as before. In
addition to topical application, analogs of pepperls
active~ agents may be added to livestock feed to prevent
2~ P PCT/US93/0476
systemic diseases as well~
Peppex, and it's active constituents provide an
important research tool in the treatment of deep tissue
fungal disorders, as well as the superficial varieties.
The almost universal interchangeability of antifungal
medications, between topical and systemic adminsitration,
suggests the use of pepper~compounds for systemic, as
well as topical use in the treatment of deep tissue
mycoses~ Pepper extracts may be given by injection into
the blood, spinal fluid, or directly into diseased tissue
for the treatment of aspergillosis, actinomycosis,
crytococcocis, entomophthoromycosis, histoplasmosis,
blastomycosis, coccidioidomycoses, paracoccidioidomycoses,
candidiaisis, and other deep tissue fungal disorders~
Analogs of pepper's active const~ituent may also be
; developed for oral administration to prevent decomposition
as a result of digestive processes~
With the very rapid increase in the incidence of
,~
deep tissue fungal disorders, and projections suggesting
even greater inciden~ce in the future, the need for safer,
more powerful treatments is more crucial than ever.
Finding opportunity in immunocomprimised patients such
as organ transplant patients r and others sn
: :
immunosuppressant drugs, and those suffering from AIDS;
these diseases are life threatening.
; Also life ~;hreatening to immunocomprimised patients,
lS treatment wlth~ prior art antifungals. Their high
toxicity~ and multiple adwerse side effects often have
devastating impact on the health of these patients, who
are already very sick. Complications from these adverse
e~fects can well en~ their lives, in addition to adding
extra misery to their already tragic circumstances.
The risk of damage to internal organs, changes in blood
composition, and adverse interactions with other
medications, along with the nausea, vomiting, diarrhea,
headache, fever t and other adverse effects associated
with prior art systemic treatment, is extremely unlikely
W0.93/23061 ~ 13 ~1 7 4 PCT/US93/0476~
~ .
occur with pepper extracts. In this way, pepper compounds
will not add illness to illness, but healing to the
patient, without discomfort, or injurious side effects.
Pepper's ability to induce an inflamatory response
in the area of administration provides an important
research tool for studying immunostimulation in the
treatment of disease~ Since inflamation precipitates
a varied array of antifungal serums, including leukocytes,
and other mononuclear cells ~o the site of infection,
this antimicrobial effect is believed to play a major
role in pepper's astounding success at curing microbial
infections of the keratin layers. These properties
are valuable in the systemic treatment of disease as
well, and particularly so for immunocomprimised patients.
Perhaps other notably pungent compounds such as
those found in garlic, onion, mustard, vanilla,
cascarilla, nicotine, lobeline, boneset, etc., also
demonstrate similar therapeutic actions as those found
in pepper. It is also probable that nearly all irritants,
whether natural, :or synthetic, possess to some degree
th~ese same: general properties, and aid cure through
induction of inflamation. ~
: The role that the active principles in pPpper play
in~the amazingly ~rapid healing, and regenerati~n of
tissue injured~ by: burns, lacerations, infections, and
disease 1~8 also important to immunocomprimised patients,
who have particular difficulty in healing, and frequently
encounter serious infection frcm even minor injuries,
and diseases~ These vulnerary actions also play an
important role in the treatment of cancers, and tumors,
and other diseases that result in cellular mutation,
and abnormal proliferation of tissue.
The astounding effectiveness of pepper compounds
to cure dandruff and seborrhea further suggests its
regenerative contributions, in addition to its antifungal
actions. Though not believed to be of microbial origin,
dandruff and seborrhea are completely cured within a
~093/2306~ ~ 3 ~ 6 ~ PCT/US93/0476~
very few topical treatments with pepper, as easily as
if it were ringworm. These healing and regenerative
powers, along with pepper's apparent keratolytic action,
also provides great promise in the treatment of all
diseases that result in an abnormal proliferation of
keratin including scaling conditions such as eczema,
psoriasis, general dermatitis, or hardened growths such
.. ..
as warts, corns, and callouses, ect. These properties
also make pepper useful in treating cancer, wrinkles,
acne, and others disorders.
The discovery of pepper's amazing effectiveness
in the treatment of dandruff and seborrhea, also suggests
that other antifungals, including those of the prior
art, may also demonstrate effectiveness in the treatment
of these, and other forms of dermatitis.
The antimicrobial actions of pepper extracts towards
pathogenlc fungi, make it an excellent prospect for
ex:perimentation with other pathogens such as bacteria,
in the development of new antiseptics and antibiotics.
Pepper's affinity for the skin also makes it a good
ca:ndidate for the treatment of staphylococcus, and other
ba:cterial infections of the skin. It's low toxicity also
favors its use in the treatment of systemic bacterial
infections including all types from ear infections to
tuberculosis.
Other products utilizing the antimicrobial properties
of pepper compounds include clothing, and shoe liners
made from capsicum wool, or any other fabric impregnated
with pepper compounds as a safeguard against harboring
these pathogens within one's clothing. For individuals
who, for example~ have a natural proclivity for
contracting athlete's foot, socks, or shoes with liners
impregnated with pepper may be worn to pre~ent
contamination leading to infection. Th~ same applies
to undergarments, and athletic wear, or anything that
has contact with the skin, and is a potential contagion
of infection.
~ ~...
W~93/23061 ~ ~6 ~ 7~ PCT/U~93/~4763
Pepper offers promise in a wide variety of
agric~ltural applications as well. Crop fields may be
sprayed or dusted with pepper preparations, or added
to irrigation water to facilitate a variety of important
operation. The anti~icrobial properties of pepper will
protect the plant from fungal, bacterial, and viral
disease. It will also protect harvested produce from
spoilage. In these two respects, crop yield is increased,
and allowable storage time extended, as microbes take
a far less signiflcant tole of the harvested crop.
Pepper's action as an irritant, further serves
incxeased crop yields by performing as a repellent for
crop destroying animals and insects, in addition to acting
as an insecticide~ In aerosol form, capsicum preparations
in particular perform like mace, or tear gas, producing
::
extreme burning and irritation of the eyes, nose throat,
lungs, and ~all mucous membranes in amazingly low
concentrations. Crops in fields treated with capsicum
and related plant species will have an intolerably
offensive taste and odort that will repel rodents, birds,
insects, and microbes that otherwise damage crops. Within
storage silos,~ pepper preparations will act as a
~.: :
preservative by~ ~continuing to stem these destructive
influences, even after~delivery to market.
The irritating constituents of pepper are also useful
or military~ and ~law enforcement purposes, as safe
alternatives~to~ma~ce~and tear gas, in addition to their
herapeutic, and~ agricultural uses~ When dispersed in
a fine mist, or vapor containing an etheral solvent such
as al~ohol, capsicum pepper in particular produces
~ . ,
extreme, and intolerable irritation to the eyes/ and
respiratory system, along with uncontrolable choking,
~` and coughing in the most minute dosages! An invisible,
and odorless vapor containing a single squirt from a
typical fine mist cosmetic bottle containing cayenne
pepper ethanol tincture is sufficient to render a fifteen
hundred square foot room uninhabitable to humans.
'
wo 93/23~6l~ 1 3 6 1 7 4 PCT/US93/04763
Dispersed within tear gas-like canisters, specially suited
for the purpose, very large areas of atmosphere could
be covered with very few distribution units.
Pepper derivatives, whether used to treat crops,
or livestock, are perfect for;use in the food industry.
Being itself a food compound, generally rPcognized as
safe tGRAS) by the U.S. Food and Drug Administration,
pepper will pose no health risks to consumers of th~se
food products. Whether applied topically to livestock,
or added to their feed, or injected as a systemic
antibiotic, pepper derivatives will not raise crucial
safety concerns, as all prior art systemics have.
Other possible areas for investigating pepper and
its derivatives include treatment of trees for Dutch
elm disease, and other disorders, and treatment of rare
painting and artifacts as a preservative, and as
.
dis~nfectant, and as a treatment against parasitic worms~
The list of possible research projects, for the
development of new ~commercial product derived from the
discovery of pepper's absolutely astonding curative
powersj is indeed endless. Wha~ new products that are
to develop from this discovery is an interesting, and
exci~ting area deservlng of much attention.
The use of pepper compounds in the treatmeht of
tumors, cancer, and other diseases involving cellular
mutation of tissue, along with immune disorders such
as AIDS, has excellent prospects for the developement
o~ many n~w drugs, and treatments.
The impact of commercial implementation of this
topical antifungal treatment alone, is to make available
to even the poorest people of the world a certain cure
for even the most severe cases of superficial mycoses.
A treatment that cures completely in mu~h less time,
in a much safer way, and for less than one penny on
the dollar for what is required with prior art treatments.
A medication that brings relief to many millions of
sufferers, rich and poor, saves our nation, and each
136174
WO93/23061 PCT/US93/04763
6 3
nation of the world millions of dollars each day in
medical costs. A medicine that provides an important
research tool in the treatmen~ of deep tissue mycoses,
and other life threa~ening infectious diseases.
While my above description includes many
specificities, these should not be regarded as limitations
on the invention, but rather as an exemplification of
certain preferred embodiments.
Accordingly, the scope of the invention should not
be determined by these illustrated embodiments, but by
the appended claims, and their legal equivalents.
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