CA2136174A1 - Therapeutic uses of pungent botanicals and their related compounds - Google Patents

Abstract

A new class of general antiinfective compounds extracted from pepper, ginger, and other plant species containing vanillyl (Fig.
3), and piperidine (Fig. 7) ring structures typical of the pungent principals found in pepper, and ginger. The role of these structures, their attached hydrocarbon groups, and other compounds found within the plant extract is demonstrated in the topical treatment of dermatophyte infections, tissue injuries, and abnormal proliferations of keratin.

Description

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 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 :

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.

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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~

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~
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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 /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 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~
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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 `
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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, :

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 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 :

~ 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 Candida~AIblcans;~:; 256 16 8 25625.00 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 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.

: ` `:

`:

1 ' .,

Claims

I claim:
1. A therapeutic composition selected from the group consisting of those useful as an antimicrobial, keratolytic, adjuvant to the therapeutic actions of an other therapeutic agent, or vulnerary, suitable for administration by injection into areas of tissue infected with disease, or other injury in humans or animals comprised of:
a therapeutically suitable carrier containing a compound selected from the group consisting of those possessing apparent antimicrobial, keratolytic, adjuvant, or vulnerary properties obtainable from water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarily having a suitable quantity of an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig.
7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in an effective amount.
2. The composition of claim 1, wherein the area of tissue is selected from the group consisting of blood, spinal fluid, skin, deep tissue, lungs, brain, bones, liver, kidneys, heart, and other internal organs.
3. The composition of claim 1, wherein the disease is caused by a microorganism selected from the group consisting of fungi, bacteria, viruses, rickettsia, and parasitic worms.
4. A therapeutic composition useful as an antimicrobial suitable for topical, or oral administration to areas of tissue infected wit? ??seases that are caused by microorganisms selected ???m the group consisting of fungi, rickettsia, paras???c worms, or the strains of bacteria that infect the skin, or vagina of humans or animals comprised of:
a therapeutically suitable carrier containing a compound possessing apparent antimicrobial properties obtainable from a water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarily having a suitable quantity of a compound that contains an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig.
7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in a therapeutically effective amount.

5. A therapeutic composition useful as an antimicrobial for topical administration to areas of tissue infected with disease caused by viruses in humans or animals comprised comprised of:
a therapeutically suitable carrier containing a compound possessing apparent antiviral properties obtainable from a water, an alcohol, or an other solvent extraction of a component of a pepper plant species, or a component of an other plant species similarily having a suitable quantity of an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig. 7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in an effective amount.

6. cancelled and incorporated into claim 5 7. A therapeutic composition selected from the group consisting of those useful as a vulnerary, or adjuvant to the therapeutic actions of an other therapeutic agent suitable for topical, or oral administration to areas of tissue infected with disease, or other injury in humans or animals comprised of:
a therapeutically suitable carrier containing a compound selected from the group consisting of those possessing apparent vulnerary, or adjuvant properties obtainable from a water, an alcohol, or an other solvent extraction of a component of a pepper plant species of the piperacea family, or a component of an other plant species similarily having a suitable quantity of an analog of piperidine (Fig. 7), as are found among said pepper plant species, or an analogous synthetic equivalent thereof in a therapeutically effective amount.

8. A composition as in any one of claims 1, or 7, wherein the injury is selected from the group consisting of wounds, lacerations, burns, abrasions, and contusions.

9. A therapeutic composition useful as a keratolytic for oral administration to humans or animals in the treatment of skin diseases that result in abnormal proliferation of keratin, and scaling comprised of:
a therapeutically suitable carrier containing a compound possessing apparent keratolytic properties obtainable from a water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarily having a suitable quantity of an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig. 7), as are found.among said pepper plant species, or an analogous synthesis equivalent thereof in a therapeutically effective amount.
10. A therapeutic composition useful as a keratolytic suitable for topical administration to humans or animals in the treatment of skin diseases that result in scaling, and other abnormal proliferations of keratin comprised of:
a therapeutically suitable carrier containing a compound possessing apparent keratolytic properties obtainable from a water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarily having a suitable quantity of an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig. 7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in a therapeutically effective amount.

11. - 14. Cancel and incorporate into 10.

15. A therapeutic composition selected from the group consisting of those useful as a keratolytic, or vulnerary suitable for administration to areas of the skin infected with disorders selected from the group consisting of acne, or wrinkles in humans or animals comprised of:
a therapeutically suitable carrier containing a compound selected from the group consisting of those possessing apparent keratolytic, or vulnerary properties obtainable from a water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarily having a suitable quantity of a compound that contains an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig.
7), as are found among said pepper plant species, or an analogous synthetic: equivalent thereof in a therapeutically effective amount.
16. A therapeutic composition useful to relieve itch discomfort of the skin of humans or animals comprised of:
a therapeutically suitable carrier containing a compound possessing apparent antiitch properties obtainable from a water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarily having a suitable quantity of a compound that contains an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig.
7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in a therapeutically effective amount.

17. A composition as in any one of claims 15, or 16, wherein the administration is selected from the group consisting of injection, topical, or oral administration.

18. Cancel (duplicate of 7).

19. A composition as in any one of claims 1, or 7, wherein the therapeutic actions include facilitating the delivery of the therapeutic agent by increasing the permeability of a cellular membrane.

20. The composition of claim 19, wherein said cellular membrane is selected from the group consisting of those that comprise blood vessels, skin, damaged tissue, tissue serums, mononuclear cells, leukocytes, and a pathogen.

21. The composition of claim 20, wherein said pathogen is a drug resistant strain.

22. The composition of claim 7, wherein the therapeutic agent is an immune response.

23. The composition of claim 22, wherein the immune response is inflammation.

24. The composition of claim 7, wherein the other therapeutic agent is a tissue serum.

25. The composition of claim 24, wherein the tissue serum is selected from the group consisting of mononuclear cells, and leukocytes.

26. The composition of claim 7, wherein the therapeutic agent is a drug.

27. The composition of claim 7, wherein the therapeutic agent is antimicrobial.

28. The composition of claim 7, wherein the therapeutic agent is antifungal.

29. A composition as in any one of claims 5, 6, 9, 10, 15 or 16, wherein said compound adjuvates another compound having similar properties.

30. A composition as in any one of claims 4, 7, 9, or 17, wherein the administration is selected from the group consisting of a tea, tincture, gargle, infusion, mouth rinse, powder, oleoresin, or food additive.

31. A composition as in any one of claims 1, 4, 7, 9, 10, or 16, wherein the diseases are selected from the group consisting of superficial mycoses, and dermatophytoses.

32. The composition of claim 31, wherein said superficial mycoses infect areas of tissue selected from the group consisting of the nails, skin, hair, mucosa, vagina, and rectum.

33. The composition of claim 31, wherein said superficial mycoses are selected from the group consisting of candidiasis, tinea, tinea pedis, tinea corporis, tinea capitis, and tinea cruris.

34. A composition as in any one of claims 1, 4, 7, 9, 10, or 16, wherein the diseases include deep tissue, or systemic mycoses.

35. The method of claim 34, wherein said deep tissue mycoses are selected from the group consisting of candidiasis, ?spergullosis, actinomycosis, blastomycoses, coccid???omycosis, cryptococcosis, torulosis, histopl?smosis, nocardiosis, paracoccidioidomycosis, and entomophthoromycosis.

36. A composition as in any one of claims 1, 4, 7, 9, 10, or 16, wherein the diseases include systemic bacterial infections.

37. A composition as in any one of claims 1, 4, 7, 9, or 16, wherein the diseases are selected from the group consisting of tuberculosis, and staphylococcus.

38. A composition as in any one of claims 1, 4 - 7, 9, 10, or 16, wherein the diseases include warts.

39. A composition as in any one of claims 1, 4 - 7, or 16, wherein the diseases result in scaly skin.
40. A composition as in any one of claims 9, 10, or 16, wherein the areas of the skin are infected with disorders selected from the group consisting of eczema, dermatitis, seborrhea, dandruff, psoriasis, or microbial infections.
41. A composition as in any one of claims 7, 9, or 10, wherein said abnormal proliferation of keratin is selected from the group consisting of warts, corns, callouses, tumors, cancers, and hardened growths of keratin.
42. A composition as in any one of claims 1, 4, 7, or 10, wherein the diseases are selected from the group consisting of cellular mutations, abnormal proliferations of tissue, cancers, and neoplasms.
43. A composition as in any one of claims 4 - 7, 10, or 16, wherein the carrier for topical administration is selected from the group consisting of a lotion, cream, tea, ointment, shampoo, tincture, infusion, poultice, powder aerosol, bath, drops, plaster, oleoresin, douche vaginal, or rectal suppository, water, alcohol, vinegar aloe vera, or an article of clothing.

44. A composition as in any one of claims 4 - 7, 10, or ?16, wherein the carrier for topical administration is selected from the group consisting of an article of clothing, underwear, socks, shoes, and shoe liners.

45. A composition useful for inducing eye, skin, or respiratory discomfort in humans and animals for the purpose of discouraging their occupation of a given area comprised of:
a suitable carrier containing an irritant compound obtainable from a water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarily having a suitable quantity of an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig.
7), as are found among said pepper plant species, or an analogous synthetic equivalent thereof distributed in vapor form by means of a device particularly well suited for producing said vapor, in an effective amount.
46. A therapeutic composition useful as an antimicrobial suitable for administration to areas of tissue infected with disease caused by microorganisms in plants comprised of:
a therapeutically suitable carrier containing a compound possessing apparent antimicrobial properties obtainable from a water, an alcohol, or another solvent extraction of a component of a pepper plant species of the solanacea family such as is available from a common commercial grade of oleoresin made therefrom, or a component of another plant species similarly having a suitable quantity of an analog of vanillyl (Fig. 3) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in an effective amount.
47. A therapeutic composition useful as an antimicrobial suitable for administration to areas of tissue infected with disease caused by microorganisms in plants comprised of:_ a therapeutically suitable carrier containing a compound possessing apparent antimicrobial properties obtainable from a water, an alcohol, or another solvent extraction of a component of a pepper plant species of the piperacea family, or a component of another plant species similarly having a suitable quantity of an analog of piperidine (Fig. 7), as are found among said pepper plant species, and within said compound, or an analogous synthetic equivalent thereof in an effective amount.

48. A composition useful as an antimicrobial, or preservative suitable for administration to areas of inanimate objects infected with microorganisms comprised of:
a suitable carrier containing a compound possessing apparent antimicrobial, or preservative properties obtainable from a water, an alcohol, or another solvent extraction of a component of a plant of the pepper species, or another plant species similarly having a component that contains a suitable quantity of an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig.
7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in an effective amount.

49. The composition of claim 48, wherein the inanimate objects include paintings, and artifacts.

50. A composition useful as an insecticide suitable for killing, or injuring insects comprised of:
a suitable carrier containing in major portion a compound possessing apparent insecticidal properties that is a mixture of compounds obtainable from a water, an alcohol, or another solvent extraction of a component of a pepper plant species of the solanacea family, or a component PCT/US9?/04763 of another plant species similarly having a suitable quantity of an analog of vanillyl (Fig. 3) as are found among said pepper plant species, or an analogous synthetic equivalent thereof, in an effective amount.

51. A composition useful as an insecticide suitable for killing, or injuring insects comprised of:
a suitable carrier selected from the group consisting of water, alcohol, vinegar, acetic acid, or aloe vera containing in major portion aeffective amount of a compound possessing apparent insecticidal properties obtainable from a water, an alcohol, or another solvent extraction of a component of a pepper plant species of the piperacea family, or a component of another plant species similarly having a suitable quantity of an analog of piperidine (Fig. 7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof, administered by means selected from the group consisting of irrigation, aerosol, or spray.

52. A composition as in any one of claims 50, or 51, wherein the insect destroys crops.

53. A composition useful as a repellent suitable for administration to crops for the purpose of preserving them from the destructive influences of animals selected from the group consisting of livestock, cattle, herd animals, food animals, rodents, and birds and comprised of:
a suitable carrier containing in major portion a compound possessing apparent repellent properties that is a mixture of compounds obtainable from a water, an alcohol, or an other solvent extraction of a component of a plant of the pepper species, or a component of an other plant species similarly having a suitable quantity of an analog of vanillyl (Fig. 3), or an analog of piperidine (Fig.7) as are found among said pepper plant species, or an analogous synthetic equivalent thereof in an effective amount.

54. A composition as in any one of claims 46 - 48, wherein the microorganisms are selected from the group consisting of fungi, bacterial, or viruses.

55. A composition as in any one of claims 45 - 47, 48, 50, or 53 wherein said carrier is selected from the group consisting of alcohol, ethanol, acetone, chloroform, ether, water, vinegar, acetic acid, tincture, tea, irrigation water, oleoresin, a mix containing about 40% water and 60% ethanol together, liquid drops, powder, aerosol, aloe vera gel, tear gas-like canister, or spray.

56. A composition as in any one of claims 1, 4 7, 9, 10, 16, 45 - 47, 48, 50, 51, or 53 wherein said other solvent is selected from the group consisting of ethanol, acetone, chloroform, ether, vinegar, acetic acid, tincture, aloe vera, or a mix containing about 40% water and 60% ethanol together.

57. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45, or 53 wherein said animals are selected from the group consisting of livestock, cattle, herd animals, herd animals, and food animals.

58. A composition as in any one of claims 45, or 53 wherein said animals are selected from the group consisting of livestock, cattle, herd animals, food animals, rodents, insects, birds, and crop destroying animals.
59. A composition as in any one of claims 1, 4, 6, 9, 10, 15, 16, 45, or 5?, wherein said pepper species includes those of the sol?r?cea family.

60. A composition as in any one of claims 1, 4, 6, 9, 10, 15, 16, 45, 46, 50, or 53, wherein said pepper species includes those of the genus capsicum.

61. The composition of claim 60, wherein said species of the capsicum genus includes those selected from the group consisting of the frutescens, annuum, baccatum, or longum species.

62. A composition as in any one of claims 1, 4, 6, 9, 10, 15, 16, 45, or 53, wherein said pepper species includes those of the piperacea family.

63. A composition as in any one of claims 1, 4 - 7, 9, 10, 15, 16, 45, or 53, wherein said pepper species includes those of the piperacea family.

64. The composition of claim 63 wherein said piperacea family includes those of the genus peperoma.

65. The composition of claim 63 wherein said piperacea family includes those of the genus piper.

66. The composition of claim 65 wherein said species of the piper genus include those selected from the group consisting of the nigrum, retrofractum, or longum species.

67. A composition as in any one of claims 1, 4 - 7, 9, 10, 45, 46, 48, 50, and 53, wherein said plant species that contains an analog of vanillyl include those of the Zingiberacea family.

68. The composition of claim 67, wherein the Zingiberaceae species are selected from the group consisting of those of the genus Zingiber, Elettaria, Curcuma, Aframonum, or Euphorbia.

69. The composition of claim 67, wherein the Zingiberaceae species are selected from the group consisting of Zingiber officinale, Elettaria cardamomum, Curcuma longa, Aframonum melegueta, Euphorbia pulcherrima, or Euphorbia resinifera species.

70. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45, 46, 48, 50, and 53, wherein said plant species that contains an analog of vanillyl includes Eugenia aromatica.

71. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45 - 48, 50, 51, or 53, wherein said compound is pungent.

72. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45 - 48, 50, 51, or 53, wherein said compound is a hydrolyte.

73. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45 - 48, 50, 51, or 53, wherein said wherein said component is selected from the group consisting of the fruit, seeds, leaves or stems, roots, or rhizomes.

74. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45, 46, 48, 50, and 53, wherein said compound is an analog of vanillyl (Fig. 3).

75. The composition of claim 74, wherein said analog of vanillyl (Fig. 3) is an analog of gingerol (Fig. 11).

76. The composition of claim 75, wherein said analog of gingerol (Fig. 11) is selected from the group consisting of analogs of shogaol (Fig. 11), paradol, zingerone, curcumin, or eugenol (Fig. 9).

77. The composition of claim 74, wherein said analog PCT/US9?/04763 of vanillyl (Fig. 3) is an analog of vanillylamide (Fig.
5).

78. The composition of claim 77, wherein said analog of vanillylamide (Fig. 5) is an analog of a capsaicinoid (Fig. 6).

79. The composition of claim 78, wherein said analog of a capsaicinoid (Fig. 6) is selected from the group consisting of capsaicin (Fig. 6), dihydrocapsaicin norcapsaicin, nordihydrocapsaicin, homocapsaicin homodihydrocapsaicin, N-vanillyl-nonamide, nonanoic acid vanillylamide, decanoic acid vanillylamide, resiniferatoxin (Fig. 12), and tinyatoxin (Fig. 13).
analog.

80. The composition of claim 72, wherein said hydrolyte is a capsaicinoid (Fig. 6) hydrolyte.

81. The composition of claim 80, wherein said capsalcinoid (Fig. 6) hydrolyte is selected from the group consisting of methoxyhydroxy enzylamine (Fig. 4), and isodecylenic acid.

82. A composition as in any one of claims 1, 4 - 7, 9, 10, 15, 16, 45, 47, 48, 51, and 53, wherein said compound is an analog of piperidine (Fig. 7).

83. The composition of claim 82, wherein said analog of piperidine (Fig. 7) is selected from the group consisting of piperine (Fig.8), chavicine, piperyline, piperettine, piperolein A, piperolein B, and piperanine.

84. The composition of claim 72, wherein said hydrolyte is a piperine (Fig. 8) hydrolyte.

85. The composition of claim 84, wherein said piperine (Fig. 8) hydrolyte is selected from the group consisting of ?havicic acid, and piperic acid.

86. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45 - 48, 50, 51, or 53, wherein said compound is an amide.

87. A composition as in any one of claims 1, 4 7, 9, 10, 16, 45 - 48, 50, 51, or 53, wherein said compound is selected from the group consisting of antioxidants, vitamins, vitamins A, B complex, B1, B2, C, D, E, mineral salts, iron, potassium, naicin, aromatic amines, phenols, amino phenols, oxidants, citric acid, carotenoids, capsanthin, capsorubin, and lipids.

88. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45, 48, 50, 51, or 53, wherein said compound is a phytoalexin.

89. The composition of claim 88, wherein the phytoalexin is capsidiol.

90. A composition as in any one of claims 1, 4 - 7, 9, 10, 16, 45 - 48, 50, 51, or 53, wherein said effective amount within said carrier is equivalent to at least an infusion, a 3:1 tincture, a powder of ground spice, or a commercial grade of oleoresin.