US006063381A United States Patent (19) 11 Patent Number: 6,063,381 Staggs (45) Date of Patent: May 16, 2000

54) THERAPEUTIC USES OF PUNGENT Kloss, Jethro. Back to Eden. 1988, pp. 122-133, 284, BOTANICALS AND THEIR RELATED 484-488. COMPOUNDS Levy, Juliette de Bairacli. The Illustrated Herbal Handbook for Everyone. 1991, pp. 49-50, 222. 76 Inventor: Jeff J. Staggs, 7474 E. Arkansas Ave. Levy, Juliette de Vairacli. The Complete Herbal Handbook #8-10, Denver, Colo. 80231 for Farm and Stable. 1991, pp. 273-276, 303-304, 331, 355-357, 401–402, 410-411. 21 Appl. No.: 08/338,489 Loder, J.W. et al. “Tumor Inhibitory Plants. Amides of Piper 22 PCT Filed: May 19, 1993 Novae-Hollandiae (Piperaceae)” in Aust. J. Chem. 1969, 22, pp. 1531–1538. 86 PCT No.: PCT/US93/04763 Lust, John. The Herb Book. Jun. 1983, p. 167. S371 Date: Mar. 18, 1997 The Merck Index. 1996, pp. 287–288, 1285–1286. Quisumbing, Edwardo. Medicinal Plants of the Philipines. S 102(e) Date: Mar. 18, 1997 1951, p. 215–217, and 835–838. Tierra, Michael. The Way of Herbs. May 1983, pp. 41-42, 87 PCT Pub. No.: WO93/23061 46-47, 133. PCT Pub. Date: Nov. 25, 1993 * de Bairacli Levy, Juliette. The Complete Herbal Handbook for Farm and Stable. 1991 pp. 275, 276, 331, 401, 402. 51) Int. Cl." ...... A61K 35/78; A61K 31/16 * de Bairacli Levy, Juliette. The Illustrated Herbal Hand 52 U.S. Cl...... 424/195.1; 514/627; 514/858 book for Everyone. 1991, pp. 49, 222. 58 Field of Search ...... 424/195.1, 514/627, * Kloss, Jethro. Back To Eden. 1988, pp. 128, 484, 485. 514/858 * Cavallito, C.J. Antibiotics From Plants, in Medicinal Chemistry. 1951, p. 248. 56) References Cited * Quisumbing, Eduardo. Medicinal Plants of the Philipines. U.S. PATENT DOCUMENTS 1951, pp. 216, 217. Duke, Purseglove, Chemical Abstracts 97(11): 92598e, 103 4,536,404 8/1985 Bernstein ...... 514/627 (25): 210886q, 112(19): 175337y, and 116(3): 18385c of 4,939,149 7/1990 Blumberg. ... 514/691 4,997.853 3/1991 Bernstein ...... 514/626 record IDS, or OA in prior case #07/886,640 filed May 21, 5,008,289 4/1991 Berstein ...... 514/159 1992. of record in IDS of prior case #08/376,045 filed Jan. 5,021,450 6/1991 Blumberg. ... 514/453 20, 1995. 5,063,060 11/1991 Berstein m 424/422 Tierra, Michael. The Way of Herbs. May 1983, p. 133. Lust, John. The Herb Book. Jun. 1983, p. 167. OTHER PUBLICATIONS Chaurasia et al., “Activity of essential oils of three medi Cavallito, C.J. Antibiotics From Plants, in Medicinal Chem cinial plants against various pathogenic fungi', (1978) istry, 1951, p. 248. Indian J. Hosp. Pharm. 15(5) pp. 139-141. Chaurasia & Kher. “Activity of Essential Oils of Three Jain et al. "Antifungal Studies on Some indigenous Volatile Medicinal Plants Against Various Pathogenic and Nonpatho oil and their combinations”, Planta. Med. (1972) 22(2), pp. genic Fungi” in Indian J. of Hosp. Pharm. (1978), 15(5), pp. 136-139. 139-141. Primary Examiner Kevin E. Weddington Duke, J.A. Handbook of Medicinal Herbs. 1986, pp. 98–99, 382-383. 57 ABSTRACT Herbort et al. “Role of Peptidergic Neurons in Ocular Herpes Simplex Infection in Mice” in The FASEB Journal. A new class of general antiinfective agents extracted from Nov. 1969, pp. 2537–2541. pepper, ginger, and other plant Species containing Vanillyl Hoffman, D. The Herbal Handbook. 1967, p. 59. and piperidine ring Structures typical of the pungent princi Hoffman, P. et al. “Separation and Quantitation of Red pal found in pepper and ginger. The role of these Structures, Pepper Major Heat Principlas by Reverse-Phase High-Pres their attached hydrocarbons groups, and other agents found sure Liquid Chromatography” i.J. Agric. Food Chem. 1983, with the plant extract is demonstrated in the topical treat 31, pp. 1326-1330. ment of dermatophyte infections, tissue injuries, and abnor Jain and Jain. “Authorized Studies on Some Indigenous mal proliferations of keratin. Volatile Oils and Their Combinations” in Planta Med. 1972, 22(2), pp. 136–139. 19 Claims, 7 Drawing Sheets U.S. Patent May 16, 2000 Sheet 1 of 7 6,063,381

OH

PHENOL CH5OH

FIG.

OH OCH

ORTHO-METHOXYPHENOL CHOCHOH

FIG 2

OH OCH

CH

WANILLYL (CHo) (OH) CH-CH2

FIG. 3 U.S. Patent May 16, 2000 Sheet 2 of 7 6,063,381

OH OCH

CH-NH

3-METHOXY-4-HYDROXYBENZYLAMINE (CHo) (OH) ch 3 -CH-NH2 2

FIG. 4

OH OCH

CH-NH-R where R is an organic hydrocarbon group

VANILLYLAMIDE (CHo) (OH)ch-CH-NH-R

FIG. 5 U.S. Patent May 16, 2000 Sheet 3 of 7 6,063,381

OH OCH

CH-NH-R

STRUCTURAL FORMULA CAPSACINOID R"-CO-(CH2)-CH=CH-CH-(CH) CAPSAICN R"-CO-(CH)-CH-(CH) DIHYDROCAPSACIN R"-CO-(CH)-CH-(CH) NORDIHYDROCAPSAICIN R"-CO-(CH)-CH-(CH) HOMODIHYDROCAPSAICN R"-CO-(CH)-CH=CH-CH-(CH) HOMOCAPSACIN R"-CO-(CH)-CH NONANOIC ACID WANILLYLAMIDE R"-CO-(CH2)CH DECANOIC ACO WANYAMIDE

CAPSAICINOIDS FIG. 6

O H

PPERIDINE (CH)NH

F.G. 7 U.S. Patent May 16, 2000 Sheet 4 of 7 6,063,381

Nen-S1 ) PPERINE O

*N-4N-4N1 N PIPERYLINE O --~~~ O) PIPERETTINE

R N-O PPEROLEIN A R" N---~~-O PIPEROLEIN B

( ) PIPERANINE N

rs-N-N-S O

O where R = ( O

PUNGENT ALKALOID PRINCIPALS OF PEPPER FIG. 8 U.S. Patent May 16, 2000 Sheet 5 of 7 6,063,381

OH N OCH

1.

CHCH C.C 2

EUGENOL CH2O2

FIG 9

(HCH-C-CH -CHSCH OH () OCH OCH CURCUMN C2 1 H2006

FIG. 10 U.S. Patent May 16, 2000 Sheet 6 of 7 6,063,381

(CH) CH: O (CH),CH O V 3

OH +HO

OCH OCH OH OH Gingerol Shogaol C17H24O3 (where n = 4,6, or 8)

O (CH),CH O

+CH3OH +CH(CH),CHO

OCH OCH OH OH Paradol Zingerone C11H1403

GNGEROLS

FIG 11 U.S. Patent May 16, 2000 Sheet 7 of 7 6,063,381

7 R as CH O CHOC

RES INIFERATOXIN

FG 2

TINYATOXIN

FIG. 13 6,063,381 1 2 THERAPEUTIC USES OF PUNGENT A young woman who develops bald patches on her Scalp BOTANCALS AND THEIR RELATED due to ringworm may feel that she has a Serious illness. It is COMPOUNDS also likely that she may feel the same about a ringworm infection of the fingernails, where the nails assume a This application is a 371 of PCT/US93/4763 filed May horrible, unsightly appearance as a result of thickening, 19, 1993. brittleneSS and discoloration typical of the disease. Add to this a year and a half of Systemic treatment to See results, and TECHNICAL FIELD She may feel that she indeed has a very Serious illness. The invention relates to a new class of general antiinfec Do people who are unemployed, low income, or without tive compounds obtainable from plant Species of the pepper, medical coverage consider an illness, that in addition to and ginger families, and chemically related Species that are causing discomfort, can cost them Several hundred dollars a also useful in the treatment of tissue injury, and skin year in treatments, and Still not be cured? Do ranchers think disorders. of ringworm as a Serious disease, when the feed lots, who are paying high prices for livestock, refuse their herd because of BACKGROUND ART 15 ringworm'? I think the answer is a resounding “yes.” There is a wide array of microorganisms that are patho Antibiotic drugs. Such as penicillin, tetracycline, and Sulfa genic to man, and other organisms. Pathogenic bacteria, ect., though often effective in the treatment of bacterial Viruses, rickettsia, and fungi may cause disease in their host infections, are useleSS against infections caused by viruses, organism whether plant, animal, or man. rickettsia, and fungi. Fungal disorders, for example require Fungal diseases of man and animals, often referred to as treatment with a separate group of antimicrobial drugs, mycoses, may be classified into two broad categories. Deep known as antifungals, or antimycotics. tissue, or Systemic mycoses involves the wide dissemination Antimycotic drugs (FIGS. 14–16) were first introduced in of pathogenic fungi growing in internal organs, and tissue, the 1950's with nystatin (1954), amphotericin B (1958), and and Superficial mycoses, which generally represent different griseofullyin (1959). These drugs were originally adminis types of pathogenic fungi than those that infect the Skin, hair, 25 tered systemically. Tolnaftate (FIG. 17) was introduced in nails and mucosa. 1965 as the first effective topical antifungal treatment. Since Deep tissue mycose S including aspergillosis, the 1970's, a number of “azole' derivative antifungals such actinomycosis, blastomycosis, coccidioidomycosis, as clotimazole (FIG. 20), miconazole (FIG. 21), econazole cryptococcosis, histoplasmosis, no cardioS is, (FIG.22), ketoconazole, and others have made their appear paracoccidioidomycosis, entomophthoromycosis and occa ance as antimycotics for both Systemic, and topical admin Sionally candida, may infect the lungs, brain, bones, Spinal istration. The more current trend has been toward the fluid, liver, heart, kidneys, and other internal organs, as well developement of a “triazole” (FIG. 23) class of antifungals, as the skin. Depending on Severity, deep tissue mycoses may including such derivatives as fluconazole (FIG. 24), tercona cause illness that ranges from asymptomatic to life threat zole (FIG. 25), and itraconazole ect. ening. 35 Prior art treatments for Superficial mycoses, in addition to Superficial mycoses, also called dermatophytosis, being expensive, require repeated application before describe disorderS Such as ringworm, athlete's foot, favus improvement can be seen in the patient. Currently available and candida, which infect the skin, hair, nails and mucosal over the counter treatments, containing clotrimazole, linings. There are perhaps three dozen or So known Species miconazole, tolnaftate, or undecylenic acid, recommend up of pathogenic fungi, and yeasts responsible for causing these 40 to Sixty applications of the product in order to provide full diseases. benefit. More treatments are often required. The National Health Survey of 1971–1974 projected from Regardless of economic impact, even wealthy its Sampling that about one out of every twelve people in the individuals, with the best health care available Suffer with all United States had some form of dermatophytosis, with men 45 the others when it comes to the discomfort, and bother of being four times more likely than women to contract infec repeated application of medication that is slow acting, and tions. often ineffective at producing cure or relief of Symptoms. Surveys of other nations reveal a much higher incidence Even prescription topical antifungals, administered by a of Superficial mycotic diseases, among the poor, and under dermatologist, may require as many as two hundred appli developed countries of Africa, Asia, South America, and 50 cations over a period of three months to cure Some cases of those areas of the World having tropical climates. athlete's foot alone. Nail infections may require eighteen Tinea is another term used to describe ringworm. It is months of multiple, daily treatment to provide cure. In usually followed by another term which describes the par addition to being very expensive and time consuming, ticular location of the infection. Hence, athletes foot is often applying the medicine repeatedly each day is botherSome. referred to as "tinea pedis”. Scalp ringworm is also known 55 Coupled with the discomfort of the fungal disorder, the as “tinea capitis', body ringworm as “tinea corporis', jock expense, and inconvenience associated with the treatment itch as “tinea cruris' etc. Though not considered to be life adds further to the misery of the condition. threatening, as Some deep tissues mycoses can be, Superfi The current cost of treating ringworm and other Superfi cial mycoses assuredly take a fair toll of man and animals in cial mycoseS eXcludes the economically disadvantaged, who misery, inconvenience, and expense. 60 Suffer most from the condition, from receiving treatment. Though not classified as a Serious illness by the medical Poor Sanitation, a lower Standard of general health, along profession, this does not necessarily reflect the view point of with the fact that it is rarely treated, adds to the greater those Sufferers of Superficial fungal infections. On a personal prevalence of ringworm, and other Superficial mycoses level, an athlete whose performance on the playing field is among lower income individuals. To a low income family in diminished because of painful cuts on the feet due to an 65 the United States, an extra five dollars a week expense to buy athlete's foot infection, may consider it to be a Serious the cheaper topical Over the counter fungal treatments can illness. cause real hardship on the household budget. For the dis 6,063,381 3 4 advantaged of many developing countries, five dollars a of liver and kidney damage, and can also result in blood week looks more like a good wage for a healthy working disorders. It interacts negatively with many cardiac man Supporting a family, than what one can afford to pay to medications, and diuretics, as well as other antibiotics. treat a skin condition that takes weeks to cure, if it can be Griseofullyin (FIG. 16), usually taken orally, for fungal cured at all. For these reasons, Superficial mycoses among infections of the skin, hair, and nails, has a risk of liver the poor usually go untreated, being prohibitive because of damage. Reduced bone marrow function, with lowered the cost of treatment. white cell levels is another possible adverse effect of treat In this respect, the current array of prior art antifungal ment. Drug interactions with anticoagulants, and barbitu treatments have failed to Significantly heal Superficial rates reduce effectiveness, and the risk to pregnancy often mycoses throughout the World, being inaccessible to most of forbids treatment. the world because of cost. In addition to the misfortune of Ketoconazole, taken orally for Systemic fungal infections, not having viable treatment for tens of millions of Sufferers also carries the risk of liver damage as a result of treatment. of fungal infection, no markets are created, and no products The effectiveness of ketoconazole is diminished by interac Sold, to the advantage of no one. Prior art antifungal treat tion with various antacids, and other gastric medications. ments keep the price of treatment high, the market Volume 15 Ketoconazole increases the potency of other drugs, and is Small, and undiverse, and only bring marginal relief to a reduced in potency by Some antibiotics. relative few of the many suffers. Miconazole (FIG. 21), taken by injection for fungal The bad economics of currently available topical antifun infection of the lungs, brain, kidney, and lymph nodes, can gals prohibits their use in the livestock industry, as well. The alter blood chemistry resulting in anemia. Miconazole also cost of the medicine, coupled with the labor required for interacts negatively with medications for diabetes, epilepsy repeated application to livestock, forbids the creation of a and anticoagulants. The effectiveness of amphotericin B is Significant market for these medicines within the industry. reduced by miconazole. AS Stated earlier, livestock infected with ringworm are Nystatin (FIG. 15), taken orally for candida disorders, is refused by feed lots. The rancher holding them back, in turn, of little use in the treatment of Systemic fungal infections. raises his prices to cover this liability; effecting all proces 25 Though having far fewer adverse side effects than the other Sors and consumers of meat products. antifungal drugs, it is ineffective against most fungal infec Ringworm, being highly contagious, can spread through a tions except candida, and aspergillus, making it of limited herd within a few short weeks, not allowing enough time for uSage. treatment and recovery in the weeks prior to going to Treatment with these Systemic antifungals often produces market, even if they are treated. With the current way of many other very unpleasant Side effects, in addition to the topical antifungals, treating food animals for ringworm is an adverse effects upon blood composition, internal organs and absurd notion. The cost involved in applying a medicine, other medications being taken by the patient. Taken perhaps fifty times, to a single head of livestock could never internally, amphotericin B, griseofullyin, ketoconazole, be justified. For this reason, treatment is withheld, to the 35 miconazole and nyStatin, may cause nausea, vomiting, disadvantage of both the rancher and the animal, which in diarrhea, dizziness, headache, fever and other disorders addition to Suffering discomfort, spreads the disease to other during the coarse of treatment. These Symptoms, though animals, perpetuating the cycle further. In addition to money unpleasant enough for the patient, can also lead to more lost, no viable Solution is offered by pharmaceutical manu Serious complications, further advancing the ill health of the facturers which would otherwise enjoy a new, very large 40 patient. Beside these known adverse effects, others yet potential market. unknown, will be discovered with further research. The full Whether or not one feels the economic impact of Super effect of internal treatment with antibiotics on the body is a ficial mycoses, all Suffers experience the inconvenience of very complex matter, and warranting much caution. having to make repeated application of currently available Topical treatment of Superficial mycoses is much Safer prior art topicals. The necessity of making repeated appli 45 than internal treatments. The prior art, however, has failed to cations is an indication of weak drug action, and that is produce topical antifungal medications effective enough to another great flaw of prior art antifungal treatments. deal with more Serious infections. This necessitates the use Systemic antifungal drugs are also used to treat Superficial of Systemic treatments, which are more dangerous, costly, mycoses, in addition to the deep tissue diseases. Drugs like time consuming, and associated with many other unpleasant amphotericin B, clotrimazole, enconazole, griseofluvin, 50 illnesses to treat even Superficial mycoses. ketoconazole, miconazole, and nyStatin, are administered The adverse effects of prior art Systemic antifungal treat internally, usually orally, or by injection. Like the topical ments is a more Serious complication of treatment for deep antifungals described earlier, most of the Systemics treat tissue mycoses than Superficial mycoses. Patients Suffering ments require multiple doses in order to be effective. SyS from deep tissue disorders, Such as cryptococcosis, temic treatments are the most costly of all, requiring the 55 histoplasmosis, blastomycosis, coccidioidomycosis, Supervision of a physician. They are most dangerous to the paracoccidioidomycoses, and others, are generally in a much patient, with undesirable Side effects that can further endan poorer State of health than patients being treated for der ger the health of the patient. The risk of damage to internal matophytosis. For this reason, the adverse effects of SyS organs, and adverse reactions to other medications, are temic treatment have greater impact on the overall health of factors that must be carefully weighed by physicians admin 60 patients being treated for deep tissue mycoses. This is of istering Systemic antifungals. With this, other leSS Severe, particular significance in the treatment of immunocompri yet unpleasant Side effects, include nausea, vomiting, mised patients. headache, dizziness, fever, diarrhea, and many other adverse Deep tissue mycoses find their greatest opportunity in effects that contribute to the misery and ill health of the immunocomprimised patients. These include cancer, organ patient. 65 transplant patients, and others on immunosuppressant Amphotericin B (FIG. 14), given by injection in the medication, and particularly with patients Suffering from treatment of Systemic fungal infection, carries with it the risk immune disorderS Such as acquired immune deficiency 6,063,381 S 6 syndrome, otherwise known as AIDS. These patients, who making repeated applications with meager results adds fur are very ill indeed, are highly Susceptible to infection from ther to the misery and discomfort of the disease. Even mild these diseases, as their natural defenses against the patho to moderate cases of tinea can easily require more than Sixty genic microbes is greatly reduced. applications of these products before the condition improves. The weak therapeutic action of these prior art, The adverse effects of treatment with currently available over the counter treatments is often insufficient to produce prior art Systemic antifungals, are devastating to immuno adequate results, and must be treated by a physician, using comprimised patients, to the point of being themselves life prescription topical, and Systemic antifungals taken inter threatening to the patient- To those patients in greatest need nally. of treatment for deep tissue mycoses, the medication is most Prescription treatment with antifungal medications is the dangerous to administer. most expensive of all treatments. Beside the cost of having With the Steady rise in treatment with immunosuppreSSant an attending dermatologist, the medications themselves are drugs, and the much more dramatic rise in the number of more expensive than the over the counter varieties. This type cancer, and AIDS cases reported, and anticipated for the of treatment, being the best the prior art has to offer, Still may future, the demand for Safe, effective, and low cost treat 15 require Several months of multiple daily doses of the anti ments for both deep tissue, and Superficial mycoses, is more fungal medication to cure Some kinds of ringworm. Treat urgent than ever. The prior art has largely failed to meet this ment for athlete's foot may require up to three months of criteria as a result of high cost, low ineffectiveness, and the multiple daily doses of the medicine before the condition high toxicity of their antifungal medications. can be cured. Ringworm infections of the toe nails can take The focus of the prior art upon the development of azole up to eighteen months to heal. So adding the expense of derivatives, is perhaps largely responsible for keeping the Visits to a dermatologist, time lost from work or leisure, the cost high, and the effectiveness of antifungal treatments. So time and inconvenience of applying the medicine, the cost of low. The newer generation triazole (FIG. 23) derivatives, the medicine, and the ongoing discomfort of the disorder, all including fluconazole (FIG. 24), terconazole (FIG. 25), have an economic impact that is quite considerable, in itraconazole, and others, cost many millions of dollars to 25 addition to the discomfort of both the disease and the side develop, and apparently are not that much more effective effects of treatment. than the prior generation imidiazole (FIG. 19) derivatives, Systemic treatment with antifungal drugs, Such as ampho and certainly are doing nothing to make treatment more tericin B, clotrimazole, griseofullyin, ketoconazole, affordable, or convenient. Beside this, they have much miconazole, nyStatin and others, in addition to being expen narrower application than the imidiazoles, and are consid Sive and time consuming, have many bad Side effects that ered auxiliary, and not mainline treatments. can further endanger the health of the patient. These drugs, It seems doubtful at this point, that either of the azole taken internally, carry the risk of damage to liver and other groups will produce derivatives of Significantly greater internal organs, and adverse effects upon blood chemistry. effectiveness in the treatment of fungal disorders, than what Patients receiving Such treatments must be monitored for is currently available with prior art treatments. 35 changes in blood and organ function, as a Safeguard against Serious damage that can result from treatment. Prior art DISCLOSURE OF INVENTION Systemic antifungals also interact adversely with a large Accordingly, Several objects and advantages of my inven number of other medications, another area that requires tion include a method for treating fungal infections, other close attention by the attending physician. Beside this, other wise known as mycoses, in which cure is complete with as 40 adverse effects include nausea, vomiting, diarrhea, fever, few as one Single application of my medication. Rather than headache, and other unpleasant Symptoms that accompany making Scores of applications, usually required by prior art the discomfort of the disease. antifungal medications, my medication usually requires just With my medication, a Single topical application is all that one treatment to affect full cure. The effectiveness of my is usually required to completely cure most types of der medication is nothing short of astounding, and is truly 45 matophytosis. Even recalcitrant cases of athlete's foot are generations ahead of currently available antifungals. healed in as few as half a dozen doses of my medicine. Body I have discovered that plants of the pepper family, and and Scalp ringworm lesions disappear, usually within the plant Species with Similar chemistry contain active agents first day after treatment, and require no follow up dosages. that provide complete cure when applied to areas infected With my treatment, Systemic treatment of Superficial with mycotic diseases. These agents may be administered in 50 mycoses is a thing of the past. Instead of making Several the wide range of commonly used drug vehicles and carriers, Visits to a dermatologist, and taking repeated doses of drugs with results that are absolutely unprecedented when com that are expensive, dangerous, Slow acting, and create other pared to prior art treatments. illnesses as a Side effect, one need only make a Single, or few Tinea, in its various forms, otherwise known as athlete's topical applications of my treatment for complete cure. In foot, jock itch, favus, and ringworm, along with other types 55 addition to effectiveness that is truly astounding, these of dermatomycoses Such as candida, may be completely pepper compounds are completely Safe, being derived from healed after a single treatment with my medication. Topical commonly consumed food. Topical applications of my treat treatment of these diseases, in the form of an infusion, bath, ment generally require leSS active agents, than what might be douche, Shampoo, lotion, drops, tincture, plaster, powder, commonly consumed in a meal that includes any of the aeroSol, or other carriers, all provide Outstanding results. 60 pepper Species. In addition to that, there is no long term, Currently available prior art over the counter topical chronic exposure to the medicine, as is required with prior treatments for ringworm containing clotrimaZole, art topical antifungals, that have only a long term therapeutic miconazole, tolnaftate, or undecylenic acid, usually require effect, if any at all Several weeks of daily multiple treatments before improve The prophylactic action of pepper constituents continues ment can be observed in the condition. In addition to the 65 to protect damaged tissue from reinfection, by maintaining considerable expense of having to buy Several containers of its antifungal action for days after treatment, in addition to the medication, the time, and inconvenience involved in it's direct, and immediate fungicidal action. This further aids 6,063,381 7 8 rapid healing, by allowing diseased tissue to regenerate, reported. The sensation lasts for about the first five minutes rather than concentrate energy on combating disease after application, and is not uncomfortable. The plaster is left Pepper also appears to act as an immunostimulant, by on the skin for about one hour, then rinsed off with water. precipitating leukocytes, and other mononuclear cells, along Afterward, the lesions appear redder than they did prior to with a variety of antifungal compounds from the blood, and application of plaster. After Six hours, the lesions appear to Surrounding tissue, to the area of infection. Though done be whiter, with the coloration being more similar to the skin primarily through inducing inflamation, pain and discomfort tone of the healthy skin, than prior to treatment. At twenty are not required in order to receive the full therapeutic hours, all three lesions appear healed, as it requires very benefit. Pepper compounds are also believed to aid in the close examination to reveal the site of the prior lesion. The delivery of these antifungal immune resposes of the body, characteristic patch of lighter colored skin that normally and increase their potency in addition to its own antifungal accompany lesions that have healed by themselves is not actions. present. Healing, and excellerated regeneration of diseased tissue The other dozen or So lesions found on the man are is another important therapeutic action opepper compounds. examined, and found to be Substantially unchanged from While whole, healthy skin is the best protection against 15 their last examination the day before. Another examination infection from dermatophytes, pepper's ability to regenerate on the third day yields the same results, with no sign of the diseased skin is equally astounding to its antifungal action. three lesions that were treated and healed, and little change The healing, and tissue regeneration actions are further in the untreated lesions. demonstrated in the treatment of other forms of dermatitis Also, on the third day after initial treatment, the other Such as dandruff, Seborrhea, eczema, warts, corns ect. These dozen ringworm lesions on the arms and trunk of the man, chronic skin disorders, which are not currently recognized as are treated with the same capsicum plaster, with identical being of microbial origin, also respond with complete cure results. All twelve lesions, regardless of location, are healed when treated with pepper compounds, often in the Same way with the exact location of the prior lesion being difficult to as Superficial mycoses. These diseases, for which the prior determine because of the advanced degree of healing of the art believes incurable, may also be completely cured with 25 skin in that area. my invention, often as easily as Superficial mycoseS Such as One week later, the woman is treated with the same ringworm are cured. capsicum plaster as the man, with Similar results. At three In a Study of eight patients, all infected with various forms days after treatment, all six lesions are completely healed in of dermatophytosis, complete cure is obtained after one Similar fashion to those on the man. topical application of the medication of the current invention One week after the woman is treated, the infant girl is also in five of the eight cases Studied. The other three cases treated with the capsicum plaster in the same manner as both Studied are cured within half a dozen treatments or less. her parents, and is healed in the Same way, with the None of the patients are taking any kind of medication for disappearance of all lesions within about one day. It is also ringworm, or for any other disorder, and no special Steril 35 interesting to note that the infant girl displays no sign of ization measures of clothing, furniture or bedding are taken, discomfort when the medication is applied, and does not cry, beyond otherwise good personal hygiene. or even appear to take notice of the treatment. In the first portion of the study, a family of three, all Regular examinations of these three patients, over a afflicted with ringworm, are completely healed after a single period of Several months, fails to identify the reappearance topical treatment with a pepper compound. 40 of one single ringworm lesion in any one of them. Each The infant has developed approximately six ringworm lesion of the patient is completely healed of ringworm, after lesions about the back of the Scalp, and back, and right Side just one single topical treatment with my medicine. 100% of the neck. The first few lesions were noticed a month cure of twenty-eight lesions on three Subjects is accom before. plished after a single dose of my medication, without 45 reappearance of a single lesion. This is done without Ster The mother of the infant has about six ringworm lesions ilization measures, and aside from any other medication on the right arm, most on the outside bicep. The appearance whatever. of the lesions was first noticed approximately three months In another portion of the Study, a woman in her middle before. thirties is healed of athlete's foot within hours of a single The father of the infant has approximately eight ringworm 50 treatment of my medication. The woman works a full time lesions on the left arm, most on the outside bicep. The right job, in which she is required to be on her feet most of the arm has four lesions, also on the outside of the bicep. Four time. Approximately one week after having purchased a other lesions appear on the shoulders, and lower back. The more comfortable pair of shoes for work, the woman devel man first noticed lesions of this type approximately eight opS an inflammatory variety of athlete's foot. The primary years earlier. 55 Symptoms are intense itching on top of the toes and foot, felt On all three Subjects, the ringworm lesions have the same mostly in bed at night, along with a bad, musty foot odor. general appearance. The lesions are ring shaped, with The itching is now interfering with sleep each night. Slightly raised outer borders that are Sometimes crusty. The The Woman Soaks her feet in a bath, prepared from lesions are red, with a Smooth, and Sometimes Scaly interior. infusion of capsicum, for fifteen minutes. The woman A clear, Sticky fluid Sometimes covers the lesion. The 60 reports a warm, tingling Sensation that lasts about ten average diameter of the ring is about 15 mm (0.6"), with minutes. This treatment is administered at 8:00 p.m. The Some as large as 20 mm (0.8"). The lesions appear, and woman retires for the evening at 10:00, and does not remain for Several weeks, Sometimes disappearing, leaving experience any of the itching characteristics of the previous lighter colored skin at the Site of the prior lesion. evenings. For three weeks the woman reports not a single The man is first to be treated with a preparation of 65 recurrence of the itching on the feet. She continues to wear capsicum, wherein a plaster is applied to three lesions on the the same footwear as before, and does not take any kind of left bicep. A very Slight, momentary tingling Sensation is Sanitary, or other precautions to avoid reinfection. 6,063,381 9 10 After about three weeks, the woman begins to notice a At Six weeks, the girl's feet have returned to the pretreat gradual return of the itching on top of the feet that she had ment condition. The skin on the Sole of the feet is thickened experienced before. Within another week or two, the itching and calloused. The Skin on the Soles and between the toes is is as intense as ever, and is again interfering with sleep. peeling and has a ragged appearance. Cuts appear periodi The Woman's feet are treated with a lotion of capsicum, cally at the base of the toes, on the heel and at the ball of the using raw aloe Vera gel as the lotion carrier. Lotion is applied foot. The dry athlete's foot is back in full force. to the feet, and rinsed off with water at the end of half an The reinfection of the girl's feet is not presumed to be the hour. The treatment is administered at 8:00 in the evening, result of recontamination, as no Sanitary measures have been before the woman retires for the evening at 10:00. The taken to prevent reinfection, and the girl continues to wear woman reports no itching that evening, nor afterwards, for the same footwear as before the treatment. AS these patho many months. She disposes of the comfortable shoes, she genic fungi find opportunity in damaged skin tissue Such as had bought for work, and has no further recurrence of that described, the Skin must be healed to prevent reinfec athlete's foot symptoms. The woman is completely healed of tion. The best protection from reinfection being healthy, athlete's foot after just one Single treatment with my medi undamaged skin. cation 15 This is one reason why the prior art has such difficulty The sixth case involves a five year old girl, who is curing this type of ringworm. The therapeutic action of prior completely healed of a recalcitrant case of dry athlete's foot. art antifungals is So weak and Slow acting, it arrests the Prior to treatment, the child's feet are peeling severely in the resident fungi only enough to allow the healing process of areas between the toes, and on the entire Sole of the foot. the skin a slight advantage. Loose skin, in pieces as large as about 4 mm (/s") Square are This is why a case of dry athlete's foot can easily require hanging around the lower edge of the ball of the foot. The twelve weeks of daily, multiple treatments with prior art entire Sole of the foot is calloused, and has a wrinkled medications to provide cure, which is usually only tempo appearance. Deep cuts occur periodically on the ball of the rary. foot and around the base of the toes, particularly the great The dramatic improvement of the girl's feet between the and small toes. The child often complains that her feet hurt 25 last treatment on day five, and the examination on day from the cuts, but otherwise describes no other discomfort or fourteen, Suggests accelerated healing over any activity of Symptoms. The girl has had these Symptoms for about three fungi during this interval. It also Suggests a prophylactic years, since age two years. action by my medicine that may provide protection for At age two years, the girl develops a particular affection perhaps Seven days or more. for a certain pair of Shoes, and wears them constantly, Recalling complete cure after a Single dose of my medi refusing to wear other Shoes. Weeks later, the girl develops cine in the first five cases leads to the conclusion that the a very offensive foot odor. Afterward, her feet gradually fungi are eradicated on initial contact with my medication. develop the Symptoms described above, becoming chronic What distinguishes them from this sixth case is the relatively over the next three years. minor degree of skin damage they Suffered, in relation to the An ethanol tincture of capsicum is applied to the girl's 35 present case. This further Supports the notion of the prophy feet. The girl complains about a Stinging Sensation in the cuts lactic action of my medicine, as Seven days or leSS is ample around her great and Small toes. The girl cries for about five time to heal the minor skin damage caused by the body or ten minutes, then reports that the Sting is gone. The girl ringworm lesions. is also treated with the same capsicum tincture on days three In an attempt to determine the maximum duration of and five, after the initial treatment. The investigator per 40 capsicum's prophylactic effect, and to compare it's perfor forms these Second and third treatments because he is not mance with that of Synthetic capsaicin, the Synthetic version Sure if the first treatment is Sufficient to penetrate Such thick of the primary irritant found within natural capsicum, the callouses on the Soles of the feet, having never treated Such girl's feet are again treated. badly damaged skin with this particular treatment. On day 45 Prior to treatment, the girl's feet have again returned to three, just prior to the Second treatment, the feet are exam their original, recalcitrant condition that was noted prior to ined and appear Slightly improved. The cuts around the toes the first treatment. The girl's feet are peeling Severely on the have formed Scabs, and no discomfort is reported by the girl bottom and sides of the toes, and on the ball of the foot. The after application of the tincture. skin in this area is thickened, and calloused, with deep On day five, the feet are again examined before receiving 50 cracks. Sometimes resulting in painful cuts. The skin has a the third treatment, and again appear to be further improved. Wrinkled, dry, and ragged appearance, with intermittent red The cuts are continuing to Scab over and heal, and the girl blotches, occupying about half the total Surface area. Small reports no discomfort from the medicine. This general trend cuts appear periodically around the base of the great and continues for the next Several days, yet treatment is not again Small toes, which often cause pain, especially when walking. administered. 55 A lotion of capsicum, consisting of 4 cm (4 teaspoon) of By the fourteenth day, the feet are nearly, completely ground red pepper mixed with 48 cm (12 teaspoons) of raw, healed. There are no cuts or Scabbed cuts, and no pealing or aloe Vera gel, is applied to the child’s left foot. The girl loose skin. The callouses are nearly, completely reduced, describes a tickling Sensation as lotion is being applied, and and the skin has a healthy color and texture, and no longer is laughing. About three minutes afterward, the girl begins has a wrinkled, ragged appearance. It is not possible to 60 crying, Saying that the cuts on her toes are burning. She determine that the girl has ever had athlete's foot, as her feet continues to cry for about ten more minutes, and afterward are healthy and normal. The child is excited that her feet are indicates that the burning has gone. "like new again”. At the same time, an ointment of capsaicin, consisting of On day twenty one, the girl's feet are again examined. The about 0.03 percent capsaicin (from oleoresin) in turpentine skin around the bottom and Sides of the toes has Succumbed 65 oil is applied to the right foot. There are no cuts on the right to reinfection, as the skin is again peeling, though not as foot at this time, and the girl reports no discomfort from the severely as before the first treatment. medication. 6,063,381 11 12 The medications described above are applied once each feet have peeling skin between the toes, and thickened Soles week for the next two weeks, and observed regularly over with cuts on the underside of the heal. the next three weeks, with little notable change the first few The Woman's feet are Soaked in a capsicum tea for fifteen days. minutes at a time, once a day, for five days. On the Second On day three, the feet are examined, and appear to be day, the Woman complains that her feet are very dry, and that showing Signs of improvement. The peeling does not seem one of the cuts on her heel is making walking difficult as Severe, and the red blotches look as if they are fading. The because of the pain. By the fourth day, she indicates the cuts on the left foot are healing, and show no Sensitivity cessation of those Symptoms. After eight weeks, the feet are when firmly Squeezed with the fingers. examined and the skin appears healthy, with no sign of On day four, the feet are again examined, and look much better than the previous day. The peeling is again reduced, peeling or thickening of the skin. The woman indicates that and the red blotches have completely disappeared. The right after the fourth day of treatment, she did notice the reim foot looks slightly better than the left, Suggesting the thera mergence of Symptoms at the time of the eight week peutic effectiveness of the capsaicin ointment. The cuts on examination, and felt cured since. the left foot show further progreSS in healing. In the eighth case Study, a boy of thirteen is completely Upon examination on the Sixth day after treatment, the 15 healed of a Severe fungal infection of the face, and neck after child's feet look very much improved. The loose skin has for just two weeks of treatment with my medication. the most part worn away, being replaced by healthy skin that Over a period of nearly five months, the boy has been shows no Scaling, or discolor. The cuts on the left foot have Suffering from what is described as an angry, bright red rash disappeared, and both feet Show reduced Skin thickness, and about the face, from beneath the eyes, down to the bottom, only faint reminder of cracks that are mostly healed. Both and sides of the neck. The boy's father describes the disorder feet look about the same, Suggesting equivalent therapeutic as “literally eating his Son's face away.' The boy, and his performance between capsicum and capsaicin preparation. family are for Some time quite distressed, as treatment The examination of day Seven reveals little change in the administered by a general practitioner, and two dermatolo condition of the feet from day Six except that they appeared gists over more than four months, fails to heal the condition. Slightly better on day Six. Small cuts along the base of the 25 The expense of treatment is nearing S1,000 out of pocket. Small toe on the right foot are not causing discomfort, as the The Visits to the physician, have cost the parents more than medicine is applied for the Second time. twenty hours away from work, and the boy must be excused Subsequent examinations of the next Seven days reveal a from school the same amount of time. The boy is of coarse Similar pattern to that of the prior week. Little change is doubly distressed, as in addition to the discomfort of the observed the first few days after treatment, with very notice disease, he must bear the humiliation of wearing this rash on able improvement being observed between the fourth and his face that is more horrible in appearance than a Severe Sixth day after treatment. This pattern is also established on case of acne days eleven through thirteen, yet without Substantial Askin Scraping sent to a laboratory reveals the presents of advance in the Stage of healing beyond that observed on the 35 fungal hyphae, not of the ringworm variety. Sixth day. The boy is given griseofullyin orally, but must discontinue It is evident that a single weekly application of my treatment after one week as a result of Severe nausea. The medicine produces Substantial improvement in recalcitrant boy is then given tolnaftate topically, and has shown no cases of athletes foot. Though this improvement is Significant improvement in the condition over a period of Several weekS. Sustained, it is not usually Sufficient to induce full cure, at 40 least within a three week span. Nor does the degree of The boy is then given lotion prepared with capsicum, and improvement compare to the results of the prior Study, in instructed to apply the medication once every other day after which the medication was applied three times within the first bathing until Symptoms disappear. All other treatments are week. Depending upon the case, two to four applications per also discontinued. week should be Sufficient to provide complete, and Sustained 45 The boy's father administers the treatment as prescribed, cure for recalcitrant cases of athlete's foot. and is Seeing noticeable improvement by the third day. The To demonstrate a complete cure for recalcitrant athlete's condition continues to improve over this period, and by the foot, and to compare the performance of a red pepper tenth day the skin is almost completely healed, with barely (capsicum frutescens) extract with that of one made from a remanent of the prior disease remaining. To say the least, black pepper (piper nigrum), the girl's feet are again treated. 50 the boy's family and friends are amazed, and astounded at The girl's right foot is treated with an ethanol tincture of the rapidity of cure of this horribly unsightly condition, that capsicum made from ground red pepper, while the left foot had persisted for so many months before without is at the same time treated with a similar tincture prepared improvement, often referring to the medicine as "a literal instead with an equal amount of black pepper. The girl's feet Godsend are treated eleven times, once every other day, over a period 55 The treatment is discontinued after only two weeks, and of three weeks. The pattern of previous tests is also observed the boy is healed without relapse after many weeks of in this trial, with both the red, and black pepper tinctures observation even until the time of this writing. performing with equal effectiveness. AS in the other tests AS can be seen from these Several examples, the effec with the girl, Significant improvement is observed between tiveness of my topical antifungal medication is truly the fourth, and Sixth day after treatment, with dramatic 60 astounding. Single application cure of dermatophytosis, improvement being noted at two weeks. At three weeks, being unheard of among prior art treatments, is the usual very little Sign of the prior disorder remains, and the result with the medication of my invention. No longer is it condition does not return after weeks of observation. The necessary for Suffers to endure prescription therapies, which girl is healed of recalcitrant athlete's foot, with just eleven are slow acting, time consuming, expensive and potentially topical treatments over a period of less than three weeks. 65 dangerous with many other unpleasant adverse effects. With In the Seventh case Study, a woman of Sixty is cured of a my medication, embodied in the form of a topical, over the dry variety of athlete's foot. Prior to treatment, the woman's counter treatment, even recalcitrant cases of athlete's foot 6,063,381 13 14 can be cured with a few periodic applications of my medi ringworm, and other Superficial mycoses within the live cine. Instead of months of antibiotic therapy, administered Stock industry. The current economics of treating food by a dermatologist, the Sufferer can cure the condition animals for ringworm, with available prior art treatments, themselves, with a safe, inexpensive and astonishingly forbids the practice. The economic impact of ringworm power medicine, Such as mine. within the livestock industry is felt first by the rancher, whose head are refused by the feed lot because of it. Being The Savings in health care cost that my invention provides highly contagious, and finding particular opportunity under for the treatment of dermatophytosis alone is astronomical. certain weather conditions, an outbreak of ringworm can Prior art treatments, that cost many hundreds of dollars and infest a herd within a very short amount of time, and prevent represent considerable loSS of time from work and leisure, them from market. This economic liability is then added to are no longer required. With my medication, these same the cost of the food product, which eventually impacts disorders can be cured for pennies, with only minutes of everyone. Ringworm and other Superficial mycoses are just time required by the sufferer, and without the attention of a another business liability, for which prior art treatments have physician. failed to remedy, much leSS establish a market for. With the very considerable cost savings my medicine With the treatment of the current invention, the combi provides, the Sufferer also gets prompt relief from the 15 nation of unprecedented effectiveness, and lower cost, make Symptoms of dermatophytosis. Instead of waiting days, or it now economically feasible to establish a product for weeks to gain relief from ringworm itch, as is the require treatment of ringworm, candida, and other Superficial ment of prior art topicals, my treatment provides relief in mycoses, within the livestock industry. My medication is just minutes! Instead of enduring weeks, or months of especially appropriate for this application, being itself Systemic antifungal treatment to see improvement in a derived from food compounds, generally recognized as Safe recalcitrant case of athlete's foot, with my treatment, dra (GRAS) by the U.S. Food and Drug Administration. With matic improvement is Seen within hours, to a few days of the my medicine, an outbreak of ringworm among a herd of first treatment. The Savings here, in terms of human dis livestock within the last week before market, need no longer comfort and inconvenience is incalcuable. 25 prevent them from market as before. The amazing healing power of my medicine, coupled with The astonishing effectiveness of my medicine, in com tremendous economic advantage it provides, opens the parison to prior art topical and Systemic antifungals, has doorway for the creation of many new, and very large crucial bearing in the treatment of deep tissue, as well as, markets for topical treatment of Superficial mycoses. Rather Superficial mycoses. The common interchangability of cur than exclude the economically disadvantaged from a viable rently prescribed prior art medications between topical and treatment, as prior art antifungals do because of their high Systemic administration, Suggests the use of my invention cost, and lack of effectiveness, my treatment can be pro for Systemic treatment of deep tissue mycoses as well. AS duced and Sold at a very low price relative to prior art prior art antifungals, Such as amphotericin B, econazole, topicals, and still provide a very large profit margin for griseofullyin, ketoconazole, miconazole, nyStatin, and marketers. My product will greatly expand the market base 35 related drugs are administered as Systemics, as well as for ringworm medicines, by tens of millions of individuals topicals, my treatment shows excellent promise as a Sys Worldwide, and most important, provide effective medical temic antifungal, as well as a topical. care for those in greatest need of it. Severe cases of The active principals found within capsicum, and piper ringworm can be completely cured for less than a penny in Species, and related families provide an important research actual cost of the active agents within my medication. If 40 tool in the Systemic treatment of deep tissue mycoses, Such Such a product is Sold for a dollar, it would open the market as a Spergilliosis, actinomycosis, no cardioSiS, up to many millions of people world wide, and provide a cryptococcosis, histoplasmosis, blastomycosis, tremendous commercial opportunity for drug manufactur coccidioidomycosis, paracoccidioidomycosis, CS. entomophthoromycosis, candidiasis, and others. Pepper In the United States, a topical ringworm treatment, Such 45 extracts may be given by injection into the blood, Spinal as mine, costs less to produce than the current prior art over fluid, or directly into diseased tissue. Analogs of these active the counter brands, yet, is Scores times more effective. If constituents may be developed for oral administration, Sold at competitive prices to prior art brands, the Superior however, Some modification of the molecular structure may effectiveness of my medication will radically outsell the be required to prevent decomposition of the active agents competitor brands. The high effectiveness of my treatment 50 that occur as a result of digestive processes. will also attract the purchase of low income individuals, who With the very rapid increase in the incidence of deep otherwise are not able to afford prior art medications. tissue fungal disorders, and projections Suggesting even Because of the need to purchase Several containers of prior greater increases for the future, the need for more powerful, art over the counter topical treatments to cause even tem Safer treatments is more crucial than ever. Finding oppor porary cure, of a Single case, low income people do not buy 55 tunity in immunocomprimised patients Such as cancer, organ the medication because of the cost, and Simply go untreated. transplant patients, and others on immunosuppreSSant drugs, In addition to adding more misery to their already unfortu and those suffering from AIDS: these diseases are life nate circumstances, it further contributes to the spread of the threatening. Also life threatening to these patients is Sys disease, thereby perpetuating this undesireable cycle. temic antifungal treatment with prior art medicines. Their Prior art topical treatments for dermatophytosis, Such as 60 high toxicity, and multiple adverse Side effects, often have clotrimazole, miconoZale, tolnaftate, and undecylenic acid, devastating impact on the health of these patients, who are are not effective for dealing with the problem. Their weak already Very sick. Complications arising from treatment drug action, coupled with their high prices, preclude their with prior art antifungals can end their life, in addition to use among the economically disadvantaged and have not adding additional misery to their already tragic circum been able to establish a market for them. 65 StanceS. The expense and weak action of prior art antifungals has Even immunocompetent patients can become very ill as also occluded creation of a market for treatment of an adverse effect of Systemic antifungal treatment. Serious 6,063,381 15 16 adverse effects include damage to liver, kidneys, and other While providing considerable Savings to each nation of internal organs. Changes in blood composition often lead to the World, my medication will greatly expand the size of the enemia. LeSS Serious adverse effects, yet ones that are antifungal drug market. The economically disadvantaged capable of causing considerable misery for the patient throughout the world, who are currently excluded from this include nausea, vomiting, diarrhea, dizziness, headache, market because of high cost, and weak performance of the fever and other disorders. These adverse effects are hard prior art over the counter topical treatments, will purchase enough to bear for an otherwise healthy patient being treated for athlete's foot, let alone a patient having just undergone my product because of its dramatic effectiveness. New an organ transplant, or in the advanced Stages of AIDS, or Veterinary uses, not currently existing, will also contribute to cancer a larger consumer market than ever before. Add to this an Pepper, on the other hand, being itself a food compound OverSeas market, aimed at producing a product for devel consumed by man, is good for the body, not harmful as the oping countries, and the total consumer base for these prior art antifungals can be. All of mankind, throughout the products will expand by hundreds of millions of individuals, World has used these plants for food, and from long expe currently excluded from the market by the high cost, and rience of thousands of years, knows them to be Safe and ineffectiveness of prior art treatments. healthful to the body. Pepper compounds, being far less toxic 15 Now, and finally, an antifungal treatment exists that can than prior art antifungals, will not induce further illness in Save our nation alone, billions of dollars each year in the the patient, like prior art treatment, as dosages are usually treatment of dermatophyte infections alone. A drug that will less than the amounts commonly eaten at one time by those greatly expand the size of the market for antifungal who enjoy the fruit, or Spice. treatments, bring rapid cure to tens of millions of Suffers in Solanacea, piperacea, and related Species of plants are our country, and around the World, and provide an important widespread throughout the World, and are grown in Virtually weapon in the war against the more Serious infectious every country of the world. Their active constituents have all diseases that will Save lives as well. been Synthesized, and Some can be obtained very cheaply BRIEF DESCRIPTION OF THE DRAWINGS from existing commercial Sources. Pepper extracts are 25 Versatile, and work very well in all conventional drug FIG. 1 is a molecular diagram of phenol. vehicles and carriers, allowing for the maximum amount of FIGS. 2-13 show molecular diagrams of compounds of product embodiments. the current invention. Today, more than every before, the importance of having medications that are not only Safe, and effective, but cost FIG. 2 is a molecular diagram of ortho-methoxyphenol. effective as well, is becoming critical to the preservation of FIG. 3 is a molecular diagram of vanillyl. our very way of life. The escalating cost of health care in the FIG. 4 is a molecular diagram of 3-methoxy-4- United States is causing real hardship on the middle and hydroxybenzylamine. lower economic classes to the extent that about 1 in 6 FIG. 5 is a molecular diagram of vanillylamide. americans cannot even afford health care insurance. 35 FIG. 6 is a molecular diagram of the capsaicinoids. Health care costs are consuming a greater share of the FIG. 7 is a molecular diagram of piperidine. middle class budget with each new year. Money that would otherwise be spent on better housing, college educations, FIG. 8 is a molecular diagram of the pungent alkaloid early retirement, entertainment, and many consumer goods principals of pepper. must instead be spent to cover the cost of health care. In 40 FIG. 9 is a molecular diagram of eugenol addition to lowering the Standard of living for our citizens, FIG. 10 is a molecular diagram of curcumin. it takes much needed capital away from many key industries FIG. 11 is a molecular diagram of gingerol. that provide employment for our citizens and create tax FIG. 12 is a molecular diagram of resiniferatoxin. revenues that pay the national debt, and Support our gov FIG. 13 is a molecular diagram of tinyatoxin. ernment. 45 Rising health care costs have eXcluding our lower income FIGS. 14-25 show molecular diagram of common prior citizens from adequate medical care, and are the primary art antifungal drugs. contributor to the national debt. They are moving this FIG. 14 is a molecular diagram of amphotericin B. country, and others closer, and closer toward economic ruin, FIG. 15 is a molecular diagram of nyStatin. while excluding increasingly larger Segments of our Society 50 FIG. 16 is a molecular diagram of griseofullyin. from adequate health care. How is a Society benefitted by a System that provides adequate health care at the cost of FIG. 17 is a molecular diagram of tolnaftate. economic ruin? At best, that is merely trading one illness for FIG. 18 is a molecular diagram of ciclopiroX. another, i.e., a physical illness for an economic one. FIG. 19 is a molecular diagram of imidazole. A medication, Such as put forth by the current invention, 55 FIG. 20 is a molecular diagram of clotrimazole. counters this trend of escalating health care costs being FIG. 21 is a molecular diagram of miconazole nitrate. economically, as well as medically therapeutic. It is very Safe, and of unprecedented effectiveness. It provides far FIG. 22 is a molecular diagram of econazole nitrate. more complete, and rapid cure of disease than prior art FIG. 23 is a molecular diagram of triazole. medications, and at a cost of just pennies on the dollar. 60 FIG. 24 is a molecular diagram of fluconazole. The concepts set forth by the invention further serve as a FIG. 25 is a molecular diagram of terconazole. model by which government medicaid, and medicare pro grams would save hundreds of millions of dollars each year BEST MODES FOR CARRYING OUT THE in expenditures. Nationally, the total Savings in GroSS INVENTION National Product for the United States could exceed 20 65 A medicinal preparation of pepper, and its active con billion dollars annually if the treatment for dermatophyte Stituents may be administered in a wide range of conven infections alone were fully implemented. tional drug vehicles and carriers. Capsicum, and black 6,063,381 17 18 pepper are available commercially as oleoresin, in a wide N-Vanillyl-n-nonamide. C7H7NO. range of concentrations, and pungencies, and may be used in (N-(4-hydroxy-3-methoxyphenyl)methyl-n-nonamide). place of the plant product described below. Nonanoic acid Vanillylamide. C7H9NO The various preparations described below are made from Decanoic acid Vanillylamide. CHNO a moderate pungency commercial grade of ground cayenne Other capsaicinoids, not listed here, are identified in pepper (capsicum frutescens), or black pepper (piper research literature as trace elements within capsicum, and nigrum), as an indicator of approximate concentration may be used in medicinal preparations as well, along with within each carrier. Their equivalents may be estimated, and other analagous compounds. prepared from commercially available oleoresin, or from Capsaicinoids may be generally classified as acid amide any of the pungent principals, Some of which are also derivatives of phenol (FIG. 1). The characteristic pungent, available commercially in pure natural, or Synthetic form. irritating Sensory effects of these compounds are typical of The term "pepper', or "pepper compounds are used acid amides, whether derived from phenol, or piperidine Somewhat generically to indicate a "pungent botanical'. (FIG. 7). Other botanicals Such as those of the Zingiberacea family Phenol (FIG. 1), though lacking pungent flavor, is highly including ginger (Zingiber officinale), turmeric (Curcuma 15 corrosive, caustic, and toxic, deriving many of its properties longa), cardamon (Elettaria cardamomum), Melegueta pep from its basic benzene structure. While this gives phenol per (Aframonum melegueta), members of the Euphorbia certain antimicrobial properties, it is generally considered to genus including Euphorbia resinifera, poinsetta (Euphorbia be unsuitable for therapeutic use in man, and animals, due to pulcherrima), clove (Eugenia aromatica), allspice (Pimenta it's high toxicity, and irritating effects on tissue. officinalis) and others having similar constituents may be With the addition of a methoxy goup (OCH) to phenol, prepared in the same way as pepper by following the general methoxyphenol is formed. In the ortho position, we have procedures outlined below in the capsicum pepper illustra ortho-methoxyphenol (FIG. 2), also known as guaiacol, an tion below. Included among this list of botanicals is of extract obtainable from trees of the guaiacum genus. The course the other members of the Solanacea pepper family effect of this methoxy group in part is an increase in including members of the capsicum genus with the annuum, 25 aromacy, and a decrease in toxicity, and caustic properties baccatum, and longum Species. Among the Piperacea family, otherwise existing in phenol, yet without apparent decrease Species of the peperoma, and piper genus which include the in antimicrobial properties. The attachment of hydrocarbon retrofractum, nigrum, and longum Species. Other Species of groups to the ring structure, to form higher analogues plants having Similar chemistry may also be used in place of apparently increases the antimicrobial properties of the above. methoxyphenol, and phenol. It is presumed that the meta, or The performance of each preparation will of course para isomers of methoxyphenol have Similar properties to depend on type, and concentration of botanical, carrier, and the ortho, in like manner to the similarities between the Solvent used in relation to the particular pathogenic organ phenol isomers. ism involved. The chemical properties, and solubility of The addition of the methylene group (CH) in the para many of these botanical compounds, including information 35 position to ortho-methoxyphenol produces vanillyl (FIG.3). on Separation, and quantitation of their constituents are also Like phenol, and methoxyphenol, it is presumed that chang available from Similar Sources in the Scientific literature, and ing the position of the methylene group to form other and may be consulted for more detailed investigations. Vanillyl isomers will produce compounds of Similar, For purposes of research, or the treatment of disease, the although not exact properties to that of Vanillyl. individual compounds responsible for the pungent quality of 40 The Vanillyl Structure on which the capsaicinoids are red peppers, and other capsicums may be obtained directly constructed is also typical of the pungent principals found in from ground red pepper, according to procedures described ginger (Zingiberacea) Species of plants. in the article “Separation and Quantitation of Red Pepper Collectively known as gingerol (FIG. 11): Shogaol, Major Heat Principals by Reverse Phase High-Pressure paradol, Zingerone, gingerol and other analogs, have a Liquid Chromatography” by Patrick Hoffman et. al., in the 45 different Side chain than the capsaicinoids, and lacking an Journal of Agricultural Food Chemistry 1983, Vol. 31, ammonia (NH) group, are neither amines, or amides like pages 1326-1330. Though several related capsaicinoids the capsaicinoids or piperidines. Hydrolysis of gingerols have been identified in trace amounts, the major capsaici yield vanillyl, and a fatty acid side chain, both of which noids (FIG. 6) include: demonstrate like therapeutic properties to the capsaicinoid Capsaicin. CH2, NO 50 hydrolytes. (N-(4-hydroxy-3-methoxyphenyl)methyl8-methyl-6- Also members of the ginger, or Zingiberacea family, nonenamide). turmeric (Curcuma longa L.) contains the compound cur Dihydrocapsaicin. CH NO cumin (FIG. 10), actually a vanillal derivative differing from (N-(4-hydroxy-3-methoxyphenyl)methyl-8- vanillyl by one hydrogen (H) atom having an (CH) methylnonanamide). 55 Substituent, rather than a methylene (CH) in the para Norcapsaicin. C2HNO position. This analog differs further with a side chain unique (N-(4-hydroxy-3-methoxyphenyl)methyl 7-methyl-5- from the others. Cardamon, allspice, clove, black pepper, octenamide). and many others contain eugenol, another Vanillyl analog Nordihydrocapsaicin. C7H7NO. with yet another hydrocarbon Side chain. (N-(4-hydroxy-3-methoxyphenyl)methyl-7- 60 Other botanical Sources of Vanillyl analogs include gum methyloctanamide. euphorbium, and extract of certain species of the Euphorbia Homocapsaicin. CoHoNO genus, which contain the capsaicin analog resiniferatoxin (N-(4-hydroxy-3-methoxyphenyl)methyl-9-methyl-7- (FIG. 12), along with its analog tinyatoxin (FIG. 13) and decenamide). others. Homodihydrocapsaicin. CoHNO 65 Replacement of one of the hydrogen (H) atoms of ammo (N-(4-hydroxy-3-methoxyphenyl)methyl-9- nia (NH), with vanillyl, and the replacement of the other methyldecanamide). hydrogen (H) atom with an organic hydrocarbon group 6,063,381 19 20 produces vanillylamide (FIG. 5). In the case of the capsai Other active agents found within capsicum include citric cinoids (FIG. 6), or capsaicin analogs for example, this acid, Vitamins A, B, B, C, and E, iron, potassium and organic hydrocarbon group is a chain acid (R), varying from niacin in Significant quantities, along with other lipids, and about 8, to 14 carbon atoms, depending upon the particular carotenoids including capSanthin, capSorubin, and others. capsaicinoid. These side chains, both Saturated, and unsat Vitamin C concentrations of 100 milligrams per ounce, are urated (including add to the pungency of capsicums, and the highest of any natural food compound. Vitamin A themselves possess antimicrobial properties of their own, content is also high, with 6170 I.U. per ounce. without apparently contributing corrosiveness, or toxicity to An infusion of pepper may be prepared by Soaking vanillylamide. approximately 4 cm (4 teaspoon) of commercially avail Hydrolysis of capsaicinoids yield active agents as well. able ground red, or black pepper, to one liter (1 quart) of The Splitting off of the Side acid chain, and its replacement water of sensibly comfortable temperature. Infusion should with a hydrogen (H) atom yields the primary amine be allowed to Soak at least ten minutes before use for best vanillylamine, or 3-methoxy-4-hydroxybenzylamine (FIG. results. According to preference, infusion may, or may not 4) from vanillylamide (FIG. 5), in the case of all capsaici be Strained to remove plant residue before use. noids. Conversely, the Side acid chain, receiving a hydroxy 15 A tea of is a more potent version of infusion above, using (OH) group, is converted to a fatty acid, and yields a about 16 cm (1 teaspoon) of ground pepper for each liter different hydrolyte for each individual capsaicinoid. In the (quart) of Sensibly comfortable water. Tea may also be case of capsaicin (FIG. 6), hydrolysis of the Side acid chain prepared from boiling water, or itself be boiled in water R" (FIG. 6) CO-(CH-)-CH=CH-(CH yields iso before use. Boiling pepper in water assures complete decylenic acid COOH-(CH) -CH=CH-CH-(CH). hydrolysis of the pungent principals, which are also active The piperidines (FIGS. 7 & 8)), represent a group of agents. analogous alkaloid compounds from which most of the A tincture may be prepared by Soaking ground red, or pungent principals found within plants of the piperacea black pepper in a Solution containing approximately 60% family, of which black pepper (piper nigrum) is a member, ethanol, and 40% water. Pure ethanol, and other solvents are found. Also classified as acid amides, the piperidines, 25 Such as acetone, chloroform, Vinegar (acetic acid), and like the capsaicinoids found in capsicum Species, are pri others may also be used. The fluid volume of the solution marily responsible for the characteristic Sharp, pungent taste may be about three, or four times that of the dry volume of of black pepper. the ground pepper. The mixture should be agitated, at least The piperidine ring (FIG. 7) structure is diverse from that occassionally, over a period of at least two hours, with of phenol (FIG. 1). Though also a six membered, carbocy maximum extraction being obtained after about Six hours. clic compound, piperidines instead contain one nitrogen (N) Allowing the mixture to sit over night produces excellent hetero atom within the ring. Piperidine is heteroparaffinic, results. Before use, the residual ground pepper may be and contains no double bonds. The hetero nitrogen atom Strained off, and liquid tincture Saved for use. within the ring is a contributor to the pungency of these A preparation of pepper drops may be obtained by reduc compounds. The attachment of a hydrogen (H) atom to the 35 ing tincture through heat, or passive evaporation. Drops hetero nitrogen atom within the ring forms the amine made by this method are similar in purity to Some grades of Structure. Attachment of a hydrocarbon group, in the form of commercially available oleoresin of capsicum, and black a side acid chain (R" FIG. 8) attached to a benzene structure pepper. establishes the acid amide Structure. These compounds A plaster, or poultice may be prepared by mixing ground include; piperine C, HNO (FIG. 8), chavicine 40 pepper with water, until it has a paste-like consistency that C7H9NO, piperettine CoHON, piperidine (CH2)5NH, will assure good adherence to the Skin, or cloth to which it piperyline, piperolein A, piperolein B, piperanine, and oth is applied. CS. A lotion, cream, or Shampoo may be obtained by adding Hydrolysis of piperidines, like the capsaicinoids, yield to any commercially available Shampoo, cream, or lotion, a active, pungent compounds. Chavicine, for example is 45 portion of drops, or tincture equal to approximately 25% of hydrolysed to piperidine, which receives an additional the Volume of lotion, cream, or Shampoo carrier. hydrogen (H) atom to form a primary amine, and chavicic A douche is prepared from infusion, or tea that is Strained acid, which receives the hydroxy (OH) group to form the of the plant residue material before use. fatty acid. A Suppository is made from drops in cocoa butter, or Hydrolysis of these capsaicinoid, and piperidine acid 50 gelatin in the same Strength as douche, or lotion. amides, as well as the other listed compounds may be An injection is prepared from a purified version of accomplished with chemical catalysts, or by boiling a liquid infusion, tea, drops, etc., administered intravenously, in preparation of these compounds with water. Hydrolysis does tissue, or mixed with, and injected into the Spinal fluid. not appear to diminish the pungency of these compounds, A powder is pepper in ground form, or extracts mixed, and in Some cases actually appears to enhance both their 55 and/or bound within a binding powder carrier Such as talc. pungency, and therapeutic action. Pepper, and any of its active constituents may be admin The carbonyl group (C=O) side chain substituent, com istered as a general antiinfective in the treatment of disorders mon to all the above compounds (except eugenol) is also including fungal, and bacterial infections. believed to be a contributor to antimicrobial activity. Pepper extracts may be administered within conventional The chemical structure of prior art antifungals (FIGS. 60 drug vehicles, and carriers, and are recommended for use in 14-25) use neither the phenolic, or piperidine (FIGS. 7 & 8) four basic concentrations. Recommendations for treatment amine, or amide Structures. The current trend appearing to given below are general, and may be altered to Suit specific favor azole derivatives. These include the imidazole (FIG. conditions. If one recommended concentration for Some 19) derivatives such as clotrimazole (FIG. 20), miconazole reason appears unsuitable, the next graduation should be (FIG. 21), ketoconazole, econazole (FIG. 22), and others. 65 used. The newer triazole (FIG. 23) class includes fluconazole Other botanicals. Such as ginger, turmeric, cardamon, (FIG. 24), terconazole (FIG. 25), itraconazole, and others. clove, poinSetta, ect. which have many therapeutic proper 6,063,381 21 22 ties in common with pepper, may be used in place of pepper A pepper aerosol may be inhaled in the treatment of described below. Though these botanicals share common throat, and respiratory infections. In this administration, properties with pepper, variable results between the two are aeroSol should be derived from a lower concentration Such to be expected according to concentration of botanical as infusion, as pepper is extremely irritating to the nose, product, the carrier, and Solvent used, and the particular throat, lungs, and eyes, especially when airborne. This is pathogenic organism involved. With this in mind, modifi especially true of capsicum aeroSol. For this reason, aeroSol cations to the recommendations given below are Sometimes is Somewhat limited in its medicinal application. warranted depending on Specific circumstances. If one rec The irritating effects of pepper aeroSol, and particularly ommended concentration is not Suitable, a different one may capsaicum, is greater when distributed within an etheric be tried. Factors to consider are the degree of tissue damage, tincture Solution, Such as alcohol, ether, chloroform, or patient Sensitivity to the medication, and certainly how 1O acetone. Once airborne, even minute concentrations have a anxious the patient is to be rid of the disorder! In most, if not tear gas, or macelike effect on the eyes, and respiratory all cases, daily treatment need not be continued beyond the System. A Single, half Second Spray of a cayenne pepper first few weeks to completely resolve dermatophyte infec ethanol tincture (60% ethanol/40% water works well) aero tions. Sol from a hand held dispenser is sufficient to render a fifteen In the lower concentrations, an infusion may be used in 15 hundred Square foot enclosed area uninhabitable to humans, the treatment of milder microbial infections including der and animals, as choking, coughing, and burning irritation to matophyte infections, particularly when tissue damage is the eyes and respiratory System make habitation of the room minimal. Infusion works well as a Scalp rinse, a bath for the intolerable. feet, and Skin, and as a douche in the treatment of candida, While this may limit the use of aerosol for medicinal and other vaginal disorders. Infusion is also recommended if applications, it appears to have tremendous potential for patient Sensitivity to the higher concentrations becomes military, and paramilitary applications, particularly as a safe Significant. and more effective alternative to tear gas, and other antiper In higher concentrations, a tincture, a powder, a poultice, Sonnel aeroSols. Pepper aerosol also show great potential in and a preparation of drops, are recommended in the treat agriculture as a crop antiinfective/antifungal, insecticide, ment of Severe dermatophytosis. High concentrates, Such as 25 and pest repellent. these, are preferred where tissue damage is Significant, and Pepper powder is also very irritating when airborne, and where infection sites are causing considerable discomfort for like aeroSol, has a more limited medical application than the the patient. Drops, for example, work well for topical other carriers. If used as a foot powder for example, it is best treatment of nail infections, ringworm lesions, and infected to fix the pepper compounds within a powder binder Such as hair. These high concentrates generally produce cure after talc, to prevent, or lessen escape of airborn particulate. the first dose when treating skin lesions, and have a pro AS to the therapeutic properties of pepper compounds, phylactic action of greatest duration, lasting up to about five and are several actions I believe to be at work in the days after application. AS it is usually necessary to induce operation of the medication of the current invention. While Substantial healing of the Skin as a measure against Some of the actions described below are factual, others are recontamination, and reinfection of dermatophytes, the 35 theoretical, or hypothetical, and are Set forth as possibilities, higher concentrates appear to be most effective as prophy and are not intended to be binding. They represent an lactics as well. attempt to further explain the operation of the current A tea represents a moderate concentration of pepper invention, and to give direction to areas warranting further compounds. It may be used in the same manner as infusion, research. or in the treatment of more Severe cases of dermatophytosis. 40 The first therapeutic action of pepper extracts upon Tea should be used if infusion fails to bring immediate relief administration is that of an irritant, or as I prefer to call an of Secondary Symptoms, Such as itching in athlete's foot, inflamatory. The irritant constituents of capsicum, namely candida, or jock itch, within one hour of the first treatment. the capsaicinoids (FIG. 6), their hydrolytes, and the other Tea may also be used in place of the higher concentration acid amide piperidines (FIGS. 7 & 8), and their hydrolytes carriers, Such as drops or tincture. It is often equally effective 45 found in black pepper, and related compounds are all instru in curing Severe cases of dermatophytosis, in which there is mental in precipitating a rapid inflamatory response in the Significant tissue damage, as the high concentrates. In this area of administration. This is observed, for example, when case, tea is preferred over the high concentrates, particularly applied to skin in the treatment of various forms of tinea. if the patient Sensitivity to the medication is causing Sig The area of treatment often turns red, or pink, and feels nificant discomfort. 50 warm or hot. Burning, or warm tingling is Sometimes Tea is also Suitable as a gargle, or mouth rinse for thrush, reported by patients after topical administration of pepper or other fungal infections of the throat, and oral cavity. extracts, usually the result of excessive dosage, or exposure For an injection of pepper compounds in deep tissue, to open cuts in tissue. Though this burning Sensation can Spinal fluid, or intravenously, milder concentrations, Such as become quite intense, it does not usually last beyond the first infusion are recommended for initial treatment. While injec 55 five or ten minutes after treatment. The burning Subsides into tion of pepper extracts Such as capsaicin have been admin a warm, tingling Sensation that is no longer uncomfortable istered Safely in animal testing of analgesics, it is not known to patients. The induction of inflammation to the point of at this writing if data exists on treating humans with injec pain is accidental, and not necessary for cure. Inflammatory tion of pepper compounds. responses associated with even Slight warmth and redness A lotion, or shampoo may be prepared with any com 60 are more than adequate to provide Sufficient therapeutic monly available lotion, or Shampoo, and applied to infected action. areas in its intended manner. Other therapeutic agents, in The therapeutic value of inflammation, is the Stimulation addition to pepper extracts, may be added to Shampoo and of the body's own immune response in the area of infection. lotion. If irritation is a concern, a topical anesthetic, Such as This precipitates a varied array of fungistatic Serums, includ lidocaine, or benzocaine may be added to lotion to reduce 65 ing leukocytes, and other mononuclear cells in the area of Severity. If Skin is very dry, emollients may also be added to infection. These fungistatic Serums inhibit the growth of lotion. pathogenic fungi. 6,063,381 23 24 Inflamation also increases the rate of skin Shedding, in this Screen. These Strains, being most resistant to Standard which combats penetration of the fungus, or other organism drug therapies, pose the greatest potential for causing life into the Skin. In this mode of action, the microbe is essen threatening illnesses. The necessity of prolonged treatment tially “cast off with the diseased tissue. Perhaps or this with high dosages of highly toxic antifungal drugs required reason, those varieties of dermatophytosis that are accom to treat these diseases is often itself life threatening to the panied by inflammation often eventually heal on their own. patient. The noninflammatory varieties Such as dry athlete's foot, Another important feature of these test findings is evi however become chronic, and are very difficult to heal. The dence of the presence of multiple antimicrobial compounds lack of participation of the immune responses of the host prevents healing, and cure. within the Samples. In comparing Samples A & F for Pepper compounds are believed to act as an adjuvant to example, it is apparent that the antimicrobial action of these fungistatic Serums, by facilitating their pathways cayenne pepper (Sample A) cannot be wholly attributed to through the blood vessels, and Skin of the host, and through the presence of capsaicin alone in the ground Spice. the cell wall of the fungi, or other pathogen. Being com A review of the aforementioned article “Separation and posed primarily of lipids, capsicum for example is believed 15 Quantitation of Red Pepper Major Heat Principals by to increase the permeability of the cellular membrane of Reverse Phase High Pressure Liquid Chromatograph” indi both the host, and fungi. In addition to aiding the delivery of cates by rigorous testing a total “capsaicinoid” content not antifungal Serum, the increase in cell membrane permeabil exceeding about 1.9 mg/gram in common red pepper. ity also facilitates the delivery of undecylenic acid, another Sample A being diluted 3 times with ethanol would fix its antifungal compound found in Sweat, into the fungi. With maximum capsaicinoid content at perhaps 0.063%, or about the aid of increased permeability provided by pepper 630 ug/ml. Capsaicin accounting for about half of the total compounds, these antifungal compounds, which are nor capsaicinoid content of common red pepper, would fix the mally fungistatic, become fungicidal. capsaicin content of Sample A at about 0.032%, or about 320 The direct antimicrobial properties of pepper and another ug/ml. This diluted 256 times shows Sample A as having of the notably pungent botanicals ginger may be observed in 25 activity against C. albicans ATCC 38247 at a capsaicin vitro, in addition to those observed in vivo in the actual concentration of less than 1.25 ug/ml., and total capsaici treatment of disease. noid content of less than 2.5 lug./ml against which Ampho A Series of in vitro tests are conducted on 3 tincture tericin B requires a concentration of 25 ug/ml. Additionally, Samples prepared from the ground Spice of cayenne pepper capsaicin though the most toxic compound found in any (Sample A), black pepper (Sample B), and ginger (Sample Significant amount in capsicum peppers, is much leSS toxic C). Each spice is measured, and mixed with pure ethanol in than Amphotericin B an amount three times the measured Volume. The mixtures In comparison, Sample F has a concentration of pure are stored for 18 hours at room temperature (22 C.), and capsaicin at 25 mg/ml.-about 40 times the total capsaici agitated on 5 Separate occassions over the period. The noid content of Sample A, yet is still short of the Sample A mixtures are then Strained of residue, and Submitted for 35 performance accroSS the board. This can only mean the testing. Also included is Sample F, a tincture prepared with presence of another antifungal compound, and/or a Syner commercially pure capsaicin (8-methyl-N-Vanillyl-6- gistic relationship between the mix of capsaicinoids and nonenamide) at a concentration of 25 mg/ml. pure ethanol. other compounds within the botanical that account for the Initial in vitro tests performed by a medical university total antimicrobial effect. It may also Suggest that the laboratory report that none of the Samples A, B, C, or F 40 therapeutic actions of these botanicals are not generally show antimicrobial activity against Candida albicans, or improved by extensive isolation of their individual Neurospora crassia on a Solid medium, carrot juice agar (pH constituents, and that the total therapeutic mechanisms 6) screening. A liquid assay in vitro Screen performed by a involved are quite complex, involving a Substantial number major U.S. pharmaceutical company however, reveals activ of compounds in addition to the phenols, and piperidines ity against all 11 Strains of pathogenic fungi tested, including 45 present. In this respect, high purification of individual con 7 Strains of Candida. These pathogenic Strains are respon Stituents has the undesireable effect of to Some degree Sible for deep tissue mycotic infection, although the Candida dismantling the full therapeutic action of the compound. Strains also cause Superficial mycotic infections of the skin, Sample F is the exception containing a purified isolate and mucosa as well. (capsaicin) of the primary pungent principal found in red At first glance, a general hierarchy of activity relative to 50 pepper and other capsicums. Sample F also has perhaps 3 the degree of pungency among the botanical Samples A, B, times the capsaicinoid, and 6 times the capsaicin content of & C is evident, with cayenne pepper being most pungent, the most pungent Species of capsicum known to exist in followed by black pepper, and then ginger. Though excep nature. Yet accross the board, Sample F falls short of the tions are evident in the tests, degree of pungency is an basic botanical extract Sample A even though it has 40 times accurate general “rule of thumb' with regard to evaluating 55 the capsaicinoid concentration of Sample A the relative effectiveness of the botanicals. This observation While the above tests provide important insight into some however, for reasons set forth below, should not be inter of the therapeutic actions of the current invention, they are preted as an indication that the therapeutic effects of the of course only partially indicative of the full antimicrobial botanicals are determined Solely by the degree, and quantity action present, even as the earlier carrot juice agar tests of pungent principals present in the Samples, though it is a 60 failed to reveal any activity at all. The fuller antimicrobial factor. This will be further addressed below. activity of the compounds described above are of course Perhaps most intriguing of the test results below is that observed in Vivo in the actual treatment of disease, wherein Samples A, B, C, & F of the current invention show greatest the bodily immune responses are also modulated. These activity against those fungal Strains most resistant to the compounds repeatidly cure dermatophyte infections in as drug Standard Amphotericin B. In particular, C. albicans 65 few as a Single application. Can this be said of Amphotericin ATCC 38247, C. kefyr ATCC 28838, and T. glabrata ATCC B, or any of the other currently available topical treatments? 15545 show particular sensitivity to Samples A, B, C, & F Absolutely not 6,063,381 25 26 permeability, or the formation of Salts on the skin, the skin, though drier, is not uncomfortably So, and may have at least a fungistatic effect as a result of reduced hydration. Minimum Inhibitory Concentration The prophylactic action of pepper extracts is another important therapeutic feature of the current invention. In test sample standard addition to having immediate fungicidal action in the treat number of dilutions itg/ml ment of Superficial mycoses, pepper compounds remain in Organism A B C F Amphoter. B the Skin for perhaps ten days after treatment, to prevent Candida Albicans 6 16 8 8 1.56 reinfection. Patients often report the reoccurrence of the ATCC 10231 warm, tingling Sensation in treated areas while bathing, days Candida Albicans 6 16 8 8 1.56 after treatment. Exposure to water appears to also restimu 579a late its therapeutic action as well. If feet, or skin become Candida Albicans 6 16 16 16 1.56 moist, and Sweaty, the therapeutic action is intensified, at the 442 Same pathogenic fungi would otherwise proliferate. This Candida Albicans 256 16 8 256 25.OO provides a shield against reinfection due to recontamination, ATCC 38247 15 Candida Albicans 6 16 8 8 1.56 and protects the skin while it heals. ATCC 62376 Pepper compounds also function as a Vulnerary, aiding, Candida tropicalis 6 32 16 16 1.56 and accelerating the healing and regeneration of tissue. AS NRRL-Y-112 tissue damage can be Severe in certain forms of Candida kefyr 64 32 16 16 3.12. ATCC 28838 dermatophytosis, Such as favus, nail infections, and athlete's Torulopsis glabrata 6 32 16 8 3.12. foot, it becomes necessary to heal the damaged tissue before ATCC 15545 full cure is possible. Pathogenic fungi, finding opportunity in CryptococcuS albidus 4 8 8 16 1.56 damaged skin for example, will often continue to reinfect ATCC 34140 Saccharomyces cerevisiae 6 16 8 16 1.56 those areas unless the skin is healed. This is one reason prior GS-36 art medications are So ineffective towards cure. It becomes Aspergilius niger 6 4 4 4 1.56 25 necessary to heal the Skin to Safeguard against repeat ATCC 16404 infection, as healthy, whole skin is the best protection against reinfection. AS capsicum for example, is particularly Spec: Yeast extract Nitrate Broth + Glucose, water solvent, 48 hour Incubation, all Samples precipitate at 50% in YNB + G. high in Vitamins, and other nutrients, they also appear to Sample A = cayenne pepper have a healing effect on damaged tissue. Sample B = black pepper* The power of pepper compounds to excellerate healing of Sample C = ginger Sample F = capsaicin injured tissue is also quite dramatically demonstrated in the (commercially pure 8-methyl-N-vanillyl-6-nonenamide) 25 mg/ml pure treatment of lacerations. We commonly have treated the ethanol. most Stubborn, long lasting laceration infections with pepper *tinture 3:1 ground spice and ethanol 18 hours (Q) 22 C. compounds (lotion containing hydrolysed black pepper The irritant acid amides found within both kinds of 35 drops is a personal favorite), only to witness within just pepper, and their hydrolytes, appear to have direct fungicidal hours, reductions in redness, Swelling, Sensitivity, and eXu actions. Isodecylenic acid, one of the hydrolytes of date that are quite frankly hard to believe One is equally capsaicin, is believed to have antifungal properties Superior astounding upon witnessing the improvement Seen in just a to it's fatty acid chain relative, undecylenic acid, and offers day or two after treatment important clues to the developement of Still other 40 A medication Such as described above is an invaluable antimicrobials, Structured Similarily for increased effective wound healing treatment, particularly for the immune neSS. Another hydrolyte of the capsaicinoids, 3-methoxy-4- Suppressed, and should be used to treat cancers, and other hydroxybenzylamine (FIG. 4), Suggests a new class of neoplasms. amine antimicrobial compounds, derived from this, and Pepper compounds are also unbelieveably effective in the other analogus Structures. 45 treatment of burns, and abrasions. On Several occassions I Other possible antimicrobial agents found in pepper have treated burns with pepper lotion with results as plants, that may play a role in producing curative results, are astounding as with lacerations. The improvement in the known as phytoalexins. Phytoalexins, Such as the compound healing of the skin is quite notable within hours, with capsidiol, found in plants of the Solanacea family which continued improvement in the following days that is nothing includes capsicums, are a group of antimcrobial agents, not 50 Short of astounding. This also is very important to burn normally present in the plant, that are produced by the plant, patients, and is likely to excellerate recovery to a degree that only in response to trama caused by heat, cold, mechanical will save the lives of many that would otherwise die from injury, or attack by insects, or microbes. Capsidiol, and other their injuries. of the phytoalexins produced by Solanacea Species, are Pepper compounds could be injected into deep tissue to known to have antifungal properties against fungi that are 55 excellerate the healing of buises and contusions. This would pathogenic to Solanacea Species of plants. While these fungi be of great benefit to athletes, and accident victims. are not patogenic to man, it is possible that capsidiol, or Other antimicrobial actions of pepper compounds are another phytoalexin produced in response to their challenge, perhaps due to the high concentration of antioxidant com has antifungal action against fungi that are pathogenic to pounds Such as Vitamin E, aromatic amines, phenols, and man, as well as those pathogenic to plants. It is therefore 60 amino phenols found in pepper, particularly capsicum. possible that capsidiol, or another phytoalexin may play a These antioxidants may interfere with the action of digestive role in curing fungal disorders in man and animals, as well enzymes Secreted by the fungi, that are necessary for inges as plants. tion of nutrition, in effect Starving the fungi. It is also Dehydration is another possible therapeutic action of possible that high concentrations of citric acid, or Vitimins pepper compounds. In the treatment of Superficial mycoses, 65 found in pepper, are directly toxic to the fungi. pepper extracts appear to dry the skin to a degree that may Conversely, the very high concentration of Vitamin C, a be inhospitable to fungi. Perhaps the result of increased known oxidant, may also interfer with the ability of the fungi 6,063,381 27 28 to digest, and ingest nutrition, by instead oxidizing its food The boy has a large, brownish colored plantar wart on the compounds before they can be absorbed, also depriving the upper inside portion of the heel of his right foot. For more fungi of food. than two years, the wart has caused the boy mild, to extreme Since capsicum is So high in VitaminA, the B complex, C, discomfort, particularly when walking. On numerous occa D, and E, it can be used to treat Several nutritional disorders SSions over the course of this period, the wart has been including Scurvy, pellagra, beriberi, rickets, Xerophthalmia, treated with Several over the counter, and physician pre and a host of related diseases. Significant amounts of iron, Scribed topical medications that yield no noticable improve and potassium, make it excellent for correcting fluid ment in the condition. The boy is accustomed to shaving the absorption, and retention imbalances that result from dehy wart off at the skin Surface at regular intervals to reduce the dration due to diarrhea, and Vomiting. Infusion, or tea of 1O size, and hence the degree of discomfort associated with its capsicum may be given to correct dehydration due to rapid growth. When the upper layers of the wart are removed diarrhea. Soaking the ground powder only briefly in cool in this manner, the remainder of the tumor appears as a water, to produce a cold tea, or infusion should be Sufficient cluster of milky-white stones buried below the translucent to release the water Soluble C, and B vitamins, and mineral layers of skin on the heel. Regardless of these continued Salts, without releasing as many of the pungent principals, 15 treatments, the wart continues to grow back causing the which may make ingestion difficult. usual discomfort. Other evidence of the healing, and regenerative properties Prior to treatment with pepper drops, the wart is of pepper is observed in the treatment of other skin diseases examined, and appears to occupy a brownish, rough area of Such as psoriasis, dandruff, Seborrhea, and other forms of the heal approximately 25 mm. (1") in diameter at the base. eczema. Topical treatment of these disorders with pepper, The central portion is raised, forming a nodule approxi within the same drug vehicles and carriers described here in mately 6 mm. (4") above the skin surface. the treatment of fungal disorders, produces curative results The wart is treated topically with one (1) drop of pepper that are equally astounding. AS these diseases are not drops that were prepared from a Standard 4:1 red pepper believed to be of microbial origin, they are none the leSS acetone tincture that was reduced 40 times by room tem completely healed, usually without relapse, after as few as 25 perature evaporation. Upon application, the boy reports no one Single treatment. This is further evident that pepper notable Sensation from the treatment. compounds Stimulate the healing process of the skin, and Eight weeks after this Single treatment, the boy's heel is encourage regeneration, growth, and normalization of tissue again examined, and to the astonishment of the boy and his function. mother the wart is completely disappeared Close examina Pepper compounds also appear to possess keratolytic tion of the entire foot shows no evidence of warts. The actions, which aid healing of these general forms of previously infected area of skin looks perfectly normal and dermatitis, by aiding in the breakdown of keratin in the skin. healed, with no trace of disease, or abnormality. This also makes them useful in the treatment of warts, corns, When asked about details of the course of healing of the callouses, acne, wrinkles, and cancers. Keratolytic action wart, the boy replied that after treatment with the pepper may also have an antimicrobial effect, by perhaps interfering 35 drops, he had experienced no further discomfort in the area with the ability of pathogenic microorganisms. Such as fungi of the wart. This lack of discomfort caused him to forget to digest, or ingest the keratin on which they feed. about the wart, and he had not looked at it since treatment. In one Study, a four year old girl, with chronic Seborrhea The above illustration in addition to demonstrating the of the Scalp, was completely healed of the disorder after just keratolytic activity of pepper compounds also Suggest the three treatments with capsicum drops. The girl has two 40 possibility of antimicrobial activity. Viruses being a known lesions, approximately 25 mm (1") diameter on the top cause of warts are probably inhibited by pepper compounds. portion of her Scalp, that she has had since infancy. The This in combination with the keratolytic, and perhaps Vul lesions are tightly packed with thick, yellowish white Scales nerary action of pepper are responsible for Such dramatic approximately 2 mm (/16") in diameter. The area above the healing results. It has been many months at this writing Since lesions is covered with loose Scales, that are seen whenever 45 the boy's treatment. The wart has not returned, nor have new the hair is parted. ones arisen. The two seborrhea lesions are treated topically, with From these examples, we see the multiple therapeutic capsicum drops, prepared from heat evaporated tincture. The actions of pepper, its constituents, and related compounds dosage is once a day for three consecutive dayS. for Stimulating healing, and regeneration of tissue damaged Within the first few weeks, the lesions gradually lose their 50 by both disease, and injury, in addition to its antiinfective Superficial loose Scales, leaving only the tightly packed uses, and how pepper appears to interact with the body's Scales that are the lesion itself. At three weeks, however, own regenerative capabilities to normalize health, and func even the tightly packed Scales have disappeared, and no tion of tissue. Many other examples exist which illustrate lesions can be found; the patient is completely healed The these same therapeutic actions at work in the treatment of area of Scalp previously infected with Seborrhea is now 55 diseases that cause abnormal growth, and proliferation of healthy, and normal, and completely indistinguishable from keratin including eczema, general dermatitis, and practically the rest of the scalp, which is healthy. It is not possible to all other dermatologic disorders. determine if the girl had ever even had Seborrhea, as no Industrial Applicability evidence of the prior disease can be found on very close Thus the reader will see, that the current invention pro examination. Subsequent examinations over a period of 60 vides an antimicrobial treatment, with a degree of effective Several months indicate a healthy Scalp, with no recurrence neSS in the treatment of fungal diseases that is many gen of Seborrhea or any other dermatologic disorder. erations ahead of the prior art. Another illustration of the keratolytic properties of pepper Naturally occuring compounds, found in pepper plant compounds involves a 12 year old boy, afflicted with a large Species of the Solanacea family, which include the capsicums plantar wart on the heel of his foot, in which the boy is 65 C. fruiteScens, C. annuum, C. Baccatum, and the piperacea completely healed after a single treatment with a pepper family which includes the peperoma, and piper genera, and eXtract. the well known retrofractum, nigrum, and longum Species 6,063,381 29 30 among others, and related compounds, are found to have Even Severe cases of dermatophytosis, which cost hun profound therapeutic actions in the treatment of fungal dreds of dollars to treat with prior art antifungals, can be disorders. These compounds may be administered in most completely cured in less time, and for less than one cent commonly used drug delivery vehicles, and carriers, with Worth of pepper. A product Such as this, Sold for just one outstanding results. dollar, will attract many millions of consumers to the A Single topical treatment with my medication is all that market, who are currently excluded because of the high cost is usually necessary to provide complete cure for most and ineffectiveness of currently available prior art topical Superficial mycoses including ringworm, inflamatory ath antifungals. The high effectiveness, low toxicity, and very low cost of lete's foot, jock itch and candida. The onset of effect is My medication will greatly broaden the size of the veteri immediate, with cessation of Symptoms usually within the 1O nary market for treatment of mycoses. The high first hour of treatment, and complete healing within the first effectiveness, low toxicity, and very low cost of my medi few dayS. cine also makes feasible the creation of a Significant market Prior art topical medications, on the other hand, usually for treatment of mycoses within the livestock industry. require Scores of applications before full results are Seen, Being highly contagious, and finding opportunity under and often do not provide adequate cure, much leSS relief of 15 certain common weather conditions, dermatophytoses Such Symptoms even with long term use. as ringworm for example, can become epidemic within a Even recalcitrant cases of dry athlete's foot, which often herd, within a very short time, disqualifying them from Sale require months of treatment with prior art Systemics, is at the feed lots. completely healed usually within less than a dozen topical The weak therapeutic action, and high cost of prior art treatments with my medicine. Severe cases of dermatophy topical antifungals has prevented the formation of a market tosis. Such as this, and others, may now be treated topically for the treatment of livestock for Superficial mycoses. To by the sufferer, with a relative few applications of an over the treat food animals Such as cattle, with any of the prior art counter treatment containing pepper extracts. topical antifungals before market is an absurd notion. The Prior art Systemic treatments, which require the atten cost of medicine, its very slow action, coupled with the very dance of a dermatologist, and daily multiple doses of the 25 considerable amount of labor required to repeatedly admin medication over a period of Several months, can cost hun ister the medicine, can never be justified from an economic dreds of dollars to treat, and are often unsuccessful in Standpoint. For this reason, no significant market exists providing complete cure. In addition to this considerable within the livestock industry for such products. cost in time, money, and inconvenience, prior art Systemic With the treatment of the current invention, however, the antifungals have many adverse effects, which are not only combination of Safety, low cost, and astonishing unpleasant, but can themselves cause Serious health prob effectiveness, make it now economically feasible to estab lems. The risk of damage to internal organs, blood compo lish a product for treatment of ringworm, candida, and other Sition and adverse interactions with other medications, are Superficial mycoses within the livestock industry, as well as factors that must be carefully weighed by physicians admin for deep tissue microbial infections. Being derived from istering prior art Systemic antifungals. With this, other leSS 35 food compounds generally recognized as safe (GRAS) by Sever, yet unpleasant Side effects include nausea, vomiting, the U.S. Food and Drug Administration, my medication is headache, dizziness, fever, diarrhea, and many other disor especially appropriate for use in the livestock industry. With ders that contribute to the misery and ill health of the patient. my medication, an outbreak of ringworm within a herd, in With pepper compounds, Systemic treatment with prior art the last week before market, need no longer prevent them antifungals, with their high cost, weak therapeutic action, 40 from market as before. In addition to topical application, and adverse side effects are no longer necessary to treat analogs of pepper's active agents may be added to livestock Superficial mycoses. Instead of months of Systemic therapy feed to prevent Systemic diseases as well. that is very costly, time consuming, Slow to provide results, Pepper, and it's active constituents provide an important and an endangerment to health, the Sufferer can cure the research tool in the treatment of deep tissue fungal disorders, condition themselves, with a safe, inexpensive, and aston 45 as well as the Superficial varieties. The almost universal ishingly powerful medicine Such as mine. interchangeability of antifungal medications, between topi Pepper compounds are Safe, being a food, consumed by cal and Systemic adminSitration, Suggests the use of pepper man for thousands of years, and do not induce illness in the compounds for Systemic, as well as topical use in the patient as prior art antifungals often do. Pepper is wide treatment of deep tissue mycoses. Pepper extracts may be Spread throughout the world, and is grown in Virtually every 50 given by injection into the blood, Spinal fluid, or directly into country. Its active constituents, most of which are pungent diseased tissue for the treatment of aspergillosis, acid amide compounds, easily obtainable from the ground actinomycosis, crytococcocis, entomophthoromycosis, product, have all been Synthesized, and many are available histoplasmosis, blastomycosis, coccidioidomycoses, from commercial drug and chemical manufacturers. paracoccidioidomycoses, candidiaisis, and other deep tissue The amazing healing power of my medicine, coupled with 55 fungal disorders. Analogs of pepper's active constituent may the tremendous economic advantage it provides, paves the also be developed for oral administration to prevent decom way for the creation of many new and very large markets for position as a result of digestive processes. topical treatment of dermatophytosis. Rather than exclude With the very rapid increase in the incidence of deep the economically disadvantaged from treatment, as prior art tissue fungal disorders, and projections Suggesting even antifungal do because of their high cost, and meager 60 greater incidence in the future, the need for Safer, more effectiveness, my treatment can be produced, and Sold for powerful treatments is more crucial than ever. Finding less than prior art topicals, and Still provide a larger profit opportunity in immunocomprimised patients Such as organ margin for marketers than is common within that industry. transplant patients, and others on immunosuppreSSant drugs, My product will greatly expand the market base for tinea and those suffering from AIDS; these diseases are life medicines alone by tens of millions of individuals 65 threatening. Worldwide, and most importantly, provide effective medical Also life threatening to immunocomprimised patients, is care for those most in need of it. treatment with prior art antifungals. Their high toxicity, and 6,063,381 31 32 multiple adverse Side effects often have devastating impact from capsicum wool, or any other fabric impregnated with on the health of these patients, who are already very sick. pepper compounds as a Safeguard against harboring these Complications from these adverse effects can well end their pathogens within one's clothing. For individuals who, for lives, in addition to adding extra misery to their already example, have a natural proclivity for contracting athlete's tragic circumstances. The risk of damage to internal organs, foot, Socks, or Shoes with liners impregnated with pepper changes in blood composition, and adverse interactions with may be worn to prevent contamination leading to infection. other medications, along with the nausea, vomiting, The same applies to undergarments, and athletic wear, or diarrhea, headache, fever, and other adverse effects associ anything that has contact with the skin, and is a potential ated with prior art Systemic treatment, is extremely unlikely contagion of infection. occur with pepper extracts. In this way, pepper compounds Pepper offers promise in a wide variety of agricultural will not add illness to illness, but healing to the patient, applications as well. Crop fields may be sprayed or dusted without discomfort, or injurious Side effects. with pepper preparations, or added to irrigation water to Pepper's ability to induce an inflamatory response in the facilitate a variety of important operation. The antimicrobial area of administration provides an important research tool properties of pepper will protect the plant from fungal, for Studying immunostimulation in the treatment of disease. bacterial, and Viral disease. It will also protect harvested Since inflamation precipitates a varied array of antifungal 15 produce from Spoilage. In these two respects, crop yield is Serums, including leukocytes, and other mononuclear cells increased, and allowable Storage time extended, as microbes to the site of infection, this antimicrobial effect is believed take a far leSS Significant tole of the harvested crop. to play a major role in pepper's astounding Success at curing Pepper's action as an irritant, further Serves increased microbial infections of the keratin layers. These properties crop yields by performing as a repellent for crop destroying are valuable in the Systemic treatment of disease as well, and animals and insects, in addition to acting as an insecticide. particularly So for immunocomprimised patients. In aerosol form, capsicum preparations in particular perform Perhaps other notably pungent compounds Such as those like mace, or tear gas, producing extreme burning and found in garlic, onion, mustard, Vanilla, cascarilla, nicotine, irritation of the eyes, nose throat, lungs, and all mucous lobeline, boneset, etc., also demonstrate Similar therapeutic membranes in amazingly low concentrations. Crops in fields actions as those found in pepper. It is also probable that 25 treated with capsicum and related plant species will have an nearly all irritants, whether natural, or Synthetic, possess to intolerably offensive taste and odor, that will repel rodents, Some degree these same general properties, and aid cure birds, insects, and microbes that otherwise damage crops. through induction of inflamation. Within Storage Silos, pepper preparations will act as a The role that the active principles in pepper play in the preservative by continuing to Stem these destructive amazingly rapid healing, and regeneration of tissue injured influences, even after delivery to market. by burns, lacerations, infections, and disease is also impor The irritating constituents of pepper are also useful for tant to immunocomprimised patients, who have particular military and law enforcement purposes, as Safe alternatives difficulty in healing, and frequently encounter Serious infec to mace and tear gas, in addition to their therapeutic, and tion from even minor injuries, and diseases. These Vulnerary agricultural uses. When dispersed in a fine mist, or vapor actions also play an important role in the treatment of 35 containing an etheral Solvent Such as alcohol, capsicum cancers, and tumors, and other diseases that result in cellular pepper in particular produces extreme, and intolerable irri mutation, and abnormal proliferation of tissue. tation to the eyes, and respiratory System, along with uncon The astounding effectiveness of pepper compounds to trolable choking, and coughing in the most minute dosages cure dandruff and Seborrhea further Suggests its regenerative An invisible, and odorleSS Vapor containing a single Squirt contributions, in addition to its antifungal actions. Though 40 from a typical fine mist cosmetic bottle containing cayenne not believed to be of microbial origin, dandruff and sebor pepper ethanol tincture is Sufficient to render a fifteen rhea are completely cured within a very few topical treat hundred Square foot room uninhabitable to humans. Dis ments with pepper, as easily as if it were ringworm. These persed within tear gas-like canisters, Specially Suited for the healing and regenerative powers, along with pepper's appar purpose, very large areas of atmosphere could be covered ent keratolytic action, also provides great promise in the 45 with very few distribution units. treatment of all diseases that result in an abnormal prolif Pepper derivatives, whether used to treat crops, or eration of keratin including Scaling conditions Such as livestock, are perfect for use in the food industry. Being eczema, pSoriasis, general dermatitis, or hardened growths itself a food compound, generally recognized as Safe Such as warts, corns, and callouses, ect. These properties (GRAS) by the U.S. Food and Drug Administration, pepper also make pepper useful in treating cancer, wrinkles, acne, 50 will pose no health risks to consumers of these food prod and others disorders. ucts. Whether applied topically to livestock, or added to their The discovery of pepper's amazing effectiveness in the feed, or injected as a Systemic antibiotic, pepper derivatives treatment of dandruff and Seborrhea, also Suggests that other will not raise crucial Safety concerns, as all prior art SyS antifungals, including those of the prior art, may also temics have. demonstrate effectiveness in the treatment of these, and 55 Other possible areas for investigating pepper and its other forms of dermatitis. derivatives include treatment of trees for Dutch elm disease, The antimicrobial actions of pepper extracts towards and other disorders, and treatment of rare painting and pathogenic fungi, make it an excellent prospect for experi artifacts as a preservative, and as disinfectant, and as a mentation with other pathogens Such as bacteria, in the treatment against parasitic worms. development of new antiseptics and antibiotics. Pepper's 60 The list of possible research projects, for the development affinity for the skin also makes it a good candidate for the of new commercial product derived from the discovery of treatment of Staphylococcus, and other bacterial infections pepper's absolutely astonding curative powers, is indeed of the skin. It's low toxicity also favors its use in the endless. What new products that are to develop from this treatment of Systemic bacterial infections including all types discovery is an interesting, and exciting area deserving of from ear infections to tuberculosis. 65 much attention. Other products utilizing the antimicrobial properties of The use of pepper compounds in the treatment of tumors, pepper compounds include clothing, and shoe liners made cancer, and other diseases involving cellular mutation of 6,063,381 33 34 tissue, along with immune disorderS Such as AIDS, has administration to an area of disease a Suitable carrier excellent prospects for the developement of many new containing a primary anti-infective agent obtainable drugs, and treatments. from a pepper plant of the genus Capsicum, Peperoma, The impact of commercial implementation of this topical or species Piper retrofractum, Piper longum, or Piper antifungal treatment alone, is to make available to even the nigrum in a therapeutically effective amount. poorest people of the World a certain cure for even the most 5. A method of treating the Superficial manifestations of Severe cases of Superficial mycoses. A treatment that cures fungal disease in the areas of the body about the face, ear, mouth, neck, and below and deep tissue, or Systemic fungal completely in much less time, in a much safer way, and for diseases comprising: administration to the area of disease a less than one penny on the dollar for what is required with Suitable carrier containing a primary anti-infective agent prior art treatments. A medication that brings relief to many 1O obtainable from pepper, or an equivalent wherein a thera millions of Sufferers, rich and poor, Saves our nation, and peutically effective amount is a concentration similar to each nation of the world millions of dollars each day in oleoresin or leSS. medical costs. A medicine that provides an important Search 6. A method of treating the Superficial manifestations of tool in the treatment of deep tissue mycoses, her life fungal disease or Systemic fungal diseases comprising: threatening infectious diseases. 15 administration to the area of disease a Suitable carrier While my above description includes many specificities, containing a primary anti-infective agent obtainable these should not be regarded as limitations on the invention, from pepper, or an equivalent wherein a therapeutically but rather as an exemplification of certain preferred embodi effective amount is a concentration within the range of mentS. ground Spice or oleoresin. Accordingly, the Scope of the invention should not be 7. A method as in any one of claims 5 or 6, wherein the determined by these illustrated embodiments, but by the disease infects the feet. appended claims, and their legal equivalents. 8. A method as in any one of claims 5 or 6, wherein the I claim: disease infects the body area. 1. A method of treating deep tissue, or Systemic fungal 9. A method as in any one of claims 5 or 6, wherein the diseases comprising: 25 disease infects the crotch area. 10. The method of claim 6, wherein the disease infects the administration to an area of disease a Suitable carrier Scalp. containing a primary anti-infective agent obtainable 11. A method as in any one of claims 1-6, wherein the from capsicum pepper, or an equivalent in a therapeu disease is candidiasis. tically effective amount. 12. A method as in any one of claims 1-6, wherein Said 2. A method of treating Systemic fungal diseases Selected agent is a Synthetic. from the group consisting of blastomycosis, 13. A method as in any one of claims 2, 3, 5, or 6, wherein coccidioidomycosis, entomophthoromycosis, or paracoccid Said pepper is a Capsicum. ioidomycosis comprising: 14. A method as in any one of claims 1-6, wherein Said administration to an area of disease a Suitable carrier agent is a capsaicinoid analog. containing a primary anti-infective agent obtainable 35 15. A method as in any one of claims 2, 3, 5, or 6, wherein from pepper, or an equivalent in a therapeutically Said plant is piperaceous. effective amount. 16. A method as in any one of claims 2, 3, 5, or 6, wherein 3. A method of treating Systemic fungal diseases Selected Said agent contains a piperidine constituent. from the group consisting of aspergillosis, candidiasis, 17. A method as in any one of claims 1-6, wherein said cryptococcosis, or histoplasmosis comprising: 40 pepper is cayenne. Systemic administration to an area of disease a Suitable 18. A method as in any one of claims 1-6, wherein said carrier containing a primary anti-infective agent obtain pepper is paprika. able from pepper, or an equivalent in a therapeutically 19. A method as in any one of claims 1-6, wherein said effective amount. pepper is black. 4. A method of treating fungal infections of the mucosa 45 comprising: UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 6,063,381 Page 1 of 13 DATED : May 16, 2000 INVENTOR(S) : Staggs

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Reprint specification with the attached.

Signed and Sealed this Twenty-third Day of May, 2006 WDJ

JON. W. DUDAS Director of the United States Patent and Trademark Office Page 2 of 13 6,063,381 1 2 ANT FUNGAL BOTANC EXTRACTS AND bone marrow function, with lowered white cell levels is another possible adverse effect of treatment. Drug interac RELATED COMPOUNDS tions with anticoagulants, and barbiturates reduce effectiveness, and the risk to pregnancy often forbids treat TECHNICAL FIELD s net. The invention relates to a new class of general antifungal Ketoconazole, taken orally for systemic fungal infections, compounds obtainable from plant species of the pepper, and also carries the risk of liver damage as a result of treatment. ginger families, and chemically related species useful in the The effectiveness of ketoconazole is diminished by interac treatment of fungal disorders. tion with various antacids, and other gastric medications. 10 Ketoconazole increases the potency of other drugs, and is BACKGROUND ART reduced in potency by some antibiotics. There is a wide array of fungi pathogenic to man and Miconazole, taken by injection for fungal infection of the animals. The disease they cause are classified into two broad lungs, brain, kidney, and lymph nodes, can alter blood categories; as deep tissue, or systemic mycoses, and super chemistry resulting in anemia. Miconazole also interacts ficial mycoses. s negatively with medications for diabetes, epilepsy and anti Deep tissue, or systemic mycoses including aspergillosis, coagulants. The effectiveness of amphotericin B is reduced blastomycosis, coccidioidomycosis, cryptococcosis, by miconazole. histoplasmosis, paracoccidioidomycosis, entomophthoro Nystatin, taken orally for candida disorders, is of little use mycosis and candidiasis may involve widespread growth, in the treatment of systemic fungal infections. Though and dissemination of fungi in internal organs, and tissue. The 20 having far fewer adverse side effects than the other antifun lungs, brain, bones, spinal fluid, liver, heart, kidneys, other gal drugs, it is ineffective against most fungal infections internal organs, and skin being subject to infection that can except candida, and aspergillus, making it of limited usage. be life threatening. These adverse effects are particularly devastating to Prevalence of deep tissue mycoses is on the rise due to the immunocompromised patients, those in most need of treat high susceptibility, and ever growing number of immuno ment. Complications from treatment may well end their life. compromised patients. These include cancer, organ trans Similar problems of low effectiveness, prolonged plant patients, and others on immunosuppressant treatment, and high cost of prior art antifingals affect the medication, and particularly with patients suffering from treatment of Superficial mycoses. immune disorders such as acquired immune deficiency 30 Superficial mycoses, also called dematophytoses the syndrome (AIDS). skin, hair, nails, or mucosal linings are infected with any of Antibiotic drugs such as penicillin, tetracycline, and sulfa three dozen or so different species of yeast and fungi. More ect, though often effective against bacterial infections, are specifically, ringworm (tinea) init's various forms including useless against infections caused by fungi. Treatment with a athlete's foot (tinea pedis), favus, or scalp ringworm (tinea separate group of antifungal, or antimycotic antimicrobial 35 capitis), body ringworm (tinea corporis) jock itch (tinea drugs is required. cruris) etc., and skin, and mucosal candidiasis among others. Antimycotic drugs were first introduced in the 1950's The National Health Survey of 1971-1974 projected from with nystatin (1954), amphotericin B. (1958), and griseof. its sampling that about one out of every twelve people in the ulvin (1959). These drugs were originally administered United States had some form of deratophytosis, with men systemically. Tolnaftate was introduced in 1965 as the first 40 being four times more likely than women to contract infec effective topical antifungal treatment. Since the 1970's, a tions. number of "azole' derivative antifingals such as clotrimazole, miconazole, econazole, ketoconazole, and oth Surveys of other nations reveal a much higher incidence ers have made their appearance as antimycotics for both of superficial mycotic diseases, among the poor, and under systemic, and topical administration. The more current trend is developed countries of Africa, Asia, South America, and has been toward the development of a "triazole' class of those areas of the world having tropical climates. antifungals, including fluconazole, terconazole, and itracor Though not considered life threatening, as some deep nazole etc. tissues disorders can be, the superficial varieties assuredly Systemic treatment with antimycotic drugs is prolonged, take a fair toll in misery, inconvenience, and expense. very expensive, and dangerous, with many adverse effects. so Certainly anyone with painful cuts on the feet, bald Complications arising from therapy can itselfbe life threat patches on the scalp, unsightly thickening, brittleness, and ening due to the high toxicity of these drugs. The risk of discoloration of the fingernails, or an unsightly, itchy rash damage to internal organs, adverse effects on blood due to a chronic fungal infection may feel they have a composition, and adverse reactions to other medications is a serious illness. very complex matter that must be carefully monitored by ss Certainly, the economically disadvantaged would con administering physicians. With this, other less severe, yet sider any disorder that in addition to causing discomfort, unpleasant side effects, include nausea, vomiting, headache, could cost them several hundred dollars a year in treatments dizziness, fever, diarrhea, and many others that contribute to without cure 'serious'. complications, and the misery and ill health of the patient. Likewise, those in the livestock industry may think of Other adverse effects, now unknown may yet be discovered. so ringworm as a serious disease when herds are refused Amphotericin B, given by injection in the treatment of because of ringworm infestation. Being highly contagious, systemic fungal infection, carries with it the risk of liver and this can occur injust a few weeks without remedy. kidney damage, and can also result in blood disorders. It Prior art treatments for superficial mycoses, in addition to interacts negatively with many cardiac medications, and being expensive, require repeated application before diuretics, as well as other antibiotics. improvement can be seen in the patient. Currently available Griseofulvin, usually taken orally, for fungal infections of over the counter treatments, containing clotrimazole, the skin, hair, and nails, has a risk of liver damage. Reduced miconazole, tolnaftate, or undecylenic acid, recommend up Page 3 of 13 6,063,381 3 4. to sixty applications of the product in order to provide full effectiveness of antifungal treatments low to the detriment of benefit. More treatments are often required. patient and healthcare economics. The newer generation Even prescription topical antifungals; administered by a triazole derivatives, including fluconazole, terconazole, dermatologist, may require as many as two hundred appli itraconazole, and others, cost many millions of dollars to cations over a period of three months to cure some cases of 5 develop, and apparently are not that much more effective athlete's foot alone. Nail infections may require eighteen months of multiple, daily treatment to provide cure. In than the prior generation imidazole derivatives, and cer addition to being very expensive and time consuming, tainly are doing nothing to make treatment more affordable, applying the medicine repeatedly each day is bothersome. or convenient. Beside this, they have much narrower appli Coupled with the discomfort of the fungal disorder, the cation than the imidazoles, and are considered auxiliary, and expense, and inconvenience associated with the treatment not mainline treatments. adds further to the misery of the condition. It seems doubtful that the azole groups will produce Regardless of economic impact, even wealthy derivatives of significantly greater effectiveness in the treat individuals, with the best health care available suffer with all ment of fungal disorders, than what is currently available the others when it comes to the discomfort, and bother of with prior art treatments. The need for a safe, effective, and repeated application of medication that is slow acting, and low cost treatments is more urgent than ever. often ineffective at producing cure or relief of symptoms. The high cost, low ineffectiveness, and dangerously high The current cost of treating ringwomand other superf toxicityofprior art medications is not suited to deal with the cial mycoses excludes the economically disadvantaged, who steadily rising number of cancer, AIDS, and innunosup suffer most from the condition, from receiving treatment. pressant drug treatment cases reported now, and anticipated Poor sanitation and a lower standard of general health adds 20 for the future. to the greater prevalence of ringwom, and other superficial The importance of having medications that are cost effec mycoses among the poor, and because it is rarely treated tive as well, is becoming critical to the preservation of our because the effectiveness of treatment does not justify the very way of life. Escalating healthcare costs are the primary expense. contributor to the national debt. The high cost of health care In this respect, the current array of prior art antifungal insurance in the United States now exclude 1 in 6Americans treatments have failed. In addition to the misfortune of not from coverage while consuming a greater share of the having viable treatment for tens of millions of sufferers of household budget with each new year. Money otherwise fungal infection, no markets are created, and no products spent on housing, college, retirement, entertainment, and sold, to the advantage of no one. Prior art antifungal treat consumer goods must instead go to cover the cost of health ments keep the price of treatment high, the market volume 30 care. In addition to a lower standard of living, this takes small, and undiverse, and only bring marginal relief to a capital away from industries that provide employment, and relative few of the many suffers. tax revenues that pay the national debt. Cost, and ineffectiveness prohibit use of prior art topical Should economic ruin be a necessity of adequate health antifungals in the livestock industry, as well. The cost of the care? Is trading bodily ills for economic ills the only viable medicine, coupled with the labor required for repeated option? application to livestock, forbids the creation of a significant People of developing countries of the world experience market for these medicines within the industry. near total exclusion of healthcare because of cost. Livestock infected with ringworm are refused by feed lots. Being highly contagious, ringworm can spread through DSCLOSURE OF INVENTION a herd within a few short weeks, not allowing enough time Several objects and advantages of my invention include for treatment and recovery in the weeks prior to going to an improved treatment for fungal infections of unparalleled market, even if the animals are treated. effectiveness. A treatment that saves the lives, and misery of With the current way of topical antifungals, treating food millions of sufferers. A low toxicity treatment for fungal animals for ringwon is an absurd notion. The cost of 4s infections. A low cost treatment for fungal infections also applying a medicine, perhaps fifty times, to a single head of affordable to the poor. A treatment for fungal infections of livestock could never be justified. For this reason, treatment broader commercial feasibility. A treatment that saves bil is withheld, to the disadvantage of both the rancher and the lions of dollars annually. A treatment that becomes a model animal, which in addition to suffering discomfort, spreads for demonstrated savings in healthcare costs including gov the disease to other animals, perpetuating the cycle further, SO ernment sponsored healthcare programs such as Medicare, In addition to money lost, no viable solution is offered by and Medicaid. A veterinary treatment for fungal infections. pharmaceutical manufacturers which would otherwise enjoy I have discovered that pepper, and chemically related a new very large potential market. compounds, and species of plants contain active agents of Whether or not one feels the economic impact of super unparalleled effectiveness in the treatment of superficial ficial mycoses, all suffers experience the inconvenience of ss fingal infections. These agents may be administered in the having to make repeated application of currently available wide range of commonly used drug vehicles and carriers in prior art topicals. The necessity of making repeated appli the form of a lotion, drops, tincture, plaster, aerosol, and cations is an indication of weak drug action, the great flaw other vehicles with a level of effectiveness truly generations of prior art antifungal treatments. ahead of currently available prior art antifungal. Topical treatment of superficial mycoses is much safer 60 Ringworm in its various foms, inchuding athlete's foot, than internal treatments. The weak action of prior art topical jockitch, and favus, along with other types of dematomy antifungal medications often necessitates the use of systemic coses such as candida, may be completely healed in as few treatments, which are more dangerous, costly, time as a single treatment with this medication. Body and scalp consuming, and associated with many other unpleasant ringworm lesions disappear, usually within the first day after adverse effects mentioned above. treatment, and require no follow up dosage. Recalcitrant The focus of the prior art upon the development of azole cases of athlete's foot are healed in as few as half a dozen derivatives will continue to keep the cost high, and the doses of my medicine rather than scores of applications, Page 4 of 13 6,063,381 S 6 usually required by prior art antifungal medications that notion. The cost of medicine, its very slow action, coupled often do not cure. with the very considerable amount of labor required to Currently available prior art over the counter topical repeatedly administer the medicine, can not be justified treatments for ringworm containing clotrinazole, economically. For this reason, no significant market exists miconazole, tolnaftate, or undecylenic acid, usually require within the industry for such products. several weeks of daily multiple treatments before improve With the treatment of the current invention, however, the ment can be observed in the condition. In addition to the scope of product possibilities is enlarged by making treat considerable expense of having to buy several containers of ment of these disorders economically feasible. the medication, the time, and inconvenience involved in The many therapeutic properties, and beneficial compo making repeated applications with meager results adds fur O nents foundin pepper provide the ideal profile for a systemic ther to the misery and discomfort of the disease. Even mild treatment for the more serious, and often life threatening to moderate cases of tinea can easily require more than sixty deep tissue, and systemic fungal disorders. applications of these products before the condition Systemic treatment with antifungal drugs, such as am improves. The weak therapeutic action of these prior art, photericin B, clotinazole, griseofylvin, ketoconazole, over the counter treatments is often insufficient to produce s miconazole, nystatin and others, in addition to being expen adequate results. Often, the disorder must be treated by a sive and time consuming, have many bad side effects that physician, using prescription topical, and systemic antifian can further endanger the health of the patient. These drugs, gals taken internally. taken internally, carry the risk of damage to liver and other Prescription treatment with antifungal medications is the internal organs, and adverse effects upon blood chemistry. most expensive of all treatments. Beside the cost of having 20 Patients receiving such treatments must be monitored for an attending dermatologist, the medications themselves are changes in blood and organ function, as a safeguard against more expensive than the over the counter varieties. This type serious damage that can result from treatment. Prior art oftreatment, being the best the prior arthas to offer, still may systemic antifungals also interact adversely with a large require several months of multiple daily doses of the anti number of other medications, another area that requires dose fungal medication to cure some kinds, of ringworm. Treat 25 attention by the attending physician. Beside this, other ment for athlete's foot may require up to three months of adverse effects include nausea, vomiting, diarrhea, fever, multiple daily doses of the medicine before the condition headache, anemia, and other unpleasant symptoms that can be cured. Ringworm infections of the toe nail can take up to eighteen months to heal. So adding the expense of accompany the discomfort of the disease. visits to a derinatologist, time lost from work or leisure, the 30 The high cost, low ineffectiveness, and dangerously high time and inconvenience of applying themedicine, the cost of toxicityofprior art medications is not suited to deal with the the medicine, and the ongoing discomfort of the disorder, all steadily rising number of cancer, AIDS, and immunosup have an economic impact that is quite considerable, in pressant drug treatment cases reported now, and anticipated addition to the discomfort of both the disease and the side for the future. effects of treatment. Pepper compounds are an important research tool in the With my treatment, systemic treatment of superficial war against the increased incidence of life threatening deep disorders is likely a thing of the past. tissue, and systemic fungal disorders. The high effectiveness of pepper appears to be due to The impact of commercial implementation of this topical multiple therapeutic actions in addition to direct antifungal antifungal treatment alone, is to make affordable to even the action. Case observations suggest general healing, 40 poorest people of developing countries a certain cure for keratolytic, immunostimulation and modulation, adjuvant, even the most severe cases of superficial mycoses who are drug delivery, and prophylactic properties beyond direct now excluded from care because of the high cost, and low fungicidal. In vitro antifungal screens prove proportionally effectiveness of prior art antifungals. increased potency against terminal drug resistant fungi A treatment that cures completely in much less time, in a strains. much safer way, without the need of an attending physician, it appears that the high nutrient concentration found in and for less than one penny on the dollar for what is required pepper including vitamins, minerals, carotenoids, lipids, and of prior art treatments in will bring relief to many hundreds others assist the above therapeutic effects addition to the ofmillions of sufferers, rich and poor alike while expand the pungent compounds. Pepper compounds are safe, and have consumer demand base for products accordingly. been in widespread use as food for thousands of years and SO Full scale implementation of these medications will save do not induce illness as do prior art antifungals. in excess of S20 billion dollars in Gross National Product in As a generally recognized as safe (GRAS) listed nutrient the treatment of superficial disorders in the U.S. alone not to food compound, pepper medications are ideal for livestock mention the world. use. Systemic treatments, and topical medications to control 55 This enhanced level of safety, effectiveness, and dramatic ringworm, candida, and other disorders can be developed. cost savings of these medications should serve as a model to Pepper derivatives may be added to feed to prevent systemic government healthcare programs such as Medicaid, and disease as well. ' Medicare save billions of dollars in medical expenditures The veterinary market for treatment of mycoses can be while providing the best care for recipients. greatly broadened given the high effectiveness, low toxicity, 60 Now and finally, an antifungal treatment exists that can and very low cost of my medication. Dermatophyte infec save our nation, and many nations of the world millions of tions such as ringworn need no longer prevent sale of dollars each day in medical costs, and lost productivity, livestock as before. provide highly lucrative products for commercial Prior art topical antifungals have prevented the formation exploitation, provides an important research tool in the of a market for the treatment of livestock superficial 6s treatment of life threatening illness, and bring speedy relief mycoses. To treat food animals such as cattle, with any of the to hundreds of millions of suffers of fungal disorders, and prior art topical antifungals before market is an absurd perhaps even save lives; man and animal alike. Page 5 of 13 6,063,381 7 8 BRIEF DESCRIPTION OF THE DRAWINGS from ground red pepper, according to procedures described in the article "Separation and Quantitation of Red Pepper FIG. 1 is a molecular diagram of phenol. Major Heat Principals by Reverse Phase High-Pressure FIG.2-13 show molecular diagrams of compounds of the Liquid Chromatography" by Patrick Hoffman et. al., in the current invention. s Journal of Agricultural Food Chemistry 1983, Vol. 31, FIG. 2 is a molecular diagram of ortho-methoxyphenol. pages 1326-1330. Though several related capsaicinoids FIG. 3 is a molecular diagram of vanilly. have been identified in trace amounts, the major capsaici FIG. 4 is a molecular diagram of 3-methoxy-4- noids (FIG. 6) include: hydroxybenzylamine. Capsaicin. CHNO FIG. 5 is a molecular diagram of vanillylamide. O N-(4-hydroxy-3-methoxyphenyl)methyl)8-methy-6- FIG. 6 is a molecular diagram of the capsaicinoids. nonenamide). Dihydrocapsaicin, CHNO FIG. 7 is a molecular diagram of piperidine. (N-(4-hydroxy-3-methoxyphenyl)methyl FIG. 8 is a molecular diagram of the pungent alkaloid 8methylnonanamide). Norcapsaicin. principals of pepper, s FIG. 9 is a molecular diagram of eugenol. (N-(4-hydroxy-3-methoxyphenyl)methyl-7-methyl FIG. 10 is a molecular diagram of curcumin. 5octenanide). FIG. 11 is a molecular diagram of gingerol. Nordihydrocapsaicin. C, HNO FIG. 12 is a molecular diagram of resiniferatoxin. 20 (N-(4-hydroxy-3-methoxyphenyl)methyl-7- FIG. 13 is a molecular diagram of tinyatoxin. methyloctanamide. Homocapsaicin. CHNO BEST MODES FOR CARRYING OUT THE N-(4-hydroxy-3-methoxyphenyl)methyl-9-methyl INVENTION 7decenamide), A medicinal preparation of pepper, and its active con Honodihydrocapsaicin, CHNO, stituents may be administered in a wide range of conven N-(4-hydroxy-3-methoxyphenyl)methyl)- tional drug vehicles and carriers. Capsicum, and black 9methyldecanamide). pepper are available commercially as oleonesin, in a wide range of concentrations, and pungencies, and may be used in N-vanillyl-n-nonamide. CHN 30 (N-(4-hydroxy-3-methoxyphenyl)methyl-n-nonamide). place of the plant product described below. Nonanoic acid vanillylamide. CHNO The preparations described below are made from a mod Decanoic acid vanillylamide. CHNO erate pungency commercial grade of ground cayenne pepper Other capsaicinoids, not listed here, are identified in (Capsicum futescens), or black pepper (Piper nigrum), as research literature as trace elements within capsicum, and an indicator of approximate concentration within each car may be used in medicinal preparations as well, along with rier. Their equivalents may be estimated, and prepared from 3S other analogous compounds. commercially available oleoresin, or from any of the pun Capsaicinoids are generally classified as acid amide gent principals, some of which are also available commer derivatives of Phenol (FIG. 1). The characteristic pungent, cially in pure natural, or synthetic form. irritating sensory effects of these compounds are typical of The term "pepper, or "pepper compounds" are used acid amides, whether derived from phenol, or piperidine somewhat generically to be inclusive ofrelated botanicals of (FIG. 7). the Zingiberaceae family including ginger (Zingiber Phenol (FIG. 1), though lacking pungent flavor, is highly afficinale), tumeric (Curcuna longa), cardiamon (Elettaria corrosive, caustic, and toxic, deriving many ofits properties cardamomum), Melegueta pepper (Afamonum melegueta), from its basic benzene structure. While this gives phenol members of the Euphorbia genus including Euphorbia certain antimicrobial properties, it is generally considered to resinifera, poinsettia (Euphorbia pulcherrima), clove be unsuitable fortherapeutic use in man, and animals, due to (Eugenia aromatica), allspice (Pimenta officinalis) and oth it's and irritating effects on tissue. ers such as vanilla having similar constituents may be With the addition of a methoxy group (OCH3) to phenol, prepared in the same way as pepper by following the general methoxyphenol is formed. In the ortho position, we have procedures outlined below in the capsicum pepper illustra 50 ortho-methoxyphenol (FIG. 2), also known as guaiacum, an tion below. Included among this list of botanicals is of extract obtainable from trees of the Guaiacum genus. The course the other members of the Solanaceae pepper family effect of this methoxy group in part is an increase in including members of the Capsicum genus with the annuum, aromacy, and a decrease in toxicity, and caustic properties baccatum, and longum species. otherwise existing in phenol, yet without apparent decrease Among the Piperaceae family, species of the Peperoma, in antimicrobial properties. The attachment of hydrocarbon and Piper genus which include the retrofactum, nigrum, and groups to the ring structure, to form higher analogues longun species. Other species of plants having similar apparently increases the antimicrobial properties of chemistry may also be used in place of the above. methoxyphenol, and phenol. It is presumed that the meta, or Variations in performance of each preparation will vary para isoners of methoxyphenol have similar properties to with type, and concentration of extract, carrier, and solvent so the ortho, in like manner to the similarities between the used in relation to pathogenic organism involved. The phenol isomers. scientific literature may be consulted for more detailed The addition of the methylene group (CH2) in the para investigations as to chemical properties, solubility, position to ortho-methoxyphenol produces vanillyl (FIG.3). separation, and quantitation of constituent compounds, Like phenol, and methoxyphenol, it is presumed that chang For purposes of research, or the treatment of disease, the 65 ing the position of the methylene group to form other individual compounds responsible for the pungent quality of vanillyl isomers will produce compounds of similar, red peppers, and other capsicums may be obtained directly although not exact properties to that of vanillyl. Page 6 of 13 6,063,381 9 10 The vanillyl structure on which the capsaicinoids are compounds include; piperine CHNO (FIG. 8), chavi constructed is also typical of the pungent principals found in cine CHNO, piperettine C1903N, piperidine ginger (Zingiberaceae) species of plants. (CH).H, piperyline, piperolein A, piperoleinB, piperanine, Collectively known as gingerol (FIG. 11): shogaol, and others. paradol, zingerone, gingerol and other analogs, have a s Hydrolysis of the piperidine series, like the capsaicinoids, yield active, pungent compounds. Chavicine, for example is different side chain than the capsaicinoids, and lacking an hydrolysed to piperidine, which receives an additional ammonia (NH) group, are neither amines, or amides like hydrogen (H) atom to form a primary amine, and chavicic the capsaicinoids or piperidine series. Hydrolysis of gin acid, which receives the hydroxy (OH) group to form the gerols yield vanillyl, and a fatty acid side chain, both of fatty acid. which demonstrate like therapeutic properties to the capsai O Hydrolysis of these capsaicinoid, and piperidine acid cinoid hydrolytes. amides, as well as the other listed compounds may be Also members of the ginger or Zingiberaceaer family accomplished with chemical catalysts, or by boiling a liquid turmeric (Curcuna longa L) contains the compound cur preparation in water, Hydrolysis does not appear to diminish cumin (FIG. 10), actually a vanial derivative differing from pungency, and in some applications appears to enhance both vanillyl by one hydrogen (H) atom having an (CH) s pungency, and therapeutic action. substituent, rather than a methylene (CH2) in the para The carbonyl group (C=O) side chain substituent, com position. This analog differs further with a side chain unique mon to all the above compounds (except eugenol) is also from the others. Cardamon, allspice, clove, black pepper, believed to be a contributor to antifungal activity. and many others contain eugenol, another vanillyl analog Other active agents found within capsicum include citric with yet another hydrocarbon side chain. acid, vitamins A, B1, B2, C, and E, iron, potassium and Other botanical sources of vanillyi analogs include gum niaci in significant quantities, along with other lipids, and euphorbium, and extract of certain species of the Euphorbia carotenoids including capsanthin, capsorubin, and others. genus, which contain the capsaicin analog resiniferatoxin Vitamin C concentrations of 100 milligrams per ounce, are (FIG. 12), along with its analog tinyatoxin (FIG. 13) and the highest of any natural food compound. Vitamin A Others. content is also high, with 6170 I.U. per ounce, Replacement of one of the hydrogen (H) atoms of ammo An infusion of pepper may be prepared by soaking nia (NH3), with vanilly, and the replacement of the other approximately 4 cm3 (% teaspoon) of commercially avail hydrogen (H) atom with an organic hydrocarbon group able ground red, or black pepper, to one liter (1 quart) of produces vanillylamide (FIG. 5). In the case of the capsai water of sensibly comfortable temperature. Set at least ten cinoids (F.G. 6), or capsaicin analogs for example, this 30 minutes before use for best results. Strain plant residue organic hydrocarbon groupis a chain acid (R), varying from before use if desired. about 8, to 14 carbon atoms, depending upon the particular A more potent tea uses about 16 cm3 (1 teaspoon) of capsaicinoid. These side chains, both saturated, and unsat ground pepper for each liter(quart) of sensibly comfortable urated (including add to the pungency of capsicums, and water. Tea may also be prepared from boiling water, or itself themselves possess antimicrobial properties of their own, be boiled in water before use. Boiling pepper in water without apparently contributing corrosiveness, or toxicity to assures complete hydrolysis of the pungent principals, vanillylamide. which are also active agents. Hydrolysis of capsaicinoids yield active agents as well. A tincture may be prepared by soaking ground red, or The splitting off of the side acid chain, and it's replacement black pepper in a solution containing approximately 60% with a hydrogen (H) atom yields the primary amine 40 ethanol, and 40% water. Pure ethanol, and other solvents vanillylamine, or 3-methoxy-4-hydroxybenzylamine (FIG. such as acetone, chloroform, vinegar (acetic acid), and 4) from vanillylamide (FIG. 5), in the case of all capsaici others may also be used. The fluid volume of the solution noids. Conversely, the side acid chain, receiving a hydroxy may be about three, or four times that of the dry volume of (OH) group, is converted to a fatty acid, and yields a the ground pepper. The mixture should be agitated, at least different hydrolyte for each individual capsaicinoid. In the occasionally, over a period of at least two hours, with case of capsaicin (FIG. 6), hydrolysis of the side acid chain maximum extraction being obtained after about six hours. R" (FIG. 6) CO-(CH)-CH=CH-(CH), yields iso Allowing the mixture to sit over night produces excellent decylenic acid COOH-(CH)-CH=CH-CH-CH). results. Strain of the residual ground pepper. The piperidine series (FIG. 7 & 8)), represent a group of A preparation of pepper drops may be obtained by reduc analogous alkaloid compounds from which most of the so ing tincture through heat, or passive evaporation. Drops pungent principals found within plants of the Piperaceae made by this method are similar in purity to some grades of family, of which black pepper (Piper nigrum) is a member, commercially available oleoresin. are found. Also classified as acid amides, the piperidine A plaster, or poultice may be prepared by mixing ground series, like the capsaicinoids found in capsicum species, are pepper with water, until it has a paste-like consistency that primarily responsible for the characteristic sharp, pungent SS will assure good adherence to the skin, or cloth to which it taste of black pepper. is applied. The piperidinering (FIG. 7) structure is diverse from that A lotion, cream, or shampoo may be obtained by adding of phenol (FIG. 1). Though also a six membered, carbocy to any commercially available shampoo, cream, or lotion, a clic compound, the piperidine series instead contain one portion of drops, or tincture equal to approximately 25% of nitrogen (N) hetero atom within the ring. Piperidine is 60 the volume of lotion, cream, or shampoo carrier. heteroparaffinic, and contains no double bonds. The hetero A douche is prepared from infusion, or tea that is strained nitrogen atom within the ring is a contributor to the pun of the plant residue material before use. gency of these compounds. The attachment of a hydrogen A suppository is made from drops in cocoa butter, or (H) atom to the hetero nitrogen atom within the ring forms gelatin in the same strength as douche, or lotion. the amine structure. Attachment of a hydrocarbon group, in SS An injection is prepared from a purified version of the form of a side acid chain (R" FIG. 8) attached to a infusion, tea, drops, etc., administered intravenously, in benzene structure establishes the acid amide structure. These tissue, or mixed with, and injected into the spinal fluid. Page 7 of 13 6,063,381 11 12 A powder is pepper in ground form, or extracts mixed, areas in its intended manner. Other therapeutic agents, in and/or bound within a binding powder carrier such as talc. addition to pepper extracts, may be added to shampoo and A pepper impregnated fabric include clothing, and shoe lotion. Ifinitation is a concern, a topical anesthetic, such as liners made from capsicum wool, or any other pepper lidocaine, or benzocaine may be added to lotion to reduce compound as a safeguard against harboring these pathogens s severity. If skin is very dry, emollients may also be added to within one's clothing. For individuals who, for example, lotion. have a natural proclivity for contracting athlete's foot, socks, or shoes with liners impregnated with pepper may be worn A pepper aerosol may be inhaled in the treatment of to prevent contamination leading to infection. The same throat, and respiratory infections. In this administration, applies to undergarments, and athletic wear, or anything that aerosol should be derived from a lower concentration such has contact with the skin, and is a potential contagion of O as infusion, as pepper is extremely initating to the nose, infection. throat, lungs, and eyes, especially when airborne. This is Treatment recommendations given below are general especially true of capsicum aerosol. For this reason, aerosol guidelines and may be altered to suit specific conditions. If is somewhat limited in it's medicinal application. one recommended concentration appears unsuitable, the The irritating effects of pepper aerosol, and particularly next graduation should be used. capsicum, is greater when distributed within an etheric Consideration as to the degree of tissue damage, patient tincture solution, such as alcohol, ether, chloroform, or sensitivity to the medication, and certainly how anxious the acetone. Once airborne, even minute concentrations have a patient is to be rid of the disorder. In most, if not all tear gas, or mace like effect on the eyes, and respiratory dermatophyte infections, should see results not within the system. first few weeks of daily treatment. 20 Pepper powder is also very initating when airborne, and In the lower concentrations, an infusion may be used in like aerosol, has a more limited medical application than the the treatment of milder microbial infections including der other carriers. Ifused as a foot powder for example, it is best matophyte infections, particularly when tissue damage is to fix the pepper compounds within a powder binder such as talc, to prevent, or lessen escape of airborn particulate. Infusion works well as a scalp rinse, a bath for the feet, Below are theories as to the therapeutic actions ofpepper and skin, and as a douche in the treatment of candida, and compounds based largely on observation, and set forth to other vaginal disorders. Infusion is also recommended if further explain the operation of the current invention, and to patient sensitivity to the higher concentrations becomes give direction to areas warranting further research. significant. The irritating nature of the pungent compounds are instru In higher concentrations, a tincture, a powder, a poultice, 30 mental in precipitating a rapid inflammatory response in the and a preparation ofdrops are recommended in the treatment area of administration. In sufficient concentrations, this is of severe dematophytosis. High concentrates, such as these, observed when applied to skia in the treatment oftinea. The are preferred where tissue damage is significant, and where area of treatment often turns red, or pink, and feels warm or infection sites are causing considerable discomfort for the hot. Burning, or warm tingling is sometimes reported by patient. Drops for example, work well for topical treatment patients after topical administration of pepper extracts, usu ofnail infections, ringworm lesions, and infected hair. These ally the result of too high a dosage. Though this burning high concentrates generally produce cure after the first dose sensation can become quite intense, it does not usually last when treating skinlesions, and have a prophylactic action of beyond the first five or ten minutes after treatment. The greatest duration, lasting up to about five days after appli burning subsides into a warm, tingling sensation that is no cation. As it is usually necessary to induce substantial 40 longer uncomfortable to patients. The induction of inflam healing of the skin as a measure against recontamination, mation to the point of pain is accidental, and not necessary and reinfection of dermatophytes, the higher concentrates for cure. Inflammatory responses associated with even slight appear to be most effective as prophylactics. warmth and redness are likely adequate to provide sufficient A tea represents a moderate concentration of pepper therapeutic action. compounds. It may be used in the same manner as infusion, Pepper also appears to act as an immunostimulant, by or in the treatment of more severe cases of dematophytosis. precipitating leukocytes, and other mononuclear cells, along Tea should be used if infusion fails to bring immediate relief with a variety of antifungal compounds from the blood, and of secondary symptoms, such as itching in athlete's foot, surrounding tissue, to the area of infection. Though done candida, or jockitch, within one hour of the first treatment. primarily through inducing inflammation, pain and discom Tea may also be used in place of the higher concentration SO fort are not required in order to receive the full therapeutic carriers, such as drops or tincture. It is often equally effective benefit. Pepper compounds are also believed to aid in the in curing severe cases of dermatophytosis, in which there is delivery of these antifungal immune responses of the body, significant tissue damage, as the high concentrates. In this and increase their potency in addition to its own antifungal case, tea is preferred over the high concentrates, particularly actions. if the patient sensitivity to the medication is causing sig 55 The therapeutic value of inflammation, is the stimulation nificant discomfort. of the body's own immune response in the area of infection. Tea is also suitable as a gargle, or mouth rinse for thrush, This precipitates a varied array of fungistatic serums, includ or other fingal infections of the throat, and oral cavity. ing leukocytes, and other mononuclear cells in the area of For an injection of pepper compounds in deep tissue, infection. These fungistatic seruns inhibit the growth of spinal fluid, or intravenously, milder concentrations, such as SO pathogenic fungi. infusion are recommended for initial treatment. While injec Inflammation also increases the rate of skin shedding, tion of pepper extracts such as capsaicin have been admini which combats penetration of the fungus, or other organism istered safely in animal testing of analgesics, it is not known into the skin, in this mode of action, the microbe is essen at this writing if treating humans by injection has been tially "cast off" with the diseased tissue. Perhaps or this attempted. 6. reason, those varieties of dermatophytosis that are accom A lotion, or shampoo may be prepared with any con panied by inflamnation often eventually heal on their own. monly available lotion, or shampoo, and applied to infected The noninflammatory varieties such as dry athlete's foot, Page 8 of 13 6,063,381 13 14 however become chronic, and are very difficult to heal. The within the Samples. In comparing Samples A & F for lack of participation of the immune responses of the host example, it is apparent that the antimicrobial action of prevents healing, and cure. cayenne pepper (Sample A) cannot be wholly attributed to It is further possible that pepper compounds act as an the presence of capsaicin alone in the ground spice. adjuvant to these fungistatic serums, by facilitating delivery through blood vessel, skin, and fungal cell membrane path A review of the aforementioned article "Separation and ways. Being composed primarily of lipids, capsicum, for Quantitation of Red Pepper Major Heat Principals by example, may increase the permeability of the cellular Reverse Phase High Pressure Liquid Chromatograph" indi membrane of both host, and fungi. In addition to aiding cates by rigorous testing a total "capsaicinoid" content not delivery of antifungal serum, the increase in cell membrane exceeding about 1.9 mg/gram in common red pepper, permeability may facilitate the delivery of undecylenic acid, 10 Sample A being diluted 3 times with ethanol would fix its anotherantifungal compound found in sweat, into the fungi. maximum capsaicinoid content at perhaps 0.063%, or about With the aid of increased permeability provided by pepper 630 g/ml. Capsaicin accounting for about half of the total compounds, antifingal compounds which are normally capsaicinoid content of common red pepper, would fix the fingistatic, become fungicidal. capsaicin content of Sample Aat about 0.032%, or about 320 Apart from host response possibilities, the direct antini s ug/nl. This diluted 256 times shows Sample A as having crobial properties of pepper and another of the notably activity against C. albicans ATCC 38247 at a capsaicin pungent botanicals ginger are observed in vitro, in addition concentration of less than 1.25 g/ml, and total capsaici to those observed in the actual treatment of disease. noid content of less than 2.5 g/ml against which Ampho A series of in vitro tests are conducted on 3 tincture tericin B requires a concentration of 25 g/ml. Additionally, samples prepared from the ground spice of cayenne pepper 20 capsaicin though the most toxic compound found in any (Sample A), black pepper (Sample B), and ginger (Sample significant amount in capsicum peppers, is much less toxic (C). Each spice is measured, and mixed with pure ethanol in than Amphotericin B. an amount three times the measured volume. In comparison, Sample F has a concentration of pure The mixtures are stored for 18 hours at room temperature capsaicin at 25 mg/ml.-about 40 times the total capsaici (22 C.), and agitated on 5 separate occasions over the noid content of Sample A, yet is still short of the Sample A period. The mixtures are then strained of residue, and performance across the board. This can only mean the submitted for testing. Also included is Sample F; a tincture presence of another antifungal compound, and/or a syner prepared with commercially pure capsaicin (8-methyl-N- gistic relationship between the mix of capsaicinoids and vanillyl-6-nonenamide) at a concentration of 25 mg/ml. other compounds within the botanical that account for the pure ethanol. 30 total antimicrobial effect. It may also suggest that the Initial in vitro tests performed by a medical university therapeutic actions of these botanicals are not generally laboratory report that none of the Samples A, B, C, or F improved by extensive isolation of their individual show antimicrobial activity against Candida albicans, or constituents, and that the total therapeutic mechanism Neurospora crassia on a solid medium, carrot juice agar (pH involved is quite complex, involving a substantial number of 6) screening. ' compounds in addition to the phenols, and piperidine com Aliquid assay in vitro screen performed by a major U.S. pounds present. In this respect, isolation of individual con pharmaceutical company however, reveals activity against stituents produce the undesirable effect of to some degree all 11 strains of pathogenic fungi tested, including 7 strains dismantling the full therapeutic action of the compound. of Candida. These pathogenic strains are responsible for Sample F is the exception containing a purified isolate deep tissue mycotic infection, although the Candida strains 40 (capsaicin) of the primary pungent principal found in red also cause superficial mycotic infections of the skin, and pepper and other capsicums. Sample F also has perhaps 3 Inucosa as Well. times the capsaicinoid, and 6 times the capsaicin content of At first glance, a general hierarchy of activity relative to the most pungent species of capsicum known to exist in the degree of pungency among the botanical Samples A, B, nature. Yet across the board, SampleF falls short of the basic & C is evident, with cayenne pepper being most pungent, botanical extract Sample A even though it has 40 times the followed by black pepper, and then ginger. Though excep capsaicinoid concentration of Sample A. tions are evident in the tests, degree of pungency is an While the above tests provide important insight into some accurate general "rule of thumb' with regard to evaluating of the therapeutic actions of the current invention, they are the relative effectiveness. This observation however, for of course only partially indicative of the fill antimicrobial reasons set forth below, should not be interpreted as an SO action present, even as the earlier carrot juice agar tests indication that therapeutic affects are determined solely by failed to reveal any activity at all. The filler antimicrobial the degree, and quantity of pungent principals present, activity of the compounds described above are of course though it is a factor. This will be further addressed below, observed in the actual treatment of disease, wherein the Perhaps most intriguing of the test results below is that bodily immune responses are also perhaps modulated. These Samples A, B.C., & F of the current invention show greatest SS compounds repeatedly cure dematophyte infections in as activity against those fungal strains most resistant to the few as a single application. This cannot be said of Ampho drug standard Amphotelicin B. In particular, C. albicans tericin B, or any of the other currently available prior art ATCC 38247, C. kefyr ATCC 28838, and T. glabrata ATCC topical treatments. 15545 show particular sensitivity to Samples A, B. C., & F The irritant acid amides found within both kinds of in this screen. These strains, being most resistant to standard pepper, and their hydrolytes, appear to have direct fungicidal drug therapies, pose the greatest potential for causing life actions. Isodecylenic acid, one of the hydrolytes of threatening illnesses. The necessity of prolonged treatment capsaicin, may have antifungal properties superior to it's with high dosages of highly toxic antifungal drugs required fatty acid chain relative, undecylenic acid, and offer impor to treat these diseases is often itself life threatening to the tant clues to the development of still other antimicrobials, patient. 6S structured similarly for increased effectiveness. Another Another important feature of these test findings is evi hydrolyte of the capsaicinoids, 3-methoxy-4- dence of the presence of multiple antimicrobial compounds hydroxybenzylamine (FIG. 4), suggests a new class of Page 9 of 13 6,063,381 15 16 amine antimicrobial compounds, derived from this, and to also restimulate its therapeutic action as well. If feet, or other analogous structures. skin become moist, and sweaty, the therapeutic action is intensified, at the same pathogenic fungi would normally proliferate. This provides a shield against reinfection due to s recontamination, and protects the skin while it heals. Minimugan inhibitory Concentration Pepper compounds also appear to function as a vulnerary, test sample aiding, and accelerating the healing and regeneration of Organism (number of dilutions) standard tissue. As tissue damage can be severe in certain forms of dermatophytosis, such as favus, nail infections, and athlete's Amphoter.B A. B C F ugfin 10 foot, it becomes necessary to heal the damaged tissue before Candida Albicans 6 s 8 8 S6 full cure is possible. Pathogenic fungi, finding opportunity in ATCC 1023 damaged skin for example, will often continue to reinfect Candida Albicans 16 16 8 8 S6 S79a those areas unless the skin is healed. This is perhaps one Candida Albicans s s 6 16 S6 reason prior art medications are so ineffective towards cure. 442 1S The skin is not allowed to heal quickly enough to safeguard Candida Albicans 2S6 16 8 2SS 2500 against repeat infection, as healthy, whole skin is the best ATCC 38.247 Candida Albicans 6 16 8 8 156 protection againstreinfection. The particularly high vitamin, ATCC 6236 and other nutrient content of capsicum for example, may Candida tropicalis 16 32 6 16 1S6 have a firrther healing effect, as pepper compounds appear to NRRY-12 20 stimulate the healing process of the skin, and encourage Candida kefyr 64 32 15 5 3.2 ATCC 28838 regeneration, growth, and normalization of function, Torulopsis glabrata 6 32 16 8 3.2 The high concentration of antioxidant compounds such as ATCC SS4S vitamin E, aromatic amines, phenols, and amino phenols Cryptococcus albidus 4. s 8 s 1.56 found in pepper, particularly capsicum may also facilitate an ATCC 34140 2S Saccharomyces cerevisiae 13 s 3. 15 s antifungal effect beyond a generalized aid to healing. These GS-36 antioxidants may interfere with the action of digestive Aspergillus niger 6 4 4. 4. 1S6 enzymes secreted by the fungi, that are necessary for inges ATCC 6404 tion of nutrition; in effect starving the fungi. Spec; Yeast extract Nitrate Broth + Glucose, water solvent, 48 hour Conversely, the very high concentration of vitamin C, a Incubation, all Samples precipitate at 50% in YNB + G. 30 known oxidant, may also interfere with the ability of the Sample A = cayennep fungito digest, and ingestnutrition, by instead oxidizing it's Sample B = black pepper' Sample C = ginger' food compounds before they can be absorbed. Sample F = capsaicin (commercially pure 8-methyl-N-vanillyl-6- It is also possible that high concentrations of citric acid, nonenamide) 25 mg/ml pure ethanol. or vitamins found in pepper, are directly toxic to the fungi. tincture 3; ground spice in ethanol 18 hours 6 220 The observed keratolytic action may also have an anti Other possible antimicrobial agents found in pepper microbial effect, by perhaps interfering with the ability of plants, that may play a role in producing curative results, are pathogenic microorganisms such as fungi to digest, oringest the phytoalexins such as the compound capsidiol, found in the keratin on which they feed, plants of the Solanaceae family which includes capsicums. Lastly, it will prove further helpful to witness the dramatic A group of antimicrobial agents not normally present in the 40 healing effect of pepper compounds in actual treatment of plant, phytoalexins are produced by the plant, only in disease. response to trama caused by heat, cold, mechanical injury, or In a study of eightpatients, all infected with various forms attack by insects, or microbes. Capsidiol, and other of the of dematophytosis, complete cure is obtained after one phytoalexins produced by Solanaceae species, have antifun topical application of the medication of the current invention gal properties against fungi that are pathogenic to the plant. in five of the eight cases studied. The other three cases While these fungi are not pathogenic to man, it is possible studied are cured within half a dozen treatments or less. that capsidiol, or another phytoalexin produced in response None of the patients are taking any kind of medication for to their challenge has antifingal action against fungi that are ringworm, or for any other disorder, and no special steril pathogenic to man, as well as those pathogenic to plants. It ization measures of clothing, furniture or bedding are taken, is therefore possible that capsidiol, or another phytoalexin SO beyond otherwise good personal hygiene. may play a role in curing fungal disorders in man and In the first portion of the study, a family of three, all animals, as well as plants. afflicted with ringworm, are completely healed after a single Dehydration is another possible therapeutic action of topical treatment with a pepper compound. pepper compounds. In the treatment of superficial mycoses, The infant has developed approximately six ringworm pepper extracts appear to dry the skin to a degree that may 55 lesions about the back of the scalp, and back, and right side be inhospitable to fingi. Perhaps the result of increased of the neck. The first few lesions were noticed a month permeability, or the formation of salts on the skin, the skin, before. though drier, is not uncomfortably so, and may have at least The mother of the infant has about six ringworm lesions a fungistatic effect. on the right arm, most on the outside bicep. The appearance The prophylactic action of pepper extracts is another 60 of the lesions was first noticed approximately three months important therapeutic possibility. In addition to having before. apparent immediate fungicidal action in the treatment of The father ofthe infanthas approximately eight ringworm superficial mycoses, pepper compounds also appear to lesions on the left arm, most on the outside bicep, The right remain in the skin for perhaps ten days after treatment, to arm has four lesions, also on the outside of the bicep. Four prevent reinfection. Patients often report the reoccurrence of 65 other lesions appear on the shoulders, and lower back. The the warn, tingling sensation in treated areas while bathing, man first noticed lesions of this type approximately eight sometimes days after treatment. Exposure to water appears years earlier. Page 10 of 13 6,063,381 17 18 On all three subjects, the ringworm lesions have the same The woman soaks her feet in a bath, prepared from general appearance. The lesions are ring shaped, with infusion of capsicum, for fifteen minutes. The woman slightly raised outer borders that are sometimes crusty. The reports a warm, tingling sensation that lasts about ten lesions are red, with a smooth, and sometimes scaly interior. minutes. This treatment is administered at 8:00 p.m. The A clear, sticky fluid sometimes covers the lesion. The s woman retires for the evening at 10:00, and does not average diameter of the ring is about 15 mm (0.6), with experience any of the itching characteristics of the previous some as large as 20 mm (0.8), The lesions appear, and evenings. For three weeks the woman reports not a single remain for, several weeks, sometimes disappearing, leaving recurrence of the itching on the feet She continues to wear lighter colored skin at the site of the prior lesion. the same footwear as before, and does not take any kind of The man is first to be treated with a preparation of 10 sanitary, or other precautions to avoid reinfection. capsicum, wherein a plaster is applied to three lesions on the After about three weeks, the woman begins to notice a left bicep. A very slight, momentary tingling sensation is gradual return of the itching on top of the feet that she had reported. The sensation lasts for about the first five minutes experienced before. Within another week or two, the itching after application, and is not uncomfortable. The plasteris left is as intense as ever, and is again interfering with sleep. on the skin for about one hour, then rinsed off with water. s The woman's feet are treated with a lotion of capsicum, Afterward, the lesions appear redder than they did prior to using rawaloeveragel as the lotion carrier.Lotion is applied application of plaster. After six hours, the lesions appear to to the feet, and rinsed off with water at the end of half an be whiter, with the coloration being more similar to the skin hour. The treatment is administered at 8:00 in the evening, tone of the healthy skin, than prior to treatment. At twenty before the woman retires for the evening at 10:00. The hours, all three lesions appear healed, as it requires very 20 woman reports no itching that evening, nor afterwards, for close examination to reveal the site of the prior lesion. The many months. She disposes of the comfortable shoes, she characteristic patch of lighter colored skin that normally had bought for work, and has no frther recurrence of accompany lesions that have healed by themselves is not athlete's foot symptoms. The womanis completely healed of present. athlete's foot after just one single treatment with my medi The other dozen or so lesions found on the man are cation. examined, and found to be substantially unchanged fom The sixth case involves a five year old girl, who is their last examination the day before. Another examination completely healed of a recalcitrant case of dry athlete's foot, on the third day yields the same results, with no sign of the Prior to treatment, the child's feet are peeling severely in the three lesions that were treated and healed, and little change areas between the toes, and on the entire sole of the foot. in the untreated lesions. 30 Loose skin, in pieces as large as about 4mm (%") square are The other dozen ringworm lesions on the arms and trunk hanging around the lower edge of the ball of the foot. The of the man, are treated with the same capsicum plaster, with entire sole of the foot is callused, and has a wrinkled identical results. All twelve lesions, regardless of location, appearance. are healed with the exact location of the prior lesion being Deep cuts occur periodically on the ball of the foot and difficult to determine because of the advanced degree of 35 around the base of the toes, particularly the great and small healing of the skin in that area. toes. The child often complains that her feet hurt from the One week later, the woman is treated with the same cuts, but otherwise describes no other discomfort or symp capsicum plaster as the man, with similar results. At three toms. The girl has had these symptoms for about three years, days after treatment, all six lesions are completely healed in since age two years. similar fashion to those on the man. 40 At age two years, the girl develops a particular affection One week after the woman is treated, the infant girl is also for a certain pair of shoes, and wears them constantly, treated with the capsicum plaster in the same manner as both refusing to wear other shoes. Weeks later, the girl develops her parents, and is healed in the same way, with the a very offensive foot odor. Afterward, her feet gradually disappearance of all lesions within about one day. It is also develop the symptoms described above, becoming chronic interesting to note that the infant girl displays no sign of 45 over the next three years. discomfort when the medication is applied, and does not cry, An ethanol tincture of capsicum is applied to the girl's or even appear to take notice of the treatment. feet. The girl complains about a stinging sensation in the cuts Regular examinations of these three patients, over a around her great and small toes. The girl cries for about five period of several months, fails to identify the reappearance or ten minutes, then reports that the sting is gone. The giri of one single ringworm lesion in any one of them. Each 50 is also treated with the same capsicum tincture on days three lesion of the patient is completely healed ofringworm, after and five, after the initial treatment. The investigator per just one single topical treatment with my medicine, 100% forms these second and third treatments because he is not cure of twenty-eight lesions on three subjects is accom sure if the first treatment is sufficient to penetrate such thick plished after a single dose of my medication, without calluses on the soles of the feet, having never treated such reappearance of a single lesion. This is done without ster SS badly damaged skin with this particular treatinent. ilization measures, and aside from any other medication On day three, just prior to the second treatment, the feet whatever. are examined and appear slightly improved. The cuts around In another portion of the study, a woman in her middle the toes have formed scabs, and no discomfortis reported by thirties is healed of athlete's foot within hours of a single the girl after application of the tincture, treatment of my medication. The woman works a full time SO On day five, the feet are again examined before receiving job, in which she is required to be on her feet most of the the third treatment, and again appear to be further improved. time. Approximately one week after having purchased a The cuts are continuing to scab over and heal, and the girl more comfortable pair of shoes for work, the woman devel reports no discomfort from the medicine. This general trend ops an inflammatory variety of athlete's foot. The primary continues for the next several days, yet treatment is not again symptons are intense itching on top of the toes and foot, felt administered. mostly in bed at night, along with a bad, musty foot odor. By the fourteenth day, the feet are nearly, completely The itching is now interfering with sleep each night. healed. There are no cuts or scabbed cuts, and no pealing or Page 11 of 13 6,063,381 19 20 loose skin. The calluses are nearly, completely reduced, and is laughing. About three minutes afterward, the girl begins the skin has a healthy color and texture, and no longer has crying, saying that the cuts on her toes are burning. She a wrinkled, ragged appearance. It is not possible to deter continues to cry for about ten more minutes, and afterward mine that the girl has ever had athlete's foot, as her feet are indicates that the burning has gone. healthy and normal. The child is excited that her feet are 5 At the same time, an ointment of capsaicin, consisting of "like new again". about 0.03 percent capsaicin (from oleoresin) in turpentine On day twenty one, the girl's feet are again examined. The oil is applied to the right foot. There are no cuts on the right skin around the bottom and sides of the toes has succumbed foot at this time, and the girl reports no discomfort from the to reinfection, as the skin is again peeling, though not as medication. severely as before the first treatment. O The medications described above are applied once each At six weeks, the girl's feet have returned to the pretreat week for the next two weeks, and observed regularly over ment condition. The skin on the sole of the feet is thickened the next three weeks, with little notable change the first few and callused. The skin on the soles and between the toes is days. peeling and has a ragged appearance. Cuts appear periodi On day three, the feet are examined, and appear to be cally at the base of the toes, on the heel and at the ball of the showing signs of improvement. The peeling does not seem foot. The dry athlete's foot is back in full force. as severe, and the red blotches lookas if they are fading. The The reinfection of the girl's feet is not presumed to be the cuts on the left foot are healing, and show no sensitivity result of recontamination, as no sanitary measures have been when firmly squeezed with the fingers. taken to prevent reinfection, and the girl continues to wear On day four, the feet are again examined, and look much the same footwear as before the treatment. As these patho 20 better than the previous day. The peeling is again reduced, genic fungi find opportunity in damaged skin tissue such as and the red blotches have completely disappeared. The right that described, the skin must be healed to prevent reinfec foot looks slightly better than the left, suggesting the thera tion. The best protection from reinfection being healthy, peutic effectiveness of the capsaicin ointment. The cuts on undamaged skin. the left foot show further progress in healing. This is one reason why the prior art has such difficulty 25 Upon examination on the sixth day after treatment, the curing this type ofringworm. The therapeutic action of prior child's feet look very much improved. The loose skin has for art antifungals is so weak and slow acting, it arrests the the most part worn away, being replaced by healthy skin that resident fungi only enough to allow the healing process of shows no scaling, or discolor. The cuts on the left foot have the skin a slight advantage. disappeared, and both feet show reduced skin thickness, and This is why a case of dry athlete's foot can easily require 30 only faint reminder of cracks that are mostly healed. Both twelve weeks of daily, multiple treatments with prior art feet look about the same, suggesting equivalent therapeutic medications to provide cure, which is usually only tempo performance between capsicum and capsaicin preparation. rary. The examination of day seven reveals little change in the The dramatic improvement of the girl's feet between the condition of the feet from day six except that they appeared last treatment on day five, and the examination on day 35 slightly better on day six. Small cuts along the base of the fourteen suggests accelerated healing over any activity of Small toe on the right foot are not causing discomfort, as the fungi during this interval. It also suggests a prophylactic medicine is applied for the second time. action by my medicine that may provide protection for Subsequent examinations of the next seven days reveal a perhaps seven days or more. similar pattern to that of the prior week. Little change is Recalling complete cure after a single dose of my medi- 40 observed the first few days after treatment, with very notice cine in the first five cases leads to the conclusion that the able improvement being observed between the fourth and fungi are eradicated on initial contact with my medication. sixth day after treatment. This patten is also established on What distinguishes them from this sixth case is the relatively days eleven through thirteen, yet without substantial minor degree of skin damage they suffered, in relation to the advance in the stage of healing beyond that observed on the present case. This further supports the notion of the prophy- 45 sixth day. lactic action of my medicine, as seven days or less is ample It is evident that a single weekly application of my time to heal the minor skin damage caused by the body medicine produces substantial improvement in recalcitrant ringworn lesions. cases of athlete's foot. Though this improvement is In an attempt to determine the maximum duration of sustained, it is not usually sufficient to induce fill cure, at capsicum's prophylactic effect, and to compare it's perfor- 50 least within a three week span. mance with that of synthetic capsaicin, the synthetic version Nor does the degree of improvement compare to the of the primary inritant found within natural capsicum, the results of the prior study, in which the medication was girl's feet are again treated. applied three times within the first week. Depending upon Prior to treatment, the girl's feet have again returned to the case, two to four applications per week should be their original, recalcitrant condition that was noted prior to SS sufficient to provide complete, and sustained cure for recal the first treatment. The girl's feet are peeling severely on the citrant cases of athlete's foot. bottom and sides of the toes, and on the ball of the foot. The To demonstrate a complete cure for recalcitrant athlete's skin in this area is thickened, and callused, with deep cracks foot, and to compare the performance of a red pepper sometimes resulting in painful cuts. The skin has a wrinkled, (Capsicum futescens) extract with that of one made from dry, and ragged appearance, with intermittent red blotches, 60 black pepper (Piper nigrum), the girl's feet are again treated. occupying about half the total surface area. Small cuts The girl's right foot is treated with an ethanol tincture of appear periodically around the base of the great and small capsicum made from groundred peppe, while the left foot toes, which often cause pain, especially when walking. is at the same time treated with a similar tincture prepared A lotion of capsicum, consisting of 4 cm3 (4 teaspoon) of instead with an equal amount of black pepper. groundred pepper mixed with 48 cm3 (12 teaspoons) ofraw, 63 The girl's feet are treated eleven times, once every other aloe Vera gel, is applied to the child's left foot. The girl day, over a period of three week's. The pattern of previous describes a tickling sensation as lotion is being applied, and tests is also observed in this trial, with both the red, and Page 12 of 13 6,063,381 21 22 black pepper tinctures performing with equal effectiveness. effectiveness that is many generations ahead of the prior art. As in the other tests with the girl, significant improvement Single application cure of dermatophytosis, being unheard is observed between the fourth, and sixth day after of among prior art treatments, is the usual result with the treatment, with dramatic improvement being noted at two medication of my invention. No longer is it necessary for weeks. At three weeks, very little sign of the prior disorder 5 suffers to endure prescription therapies, which are slow remains, and the condition does not return after weeks of acting, time consuming, expensive and potentially danger observation. The girl is healed of recalcitrant athlete's foot, ous with many other unpleasant adverse effects. With my with just eleven topical treatments over a period of less than medication, embodied in the form of a topical, over the three weeks. counter treatment, even recalcitrant cases of athlete's foot In the seventh case study, a woman of sixty is cured of a can be cured with a few periodic applications of my medi dry variety of athlete's foot. Prior to treatment, the woman's O cine. Instead of months of antibiotic therapy, administered feet have peeling skin between the toes, and thickened soles by a dermatologist, the sufferer can cure the condition with cuts on the underside of the heal. themselves, with a safe, inexpensive and astonishingly The woman's feet are soaked in a capsicum tea for fifteen power medicine, such as mine. minutes at a time, once a day, for five days. On the Second While my above description includes many specificities, day, the woman complains that her feet are very dry, and that s these should not be regarded as limitations on the invention, one of the cuts on her heel is making walking difficult but rather as an exemplification of certain preferred embodi because of the pain. By the fourth day, she indicates the ents. cessation of those ms. After eight weeks, the feet are Accordingly, the scope of the invention should not be examined and the skin appears healthy, with no sign of determined by these illustrated embodiments, but by the peeling or thickening of the skin. The woman indicates that 20 appended claims, and their legal equivalents. after the fourth day of treatment, she did notice the reemer What is claimed is: gence of symptoms at the time of the eight week 1. A method of treating deep tissue, or systemic fungal examination, and felt cured since. diseases comprising: In the eighth case study, a boy of thirteen is completely administration to an area of disease a suitable carrier containing a primary anti-infective agent obtainable healed of a severe fungal infection of the face, and neck after from capsicum pepper, or an equivalent in a therapeu just two weeks of treatment with my medication. tically effective amount. Over a period of nearly five months, the boy has been 2. A method of treating systemic fungal diseases selected suffering from what is described as an angry, bright redrash from the group consisting of blastomycosis, about the face, from beneath the eyes, down to the bottom, coccidioidomycosis, entomophthoromycosis, or paracoccid and sides of the neck. The boy's father describes the disorder 30 ioidomycosis comprising: as “literally eating his son's face away". The boy, and his administration to an area of disease a suitable carrier family are for some time quite distressed, as treatment containing a primary anti-infective agent obtainable administered by a general practitioner, and two dematolo from pepper, or an equivalent in a therapeutically gists over more than four months, fails to heal the condition. effective amount. The expense of treatment is nearing $1,000 out of pocket 35 3. A method of treating systemic fungal diseases selected The visits to the physician, have cost the parents more than from the group consisting of aspergillosis, candidiasis, twenty hours away from work, and the boy must be excused cryptococcosis, or histoplasmosis comprising: from school the same amount of time. The boy is of course systemic administration to an area of disease a suitable doubly distressed, as in addition to the discomfort of the carrier containing a primary anti-infective agent obtain disease, he must bear the humiliation of wearing this rash on 40 able from pepper, or an equivalent in a therapeutically his face that is more horrible in appearance than a severe effective amount. case of acne. 4. A method of treating fungal infections of the mucosa A skin scraping sent to a laboratory reveals the presence comprising: of fungal hyphae, not of the ringworm variety, administration to an area of disease a suitable carrier The boy is given griseoflvin orally, but must discontinue 45 containing a primary anti-infective agent obtainable treatment after one week as a result of severe nausea. The from a pepperplant of the genus Capsicum, Peperoma, boy is then given tonaftate topically, and has shown no or species Piper retrofactum, Piper longun, or Piper significant improvement in the condition over a period of nigrum in a therapeutically effective amount. several weeks. 5. A method of treating the superficial manifestations of The boy is then given lotion prepared with capsicum, and SO fungal disease in the areas of the body about the face, ear, instructed to apply the medication once every other day after mouth, neck, and below and deep tissue, or systemic fungal bathing until symptoms disappear. All other treatments are diseases comprising: administration to the area of disease a also discontinued. suitable carrier containing a primary anti-infective agent The boy's father administers the treatment as prescribed, obtainable from pepper, or an equivalent wherein a thera and is seeing noticeable improvement by the third day. The 55 peutically effective amount is a concentration similar to condition continues to improve over this period, and by the oleoresin or less, tenth day the skin is almost completely healed, with barely 6. A method of treating the superficial manifestations of a remnant of the prior disease remaining. To say the least, the fungal disease or systemic fungal diseases comprising: boy's family and friends are amazed, and astounded at the administration to the area of disease a suitable carrier rapidity of cute of this horribly unsightly condition, that had 60 containing a primary anti-infective agent obtainable persisted for so many months before without improvement, from pepper, or an equivalent wherein a therapeutically often referring to the medicine as "a literal Godsend' effective amount is a concentration within the range of The treatment is discontinued after only two weeks, and ground spice or oleonesin. the boy is healed without relapse after many weeks of 7. A method as in any one of claims 5 or 6, wherein the observation even until the time of this writing. disease infects the feet, Thus the reader will see from these several examples that 8. A method as in any one of claims 5 or 6, wherein the treatments containing pepper extracts provide a degree of disease infects the body area. Page 13 of 13 6,063,381 23 24 9. A method as in any one of claims 5 or 6, wherein the 15. A method as in any one of claims 2, 3, 5, or 6, wherein disease infects the crotch area. said plant is piperaceous, 10. The method of claim 6, wherein the disease infects the 16. A method as in anyone of claims 2, 3, 5, or 6, wherein scalp. said agent contains a piperidine constituent. 11. A method as in any one of claims 1-6, wherein the 5 17. A method as in any one of claims 1-6, wherein said disease is candidiasis. pepper is cayenne. 12. A method as in any one of claims 1-6, wherein said 18. A method as in any one of claims 1-6, wherein said agent is a synthetic. pepper is paprika. a a 13. A method as in any one of claims 2, 3, 5, or 6, wherein 19. A method as in any one of claims 1-6, wherein said said pepper is a Capsicum. 10 pepper is black. 14. A method as in any one of claims 1-6, wherein said agent is a capsaicinoid analog. 2 : k is k