CA2326614A1 - The use of polyamines in the treatment of dermatological symptoms - Google Patents

Abstract

This invention provides for the use of non-toxic polyamines in the palliative treatment of chronic diseases and disorders of epithelial tissue. The effectiveness of treatment is evidenced by alleviation of symptoms and disorders manifesting in epithelial tissue such as skin, including pruritus, erythema, pain, parastesia and general discomfort, due to the topical administration of certain polyamines. Such symptoms arise from and/or are associated with chronic conditions such as: (i) skin diseases such as inflammatory dermatoses which include atopic and contact eczema, including xerosis such as dry skin and Winter itch; (ii) infection of epithelial tissue (eg. nasal, vulvar or anal passages) with trichomonas or fungi, anal fissures, fistula discharge, wound effluent, or surgical wound drainage; (iii) "secondary disease" in which epithelial tissue exhibits manifestations of the primary underlying disease such as AIDS, chicken pox and metabolic disorders (i.e., diabetes, hepatic and kidney dysfunction and hematopoesis); and (iv) disorders arising out of direct insult to the epithelial tissue following natural (local tumors, hemorrhoids) or surgical intervention and accompanying scar formation or radiation therapy.

Description

THE USE OF POLYAV1INES IN THF: TREATMENT
OF DERMATOLOGICAL SYrvIPTOMS
FIELD OF INVENTION
The present invention relates to the use of non-toxic polyamincs in the palliative treatment of chronic diseases and symptoms associated with epithelial tissue.
BACKGROUND OF THE INVENTION
Epithelial tissue forms a continuous layer. or sheet. over the entire body surface and most of the body's inner cavities. On the external surface, itfomzsacoveringthat.lliketheepidermisinplants.protectsthe animal from injury and drying out. On intemai surfaces, this tissu,emay bespecialized forother functions in addition to protection. The epithelium may be stratified which means to exist as layers piled one over the other. The nose, mouth, anal canal. and vagina are all lined by stratified squamous epithelium. The outer layer of skin is also stratified squamous epithelium, except here the cells have been reinforced by keratin. a protein that strengthens cells.
The skin is an organ because itconsists of tissues structurally joined together to perform specific activities.
It is one of the larger organs of the body in terms of surface area. The skin is complex in structure and perfom~ts several functions essential far survival. which may be grouped as Collows: maintenanceof body temperature. protection by providing a physical barrier that protects underlying tissues from physical abrasion, bacterial invasion, dehydration and ultraviolet radiation:
perception of stimuli because the skin contains numerous nerve endings and receptors that detect stimuli related to temperature, touch, pressure and pain: excretion, wherein perspiration assists in the excretion of small amounts of water, salts and several organic compounds: synthesis of vitamin D: and immunity. From a clinical perspective. the skin reflects physiological and pathological changes in other areas of the body, such that skin chances can be used to aid medical diaenosis.
Acute Exacerbation and Skin Irritation 3~ ln-itation is def fined cenerallv as a reaction to that which is irritatine. The term, irritation. characterizes an abnormal state of the skin that is produced in reaction to an acute exacerbation or a stimulant le.g..

Substitute Sheet (Rule 2.6) chemical or mechanical). Typical symptoms thatcan result from inztation include itching (pruntus). stinging.
burning. tingling. "tightness." erythema (redness) or edema t..<;weliing).
A great many chemical compounds are known to cause dermatolocic irritation of the skin upon contact.
The reaction of the skin to such contact can range from a simple reddening and drying, as is common following repeated contact withdetergent solutions during dishwashing and housework. to very severe blistering of the skin such as that whichoccurs following contact with poison ivy. Theusefuiness of a great many chemical compounds is severely limited because of their tendency to cause skin irritation.
'There are a numberof known treatments for acute skin irritations - many of which are over-the-counter pharmaceuticals compositions. Many attempts have been made to ~~reduce the irritation potential of topical products by identifying chemicals which tend to cause irritation and reducing theirconcentratian. Various amine-containing compounds have been used as anti-irritants. Forexample, salts of glutamic acid, an amino acidcontaining an acidic negatively-charged side chain. have been found to be useful as topical agents in relieving the discomfort associated with insect bites (Sere U.S.
Patent No. 4.062.937). Sodium dihydroxyethylglycine has been used in formulating cleansing and disinfecting solutions which are also claimed to reduce pain and itching (See U.S. Patent No. 4.86fs.213).
PCT application PCT/US9610I289 describes the useof mufti-protonated organic polyamines to provide topical skin anti-irritant effects, and formulations containing such compounds. These formulations are directed to suppress skin irritation due to chemical or environmental exposure, tissue inflammation, injury or other skin pathology, in addition to treating irritation caused by topical application of products. The use is also directed towards et iminating the skin irritation caused by s k in diseases or other conditions such as environmental exposure to irritating chemicals orenvironmental inMuences, such as wind. In each of these demzatological situations, however, the focus of the treatment is treatment of irritation.
10 Chronic Manifestations ojSkin Diseases and Disorders Skin diseases, scars. and infections are all examples of chronic disorclers that manifest in the skin. Diseases.
such as excema. exhibit a primary manifestation in the skin. whereas diseases such as AIDS present a secondary manifestation intheskin. Skin damage caused byaccidernorsurgerypresentswithsymptoms 1 ~ acquiring chronic care for the duration of the wound healing process which can last 1- 2 years. Infections of epithelial tissue, such as herpes virus. can also manifest in t;he skin as a chronic disorder.
Dermatoses refer to diseases o~theski~n. which exhibit any skin les ion or groupof lesions. oreruptions of any kind. Inflammatory dermatoses are usually associated with pruritus, ervthema and scalint=.. The CA 02326614 2000-09-29 Substitute Sheet (Rule 26;~

inflammatory dermatoses include contact eczema. atopic dern~atosis and xerosis.
There are a numberof symptoms and disorders that can chronicall!r manifest in the skin. either as adirect result of disease or injury (physical, chemical. microbiological, radiation) to theskin, oral adisease that manifests elsewhere in the body. Pruritus. crythema and pain are common chronic symptoms that accompany diseases of and insults to the skin: and. inparticular inflammatory dermatoses (atopic and crlntacteczema. xerosis). including the pnuiac components of otherdiseases and conditions such as wound healing.
Eczema represents an inf lan~unatory response of the skin to a spexavm of external and internal factors that act alone or in combination to induce the response. Histologically, eczema is defined by: the presence of an inf i 1 crate. predominantly i vmphohistiocytic that surrounds the upper dem~al blood vessels: association with spongiosis: and varying degrees of acanthosis. Classification of ttte principal forms of eczema is difficult because of the multiplicity of potential contributive factors: nonetheless. a summary of the various fomu of eczema induced by external and internal factors is provided in Table 1.
TABLE I
ZO External (Exogenous) Eczemas Internal (Endoeenous) Eczemas Irritant Dermatitis Atopic eczema Allergic contact dem~atitis Seborrhoeic dermatitis and Pityrosporal folliculitis Photoallergic contact dermatitis Asteatotic eczema 15 Eczematous polymorphic light eruption Discoid eczema Infective dermatitis Exudative discoid and fichenoid dermatitis Dermatophytide Chronic scaly superficial dermatitis Pityriasis alba 20 Hand eczema Gravitational eczema Juvenile plantar dermatosis Metabolic eczema. or eczema associated with systemic disease 25 Eczematous drug eruptions Atopic dermatitis is a chronic, pruritic. eczematous condition of the skin that is associated with a personal or fami lv history of atopic disease (e.g.. asthma. aliertic rhinitis. or atopic dermatitis). There appears to be a geneticpradisposition that can be exacerbated by numerous factors including food allergy. skin infections.
30 irritating clothes or chemicats and emotions. Lichenification is the clinical hallmark. Patients with atopic demTatosis usually have a histon~ of allergy and are generally untreatable.
The allergic response gives rise CA 02326614 2000-09-29 Substitute Sheet (Rule 26) to an inflammatory response that manifests in nasal. lung or other dermal tissue.
There are six general symptoms or signs associated with atopic dermatitis or eczema and these are:
erythema, exudation. excoriation. dryness, cracking and lichenific:ation.
Briefly, exudationor cueaneous eruption is an early feature of eczema and refers specif icallv to thE:
translation of eczema from the Greek meaning "boiling over". In chronic cases, theskin exhibits key fean;~res such as scaling. excoriation. dryness and cracking. Eventually. the skin acquires a leathery appearance with hyperkeratosis (Iichenificaiionl usually exacerbated by concomitant symptoms such as itching.
F'raritus Pruritus is an unpleasant sensation that elicits the desire to scratch. It is a distressing symptom that can cause discomfort and threaten the effectiveness of the skin as a maj or protE;ctive barrier. Because of the subjective nature of pruritus, the lack of a precise definition. and the lack ol'suitable animal models, pnrritus is a I5 disorder that has not been researched adequately.
Pruritis and pain can accompany scar formation. Scar tissue is formed during healing of wounds, caused forexample by bum, traumatic injury and elective operative incisions. Often unpredictably. hypertrophy of the scar tissue occurs. Hypertrophic scar formation is characterized by the accumulation of col lagen type III out of proportion to collagen type I.
Hematologic disorders that cause pruritus include polycythemia, vera. Some conditions that cause iron deficiency. including exfoiiativeskindisorder, alsocause pnuicus. Diabetes and thyrotoxicosis are endocrine causes of prtrritus (Abel. E.A.. Farber. E.M. "Malignantcutaneous ourrtours"
In Rubenstein. E.. Fedemtart.
D.D., ed.s Scientific American Medicine (New York: Scientific ~tmerican. Inc.
Chapter2. Dermatology Section XII).
Pruritus is a frequent clinical manifestation of people with AIDS. AIDS-related Kaposi's sarcoma, and AIDS-related opportunistic infections. Pruritus with or without rash has been reported in approximately 84% of people with AIDS and 35.5% of those with AIDS-related Kaposi's sarcoma.
The incidence of pruritus associated with AIDS-related opportunistic infections apyproaches 100% (Dangel. R.B.. Pruritus and cancer. Oncology Nursing Forum 13 (1): 17-21. 1986).
V arious malignant diseases are known to produce pruritus. Hodekin's diseasecauses pruritus in 10'0 - 25%
of patients. In some instances, pruritus precedes diagnosis of the lymphoma (Abel EA. F'arber EM:
Malignantcutaneous tumors. In: Rubenstein E. Federman DD. Eds.: Scientific American. Medicine. New CA 02326614 2000-09-29 Substitute Sheet {Rule 26) York: Scientific American. Inc. Chapter 2: Dermatology. Section XII). and may be an inaicatorof a less favorable prognosis when associated withsignifi.cant feverorweie;ht loss ("B"
symptoms) BemrtardJD:
Clinical aspects of pruritus. In: Fitzpatrick TB. Eisen AZ. Wolff K. et al..
Eds.: Dermatology in General Medicine. New York: McGraw-Hill. 3rd ed..1987, pp 78-90). Pruritus associated with Hodgkin's disease is characterized by symptoms of burning and intense itching occurring on a localized skin area. frequently on the lower legs. Other lymphomas and lcukemias have been associated with a less intense but more generalized pruritus. Adenocarcinomas and squamous cell carcinomas of various organs (i.e.. stomach.
pancreas. lung, colon. brain. breast. and prostate) sometimes produce generalized pruritus that is more pronounced on the legs, upper trunk. and extensor surfaces of the upyper extremities (Abel EA. Farber EM:
Malignantcutaneous tumors. In: Rubenstein E. FedermanDD, Eds.: Scientific American. Medicine. New York: Scientific American. Inc. Chapter 2: Dermatology, Section XII:
BemhardJD: Clinical aspects of pnuitus. In: Fitzpatrick TB. Eisen AZ. Wolff K. et ai.. Eds.: Dermato logy in General Medicine. New York:
McGraw-Hill. 3rd ed.. 1987, pp 78-90).
IS
Pruricusassociatedwithmalignantdiseaseshasbeenobservedtodirninishordisappearwit heradicationof the tumor and reappear with recurrence of disease Bemhard JD: Clinical aspects of pruritus. In: Fitzpatrick Tf3. Eisen AZ, Wolff K. et al.. Eds.: Dermatology in General Medicine. New York: McGraw-Hilt. 3rd ed..
1987, pp 78-90).
Drugs associated with secondary pruritus include opium derivativE;s (cocaine, morphine, butorphanol).
phenothiazines, tolbutamide, erythromycin estolate, anabolic hormones.
estrogeru, progestiru, testosterone and subsequent cholestasis, aspirin, quinidine and other antimalarials, biologics such as monoclonal antibodies, and vitamin B complex. Subclinical sensitivity toany drug may be related topruritus (Bernhard JD: Clinical aspects of pruritus. in: FitzpatrickTB. Eisen AZ. Wolff F;. et al.. Eds.: Dermatology in General Medicine. New York: McGraw-Hill. 3rd ed.. 1987, pp 78-90).
Hypothesized mechanisms of pnuitus have been inferred from studies of pain, since pain and itching share common molecuiarandneurophysialogical mechanisms (Greaves IVIW:
Pathophysiologyof pruritus.In:
Fitzpatrick TB. Eisen AZ. Wolff K, et al.. Eds.: Dermatology in Genera!
Medicine. New York:
McGrawHill. 3rd ed..1987. pp 7478). Both itch and pain sensations result from the activationof a network of free nerveendings at the dermalepidemzat junction. Activation may be the result of internal or external thermal. mechanical, chemical. or electrical stimulation. Thecucarteous nerve stimulation is activated or mediated by several substances including histamine. vasoactive peptides.
enkephalins. substance P (a tachvkinin chataffects smooth muscle), and prostaglandins. It is believed that nonanatomic factors lsuch as 3~ psychological stress. tolerance, presence and intensity of other sensations andlordistractions) determine itch sensitivity in different rceians of the body.
CA 02326614 2000-09-29 Substitute Sheet (Rule 2ti) The itch impulse is aarumitted along the same neural pathway as pain impulses, i.c., traveling f rom peripheral nerves to the dorsal horn of the spinal cord, across the cord via the anterior commissure. and ascending along the spinothalamic tract to the laminar nuclei of the contralateral thalamus. Thalamocortical tracts of tertiary neurons are believed to relay the impulse through the integrating reticular activating system of the thalamus to several areas of the cerebral cortex. Factors that are believed to enhance the sensation of itch irtciude dryness of the epidermis and dermis. anoxia of tissues. dilation of the capillaries. irritating stimuli, and psychological responses (Abel EA. FarberEM. Malignant cutaneous tumors. In:
Rubenstein E.. Federman DD. Eds.: Scientific American. Medicine. New York: Scientific American. lnc.
Chapter2: Dermatology, Section XII: BernhardJD. Clinical aspects of pruritus. in: FitzpatrickTB.
Eisen AZ. Wolff K. et al.. Eds.:
Dermatology in Genera! Medicine. New York: McGrawHiIl. 3rd ed.. 1987, pp 7890:
Greaves MW, Pathophysiology of pruritus. In: Fitzpatrick T'B. Eisen AZ. Wolff K. et al..
Eds.: Dermatology in General Medicine. New 'York: McGrawHill. 3rd ed.. 1987, pp 7478: Duncan WC. Fenske NA.
Cutaneous signs of internal disease in the elderly. Geriatrics 45(8): 2430. 1990).
IS The motor response of scratching follows the perception of i~:ch.
Scratching is modulated at the corticothalamic center and is a spinal reflex. After scratching, itching may be relieved for I 5 to 25 minutes.
The mechanism through which the itch is relieved by scratching is unknown. It is hypothesized that scratching generates sensory impulses. which break circuits in the relay areas of the spinal cord. Scratching may actually enhance the sensation of itching, creating a characteristic itch-scratch-itch cycle. Otherphysical stimuli such as vibration, heat. cold, and ultraviolet radiation diminish itching and increase the releaseof proteolytic enzymes potentially eliciting the itch-scratch-itch cycle.
A pinprick nearor in the same dermatome as an itchy point will abolish the itch sensation (Bernhard JD:
Clinical aspects of ptwitus. in: FitzpatrickTB. Eisen AZ. Wolff K. etal..
Eds.: Dermatology in General ZS Medicine. New York: MeGrawHill. 3rd ed.. 1987, pp 7890). llt is known that hard scratching may substitute pain for the itch, and in some ins lances. the patient might find pain the more tolerable sensation.
It is thought that spinal modulation of afferent stimuli (Gate theory) and central mechanisms may play a role ir, the relief of itch (Bernhard JD, supra).
Hypothesized pathogeneses of pruritus associated with underlying diseasestates are varied Biliary. hepatic.
renal. and malignant diseases are thought to produce pruritus through circulating toxic substances. Histamine released from circulating basophils and the release of leukopeptidase from white blood cells may trigger pnuitus associated with lymphomas and leukemias. Elevated blood hovels of kininogen in Hodgkin's disease.
release of histamine or bradykinin precursors from solid tumors, arid release of serotonin in carcinoid may all be related to pruritus (Abel EA. Farber EM : Malignant cutaneonis tumors.
In: Rubenstein E. Federman DD. Eds.: Scientific American. Medicine. New York: Scientific American. Inc.
Chapter?: Dermatology, CA 02326614 2000-09-29 Substitute Sheet (Rule 26) Section XII: Abel EA. Farber EM: Drug eruptions and urticaria. ln: Rubenstein E. Federman DD. Eds.:
Scientific American. Medicine. New York: Scientific American. Inc. Chapter 2:
Dermatology, Section V1).
People receiving cytotoxic chemotherapy, irradiation. and/or bioloeic response modifiers for treatment of malignancy are likely to experience pmritus. This same population is quite likely to beexposed to manyof the otheretioiogic factors relating to pniritus ranging from nutritionally relatedxerosis (dry skin) to radiation dfsquamation, chemotherapy and biologic agent-induced side effects, antibiotic reactions. and otherdrug sensitivities.
Eachof the major classes of antineoplastic agents (alkylating agents.
antimetabolites, antibiotics, plant alkaloids, nitrosoureas, and enzymes) include drugs capableof producing cutaneous reactions including pruritus. Patients nyceiving antineoplastic drugs frequently report d.ry skin and scaling thought to be related to effects on sebaceous and sweat glands (Dunagin WG: Clinical toxicity of chemotherapeutic agents:
demlatologic toxicity. Seminars in Gncology 9 (1 ) : 14-22.1982: Hood AF:
Cutaneous side effects of cancer chemotherapy. Medical Clinics of North America 70( 1 ): 187-209. 1! 986). Many problems are self limiting and require no active intervention. Other problems warrant anticipation and implementation of preventive measures.
Hypersensitivity to cytotoxic agents can be manifested by pruritus, edema, urticaria, and erythema.
Hypersensitivity reactions vary in symptomatology and depend on the drug, the dosage, and the allergy historyofthepatient. The agents most associated withhypersensitivitiesincludedoxorubicin.daunorubicin, cytarabine. Lasparaginase, paclitaxel, and cisplatin. In most reports, these reactions have been localized to the area of the vascular access and dissipate within 30 to 90 minutes (Gullo SM: Adriamycin extravasation versus flare. Oncology Nursing Forum 7(4): 7.1980: Barlock AL. Howser DM.
Hubbard SM: Nursing management of Adriamycin flare. American.loumal of Nursing 7~~(1):94-96.1979).
Moredramaticand even life-threatening reactions can occur, and the development of pruritus may represent an early stage of serious hypersensitivity reactions (Weirs RB: Hypersensitivity reactions tocancerchemotherapy. In: Petty MC, YarbroJW, Eds.: Clinical Oncology Monographs: Toxicity of Chemotherapy.
Orlando. FL: Grune and Stratton. Inc.. 1984, pp 101-123).
Radiation therapy-related pruritus is usually associated with drv desquamation of skin within the treatment field. Dryness and pruritus may occur at an accumulated dose of 2.000 to 2800 cGy, (Hassey iCM. Rose CM: Altered skin integrity in patients receiving radiation therapy. Oncology Nursing Forum 9(4): 44-50.
1982) and is caused by obliteration ol'sebaceous glands within the field. This is an acute phenomenon that correlates with the depletion of actively proliferating basal cells in the epidermal layerof the skin. a fixed percentageof which dies with each dose fraction of irradiation. Remaining basal cells undergo comif ication CA 02326614 2000-09-29 Substitute Sheet (Rule 26) and shed at an increased rate, while nonproliferating basal cells are stimulated and their cell cycle shortened.
subsequent peelin g of the skin is defined as dry desquamation. The skin becomes dry and the patient may notice itchine and burning sensations (Hassev KM. Rose CM: Altered skin integrity in patients receiving radiation therapy. Oncology Nursing Forum 9(4) : 44-50.1982). Dry skin is susceptible to further. irtjtuy throueh scratching and/or formation of fissures. augmenting the risk of infection and tissue necrosis.
I f the desquamation process continues. the dermis will eventually be exposed and moist desquamation results. This side effect increases the risk of infection, discorrufort, and pain. possibly necessitating interruption of a treatment plan to allow for healing. This can compromise the final outcome of cancer therapy. For this reason, it is desirable to anticipate and prevent the progression of skin reactions to this stage (Miaskowski C: Potential and actual impairments in skin. integrity related to cancer and cancer treatment. Topics in Clinical Nursing 5(2): 64-71. 1983).
)~xtema! beam therapy with electrons may elicit more skin reactions than photon therapy since thedepth of penetration and linear energy transfer is closer to the skin surface with electrons. Radiation delivery techniques (bolus doses and tangential fields) also influence the degree of reaction.
Fields that includeskin folds (i.e., the axilla, breast. perineum, and gluteus) are anticipated to have incm"ased reactions because of friction, higher moisture content. and low aeratinn (ORourke ME: Enhanced cutaneous effects in combinedmodality therapy. Oncology Nursing Fontun 14(6):31-35.1987:
Hassey KM: Skincare forpatients receiving radiation therapy forrectal cancer. Journal of Enterostomal Therapy 14(5):197-200, 1987).
Biologic response modifiers used in the treatment of malignant di'~ease are associated with a wide variety of sideeffects and toxic effects. Pruritus has been a side effect asso~~iated with several biologics. but has so farbeen most reported in patients receiving interferon (Mayer DK. Smalley RV:
Interferon: currentstatus.
Oncology Nursing Forum 10(4): 14-19.1983: Krown SE: Interferons and interferon inducers in cancer treatment. Seminars in Oncology 13(2): 207-217.1986: Spiegel RJ: Intron A f Interferon Alfa-2B): clinical overview and future directions. Seminars in Oncology 13(3. Suppl2): 89-101.1986: lrwin MM: Patients rcxeiving biological response modifiers: overview of nursing care. ~Dncoiogy Nursins: Forum 14(Suppl 6):
32-37. 1987).
To date. reports of pruritus as a side effect of bioioeics are primarily anecdotal and have not been a focus of attention.
Graft-versus-host disease (GVHD) affects 25~"c - 5010 of patients who live longer than I 00 days after bone CA 02326614 2000-09-29 Substitute Sheet (Rule 26) marrow transplantation. The incidence of skin GVHD is reported to be 80%- 90%a and symptoms vary in severity and type (Sullivan KM. Deeg HJ. Sanders JE, et al.: Late complications after marrow transplantation. Seminars in Hematology 21 (1): 53-63. 1984).
Reported skin changes include dryness and pruritic. ervthematou~;.
maculopapular rashes. Onset can be subtle or sudden: skin G VHD can progress to scieroderma and contracture (Nims J~V. 5trom S: Late complications of bone marrow transplant recipients: nwsing care issuca.
Seminars in Oncotogy Nursing 4( 1 ):
4 ~ -54. 1988).
Manypharmacologicagentsemployedatanypointduringthecancercourse.whetherinaprimar ytreatment plan or incorporated into a symptom control or supportive care prog ram. are capable of eI icitin,g a prutitic reaction. These drugs include morphine, other opiwn derivatives. and aspirinused inpain management:
corticosteroids: antibiotics: phenochiazines: and to a tesserdegree, hormonal agents (estrogen, progestins.
and testosterone) (BemhardJD: Clinical aspects of pruritus. In: Fitzpatrick TB. Eisen AZ. Wolff K, et al..
Eds.: Dermatology in General Medicine. New York: McGraw-Hill. 3rded.,1987, pp 78-90). Mechanisms of these reactions range from hypersensitivity to chemical interferene~~ with newal pathways (Greaves MW:
Pathophysiology of pruritus. In: Fitzpatrick TB. Eisen AZ. Wolff K., et al..
Eds.: Dermatology in General Medicine. New York: McGraw-Hill, 3rd ed.. 1987, pp 74-78).
Chronic infections and disorders of epidermal tissuecan also give rise to symptoms such as pnrricus. Pnzrittrs involving anal or vulvar areas might be caused by infections with trichomonas or fungi, local tumors.
hemorrhoids, anal fissures, fistula discharge, wound effluent, or surgical wound drainage.
Herpes simplex virus (HSV) is a medium-sized DNA virus that replicates within the cell nucleus. It is ZS divided into two types - HSV-1 and HSV-2. Usually. HSV-1 causes oral infection, and HSV-2 causes genital infection. Primary infections with these viruses are characteristically followed by recwrent attacks.
which are often preceded by localized itching or burning and characterized by occurrence in the same location. It is estimated that 100 millionepisodes of oral herpes and one-half million new cases of genital herpes occur each vear in the United States. HS V infection is not limited to the lips and genital area: either type can infect anv area of skin.
Oneexample of achronicdisorderof epidermal tissue that can eiv~e rise to pruritus is hemorrhoids ipiles) which result from varicosities of the rectal veins. Initially contained within the anus (first degree). thev gradually enlarge unti 1 thcy proiapse or extend outward on defecation (second degree) and finally remain prolapsed through the anal orifice (third degree).

CA 02326614 2000-09-29 Substitute Sheet (Rule 26) Ervthema Erythema (redness of the skin) is acardinal symptom of an inflammatory response within the skin. Other symptoms include swelling, heat and pain.
The underlying inflammatory processes are respons ib fe for the red appearance and are observable due to the numbers and v isibility of red blood cells in theskin. The cause of the increase in red blood cells includes:
increased blood flow throughdilated blood vessels: direct stimulu;~ upon the supe~cial blood vessels: or.
from obstructions in deeper vessels causing a shunting of blood through the superficial vessels.
Paresthesia Altered or abnormal skin sensation can manifest in patients in a number of ways: numbness, tingling, prickling, burning, crawling sensations. itch. increased awareness amd pain.
These paresthesias have many different causes but generally reflect damage to particularsensory neurons such as the peripheral nerve fibers.
Many, if not most, ailments of the body cause pain. Pain is a protective mechanism for the body: it occurs whenever any tissues are being damaged and it causes the individual to react to remove the painful stinnrlus.
Pain receptors in the skin and other tissues are nerve terminals, that lack any special characteristics, and they are likely triggered by a chemical stimulus when potential tissue damage occurs. There appear to be two types of terminals: one responds to many types of painful stimuli. whereas the otherspecifically responds to either mechanical or thermal energy.
The receptors that are sensitive to various chemical substances and are called chemosensitive pain receptors. Some of the different chemicals that excite thechemosensitivereceptorsincludebradykinin, serotonin, histamine, potassium ions. acids. prostaglandins, acetylcholine.
and proteolytic enzymes.
Extracts from damaged tissues cause intense pain when injected beneath the normal skin. Among the substances in such extracts that are especially painful are bradykir~in.
histamine. prostaglandins, acids.
excesses of potassium ions, serotanin. and proteolytic enzymes. which are the same substances that are known fromelectrophysiological data to excite the pain nerveendings.
Obviously. many of thesesubstanoes could cause direct damage to the pain nerve endings, especially the proteolvtic enzymes. But same of the other substances. such asbradykininandsomeoftheprostaglandinscancausedirectextremestimulation ~f pain nerve fibers without necessarily damaging them.
CA 02326614 2000-09-29 Substitute Sheet (Rule 26;1 Release of the various substances listed above not onl v stimulates the chemosensitive pain endings but also greatiydecreases the threshold forstimulation of the mechanosensitive and thermosensitive pain rt:ceptors as well. A widely known example of this is the extreme pain caused by slight mechanical or heat stimuli following tissue damage by sunburn.
Accordingly, a need exists for topical and non-toxic therapeutic agents for the treatment of pturitus.
erythema and associated pain.
Pharmacologic Therapy Eczema is a chronic condition with periods of remiss ion and exacerbation:
management of the disease is based on avoidance. reduction or elimination of itch and appropriate therapy.
Avoidance guidelines stress the need to monitordiet. use of cosmetics, fabric composition of clothing and reactions to various medications. It is also understood that strong topical sensitizers (neomycin.
anti-histamines), suddenchanges orextremes of temperature or husrtidity, and various air-borne irritants should be avoided.
If treatment of the underlying disease and/or control of other aggravating factors provide inadequate relief of pruritus, topical and oral medications may be useful.
Topical steroids may provide relief when symptoms are related to a steroid-responsive dem7atosis, but anticipated benefits must be weighed against the vasoconstrictive side effects. Topical steroids have no role in the management of pruri;tus of unknown origin. Topical steroids should not be applied to skin surfaces inside a radiation treatment field.
Systemic medications useful in the management of pmritus include those directed toward theunderlying disease or control of symptoms. .Antibiotics can reduce symptoms associated with infection. Oral antihistamines may provide symptomatic relief in histamine-n~lated itching.
Aspirin seems to have reduced pruritus in some individuals while increasing pruritus in others.
T!uombocytopenic cancer patients should be cautioned against using aspirin.
Cimetidine alone or in combination with aspirin has been used with some effectiveness forpruritus associated with Hodgkin's disease andpotycvthemia vera (Daly, B.M.. Shunter. S. "Effect of aspirin onpruritus. "British Medical Journal 293 (6~~2?:907-908. 1986).

CA 02326614 2000-09-29 Substitute Sheet (Rule 26;) Symptoms Associated with i~4ound and Sore Healing A scar is a mark left in the skin or an internal organ by the healirtg of a wound. sore. or injury because of replacement by connective tissue of the injured tissue. Scar tissue; may form during the healing of wounds, lesions of diseases. surgical operations, in adiation, laceration. burns or infections.
Often unpredictably. hvpenrophy of the scar tissue occurs. A hvpnnrophic scar is an excessive wound scar which by definition has grown in size beyond that required for normal wound healing. Hyperirophic scars can emerge from many wound types, such as from a bum or a sharp incision.
Keloids, a more severe form I 0 of hypertrophic wound scar, form firm dermal nodules of scar which are most commonly preceded by trauma at the site of origin They art; usual ly larger than hypertrophic scars and differ in that they frequently invade the normal skin adjacent to the wound. Hypertrophic scar formation is characterized by the accumulation of collagen type iII out of proportion to collagen type I.
1 S lnnormai wound-healing orsore-healing processes, the abundant vascular network is regenerated in the 'wound or the sore during the maturing phase and the collagen fibexs collect in large bundles. Sometimes this maturing process fails to occur, so that granulation tissue remains beneath the covering epithelium for a relatively Iong period of time and may even develop and become enlarged.
This is the clinical nature of a hypertrophic scar.
A hypertrophic scar is a raised, red and itching enlargement. The scar may be tender to the touch and to other external pressure and can form on every afflicted part of the t~ody, although it is most prevalent after burn injuries and as a result of wounds across the breastbone and in the shoulder regions.
i-Iypertrophic scars often remain for a very tong time. sometimes until the person dies. In the case of adults, the hypertrophic scar wil I normal t y transform to a typical sof t and pale scar after a year or so. In addition to itching and being relatively unsightly, hypertrophicscars in the regionof joints can also impair joint mobility.
The Therapeutic Use of Polvamines For Cell Growth Regulation and as Anti-Fibrottc .Agents 'I'heuseofpoiyaminesforthethcrapeutictreatmentoftissuedamareisknowninthean.
Farexamplc.
polavmines are thoueht to function as inhibitors of transglutaminas~~ and/or iysyl oxidase, affectine coliaeen formation.

CA 02326614 2000-09-29 Substitute Sheet (Rule 2bi) Forexample. Raisfeld describes the use of compositions inctucling polyamines to reeuiate. stimulate or inhibit, epithelial cell growth in United States Patent No. 4.507.321. In particular this method teaches compositioru containing polyamines which art' useful in low concentration to stimulate epithelial cell growth and are useful in high concentration to inhibit fibroblast growth to diminish scar formation. by reducing the degree to which fibroblasts proliferate and produce collagen. thereby forming scar tissue. In low concentrations. these compounds are useful in promoting wound healing, treating bums. treating ischemic debubitus and peptic ulcers, plastic and reconstructive surgery', dermatological disorders, promoting autograft and homograft growth, stimulating organ and tissue regeneration in vitro and in vivo, as a component in defined (serum protein-free) media for cultured cells.
Compositions containing these compounds in higher concentrations are useful in the inhibition of cell growth and are useful in the treatment of psoriasis and in retardation of fibrosis after injuries to the spinal cord and nervous system.
As described by Kagan and Gacheru in United States Patent No. 4,997.854.
adjacently positioned diamutes have been used as anti-fibrotic agents. by inhibiting the activity of lysyl oxidase. Thesecompounds gave been used to treat a wide variety of different pathological fibrotic diseases. disorders, and abnormalities where the pathology involves cross-linking of the individual collagen alpha chains. Lysy! oxidase creates a critical modification between the collagenpolypeptide alpha chains by creating cross-linkages which is the basis of theswctural stability, maturation. and strengthof collaF;en andscartissue in general. Thecross-linking of the individual collagen alpha chains is the majorcontributor to the tensile strengthof the cross-linked fibrils. Depending upon the location of the collagen chain formation and its cross-linking viathe enzyme lysyl oxidase, the abnormalities may take form in a variehr of clinically identifiable and disgnosed conditions. It has been proposed that by preventing the oxidative deamination of lysine and hydroxylysine amino groups within the collagen alpha chains, which is the enzymatic function and specific activity of lysyl oxidase. the physical properties of the collaeenscartissueand the resulting fibroticpathological state could be substantialiv reduced.
Polyamines have beenused as a transglutaminase inhibitor fora numberof applications. In United States Patent No. x.124.358, a method is described for blocking maturation and production of microfilariae in adult filarial nematodes, applying this method to several Brugia filarial infections.
To date. the only generalized treatment of the symptoms of pruritus and erythema involves the useof steroids. These compounds can only safely be used for short periods of time.
on theorderof 7-lOdavs.
Thus. they are not safe and effective for lone term treatment of the symptoms.
'hheretore. it is apparent that a need remains for a means of managing the symptoms associated with dermatolo eical disorders and insul is to the skin. A particular need remains for a compound that may be CA 02326614 2000-09-29 Substitute Sheet (Rule 2E~) applied topically in the palliative treatment of chronic diseases ;and disorders of epithelial tissue. The effectiveness of treatment is evidenced by alleviation of symptom: and disorders manifesting in epithelial tissue such as skin. including pnuitus. erytttema. pain, parasthesia and eeneral discomfort, due to the topical administration of certain polyamines. Such symptoms arise from and/or are associated with chronic conditions such as: ( i) skin diseases such as inflammatory dermatoses which include atopic and contact eczema. including xerosis such as dry skin and Winter itch: (ii) infet;tion of epithelial tissue leg. nasal. vulvar oranaipassages) with trichomonas or fungi, anal fissures. fistuladischarge, wound effluent, or surgical wounddrainage; (iii) "secondary disease' in which epithelial tissue exhibits manifestations of theprimaw underlying disease such as AIDS, chicken pox and metabolic disorders (i.e., diabetes, hepatic and kidney dysfunction and hematopoesis): and f iv) disorders arising out of direct insult to the epithelial tissue following natural (local tumors, hemorrhoids) or surgical intervention and accompanying scar formation c>r radiation therapy.
IS SUMMARY OF THE INVENTION
It is, therefore, an object of this invention to provide a use for ~oolyamines as a topical, a non-toxic therapeutic for the pal li ative treatment o f skin disorders associated with disease and insul is to the skin. In particular, symptoms and disorders manifesting in the skin such as F~ruritus.
erythema, pain, paresthesiaand general discomfort can be alleviated by the topical administration o f one or more polyanunes as part of the palliative treatment of the underlying skin disorder.
It is a further abject of this invention to provide a use for polyami nes to treat symptoms that arise from and/or are associated with skin diseases such as inflammatory derma.toses which include atopic and contact eczema, including xerosis such as dry skin and Winter itch.
It is yet a further object of this invention to provide a use for polyamines to treat symptoms that arise from andlorare associated with infection of epithelial tissue leg. nasal. vul varor anal passages) with trichomonas or fungi, anal fissures. fistula discharge, wound effluent. or sureical wound drainage.
It is yet a furtherobject of this invention to provide a use for polyamine;s to treat symptoms in epithelial tissue that arise from and/or are associated with "secondary disease' in which epithelial tissue exhibits manifestations of the primary underlying disease such as AIDS, chicken pox and metabolic disorders (i.c..
diabetes. hepatic and kidney dysfunction and hematopoesis).
It is still a furtherobject of this invention to provide a use forpolyarrtines to treat symptoms that arise from CA 02326614 2000-09-29 Substitute Sheet (Rule 26,'I

andior are associated with epithelial disorders arisine out of direct insult to the epithelial tissue following natural (local tumors, hemorrhoids) or sureical intervention and accompanyine scar formation orradiation therapy.
~'he present invention relates to composi dons containing polyamines an amount which enables them to act ~s palliative andlor therapeutic agents for skin disorders. wherein the polyamine is selected from the group consisting of aliphaticdi-and polyamines with straight or branched chains of length from 2 to 14 carbon atoms lone bearing 2 to 6 amine groups. and agmatine: and the phamzaceuticaily acceptable acid addition salts thereof. The aliphatic di- and polyamines of this invention are derived from aikanes, such as n-propane. isopropane, butane, isobutane. tert-butane. hexane, isohexane, heptane, octane, nonane, decane.
and dodecane. The corresponding branch chain analogs of there groups are also included. The 2 to 6 amine groups contained by the aliphatic di- and polyamines may be eitherprimaryor secondary and may be located either in a terminal position. within the alkane chaiin. or both.
I 5 Preferred compounds for use in the compos i dons and methods of the present invention are spermidine (4.
4'- iminobis butylamine), spermine, and putrescine (1. 4-diaminobutane). and cadaverine.
Synthetic polyamines, such as. N,N'-Bis-(3-ethylamino) - propyl]- I .7-heptane diamine (BEPH), are also within the scope of the invention..
The palliative and/or therapeutic diamines and po l yamines of this invention may be utilised as their free bases or as their pharmaceutically acceptable acid addition salts. Such .acid addition salts can be derived from a variety of inorganic andorganicacids suchas hydrochloric, sulfuric, phosphoric, methanesulfonic, sulfamic.
ci tric. lactic, pyruvic, oxalic, malefic. s tearic. succinic. tartaric.
fumaric. cinnamic, aspartic. acetic. benzoic.
salicylic, gluconic, ascorbic, and related acids. The salts lack the odor of the free bases. which is an additional advantage in treatment.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 presents the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study I . The results of treatment to the left and right hands are provided in the A and B figures. respectively. In Figure 1 A, the left hand received no tre~itment over the first 6 visits, however once putrescine treatment was initiated after visit 6 all signs and symptoms scores dropped indicating an improvement in skin condition. Figure 1 B demonstrates the observations of treatment wherein during the first 6 visits, the patient applied putrcscine with a resultant decline in scones indicatine improvement in skin I~
CA 02326614 2000-09-29 Substitute Sheet (Rule 26) condition. Durine the period (visits 6 - 9) the patient ceased treating the area with a resultant increase in scores of all signs and symptoms indicating a deterioration of skin condition.
Figure 2 presents the response to treatment and subsequent Paticrn and Physician Global Evaluations of the patient pmsentsd in Case Study 1. The results of treatment to the left ~md right hands are provided in Figures

2.~ and 2B. respectively.
Figure 3 presents data similar to Figure 2. except for the absence of the total signs and symptoms scores.
The results of treatment to the left and right hands arc provided in Figures 3A and 3B. respectively.
Figure 4 presents the response to treatment and subsequent total siF;ns and symptoms and pruritus of the patient presented in Case Study 1. The results of treatment to the: left and right hands are provided in Figures 4A and 4B. respectively.
1 S Figure 5 demonstrates the response to treatment and subsequent ennhema and pruritus scores by left hand (Figure SA) and right hand (Figure 5B) of the patient in Case Study 1.
Figure 6 demonstrates the response to treatment and subsequent global evaluations, patient itch assessment and pnu-itus scores by the left hand (Figure 6A) and right hand (Figure 6B) of the patient in Case Study 1.
Figure 7 presents the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study 2. The results of treatment to the left and right shins are provided in the A and B figures. respectively.
Figure 8 presents the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study 2. The results of treatment to the left and right hands are provided in the A and B
figures. respectively.
Figure 9 the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study 3. The results of treatment to the left and right hands are provided in the A and B figures.
respectively.
Figure 10 presents the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study 4. The results of treatment to the lef t and riight amls are provided in the A and B
figures, respectively.

CA 02326614 2000-09-29 Substitute Sheet (Rule 26) Figure 1 I is asummarv of signs and symptoms of patients from case studies 2 --t, initially treated with putrescine.
Thedatademonstratesthattheimportantsiensandsymptomsassociatexiwiehtheskindiseas e are alleviated by daily putrescine treatment as indicated by the; reduced scores. Further. removal of lautrescine results in a return of those signs and symptoms as indicated by an elevated score.
Figure 12 presents asummary of global physician scores of patients from case studies 2 - 4, initially treated with putrescine. The data illustrates the positive response to treatment as described by the attending physician. Removal of treatment resulted in a poorer assessment.
DETAILED DESCRIPTION OF THE INVENTION
The following terms and abbreviations are used throughout the specification and in the claims.
The term. "therapeutic" means having healing properties.
The term, "palliative", means relieving or alleviating without curing.
'lfie term. "symptom", means any perceptible change in the body or its functions that indicates disease or the kind or phase of disease.
The term, "pruritus", means severe itching; it may be a symptonn of a disease process, such as allergic response, or may be due to emotional factors: the predisposing factor is cutaneous hyperesthesia.
The term. "polyamine: ' means any compound. e.g., spermine and spe~mzidine , containing two or more amino groups. Thus, the term polyamine includes diamines.
The term "variants" and "conservative substitution" for purposes of one of the pofyamines of the present invention means any chemical structure that is a derivative of such polyamines achieved through substitution of side groups, yet still exhibits the same or similar therapeutic properties as putricine.
The term "derivative" means any chemical compound derived frnm. or regarded as being derived from.
anothercompound eitherdirectly or by modificationorpanial substitution: thus, a polyaminederivative is a chemical compound thateither was. is. orcan be regarded as having been derived from polvamine. For example, a compound such as putricine can be considered as derived from a member of the poiyamine class of compounds are considered within the scope of this invention.

3~
The term "anaioeuc" means a chemical compound having a structure s imi f ar to that of another compound CA 02326614 2000-09-29 Substitute Sheet (Rule 26) but differing from it in respect to a certain component: thus. for exarnple. a putricine anaioeue is a chemical compound with a structure similar to that of putricine.
The term "erythema" means a formof macula (spot orcolorexiarea;l showing diffused redness of theskin.
caused by capillary congestion usual ly due to dilation of the superficial arterioles as a insult of some nervous mechanism within the body; inflammation: or some external influence such as heat. ionizing radiation.
sunlight, or cold.
The term "parasthesia" means a sensation of numbness. prickling, or tingling:
heightened sensitivity; it is experienced in central and peripheral nerve lesions and in locomotor ataxia.
The term "hyperesthesia", means an increased sensitivity to sensory stimuli.
such as pain or touch.
The term. "demnatitis", means inflammation of skin evidenced by itching, redness, and various skin lesions:
it may be due to oneof several causes: systemic disease: skin irritarus such as poison ivy, conrosives. acids.
and alkalies: or hypersusceptibility to conditions that would not normally cause skin irritation. Atopic dem~atitis is dermatitis of unknown etiology marked by itching and scratching in an individual with inherently irritable skin. There may be allergic, hereditary, or psychological components.
Thepresent invention is basedupon the discovery that the topical adrr~inistration of a poiyamine compounds, such as putrescine, can alleviatemany demtal-manifested symptoms and discomfort associated with disease artd/orskin disorders. In particular, symptoms manifesting in the. skin such as pruritus, erythema, pain, parasthesia and general discomfort can be alleviated by the topical administration of certain poiyaunines.
Such symptoms arise from and/or are associated with: skin diseases such as inflammatory dermatoses which include atopic and contacteczema~, including xeros is such as dry skin and W
inter itch: disease in which the skin is nottheprimary manifestationof thedisease such ass AIDS: aunddisorders arisine out of insult to the skin such as radiation therapy and scar management.
Pnlyamines of the Invention The compounds useful in the composition and methods of the present invention arc known in the chemical art. Details of the synthetic preparation of many of the compounds utiiizabie in the compositions and methods of the present invention may be found in Beilsteins Hand6uch Der Organischen Chemie. The Merck Index. 9'~ edition. also references manv of the preferred compounds of this invention.
The chemical structure of the polyamines of this invention is baised upon the presence of an organic supportive structure- acarbon backbone having at least twocarbonatoms available for theattachmentof CA 02326614 2000-09-29 Substitute Sheet (Rule 26) I:N:~-A91 !CfvC)-it=.~\' Q-~ . ~~_~ _ i ; - ~:1 : ~?U : 7 1Z : ~.S):~1 ~. ('a.
- +=~~; Fi.7 '?:3:'334-~1~(~5 : yt c, 200L3. . . ~'tJT~~A9~JOQ2$~ DDS
primary acninrgroups. Thcscurganic Supporting structures and lheird~~rrivativc~smaycompriSesaturdted arrilurun5atur~rnr~leculc~; straight ~ ~h~ ~r~~~: ~nblc arcd muJtiplcrings inchxiing a.varieiy of hcierocychc ring structures; and any combination of these as rz~nome:rs, dimcrs, and polymers. In t~cldiuon. each of these orbanic su.;~mr'tinl; siructur~ may also con~ain substituted hydrocatixi,ne and urganic a grt~ups to form derivati.~rc;d Corms.
Tht: prefernx~icomp~:rrurxis u~u 1 in lhetx~mposition5 and methods of the jiresent inventiun arec:ncancxl by ltie fallc~wirrg formula 1:
a F H
H,~~ tcg2) r"- (N) p~ (CH1) q-(;) pz /(CH1) r . , FIzIS-cCH.,)ri".-(Fa)p~ (G~;z)s-iN)P~ .
1 ~~ ~ ~
wl>en.:in p,, pz, Pa. Pd~'c i~ently 0 or 6 ; m and n arc: indepc:ndcnlly 1-7:. q, r. s arc i ruiepcndently 0-i:withtheproviaosthatn+m+q+r+Sarf:lcas thannrcqualtol4.
LXi~hlyprefarr~c,~dcomp(~undsof formula 1 arr: those wherein m is 3, n is 4. Px. P.;. Pa, q~ r, ~ s arc ~b and pl. i5 1: m and n are 2, p,- pz.
P3. Pa~ rl. r. and s a(rc 0: and rn is 3, ~ is d, r is 2. p,, and p2, a-~c; 1.
P3 and P4 are 0, s is 0 arid n is 1.
i5 5pe.~cif ie crrmpuund 5 utrlizak~le in the compc~silinn and mell~c~ds of the lme.~tcnt invea;ticm ane lhefol lc swing: (a reference indicated i n L 1 immediately fol lowing each mmpovnd is a rc;fercnce to the chemical rion of the compound) r 5p~;rmidine (4.4'-iminobisbutylarriine) l~eil. ~ (2) ~d~.~:
!' Six;rnune. LBfiL 4 (Z) 7041, Merck hate-x 9.85151:
Yutsescine ( 1.4 diaminobutanc) fBe<<. 4 2641:
1.3-diacninapropant;. lBeil. 4 2bi3:
Agn7.atine. ((4-aminc~butyl)l;uanidi:~~. (HerL 4(1)420. Merck Jnalex 9. 7G41~;
25 1.2-diaminupropane. [Bell 4, t57, Merck Ind~r. 9. 7ti411:
1.7.0-diamirtodecanc. (Bell 4, 2?3]:
1.1.2-diarnincxiodecan~ lBeil. 4 2~3~;
3.3'~ iminobispnpylamine. 'X><c?Churn ~roplys. Rrs. Ccrmmun.. 63. 69(1975)l;
1.:~-diaminoheptdnr:. (bell. 4, 2711:
!9 ::::::::::v::::~::CA;: 0 2.: _ ., ... .:. - 0 9 - 2 9 ;:r~:
~!i~i~il~dt~li=~:~~flt~ 4 2 0 0 0 ~ '~>=

Z.b-diaminohexane. (Bell. -i. 269. Mercklr:dex 9.4564);
1 2-diamino-2-methylpropane. )Bell. -1. 266) I 9-diaminononane. (Bell. 4. 272);
1, 8-diaminoctane. [Bell. 4. 271 ): Cadaverine. ) 1.5-diaminopentane. (Bell. -t. 266. Merck Index 9, b914[;
triethylenetetraamine. [Bell. 4. 255. Fieser. Reagents jor Organic Synthesis.
1. 1204[;
triethylcnetetraamine tetrahydrochloridc. )Bell. 4. 255[:
N-(2-aminoethyi)-1.3 -propanediamine:
diethyienetriamine. (Bell. 4, 255):
ethylenediamine. [BeiL 4, 230. Mercklndex. 9.3731. Fieser.
ReagentsjorOrganicSvnthesis. l, 372.

4, X31[;
ethylenediamine dihydrochioride [Bell. 4. 230. Merck Index. 9.,3731 [; and tetraethylenepentamine.
The free base form of the compounds util izable in the present inventiion may be conveniently converted to the corresponding acid addition salt by contacting a solution of the; free base with the appropriate acid.
Particularly preferred salts are the acid additionsalts formed with hydrochloric and sulfuric acids, e.g., hydrochloride and sulfate.
The palliative activity of the compounds utitizable in thecomposition method of the present invention may be determined by measurementof the effect of the test compound in a clinical test, such as demonstrated in E;xampte I. The term "palliative" is used to denote decreased skin disorder without implying a mechanism of action.
Thccompositionsofthepresentinventioncompriseoneormoreoftheabove-mentioned compoundsina palliative amount together withasuitablepharmaceuticalcarrier.
Apalliativeamountisdefinedasthe amount of compound necessary to provide more relief from ihesignorsymptom than an untreated state.
or by vehicle alone. In the usual course of therapy, the active compound is incorporated into an acceptable vehicle to form a composition for topical administration to the affected area or into a form suitable fororal or parenteral administration, such as tablets. capsules. pills, suspensions.
injectablcs. and solutions.
Compositions for topical application may be exemplified by ointments. creams.
lotions. solutions SuS~~nSIUtIS. aerosols, gels, dusting powder. and impregnated bandages and dressings. Such compositions would normally be based upon standard carriers such as pharmaceutiically acceptable vegetable oils and gelatins. Bums and petrolatum. Other ingredients to the composition of the present invention may be preservatives. coloring, flavoring, sweetening. thickening, suspending.
disbursing. emulsifying. swelling.
CA 02326614 2000-09-29 Substitute Sheet (Rule 26) stabifizine and bufferine aeent as required by the specific fon~nulation.
Suchcompositions arc envisioned to contain the active ingredient in from about 0.08 to about 8% by weight volume in a cream base. For topical application a concentration from about 0.5 mmoles to about 500 mmoles polyamine in a suitable salt. in the vehicle. wherein the vehicle, between 99.92 and 9'?% (w1v) of final product is optimal. The approximate therapeutic concentration is two times the tissue concentration.
or greater.
Itshould be pointed out, however. that the dividing line between a dosage whichdemonstrates a palliative I 0 effect for one sk in disorder is not precise and must be derived for a particular compound and a particular disorder.
Compositions for oral or parenteral administrations, other than i.he dosage units mentioned above are exemplified by lozenges. dragees. powders, granulates. solutions, suspensions or elixirs.
The required daily dosage fororal orparenteral administration ma;y be administered in single ordivided dosages.
In patients, the exact dosage to be administered w ill, or course. be dependent upon the particular compound employed. the disorder being treated. otherdiseases present. the apse and weight of the subject, the hepatic and renal status and the subject patient's individual response.
Thepresent invention relates to compositions containing polyamines an amount which enables them to act as palliative and/or therapeutic agents for skin disorders. wherein the polyamine is selected from the group consisting of aliphatic polyamines withstraightorbranchod chains of length from2 to 14 carbon atoms long being 2 to 6 amine groups, and agmatine: and the pharmaceutical ly acceptable acid addition satts thereof.
The aliphatic polyamines of this invention are derived from alkanes. such as n-propane, isopropane. butane.
isobutane. ten-butane, hexane. isahexane, heptane. octane, nortane. decane, and dodecane.
The corresponding branch chain analogs of these groups arc also included. The 2 to 6 amine groups contained by the aliphatic polyamines may be eitherpriman~ or secondary and may be located either in a terminal position. within the alkane chain, or both.
3~ Preferred compounds for use in the compositions and methods of the present invention are spermidine (4.
4'- iminobis butvlamine). spermine. and putrescine ( 1. -t-diaminobutane).

CA 02326614 2000-09-29 Substitute Sheet (Rule 26) Synthetic Analogs Known non-toxic polyamines of the present invention include putrescine and cadaverine. However. it is within the scope of the present invention to include synthetic polyamines such as N.N'-Bis-(3~-ethvlamino) propy!]-I.7-heptane diamine lI3EPH).
°harmaceuticallv Acceptable Sults The palliative polyamines of this invention may be utilized as theu~ free bases or as their pharmaceutically acceptable acid addition salts. Such acid addition salts can be d'.erived from a variety of inorganic and organic acids such as hydrochloric, sulfuric, phosphoric, methane;~ulfonic.
sulfamic, citric, lactic, pyruvic.
oxalic. malefic. stearic, succinic, tartaric. fumaric. cinnamic, aspartic.
acetic. benzoic, salicylic, gluconic.
ascorbic, and related acids. The salts lack the odor of the free bases. which is an additional advantage in treatment.
Compositions and Preparations of Polyamines The following discussionpresents examples of different types of compositions and preparations, described in detail illustrative of the present invention. It will be apparent to those skilled in the art than many modifications, both of materials methods may be practiced without departing from the purpose and intent ofthe disclosure.
'reparation l: Ointment formulation Ingredient Amount Spermidine, micronized 0.05 micro moles-1 millimole Mineral oil. USP 50.0 mg lneredient 'White Petroleum 1.0 g CA 02326614 2000-09-29 Substitute Sbeet (Rule 26) A weighted quantity of white petrolatum and mineral oil is heated to 65 ° C. and uniiormlb~mixed. The mixture is cooled to 50 °- 55 ° C. with stirring. The stated active in~tgredient which has been d ispersed in a portion of the mineral oil and milted is added to the above with stirring. The ointment is cooled to room temperature.
Preparation 2: Jelly formulation Ingredient Amount Spermtine, micronized 0.05 micro moles -1 millimole Water 5 ml K.Y.~Jelly* 1.0 g *awatersoluble jelly lubricant manufactured and trademarked by Johnson &Johnson. New Brunswick.
NJ containing water, glycerine, sodium alginate. sodium carboxymethyl cellulose. propylene glycerol, potassium, hydroxide, propylene glycerol and chlorhexidine ;gtyconate preservative.
A weighted quantity of white petrolatum and mineral oil is heated to 65 ° C. And uniformly mixed. The mixture is cooled to 50 °-55 ° C. with stirring. The stated active ingredient which has been dispersed in a portion of the mineral oil and milled is added to the above with:~tirring.
The ointment is coo led to room temperature.
Preparation 3: Ointment formulation Ingredient Amount Putrescine 0.05 micro moles - 1 millimole Mineral oil. USP 50 0 mg White Petrolatum. USP to make 1 0 g A weighted quantity of white petrol arum and a mineral oil is heated to 65 ° C. and uniformly mixed. The mixture is cooled to 50 °-55 ° C. with stirring. The stated active in;~redient which has been dispersed in a portionof the mineral oil and milled is added to the above with sti wing. The ointment is cooled to room temperature.

CA 02326614 2000-09-29 Substitute Sheet (Rule 26;1 1 n accordance with the above procedure. but where in place of the: free base there are utilized in the acid addition salts with hydrochloric. sulfuric. phosphoric. methanesuifonic.
sulfamic, citric. lactic. gvruvic, oxalic.
malefic. stearic. succinic, tartaric. fumaric. cinnamic, aspartic acetic.
benzoic. salicylic, gluconic. ascorbic acids and a similar product is obtained.

Preparation 4: Ointment formulation ingredient Amount ~permidine. micronized 0.05 micro moles - I millimole Mineral oil, USP 50 0 mg White Petrolatum. USP to make 1 0 g A weighted quantity of white petrolatum and mineral oil is heated to 65 ° C. and unifotTrtlv mixed. The mixture is cooledto50 °-SS °C. with stirring. The stated active ingredientwhichhasbeendispersedina portion of the mineral oil and milled is added to the above with stirring. The ointment is cooled to room temperature.
In accordance with the above procedure, but where in placeof spemrtidine, there is utilized spetmine, or agmatine sulfate. a similar composition is obtained.
Preparation 5: Lotion formulation Ingredient Amount Spermidine, micronized 0.05 micro mole~~ - I miliimole Aluminum monostearate 50 0 mg isopropyl myristate to make 1 0 g About 90% of the required isopropyl mvristate is heated to 60 ° C. wnd aluminum and monostearate added with stirring and maintenance of heat to dissolve the aluminum monostearate.
The active ineredient is dissolved in remainine quantity of isopropyl myristate. Thesolution of the active ingredient is added to the thickened solution of the aluminumminostearateinisopropylmv~~istatepreviouslvcooiedto45°C. with stirrinL. The lotion is cooled to room temperature with agitation.

CA 02326614 2000-09-29 Substitute Sheet (Rule 26)~

in accordance with the above procedure, but where in place of spetmidine there is utilized spemzine.
agamtine. putrescine or cadaverine as free base or as any of the acid salts of acids, a similar lotion is obtained.
Preparation 6: Gel forrttulation Ingredient Amount SpetTrtidine. micronized 0.05 micro moles - l millimole Polyethylenes and Copolymers 100.0 mg.
(A-C8) Mineral oil. light to make 1 0 g A portion of the mineral oil (about 90%) in a suitable vessel is heated to about 80 ° C.. and polyethylene (A-C8) added to the mineral oil. The mixture is agitated slowly while hot until all the polyethylene is dissolved.
The above mixture is cooled quickly by placing the vessel in a.cooling bath of 10° to I5°C., and the agitation resumed at normal speed. Once the content of the vessel has reached approximately 45 ° C., a solution of the active ingredient which was dissolved in the remaining mineral oil at 45 ° C. is added to the above polymer solution. The mixture is aircooled with slow agitation. This will result in a gel fotmt. In accordance wi th the above procedure, but where in piaceof spemudine there is utilized spermine, aginatine or putrescine either as free base or as any of the salts of acids, a similar lotion is obtained.
Preparation 7: Intramuscular or Subcutaneous oil injectable Ingredient Amount Spermidine 0.05 micro moles - 1 millimole/ml Aluminum monostearante USP 20.0 mg/ml Sesame oil. heat treated USP 1.0 ml q.s. ad.
The above ingredients are mixed together and filled into sterile. ampules.
In accordance with the above procedure. but where in place of sF~ermidine there is utilized spermine.
agmatine. or putrescine either as free base or as anv of the salts of acids. a similar iniectable is obtained.
CA 02326614 2000-09-29 Substitute Sheet (Rule 26) Preparation 8: Aerosol formulation Ingredient Amount Spermidine, micronized 10.0 to 50.0 mg t)leic Acid 1.0 mg.
Fluorotrichioromethane 4.739.0 mg.
Uischlorodifluoromethane 12.250.0 mg.
Oleic acid is added to previously cooled fluorotrichloromethane and mixed with a high shearmixer. During mixing, the required amount of the active ingredient is added and m;ixine continued until homogeneous. I f necessary, ihesuspension is adjusted to the required weight with fluorotrichlormethane. The required 1 S amount of suspension is metered into each aerosol canister, the valves are crimped onto the canister which is pressure filled through valves with the required amount of dichlorodifluoromethanc. This aerosol formulation can be utilized in the palliative treatment of skin disorders whereextremely sensitive areas prevent manual application of such compositions as creams, ointments, lotions etc.
In accordance with the above procedure, but where in place of spermidine there is utilized spermine.
agmatine orputrescine either as free base or as any of the acid salts. of acids, a similaraerosol is obtained.
Preparation 9: Tablet formulation Ingredient Amount Spermidine 0.05-10 millimoles per tablet Lactose, direct compression grad: i 73 mg Sodium lauryi sulfate 20 mg Com Starch 25 mg Magnesium stearatc 2 mg The stated active ineredients. lactose, microcrystaline cellulose. sodium lauryl sulfate and com starch are mixed together and passed throueh a lVo. 46 screen. Maenesium stearate. Is added and the product mixed and compressed into the desired shape on the tablet machine.

CA 02326614 2000-09-29 Substitute Sheet (Rule 26,) ,v:Y;l-111_E?~OHI~:~! (1:3 :yo_ t;- 1! : p(i: 1H : ~'~t'~~i .~ CU.._ -F~~; 8s =~,3:-y,l.:l.F;G':l.tC1 .iLO~~: . , PCTI~fiJ~,U~2~b= DDS
1n accord:u~ec with the at>Jv a pmcetiure but utilizFng spemuine, puxre;sciinc:, and agmatine s ulfalc in piece of the spcrmidinc, a similar produel is ulst3ined.
Pr~,rar,~oe IQ; Capsule formul:>Ltion Zngrled ient A mo unt ' .._ i Spc:rrt~idine, rnicronizcd 54 mg -_.

Lacto..e. USP ~;3 mb 's l0 Micmcrystalline cellulr>'se3D mg _ , Sodium lauryl sulfate 20 mg .

Corn ~3tarch ~~ mg ~ .

Magnesiulm stcaralc 2 mg .

_-' _ . . .--- .--.-.
Mix togethfxlheacuveingrc.dient, laciosc, n~ierystallinccellulose, tsodi:umlauryl sulfate isndcorn starch. . '' Pass thrcmgh a i~lo. 8Q.scrccn.. Addmagnc;,~ium stc:ara~e, mix:tndencaps ulale into the propcrsue 2-~pirx:~ '.' gclatin~ransuie. This capsule may beuxcad whe~rvcranoral dc~sagc n>ute is desircxj such as the injury and di.~eatsc slate. 1 ct act:c~rd;ince ivilh the aboveproduct 1>ut a tilixi ng spem~inn, putresci nc, or agrnatine s a If ale .
0 in place of the s~ermidine, a similar pr,~duct is obtained.
lxlrcparution I l: Pawdcr formulatiun r Ing rodienl Amount - ' , Spermidine, Microniceci 0.2-10 rnitlimoics Lacms : 150 g Mix the akxwc po~vdcx with 250 millilitrra wacor andaclminister orally (with added flavorings) orwith l lice water to be utilized as a drench lv irnpregnatc or soak bendagca. This type of fnnnulaticm can tie administered orally wher~:vcr an oral dosage route is de,Sirad or lop:~tlly ~,rht;rever such ~t regimen is ' nee:ey,~ry, Byutili~ings~rminc:,puurscineclragmatinc;sulfateinplaeeofspc;t'midine,asin'tila rlyuseful cr~mposition is obtained.
i E,~'~'sct~'ve Dovciges Y

. _::.:::::....::: :.:::....:. 0 2 . .. ...., :,:...:::.::::.::.y:. ... . 3266 _ _ ::.....:..
::.::::.:::::..~-_ ~~u.
. ., . ::~,CA . _ ,. . 14 2000 09 29 .:. ..., Fortopicai applications. the effective amountof the active compound is in theraneeof 5 to X00 mM. Once the composition is applied to thescarorotherarea. it may advantageously be occluded with adressing or incorporated into a transepidemval patch dressing.
It will be appreciated that. although the compositions according to thepmsent invention are particularly useful for topical application to external areas. i«s also to beexipected to be of value in the treatmentof internal tissue. In such cases. the composition may be applied by catheter infusion or by an implantable time release mechanism.
Polyamine compounds of this invention may be administered topically, parenterally, by inhalation or spray cm rectally in dosage unit formulations containing conventional non-toxicphanmaceutically acceptable carriers. adjuvants and vehicles. The polyamines of this invention can also be applied as a topical ointment.
1 n addition, there is provided a pharmaceutical formulation comprising one or more polyamines of this i nvention and a pharmaceutically acceptable carrier. One or more;
polyaminecompounds may be present inassociationwithoneormorenon-toxicpharmaceuticallyacceptablecarriersand/ordiluentsand/or adjuvants and if desired other active ingredients. The phamzaceutiG~l compositions containing the polyamine compounds of this invention may be in a form suitable for topical use, for example, as aqueous oroily suspensions, dispersible powders, granules, or emulsions.
Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
Suchexcipientsaresuspendingagents.forexamplesodiumcarboxymethylcellulose.
methyl cellulose. hydrnpropylmethylcellulose. sodium alginate.
polyvinylpyrrolidone, gum tragacanth and gum acacia. Dispersing or wetting agents may be a naturally-occurring phosphatide. forexample, lecithin.
orcondensation products of an alkylene oxide with fatty acids, fnrexamplepolyoxyethyene~stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethyleneoxycetanol. orcondensation products of ethylene oxide with partial esters derived from fatty acids and ahexitol such as polyaxyethylenesorbitol monooleat.e, orcondensation products of ethylene oxide with partial esters derived from fatty acids and hexitot anhydrides.
forexample polyethylene sorbitan monooleate. The aqueous suspensions may also contain tine or more preservatives, for example ethyl, or n-propyl p-hydroxv-benzoate, or one or more coloring agents.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil. for example arachisoil.oliveoil.sesameoilorcoconutoil.orinamineraloilsuch~~siiquidparaffin.
Theoilysuspensions may contain a thickening agent. for example beeswax. hard paraf f in orcetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added u~ provide palatable oral preparations.
These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

CA 02326614 2000-09-29 Substitute Sheet (Rule 2b) l7ispersible powders and granules suitable forpreparation of anaqumus suspension by the addition of water provide the active ingredient in admixture with a dispersing or wenting agent.
suspending agent and oneor rnorepreservatives. Suitabledispersine or wetting agents and suspnding agents are exemplified by those already mentioned above. Additional excipients. forexample sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-wateremulsions. The oils phase may be a vegetableoil. forexampleolive oil orarachis oil. ora mineral oil, forexample liquid paraffin crmixturesofthese. Suitable emulsifying agents may be naturally-occurring gums,forexamp(egumacacia or gum tragacanth, naturally-occurring phosphatides. forexample soy bean, lecithin, andesters orpartial esters derived from fatty acids and hexitol, anhydrides, forexamplnsorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
The pof yamine compounds) of this invention may be administered, together or separately, in the form of 1 S suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug v~~ith a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the dnig. Such materials arecocoabutterand polyethylene glycols.
Polyamine compounds) of this invention may be administered, tog;etherorseparately, parenterally insterile medium. The dnzg, depending on the vehicle and concentration used, can either be suspended ordissolved in the vehicle. Advantageously, adjuvants such as focal anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For the compounds of this invention, thedose to be administered. whether a single dose, multiple doses.
oradailydose.willvarywiththepanicutarcompoundbeingused.
F'actorstoconsiderwhendecidingupon a dose regimen include potency of the compound, route of administration, sizeof the recipient and the nature of- the patient's condition.
Thedosage to be administered is not subject to defined limits, but in will usually be an effective amount. It will usually be the equivalent. on a molar basis of the pharmacologically active free form produced from a do>sace formulation upon the metabolic release of the active freedru~z to achieve itsdesirod pharmacological and physiological effects.
An physician skilled in the an of modical treatment will beable to ascertain.
without undue experimentations.
appropnate protocols for effective administration of the compounds of this present invention.

CA 02326614 2000-09-29 Substitute Sheet (Rule 26) WO 99!51213 PCT/CA99/00285 The following references are hereby incorporated by reference: Steclman's Medical Dictionary. 24th edition 1984, p 382: Rook et al. Textbook of Dermatology. Ch.14., p 537:, Rudzki. E., et al.. ( 1994) Dermtatology 189: 41-45: Dolynchuk KN. Ziesmann Monday. SerlettiJM. ( 199~i) Piast Reconst.
SurgJan: 97:1 I7-123.
EXAMPLE I: CASE I
In the example that foI lows, the active compound employed was Fnrtrescine.
Putrescine was selected, as it is naturally occurring, highly specific and readily available. Putrescine (putrescine dihvdrochloride. Sigma Chemical Co.. St. Louis. Mo.. USA) was compounded inaeutecticbase (Glaxo Wellcome. Mississauga.
Ontario) at 0.08% (WN) concentration (SO mM).
Patients applied the cream daily. 1f removed for any reason the cream was to be reapplied as soon as possible. Patients were to report any adverse events immediately.
A clinical evaluation was carried out in a 34 year ofd female patient (patient #002:CAT) who presented with localized atopic dermatitis of the hands, a condition that has persisted since birth.
The objective of the evaluation was to determine whether the topical cream (formulated as putrescine dihydrochloride in eutectic base. 0.8%, WM would treat thesigns orsymptoms of inflammatory dermatosis such as atopic dermatitis. The patient had a current flare of eczema, or pruritus and had a moderate to severe scoring in Severity. The target area was greater or equal to 25 cmZ.
The patient had no infected skin lesions and had not been using medication such as steroids in the last three months. The patient's history overthepasttwo years was recorded pertaining to treatments. allergy, skin disease and family history.
Methods:
The patient had followed five treatment reeimens:
Treatment regimen # 1: Topical putrescine dihydrochloride in Glaxal Base (0.8%. WN) was applied BID
to all affected areas on the right hand: the left hand received no treatment.
The duration of treatment was 8 weeks.
Treatment reeimen #2: The treatment was reversed. Topical putrescine dihydrochloride in Glaxat Base (0.8%. WNI was applied BiD to all affected areas on the left hand: the right hand received no treatment. The duration of treatment was 3 weeks.
Treatment regimen #3: Topical putrescine dihvdrochloride in Glaxal Base (0.8%.
W/V ) was applied BID
CA 02326614 2000-09-29 Substitute Sheet (Rule 26) to all affected areas on both hands. The duration of treatment was 1 week.
'treatment regimen ~4: Topical putrescine dihydrochloride in Glaxal Base (0.8%. W/V) was applied BID
to all affected areas on the left hand: the left hand received Glaxal Base without active material BID. The duration of treatment was i week.
S Treatment regimen ~5: The treatment was reversed. Topical putrescinedihydrochloride in Glaxal Base (0.8%. W/V ) was applied B ID to all affc~~ted areas on the right hand; the left hand received Glaxa! Base without active material BID. The duration of treatment was 1 week.
TREATMENT
CLINIC VISIT LEFT HAND RIGHT HAND

NO TREATMENT PUTRESCINE

NO TREATMENT PUTRESCINE

PUTRESCINE NO TREATMENT' PUTRESCINE NO TREATMENT

The Hanifin & Rajka (Rudzki. E. et al. Dermatology 189: 41-46), incorporated herein by reference. method was used to score the following target area signs and symptoms: ervthema.
pnuitus. edemaipapuiation.
oozinglcrusting, lichenification, and excoriation.
Target Signs and Svmptoms Scores In the currentevaluation. at each visit. the physician examined the patient and scored a value foreach of these symptoms on the following basis:
U. 0.5. 1, 1.5. 2. 2.~. 3: where. a score of 0 indicated a clearance of symptoms and a value of 3 was :JO attributed to exacerbation of symptoms.

CA 02326614 2000-09-29 Substitute Sheet {Rule 26) .~,t each visit. each symptom was independently evacuated in this m,annerand then the values weresummed to provide a total aggregate value chat was used to assess overall treatment effects.
Global EvaluatiorrS
J
Additionally, the physician compiled a Physician's Global Evaluation (PGE) in retard to the ability of the treatment to treat thesigns and symptoms. The patient also provided a gloval impressionof treatmentat each visit (Patient Global Evaluation. or PtGE). The Physician and Patient Global evaluations are scaled from -1 to +4. where:
4 indicates an eradication of the sign and/or symptom 3 indicates marked improvement 2 indicates moderate improvement 1 indicates slight improvement 0 indicates no change -1 indicates exacerbation Patient Evaluation oJPruritis The patient was requested to evaluate and score their perceptions o f pruritus using a visual analog scale (VAS). The measure of itch by the patient is on a scale of 0 - 10 (where 10 indicates excessive itching).
Patient Evaluation ojDiscomfort Discomfort as evidenced through sleep loss was polled at each clinic visit.
Results The results are provided in Figtues I ,A/1 B through 6A/68. where the: results of treatment to the left and right hands are provided in the A and B figures. respectively. The treatment regimen f or the left and right hands as described above.
Slgns and Symptoms Overall Summan From Figure 1 A. the left hand received no treatment over the first ~~ visits:
and consequently. all signs and symptoms scorns remained relatively high. Once putrescine treatment was initiatcri. all signs and symptorru CA 02326614 2000-09-29 Substitute Sheet (Rule 26) WO 99!51213 PCT/CA99/00285 scores dropped indicatine improvement inskin condition. This effect persisted until the 1 I '" isit when the patient stopped putrescinc treatment. refrained from treatment for 1 week. and then applied the curette base.
The signs and symptoms appeared to deteriorate in the absence of putrescine.
From Figure 1 B, the data accumulated from observations of treaunent to the right hand provided similar results. In brief, during the first visits, the patient applied putrescine to the treatment area with a resultant dtxline inscores indicating improvement inskincondition. During the next 3 visits (visits 7 - 9) the patient ceased treating the area with a resultant increase in scores of gall signs and symptoms indicating a deterioration of skin condition. Upon re-application of putresc;ine between visits 9 - 11, the scores decreased dramatically. Applicationof theeutextic base during visits I 1 and 12 again resulted in a slight deterioration of skin condition. Finally, re-introduction of putrcacine treatment (visits 12 - 13). skin conditions showed a marked improvement.
Total Signs and Svmproms Scores and Global Evaluations Figures 2A and 2B demonstrate the response to treatment and subsequent Patient and Physician Global Evaluations by the left and right hands, respectively. Once again putrescine treatment lowers the: total sighs and symptoms scorns and both global evaluations show improvement in skin condition overall. The ttrmoval of putrescine and/or the addition of eutectic base results in a dc;terioration of skin condition.
Patient and Physician Global Evaluation Figures 3A and 38 provide similardata to Figures 2A and 2B except for the absence of the total signs and symptoms scores.
Total Sigru and Symptoms Scores and Praritus Figures 4A and 4B demonstrate the response to treatment and subseduent total signs and symptoms and ptwitus by the left and right hands, respectively. Once again putrescine treatment lowers the total signs and symptoms scores and the pruritus evaluations show improvement in skin condition overall. The removal of putrescine and/or the addition of eutectic base results in a deterioration of skin condition.
Ervthema and Pruritus Figures 5A and 5B demonstrate the response to treatment and subsequent erythema and pruritus scores by the left and right hands. respectively. Once again. putrescine treatment lowers both ervthema and pruritus showier overall improvement in skin condition. The removal of putrescine and/or the addition of r~utectic base results in a deterioration of skin condition.

CA 02326614 2000-09-29 Substitute Sheet (Rule 26) Global Evaluations. Patient lteh Evaluation and Pruritus Figures 6A and 6B demonstrate the response to treatment and subsequent eiobal evaluations, patient itch assessment and pturitus scores by the lef t and ri ght hands, respectively.
Once again putrescine treatment lowers itch and pruritus and the elobal evaluations show improvement in skin condition overall. The removal of putrescine and/or the addition of eutectic base results in a deterioration of skin condition.
A t the beginning of the evaluation the baselineevaluation of the p atient's symptoms were as follows:
moderately severe itch (VAS score of 6.5): moderately severe pruritus (2 out of a scoreof 3) and severe lichenification (3 out of ascore of 3) as evaluated by the physician. 'Within

5 days, clinical changes were observed. The treated hand (Right Hand) had begun to respond t~~ treatment and within 2 weeks, the Physician Evaluation had indicated marked improvement in sympu~ms: the patient noted a 50% r~aduction in itch as well as a marked improvement in pruritus and lichenification. On the other hand, all symptoms remained on the left hand for the duration of the treatment period. The effects continued to theend of Treatment Period #1.
The treatment was crossed over in the second treatment phase and within 1 week the symptoms were exacerbated in the right hand !Untreated) and clear improvements were observed in the left hand (Treated).
The third phase had both hands receiving treatment and both responded to treatment within 1 week. The introduction of Glaxal Base as a treatment arm should have provideaj a level of therapeutic improvement that one would expect with the use of an emollient.
Although discomfort was not fully evaluated. there was a cowelation between reduced itch and excoriation and reduced discomfort due to parasthesia.
The results show the utility of the invention to treat the signs and symptoms of inflammatory dermatoses as in this atopic detzrratosis patient. The treatment effects of topical putrescine are evident immediately and appear to be reversible. A1! symptoms improved with daily application.
EXAMPLE II: CASE II
Patient 003 is a 32 year old male with an allergy but no atopic hisitoy .
There is some history of skin di;yease amongst his parents. Treatmern was initiated on his left shin with his riehtshin acting as control.
Daily applications were followed up at the next visit (Day ~). Treatnnent was withdrawn to the lef t shin at this time becauseof marked improvement in his S&S scorns. Treatment was initiatedon the riQhtskin and monitored at the next visit lDav 19) where no change in S&S scores were observed.

CA 02326614 2000-09-29 Substitute Sheet (Rule 25) i=P4 ail l:':Clii=~: U3 -_~_o_ f;_ n ~U 1L' iti:'~1 ~ CO--~ +4:3 !;~
='3~l:J~ia~~ 1111 .
F'CTlCh9~3;i00~8~. D~SG
2fl0fl: , :; . ~ .
T'reaunent was also e-ffccied on his hands with ihc lefthartd ~;rvinb ac the treatnnent area andthe right actin~~ as control. ?'here wa: marked improvement in his S& S scores aruitreiitment was withdra9vn and -i dire~lcxi to the right hand fc~r 1~1 days. No treatmt;nt effects were n«trd to the right hand_ ~XA.MpLE ldl: CASE T1t Patient 008 is a 12 year old paticrrt wlto had b:~n troalcd for atopic dermatitis in the past (h5~drr>xy a>ctiscync)andhacfasignific-antatlcrgyhislory.
Ther:u6etaliosscan,dwristoftherightarmweretrea,tcd initiallywithsirndaran~sonthcieftarmactingaacnnt~roi.
Thcnewasrr>klrginalimpruvc;mentotlhepis.
S&S acores. Cross-over Irvaimcnt of the left arm had no observable t;ffect on the S&5 score;.
EXA'.~LPT.dr: Iv: CASE IY
Patient 009 is a 37 year old paticxU who had been treated fc.~r atopie tiermaltitis and had an atlcrL2y history, ~
TherighthandandwrislwcetrL~aretlinitiaLVwithsirrrilararc:atonthclel'tarmactinga sccn,trr~l.Thc:re was marked improvement of the 1W. S3~S 5C(7TCS. Crass-truer treatment c>f the left arrn hart a marked positive: improvement effect an thG S&S scorn, ~ -EXAMFLE V: CASE V
A 28 year old female patic:rtt prc,~seni~d arith a sc~x:ondary hyhertmphic scar an t~.cr chest. The scar result~i from removal of smote, The ~;~u and ity retatedpruritus wene treutc;d variously and withurut 5 ucc~s. The patient was ptac;;don a daily treatment regimen of putirscinc:
that rt"~utvc:Q the: intcn~ itch within an hour of trealment-EXAMPLE VI: EASE VT
A 16 year olrl female patient prescnt~cl with a scald burn on her Iefl mrixt and hand. Follawin~; lhc appGcationofsceni-ucclusivcdressings,thcpaticntretwncdwithcomplainls.
Shewasdiaf;nosedwith signii'ic;autpnrritu~ardhypertmphyoftfsenaaJltanlxar.
A.ftcraninitialcx~~ursenfrreatmeatofputre.wine, the prurilus was found to be resolved within an he>ur.
Ttre above-dt;scribed pt~oferr~ emlxkiirnents ofthe present inventionarenot inlc:nded to limitihc scc~pc;
t~fthepr~scnt invc;ntian asdemcmstratcxtby lheelairt>s whit:hfall.~w, lltshouidbeunderstcKid nirrttk~
frrregVingrelatcs anly tU prrrfcxr~d anhodimc~~ts of tlx: print i nvcntion and dial r mmcnrus rxxlificattans c>'r alterations may be matte therciu wi thou t departing from the scope vi' the in vernion r~s set forth in the appended claims.
:.::.:CA 02326614 2000-09-29 ~~ 3~~tt~~ .:'-~3~-~1 .:E'~:.:-;:.:~:.:::::::::.:.. ::::::::...:.............

Claims (8)

What is claimed is:

1. The use of one or more diamines or polyamines as a topical, non-toxic therapeutic for the palliative treatment of one or more symptoms selected from the group comprising: pruritus, erythema, pain, parasthesia and general discomfort, arising from chronic discases or chronic disorders of epithelial tissue.

2. The use as in claim 1, wherein said polyamines are selected from the group consisting of aliphatic di- and polyamines with straight or branched chains of lenth from 2 to 14 carbon atoms long bearing 2 to 6 amine groups, the corresponding branch chain analogs and agmatine; wherein the 2 to 6 amine groups contained by the aliphatic di- and polyamines may be either primary or secondary and may be located either in a terminal position, within the alkane chain, or both and the pharmaceutically acceptable acid addition salts thereof.

3. The use as in claim 1, wherein said polyamines are encompassed by formula I:

wherein p1, p2, p3, p4 are independently 0 or 1; m and n are independently 1-7: q, r, s are independently 0-7: with the provisos that n + m + q + r + s are less than or equal to 14. Highly preferred compounds of formula 1 are those wherein m is 3, n is 4, p2, p3, p4, q, r, and s are 0 and p1 is 1: m and n are 2, p1, p2, p3, p4, q, r, and s are 0: and m is 3, q is 4, r is 2, p1, and p2, are 1, p3 and p4 are 0, s is 0 and n is 1.

The use as in claim 1, wherein the polyamines are selected from the group comprising:
Spermidine (4,4'-iminobisbutylamine): Spermine.: Putrescine (1,4 diaminobutane):1,3-diaminopropane: Agmatine. [(4-aminobutyl)guanidine]: 1,2-diaminoporopane:
1.10-diaminodecane: 1.12-diaminododecane: 3.3'-iminobispropylamine: 1.7-diaminoheptane;1.6-disminohexane; 1.2-diamino-2-methylpropane;1.9-diaminomononane; 1.8-diaminoctane;
Cadavcrine, [1.5-diaminopentane; triethylenetetraamine; triethylentetraamine tetrahydrochloride;

N-(2 aminoethyl)-1.3-propanediamine; diethylenetriamine; ethylenediamine;
ethylenediamine dihydrochloride; and tetraethylenepentamine.

5. The use as in claim 1, wherein said chronic disease is selected from the group comprising inflammatory dermatoses which include atopic and contact eczema, including xerosis such as dry skin and Winter itch.

6. The use as in claim 1, wherein said skin disorder is scarring

7. The use as in claim 1, wherein said polyamines are selected from the group comprising:
spermidine (4,4'-iminobisbutylamine), spermine, and putrescine (1,4-diaminobutane), and cadaverine.

8. The use as in claim 1, wherein said polyamines are selected from the group of synthetic polyamines N,N'-Bis-(3-ethylamino) - propyl]-1,7-heptane diamine (BEPH).