MXPA00009705A - The use of polyamines in the treatment of dermatological symptoms. - Google Patents

Abstract

This invention provides the use of non-toxic polyamines in the palliative treatment of diseases and chronic alterations in epithelial tissue. The effectiveness of the treatment is evidenced by the relief of symptoms and alterations that manifest in the epithelial tissue such as the skin, including itching, erythema, pain, parastasia and general discomfort, due to the topical administration of certain polyamines. Such symptoms arise from and / or be associated with chronic conditions such as: (i) skin diseases such as inflammatory dermatosis including atopic and contact eczema, including xerosis such as dry skin and winter puritus; (ii) infection of the epithelial tissue (for example the nasal, vulval or rectal passages) with trichomonas or fungi, anal fissures, fistula discharge, wound effluent or surgical wound drainage; (iii) "secondary disease" in which the tissue Epithelial disease exhibits manifestations of the underlying primary disease such as AIDS, varicella and metabolic disorders (diabetes, liver and kidney dysfunction and hematopoiesis), and (iv) disorders arising from direct aggression to epithelial tissue after natural or surgical intervention (tumors local, hemorrhoids) and the scar formation that accompanies it or radiation therapy

Description

THE USE OF POLYAMIDES IN THE TREATMENT OF DERMATOLOGICAL SYMPTOMS FIELD OF THE INVENTION The present invention relates to the use of non-toxic polyamines in the palliative treatment of diseases and chronic symptoms associated with epithelial tissue.

BACKGROUND OF THE INVENTION The epithelial tissue forms a continuous or covering layer over the entire body surface and most of the internal cavities of the body. On the outer surface, it forms a cover that, like the epidermis on the plants, protects the animal from injuries and dryness. On internal surfaces, the tissue can be specialized for other functions besides protection. The epithelium may be stratified meaning that layers are stacked one on top of the other. The nose, mouth, and anal canal and vagina are covered by stratified squamous epithelium. The outer layer of the skin is also stratified squamous epithelium, except where the cells have been reinforced by keratin as a protein that reinforces the cells. A skin is an organ because it consists of structurally bound tissues to perform specific activities. It is one of the largest organs of the body in terms of surface area. The skin is complex in structure and performs several essential functions for subsistence, which can be grouped as follows: maintenance of body temperature, protection by providing a fixed barrier that protects the underlying tissues from physical abrasion, invasion of bacteria, dehydration and ultraviolet radiation; the perception of stimuli since the skin contains numerous endings and nervous receptors that detect stimuli related to temperature, touch, pressure and pain; excretion, where perspiration helps in the excretion of small amounts of water, salts and various organic compounds; synthesis of vitamin D; and immunity. From a clinical perspective, the skin reflects the physiological and pathological changes in other areas of the body, so that changes in the skin can be used to aid in medical diagnosis.

Acute Exacerbation and Skin Irritation Irritation is generally defined as. a reaction to what is irritating. The term irritation, characterizes a normal state of the skin that is produced in reaction to an acute exacerbation or to a stimulant (for example chemical or mechanical). Typical symptoms that can result from irritation include stinging (pruritus) stinging, burning, tingling "tension" erythema (redness) or edema (inflammation). A large majority of chemical compounds are known to cause dermatological skin irritation on contact. The reaction of the skin to the contact can vary from a simple reddening and résequedad, as it is common after the repeated contact with detergent solutions during the washing of frets and the housework, until a very serious formation of blisters of the skin such as the one that It occurs after contact with poison ivy. The utility of a vast majority of chemical compounds is narrowly limited due to their tendency to cause skin irritation. There are several known treatments for severe skin irritations, many of which are pharmaceutical compositions available to the consumer. Many attempts have been made to reduce the potential irritation of topical products by identifying the chemicals that tend to cause irritation and reduce their concentration. Several compounds containing amines have been used as anti-irritants. For example, salts of glutamic acid, an amino acid containing a negatively charged acidic side chain, have been found to be useful as a topical agent in relieving the discomfort associated with insect stings (See US Pat. No. 4)., 062,937). Sodium dihydroxyethylglycine has been used in the formulation of cleansing and disinfecting solutions that are also said to reduce pain and itching (See US Patent No. 4,868,213). PCT application PCT / US96 / 01289 describes the use of multiprotonated organic polyamines to provide anti-irritant skin effects in topical form and formulations containing such compounds. These formulations are aimed at suppressing skin irritation caused by exposure to chemical agents, or to the environment, tissue inflammation, injury or other skin pathology, in addition to treating irritation caused by topical application of the skin. products. The use is also aimed at eliminating skin irritation caused by skin diseases or other conditions such as environmental exposure to chemical irritants or environmental influences, such as wind. In each of these dermatological situations, the treatment approach is the treatment of irritation.

Chronic Disease Manifestations and < Alterations of the Skin Skin diseases, scars and infections are all examples of chronic disorders that manifest themselves in the skin. Diseases such as eczema, exhibit a first manifestation in the skin, considering that diseases such as AIDS have a secondary manifestation in the skin. Damage to the skin caused by accidents or surgery occurs with symptoms that acquire chronic care for the duration of the wound healing process which can last for 1-2 years. Epithelial tissue infections, such as the herpes virus, can also manifest in the skin as a chronic disorder.

Dermatoses refer to diseases of the skin, which exhibit any skin lesion or group of lesions, or rashes of any kind. Inflammatory dermatoses are usually associated with pruritus, erythema and scaling. Inflammatory dermatoses include contact eczema, atopic dermatosis, and xerosis. There are several symptoms and alterations that can be manifested chronologically in the skin, either as a direct result of the disease or injury (physical, chemical, microbiological, by radiation) to the skin, or as a disease that manifests itself in any other body part. Pruritus, erythema and pain are common chronic symptoms that accompany diseases of and attack the skin; and, in particular inflammatory dermatoses (atopic and contact eczema, xerosis), which include the pruritic components of other diseases or conditions such as the healing of a wound. Eczema represents an inflammatory response of the skin to a spectrum of internal factors that act alone or in combination to induce the response. Histologically, eczema is defined by: the presence of an infiltrate, predominantly lymphohistiocytic, that surrounds the superior dermal blood vessels; the association with spongiosis; and varying degrees of acanthosis. The classification of the main forms of eczema is difficult due to the multiplicity of potential contributing factors: however, a summary of the different forms of eczema induced by external and internal factors is given in Table 1.

TABLE I External Eczemas (Exoqenos) Internal Endogenous Eczemas Internal dermatitis Atopic eczema Allergic contact dermatitis Seborrheic dermatitis and phytosposal folliculitis Contact dermatitis photo Astheatotic eczema Allergic Light polymorphic eruption Discid cematose eczema Infective dermatitis Exfoliating discid and dermatitis, lichenoid Dermatophyte Chronic squamous surface dermatitis Pityriasis alba Eczema of the hand Gravitational eczema Dermatosis Juvenile plantar Metabolic eczema or eczema associated with systemic disease. Eruptions by eczematous drug Atopic dermatitis is a chronic pruritic eczematous condition of the skin that is associated with a personal or family history of atopic disease (eg asthma, allergic rhinitis or atopic dermatitis). This seems to be a genetic predisposition that can be exacerbated by numerous factors including food allergies, skin infections, irritant clothes or chemicals and emotions. Lichenification is the clinical hallmark. Patients with atopic dermatosis usually have a history of allergy and are usually not treatable. The allergic response gives rise to an inflammatory response that manifests itself in the pulmonary or other nasal dermal tissue. There are six general symptoms or signs associated with atopic dermatitis or eczema and these are: erythema, exudation, excoriation, dryness, cracking and lichenification. In summary, exudation or rash is. an initial characteristic of eczema and refers specifically to the translation of eczema from the meaning of the Greek "burn". In chronic cases, the skin exhibits key features such as flaking, scorching, drying and cracking. Finally, the skin acquires a corny appearance with hyperkeratosis (lichenification) usually exacerbated by concomitant symptoms such as stinging.

Itching Pruritus is an unpleasant sensation that prompts the desire to scratch. It is a disturbing symptom that can cause discomfort and threatens the effectiveness of the skin as a main protective barrier. Due to the subjective nature of the pruritus, the lack of a precise definition and the lack of adequate animal models, itching is a disorder that has not been investigated adequately. Pruritus and pain can accompany the formation of scars. The scar tissue is formed during the healing of the wounds, caused for example by burn, traumatic injury and by the incisions of selective operations. The hypertrophy of scar tissue is often unpredictable. Hypertrophic scar formation is characterized by the accumulation of type III collagen outside the ratio of type I collagen. - Hematological disorders that - cause pruritus include polycythemia vera. Some conditions that cause iron deficiency, including exfoliative skin disease, also cause 'pruritus. Diabetes and thyrotoxicosis are endocrine causes of pruritus (Abel, EA, Farber, EM "Malignat cutaneous tumours" in Rubesteint, E., Federman, DD, Eds Scientific American Medicine (New York: Scientific American, Inc. Chapter 2, 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 cases. people with AIDS and 35.5% of those with AIDS-related Kaposi's sarcoma The incidence of pruritus associated with opportunistic infections related to AIDS is close to 100% (Dangel, RB, Pruritus and cancer, Oncology Nursing Forum 13 (1): 17-21, 1986.) Several malignancies are known to produce pruritus.Hodgkin's disease causes pruritus in 10% -25% of patients.In some cases, pruritus precedes diagnosis of pruritus. the lymphoma (Abel, EA, Farber, EM "Malignat cutaneous tumours" in Rubesteint, E., Federman, DD, Eds Scientific American Medicine (New York: Scientific American, Inc. Chapter 2, Dermatology Section XII), and may be a minus indicator favorable prognosis when associated with fever or significant weight loss ("B" symptoms) (Bernhard JD: Clinical aspects of pruritus.) In: Fitzpatick 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 intense burning and stinging that occur in a localized area of skin, with frequency on the lower legs Other lymphomas and leukemias have been associated with a less intense but more generalized pruritus, adenocarcinomas and squamous cell carcinomas of various organs (ie, stomach, pancreas, lung, colon, brain). , chest and prostate) sometimes produces Generalized pruritus that is more pronounced on the legs, upper trunk and extension surfaces of the upper extremities (Abel, E.A., Farber, E.M. "Malignat cutaneous tumours" in Rubesteint, E., Federman, DD, Eds Scientific American Medicine (New York: Scientific American, Inc. Chapter 2, Dermatology Section XII, Bernhard JD: Clinical aspects of pruritus, In: Fitzpatick TB, Eisen AZ. Wolff K. et al., Eds .: Dermatology in General Medicine, New York: McGraw-Hill, 3rd ed., 1987, pp. 78-90). The pruritus associated with malignant diseases ^ has been shown to diminish or disappear with the eradication of the tumor and reappears with the recurrence of the disease (Bernhard JD: Clinical aspects of pruritus, in: Fitzpatick TB, Eisen AZ, Wolff K. et al., Eds .: Dermatology in General Medicine, New York: McGraw-Hill, 3rd ed., 1987, pp. 78-90). Drugs associated with secondary pruritus include opiate derivatives (cocaine, morphine, butorphanol), phenothiazines, tolbutamides, erythromycin estolato, anabolic hormones, estrogens, progestins, testosterone and subsequent cholestasis, aspirin, quinidine and other antimalarials, biological compounds such as monoclonal antibodies, and vitamin B complex. Subclinical sensitivity to any The drug may be related to pruritus (Bernhard JD: Clinical aspects of pruritus, in: Fitzpatick TB, Eisen AZ, Wolff K. et al., Eds .: Dermatology in General Medicine, New York: McGraw-Hill, 3rd ed., 1987, pp 78-90). The theoretical mechanism of pruritus has been inferred from pain studies, since pain and itching share common molecular and neurophysiological mechanisms (Greaves MW: Pathophysioiogy of Pruritus, in: Fitzpatick TB, Eisen AZ, Wolff K. et al. , Eds .: Dermatology in General Medicine, New York: McGraw-Hill, 3rd ed., 1987, pp. 7478). The sensations of both stinging and pain result from the activation of a network of free nerve endings in the dermicepidermal junction. Activation can be the result of internal or external thermal, mechanical, chemical or electrical stimulation. The cutaneous nervous simulation is activated or mediated by several substances that contain histamine, vasoactive peptides, enkephalins, substance P (a tachykinin that affects the smooth muscles, and prostaglandins.) It is considered that non-anatomical factors (such as physiological tension, tolerance , presence and intensity of other sensations and / or distractions) determine the sensitivity of the stinging in different regions of the body.; The sting impulse is transmitted along the same nerve pathway as the pain impulses, that is, they move from the peripheral nerves towards the dorsal horn of the spine, through the spine through the inner commissure and ascend along the spinothalamic fascicle to the lamellar nuclei of the contralateral thalamus. The thalamocortical fascicles of the tertiary neurons are considered to support the use through the reticular articulation system of integration of the thalamus into several areas of the cerebral cortex. Factors considered to improve the burning sensation include dryness of the epidermis and dermis, tissue anoxia, dilatation of capillary vessels, irritant stimuli, and psychological responses. (Abel, EA, Farber, EM "Malignat cutaneous tumours" in Rubesteint, E., Federman, DD, Eds Scientific American Medicine (New York: Scientific American, Inc. Chapter 2, Dermatology Section XII, Bernhard JD: Clinical aspects of pruritus In: Fitzpatick TB, Eisen AZ, Wolff K. et al., Eds .: Dermatology in General Medicine, New York: McGraw-HMI, 3rd ed., 1987, pp, 7890, Greaves MW, Pathophysiology of pruritus. : Fitzpatick TB, Eisen AZ, Wolff K. et al., Eds .: Dermatology in General Medicine, New York: McGraw-Hill, 3rd ed., 1987, pp 7478, Duncan WC, Fenske NA, Cutaneous signs of internal disease in the elderly, Geriatrics 45 (8): 2430, 1990) Scratch motor response follows the perception of stinging Scratch is modulated at the corticothalamic center and is a spinal reflex After scratching, the sting may be relieved during 15 to 25 minutes The mechanism through which the relieved is scratched by scratching is unknown The theory is that scratching g It has sensory impulses, which break the circuits in the relay areas of the spine. Scratching can actually improve the stinging sensation, creating a characteristic cycle of scratch-scratch-scratch. Other physical stimuli such as vibration, heat, cold and ultraviolet radiation reduce itching and increase the release of protiolytic enzymes that potentially produce the escosor-rascado-escosor cycle.

A prick near or in the same dermatome as a stinging point will eliminate the stinging sensation. Bernhard JD: Clinical aspects of pruritus. In: Fitzpatick TB, Eisen AZ. Wolff K. et al., Eds .: Dermatology in General Medicine, New York: McGraw-Hill, 3a. ed., 1987, pp 7890). It is known that intense scratching can replace the pain of stinging, and in some cases, the patient may find that pain is a more tolerable sensation. It is thought that spinal modulation of afferent stimuli (Gate's theory) and central mechanisms can play an important role in the release of itching (Bernhard JD. Supra). The pathogenesis of pruritus hypotheses associated with the underlying disease states are varied. Biliary, hepatic, renal and malignant diseases are considered to produce pruritus through circulating toxic substances. Histamine released from circulating basophils and the release of leucopectidase from white blood cells can trigger the pruritus associated with lymphomas and leukemias. Elevated blood levels of quiniogenone in Hidgkin's disease release histamine or bradykinin precursors from solid tumors and release serotonin into carcinoids that may all be related to pruritus (Abel, EA, Farber, EM Malignat cutaneous tumours En Rubesteint , E., Federman, DD, Eds Scientific American Medicine New York: Scientific American, Inc. Chapter 2, Dermatology Section XII, Abel, EA, Farber, EM Drug eruptions and urticaria, in Rubesteint, E., Federman, DD, Eds Scientific American (Medicine (New York: Scientific American, Inc. Chapter 2, Dermatology Section VI), People receiving cytotoxic chemotherapy and radiation and / or "biological response modifiers for the treatment of malignancy are similar to experiencing pruritus. The same population is very prone to be at the expense of many of the etiological factors that are related to pruritus that vary from serotonins related to nutrition. tion (dry skin) to radiation desquamation, side effects induced by chemotherapy and biological agents, antibiotic reactions and other drug sensitivities. Each of the main classes of antineoplastic agents (antimetabolite alkylating agents, antibiotics, plant alkaloids, nitroureas and -enzymes) includes drugs capable of producing skin reactions including pruritus. Patients who receive antineoplastic drugs frequently report dry skin and scaling that are thought to be related to the effects on the sebaceous and sweat glands (Dunagin WG: Clinical! Toxicity of chemotherapeutic agents; dermatologic toxicity.) Seminars in Oncology 9 (1): 14 -22, 1982; Hood AF: cutaneous side effects of cancer chemotherapy, Medical Clinics of North America 70 (1): 187-209, 1986). Many therapies are self-limiting and do not require active intervention. Other problems guarantee the anticipation and implementation of preventive measures.

Hypersensitivity to cytotoxic agents can be manifested by pruritus, edema, urticaria, and erythema. Hypersensitivity reactions vary in their symptoms, and depend on the patient's drug, dose and allergy history. The agents most associated with hypersensitivity include doxorubicin, daunorubicin, cytarabine, lasparaginase, paclitaxel, and cisplatin. In most reports, these reactions have been located in the area of vascular access and dissipate at 30 to 90 minutes. (Gullo SM: Adriamycin extravasation versus fiare, Oncology Nursing Forum 7 (4): 7, 1980: Barlock AL, Howser DM, Hubbard SM: Nursing management of Adriamycin fiare, American Journal of Nursing 79 (1): 94-96, 1979) . The most dramatic and even life-threatening reactions can occur, and the development of pruritus may represent an early stage of serious hypersensitive reactions (Weiss RB: Hypersensitivity reactions to cancer chemotherapy.) In: Perry MC, Yarbro JW, Eds .: Clinical Oncology onographs: Toxicity of chemotherapy, Orlando. FL: Grunt and Stratton, Inc., 1984, pp. 101-123). Pruritus related to radiation therapy is usually associated with dry desquamation of the skin within the treatment field. Dryness and pruritus can occur in a cumulative dose of 200 to 2800 cGy. (Hassey KM, Rose CM: Altered skin integrity in patients receíving radiation therapy, Oncology Nursing Forum 9 (4): 44-50, 1982) and is caused by obliteration of the sebaceous glands within the field. This is an acute phenomenon that correlates with the depletion of actively proliferating basal cells in the epidermal layer of the skin, a fixed percentage of which dies within each irradiation dose fraction. The remaining basal cells undergo cornification and hanging at an increasing rate, while the non-proliferative basal cells are stimulated and their cell cycle is reduced. The subsequent exfoliation of the skin is defined as dry desquamation. The skin becomes dry and the patient may notice the stinging and burning sensations (Hassey KM, Rose CM: Altered skin integrity in patients receiving radiation therapy, Oncology Nursing Forum 9 (4): 44-50, 1982). Dry skin is susceptible to additional injuries through scratching and / or cracking, increasing the risk of infection and tissue necrosis. If the desquamation process continues, the dermis will eventually be exposed and result in wet desquamation. This side effect increases the risk of infection, discomfort and pain, possibly necessitating the interruption of a treatment plan to allow healing. This may compromise the final effect of cancer therapy. For this reason, it is desirable to anticipate and prevent the progression of skin reactions for 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. 1 >983). External chromotherapy with electrons can produce more reactions in the skin than photon therapy since, the depth of penetration and the transfer of linear energy is closer to the surface of the skin with the electrons. In radiation delivery techniques, (bolus dose and tangential fields) also influences the degree of reaction. Fields that include skin folds (ie, the armpit, breast, perineum and buttocks) are anticipated to have increased reactions due to friction, higher moisture content and lower aeration (O'Rourke ME: Enhanced cutaneous effects n combined modality therapy Oncology Nursing Forum 14 (6): 31-35, 1987, Hassey KM: Skin care for patients receiving radiation therapy for rectal cancer Journal of Enterostomal Therapy 14 (5): 197-200, 1987 ). The biological response modifiers used in the treatment of malignant disease are associated with a wide variety of side effects and toxic effects. Pruritus has been a side effect associated with several biological effects, although it has been reported more frequently in patients receiving interferon (Mayer DK, Smalley RV: Interferon: current status, Oncology Nursing Forum 19 (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 (interferon Alfa-2B); clinical overview and future directions. .S, uppl.2): 89-101, 1986: Irwin MM: Patients receiving biological response modifiers: overview of nursing care, Oncology Nursing Forum 14 (Suppl 6): 32-37, 1987).

To date, reports of pruritus as a side effect of biological agents are mainly anecdotal and have not been a focus of attention. The graft-versus-host disease (GVHD) affects 25% -50% of patients who live more than 100 days after bone marrow transplantation. The incidence of GVHD is reported to be 80% -90% and the symptoms vary in severity and type (Sullican KM, Deeg HJ, Sanders JE, et al., Late post-marrow transplantation, Seminars in Hematology 21 (1): 53-63, - 1984). Changes reported in the skin include dryness and pruritus, erythematosus and maculopapular rashes. The onset can be subtle or sudden. GVHD can advance to scleroderma and contracture (Nims JW Strom S: Late markers transplant recipients: nursing care issues Seminar in Oncology Nursing 4 (1): 47-54, 1988). Many pharmacological agents used at any point during the course of the cancer, whether in a primary treatment plan or incorporated into a symptom control or supportive care program, are capable of producing a pruritus reaction. These drugs include morphine, other opiate derivatives and aspirin used in pain management; corticosteroids; antibiotics; phenothiazines; and to a lesser degree hormonal agents (estrogen, progestins and testosterones) (Bernhard JD: Clinical aspects of pruritus, in: Fitzpatick TB, Eisen AZ, Wolff K. et al., Eds .: Dermatology in General Medicine, New York: McGraw -HHI, 3rd ed., 1987, pp. 78-90). The mechanisms of these reactions vary from hypersensitivity to chemical interference with nerve trajectories (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). Infections and chronic diseases of the epidermal tissue can also give rise to symptoms such as pruritus. The pruritus that involves the areas of the rectum or vulva can 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 reproduces within the nucleus of the cell. It is 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 recurrent attacks, which are often preceded by localized stinging or burning and characterized by occurrence in the same location. It is estimated that 100 million cases of oral herpes and half a million new cases of genital herpes occur in the United States. HSV infection is not limited to the lips and genital area; any type can infect any area of the skin. An example of a chronic epidermal tissue disorder that can give rise to itching is hemorrhoids (piles) resulting from varicose veins of the rectal veins. Initially contained within the anus (first degree), they gradually lengthen until they prolapse or extend outward to the defecation (second degree) and finally remain prolapsed through the rectal orifice (third degree).

Erythema Erythema (reddening of the skin) is an important symptom of an inflammatory response within the skin. Other symptoms include inflammation, heat and pain. The underlying inflammatory processes are responsible for the reddish appearance and are observable due to the numbers and visibility of red blood cells in the skin. The cause of the increase in red blood cells includes: increased blood flow also through the dilated blood vessels: direct stimulation on the superficial blood vessels; or, from obstructions in deeper vessels that cause a deviation of the blood through the superficial vessels.

Paresthesia The sensation of altered or abnormal skin may manifest in patients in a number of ways: numbness, itching, stinging, burning, tingling, stinging, increased awareness and pain. These paresthesias have many different causes although they generally reflect damage to particular sensitive neurons such as peripheral nerve fibers. Many, if not most, of the diseases of the body cause pain. Pain is a protective mechanism for the body; It is always present in any tissues that are damaged and causes the individual to react to remove the painful stimulus. The pain receptors in the skin and other tissues are the nerve terminals, which lack any special features and which are also triggered by a chemical stimulus when potential tissue damage occurs. It seems that there are two types of terminals: one responds to many types of painful stimuli, while the other responds specifically to either mechanical or thermal energy. The receptors that are sensitive to various chemical substances and are called surgical pain receptors. Some of the different chemical agents that excite chemosensitive receptors include bradykinin, serotonin, hystamine, potassium ions, acids, prostaglandins, acetylcholine, and proteolytic enzymes. Extracts from damaged tissue cause intense pain when they are injected behind normal skin. Among the substances in such extracts that are especially painful are bradykinin, histamine, prostaglandins, acids, excesses of potassium ions, serotonin and proteolytic enzymes, which are the same substances that are known from electrophysiological data to excite nerve endings. from pain. Obviously, many of these substances could cause direct damage to the nerve endings of pain, especially to proteolytic enzymes. Although some other substances such as bradykinin and some of the prostaglandins can cause direct extreme stimulation of the nerve fibers of pain without necessarily damaging them. The release of the various substances listed above not only stimulates chemosensory pain endings but also greatly decreases the threshold for the stimulation of mechanosensitive and thermosensitive pain receptors alike. A well-known example is the extreme pain caused by the mechanical or thermal light stimuli that follow the pain of the tissue by burning! Sun. Accordingly, there is a need for topical and non-toxic therapeutic agents for the treatment of pruritus, erythema and associated pain.

Pharmacological therapy Eczema is a chronic condition with periods of remission and exacerbation; The management of the disease is based on avoiding, reducing or eliminating the stinging and the appropriate therapy. The handicap guides emphasize the need to monitor diet, the use of cosmetics, the composition of clothing fabrics and reactions to various medications. It is also understood that strong topical sensitizers (neomycin, antihistamine), sudden changes or extremes of temperature or humidity and various irritants transported in the air should be avoided. If treatment of the underlying disease and / or control of other aggravating factors provide an inadequate release of pruritus, topical and oral medications may be useful. Topical steroids may provide relief when the symptoms are related to a dermatosis that responds to steroids, although the anticipated benefits should be compared against vasoconstrictive side effects. Topical steroids have no role in the management of pruritus of unknown origin. Topical steroids should not be applied to skin surfaces within a treatment field1 of radiation. Systemic medications useful in the management of pruritus include those directed toward the underlying disease or symptom control. Antibiotics can reduce the symptoms associated with the infection. Oral antihistamines may prove symptomatic relief of burning related to hysteria. Aspirin appears to have a reduced itching in some individuals while itching increases in others. Patients with thrombocytopenic cancer should be warned against the use of aspirin. Cimetidine alone or in combination with aspirin has been used with some effectiveness for pruritus associated with Hodgkin's disease and polycythemia vera (Daly, B.M., Shuster, S. "Effect of aspirin on pruritus", British Medical Journal 293 (6552); 907-908, 1986).

Symptoms Associated with Wound and Ulcerated Scarring A scar is a mark left on the skin or in an internal organ by the healing of a wound, ulcer or injury due to the replacement of the connective tissue of the injured tissue. The scar tissue can be formed during the healing of wounds, disease injuries, surgical operations, irradiation, laceration, burns or infections. The frequently non-predictable hypertrophy of scar tissue occurs. A hypertrophic scar is an excessive wound scar which by definition has a growth in size beyond that required for normal healing of the wound. Hypertrophic scars can emerge from various types of wounds such as a burn or a sharp incision. Keloids, a more severe form of hypertrophic wound scar, firm scar dermal nodule forms that are more commonly preceded by trauma at the site of origin. They are usually larger than hypertrophic scars and differ in that they often invade normal skin adjacent to the wound. Hypertrophic scar formation is characterized by the accumulation of type III collagen out of proportion to type I collagen. In normal wound healing, or in ulcer healing processes, the abundant vascular network is regenerated in the wound or ulcer during the maturation phase and the collagen fibers are "collected in large groups. maturation does not occur, so that the granulation tissue remains behind the cover epithelium for a relatively long period and can even develop into a larger one.This is the clinical nature of a hypertrophic scar.A hypertrophic scar is an elongation elevated, reddish and stinging The scar can be soft to the touch and other external pressure and can form on each affected part of the body, although it is more prevalent after burn injuries and as a result of wounds through the sternum and in the regions of the shoulders.Hypertrophic scars often remain for a long period, sometimes until the A person dies In the case of adults, the hypertrophic scar usually transforms to a soft, pale scar after a year or so. In addition to stinging and being relatively invisible, hypertrophic scars in the region of the joints can also impart articulation mobility.

The therapeutic use of polyamines for regulation of cell growth and as antifibrotic agents. The use of polyamines for the therapeutic treatment of tissue damage is known in the art. For example, polyamines are believed to function as inhibitors of transglutaminase and / or lysyl oxidase, which affect the formation of collagen. For example, Raisfeld describes the use of compositions that include polyamines to regulate, stimulate or inhibit epithelial cell growth in U.S. Patent No. 4,507,321. In particular this method teaches compositions containing polyamines which are useful in low concentration to stimulate epithelial cell growth and are useful in high concentration to inhibit the growth of fibroblasts in order to decrease scar formation, by reducing the degree to which they proliferate fibroblasts and produces collagen, thus forming scar tissue. 'In low concentrations these compounds are useful to promote wound healing, burn treatment, treatment of ischemic debubitus and peptic ulcers, plastic and reconstructive surgery, dermatological disorders, promotion of autograft and homograft growth, stimulation of regeneration of organ and tissue in vitro and in vivo, as a component in defined media (free of serum protein) 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 the retardation of fibrosis after injuries to the spine and the nervous system. As described by Kagan and Gacheru in US Patent No. 4, 997,854 the adjacent placed diamines have been used as antifibrotic agents, by the inhibition of the lysyloxidase activity. These compounds have been used to treat a wide variety of different pathological fibrotic diseases, abnormalities and abnormalities where the pathology involves the entanglement of the individual collagen alpha chains. Lysyl oxidase creates a critical change between the alpha chains of collagen polypeptide by creating entanglements that are the basis of structural stability, and resistance maturation of collagen and scar tissue in general. The entanglement of the individual collagen alpha chains is the main contributor to the tensile strength of the interlaced fibrils. ' Depending on the creation of collagen chain formation and its entanglement through the enzyme lysyloxidase, the abnormalities may take the form of a variety of clinically identifiable and diagnosed conditions. It is proposed that by preventing the oxidative deamination of Tisina and hydroxylysine amino groups within the alpha chains of collagen, which is the enzyme function and the specific activity of lysyl oxidase, the physical properties of scar tissue collagen and the resulting phytotic pathological state could be substantially reduced. The polyamines have been used as an inhibitor of transg lutam inasa for a number of applications. In US Patent No. 5,124,358 a method is described for blocking the maturation and production of mycorrhizals in adult filral methods, applying these methods to several filiaric infections of B rug i a. To date, the only generalized treatment of pruritus and erythema symptoms involves the use of spheroids. These compounds can be used safely only for short periods, in the order of 7-10 days. Therefore, they are not safe and effective for long-term treatment of symptoms. Therefore, it is evident that there remains a need for a means to manage the symptoms associated with dermatological disorders and aggressions for the skin. There remains a need for a compound that can be applied topically in the palliative treatment of diseases and chronic alterations of the epithelial tissue. The effectiveness of treatment is evidenced by relief of symptoms and alterations that occur in epithelial tissue such as skin, including pruritus, erythema, pain, paresthesia and general discomfort due to the topical administration of certain polyamines. Such symptoms arise from and / or are associated with chronic conditions such as skin disease such as inflammatory dermatoses including (i) atopic eczema and contact, including xerosis as dry skin and winter itch; (i¡) Epithelial tissue infection (eg, nasal, vulval or rectal passages) with trichomonas or fungi, rectal fissures, fistula discharges, wound effluent or surgical wound drainage; (ii) "secondary disease" in which the epithelial tissue exhibits manifestations of the underlying primary disease such as AIDS, varicella and metabolic disorders (ie, diabetes, hepatic and kidney dysfunction and hematopoiesis); and (iv) alterations that arise from the direct aggression to the epithelial tissue that follows the natural or surgical intervention (local tumors, hemorrhoids) and that accompany scar formation or radiation therapy.

BRIEF DESCRIPTION OF THE INVENTION Therefore, it is an object of this invention to provide a use for polyamines as a topical, non-toxic therapeutic agent for the palliative treatment of skin disorders associated with the disease and skin insults. In particular, symptoms and alterations that manifest in the skin such as pruritus, erythema, pain, paresthesia and general discomfort can be alleviated by topical administration of one or more polyamines as part of the palliative treatment of the underlying skin disorder. It is a further object of this invention to provide the use of polyamines to treat symptoms that arise from and / or are associated with skin diseases such as inflammatory dermatoses which include atopic and contact eczema, including pserosis such as dry skin and pruritus. wintry. It is a further object of the invention to provide a use of polyamines. for treating symptoms that arise from and / or are associated with epithelial tissue infection (eg, nasal passages, vulva and rectum) with trichomonas or fungi, anal fissures, fistula discharges, wound effluent, or drainage of surgical wound. It is another object of this invention to provide a use of polyamines to treat epithelial tissue symptoms that arise from and / or are associated with "secondary disease" in which the epithelial tissue exhibits manifestations of the underlying primary disease such as AIDS, chicken pox and metabolic disorders (ie, diabetes, liver and kidney dysfunction, and hematopoiesis). It is a further object of this invention to provide a use of polyamines to treat symptoms that arise from and / or are associated with epithelial alterations arising from direct aggression to epithelial tissue after natural intervention (local tumors, hemorrhoids) or surgical and that accompany the scar formation or irradiation therapy. The present invention relates to compositions containing polyamines in an amount that allows them to act as palliative and / or therapeutic agents for skin alterations, wherein the polyamine is selected from the group consisting of afilic diamines and polyamines with straight chains or branched with a length of 2 to 14 carbon atoms that have 2 to 6 amine and agmantine groups; and the pharmaceutically acceptable acid addition salts thereof. The aliphatic diamines and polyamines of this invention are derived from alkanes, such as n-propane, isopropane, butane, isobutane, tert-butane, hexane isohexane, heptane, octane, nonane, decane or dodecane. The corresponding branched chain analogs of those groups are also included. The groups of 2 to 6 amines contained by the aliphatic diamines and polyamines may be primary or secondary and may be located either in a terminal position within the alkane chain or both. Preferred compounds for use in the compositions and methods of the present invention are spermidine (4,4'-aminobisbutylamine), spermine, and .putrescine (1,4-diaminobutane) and cadaverine. Synthetic polyamines, such as N, N'-Bis- (3-ethylamino) -propyl-1,7-heptanediamine (BEPH) are also within the scope of the invention. The palliative and / or therapeutic diamines and the polyamines of this invention can be used as their free bases or as their pharmaceutically acceptable acid addition salts. Such acid addition salts may be derived from a variety of inorganic and organic acids such as hydrochloric, sulfuric, phosphoric, methanesulfonic, sulfamic, citric, lactic, pyruvic, oxalic, maleic, stearic, succinic, tartaric, fumaric, cinnamic acids. aspartic, benzoic acetic, salicyclic, gluconic, ascorbic, and related acids. The salts lack the odor of the free bases, which is an additional advantage in the treatment.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 presents the results of one. experimental evaluation of the signs and symptoms of the patient presented in the Case Study 1. The treatment results on the left and on the right are provided in Figures A and B respectively. In Figure 1A, the left side did not receive treatment during the first 6 visits, although once the putrescine treatment was started during visit 6 all the signs and symptoms decreased indicating an improvement in the skin. Figure 1B shows the observations of the treatment where during the first 6 visits, it was applied to the putrescine patient with a resulting decrease in the scores indicating improvements in the skin condition. During the period (visit 6-9) the patient was no longer treated in the area with a resultant increase in scores of all signs and symptoms that indicate a deterioration of the skin condition. Figure 2 presents the response to treatment and the subsequent global evaluations of the patient and the patient's physician presented in the Case Study 1. The treatment results on the right and on the left are provided in Figures 2A and 2B respectively.

Figure 3 presents data similar to Figure 2, except for the absence of the total records of signs and symptoms. The results of the treatment on the left and on the right are given in Figures 3A and 3B respectively. Figure 4 presents the response to treatment and the subsequent total signs and symptoms and the pruritus of the patient presented in Case Study 1. The treatment results on the left and on the right are provided in Figures 4A and 4B respectively. Figure 5 demonstrates the response to treatment and the subsequent erythema and pruritus scores on the left Figure 5A and on the right Figure 5B of the patient from the Case Study 1. Figure 6 demonstrates the response to treatment and subsequent global assessments, the determination stinging / patients and the pruritus scores on the left Figure 6A and on the right Figure 6B of the patient in the 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 treatment results on the left and on the right are given in Figures A and B respectively. Figure 8 presents the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study 2. The treatment results on the left and on the right are given in Figures A and B respectively. Figure 9 shows the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study 3. The treatment results on the left and on the right are provided in Figures A and B respectively. Figure 10 presents the results of an experimental evaluation of the signs and symptoms of the patient presented in Case Study 4. The treatment results on the left and on the right are given in Figures A and B respectively. Figure 11 is a summary of the signs and symptoms of patients from case studies 2-4, initially treated with putrescine. The data show that the important signs and symptoms associated with skin disease are alleviated by daily treatment with putrescine as indicated by the reduced records. In addition, the removal of the results of putrescine in a return to those signs and symptoms is indicated by a high register. Figure 12 presents a summary of the global medical records 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. The removal of the treatment resulted in a lower determination.

DETAILED DESCRIPTION OF THE INVENTION The following terms and abbreviations are used throughout the specification and the claims.

The term "therapeutic" means that it has healing properties. The term "palliative" means that it eliminates or alleviates uncured. The term "symptoms" means any perceptible change in the body or its functions that indicates the disease or type or phase of the disease. The term "pruritus" means severe itching, it may be the symptom of a disease process, such as an allergic response, or it may be due to emotional factors: the predisposing factor is cutaneous hyperesthesis. The term "polyamine" means any compound, for example spermine and spermidine, that contain two or more amino groups. Therefore, the term polyamine includes diamines. The term "variant" and "substitution of preservation" for the purpose of one of the polyamines of the present invention means any chemical structure that is a derivative of such polyamines achieved through the substitution of side groups, although it still exhibits the same properties or similar therapeutic to putrescine. The term "derivative" means any chemical compound derived from or considered to be derived from, another compound either directly or through modification or partial substitution.; thus a polyamine derivative is a chemical compound that was, is or can be considered to have been derived from the polyamine. For example, a compound such as putrescine can be considered as derived from a member of the polyamine class of compounds that are considered to be within the scope of this invention. The term "analogue" represents a chemical compound that has a structure similar to that of another compound although it differs from it with respect to certain components, therefore, for example, a putrescine analogue is a chemical compound with a structure similar to that of putrescine The term "erythema" represents a form of macula (spot or area with color) showing a diffuse reddening of the skin caused by capillary congestion, usually due to dilatation of the superficial arterioles as a result of various nervous mechanisms within the body; inflammation or some external influence such as heat, ionizing radiation, sunlight or cold. The term "paresthesia" means a feeling of numbness, stinging, or itching; increased sensitivity; it is experienced in central and peripheral nerve injuries and in locomotor ataxia. The term "hyperesthesia" means an increased sensitivity to sensitive stimuli, such as pain or contact. The term "dermatitis" means inflammation of the skin evidenced by itching, redness and several skin lesions: it may be due to one of several causes: systemic diseases; skin irritants such as poison ivy, corrosives and alkalis; or hypersusceptibility to conditions that would not normally cause skin irritation. Atopic dermatitis is a dermatitis of unknown etiology marked by stinging and scratching in an individual with inherently irritable skin. They can be allergic, hereditary or physiological components. The present invention is based on the discovery that topical administration of the polyamine compounds, such as putrescine, can alleviate many manifested dermal symptoms and the discomfort associated with the disease and / or skin alterations. In particular, skin symptoms such as pruritus, erythema, paresthesia pain and general discomfort can be alleviated by topical administration of certain polyamines. Such symptoms - arise from and / or are associated with: skin diseases such as inflammatory dermatoses including atopic and contact eczema, including xerosis such as dry skin and winter itch; the disease in which the skin is not the primary manifestation of the disease such as AIDS; and the alterations that arise from the aggression to the skin such as radiation therapy and scar management.

Polyamine of the invention The compounds useful in the composition and the useful methods of the present invention are known in the chemical art.

Details of the synthetic preparation of many of the compounds usable in the compositions and methods of the present invention can be found in Beilsteins Handbuch Der Organischen Chemie. The Merck Index, 9th edition, where many of the preferred compounds of this invention are also referred to. The chemical structure of the polyamines of this invention is based on the presence of an organic support structure, a carbon structure having at least two carbon atoms available for attachment to the primary amine groups. These organic support structures and their derivatives may comprise saturated and / or unsaturated molecules; Straight or branched linear chains; individual and multiple rings that. they include a variety of those such as monomers, dimers and polymers. In addition, each of these organic support structures may also contain substituted hydrocarbons and organic groups to form derivative forms. Preferred compounds useful in the compositions and methods of the present invention are encompassed by the following formula 1: H H H2N- (CH.) M- (N) p- (CH.) Q- (N) p (CHJr / (CHJn- (N) p- (CHJs- (N) p, I I H H where? · ,, p2, P3 and p4 are independently 0 or 1; n is independently 1-7; q, r, s are independently 0-7; with the proviso that n + m + q + r + s is less than or equal to 14. The highly preferred compounds of formula 1 are those wherein m is 3, n is 4, p2, P3, p4, q, rys are 0 and p is 1; m is 4, p ,, P2, P3, P4, q, r, s and n are 0; and m is 3, q is 4, r is 3, and p2 is 1, p3 and p4 are 0, and s is 0. The specific compounds usable in the composition and methods of the present invention are as follows: a reference indicated between [] immediately after each compound is a reference to the chemical preparation of the compound: Spermidine (4,4'-aminobisbutylamine) [Beil. 4 (2) 704.}.; Spermina [Beil, 4 (2) 704], Merck Index 9.8515]; , 'Putrescine (1,4-diaminobutene) [Se / 7. 4 264]; 1,3-diaminopropene [Beil. 4 261]; Agmatina [(4-aminobutyl) guanidine], [Beil. 4 (1) 420. Merck Index 9.7641]]; 1,2-d-aminopropane, [Be / 7. 4 257, Merck Index 9, 7641]; 1, 0-diaminodecane, [fie / 7. 4, 273]; 1, 12-diaminododecane, [fie / 7. 4 273;] 3,3'-iminobispropylamine [Biochem Biophys, Res. Commun., 63, 69 (1975)]; 1, 7-diaminoheptane [Beil. 4, 271]; 1, -diammohexane, [fie / 7. 4, 269, Merck Index 9, 4564]; 1,2-diamno-2-methypropane [Se / 7. 4, 266]; 1, 9-diaminononane [Be / 7. 4, 272]; 1,8-diamino octane [Be / 7. 4, 271]; Cadaverine [1, 5-diaminopentane, [fie / 7. 4 266, Merck Index 9, 6914]; trietilenetetraam ina, [fie / 7. 4,255, Fieser, Reagents for Organic 'Synthesis,, 1204;]; triethylenenetetramine tetrahydrochloride, [fie / 7. 4, 255]; N- (2-aminoetyl) -, 3-propanediamine; Dietilenetriarrina, [fie / 7. 4, 255]; Ethylene diamine [fie / 7. 4, 230, Merck Index, 9.3731, Fieser, Reagents for Organic Synthesis, 1, 372, 4, 231]; Ethylenediamine dichloride [fie / 7. 4, 230, Merck Index, 9, 3731]; and Tetraethylenepentamine. The free base form of the compounds usable in the present invention can be converted conveniently to the corresponding acid addition salt by contacting a solution of the free base with the appropriate acid. Particularly preferred salts are the acid addition salts formed with hydrochloric and sulfuric acids, for example sulfate hydrochloride. The palliative activity of the compounds usable in the compositional method of the present invention can be determined by measurement of the test effect in a clinical trial, as demonstrated in Example 1. The term "palliative" is used to denote the decreased disorder of the skin without implying a mechanism of action. The compositions of the present invention comprise one or more of the aforementioned compounds in a palliative amount together with a suitable pharmaceutical carrier. A palliative amount is defined as a quantity of compound necessary to provide greater relief from the symptom more important than a state without treatment or only by vehicle. In the usual course of therapy, the active compound is incorporated into the acceptable vehicle to form a composition for topical administration to the affected area or in a form suitable for oral or parenteral administration, such as tablets, capsules, pills, suspensions, injectables and solutions Compositions for typical application can be exemplified by ointments, ointments, creams, lotions, solutions, suspensions, aerosols, gels, dispersion powders and impregnated bandages and covers. Such compositions would normally be packaged in standard carriers such as pharmaceutically acceptable vegetable oils, and gelatins, gums and petrolatums. Other ingredients for the composition of the present invention may be preservatives, colorants, flavors, sweeteners, thickeners, suspending agents, expense agents, swelling emulsification, stabilization and pH regulation as required by the specific formulation. In such compositions it is contemplated that they contain the active ingredient from about 0.08 to about 8% by volume weight in a cream base. For topical application a concentration from about 0.5 mmoles, to about 500 mmoles of polyamine in a suitable salt, in the vehicle, wherein the vehicle between 99.92 and 92% (w / v) of the final product is optimal. The approximate therapeutic concentration is twice the tissue concentration or more. It should be noted, however, that the dividing line between a dose demonstrating a palliative effect for skin alteration is not precise and must be derived for a particular compound and a particular alteration. Compositions for oral or parenteral administrations, other than the aforementioned dosage units, are exemplified by dragees, pills, powders, granules, solutions, suspensions or elixirs. · The daily dose required for oral or parenteral administration can be administered in individual or divided doses, in patients, the exact dose to be administered will depend of course on the particular compound used, the alteration to be treated, other diseases present, the age and weight of the subject, liver and kidney status and the patient's individual response. The present invention relates to compositions containing polyamines in an amount that allows them to act as palliative and / or therapeutic agents for alterations of the skin, wherein the polyamine selected from the group consisting of aiiphatic polyamines with straight or branched chain of lengths 12 to 15 carbon atoms that are from 2 to 6 amine and agmantine groups; and the pharmaceutically acceptable acid addition salts thereof. The aiiphatic polyamines of this invention are derived from alkenes, such as n-propane, isopropane, butane, sobutane, tert-butene, hexane, so-hexane, heptane, octane, nonane, decane and dodecane. Branched chain analogues corresponding to those groups are also included. The groups of 2 to 6 amines contained by the aiiphatic polyamines may be primary and may be located in a terminal position within the alkane chain or both. Preferred compounds for use in the compositions and methods of the present invention are spermidine (4,4'-aminobisbutylamine), spermine, and putrescine (, 4-diaminobutane).

Synthetic analogues The 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-ethylamino) -propl] -1,7-heptan diamine (BEPH).

Pharmaceutically Acceptable Salts The palliative polyamines of this invention can be used as their free bases as their pharmaceutically acceptable acid addition salts. Such acid addition salts may be derived from a variety of organic and inorganic acids such as hydrochloric, sulfuric, phosphoric, methanesulfonic, sulfamic, citric, lactic, pyruvic, oxalic, maleic, 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 the treatment.

Compositions and Preparations of the Polyamines The following description presents examples of different types of compositions and preparations, described in illustrative detail of the present invention. It will be apparent to those skilled in the art that many modifications, both of material methods, can be practiced without departing from the purpose and intent of the description. ' Preparation 1: Formulation of Ointment Ingredient Amount Spermidine, micronized 0.05 micro moles- 1 millimole Mineral Oil, USP 50.0 mg I ngredient White Oil 1.0 g A weighed quantity of white oil and mineral oil is heated to 65 ° C and mixed uniformly. The mixture is cooled to 50 ° -55 ° C with stirring. The established active ingredient that has been dispersed in a portion of the mineral and crushed oil is added to the former with agitation. The ointment is cooled to room temperature.

Preparation 2: Formulation of jelly Ingredient Quantity Micronized spermine 0.05 micro moles - 1 millimole Water 5 mi K.Y.®Jelly * * a water-soluble jelly lubricant manufactured and marketed by Johnson & Johnson, New Brunswick NJ .that contains water, glycerin, sodium alginate, sodium carboxymethyl celu.losa, propylene glycerol potassium hydroxide, glycerol and propylene conservative conservative chlorhexidine.

A measured amount of white petrolatum and mineral oil is heated to 65 ° C and mixed evenly. The mixture is cooled to 50 ° -55 ° C with stirring. The established active ingredient that has been dispersed in a portion of the mineral and crushed oil is added thereto with agitation. The ointment is cooled to room temperature.

Preparation 3: Ointment preparation Ingredient Quantity Putrescine 0.05 microbes - 1 millimole Mineral oil, USP 50.0 mg USP white petrolatum for processing 10 g A measured quantity of white petrolatum and mineral oil is heated to 65 ° C and mixed evenly. The mixture is cooled to 50 ° -55 ° C with stirring. The established active ingredient that has been dispersed in a portion of the mineral and crushed oil is added thereto with agitation. The ointment is cooled to room temperature. According to the above procedure, but instead of the free base used in the acid addition salts with hydrochloric, sulfuric, phosphoric acids ', methanesulfonic, sulfamic, citric, lactic, pyruvic, oxalic,' maleic, stearic, succinic , tartaric, fumaric, cinnamic, acetic, benzoic, salicylic, gluconic, ascorbic and a similar product is obtained.

Preparation 4: Ointment formulation Ingredient Amount Micronized spermidine 0.05 micro moles - 1 millimole Mineral oil, USP 50.0 mg USP white petrolatum for processing 10 g A measured quantity of white petrolatum and mineral oil is heated to 65 ° C and mixed evenly. The mixture is cooled to 50 ° -55 ° C with stirring. The established active ingredient that has been dispersed in a portion of the mineral and crushed oil is added thereto with agitation. The ointment is cooled to room temperature. According to the above procedure, although spermine or agmantine sulfate was used instead of spermidine, a similar composition is obtained.

Preparation 5: Formulation of lotion Ingredient Amount Micronized spermidine 0.05 micro-moles - 1 millimole Aluminum monostearate 50.0 mg Isopropyl myristate for processing 10 g Approximately 90% of the isopropyl myristate is heated to 60 ° C and the aluminum monostearate is added with stirring and the heat is maintained to dissolve the aluminum monostearate. The active ingredient is dissolved in the remaining amount of isopropyl myristate. The solution of the active ingredient is added to the thickened solution of aluminum monostearate in isopropyl myristate previously cooled to 45 ° C with stirring. The lotion is cooled to room temperature with agitation. According to the above procedure, although spermine, agmantine, putrescine or cadaverine were used as free base or as any of the acid addition salts of the acids in place of spermidine, a similar lotion is obtained.

Preparation 6: Formulation of gel Ingredient Amount Micronized spermidine 0.05 micro-moles - 1 millimole Polyethylenes and copolymers 100.0 mg (A-C8) Mineral oil, light for processing 10 g A portion of the mineral oil (approximately 90%) in a suitable vessel is heated to approximately 80 ° C, and polyethylene (A-C8) was added to the mineral oil. The mixture is stirred slowly while it is hot until all the polyethylene dissolves. The above mixture is rapidly cooled by placing the vessel in a cooling bath of 10 ° to 15 ° C and resuming the agitation at normal speed. Once the contents of the container have reached approximately 45 ° C, a solution of the active ingredient that was disposed in the remaining mineral oil at 45 ° C, is added to the previous polymer solution. The mixture is cooled with air with slow stirring. This will result in a gel form according to the above procedure, although spermine, aginatin or putrescine were used instead of spermidine as the free base or as one of the acid salts, a similar lotion is obtained.

Preparation 7: Intramuscular or subcutaneous injectable oil Ingredient Quantity Spermidine 0.05 micro moles - 1 millimole Aluminum monostearate USP 20.0 mg / ml Heat treated sunflower oil USP 1.0 ml q.s. ad.

The above ingredients are mixed together and filled into sterile ampules. According to the previous experiment, although spermine, agmantine or putrescine were used instead of spermidine as a free base or as any of the salts of acids, a similar injectable solution is obtained.

Preparation 8: Aerosol formulation I ingredient Amount Micronized spermidine 10.0 to 50.0 mg Oleic acid 1.0 mg Fl uorotrichloromethane 4,739.0 mg Disclorodifluoromethane 12.250.0 mg The oleic acid is added to the fluorotrichloromethane previously cooled and mixed with a high shear mixer. During mixing, the required amount of the active ingredient is added and mixed until it is homogeneous. If necessary, adjust the suspension to the required weight with fluorotrichloromethane. The required amount of; Suspension is measured in each aerosol can, valves are folded over the can that is filled under pressure through valves with the required amount of dichlorodif luoromethane. This aerosol formulation can be used in the palliative treatment of skin disorders where extremely sensitive areas avoid the manual application of such compositions as creams, ointments, lotions, etc. According to the above procedure, although spermine, agmantine or putrescine were used instead of spermidine, either as a free base or as acid salts of the acids, a similar aerosol is obtained.

Preparation 9: Formulation of tablet I ngrediente Amount Spermidine 0.05 - 10 millimoles per tablet Lactose, direct compression degree 173 mg Sodium lauryl sulfate 20 g Corn starch 25 mg Magnesium stearate 2 mg The established active ingredients, lactose, microcrystalline cellulose, sodium lauryl sulfate and corn starch are mixed together and passed through a No. 46 sieve. It is magnesium stearate, is added and the mixed product is compressed into the form mixed in a tablet machine. According to the above procedure but using spermine, putrescine and agmantine sulfate instead of spermidine a similar product is obtained.

Preparation 10: Capsule formulation Ingredient Amount Micronized spermidine 50 mg Lactose USP 173 mg Microcrystalline cellulose 30 mg Sodium lauryl sulfate 20 mg Corn starch 25 mg Magnesium stearate 2 mg The active ingredient, lactose, microcrystalline cellulose, are mixed together sodium lauryl sulfate and corn starch. They are passed through a No. 80 sieve. Magnesium stearate is added, mixed and encapsulated in the appropriately sized two-piece gelatin capsule. This capsule can be used whenever an oral dose route such as in the state of injury and disease is desired. According to the previous product but using spermine, putrescine or agmantine sulfate instead of spermidine a similar product is obtained.

Preparation 11: Formulation in powder Ingredient Amount Micronized spermidine 0.2 - 10 millimole Lactose 150 mg The above powder is mixed with 8 ounces of water and administered orally (with added flavors) or with 32 ounces of water to be used as a portion to increase or moisten bandages. This type of formulation can be administered orally whenever an oral dose route is desired or topical whenever a regimen is necessary. By the use of spermine, putrescine or agmantine sulfate instead of spermidine, a similarly useful composition is obtained.

Effective doses For topical applications, the effective amount of the active compound is on a scale of 5 to 500 mM. Once the composition is applied to the scar or other area, it can be advantageously occluded with a dressing or incorporated in a transdermal patch dressing. It will be appreciated that the compositions according to the present invention are particularly useful for topical application in external areas, they are also expected to be of value in the treatment of internal tissue. In such cases, the composition can be applied by catheter infusion or by an implantable delivery mechanism with time. The polyamine compounds of this invention can be administered topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing pharmaceutically acceptable non-toxic carriers, auxiliaries and vehicles. The polyamines of this invention can be applied as a topical ointment. In addition, a pharmaceutical formulation comprising one to more polyamines of this invention and a pharmaceutically acceptable carrier is provided. One or more of the polyamine compounds may be present in association with one or more pharmaceutically acceptable non-toxic carriers and / or diluents, and / or auxiliaries and if desired other active ingredients. The pharmaceutical compositions containing the polyamine compounds of this invention may be in a form suitable for topical use, for example, as aqueous or oil suspensions, dispersible powders, granules or emulsions. Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hideopropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum. The dispersing or wetting agents can be natural phosphatide, for example lecithin or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexietol such as the polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-h idroxy-benzoate, or one or more coloring agents. The oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sunflower oil or coconut oil or a mineral oil such as para-fine liquid. The oil suspensions may contain a thickening agent, for example hard paraffin wax or cetyl alcohol. Sweetening agents such as those set forth above and flavoring agents may be added to provide oral preparations of good taste. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient and mix with a dispersible wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by those previously mentioned. Additional excipients, for example sweeteners, flavoring agents and colorants may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example an olive oil or arachis oil, or a mineral oil, for example liquid paraffin or a mixture thereof. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum, or tragacanth gum, naturally occurring phosphatides, for example, soybeans, lecithin and esters or partial esters derived from fatty acids and hexitone! anhydrides, for example sorbitan monooleate and condensation products of the partial esters with ethylene oxide, for example polyethylene sorbital monooleate. The polyamine compounds of this invention can be administered together or separately, in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures although it becomes liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The polyamine compound of the invention can be administered together or separately, parenterally in a sterile medium. The drug, depending on the vehicle and the concentration used can be suspended and dissolved in the vehicle. Advantageously, auxiliaries such as local anesthetics, preservatives and pH regulating agents can dissolve in the vehicle. For the compounds of this invention, the dose to be administered, either an individual dose, multiple doses or a daily dose, will vary with the particular compound being used. Factors to consider when deciding on a dosage regimen include the potency of the compound, the route of administration, the size of the container and the nature of the patient's condition. The dose to be administered is not subject to defined limits, although it can usually be an effective amount. It will usually be the equivalent, on a molar basis, of the pharmacologically active free form produced from the dose formulation on the metabolic release of the active free drug to achieve its desired pharmacological and physiological effects. A physicist with experience in the medical treatment technique will be able to determine, without undue experimentation, the appropriate protocols for the effective administration of the compounds of the present invention. The following references are incorporated herein by reference: Stedman's Medical Dictory, 24th edition 1984, p 382; Rook et al. Texbook of Dermatology, Ch, 14., p537; Rudzki, e: et al., (1994) Dermatology 189: 41-45; Dolynchuk KN, Ziesmann Monday, Serletti JM (1996) Plast Reconst. Surg Jan: 97: 117-123.

EXAMPLE 1: CASE 1 In the example that follows, the active compound used was putrescine. Putrescine was selected as being of natural occurrence, highly specific and readily available. Putrescine (putrescine dichhydrochloride, Sigma Chemical Co., St. Louis, MO., USA) was composed in a eutectic base (Glaxo Wellcome, Mississauga, Ontario) at a concentration of 0.08% (W / V) (50 mM) . The cream was applied daily to the patients. If it was removed for some reason the cream was reapplied as soon as possible. The patients did not report adverse events immediately. A clinical evaluation was carried out in a patient of 34 years of age (patient # 002: CAT) which presented localized atopic dermatitis of the hands, a condition that has persisted since birth. The objective of the evaluation was to determine if the topical cream (formulated as putrescine dihydrochloride on eutectic base, 0.8% W / V) would treat the signs or symptoms of inflammatory dermatosis such as atopic dermatitis. The patient had a current eruption of eczema or pruritus and had a moderate to severe severity. The target area was greater than or equal to 25 cm2.

The patient had no infected skin lesions and had not used medications such as steroids in the past three months. The history of the patient during the last two years was recorded in relation to treatments, allergy, skin disease and family history.

Methods The patient had followed five treatment regimens: Treatment regimen # 1: Topical putrescine dihydrochloride on Glaxal base (0.8% P / V) BID was applied to all affected areas on the right hand; The left hand did not receive treatment. The duration of treatment was 8 weeks. Treatment regime # 2: the treatment was reversed. Topical putrescine dihydrochloride on Glaxal base (0.8% W / V) IDB was applied to all affected areas in the left hand: the right hand did not receive treatment, the duration of treatment was 3 weeks. Treatment regimen # 3: Topical putrescine dihydrochloride on Glaxal base (0.8% P / V) IDB was applied to all affected areas on both hands. The duration of the treatment was 1 week.

Treatment regimen # 4: Topical putrescine dihydrochloride on Glaxal base (0.8% W / V) IDB was applied to all affected areas on the left hand; the left hand received the Glaxal base without active BID material. The duration of the treatment was 1 week. Treatment regime # 5: Treatment was reversed, topical putrescine dihydrochloride on base, Glaxal (0.8% P / V) BID was applied to all affected areas in the right hand; the left hand received Glaxal base without active BID material. The duration of the treatment was 1 week.

TREATMENT CLINICAL VISIT LEFT HAND RIGHT HAND 1 WITHOUT TREATMENT PUTRESCINA 2 WITHOUT TREATMENT • PUTRESCINA 3 WITHOUT TREATMENT PUTRESCINA 4 WITHOUT TREATMENT PUTRESCINA 5 WITHOUT TREATMENT PUTRESCINA 6 WITHOUT TREATMENT PUTRESCINA 7 PUTRESCINA WITHOUT TREATMENT 8 PUTRESCINA WITHOUT TREATMENT 9 PUTRESCINA WITHOUT TREATMENT 10 PUTRESCINA PUTRESCINA 11 PUTRESCINA PUTRESCINA 12 UNEVEN BASE TREATMENT 13 BASE EUTETICA PUTRESCINA The document Hanifin & Rajka (Rudzki, E, et al., Dermatology 189: 41-46), incorporated herein by reference, was used to record the signs and symptoms of the target area: erythema, pruritus, edema / papulation, oozing / forming scab, lichenification and excoriation.

Records of objective signs and symptoms In the present evaluation, at each visit, the means that examined the patient and recorded a value in each of those symptoms is the following basis: 0, 0.5, 1, 1.5, 2, 2.5, 3; where a score of 0 initiated an absence of symptoms and a value of 3 was attributed to the exacerbation of symptoms. At each visit, each symptom is independently evaluated in this way and then added to the values to provide a total added value that was used for general treatment purposes.

Global evaluations Additionally, the physician compiled a Global Physician Assessment (PGE) regarding the treatment's ability to - treat signs and symptoms. The patient also provided an overall impression of the treatment at each visit (Global Patient Assessment, or PtGE). The Global Physician and Patient Evaluations were graduated from -1 to +4 where: 4 indicates an eradication of the sign and / or symptom 3 indicates a marked improvement 2 indicates a moderate improvement 1 indicates a slight improvement 0 indicates that there is no change -1 indicates exacerbation Evaluation of pruritus in the patient The patient was asked to evaluate and record his pruritus perceptions using a visual analogue scale (VAS). The measurement of the patient's burning is on a scale of 0 to 10 (where 10 indicates an excessive scratching sensation).

Patient discomfort evaluation i 'Discomfort was evidenced through the loss of sleep that was recorded at each clinic visit.

Results The results are given in Figures 1A / 1B to 6A / 6B, where the results of the treatment on the left and right hands are given in Figures A and B respectively. The treatment regime for the left and right hands is as described above.

General summary of signs and symptoms From Figure 1A, the left hand did not receive treatment during the first 6 visits; and consequently, all the signs and symptoms remained relatively high. Once putres- cline treatment was started, all signs and symptoms decreased indicating improvements in skin condition. This effect persisted until the 11th. Visit when the patient left the treatment with putrescine, refrained from treatment for a week and then applied the eutectic base. The signs and symptoms appeared to deteriorate in the absence of putrescine. From Figure 1B, the cumulative data from the observations during treatment to the right gave similar results. In summary, during the first visits, the patient applied putrescine to the treatment area with a resulting reduction in the records indicating the improvement in skin condition. During the next three visits (visits 7-9) the patient left the area treatment with a resulting increase in the records of all the signs and symptoms that indicate the deterioration of the skin condition. Upon reapplying the putrescine between visits 9 and 11, the records decreased dramatically. The application of the eutectic base during visits 11 and 12 resulted again in a slight deterioration of the condition of the skin. Finally, the re-introduction of the treatment with putrescine (visits 12-13) showed a marked improvement in skin conditions.

Records of total signs and symptoms and global evaluations Figures 2a and 2B show the response to the treatment and subsequent Global Evaluations of the Patient and the Physician of the left and right hands respectively. Once again the treatment with putrescine reduced the total signs and symptoms and the overall evaluations showed an improvement in the general condition of the skin. The removal of putrescine and / or the addition of the eutectic base results in a deterioration of the condition of the skin.

Overall Evaluation of Patient and Physician Figures 3A and 3B provide data similar to Figures 2a and 2B except for the absence of the total signs and symptoms.

Records of total signs and symptoms and pruritus Figures 4A and 4B show the response to treatment and the total signs and symptoms and the pruritus of the left and right hands, respectively. Once again the treatment with putrescine reduces the total signs and symptoms and the evaluations of pruritus show an improvement in the general condition of the skin. The removal of putrescine and / or the addition of the eutectic base results in a deterioration of the condition of the skin.

Erythema and pruritus Figures 5A and 5B show the response to treatment and subsequent records of erythema and pruritus of the left and right hands, respectively. Once again the treatment with putrescine reduces erythema and itching which shows a general improvement in the condition of the skin. The removal of putrescine and / or the addition of the eutectic base results in a deterioration of the condition of the skin.

Global assessments, evaluation of pruritus and itching in the patient Figures 6A and 6B show the response to treatment and subsequent global assessments, the determination of the patient's burning sensation, and the left and right pruritus registers respectively. Once again, the treatment of putrescine reduces itching and itching and overall evaluations show an improvement in the general condition of the skin. The removal of putrescine and / or the removal of the eutectic base results in a deterioration of the condition of the skin. At the beginning of the evaluation, the baseline assessment of the patient's symptoms was as follows: Moderately severe itching (VAS record of 6.5); moderately severe itching (2 out of a 3 log) and severe lichenification (3 out of a 3 log) as assessed by the doctor. After 5 days, clinical changes were observed. The treated hand (right hand) began to respond to the treatment and at 2 weeks, the doctor's evaluation had indicated a general improvement in the symptoms; the patient observed a 50% reduction in itching as well as a marked improvement in pruritus and lichenification. On the other hand, all symptoms remained in the left hand for the duration of the treatment period, the effects continued until the end of Treatment Period # 1. The treatment was crossed over the second phase of the treatment and after one week the symptoms in the right hand were exacerbated (untreated) and evident improvements were observed in the left hand (treated). The third phase had both hands receiving the treatment and both responded to it within a period of 1 week. The introduction of the Glaxal Base as a treatment resource had provided a level of therapeutic improvement that would be expected with the use of an emollient. Although the discomfort was not fully evaluated, there was a correlation between reduced stinging and excoriation and reduced discomfort due to paresthesia. The results show the utility of the invention to treat the signs and symptoms in inflammatory dermatosis as in this patient with atopic dermatosis. The effects of topical putrescine treatment are immediately apparent and appear to be reversible. All the symptoms improved with the daily application.

EXAMPLE II: CASE II Patient 003 is a 32-year-old man with an allergy but no atopic history. There is a history of skin disease among his relatives. The treatment was started on the left cheek with his right cheek acting as control. The applications were followed until the next visit (day 5). The treatment was removed to the left cheek at that time due to a marked improvement in its S & S records. Treatment was started on the right hand and monitored at the next visit (day 19) where there was no change observed in the S &S records. The treatment was also performed on his hands with the left hand serving as the treatment area and the right hand acting as the control. There was an evident improvement in his S & S records and the treatment was withdrawn and-directed to the right hand for 14 days. No treatment effects were observed for the right hand.

EXAMPLE III: CASE III Patient 008 is a 12-year-old patient who had been treated for atopic dermatitis in the past (hydroxycortisone) and had a significant history of allergy. The ulnar cavity and wrist of the right arm were initially treated with similar areas on the left arm acting as control. There is a marginal improvement of the S &S records. the cross-treatment of the left arm did not have an observable effect on the S &S record EXAMPLE IV: CASE IV Patient 009 is a 37-year-old patient who had been treated for atopic dermatitis and had a history of allergy. Right hand and wrist treated initially with similar areas of the left arm acting as control. There was a marked improvement of the S & S records. The cross-treatment of the left arm had a positive improvement effect on the S &S record.

EXAMPLE V: CASE V A 28-year-old patient presented a secondary hypertrophic scar on her chest. The scar resulted from the removal of a fleshy mass. The scar and related pruritus were treated in a diverse and successful manner. The patient was placed on a regimen of daily putrescine treatment that resolved intense stinging at the time of treatment.

EXAMPLE VI: CASE VI A 16-year-old patient had a burn on the wrist in the left hand. After the application of semiocclusive cures, the patient returned with complaints. An important pruritus and hypertrophy of the resulting scar was diagnosed. After an initial course of putrescine treatment, it was found that the pruritus had disappeared within an hour. The preferred embodiments described above of the present invention are not intended to limit the scope of the present invention as demonstrated by the following claims. It should be understood that the foregoing relates only to preferred embodiments of the present invention and that numerous modifications or alterations may be made therein without departing from the spirit and scope of the invention as set forth in the appended claims.

Claims (1)

1. CLAIMS 1. The use of one or more polyamines as topical and non-toxic therapeutic agents for the palliative treatment of alterations and skin symptoms associated with diseases and chronic alterations of the epithelial tissue. 2. The use according to claim 1, characterized in that the polyamines are selected from the group consisting of di- and aliphatic polyamines with straight or branched chains of 2 to 14 carbon atoms having from 2 to 6 groups, "corresponding branched chain and agmantine analogs wherein the 2 to 6 amine groups contained by the aliphatic di- and polyamines may be primary or secondary and may be located in a terminal position, within the alkane chain, or both, and the pharmaceutically acceptable acid addition salts thereof. 3. The use according to I to claim 1, characterized in that the polyamines are comprised by the formula 1: HN- (CH2) m- (fN) p- (CH.) Q- (N?) P2 (CHJr / 2 HN- (CH2) n- (N) p- (CH2) s- (N) p3 HH in where p ,, p2, p3 and 44 are independently 0 or 1, n is independently 1-7, q, r, s are independently 0-7, with the proviso that n + m + q + r + s is less or equal to 14. The highly preferred compounds of formula 1 are those in