EP1075254A2 - Utilisation de polyamines dans le traitement de symptomes dermatologiques - Google Patents

Utilisation de polyamines dans le traitement de symptomes dermatologiques

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Publication number
EP1075254A2
EP1075254A2 EP99913032A EP99913032A EP1075254A2 EP 1075254 A2 EP1075254 A2 EP 1075254A2 EP 99913032 A EP99913032 A EP 99913032A EP 99913032 A EP99913032 A EP 99913032A EP 1075254 A2 EP1075254 A2 EP 1075254A2
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EP
European Patent Office
Prior art keywords
skin
treatment
polyamines
symptoms
pruritus
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EP99913032A
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German (de)
English (en)
Inventor
Theodore Toney Ilenchuk
William Stuart Maddin
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Individual
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Individual
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to the use of non-ioxic polyamines in the palliative treatment of chronic diseases and symptoms associated with epithelial tissue.
  • 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, it forms a cove ⁇ ng that, like the epidermis in plants, protects the animal from injury and drying out. On internal surfaces, this tissue may be specialized for other 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 performs several functions essential for survival, which may be grouped as follows: maintenance of body temperature, protection by providing a physical bar ⁇ er that protects underlying tissues from physical abrasion, bacterial invasion, dehvdrationand ultraviolet radiation; perception of stimuli because the skm 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 diagnosis.
  • Irritation is defined generally as a reaction to that which is irritating.
  • the term, lmtauon. characterizes an abnormal state of the skm that is produced in reaction to an acute exacerbation or a stimulant (e.g., chemicaL or mechanical).
  • a stimulant e.g., chemicaL or mechanical.
  • Typical symptoms that can result from irritation include itching (pruritus), stinging, burning, tingling, "tightness.” erythema (redness) or edema (swelling).
  • a great many chemical compounds are known to cause dermatolo ic 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 with detergent solutions during dishwashing and housework, to very severe blistering of the skin such as that which occurs following contact with poison ivy.
  • the usefulness of a great many chemical compounds is severely limited because of their tendency to cause skin irritation.
  • PCT application PCT/US96/01289 describes the use of multi-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 eliminating the skin irritation caused by skin diseases or other conditions such as environmental exposure to irritating chemicals or environmental influences, such as wind. In each of these dermatological situations, however, the focus of the treatment is treatment of irritation.
  • Skin diseases, scars, and infections are all examples of chronic disorders 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 in the sk in.
  • Skin damage caused by accident or surgery presents with symptoms 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 the skin as a chronic disorder.
  • Dermatoses refer to diseases of theskin. which exhibit any skin lesionorgroupof lesions, oreruptions of any kind. Inflammatorv dermatoses are usually associated with pruritus, erythema and scaiinc. The lnflammatorv dermatoses include contact eczema, atopic dermaiosis and xerosis.
  • Eczema represents an inflammatory response of the skin to a spectrum of external and 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 upper dermal blood vessels: association with spongiosis: and varying degrees of acanthosis. Classification of thep ⁇ ncipal forms of eczema isdifficult because of the multiplicity of potential cont ⁇ buti ve factors: nonetheless, a summarv of the various forms of eczema induced by external and internal factors is provided in Table 1.
  • Atopic dermatitis is a chronic, pru ⁇ tic. eczematous condition of the skm that is associated with a personal or family history of atopic disease (e.g.. asthma, allertic rhinitis, or atopic dermatitis).
  • atopic disease e.g. asthma, allertic rhinitis, or atopic dermatitis.
  • Patients with atopic dermatosis usually have a history of allergy and are generally untreatable.
  • the allergic response gives ⁇ se to an inflammatory response that manifests in nasal, lung or other dermal tissue
  • 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 major protective bamer. Because of the subjective nature of pru ⁇ tus. the lack of a precise definition, and the lack of suitable animal models, pruritus is a disorder that has not been researched adequately.
  • Scar tissue is formed during healing of wounds, caused for example 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 collagen type III out of proportion to collagen type I.
  • Hematologic disorders that cause pruritus include polycythemia vera. Some conditions that cause iron deficiency, including exfoliative skin disorder, also cause pru ⁇ tus. Diabetes and thy rotoxicos is are endocrine causes of pru ⁇ tus (Abel. E.A.. Farber. E.M. "Malignant cutaneous tumours" InRubenstein. E.. Federman. D.D., ed.s Scientific Amencan Medicine (New York: Scientific Ame ⁇ can. Inc. Chapter 2. Dermatology
  • Pruritus is a frequent clinical manifestation of people with AIDS. AIDS-related Kaposi's sarcoma, and AIDS-related opportunistic infections. Pruritus wi th or w i thout 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 approaches 100% (Dangel. R.B.. Pruntus and cancer. Oncology Nursing Forum 13 (1): 17-21. 1986 ) .
  • Va ⁇ ous malignant diseases are known to produce pru ⁇ tus.
  • Hodgkin's disease causes pru ⁇ tus in 10% - 25% of patients.
  • pruritus precedes diagnosis of the lymphoma (Abel EA. Farber EM:
  • Pru ⁇ tus 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 leukemias 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 upper extremities (Abel EA. Farber EM: Malignant cutaneous tumors. In: Rubenstein E. Federman DD, Eds. : Scientific American. Medicine. New
  • Pruritus associated with malignant diseases has been observed to diminish or disappear with eradication of the tumor and reappear with recurrence of disease (BernhardJD: Clinicai as pec ts of pruritus. In: Fitzpatrick TB, Eisen AZ, Wolff K. etal.. Eds.: Dermatology in General Medicine. New York: McGraw-Hill.3rded., 1987, pp 78-90).
  • Drugs associated with secondary pruritus include opium derivatives (cocaine, morphine, butorphanol) , phenothiazines. tolbutamide, erythromycinestolate. anabolic hormones, estrogens, progestins. testosterone and subsequent cholestasis, aspirin, quinidine and other antimalarials, biologies such as monoclonal antibodies, and vitamin B complex. Subclinical sensitivity to any drug may be related to pruritus (Bemhard JD: Clinical aspects of pruritus. In: Fitzpatrick TB. Eisen AZ. Wolff K. etal.. Eds.: Dermatology in General Medicine. New York: McGraw-Hill. 3rd ed.. 1987, pp 78-90).
  • enkephalins substance P (a tachykinin that affects smooth muscie). and prostaglandins. It is believed that nonanatomic factors (such as psychological stress, tolerance, presence and intensity of other sensations and/or distractions) determine itch sensitivity in different regions of the body.
  • the itch impulse is transmitted along the same neural pathway as pain impulses. ⁇ .e.. traveling t rom pe ⁇ pheral nerves to the dorsal horn of the spinal cord, across the cord via the ante ⁇ or 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 include dryness of the epidermis and dermis. anoxia of tissues, dilauon of the capillaries, tr ⁇ tating stimuli, and psychological responses (AbelEA. Farber EM. Malignant cutaneous tumors. In: Rubenstein E. Federman DD. Eds.: Scientific American. Medicine. New York: Scientific American. Inc. Chapter 2: Dermatology, Section XII: Bernhard JD. Clinical aspects of pru ⁇ tus. In: Fitzpatrick TB. Eisen AZ. Wolff K. et al.. Eds. : Dermatology in General Medicine. New York: McGrawHill. 3rd ed., 1987, pp 7890: Greaves MW,
  • the motor response of scratching follows the perception of itch. Scratching is modulated at the corticothalamic center and is aspinal reflex. After scratching, itching may be relieved for 15 to 25 minutes. The mechanism through which the itch is relieved by scratching is unknowa It is hypothesized that scratching generates sensory impulses, which break circuits in the relay areas of the spinal cord. Scratching may actually enhance the sensationof itching, creating a characteristic itch-scratch-itch cycle. Other physical stimuli such as vibration, heat, cold, and ultraviolet radiation diminish itching and increase the release of proteolytic enzymes potentially eliciting the itch-scratch-itch cycle.
  • antineoplastic agents include drugs capable of producing cutaneous reactions including pruritus.
  • Patients receiving antineoplastic drugs frequently report dry skin and scaling thought to be related to effects on sebaceous and sweat glands (DunaginWG: Clinical toxicity of chemotherapeutic agents: dermatologic toxicity.
  • 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 history of the patient The agents most associated with hypersensitivities include doxorubicin. daunorubicin, cytarabine. Lasparaginase. paclitaxel. and cisplatin. In most reports, these reactions have been localized to the area of the vascular access and diss ipate 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 managementof Adriamycin flare. American Journal of Nursing 79 ( 1): 94-96, 1979). More dramatic and even life-threatening reactions can occur, and the development of pruritus may represent an early stage of serious hypersensitivity reactions (Weiss RB: Hypersensitivity reactions to cancer chemotherapy. In: Perry MC, Yarbro JW, Eds.: Clinical Oncology Monographs: Toxicitv of Chemotherapy. Orlando, FL: Grune and Stratton. Inc.. 1984. pp 101-123).
  • Radiation therapy-related pruritus is usually associated with dry desquamation of skin within the treatment field. Dryness and pru ⁇ tus may occur at an accumulated dose of 2000 to 2800 cGy , (Hassey KM. Rose CM: Altered skin integrity in patients receiving radiation therapy. Oncology Nursing Forum 9(4) : 44-50. 1982) and is caused by obliteration of sebaceous glands within the field. This is an acute phenomenon that correlates with thedepletion of actively proliferating basal cells in theepidermal layer of the skin, a fixed percentage of which dies with each dose fraction of irradiation.
  • Radiotherapy with electrons may elicit more skin reactions than photon therapy since the depth 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.
  • Biologic 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 biologies, but has so far been most reported in patients receiving interferon (Mayer DK, Smalley RV: Interferon: current status. Oncology Nursing Forum 10(4): 14-19, 1983: KrownSE: 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. Seminars in Oncology 13(3. Suppl2): 89-101. 1986: Irwin MM: Patients receiving biological response modifiers: overview of nursing care. Oncology Nursing Forum 14(Suppl6):
  • GVHD graft- versus-host disease
  • Reported skin changes include dryness and pruritic. ery thematous. macuiopapular rashes. Onset can be subtle or sudden: skin GVHD can progress to scleroderma and contracture (Nims J W. Strom S: Late complications of bone marrow transplant recipients: nursing care issues. Seminars in Oncology Nursing 4(1): 47-54. 1988).
  • pharmacologic agents employed at any point during the cancer course are capable of eliciting a pruritic reaction.
  • drugs include morphine, other opium derivatives, and aspirin used in pain management: corticosteroids; antibiotics: phenothiazines: and to a lesser degree, hormonal agents (estrogen, progestins. and testosterone) (BernhardJD: 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 involving anal or vul var 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 is a medium-sized DN A virus that replicates within the cell nucleus. It is divided into two types - HSV- 1 and HSV-2. Usually, HSV- 1 causes oral infection, and HS V-2 causes genital infection. Primary infections with these viruses are characteristically followed by recurrent attacks, which are often preceded by localized itching or burning and characterized by occurrence in the same location. It is estimated that 100 million episodes of oral herpes and one-half million new casesof genital herpes occur each year in the United States. HSV infection is not limited to the lips and genital area: either type can infect any area of skin.
  • a chronic disorder of epidermal tissue that can give rise to pruritus is hemorrhoids (piles) which result from varicosities of the rectal veins. Initially contained within the anus (first degree), they gradually enlarge until they prolapse or extend outward on defecation (second degree) and finally remain prolapsed through the anal orifice (third degree).
  • piles hemorrhoids
  • Erythema (redness of the skin) is a cardinal symptom of an inflammatory response within the skin. Other symptoms include swelling, heat and pain.
  • the underlying inflammatory processes are respons ib le for the red 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 through dilated blood vessels: direct stimulus upon the superficial blood vessels; or, from obstructions in deeper vessels causing a shunting of blood through the superficial vessels.
  • Altered or abnormal skin sensation can manifest in patients in a number of ways : numbness, tingling, prickling, burning, crawling sensations, itch, increased awareness and pain. These paresthesias have many different causes but generally reflect damage to particular sensory neurons such as the peripheral nerve fibers.
  • Pain is a protective mechanism for the body; itoccurs whenever any tissues are being damaged and it causes the individual to react to remove the painful stimulus.
  • Pain receptors in the skin and other tissues are nerve terminals, that lack any special characteristics, and they are likely triggered by achemical stimulus when potential tissue damage occurs. There appear to be two types of terminals: one responds to many types of painful stimuli, whereas the other specifically responds to either mechanical or thermal energy.
  • chemosensitive pain receptors The receptors that are sensitive to various chemicai substances and are called chemosensitive pain receptors. Some of the different chemicals that excite the chemosensitive receptors include bradykinin, serotonin, histamine. potassium ions, acids, prostaglandins. acetylcholine. and proteolytic enzymes.
  • Extracts from damaged tissues cause intense pain when injected beneath the normal skin.
  • substances in such extracts that are especially painful are bradykinin. histamine.
  • many of these substances could cause direct damage to the pain nerve endings, especially the proteolytic enzymes.
  • some of the othersubstances. such as bradykinin and someof the prostaglandins can cause direct extremestimulation of pain nerve fibers without necessarily damaging them.
  • va ⁇ ous substances listed above not only stimulates the chemosensitive pain endings but also greatly decreases the threshold for stimulation of the mechanosensitive and thermosensiti ve pain receptors as well.
  • a widely known example of this is the extreme pain caused by slight mechanical or heat stimuli following tissue damage by sunburn.
  • Eczema is a chronic condition with periods of remission and exacerbation: management of the disease is based on avoidance, reduction or elimination of itch and appropriate therapy.
  • topical and oral medications may be useful.
  • Topical steroids may provide relief when symptoms are related toasteroid-responsive dermatosis. but anticipated benefits must be weighed against the vasoconstricti ve side effects. Topical steroids have no role in the management of pruritus of unknown origin. Topical steroids should not be applied to skin surfaces inside a radiation treatment field.
  • Systemic medications useful in the management of pruritus include those directed toward the underlying disease or control of symptoms.
  • Antibiotics can reduce symptoms associated with infection.
  • Oral antihistamines may provide symptomatic relief in histamine-related itching.
  • a scar is a mark left in the skin or an internal organ bv the heaiing of a wound, sore, or injury because of replacement by connective tissue of the injured tissue.
  • Scar tissue mav form du ⁇ ng the healing of wounds. lesions of diseases, surgical operations, irradiation, laceration, burns or infections
  • a hypertrophic scar is an excessive wound scar which by definition has grown in size beyond that required for normal wound heaiing.
  • Hype ⁇ rophic scars can emerge from many wound types, such as from a bu or a sharp incision.
  • Keloids a more severe form of hypertrophic wound scar, form firm dermal nodules of scar which are most commonly preceded by trauma at the site of o ⁇ gin. They are usually larger than hypertrophic scars and differ in that they frequently invade the normal skin adjacent to the wound. Hypertrophic scar formation is characte ⁇ zed by the accumulation of collagen type III out of proportion to collagen type I.
  • 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 body, although it is most prevalent after burn injuries and as a result of wounds across the breastbone and in the shoulder regions
  • Hypertrophic scars often remain for a very long time, sometimes until the person dies. In the case of adults, the hypertrophic scar will normally transform to a typical soft and pale scar afterayearor so. In addition to itching and being relatively unsightly, hypertrophic scars in the region of joints can also impair j oint mobility
  • polyamines for the therapeutic treatment of tissue damage.
  • polavmines are thought to t unction as inhibitors of transglutammase and/or lysy 1 oxidase. affecting collagen formation
  • Raisfelddesc bes the use ot compositions including polyamines to regulate, stimulate or inhibit, epithelial cell growth in United States Patent No.4.507.321.
  • this method teaches compositions containing poiyamines which are useful in low concentration to stimulate epithelial cell growth and are useful in high concentration to inhibit fibnoblast growth to diminish scar formation, by reducing the degree to which fibroblasts proliferate and produce collagen, thereby forming scar tissue.
  • 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 pso ⁇ asis and in retardation of fibrosis after injuries to the spinal cord and nervous system.
  • the abnormalities may take form in a variety of clinically identifiable and disgnosed conditions. It has been proposed that by preventing the oxidative deamination of lysine and hydroxyiysine ammo groups within the collagen alpha chains . which is the enzymatic function and specific activity of lysyl oxidase. the physical properties of the collagen scar tissue and the resulting fibrotic pathological state could be substantially reduced.
  • Polyamines have been used as a transglutammase inhibitor for a number of applications.
  • United States Patent No.5.124.358 a method is described for blocking maturation and production of micro filariae in adult fila ⁇ al nematodes. applying this method to several Brugia filarial infections.
  • Such symptoms arise rom 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.
  • an object of this invention to provide a use for polyamines as a topical, a non-toxic therapeutic for the palliative treatment of skin disorders associated withdisease and insults to the skin.
  • symptoms and disorders manifesting in the skin such as pruritus, erythema, paia paresthesiaand general discomfort can be alleviated by the topical administration of one or more polyamines as part of the palliative treatment of the underlying skin disorder.
  • skin diseases such as inflammatory dermatoses which include atopic and contact eczema, including xerosis such as dry skin and Winter itch.
  • epithelial tissue eg. nasal, vulvaroranal passages
  • 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).
  • the present invention relates to compos itions contammg poiyamines an amount which enables them to act as palliative and/or therapeutic agents tor skin disorders, wherein thepolyammeis selected from the group consisting of aliphatic di- and polyamines with straight or branched chains of length from 2 to 14 carbon atoms long beanng 2 to 6 amine groups, and agmat e: and the pharmaceutically acceptable acid addition salts thereof.
  • the aliphatic di- and polyamines of this invention are derived from alkanes. such as n- propane, isopropane. butane, isobutane. tert-butane. hexane.
  • the 2 to 6 amine groups contained by the aliphatic di- and polyamines may be either p ⁇ mary or secondary and may be located either a terminal position, within the alkane chain, or both.
  • Preferred compounds for use in the compos itions and methods of the present invention are spermidine (4.
  • Synthetic poiyamines such as, N,N'-Bis-(3-ethylamino) - propyl]-l,7-heptanediam ⁇ ne (BEPH), are also within the scope of the invention.
  • the palliative and/or therapeutic diamines and polyamines of this invention may be utilized as their free bases or as their pharmaceutically acceptable acid addition salts.
  • Such acid addition salts can be derived from a va ⁇ ety of inorganic and organic acids such as hydrochlo ⁇ c. sulfuric, phospho ⁇ c. methanesulfonic. sulfamic. cit ⁇ c. lactic, pyruvic. oxalic, maleic. stea ⁇ c. 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.
  • Figure 1 presents the results of an expe ⁇ mental evaluation of the signs and symptoms of the patient presented in Case Study 1.
  • the results of treatment to the left and right hands are provided in the A and B figures, respectively.
  • Figure 1 A the left hand received no treatment over the first 6 visits, however once putrescme treatment was initiated after visit 6 all signs and symptoms scores dropped indicating an improvement in skin condition.
  • Figure IB demonstrates the observations of treatment wherein du ⁇ ng the first 6 visits, the patient applied putrescme with a resultant decline in scores indicating improvement in skin condition.
  • Dunne tne pe ⁇ od (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 Patient and Physician Global Evaluations of the patient presented in Case Study 1.
  • the results of treatment to the left and right hands are provided in Figures 2A 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 are provided in Figures 3A and 3B. respectively.
  • Figure 4 presents the response to treatment and subsequent total signs and symptoms and pru ⁇ tus 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.
  • Figure 5 demonstrates the response to treatment and subsequent erythema and pru ⁇ tus scores by left hand
  • Figure 6 demonstrates the response to treatment and subsequent global evaluations, patient itch assessment and pruritus scores by the left hand (Figure 6 A) 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 expenmental 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 left and ⁇ ght arms are provided in the A and B figures, respectively
  • Figure 11 is asummary of signs and symptoms of patients from case studies 2 - 4. initially treated with putrescine.
  • the data demonstrates that the important signs and symptoms associated with the skin disease are alleviated by daily putrescine treatment as indicated by the reduced scores. Further, removal of putrescine results in a return of those signs and symptoms as indicated by an elevated score.
  • Figure 12 presents a summary 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.
  • symptom means any perceptible change in the body or its functions that indicates diseaseor the kind or phase of disease.
  • polyamine means any compound. e.g., spermine and spe ⁇ nidine . containing two or more amino groups. Thus, the term polyamine includes diamines.
  • variants and “conservative substitution” for purposes of one of the polyamines 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.
  • a po lyamine derivative is a chemical compound thateither was. is. or can be regarded as having been derived from polyamine.
  • a compound such as putricine can be considered as derived from a member of the polyamine ciass of compounds are considered within the scope of this invention.
  • analogue means a chemical compound having a structure similar to that of another compound but differing from it in respect to a certain component: thus, for example, a putricine analogue is a chemical compound with a structure similar to that of putricine.
  • erythema means a form of macula (spot or colored area) showing diffused redness of the skin, caused by capillary congestioa usually due to dilation of the superficial arterioles as a result of some nervous mechanism within the body; inflammation: or some external influence such as heat, ionizing radiation, sunlight, or cold.
  • parasthesia means a sensation of numbness, prickling, or tingling; heightened sensitivity; it i is experienced in central and peripheral nerve lesions and in locomotor ataxia.
  • hypoesthesia means an increased sensitivity to sensory stimuli, such as pain or touch.
  • dermatitis means inflammation of skin evidenced by itching, redness, and various skin lesions: it may be due to oneof several causes : systemic disease: skin irritants such as poison ivy. corrosives, acids. and alkalies: or hypersusceptibility to conditions that would not normally cause skin irritation.
  • systemic disease skin irritants such as poison ivy. corrosives, acids. and alkalies: or hypersusceptibility to conditions that would not normally cause skin irritation.
  • Atopic dermatitis 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.
  • the present invention is based upon the discovery that the topical administration of a polyamine compounds, such as putrescine, can alleviate many dermal-manifested symptoms and discomfort associated with disease and/orskin disorders.
  • a polyamine compounds such as putrescine
  • symptoms manifesting in the skin such as pruritus, erythema, pain, parasthesia and general discomfort can be alleviated by the topical administration of certain polyamines.
  • Such symptoms arise from and/or are associated with: skin diseases such as inflammatory dermatoses which include atopic and contact eczema, including xerosis such as dry skin and Winter itch: disease in which the skin is not the primary manifestation of the disease such as AIDS: and disorders arising out of insult to the skin such as radiation therapy and scar management.
  • skin diseases such as inflammatory dermatoses which include atopic and contact eczema, including xerosis such as dry skin and Winter itch: disease in which the skin is not the primary manifestation of the disease such as AIDS: and disorders arising out of insult to the skin such as radiation therapy and scar management.
  • the chemical structure of the polyamines of this invention is based upon the presence of an organic suppor t ing s t ruc t ure - a carbon backbone having at least two carbon atoms available for the attachment of primary amine groups.
  • organic supporting structures and their derivatives may comprise saturated and/or unsaturated molecules: straight and branched linear chains: single and multiple rings including a variety of heterocyciic ring structures: and any combination of these as monomers, dimers. and polymers.
  • each of these organic supporting structures may also contain substituted hydrocarbons and organic groups to form derivatized forms.
  • 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 4, p 2, p 3, p 4 , q, r, and s are 0 and p,_ is 1 : m is 4, p, p 2- p 3- p 4 , q, r, s, and n are 0: and m is 3, q is 4, r is 3, p u and p 2 , are 1, p 3 and p 4 are 0, and s is 0.
  • composition and methods of the present invention are the following: (a reference indicated in [ ] immediately following each compound is a reference to the chemicai preparation of the compound):
  • the free base form of the compounds utilizable in the present invention 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 addition salts formed with hydrochloric and sulf uric acids, e.g., hydrochloride and sulfate.
  • the palliative activity of the compounds utilizable in the composition method of the present invention may be determined by measurement of the effect of the test compound in a clinical test, such as demonstrated in Example I.
  • the term "palliative" is used to denote decreased skin disorder without implying a mechanism of action.
  • the compos itions of the present invention comp ⁇ se one or more of the above-mentioned compounds in a palliative amount together with a suitable pharmaceutical earner.
  • a palliative amount is defined as the amount of compound necessary to provide more relief from thesignorsymptom than an untreated state, or by vehicle alone.
  • 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, injectables. and solutions
  • compositions for topical application may be exemplified by ointments, creams, lotions, solutions suspensions, aerosols, gels, dusting powder, and impregnated bandages and dressmgs. Such compositions would normally be based upon standard earners such as pharmaceutically acceptable vegetableoils and gelatins, gums and petrolatum.
  • Other ingredients to the composition of the present invention may be preservatives, coloring, flavoring, sweetening, thickening, suspending, disbursing, emulsifying, swelling. stabilizing and buffering agent as required by the specific formulation.
  • compositions are envisioned to contain the active ingredient in from about 0.08 to about 8% by weight volume in a cream base.
  • a concentration from about 0.5 mmoles to about 500 mmoles poiyamine in a suitable salt, in the vehicle, wherein the vehicle, between 99.92 and 92% (w/v) of final product is optimal.
  • the approximate therapeutic concentration is two times the tissue concentration, or greater.
  • compositions for oral or parenterai administrations other than the dosage units mentioned above are exemplified by lozenges, dragees. powders, granulates, solutions, suspensions or elixirs.
  • the required daily dosage for oral or parenteral administration may be administered in single or divided dosages.
  • the exact dosage to be administered will, or course, be dependent upon the particular compound employed, the disorder being treated, other diseases present, the age and weight of the subject, the hepatic and renal status and the subject patient's individual response.
  • the present invention relates to compositions containing polyamines an amount which enables them to act as palliative and/or therapeutic agents for skin disorders, wherein the poiyamine is selected from the group consisting of aliphatic polyamines with straight or branched chains of length from 2 to 14 carbon atoms long being 2 to 6 amine groups, and agmatine: and the pharmaceutically acceptable acid addition saits thereof.
  • the aliphatic polyamines of this invention are derived from alkanes. such as n-propane. isopropane. butane, isobutane, tert-butane. hexane. isohexane. heptane, octane, nonane. decane, and dodecane.
  • alkanes such as n-propane. isopropane. butane, isobutane, tert-butane. hexane. isohexane. heptane, octane, nonane. decane, and dodecane.
  • the corresponding branch chain analogs of these groups are also included.
  • the 2 to 6 amine groups contained by the aliphatic polyamines may be either primary' or secondary and may be located cither 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.
  • 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)
  • the palliative polyamines of this invention may be utilized as their free bases or as their pharmaceutically acceptable acid addition salts.
  • acid addition salts can be derived from a variety of inorganic and organic acids such as hydrochloric, sulfuric, phosphoric, methanesulfonic. sulf amic, 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 treatment.
  • White Petroleum 1.0 g A weighted quantity of white petroiatum and mineral oil is heated to 65 ° C. and unit " or l 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 stirring. The ointment is cooled to room temperature.
  • 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 stirring. The ointment is cooled to room temperature.
  • a weighted quantity of white petrolatum and a mineral oil is heated to 65 ° C. and uniformly mixed. The mixture is cooied to 50 ° -55 ° C. with stirring. The stated active ingredient which has been dispersed in a portionof the mineral oil and milled is added to the above with stir ⁇ ng. Theomtment is cooled to room temperature.
  • the acid addition salts with hydrochloric, suifuric. phosphoric, methanesuifonic. sulfamic. citric, lactic, pyruvic. oxalic, maleic. stearic. succinic. tartaric. fumaric. cinnamic. aspartic acetic, benzoic. salicylic, gluconic. ascorbic acids and a similar product is obtained.
  • 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.
  • Thestatedactiveingredient whichhasbeendispersedina portion of the mineral oil and milled is added to the above with stirring.
  • the ointment is cooled to room temperature.
  • a portion of the mineral oil (about 90%) in a suitable vessel is heated to about 80 ° C. and polyethylene ( A-
  • Oleic Acid 1.0 mg.
  • Oleic acid is added to previously cooled fluorotrichloromethane and mixed with a high shear mixer. During mixing, the required amount of the active ingredient is added and mixing continued until homogeneous. If necessary, the suspension is adjusted to the required weight with fluorotrichlormethane. The required 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 dichlorodifluoromethane.
  • This aerosol formulation can be utilized in the palliative treatment of skin disorders where extremely sensitive areas prevent manual application of such compositions as creams, ointments, lotions etc.
  • the et fective amount of the active compound is in the range of 5 to 500 mM.
  • compositions according to the present invention are particularly useful for topical application to external areas, it is also to be expected to be of value in the treatmen t of internal tissue.
  • 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 or rectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable earners, adjuvants and vehicles.
  • the polyamines of this invention can also be applied as a topical oin t ment.
  • a pharmaceutical formulation comprising one or more polyamines of this invention and a pharmaceutically acceptable earner.
  • One or more polyamine compounds may be presen t in association with one or more non- toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants 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 oily suspensions, dispersible powders, granules, or emulsions.
  • Aqueous suspens ions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethy lcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate. polyvinylpyrrolidone, gumtragacanthand gum acacia.
  • Dispersing or wettmg agents may be a naturally-occur ⁇ ng phosphatide. for example, lecithin, or condensation products of an alky lene oxide with f attv acids, for example polyoxyethvene stearate. or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethy leneoxycetanol.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hvdroxv-benzoate. or one or more colonng agents.
  • Oily suspensions mav be formulated by suspending the active ingredients in a vegetable oil.
  • a vegetable oil for example arachis oil. oliveoil.sesameoilor ⁇ conutoil.orina mineral oil suchas liquid paraffin
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agen t s such as those set forth above, and f lavo ⁇ ng agents mav be added to provide palatable oral prepara t ions
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of wa t er provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., ascorbic acid
  • suspending agent e.g., g., g., g., g., g., g., sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorb
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oils phase may be a vegetableoil. for example olive oil or arachis oil. or a mineral oil. for example liquid paraffin or mixtures of these. or gum tragacanth. naturally-occurring phosphatides. for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol. anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the polyamine compound (s) of this invention may be administered, together or separately, in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing thedrug with 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 drug.
  • 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 drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Polyamine compound (s) of this invention may be administered, together or separately, parenterally insterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the dose to be administered whether a single dose, multiple doses, or a daily dose, will vary with the particular compound being used. Factors to consider when deciding upon a dose regimen include potency of the compound, route of administratioa size of the recipient and the nature of the patient's condition.
  • the dosage 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 dosage formulation upon the metabolic release of the active free drug to achieve its desired pharmacological and physiological effects.
  • Putrescine was selected, as it is naturally occurring, highly specific and readily available. Putrescine (putrescine dihydrochloride. Sigma Chemical Co.. St. Louis, Mo., USA) was compounded in a eutectic base (Glaxo Wellcome. Mississauga, Ontario) at 0.08% (W/V) concentration (50 mM).
  • the objective of the evaluation was to determine whether the topicai cream (formulated as putrescine dihydrochloride in eutectic base, 0.8%, W/V) would treat thesigns or symptoms 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 cm 2 .
  • Treatment regimen #1 Topicai putrescine dihydrochloride in Glaxal Base (0.8%, W/V) was applied BID to all affected areas on the right hand; the left hand received no treatment. The duration of treatment was 8 weeks.
  • Topical putrescine dihydrochloride in Glaxal Base (0.8%. W/V) 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 dihydrochloride in Glaxal Base (0.8%. W/V) was applied BID 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 1 week.
  • Treatment regimen #5 The treatment was reversed. Topical putrescinedihydrochloride in Glaxal Base (0.8%. W/V) was applied BID to all affected areas on the right hand: the left hand received Glaxal Base without active material BID. The duration of treatment was 1 week.
  • PGE Physician ' s Global Evaluation
  • the patient was requested to evaluate and score their perceptions of 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).
  • Figures 2A and 2B demonstrate the response to treatment and subsequent Patient and Physician Global Evaluations by the left and nght hands, respectively. Once again putrescine treatment lowers the total signs and symptoms scores and both global evaluations show improvement in skin condition overall. The removal of putrescine and/or the addition of eutectic base results in a deterioration of skm condition.
  • Figures 3 A and 3B provide similar data to Figures 2A and 2B except for the absence of the total signs and symptoms scores
  • Figures 4A and 4B demonstrate the response to treatment and subsequent total signs and symptoms and pruntus by the left and ⁇ ght hands, respectively.
  • 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 Erythema and Pruritus
  • Figures 5 A and 5B demonstrate the response to treatment and subsequent ervthema and pruritus scores by the left and ⁇ ght hands, respectively.
  • putrescine treatment lowers both ervthema and pru ⁇ tus showing overall improvement in skin condition
  • the removal of putrescine and/or the addition of eutectic base results in a dete ⁇ oration of skin condition Global Evaluations.
  • Figures 6A and 6B demonstrate the response to treatment and subsequent global evaluations, patient itch assessment and pruntus scores by the left and nght hands, respectively. Once again putrescme treatment lowers itch and pruritus and the global evaluations show improvement in skin condition overall. The removal of putrescine and or the addition of eutectic base results in a deterioration of skm condition
  • the treatment was crossed over m 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 provided a level of therapeutic improvement that one would expect with the use of an emollient.
  • results show the utility of the invention to treat the signs and symptoms of inflammatory dermatoses as in this atopic dermatosis patient.
  • the treatment effects of topical putrescine are evident immediately and appear to be reversible. All symptoms improved with daily application.
  • Patient 003 is a 32 year old male with an allergy but no atopic history There is some history of sk disease amongst his parents. Treatment was initiated on his left shin with his right shin acting as control Daily applications were followed up at the next visit (Day 5) Treatment was withdrawn to the left shin at this time because of marked improvement in his S&.S scores. Treatment was initiated on the ⁇ ght sk and monitored at the next visit (Dav 19) where no change in S&.S scores were observed Treatment was also effected on his hands with the left hand serving as the treatment area and the right acting as control. There was marked improvement in his S&S scores and treatment was withdrawn and directed to the right hand for 14 days. No treatment effects were noted to the right hand.
  • Patient 008 is a 12 year old patient who had been treated for atopic dermatitis in the past (hydroxy cortisone) and had a significant allergy history.
  • the cubetal fosse and wrist of the right arm were treated initially with similar areas on the left arm acting as control. There was marginal improvement of the pts. S&S scores. Cross-over treatment of the left arm had no observable effect on the S&S score.
  • Patient 009 is a 37 year old patient who had been treated for atopic dermatitis and had an allergy history. The right hand and wrist wee treated initially withsimilar areas on the left arm acting as control. There was marked improvement of the pts. S&S scores. Cross-over treatment of the left arm had a marked positive improvement effect on the S&S score.
  • the scar resulted from removal of a mole.
  • the scar and its related pruritus were treated variously and without success .
  • the patient was placed on a daily treatment regimen of putrescine that resolved the intense itch within an hour of treatment.

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Abstract

L'invention concerne l'utilisation de polyamines non toxiques dans le traitement palliatif de maladies et troubles chroniques du tissu épithélial. L'efficacité du traitement est mise en évidence par l'allégement des symptômes et troubles qui se manifestent au niveau d'un tissu épithélial tel que la peau, notamment le prurit, l'érythème, la douleur, la paresthésie et l'inconfort général, et sont consécutifs à l'administration topique de certaines polyamines. De tels symptômes se produisent à partir de conditions chroniques et/ou sont associés à ces conditions chroniques, telles que: (i) maladies cutanées du type dermatoses inflammatoires comprenant l'eczéma constitutionnel et de contact, notamment le xérosis comme la peau sèche et le prurit hivernal; (ii) les infections du tissu épithélial (par exemple le passage nasal, vulvaire ou anal) par des trichomonas ou champignons, les fissures anales, l'écoulement fistulaire, le suintement de plaies, ou le drainage de plaies chirurgicales; (iii) des maladies secondaires dans lesquelles le tissu épithélial présente des manifestations de l'atteinte initiale comme le SIDA, la varicelle et les troubles du métabolisme (par exemple le diabète, les anomalies fonctionnelles hépatiques et rénales et l'hématopoïèse); et (iv) des troubles provenant d'agressions directes du tissu épithélial, soit naturelles (tumeurs locales, hémorroïdes), soit consécutives à une intervention chirurgicale et accompagnant la formation de cicatrices ou la radiothérapie.
EP99913032A 1998-04-03 1999-04-06 Utilisation de polyamines dans le traitement de symptomes dermatologiques Withdrawn EP1075254A2 (fr)

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AU3133399A (en) 1999-10-25
WO1999051213A3 (fr) 1999-12-23
JP2002510618A (ja) 2002-04-09
MXPA00009705A (es) 2003-07-14
WO1999051213A2 (fr) 1999-10-14
IL138732A0 (en) 2001-10-31

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