EP0307468A1 - Prevention et traitement des effets nocifs de l'exposition de la peau au soleil, et compositions a cet effet - Google Patents

Prevention et traitement des effets nocifs de l'exposition de la peau au soleil, et compositions a cet effet

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Publication number
EP0307468A1
EP0307468A1 EP19880904039 EP88904039A EP0307468A1 EP 0307468 A1 EP0307468 A1 EP 0307468A1 EP 19880904039 EP19880904039 EP 19880904039 EP 88904039 A EP88904039 A EP 88904039A EP 0307468 A1 EP0307468 A1 EP 0307468A1
Authority
EP
European Patent Office
Prior art keywords
ultraviolet radiation
inhibit
compound
methyl ester
delayed hypersensitivity
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19880904039
Other languages
German (de)
English (en)
Inventor
Peter M. Ross
Leon H. Bradlow
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ROSS, PETER M.
Original Assignee
Rockefeller University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rockefeller University filed Critical Rockefeller University
Publication of EP0307468A1 publication Critical patent/EP0307468A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • Skin cancer now ranks as the number one form of cancer in the United States today. The increase in the occurrence of skin cancer ranks second only to the increase of lung cancer in women.
  • Some forms of skin cancer can be attributed to chronic, year-round exposure to the ultraviolet radiation of the sun.
  • Malignant melanoma a dangerous form of skin cancer because of the speed with which it can spread through the body, is thought to stem from "severe episodic sunburn".
  • This type of sunburn is described as a sunburn obtained intermittently with no base tan. It occurs when people go out and get burnt once or twice a year; and then repeat this pattern year after year. It is frequently found in people who live in cold climates and who vacation in midwinter in warmer regions. There is no gradual exposure to the sun. They go into the sun with zero exposure, so that the skin has no chance to protect itself, and end up wi th severe sunburn.
  • UV light which causes the sunburn likewise induces other changes in the skin which are believed to predispose, or lead, an individual to skin cancer.
  • Such exposure can cause tumor graft tolerance and suppress delayed hypersensitivity (DH) [Parrish, J.A., ed. "The Effect of Ultraviolet Radiation on the Immune System", Johnson and Johnson Baby Products Company.].
  • DH delayed hypersensitivity
  • Irradiated mouse skin secretes low molecular weight protein that stimulates suppressor T cells in the spleen [Swartz, J. Invest.
  • ultraviolet radiation suppression of delayed hypersensitivity can prevent rejection of ultraviolet radiation exposed skin, at the risk of the long-term consequence of elevated skin tumor susceptibility. It would be advantageous to eliminate this effect in order to reduce or eliminate the possible long-term consequence of skin cancer in individuals who have sustained recent sun exposure.
  • the 21-oic acid methyl ester of triamcinol one acetonide (TAme), other compounds affecting the arachidonic acid cascade and other known synthesis inhibitors, and topical compositions thereof can be utilized to inhibit ultraviolet radiation suppression of delayed hypersensitivity in the epidermis of individuals exposed to ultraviolet radiation, thereby reducing or obviating the carcinogenic effects of ultraviolet radiation by administering topically to the affected area the compound or a composition thereof in an amount effective to inhibit the ultraviolet radiation suppression of delayed hypersensitivity without systemic effects.
  • TMAme triamcinol one acetonide
  • the present invention relates to the use of tr iamcinolone acetonide 21-oic acid methyl ester, compounds affecting the arachidonic acid cascade and other known synthesis inhibitors, and topical compositions thereof to reduce or obviate the carcinogenic effects of ultraviolet radiation.
  • this invention provides a method of inhibiting ultraviolet radiation suppression of delayed hypersensitivity in the epidermis of individuals exposed to ultraviolet radiation utilizing tri amcinol one acetonide 21-oic acid methyl ester, compounds affecting the arachidonic acid cascade and other known synthesis inhibitors, and topical compositions thereof without systemic effects.
  • the glucocorticoid utilized in the present invention is the 21-oic acid methyl ester of triamcinolone acetonide. It can be conveniently prepared by the synthetic routes detailed in Gorsline et al., Endocrinology, 116, pp. 263-273 (1985).
  • the active glucocorticoid, triamcinolone acetonide 21-oic acid methyl ester can be utilized in the method of the present invention alone, or more conveniently, formulated into a topical composition suitable for dermatological use.
  • Such formulations comprise the triamcinol one acetonide 21-oic acid methyl ester in a vehicle suitable for topical administration to the epidermis of an individual in need of therapy for exposure to ultraviolet radiation or sunburn.
  • the compounds affecting the arachidonic acid cascade and the prostaglandin synthesis inhibitors include, but are not limited to, aspirin, ibuprofen, indomethacin, salicylic acid, phenyl butazone, sulf inpyrazon and sulindac. These compounds may be formulated into pharmaceutical compositions with known pharmaceutically acceptable carriers for therapeutic administration.
  • compositions as are useful with the glucocorticoid of the present invention are exemplified by ointments, creams, lotions, aerosols, gels or soaps.
  • compositions will normally be based upon standard dermatological carriers which are pharmaceutically acceptable and cosmetically elegant, such as those selected from pharmaceutically acceptable polyalkylene glycols, isopropanol, gelatin, benzyl alcohol, gums, glycerol and petrolatum.
  • the compositions may contain preservatives, aerosol propellants, such as hydrocarbons, and coloring, thickening, suspending, dispersing, emulsifying, wetting, stabilizing and buffering agents.
  • compositions of the present invention may be utilized to treat the epidermis of individuals who have been exposed to ultraviolet radiation in potentially carcinogenic quantities. The amount of such exposure may vary from individual to individual and it is envisioned that a physician or other treatment administrator will consider factors such as the individual's age, weight, complexion and degree of exposure in administering the proper dosage. Treatment is envisioned to be accomplished by applying the topical composition to completely cover the affected area.
  • the dosage of the compounds is preferably in the range of 0.01 mg/m 2 to about 100 mg/m 2 skin surface area.
  • the predicted frequency of application is once or twice daily, but this may of course be varied depending upon the particular individual involved.
  • the method of treatment utilizing the compounds of this invention to treat individuals exposed to ultraviolet radiation comprises administering one or more of the compounds or a topical composition thereof to an individual in need of such therapy in an amount sufficient to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation.
  • the unique properties of the active ingredient allow treatment of the epidermis exposed to ultraviolet radiation without concommitant systemic effects. Since these compounds act only upon the epidermis in this therapeutic context, they are uniquely suited to the method of treatment of the present invention.
  • the method of the present invention will inhibit the ultraviolet suppression of delayed hypersensitivity in the epidermis.
  • the adminstration of the triamcinol one acetonide 21-oic methyl ester will prevent the induction of suppressor T lymphocytes which lymphocytes are responsible for the prevention of rejection of tumor tissue.
  • the epidermis will thus continue in a normal fashion which would thus allow the rejection of tumor tissue and prevent the carcinogenic effects of the ultraviolet radiation exposure.
  • the elicited response to treatment with the compounds of the present invention in the individual's epidermis will be rejection of the sunburned skin.
  • This rejection will result in intense infiltration, hyperproliferation and purulent crusting in the epidermis of the individual.
  • This is a manifestation of a normal immune system which is indicative of the fact that the ultraviolet radiation suppression of delayed hypersensitivity has been successfully blocked.
  • the so-treated individual will have increased his chances of rejecting to neoplasm and thus reduce or obviate his chances of sustaining ultraviolet radiation carcinogenesis.
  • TAme and the other compounds of the present invention prevent the UV suppression of delayed hypersensitivity at the site of irradiation.
  • TAme may block all cell responses by poisoning cell machinery or by vasoconstriction.
  • TAme it has been noted as having no discernible effect on unirradiated skin, but enhanced markedly neutrophilic infiltration and epidermal hyperplasia in UV-irradiated skin.
  • TAme directly prevents an epidermal signal inducing ultraviolet radiation suppression of delayed hypersensitivity.
  • Possible sources include the Langerhans cell, whose functional properties appear to be altered substantially by glucocorticoids; the keratinocyte; or arachidonic acid metabolism to prostaglandin in the skin, of which the last appears to be confirmed to date. Other explanations are possible. While there is no evidence that a steroid applied after irradiation would influence photocatalyzed conversion of urocanic acid to a suppressing substance, possible effects on its release or subsequent metabolism cannot be excluded.
  • the infiltrate and hyperplasia were absent in the TAme only group, these were not caused by simple drug effects such as irritation. However, the response did not resemble microscopically either graft rejection or delayed hypersensitivity, in that mononuclear cels were not abundant.
  • the polymorphonuclear infiltrate could be a response to cell breakdown products or to bacterial antigens. Conceivably, the neutrophils or irradiated epidermal cells secrete a growth factor. Gamma interferon secretion from macrophages or T-lymphocytes has been implicated in acanthotic changes during delayed hypersensitivity reactions, see Kaplan et al., Proc. Nat. Acad. Sci.
  • TAme-treated epidermis was ineffective at provoking or suppressing cell-mediated immunity when untreated epidermis was effective.
  • TAme did not cause direct toxicity nor did it affect sensitization or challenge at a distal site.
  • mice aged about 4 months are secured from the Rockefeller University colony established in December, 1983, from NIH Balb/CAnN stock.
  • DN CB 1-chloro-2,4-dinitrobenzene
  • TA triamcinoone acetonide
  • Sigma TAme
  • Irradiation To handle the irradiation of mice in groups, holes 2 cm on a side are cut in a cardboard mask which is then set above a bank of two GEG15T8 high pressure Hg lamps emitting primarily at 254 nm. This lamp minimizs possible systemic effects of irradiation. 254 nm light penetrates the epidermis less deeply than sunlamp radiation, which is more commonly used to study UV supression of delayed hypersensitivity. Incident dose is 12 W/m 2 as measured by an acti nometrically calibrated Black Ray model J-225 shortwave UV monitor.
  • Steroid treatment Forty micrograms of TA or TAme, dissolved at a concentration of 0.2% in absolute USP ethanol, is spread over the UV-irradiated site and spread with a microliter pipette (Rainin Pipetman P-20); the same dosage being used for both compounds since they differ only by a methyl group. ( TA is used to compare results with a glucocorticoid having undesirable systemic effects).
  • DNCB Applications Animals are shaved on the lower back to expose about 4 cm 2 skin. For experimental sensitization, 20 microliters of a 2% solution of DNCB in ethanol are applied to this shaved site. To ascertain the degree of delayed hypersensitivity; four days after the first sensitizing application, 5 microliters of DNCB freshly dissolved to 2% in ethanol are applied to the inner and outer aspects of each animal's left ear (total 200 micrograms). Ear thickness is measured just prior to this challenge and at 24 hour intervals thereafter with the aid of a dissecting microscope and a dial engineer's caliper. Histology: Abdominal skin, fixed in formalin, is embedded in paraffin; microtome sections is stained with hematoxylin-eosin.
  • mice from a colony are caged in six groups. Three of the groups of mice are exposed to 4 kJ/m 2 254 nm light; others are shaved but not irradiated. Immediately following ultraviolet exposure (day 0), mice are painted with steroid or with vehicle (ethanol) at the site of irradiation. This treatment is repeated 3 times at approximately 24 hour intervals, then discontinued. On day 5, the lower back of each animal is shaved to expose about 4 cm 2 skin. Animals to be sensitized are painted at this site with 1-chloro-2, 4-dinitrobenzene (DNCB) in ethanol, and this treatment is repeated 24 hours later (day 6).
  • DNCB 1-chloro-2, 4-dinitrobenzene
  • the test for delayed hypersensitivity response is maximal four days after the first sensitizing tratment (not shown).
  • Day 9 is chosen to challenge for contact sensitivity by application to the left ear of 1-chloro-2,-4-dinitrobenzene in ethanol.
  • Ear swelling is measurable on day 10, but it peaks on day 11, 48 hours following challenge.
  • mice The data for this experiment are summarized in Table I, where the average for each group of mice is shown as the ratio of left and right ear thicknesses.
  • the average thickness of the left and right ears for most groups was 0.24 mm on day 9.
  • the sensiti zation causes the 1-chloro-2,4-dinitrobenzene treated skin to thicken and become indurated. This response is most pronounced in the controls, the TAme only, and the ultraviolet radiation + TAme groups.
  • ears swell according to group.
  • the swelling is accompanied by a mild erythema, and a visual estimate of the extent of the erythema and swelling correlates well with the caliper measurements:
  • Ears of sensitized controls swell to about twice their normal thickness.
  • Ears of unsensitized mice do not swell.
  • the response measured here is therefore a consequence of delayed hypersensitivity rather than primary irritation, which, at higher 1-chloro-2,4-dinitrobenzene concentrations than those used here, also produces ear swelling. For instance, 1-chloro-2,4-dinitrobenzene irritation is measurable in the controls.
  • the triamcinolone acetonide only group was strongly suppressed for delayed hypersensitivity.
  • the UV + TA group exhibited a weak degree of delayed hypersensitivity comparable to that in the UV only group.
  • Mice treated with triamcinolone acetonide 21-oic acid methyl ester but not with UV on the other hand, exhibited normal delayed hypersensitivity.
  • Triamcinolone acetonide gains access to the circulation and thus may act at a distance.
  • triamcinolone acetonide could act at the spleen or at the skin to prevent delayed hypersensitivity.
  • Testing for the effect of TAme on delayed hypersensitivity at the site of sensitization is as follows: On day 0, the shaved back skin of C57B1/K6S mice are painted with 1-chloro-2,4-dinitrobenzene; with TAme; or with both compounds. On day 6, the animals are tested for delayed hypersensitivity by application of 1-chloro-2,4-dinitrobenzene or of TAme + DNCB. The data obtained shows that TAme prevents delayed hypersensitivity when applied to the back at the time of sensitization and also prevents ear swelling when applied to the ear at the time of challenge.
  • mice of the experiment shown in Table I are killed on day 3 or 12 for histological examination of the UV-exposed portion of their abdominal skin.
  • the evaluation is summarized in Table II.
  • the skin of UV only mice on day 3 contained a diffuse dermal infiltrate, consisting of about 90% neutrophils and 10% monocytes and macrophages.
  • the inflammatory changes were not accompanied by erythema and were in other ways characteristic of UV-exposed mouse skin [Photobiol. 37 , pp 623-631 (1983)].
  • the dermis of TAme-treated, UV-irradiated mice was infiltrated by polymorphonucl ear leukocytes. Macroscopically, there was induration and purulent crusting.
  • Sensitized 9 24.2 1.3 24.4 1.4 0.99 -0.2 control 10 42.6 3.6 26.9 1.5 1.58 15.6
  • Triamcinolone acetonide 21-ennoic acid methyl ester other compounds affecting the arachidionic acid cascade a other known synthesis inhibitors, and topical and pharmaceutical compositions thereof are utilized in a method of treati ultraviolet radiation exposed skin to inhibit ultraviolet radiation suppresion of delayed hypersensitivity in the epiderm thereby reducing or obviating the carcinogenic effects of the sunburn.
  • Formulations of the triamcionolone acetonide 2 ennoic acid methyl ester preferably contain about 0.005 to 1.0 percent by weight of the active ingredient.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

Un méthyle ester de l'acide 21-nonanoïque de triamcinolone acétonide, d'autres composés affectant la cascade d'acides arachidoniques et d'autres inhibiteurs de synthèse connus, ainsi que des compositions topiques et pharmaceutiques de ceux-ci sont utilisés dans un procédé pour traiter la peau exposée au rayonnement ultraviolet en vue d'inhiber la suppression par ce dernier de l'hypersensibilité retardée de l'épiderme et ainsi de réduire ou de prévenir les effets carcinogènes du coup de soleil. Des formulations du méthyle ester de l'acide 21-nonanoïque de triamcinolone acétonide contiennent de préférence environ 0,005 à 1,0 pourcent en poids du principe actif.
EP19880904039 1987-03-25 1988-03-25 Prevention et traitement des effets nocifs de l'exposition de la peau au soleil, et compositions a cet effet Withdrawn EP0307468A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3076487A 1987-03-25 1987-03-25
US30764 1987-03-25
US16154288A 1988-02-29 1988-02-29
US161542 1988-02-29

Publications (1)

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EP0307468A1 true EP0307468A1 (fr) 1989-03-22

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EP19880904039 Withdrawn EP0307468A1 (fr) 1987-03-25 1988-03-25 Prevention et traitement des effets nocifs de l'exposition de la peau au soleil, et compositions a cet effet

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EP (1) EP0307468A1 (fr)
AU (1) AU613370B2 (fr)
CA (1) CA1316827C (fr)
WO (1) WO1988007371A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4897260A (en) * 1987-05-22 1990-01-30 The Rockefeller University Compositions that affect suppression of cutaneous delayed hypersensitivity and products including same

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DE2264003C2 (de) * 1972-12-22 1982-11-04 Schering Ag, 1000 Berlin Und 4619 Bergkamen Neue Pregnansäure-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate
US4185100A (en) * 1976-05-13 1980-01-22 Johnson & Johnson Topical anti-inflammatory drug therapy
US4282216A (en) * 1977-04-20 1981-08-04 Johnson & Johnson Topical anti-inflammatory drug therapy

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8807371A2 *

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Publication number Publication date
AU1707788A (en) 1988-11-02
WO1988007371A3 (fr) 1988-12-01
AU613370B2 (en) 1991-08-01
WO1988007371A2 (fr) 1988-10-06
CA1316827C (fr) 1993-04-27

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