Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1998-07-28
1999-10-26
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
424 98, 424401, 514557, 514570, 514725, 514928, A61K 3119, A61K 4900, A61K 700, A61K 3107
Patent
active
059730072
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of inhibitors of the activity of retinoic acid to promote healing, especially of the skin.
It is known, in general, that all-trans-retinoic acid acts on the differentiation and/or the proliferation of cells by interacting with nuclear receptors of RARs (retinoic acid receptors) contained in the cell nucleus. Numerous synthetic structural analogues of all-trans-retinoic acid or of 9-cis-retinoic acid, commonly called "retinoids", have been described so far in the literature. There are so far three identified sub-types of RAR receptors called .alpha.-RAR, .beta.-RAR and .gamma.-RAR respectively. These receptors, after binding of the ligand (i.e. of all-trans-retinoic acid), interact with the promoter region of genes regulated by retinoic acid at the level of specific response elements (RARE).
Some analogues can therefore bind and activate a particular RAR (.alpha., .beta. or .gamma.) receptor sub-type. Finally, other analogues exhibit no particular selective activity towards these various receptors. To this end, and for example, all-trans-retinoic acid activates the RARs (RAR specific agonist ligand), all sub-types taken into consideration.
Retinoic acid and retinoids in general have been claimed for treating the following disorders or conditions: acne vulgaris, comedo-type acne, polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, acne medicamentosa or occupational acne; other keratinization disorders, in particular ichthyosis, ichthyosiform states, Darrier's disease, keratosis palmaris et plantaris, leucoplakia and leucoplakia-like states, skin or mucosal (buccal) lichen; other dermatological conditions linked to a keratinization disorder with an inflammatory and/or immunoallergic component and in particular all forms of psoriasis whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, or alternatively skin atopy, such as eczema or respiratory atopy or alternatively gingival hypertrophy; certain inflammatory conditions not exhibiting keratinization disorder, such as arthritis, dermal or epidermal proliferations whether benign or malignant, whether they are of viral origin or otherwise, such as verruca vulgaris, verruca plana and epidermodysplasia verruciformis, oral and florid papillomatosis and proliferations which may be induced by ultraviolet radiation especially in the case of baso- and spinocellular epitheliomas; other dermatological disorders such as bullous dermatoses and collagen diseases; certain ophthalmological disorders, especially corneopathies; skin ageing, whether photoinduced or chronologic or actinic keratoses and pigmentations or any pathology associated with chronologic or actinic ageing; the stigmas of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of skin atrophy; healing disorders or vibices; disorders of sebaceous function such as hyperseborrhoea of acne or simple seborrhoea; cancerous or precancerous states; conditions of viral origin at the cutaneous or general level (human immunodeficiency virus: HIV-1 or hepatitis B virus); alopecia; conditions of the cardiovascular system such as arteriosclerosis.
Retinoic acid and retinoids in general, by binding with the RAR receptors, make it possible to regulate the activity of the RAR receptors and to treat the above disorders or conditions.
The antagonists of retinoic acid will, on the contrary, inhibit the activity of retinoic acid or its metabolites at the cellular level. These are more particularly the RAR antagonists which bind to the RAR receptors, but do not induce the activity observed for retinoic acid or the retinoids.
Thus, it has been shown that antagonists of the .alpha.-RAR receptors inhibit the cellular differentiation induced by the retinoids on cells of the HL60 cell line or, on the contrary, reverse the inhibition of the proliferation of mouse B cells which is induced by the retinoids (C. Apfel & al., Proc. Natl. Acad. Sci. USA, 89, 1992, 7129-7133).
Various a
REFERENCES:
patent: 5808124 (1998-09-01), Beard et al.
patent: 5827500 (1998-10-01), Demarchez et al.
MacDonald et al., "Effect of retinoic acid on wound healing of laser burns to porcine retinal pigment epithelium", Can J Ophthalmol, V. 31, No. 4, pp. 175-178, 1996.
Eyrolles et al, "Retinoid anatagonists: molecular design based on the ligand superfamily concept", Med. Cell. Res., vol. 2, 1992, pp. 361-367, XP000674651.
Kaneko et al, "Retinoic antagonists", Med. Chem. Res., vol. 1, 1991, pp. 220-225, XP00674650.
McDonald et al, "Effect of retinoic acid on wound healing of laser burns to porcine retinal pigment epithelium", Can. J. Opthalmol., vol. 31, No. 4, Jun. 1996, pp. 175-178, XP000674653.
Klein, "Identification and functional separation of retinoic acid receptor neutral antagonists and inverse agonists", J. Biol. Chem., vol. 271, No. 37, Sep. 13, 1996, pp. 22692-22696, XP002048821.
Standeven: "Specific antagonists of retinoid toxicity in mice" Toxicol. Appl. Pharmacol., vol. 138, No. 1, May 1906, pp. 169-173, XP002048822.
Demarchez Michel
Jomard Andre
Rossio Patricia
Centre International de Recherches Dermatologiques Galderma
Dees Jos,e G.
Lamm Marina
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