University of Michigan

The Upjohn Co.

Other

University Patents, Inc.

John J Voorhees

Gary J Fisher

Sewon Kang

Wendell Wierenga

Charles N Ellis

Christopher E Griffiths

James Varani

Diane H Russell

Mats A Hamberg

Bengt I Samuelsson

Ulrika Pettersson

Amir Tavakkol

Geert Cauwenbergh

Sven R Hammarstrom

Yiru Xu

Anders Astrom

Anders ANGstrom

Methods are provided for ascertaining and measuring RPTP-&#x3ba; activity in response to insults such as UV irradiation and with respect to administration of a treatment and/or composition. Attenuation of EGFR activity by RPTP-&#x3ba; affects aspects of photoaging, including damage to the skin, suppression of the immune system, DNA damage, and connective tissue degradation. Intervention with respect to the effects of photoaging can include protection of RPTP-&#x3ba; from oxidation. The methods can be used for discovery of anti-aging treatments, adjuncts, or other preventative treatments, such as sunscreens.

Methods for measuring whether a treatment affects RPTP-&#x3ba; activity

Rosacea is treated with a composition comprising an antimicrobial and at least one of an anti-inflammatory and a non-retinoid inhibitor of at least one of NF-B, AP-1, MMPs, adhesion molecules, TLRs, and CD14. The composition may further comprise a retinoid.

Use of compositions for treating rosacea

Acne-affected skin has been found to be accompanied by the presence of matrix-degrading enzymes such as MMPs and neutrophil elastase, induction of neutrophils, and a reduction in procollagen biosynthesis. This invention treats scarring and inflammation accompanying acne by administering, topically or systemically, at least one of (i) an inhibitor of the matrix degrading enzymes and (ii) a cytokine inhibitor that alleviates inflammation and thus also alleviate neutrophil infiltration. Alleviating the matrix degradation and renormalizing procollagen biosynthesis allows for reduced inflammation and better natural repair of acne-affected skin. Inhibiting cytokines alleviates induction of MMPs in resident skin cells, and also alleviates inflammation with its concommitant induction of neutrophils from the blood stream bringing MMPs and elastase into the acne lesion. Dimishing the presence of matrix-degrading enzymes in the acne lesion reduces imperfect repair of the skin and thus decreases scarring in acne-affected skin.

Compositions and methods for use against acne-induced inflammation and dermal matrix-degrading enzymes

UVB radiation of about 300-310 nm wavelength and UVA radiation of about 380-390 nm wavelength, each of which exists in solar light, induces MMPs (matrix metalloproteinases) in human skin that degrade the collagen of the dermal matrix. This degradation contributes to photoaging of human skin, which can be prevented by blocking these wavelengths of solar radiation. In contrast, diseases that result in the overproduction of collagen can be treated by exposing the affected with to radiation having wavelengths in those regions, for these wavelengths not only induce MMPs but also inhibit collagen biosynthesis. For lighter skinned people so affected, the UVA wavelengths are preferred because of the reduced amount of erythema, whereas dark skinned people can be treated with the UVB radiation because they generally do not suffer from erythema.

UVA (&#x3e; 360-400) and UVB (300-325) specific sunscreens

Exposure of human skin to ultraviolet (UV) radiation from the sun not only induces the production of enzymes (matrix metalloproteinases) that degrade collagen, but also inhibits the synthesis of new collagen by inhibiting the synthesis of procollagen. This UV-induced inhibition of the synthesis of collagen can be prevented by the topical application of a retinoid or c-JUN inhibitor to the skin prior to exposure to UV radiation.

Compositions for reducing UV-induced inhibition of collagen biosynthesis in human skin

Rosacea is treated with a composition comprising an antimicrobial and at least one of an anti-inflammatory and a non-retinoid inhibitor of at least one of NF-&#x3ba;&#x3b2;, AP-1, MMPs, adhesion molecules, TLRs, and CD14. The composition may further comprise a retinoid.

Method and compositions for treating rosacea

Compositions and methods are provided for ameliorating various effects of UVA and UVB radiation from the sun. The compositions include an ingredient that prevents photoaging from MED and subMED radiation, namely a direct acting MMP (matrix metalloproteinase) inhibitor. The compositions can include another, indirect MMP inhibitor, such as a retinoid, certain other compounds (such as N-acetylcysteine, 2-furildioxime, and vitamin C), tetracyclines, and if a retinoid is used then in addition optional compounds that inhibit the CYP-26 (chytochrome P-450) mediated metabolism of retinoids such as ketoconazole and other azole compounds. In the method, the composition is applied prior to exposure to the sun; for direct acting MMP inhibitors, application should be just prior to exposure, and if indirect inhibitors such as retinoids are used in addition, then application of the indirect inhibitor should be at least about seven hours prior to exposure. Compounds that prevent erythema (skin reddening, sunburn) do not necessarily protect against UV-mediated elevation of MMP levels and activity, and similarly compounds that prevent UV-mediated elevation of MMP levels and activity are not necessarily effective against UV-induced erythema.

Compositions and methods using direct MMP inhibitors for inhibiting photoaging of skin

Chronological aging of human skin can be delayed with the topical application of an MMP inhibitor, preferably a retinoid (an indirect MMP inhbitor); retinoids also normalize procollagen biosynthesis. Chronological aging, or natural aging, is evidenced in elderly (80+ years old) skin by increased MMP levels and decreased procollagen levels when compared with younger individuals. Prophylactic treatment of not yet chronologically-aged skin with a retinoid both inhibits degradation of dermal collagen and restores procollagen synthesis. Biopsied sections from elderly skin show that a single treatment of chronologically-aged skin with a retinoid can increase epidermal thickness, improve the dermal collagen density, and promote the formation of rete pegs and dermal papillae. Such benefits are helpful in preventing bruising, tearing, and ulceration of elderly skin. Accordingly, prophylactic treatment begun much earlier in life with an MMP inhibitor and/or a retinoid delays the onset of such symptoms.

Methods and compositions for reducing collagen loss due to chronological aging in human skin

Exposure of human skin to ultraviolet (UV) radiation from the sun not only induces the production of enzymes (matrix metalloproteinases) that degrade collagen, but also inhibits the synthesis of new collagen by inhibiting the synthesis of procollagen. This UV-induced inhibition of the synthesis of collagen can be prevented by the topical application of a retinoid or c-JUN inhibitor to the skin prior to its exposure to UV radiation.

Methods and compositions for reducing UV-induced inhibition of collagen synthesis in human skin

Many human conditions, often skin conditions, are treated topically or orally with a retinoid such as retinoic acid or acetretin, which treatment often has the side effect of dry, irritated, and/or peeling skin. The use of soaps, detergents, chemical irritants, and such can also cause these same side effects. These side effects can be reduced or eliminated by the topical administration of an inhibitor, especially a natural inhibitor, of the epidermal growth factor receptor (EGFR), administered concomitantly with the retinoid, separately from the retinoid (such as on an as needed basis), or both. Administration of the two together is facilitated by a composition suitable for topical application and comprising both the retinoid and a natural EGFR inhibitor. Preferred natural inhibitors are genistein and other isoflavones extracted from natural occurring substances, or simple derivatives of such substances.

Use of natural EGFR inhibitors to prevent side effects due to retinoid therapy, soaps, and other stimuli that activate the epidermal growth factor receptor

The deleterious effects of the passage of time on human skin (i.e., chronological aging of human skin) can be prevented and treated with the topical application of a retinoid, preferably retinol. We have found that some of the same pathways (namely the stress-activated pathways, SAPs) activated in photoaging of human skin (i.e., sun-induced premature skin aging) are similarly elevated in the skin of elderly people. We have also found that other pathways (namely the mitogen-activated ERK pathway) is depressed in the same skin. Treatment of chronologically-aged skin with a non-retinoid MMP inhibitor and optionally a retinoid both inhibits degradation of dermal collagen and promotes procollagen synthesis. Biopsied sections from skin of elderly (80&plus; years old) show that a single treatment can increase epidermal thickness, improve the dermal collagen density, and promote the formation of rete pegs and dermal papillae (see FIG. ), and can decrease the amount of c-Jun and increase the amounts of Types I and III procollagen (see FIG. ). Such benefits are also helpful in preventing bruising, tearing, and ulceration of elderly skin.

Methods and compositions for preventing and treating chronological aging in human skin

Compositions and methods are provided for ameliorating various effects of UVA and UVB radiation from the sun. The compositions including an ingredient that prevents photoaging from MED and subMED radiation, such as a retinoid, certain other compounds (such as N-acetylcysteine, 2-furildioxime, and vitamin C) and optionally other MMP inhibitors such as tetracyclines and/or compounds that inhibit the P-450-mediated metabolism of retinoids such as ketoconazole and other azole compounds. In the method, the composition is applied prior to exposure to the sun; depending upon the ingredients used in the composition, application should be from 7 to 48 hours prior to exposure. Compounds that prevent erythema (skin reddening, sunburn) do not necessarily protect against UV-mediated elevation of MMP levels and activity, and similarly compounds that prevent UV-mediated elevation of MMP levels and activity are not necessarily effective against UV-induced erythema.

Compositions and methods for inhibiting photoaging of skin

Methods are provided for ameliorating various effects of UVA and UVB radiation from the sun, comprising administering compositions including an ingredient that prevents photoaging from MED and subMED radiation, such as a retinoid, certain other compounds (such as N-acetylcysteine, 2-furildioxime, and vitamin C) and optionally other MMP inhibitors such as tetracyclines and/or compounds that inhibit the P-450-mediated metabolism of retinoids such as ketoconazole and other azole compounds. In the method, the composition is applied prior to exposure to the sun; depending upon the ingredients used in the composition, application should be from 7 to 48 hours prior to exposure. Compounds that prevent erythema (skin reddening, sunburn) do not necessarily protect against UV-mediated elevation of MMP levels and activity, and similarly compounds that prevent UV-mediated elevation of MMP levels and activity are not necessarily effective against UV-induced erythema.

Methods for inhibiting photoaging of skin

Treatment of post-inflammatory hyperpigmentation (PIH) in black and asian skin is accelerated from natural healing by use of a composition comprising a retinoid and/or an inhibitor of cytochrome P-450 enzyme-mediated degradation of retinoids, the composition does not require a conventional depigmenting or bleaching agent (such as a hydroquinone) as is typically used. Healing of PIH lesions is accelerated about three to five times from normal healing. Additionally, these compositions are useful separately for lightening black or asian skin.

Method of treating post-inflammatory hyperpigmentation in black skin

Described are in vivo methods for testing the activity of vitamin D.sub.3 (1,25-dihydroxyvitamin D.sub.3) and analogs thereof in human skin and for testing the effect of a test compound on said activity. Also described are methods for enhancing the in vivo activity of vitamin D.sub.3 and analogs thereof by coadministering vitamin D.sub.3 or an analog thereof with an RXR ligand, a 24-hydroxylase inhibitor, or a mixture thereof. Preferred RXR ligand materials are retinoids, such as 9-cis retinoic acid, and precursors thereof, such as all trans retinoic acid. Preferred 24-hydroxylase inhibitors are imidazoles, especially those inhibiting cytochrome-P450 oxidative enzymes, such as ketoconazole. Also included is a method for determining whether a candidate compound inhibits 24-hydroxylase activity or induction thereof.

Growing community of inventors

Ann Arbor, MI, United States of America

John J Voorhees