The present invention relates to a method for alleviating and/or preventing skin reddening.
Facial reddened skin has been frequently found in people with fair skin in European countries and the United States of America, but also found in Asians and African Americans. Skin reddening is thought to be a first step of Rosacea and is medically defined as transient or persistent facial erythema, visible blood vessels and telangiectasia1.
Because reddened skin is found in cheeks, nose and central forehead, mainly in the center of face, reddened skin alters their social interactions, leading to problems on the job, in their marriage or in meeting new people2, 3. In contrast our knowledge about the pathology of reddened skin is surprisingly scanty maybe because of the difficulty of getting biopsy samples of skin which often appear in the center of the face. Additionally, many studies especially for rosacea do not take into account the possible influence of cosmetic skin care regimens concomitant with topical treatments4. Therefore we try to determine the histology of reddened skin, which allow us to develop a possible method to prevent and/or improve the symptom of reddened skin.
Our previous studies have revealed that pronounced angiogenesis is induced by acute UVB irradiation of human and mouse skin5, 6. Several angiogenesis factors, including vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor and interleukin-8 have been found to be upregulated in UVB-irradiated skin7-9. Recently, we have shown that targeted overexpression of VEGF-A enhances sensitivity to UVB-induced cutaneous photodamage associated with pronounced angiogenesis, whereas a systemic blockade of VEGF-A attenuated vascular abnormality and erythema induced by UVB10, suggesting that a main angiogenesis factor in skin could be a keratinocyte-derived VEGF-A. However, any contribution of VEGF-A in the mechanism of facial reddened skin has been completely unclear not only for the limited histological research but for the lack of non-invasive quantification method for VEGF-A from skin.
The aim of the present invention is to provide a novel method for alleviating and/or preventing skin reddening. As a result of extended studies, surprisingly, we found that angiogenesis, in particular, enhanced expression of VEGF-A, is involved in the cause of skin reddening. This means that inhibiting angiogenesis would result in alleviation and/or prevention of skin reddening.
Accordingly, the present invention provides a method of alleviating and/or preventing skin reddening for a subject in need thereof, by means of inhibiting angiogenesis at the site of the reddened skin. The method can be medical treatment or a cosmetic treatment.
Preferably, the inhibition of angiogenesis is attained by applying one or more vascular endothelial growth factor A (VEGF-A) inhibitor to said site.
The VEGF-A inhibitor can preferably be selected from the group consisting of Bevacizuma, Aflibercept (VEGF trap), Cediranib, Sorafenib, Sunitinib, Pazopanib and Vatalanib.
In another embodiment, the present invention provides a composition, preferably, a pharmaceutical or cosmetic composition, for alleviating and/or preventing skin reddening by means of inhibiting angiogenesis at the site of the reddened skin.
Preferably, the composition comprises one or more vascular endothelial growth factor A (VEGF-A) inhibitor which inhibits angiogenesis.
The VEGF-A inhibitor can be selected from the group consisting of Bevacizuma, Aflibercept (VEGF trap), Cediranib, Sorafenib, Sunitinib, Pazopanib and Vatalanib.
Inhibition of angiogenesis can be achieved by applying a drug having anti-angiogenesis activity to the site of skin, in particular, epidermis, of a subject in need of alleviation and/or prevention of skin reddening. The site of skin can be a portion which already shows reddening or a portion where prevention of reddening is desired. Thus, a composition, and particularly an external preparation for skin, containing such a drug as an active ingredient thereof is expected to demonstrate superior action which alleviates and/or prevents skin reddening, and is useful as a skin care pharmaceutical, over-the-counter drug or cosmetic.
Inhibition of angiogenesis in the epidermal cells can also be achieved by various genetic engineering technologies using, for example, RNA interference, anti-sense RNA-DNA, peptide and RNA-DNA aptamers, site-specific deletion, homologous recombination, dominant negative alleles or intrabodies.
Drug having anti-angiogenesis activity, in particular, VEGF-A inhibitory activity, can be any compounds already known to have such an activity or ones to be discovered in the future to have such an activity, and includes polypeptides or protein, such as monoclonal antibody, peptides, hormones, low molecular weight compound, or plant derived preparation such as crude drug or the like. Examples thereof are, but not limited to, Bevacizuma, Aflibercept (VEGF trap), Cediranib, Sorafenib, Sunitinib, Pazopanib and Vatalanib.
The drug having anti-angiogenesis activity is applied in the form of, for example, an aqueous solution, oily liquid, other type of solution, milky liquid, cream, gel, suspension, microcapsules, powder, granules, capsules or solid preparation. After having prepared the drug having anti-angiogenesis activity formed using known methods of the prior art, the drug can be coated, adhered, sprayed, injected or inserted into the body in the form of, for example, a lotion preparation, milky liquid preparation, cream preparation, ointment preparation, plaster preparation, poultice preparation, aerosol preparation, water-oil, bilayer preparation, water-oil-powder trilayer preparation or injection preparation. There are no particular limitations on the aforementioned extract in formulation to be used as inhibiting angiogenesis, and the amount thereof in terms of dry weight based on the total weight of the formulation can be, e.g., 0.000001 to 5% by weight, e.g., 0.00001 to 3% by weight or 0.00001 to 1% by weight.
Among these drug forms, externally applied skin preparations such as lotion preparations, milky lotion preparations, cream preparations, ointment preparations, plaster preparations, poultice preparations and aerosol preparations are contemplated as drug forms for the object of the present invention. Furthermore, externally applied skin preparations as referred to here include prescription pharmaceuticals, over-the-counter drugs and cosmetics.
The above-mentioned formulations suitably incorporates known vehicles and fragrances and the like corresponding to the desired drug form, as well as, for example, oils, surfactants, antiseptics, metal ion chelating agents, water-soluble polymers, thickeners,—pigments and other powdered components, ultraviolet protectants, moisturizers, antioxidants, pH adjusters, cleansing agents, drying agents or emulsions. Moreover, other pharmaceutically active ingredients can also be incorporated in the anti-graying agent of the present invention within a range that does not impair the desired effects thereof.
The facial appearance was photographed and also imaged by using videomicroscope (VMS) (INT-200, Integral, Tokyo, Japan) as previously described11. The field of view of the VMS was 585 by 410 μm (720 by 540 pixels). In VMS images, the features of capillary blood vessels were evaluated and color space (L*a*b*) of facial skin was also determined.
We obtained 2 mm biopsy from facial skin of eight female volunteers and proceed for histological analyses. All procedures involving human subjects were approved by the Institutional Review Board of Shiseido Research Center, and all subjects provided written informed consent.
Immunofluorescence analysis was performed on 6-μm cryostat sections of skins, using mouse monoclonal antibodies against CD31 (BD Biosciences, San Diego, Calif.), against Ki-67 Antigen (DAKO cytomation, Glostrup, Denmark), and against VEGF-A (LAB VISION, Fremont, Calif.). Corresponding secondary antibodies labeled with AlexaFluor488 or AlexaFluor594 (Molecular Probes, Eugene, Oreg.) were used. Routine hematoxylin-eosin staining was also performed. Sections were examined with an Olympus AX80T microscope (Olympus, Tokyo, Japan) and images were captured with a DP controller digital camera (Olympus). Morphometric analyses were performed using IP-LAB software (Snanalytics, Fairfax, Va.) as described. Three different fields of each section were examined and the number of vessels per square micrometer, the average vessels size and the relative tissue area occupied by lymphatic vessels were determined in the dermis in an area within 200 μm distance from the epidermal-dermal junction. The unpaired Student t-test was used to analyze differences in microvessel density and size. Statistical analyses were performed using the unpaired student's t-test.
Reddened skin was found by red appearance of facial skin especially in cheeks and central forehead as compared to non-red skin (
Dilation of capillary vessels were frequently found in the facial reddened skin as compared to non-red skin (
To determine the histological change in reddened skin, we obtained 2 mm of skin biopsy of reddened skin from 8 people. Hematoxylin-eosin staining of skin section revealed that reddened skin showed characteristics of epidermal hyperplasia as compared to non-red skin (
Since we found visible blood vessels by using video-microscope, we next performed, immunofluorescence analysis using antibodies against a blood vessel marker, CD31. As a result, we found that blood vessels were pronouncedly enlarged in the reddened skin (
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Number | Date | Country | |
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61528907 | Aug 2011 | US |