阅读说明：本技术 (5r)-5-羟基雷公藤内酯醇在制备治疗和/或预防皮肤炎症药物中的应用 (Application of (5R) -5-hydroxy triptolide in preparing medicine for treating and/or preventing skin inflammation ) 是由 左建平 唐炜 祁青 林泽民 何世君 吴言为 于 2019-04-15 设计创作，主要内容包括：本发明提供(5R)-5-羟基雷公藤内酯醇在制备治疗和/或预防银屑病、特应性皮炎等皮肤炎症的药物中的用途,具体而言,本发明通过咪喹莫特乳膏诱导小鼠银屑病模型,观察银屑病皮损严重程度评分、外观及皮肤病理变化,及小鼠皮损组织中细胞因子的变化；采用银屑病鼠尾模型,观察小鼠尾部皮肤的正角化率变化；通过DNCB诱导小鼠特异性皮炎模型,观察病变皮肤的病理变化。结果显示,本发明采用的(5R)-5-羟基雷公藤内酯醇对银屑病及特应性皮炎等皮肤炎症有良好的治疗作用,具有良好的临床应用前景。(The invention provides application of (5R) -5-hydroxyl triptolide in preparing a medicament for treating and/or preventing skin inflammations such as psoriasis, atopic dermatitis and the like, and particularly, the invention induces a mouse psoriasis model through imiquimod cream, observes severity scores, appearances and pathological changes of skin lesions of the psoriasis and changes of cytokines in skin lesion tissues of the mouse; observing the change of the positive angulation rate of the tail skin of the mouse by adopting a psoriasis mouse tail model; the pathological changes of the diseased skin were observed by inducing a mouse atopic dermatitis model by DNCB. The result shows that the (5R) -5-hydroxyl triptolide adopted by the invention has good treatment effect on skin inflammation such as psoriasis, atopic dermatitis and the like, and has good clinical application prospect.)

Use of (5R) -5-hydroxytriptolide alcohol in the preparation of a medicament for the treatment and or prevention of skin inflammation.

2. Use according to claim 1, characterized in that: skin inflammation includes psoriasis, atopic dermatitis.

3. The use according to claim 1 or 2, wherein the medicament for treating and/or preventing skin inflammation is a solid tablet, an ointment, a gel preparation, a liquid preparation or an aerosol.

Technical Field

The invention relates to a new application of (5R) -5-hydroxyl triptolide, in particular to an application of (5R) -5-hydroxyl triptolide in preparing a medicine for treating and/or preventing skin inflammation such as psoriasis, atopic dermatitis and the like.

Background

Psoriasis is a common chronic recurrent inflammatory skin disease, and is typically clinically manifested by clear-boundary erythema, rash, plaque and scale, and the pathogenesis of the psoriasis is complex, and the etiology is unknown. At present, the psoriasis is mainly treated locally, and steroid hormones such as hydrocortisone butyrate, mometasone furoate and the like are widely applied to the treatment of psoriasis, but have large side effects after long-term use, so that the wide application of the steroid hormones is influenced; tacrolimus, carbotriol, and the like also limit their clinical applications due to their expensive price.

Atopic Dermatitis (AD) is a chronic, recurrent, inflammatory skin disease, often accompanied by significant itching, which severely affects the quality of life of patients. Over the last 30 years, the incidence of AD in children has ranged from 15% to 30%, with adults ranging from 2% to 10%. The pathogenesis of AD is complex, and the AD mainly relates to the aspects of heredity, immune abnormality, neuroimmune factors, skin barrier dysfunction and the like. Clinically major topical medications include corticosteroids and calcineurin inhibitors. Other treatments include topical and oral antibiotics, phototherapy and systemic immunosuppressants. However, the treatment drugs for AD at present have many limitations and have unsatisfactory curative effect on patients with moderate and severe AD.

(5R) -5-hydroxy triptolide (LLDT-8) is a structural derivative of triptolide (triptolide). In vitro tests show that LLDT-8 has an inhibitory effect on lymphocyte proliferation reactions induced by various methods, and simultaneously inhibits the production of cytokines such as IL-2, IFN-g and the like, and in vivo experiments further verify that LLDT-8 can inhibit cellular immunity and humoral immunity reactions. LLDT-8 has significant prevention and treatment effects in an adjuvant-induced rat arthritis disease animal model and a bovine type II collagen-induced DBA/1 mouse arthritis disease animal model.

(5R) -5-hydroxy triptolide has the following structural formula:

at present, no application and report of (5R) -5-hydroxy triptolide for treating skin diseases exist, and the method discovers the treatment effect of (5R) -5-hydroxy triptolide on psoriasis and atopic dermatitis for the first time.

Disclosure of Invention

In order to solve the problems, the invention provides the application of (5R) -5-hydroxyl triptolide in preparing a medicament for treating and/or preventing skin inflammation. The skin inflammation includes psoriasis, atopic dermatitis, etc. In addition, the invention discovers that the curative effect and the convenience of treating psoriasis and atopic dermatitis by (5R) -5-hydroxyl triptolide can be improved and the adverse reaction is reduced by a mode of local administration.

The form of the medicament for treating and/or preventing skin inflammation (e.g., psoriasis, atopic dermatitis, etc.) is not particularly limited, and may be in the form of various substances such as a solid tablet, an ointment, a gel preparation, a liquid preparation, or an aerosol.

The inhibitory effect of (5R) -5-hydroxyl triptolide on the generation and development of mouse psoriasis models and atopic dermatitis is disclosed for the first time.

Drawings

FIG. 1 is a graph of the score of (5R) -5-hydroxytriptolide for treating skin lesions in mice with remission of psoriasis according to example 3. Imiquimod-induced BALB/c mouse psoriasis was treated topically with (5R) -5-hydroxy triptolide, applied daily and scored according to psoriasis skin area and severity index (PASI). The groups in the figure are respectively a normal control group, a model control group, a calcipotriol cream treatment group and an ointment treatment group, and each group contains 10 mice. P <0.05, P <0.01, P < 0.001.

FIG. 2 is a photograph of the appearance and pathology of (5R) -5-hydroxytriptolide treatment to alleviate skin lesions in psoriasis mice in example 3. The (5R) -5-hydroxyl triptolide is adopted for treating psoriasis of an imiquimod-induced BALB/c mouse by external application, the experimental mouse is euthanized on the 7 th day after the imiquimod-induced psoriasis molding, and skin tissues are taken for pathological detection. The figure shows the appearance of skin lesions and pathological tissue sections. The typical representative graphs of the skin injury of mice in a normal control group, a model control group, a calcipotriol cream treatment group and an ointment treatment group are respectively shown.

FIG. 3 is a horizontal bar graph of IL-17 inhibition by (5R) -5-hydroxytriptolide in imiquimod-induced dermal lesion tissue in mice of example 3. On the 7 th day after the psoriasis is induced by imiquimod, the skin of the lesion part is taken, and the IL-17 content is detected by an ELISA method. P is less than 0.05, and n is more than or equal to 5. In the figure, the groups are respectively a normal control group, a model control group and an ointment treatment group.

Fig. 4 is a schematic diagram of the positive keratometry calculation formula in example 4.

FIG. 5 is a bar graph of the skin normal keratosis rate (i.e., the length of the stratum granulosum to the length of the tail scales) of the model of psoriatic tail of example 4, promoted by (5R) -5-hydroxytriptolide. The groups in the figure are respectively a normal control group, a tretinoin ointment treatment group and an ointment treatment group, and each group contains 10 mice. P <0.01, P < 0.001.

FIG. 6 is a typical representative photograph of the (5R) -5-hydroxytriptolide ointment preparation for treating and relieving DNCB-induced skin lesions and pathological tissues of mouse atopic dermatitis in example 5. DNCB is sensitized through skin and stimulates BALB/c mouse atopic dermatitis, the acting parts of the medicine are back skin, the medicine treatment is carried out on the 15 th to 35 th days after DNCB sensitization, euthanasia is carried out on the 38 th day, and skin tissues are taken for pathological detection. The figure is a typical representation of the pathological tissue section of the skin of the mouse in the model control group and the ointment treatment group.

FIG. 7 is a photograph of skin lesions in psoriasis-alleviating mice treated with (5R) -5-hydroxytriptolide of example 6. Typical representative graphs of skin injury of mice in the (5R) -5-hydroxyl triptolide gel preparation treatment imiquimod induced psoriasis on day 15, normal control group, model control group and gel treatment group.

Detailed Description

The invention is further illustrated by the following specific embodiments. The examples are intended only to illustrate or explain embodiments of the invention and do not limit the scope of protection of the invention.