Application of iguratimod in preparation of medicine for treating systemic sclerosis

A systemic sclerosis and drug technology, applied in the field of biomedicine, can solve the problems of large side effects and poor scleroderma effect, and achieve the effect of obvious technical effect

Inactive Publication Date: 2020-01-03
RENJI HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to provide a new application of iguratimod, which will solve the te...

Method used

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  • Application of iguratimod in preparation of medicine for treating systemic sclerosis
  • Application of iguratimod in preparation of medicine for treating systemic sclerosis
  • Application of iguratimod in preparation of medicine for treating systemic sclerosis

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Embodiment 1

[0024] The present invention successfully extracts primary skin fibroblasts from normal adult skin tissue (20-year-old male, foreskin), cultures them, and transfers them to the third generation for experimentation. The present invention confirms that stimulating fibroblasts with TGF-β can promote the high expression of the transcription factor Egr1 closely related to fibrosis, and at the same time promote their differentiation into myofibroblasts, characterized by: high expression of α-SMA on the cell surface and synthesis of Increased capacity of the extracellular matrix.

[0025] However, iguratimod can significantly inhibit the above-mentioned responses of fibroblasts at the mRNA and protein levels ( figure 1 , figure 2 ).

[0026] figure 1 Iguratimod was shown to inhibit TGF-β-induced expression of Egr-1 in healthy adult skin fibroblasts. (A) shows that iguratimod can inhibit the expression of Egr-1 induced by TGF-β at the mRNA level in a concentration-dependent manne...

Embodiment 2

[0029] In the present invention, male C57 / BL6 mice are subcutaneously injected with bleomycin to form a skin fibrosis model, and are divided into a control group 1 and a test group 2 after 2 weeks of modeling, and the test group is given iguratimod every day. Suspension 30mg / kg orally or apply 2% iguratimod dimethyl sulfoxide solution to the skin of the injection site twice a day, 100ul each time. Preparation of iguratimod suspension: 0.1% sodium carboxymethylcellulose (CMC) was used as suspending agent, and 60 mg of iguratimod was added to every 10 ml of suspending agent. Crush with a glass rod and shake well before use. Compared with the random control group, iguratimod intragastric administration and external application can significantly inhibit bleomycin-induced skin fibrosis ( image 3 A, C), and reduce the number of α-SMA-positive myofibroblasts in mouse skin ( image 3 B, D), and can effectively inhibit the expression of TGF-β and Egr1 in the skin. ( Figure 4 ). ...

Embodiment 3

[0035] 2% of the 6-week-old male TSK-1 mice of the present invention were given 100 μl of iguratimod DMSO solution for partial skin application, twice a day for 6 weeks in total. At the end of the 6th week, the mice were sacrificed, and the skin tissue was harvested, and the skin thickness was detected. The thickness of the subcutaneous fibrous tissue layer in TSK-1 mice was significantly greater than that in normal mice with isogenic background. After 6 weeks of experimental treatment, we found that the thickness of the subcutaneous fibrous layer of TSK-1 mice in the iguratimod smeared group decreased, and the difference was statistically significant (2110.3±110.3μm vs 1580±73.16μm P=0.0161) .

[0036] From this, we can think that iguratimod also has a therapeutic effect on a mouse model with severe fibrosis and mild inflammatory response that simulates the late stage of systemic sclerosis. Figure 5 showed that iguratimod topical application attenuated skin fibrosis in TSK...

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Abstract

The invention provides an application of iguratimod in preparation of a medicine for treating systemic sclerosis. Inventors find that the iguratimod has application potential that an external dosage form for external use of the iguratimod can be prepared, and hardened skin can be softened by topical application. Experiments prove that a local or systemic application of the iguratimod can significantly inhibit important transcription factor EGR1 involved in fibrosis to decrease expression of pro-fibrogenic cytokine TGF-beta or decrease signals in downstream, thereby inhibiting the progression of the systemic sclerosis. The topical application of an iguratimod dimethyl sulfoxide solution can also effectively reduce and cure experimental scleroderma skin fibrosis.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to a medicine for treating systemic sclerosis, in particular to the use of iguratimod in the preparation of medicine for treating systemic sclerosis. Background technique [0002] Systemic sclerosis (SSc) is a rare and refractory autoimmune disease involving multiple system organs. Its etiology and pathogenesis are unknown, and its clinical manifestations are complex and diverse. It is mainly characterized by localized or diffuse skin thickening and fibrosis, and it can also be a systemic disease involving digestive tract, heart, lung, kidney and other internal organs. [0003] Existing treatments, such as the application of glucocorticoids and immunosuppressants, have weak or unclear curative effects on blocking the progression of the disease, and may even increase the probability of inducing scleroderma renal crisis. Moreover, the systemic application of these drugs has relatively large s...

Claims

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Application Information

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IPC IPC(8): A61K31/352A61P17/00A61P37/02
CPCA61K31/352A61P17/00A61P37/02
Inventor 沈力冲严青然李瑞陈晓翔
Owner RENJI HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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