CN-122005568-A - Application of Nidamib in preparation of drug for treating graft fibrosis

Abstract

The application discloses application of Nidamnification in preparing a drug for treating graft fibrosis, and belongs to the technical field of biological medicines. The research of the application shows that the nintedanib is shown to reduce the deposition of extracellular matrix of an allogeneic kidney transplantation model mouse after administration under the condition of no liver and kidney toxicity and intestinal side effect, improve tubular atrophy, reduce the infiltration of CD206+ macrophages of the mouse, reduce the rejection injury degree and the immune infiltration degree of kidney grafts, obviously slow down the pathological change process of chronic transplanted kidney rejection of the mouse and reduce the damage of excessively activated inflammatory cells to transplanted kidney. These results indicate that nilotica is able to delay the progression of chronic transplanted kidney fibrosis.

Inventors

• OUYANG FAN
• WANG ZIJIE
• ZHANG JUNQI
• Gui Zeping
• Ke Zongpan
• CAO HONGDI
• LUO JING
• GU MIN
• ZHU QINGYI

Assignees

• 南京医科大学第二附属医院

Dates

Publication Date

20260512

Application Date

20260320

Claims (10)

1. 1. Application of Nidamib or pharmaceutically acceptable salts, acids, esters and pharmaceutical compositions thereof in preparing medicines for preventing or treating graft fibrosis.
2. 2. The use according to claim 1, wherein the graft fibrosis is chronic graft fibrosis.
3. 3. The use according to claim 2, wherein the graft fibrosis is allograft chronic graft fibrosis.
4. 4. The use according to claim 3, wherein the graft fibrosis comprises transplanted kidney, transplanted liver, transplanted heart, transplanted lung, transplanted pancreas and/or transplanted small intestine fibrosis.
5. 5. The use according to claim 4, wherein the graft fibrosis is graft kidney fibrosis.
6. 6. The use according to any one of claims 1 to 5, wherein the dosage form of the medicament comprises a liquid dosage form, a gaseous dosage form, a solid dosage form and a semi-solid dosage form.
7. 7. The use according to claim 6, wherein the liquid dosage form comprises solutions, injections, the gaseous dosage form comprises aerosols, sprays, the solid dosage form comprises powders, tablets, the semi-solid dosage form comprises ointments, pastes.
8. 8. The use according to claim 7, wherein the solution is an oral solution.
9. 9. The use according to claim 8, wherein the solvent of the oral solution comprises polyethylene glycol.
10. 10. The use according to claims 1-9, wherein said nilamide cloth or a pharmaceutically acceptable salt, acid, ester and pharmaceutical composition thereof comprises nilamide cloth ethanesulfonate.

Description

Application of Nidamib in preparation of drug for treating graft fibrosis Technical Field The application belongs to the technical field of biological medicines, and particularly relates to application of Nidamnification in preparation of a medicine for treating graft fibrosis. Background Renal transplantation is the best treatment for end stage renal disease. In recent years, with the improvement of medical level, including the development of transplantation technique and the combined use of novel immunosuppressants, the short-term survival rate of transplanted kidney has been improved, but the long-term survival rate has not been significantly improved. Transplanted kidney fibrosis is the leading cause of long-term transplanted kidney failure. Studies have shown that about 40% of patients have transplanted kidney Interstitial Fibrosis (IF) 3-6 months after kidney transplantation, and about 65% of patients have transplanted kidney interstitial fibrosis after 2 years. The cause of transplanted kidney fibrosis is not completely clear, and comprises the viewpoints that caveolin-1, SHROOM3 and other gene polymorphisms promote the formation of kidney fibrosis, interleukin (interleukin, IL) -33 possibly influence the formation of transplanted kidney fibrosis through various ways, aldosterone plays an important role in promoting renal interstitial fibrosis, tacrolimus induces kidney fibrosis and the like. At present, no targeting drug with better curative effect can delay the progress of transplanted kidney IF, and only can reasonably match with the use of immunosuppressant in clinic to avoid the damage induced by drug toxicity to the greatest extent so as to prolong the survival time of transplanted kidney. The lack of IF targeted drugs against transplanted kidney means that some patients are faced with re-kidney transplantation in the inevitable re-failure of transplanted kidney after the first transplantation, which undoubtedly aggravates the economic, psychological and physiological burden of the transplanted kidney patient. In addition, due to the extreme shortage of kidney sources, inhibiting the progress of transplanted kidney IF, extending the working life of transplanted kidney is an important issue that needs to be addressed in the field of kidney transplantation. Nidamib (BIBF 1120) is a multiple PTK inhibitor for blocking PDGFR, VEGER, FGFR and Src family kinases, has an anti-fibrosis effect on idiopathic pulmonary fibrosis, and is currently approved by the FDA for application in treatment of idiopathic pulmonary fibrosis, such as Nidamib ethanesulfonate soft capsules (common name) with the trade name of Vigat (Ofev) and the main component of Nidamib ethanesulfonate. Idiopathic pulmonary fibrosis is initiated by injury of alveolar epithelial cells, which secrete cytokines and chemokines, attract inflammatory cells to aggregate, release pro-fibrotic factors, activate pulmonary fibroblasts to convert into myofibroblasts, synthesize a large amount of extracellular matrix, and initiate fibrosis. In animal models of pulmonary fibrosis induced by bleomycin or silica particles, nilanib can inhibit extracellular matrix deposition and reduce the transdifferentiation of fibroblasts into myofibroblasts. However, no pharmacological effect of nilamide in chronic transplanted kidney fibrosis has been reported in animal models or clinical experiments. Disclosure of Invention 1. Object of the invention The application aims to provide application of Nidamnification in preparing medicines for treating graft fibrosis, in particular transplanted kidney fibrosis, and applicant researches find that the Nidamnification can be used for treating allograft chronic transplanted kidney fibrosis. 2. Technical proposal In order to achieve the above purpose, the technical scheme adopted by the application is as follows: The application provides application of Nidamib or pharmaceutically acceptable salts, acids, esters and pharmaceutical compositions thereof in preparing medicines for preventing or treating graft fibrosis. Further, the above graft fibrosis is chronic graft fibrosis. Further, the above graft fibrosis includes fibrosis of transplanted kidney, transplanted liver, transplanted heart, transplanted lung, transplanted pancreas, and/or transplanted small intestine, and the like. Further, the above graft fibrosis is graft kidney fibrosis. As a further illustration of the present application, it was found that Nidamib administration to allogeneic kidney transplant model mice reduced tubular atrophy and reduced extracellular fibrous matrix deposition, and reduced inflammatory infiltration of immune cells of the transplanted kidney, reduced infiltration of macrophages, and reduced transdifferentiation ratio of CD68+CD206+ biscationic macrophages. Further, serum creatinine and urea nitrogen assays showed that nilamide improves transplanted kidney function. Furthermore, hepatoenterotoxicity was not observed at the concentrations