One use of konorabrini as a treatment for lymphedema.

Abstract

The present invention discloses a use of cronin as a lymphedema prevention or treatment agent, and specifically relates to the use of cronin or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating lymphedema. Cronin can effectively reduce and / or improve collagen deposition, inflammatory response or fibrosis symptoms associated with lymphedema.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to the use of konorani as a lymphedema therapeutic agent. Background Art

[0002] Lymphedema is divided into primary and secondary lymphedema. Primary lymphedema is usually due to congenital structural defects, manifested as lymphatic malformations; secondary lymphedema is mainly caused by acquired lymphatic damage caused by cancer treatment, chronic inflammation or trauma.

[0003] At present, secondary lymphedema is the main type worldwide, especially tumor-related lymphedema (hereinafter referred to as lymphedema), which is the most common type of secondary lymphedema and there is no effective treatment. According to the World Health Organization database, up to 50,000 new patients are diagnosed with lymphedema each year. Lymphedema is usually chronic, with clinical manifestations such as gradual thickening of limbs, limb dysfunction, recurrent skin infections, chronic ulcers and even skin malignancies, which seriously affect the quality of life of patients and cause a huge social medical burden. It is recognized by the World Health Organization as the second most disabling disease.

[0004] Crenolanib is an effective and selective wild-type and mutant class III receptor tyrosine kinase inhibitor, with Kd of 0.74nM, 2.1nM, and 3.2nM for inhibiting FLT3 and PDGFRα / β, respectively. The molecular formula is C26H29N5O2, the molecular weight is 443.54, and the chemical structure is as follows. Crenolanib is a highly selective PDGFRA and FLT3 inhibitor with the activity of inhibiting PDGFRαD842V mutation. Clinical investigations have shown that crenolanib has a 31% clinical benefit in treating patients with severe GIST with PDGFRA D842V mutation.

[0005]

[0006] Crenolanib was initially developed as a PDGFR inhibitor, but subsequent studies have shown that it has good activity against both FLT3-ITD and FLT3-TKD mutation subtypes, and was subsequently developed as a FLT3 inhibitor for the treatment of AML. Phase I clinical data showed that the complete remission rate was 39% and the partial remission rate was 11% for patients previously exposed to TKIs; the response rate was 41% and the complete remission rate was 17% for patients previously exposed to other FLT3 inhibitors. The overall OS population accounted for 81% of the 20.8-month period, and the complete remission rate was 85%. A Phase I clinical trial of combined use with chemotherapy and head-to-head comparison of Rvdapt in patients with newly diagnosed AML is underway. The efficacy of crenolanib combined with placebo in salvage chemotherapy, consolidation therapy (cytarabine and / or allogeneic hematopoietic stem cell transplantation) and single-agent maintenance therapy in patients with relapsed / refractory FLT3 mutant acute myeloid leukemia is in Phase III clinical trials. However, there is no literature disclosing that crenolanib can be used to treat lymphedema. Summary of the invention

[0007] The object of the present invention is to provide a use of Knolani as a preventive or therapeutic agent for lymphedema.

[0008] The present invention provides use of konoranib or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating lymphedema.

[0009] According to the above-mentioned use of the present invention, konoranib or its pharmaceutically acceptable salt can effectively reduce and / or improve collagen deposition, inflammatory response or fibrosis symptoms associated with lymphedema.

[0010] The use of the present invention is to administer an effective amount of konoranib or a pharmaceutically acceptable salt thereof to a patient with lymphedema, and the administration method includes injection or oral administration.

[0011] In the above-mentioned use of the present invention, the effective daily dose of Cnolanil is 10-200 mg, which can be taken once or twice.

[0012] In the above-mentioned use of the present invention, the pharmaceutically acceptable salt includes benzenesulfonate, p-toluenesulfonate, hydrochloride or sulfate.

[0013] Preferably, in the above-mentioned use of the present invention, the lymphedema is tumor-related lymphedema.

[0014] The present invention provides a method for preventing or treating lymphedema, comprising administering an effective amount of konoranib or a pharmaceutically acceptable salt thereof to a lymphedema patient in need thereof. Preferably, the effective daily dose of konoranib or a pharmaceutically acceptable salt thereof is 10-200 mg, taken once or twice.

[0015] Beneficial effects: The present invention provides an effective drug treatment strategy for lymphedema, a difficult-to-treat disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The tail diameter measurement results of mice in the Crenolanib group and the blank control group within 30 days;

[0017] Figure 2 The tail pictures of mice in the Crenolanib group and the blank control group after 30 days;

[0018] Figure 3 HE staining results of tail specimens of mice in the Crenolanib group and the blank control group;

[0019] Figure 4 The results of Masson's staining of tail specimens of mice in the Crenolanib group and the blank control group;

[0020] Figure 5 The results of immunohistochemistry for COL1A1 expression in the tail specimens of mice in the Crenolanib group and the blank control group;

[0021] Figure 6 These are the results of immunofluorescence staining of CD68 expression in the tail specimens of mice in the Crenolanib group and the blank control group. DETAILED DESCRIPTION

[0022] The following examples are representative and are used to further understand and illustrate the spirit of the present invention, but are not intended to limit the scope of the present invention in any way.

[0023] Example 1 Animal Test

[0024] 1. Experimental design

[0025] Crenolanib was purchased from MedChemexpress Biotechnology Company, USA (purity: 99.72%).

[0026] Clean-grade C57 mice (male, 7 weeks old, weighing 22-24 g) were purchased from Chongqing Labite Biotechnology Co., Ltd. The animals were housed in the Public Experiment Center of Clinical Medicine, Affiliated Hospital of Zunyi Medical University, in a constant temperature of 23±2°C, a humidity of 50-70%, and sterile bedding was changed twice a week, with free access to food and water.

[0027] The specific dosing and treatment of animals are as follows: After C57 mice adapted to the animal room for one week, they were divided into a Crenolanib group (20 mice, 15 mg / kg / day) and a blank control group (20 mice). The animal dosing mode was to dissolve Crenolanib in 5% glycerol formalin and administer it by intraperitoneal injection at a dose of 15 mg / kg. The administration time was the third day after modeling, and the maximum tolerated dose and time of the drug were referred to the literature, and the drug was administered continuously for 28 days.

[0028] During the administration period, the tail circumference was measured every 2 days. The animals were killed by cervical dislocation on the 7th and 30th days after model establishment, and the most swollen segment of the tail was retained for subsequent molecular, biochemical and pathological analyses.

[0029] All data were processed and statistically analyzed using Graphpad Prism 6.0 software. The mean values ​​of all samples were compared using One-way ANOVA analysis, and p < 0.05 indicated statistically significant differences.

[0030] *P<0.05, **P<0.01, ***P<0.001.

[0031] 2. Experimental results and analysis

[0032] 1) Crenolanib can significantly alleviate the degree of tail swelling in the lymphedema animal tail model

[0033] The maximum tail diameter and change trend of the two groups of lymphedema animal models during the experiment are as follows Figure 1 After 30 days, the tail swelling of mice in the Crenolanib group was significantly improved compared with that in the blank control group ( Figure 1 , 2 ). The results show that compared with the blank control group, the Crenolanib group can significantly alleviate the edema of the mouse tail. Specifically, on the 6th day after surgery, the maximum diameter of the tail of the mice in the Crenolanib group was significantly smaller than that in the blank control group, and the effect lasted until the end of the experiment. During the entire experiment, except for the common adverse reactions of Crenolanib mentioned in the literature (slight weight loss, slightly poor spirit and activity) in the mice in the Crenolanib group, no other obvious adverse reactions were observed in all mice.

[0034] 2) Crenolanib can significantly alleviate edema and collagen deposition in the tail model of lymphedema animals

[0035] The animals were killed by cervical dislocation at 7 and 30 days after modeling, and the most swollen segment of the tail was kept. The obtained mouse tail specimens were stained with HE and Masson's staining. Remarkably, H&E staining of the cross-section of the mouse tail showed that compared with the blank control group, the thickness of the subcutaneous tissue of the mice in the Crenolanib group was significantly reduced, and the inflammatory infiltration was significantly improved ( Figure 3 ); Masson staining showed that the collagen deposition in the dermis of the whole skin of the Crenolanib group mice was significantly reduced, and the arrangement of collagen fibers was more regular than that of the blank control group ( Figure 4 ).

[0036] 3) Crenolanib can significantly alleviate inflammation and fibrosis levels in the tail model of lymphedema animals

[0037] At present, the pathogenesis of lymphedema is generally believed to be the result of secondary immune imbalance in the affected area after the lymphatic system is destroyed, leading to inflammation and fibrosis progression. In this regard, we selected CD68 and COL1A1 to perform immunofluorescence staining and immunohistochemistry staining on the specimens to evaluate the inflammation and fibrosis of mice. The results confirmed that compared with the blank control group, the expression level of Cd68 in the tail tissue of mice in the Crenolanib group was significantly reduced, indicating that macrophage infiltration and inflammation were reduced. At the same time, the expression of COL1A1 was also significantly reduced compared with the blank control group, indicating that fibrosis was significantly improved ( Figure 5 , 6 ). Taken together, these results suggest that crenolanib administration can significantly reduce inflammation and fibrosis in an animal model of lymphedema, thereby alleviating lymphedema in mice.

[0038] The use of the present invention provides a new way to prevent or treat lymphedema through administration of Crenolanib. The drug Crenolanib used in the present invention can significantly alleviate the degree of swelling of the tail of the lymphedema animal model, and can effectively reduce the pathological manifestations of lymphedema such as collagen deposition, inflammatory response, and fibrosis. Its effect on improving the condition is significantly better than that of the blank control, proving its good effect on the treatment of lymphedema. The present invention provides an effective drug treatment strategy for lymphedema, a refractory disease.

Claims

1. Use of konoranib or its pharmaceutically acceptable salt in preparing a medicament for treating lymphedema.

2. The use according to claim 1, wherein the drug can effectively reduce and / or improve collagen deposition, inflammatory response or fibrosis symptoms associated with lymphedema.

3. The use according to claim 1, comprising administering an effective amount of konoranib or a pharmaceutically acceptable salt thereof to a patient with lymphedema.

4. The use according to claim 3, wherein the administration of the drug comprises injection or oral administration.

5. The use as claimed in claim 3, wherein the effective daily dose is 10-200 mg.

6. The use according to claim 5, wherein the effective daily dose is taken once or twice.

7. The use according to claim 1 or 3, wherein the salt is benzenesulfonate, p-toluenesulfonate, hydrochloride or sulfate.

8. The use according to claim 1 or 3, wherein the lymphedema is tumor-related lymphedema.

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