CN115381817B

CN115381817B - Application of Sotuletinib in preparation of medicine for treating crescent nephritis

Info

Publication number: CN115381817B
Application number: CN202210976092.1A
Authority: CN
Inventors: 徐安龙; 刘文斌; 黄光瑞; 胡海坤
Original assignee: Beijing University of Chinese Medicine
Current assignee: Beijing University of Chinese Medicine
Priority date: 2022-08-15
Filing date: 2022-08-15
Publication date: 2023-09-05
Anticipated expiration: 2042-08-15
Also published as: CN115381817A

Abstract

The invention discloses an application of Sotuletinib in preparing a medicine for treating crescent nephritis. The crescentic nephritis comprises anti-basement membrane nephritis, lupus glomerulonephritis, ANCA-related glomerulonephritis, and glomerulonephritis with parietal epithelial cell proliferation. The invention has the following advantages.

Description

Application of Sotuletinib in preparation of medicine for treating crescent nephritis

Technical Field

The invention relates to the technical field of medicines for treating crescent nephritis. More specifically, the invention relates to an application of Sotuletinib in preparing a medicine for treating crescent nephritis.

Background

The crescent nephritis is also called acute nephritis, and refers to a group of clinical syndromes that oliguria, no urine and sharply reduced renal function occur in a short period of time on the basis of nephritis syndromes (haematuria, proteinuria, edema and hypertension), and the renal function is sharply reduced. The pathology is manifested by crescent nephritis, with at least 50% of glomeruli formed. Crescent nephritis is a pathological diagnosis and can be clinically divided into three types: type I (anti-GBM antibody type), type ii (immunocomplex type) and type iii (oligoimmunocomplex type). Clinical characteristics and disease prognosis of different types of crescent nephritis are different, and researches show that the kidney survival rate of the type I crescent nephritis is the lowest, the kidney function prognosis of the type II crescent nephritis is the best, and the response of the type III crescent nephritis to treatment is the best; the cumulative survival rates of the type I, type II and type III crescent nephritis for 5 years are 17.6%, 70.1% and 44.3% respectively. In crescent nephritis, the main cause and pathological feature leading to loss of nephron function is the generation of glomerular crescent, and the main factors related to crescent formation and progression are: fibrin, tissue factor, macrophages, T cells, glomerular parietal epithelial cells, glomerular visceral epithelial cells (podocytes). Among them, prevention of the sustained proliferation of glomerular wall epithelial cells in crescent nephritis is a key to inhibiting crescent formation, and proliferation of wall epithelial cells is usually caused by podocyte injury and infiltration of immune cells.

Disclosure of Invention

It is an object of the present invention to solve at least the above problems and to provide at least the advantages to be described later.

To achieve these objects and other advantages and in accordance with the purpose of the invention, there is provided a use of Sotuletinib in the preparation of a medicament for treating crescent nephritis.

Preferably, the crescent nephritis comprises anti-basement membrane nephritis, lupus glomerulonephritis, ANCA-related glomerulonephritis, glomerulonephritis with parietal epithelial cell proliferation.

The invention at least comprises the following beneficial effects: the invention expands the clinical indications of Sotuletinib (BLZ 945). The clinical use of Sotuletinib has increased and it is clear that its way to ameliorate crescent nephritis is to protect the nephron by reducing glomerular crescent production.

Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.

Drawings

FIG. 1 is a bar chart of urea nitrogen values of animal experiment serum of the invention;

FIG. 2 is a bar graph of serum creatinine values for animal experiments in accordance with the present invention;

FIG. 3 is a bar graph of serum albumin values for animal experiments in accordance with the present invention;

FIG. 4 is a bar chart of glutamic pyruvic transaminase values of animal experiments according to the invention;

FIG. 5 is a bar chart of glutamic oxaloacetic transaminase values of animal experiment serum of the present invention;

FIG. 6 is a bar graph of the proportion of the whole glomeruli in the crescent glomeruli of the animal experiment of the invention;

FIG. 7 is a PAS staining chart of a blank group of animal experiments according to the present invention;

FIG. 8 is a PAS staining chart of an animal experiment model group according to the present invention;

FIG. 9 is a PAS staining chart of the animal experiment Sotuletinib group of the present invention.

Detailed Description

The present invention is described in further detail below with reference to the drawings to enable those skilled in the art to practice the invention by referring to the description.

The experimental methods described in the following embodiments are conventional methods unless otherwise indicated, and the reagents and materials are commercially available.

< example >

1. C57BL/6J mice (7-8 weeks old) were purchased from Peking Vitre Liwa laboratory animal technologies Co. Mice were kept in a temperature controlled, pathogen free environment and cycled for 12 hours (07:00 on, 19:00 off). Animal experiments were approved by the university of Beijing Chinese medicine animal protection and use Committee (ethical number: BUCM-4-2022062705-2069).

anti-GBM serum nephritis induction.

2. Mice were induced for crescentic nephritis with sheep anti-mouse GBM serum (Probetex, USA). 7-8 week old mice were single intraperitoneally injected with 0.4ml of a 1:1 volume emulsion mixed with normal sheep serum and complete Freund's adjuvant (Sigma, USA). After 6 days, mice were induced for crescentic nephritis by intraperitoneal injection of 0.4ml of anti-murine GBM serum or normal sheep serum per 20g of body weight.

3. Intuitib (BLZ 945) treatment: to evaluate the effect of targeted inhibition of signal interference between podocytes and PECs on PECs proliferation and glomerular crescent formation, crescent nephritis mice were perfused daily with stomach Sotuletinib (BLZ 945) (200 mg/kg) (AbMole Bioscience, USA) starting on the day of modeling. 1% sodium carboxymethylcellulose (CMC) (Selleck, USA) was used as the solvent for Sotuletinib (BLZ 945) and 1% CMC was used as the model control. Serum samples were collected 7 days after serum injection and kidneys were taken for histological examination. The number of mice in the model control group and the drug treatment group was 10 for 5 blank control groups.

< results of animal experiments >

1. Serum urea nitrogen value (Serum BUN) (mg/dl):

blank (Blank)	Model (Model group)	Sotuletinib
			19.2584	45.192	21.896
20.9944	40.152	24.864
			20.2944	73.5	23.688
19.74	28.666	18.9
			19.5944	30.128	19.992
	23.0664	19.432
				49.9744	21.896
	38.85	21.448
				69.2328	20.496
	24.2592	21.224

2. Serum creatinine value (Serum Creatinine) (mg/dl):

3. serum albumin value (Serum albumin) (g/L):

Model	Sotuletinib
		20.71	39.74
21.69	32.7
		21.34	32.74
27.28	27.96
		23.73	40.77
36.786	41.52
		27.254	44.06
26.016	42.84
		23.985	48.42
35.04	39.16

4. serum glutamic pyruvic transaminase value (Serum ALT) (U/L):

5. serum glutamic-oxaloacetic transaminase value (Serum AST) (U/L):

Model	Sotuletinib
		200.058	132.68
197.77	206.28
		205.118	157.74
170.046	115.26
		164.916	152.43
267.243	122.2
		271.953	152.22
257.093	109.44
		204.26	202.92
202.572	121.28

6. the proportion (%) of crescent glomeruli (Glomeruli with crescents) to total glomeruli:

Model	Sotuletinib
		44.6429	6
41.8182	7.8431
		35	26
42.1875	15.5172
		63.7931	11.3208
39.2857	20
		40.7407	13.4615
39.6226	11.7647
		38	25.4902
20	5.8824

< analysis of results >

As shown in fig. 1 to 8:

1. the method for preparing the model of the mice with the crescent nephritis has the advantages that the level of serum urea nitrogen and creatinine of the mice can be obviously reduced and the impaired renal function can be improved by preparing the model of the mice with the crescent nephritis and performing gastric lavage treatment for 6 days by using Sotuletinib (BLZ 945); meanwhile, serum albumin can be obviously up-regulated, which shows that the Sotuletinib has a therapeutic effect on glomerular filtration injury of mice with crescent nephritis. Meanwhile, the liver function of the mice is not obviously affected by the medicine.

2. The kidney PAS staining of mice also shows that the Sotuletinib can obviously reduce the generation of crescent glomeruli of nephritis mice and improve pathological injury.

Although embodiments of the present invention have been disclosed above, it is not limited to the details and embodiments shown and described, it is well suited to various fields of use for which the invention would be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the specific details and illustrations shown and described herein, without departing from the general concepts defined in the claims and their equivalents.

Claims

Application of Sotuletinib in preparing medicine for treating crescent nephritis.
2. Use of Sotuletinib according to claim 1 for the preparation of a medicament for the treatment of crescentic nephritis selected from the group consisting of anti-basement membrane nephritis, lupus glomerulonephritis, ANCA-associated glomerulonephritis, glomerulonephritis with parietal epithelial cell proliferation.