CN115381817A

CN115381817A - Application of Sotuletinib in preparation of drugs for treating crescent nephritis

Info

Publication number: CN115381817A
Application number: CN202210976092.1A
Authority: CN
Inventors: 刘文斌; 胡海坤; 黄光瑞; 徐安龙
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: 2022-11-25
Anticipated expiration: 2042-08-15
Also published as: CN115381817B

Abstract

The invention discloses application of Sotuletinib in preparation of a drug for treating crescent nephritis. Crescent nephritis includes anti-basement membrane nephritis, lupus glomerulonephritis, ANCA-associated glomerulonephritis, and glomerulonephritis with parietal epithelial cell proliferation. The invention has the advantages that.

Description

Application of Sotuletinib in preparation of drugs for treating crescent nephritis

Technical Field

The invention relates to the technical field of medicaments for treating crescent nephritis. More specifically, the invention relates to an application of Sotuletinib in preparation of a drug for treating crescent nephritis.

Background

Crescent nephritis is also called as rapidly progressive nephritis, and refers to a group of clinical symptoms of oliguria, anuresis and acute decline of renal function in a short period of time on the basis of nephritic syndrome (hematuria, proteinuria, edema and hypertension), and the acute decline of renal function. The pathological manifestations are crescentic nephritis, with at least 50% of glomeruli forming crescents. Crescent nephritis is a pathological diagnosis and can be clinically classified into three types: type I (anti-GBM antibody type), type ii (immune complex type), and type iii (oligoimmune complex type). The clinical features and disease outcome of different types of crescentic nephritis are also different, and studies show that the kidney survival rate of the type I crescentic nephritis is lowest, the renal function prognosis of the type II crescentic nephritis is best, and the response of the type III crescentic nephritis to treatment is best; the 5-year cumulative survival rates of crescent nephritis types I, II and III are 17.6%, 70.1% and 44.3%, respectively. In crescentic nephritis, the main cause and pathological feature of loss of nephron function is glomerular crescentic production, and the main factors associated with crescentic formation and progression are: fibrin, tissue factor, macrophages, T cells, epithelial cells of the parietal layer of the glomerulus, epithelial cells of the visceral layer of the glomerulus (podocytes). Among them, prevention of the continuous proliferation of the epithelial cells of the parietal layer of glomerulus in crescentic nephritis is a key to the inhibition of the formation of crescentic, and the proliferation of the epithelial cells of the parietal layer is usually secondarily caused by the injury of podocytes and the infiltration of immune cells.

Disclosure of Invention

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

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

Preferably, crescent nephritis includes anti-basement membrane nephritis, lupus glomerulonephritis, ANCA-associated glomerulonephritis, and 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 sotulitinib was increased and it was determined that its way to improve crescentic nephritis is by protecting nephrons by reducing glomerular crescentic 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 graph of serum urea nitrogen values for animal experiments in accordance with the present invention;

FIG. 2 is a bar graph of serum creatinine values for an animal experiment of 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 graph of serum glutamic-pyruvic transaminase values for animal experiments according to the invention;

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

FIG. 6 is a bar graph showing the proportion of crescent glomeruli to total glomeruli in an animal experiment of the present invention;

FIG. 7 is a PAS staining pattern of the animal experiment blank according to the present invention;

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

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

Detailed Description

The present invention is described in further detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.

It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.

< example >

1. C57BL/6J mice (7-8 weeks old) were purchased from Experimental animals technology, inc. of Wei Tong Li, beijing. Mice were housed in a temperature-controlled, pathogen-free environment for 12 hours of light-dark cycling (07. The animal experiments were approved by the Committee for animal protection and use of the university of Chinese medicine in Beijing (ethical number: BUCM-4-2022062705-2069).

Induction of nephritis by anti-GBM serum.

2. Murine crescent nephritis was induced with sheep anti-mouse GBM serum (Probetex, USA). 7-8 week old mice were injected intraperitoneally with a single 0.4ml emulsion mixed with normal sheep serum and complete Freund's adjuvant (Sigma, USA) in a volume of 1. After 6 days, the mice were induced to crescent nephritis by intraperitoneal injection of 0.4ml of sheep anti-mouse GBM serum or normal sheep serum per 20g of body weight as a blank control.

3. Sotulitinib (BLZ 945) treatment: to evaluate the effect of targeted inhibition of signal interference between podocytes and PECs on PECs proliferation and glomerular crescent formation, crescentic nephritis mice were gavaged daily with sotulitinib (BLZ 945) (200 mg/kg) starting on the day of modeling (AbMole Bioscience, usa). Sodium carboxymethylcellulose (CMC) (seleck, usa) 1% was used as a solvent for Sotuletinib (BLZ 945), and CMC gavage 1% was used as a model control. Serum samples were collected 7 days after injection of serum and kidneys were taken for histological examination. The blank control group had 5 mice, and the model control group and the drug-treated group had 10 mice each.

< results of animal experiments >

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

blank (Blank group)	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 (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. crescent Glomeruli (glomerili with crescents) account for the proportion of 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. preparing a crescent nephritis mouse model, and performing intragastric administration on Sotuletinib (BLZ 945) for 6 days, so that the levels of serum urea nitrogen and creatinine of the mouse can be remarkably reduced, and the impaired renal function is improved; and simultaneously, serum albumin can be obviously up-regulated, which shows that the Sotuletinib has a treatment 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. PAS staining of the mouse kidney also shows that the Sotuletinib can obviously reduce the generation of crescent glomeruli of the nephritis mouse and improve pathological injury.

While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable in various fields of endeavor to which the invention pertains, and further modifications may readily be made by those skilled in the art, it being understood that the invention is not limited to the details shown and described herein without departing from the general concept defined by the appended claims and their equivalents.

Claims

Application of Sotuletinib in preparation of drugs for treating crescent nephritis.
2. Use of sotulitinib according to claim 1, in the preparation of a medicament for the treatment of crescentic nephritis, wherein crescentic nephritis comprises anti-basement membrane nephritis, lupus glomerulonephritis, ANCA-associated glomerulonephritis, glomerulonephritis with parietal epithelial cell proliferation.