CN102716468A - Application of antagonist G31P in preparing medicine for preventing cisplatin-caused acute renal failure - Google Patents

Abstract

The invention discloses an application of an antagonist G31P in preparing a medicine for preventing cisplatin-caused acute renal failure. Through the invention, the toxic and side effects of DDP can be reduced, and the occurrence rate of DDP-caused acute renal injury is reduced; and therefore, the antagonist G31P provided by the invention can be applied to the chemotherapy of tumor together with DDP, and the dosage of the DDP is further increased based on the existing dosage so as to guarantee the therapeutic effect of DDP chemotherapy.

Description

The application of antagonist G31P in acute renal failure medicine due to the preparation prevention cisplatin

Technical field

The present invention relates to the new purposes of antagonist G31P, the especially application of antagonist G31P in acute renal failure medicine due to the preparation prevention cisplatin.

Background technology

(cisplatin DDP) is one of effective and the most the most frequently used chemotherapeutics of present clinical treatment entity tumor to cisplatin, belongs to the CCNS chemotherapeutics.Pharmaceutical research shows: the curative effect of DDP chemotherapy is directly proportional with its dosage, but DDP treatment tumor the time, also can produce the dose dependent toxic and side effects.Because kidney is the organ that receives the medicine infringement especially easily; Therefore the incidence rate of nephrotoxicity damage to occur be 28%～36% to clinical practice DDP; The dosage of its extent of damage and DDP is proportionate, and the nephrotoxicity effect of DDP has become the main cause of restriction DDP curative effect.DDP causes that the position of injury of kidney mainly occurs in kidney proximal tubule, particularly proximal tubular epithelial cells; Make it ischemia, anoxia even necrosis occur; Cause the disorder of its 26S Proteasome Structure and Function; Show as acute focal necrosis, degeneration, interstitial edema, tubular ectasia of renal cells etc.; And occur that the heavy absorption function of renal tubules reduces with urine concentration and dilution ability, urine sodium discharges and increases, can cause acute renal failure even death to ADH abnormal reaction, severe patient, clinically usually with the variation of serum creatinine, the urea nitrogen content detection index as the DDP nephrotoxicity.At present; The concrete mechanism that nephrotoxicity damages due to the DDP it be unclear that, and clinically, methods such as many clinically administration times through selection DDP, control injection speed, change route of administration are in the hope of reducing the nephrotoxicity of DDP; And adopt (1) a large amount of aquation diuresis simultaneously to increase the urine amount; Accelerate the drainage of DDP, reduction DDP gathers renal tubules, thereby has alleviated nephrotoxicity; (2) use of DDP competitive antagonist sodium thiosulfate, purpose are to use the cytotoxic effect of sodium thiosulfate with inhibition DDP, but have also reduced the therapeutical effect of DDP simultaneously; (3) use free radical scavengers such as antioxidant such as glutathion, vitamin A, C, E or thiamazole; In the hope of reducing the toxic and side effects of DDP; But mostly the application of these medicines is on aquation and diuretic basis, to carry out, and strict indication is arranged, and have shortcomings such as late result is poor, drug price height; Up to now, do not find effectively to prevent and treat the method for DDP nephrotoxicity damage as yet.

Antagonist G31P has applied for United States Patent (USP) and open (patent publication No. US20120070405; Applicant GORDON JOHN R) a kind of medicine; Be the method for using gene engineering, after the sudden change of the several amino acid in the chemotactic factor IL8 molecule, obtain the IL8 derivant of high-affinity, no chemotactic activity; Called after CXCL8 (3-73)-K11R/G31P is called for short G31P.Further discover; G31P can be at the chemotaxis of the neutrophilic granulocyte of extracorporeal blocking people, Cavia porcellus, take off functions such as granule and oxygen evolution; And can block proprietary and the CXCR1 and the bonded factor of CXCR2; Effectively antagonism people CXCL1, CXCL5 and the effect of these inflammatory mediators of CXCL8 in inflammation has tangible curative effect on the relevant treatment of infection of neutrophilic granulocyte, also find that subsequently it can be used for the treatment of malignant tumor such as carcinoma of prostate, hepatocarcinoma, melanoma.But, the relevant report of in acute renal failure medicine due to the preparation prevention cisplatin, not using at present about antagonist G31P.

Summary of the invention

The present invention finds that antagonist G31P has the function of acute renal failure due to the prevention cisplatin, thereby invention antagonist G31P is using in the acute renal failure medicine due to the preparation prevention cisplatin.

Technical solution of the present invention is: the application of a kind of antagonist G31P in acute renal failure medicine due to the preparation prevention cisplatin.

The present invention can reduce the toxic and side effects of DDP; The incidence rate of acute injury of kidney due to the reduction DDP; For this reason the present invention can with the chemotherapy of DDP common application in tumor, make DDP on the basis of existing consumption, further improve using dosage, thereby guarantee the therapeutic effect of DDP chemotherapy.

The specific embodiment

Embodiment 1:

1. experiment material and method

Get healthy C57BL/6 mice, male and female are not limit, and body weight is 19～26g, are provided by Dalian Medical Univ zoopery center.After adaptability is fed, be divided into 3 groups at random according to body weight: normal saline matched group (matched group), cisplatin medication group (DDP medication group) and cisplatin+G31P intervention group (G31P medication group), be administered once every day, logotype three days; The contrast of equivalent normal saline.

Concrete medication is following:

DDP medication group: the intraperitoneal injection of cisplatin solution 0.1ml/10g mice body weight single, the cisplatin solution concentration is 1.5mg/ml; 0.5h before the cisplatin medication, normal saline 0.1ml/10g mice body weight subcutaneous injection;

G31P medication group: the intraperitoneal injection of cisplatin solution 0.1ml/10g mice body weight single, the cisplatin solution concentration is 1.5mg/ml; 0.5h before the cisplatin medication, G31P 0.1ml/10g mice body weight subcutaneous injection, G31P concentration is 0.05mg/ml;

Matched group: 0.5h before the intraperitoneal injection of normal saline 0.1ml/10g mice body weight single, normal saline intraperitoneal injection, normal saline 0.1ml/10g mice body weight subcutaneous injection.

Detect:

(1) get each 10 of matched group, DDP medication group and G31P medication group mices respectively, the variation after the mice medication, the quantity of the 3rd, 7 day dead mouse behind the recording medicine are respectively organized in observation.

(2) after the DDP medication 6,24,48,72h gets each 10 of DDP medication group, G31P medication group and control group mice respectively, angular vein is got blood behind the etherization, collects serum, detects blood urea nitrogen and creatinine content.

2. result

(1) respectively organizes mice apparent condition and dead quantity after the medication

Group	State	Dead quantity (only)
			Matched group	The mental status is good, the hair color light, and the feed activity is good, weight increase	Do not have
DDP medication group	Lethargy, lazy moving, take food drinking-water minimizing, weight loss	5 (3 days), 10 (7 days)
			G31 medication group	The mental status can, the normal mice of feed activity reduces weight loss to some extent	Do not have

(2) respectively organize the variation of mice blood urea nitrogen and flesh liver content after the medication

Repeated experiments obtains similar result of study.

Embodiment 2:

1. experiment material and method

Get healthy Kunming mouse, male and female are not limit, and are provided by Dalian Medical Univ zoopery center.After adaptability is fed, after adaptability is fed, be divided into 3 groups at random according to body weight: normal saline matched group (matched group), cisplatin medication group (DDP medication group) and cisplatin+G31P intervention group (G31P medication group), be administered once every day, logotype three days; The contrast of equivalent normal saline.

Concrete medication is following:

DDP medication group: the intraperitoneal injection of cisplatin solution 0.1ml/10g mice body weight single, the cisplatin solution concentration is 1.2mg/ml; 0.5h before the cisplatin medication, normal saline 0.1ml/10g mice body weight subcutaneous injection;

G31P medication group: the intraperitoneal injection of cisplatin solution 0.1ml/10g mice body weight single, the cisplatin solution concentration is 1.2mg/ml; 0.5h before the cisplatin medication, G31P 0.1ml/10g mice body weight subcutaneous injection, G31P concentration is 0.05mg/ml;

Matched group: 0.5h before the intraperitoneal injection of normal saline 0.1ml/10g mice body weight single, normal saline intraperitoneal injection, normal saline 0.1ml/10g mice body weight subcutaneous injection.

Detect:

(1) get each 10 of matched group, DDP medication group and G31P medication group mices respectively, the variation after the mice medication, the quantity of the 3rd, 7 day dead mouse behind the recording medicine are respectively organized in observation.

(2) after the DDP medication 6,24,48,72h gets each 10 of DDP medication group, G31P medication group and control group mice respectively, angular vein is got blood behind the etherization, collects serum, detects blood urea nitrogen and creatinine content.

2. result:

(1) respectively organizes mice apparent condition and dead quantity after the medication

Group	State	Dead quantity (only)
			Matched group	The mental status is good, the hair color light, and the feed activity is good, weight increase	Do not have
DDP medication group	Lethargy, lazy moving, take food drinking-water minimizing, weight loss	6 (3 days), 10 (7 days)
			G31 medication group	The mental status can, the normal mice of feed activity reduces weight loss to some extent	Do not have

(2) respectively organize the variation of mice blood urea nitrogen and flesh liver content after the medication

The result shows:

Antagonist G31P has the function of acute renal failure due to the prevention cisplatin, and antagonist G31P can use in the acute renal failure medicine due to the preparation prevention cisplatin.

Claims (1)

1. the application of antagonist G31P in acute renal failure medicine due to the preparation prevention cisplatin.