阅读说明：本技术 庆大霉素在制备治疗胆汁淤积药物中的应用 (Application of gentamicin in preparation of medicine for treating cholestasis ) 是由 武新安 王欢 马彦荣 辛明彦 于 2019-08-29 设计创作，主要内容包括：本发明属于医药领域,涉及庆大霉素在制备治疗胆汁淤积药物中的应用。口服庆大霉素能够显著降低血中胆酸盐浓度,减少肝脏和回肠组织中有毒胆酸盐的浓度以及抑制肝脏病变。(The invention belongs to the field of medicines, and relates to application of gentamicin in preparation of a medicament for treating cholestasis. Oral administration of gentamicin can significantly reduce the concentration of bile salts in blood, reduce the concentration of toxic bile salts in liver and ileum tissues, and inhibit liver lesions.)

1. Use of gentamicin in the manufacture of a medicament for the treatment of cholestasis.

2. The use of claim 1, wherein the medicament for the treatment of cholestasis is capable of reducing the level of cholate.

3. Application of gentamicin in preparing medicine for treating cholestatic liver disease is provided.

4. The use according to claim 3, wherein the cholestatic liver disease is a chemical or pharmaceutical or primary cholestatic liver disease.

5. The use according to claim 3, wherein the cholestatic liver disease is intrahepatic cholestasis of pregnancy.

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of gentamicin in preparation of a medicament for treating cholestasis.

Background

Cholestasis is a liver disease caused by disturbance of secretion or excretion of bile due to various causes, which prevents bile from normally flowing into the intestinal tract and reversely flowing into blood circulation. The clinical manifestations of cholestasis include increased levels of bile acid salts, alkaline phosphatase and glutamyl transpeptidase, impaired liver function, etc. Although the pathogenesis of cholestatic liver disease is continuously and deeply analyzed at the molecular level, no specific treatment method for cholestatic liver disease is available so far, and the literature reports that the reduction of cholate level is the key of treatment, and the liver damage can be reduced, and the clinical symptoms can be relieved (Chen Xiao Qing Chun, etiology and treatment of intrahepatic cholestatic liver disease, and the practical journal of liver disease, 2018, 21(2), 163-plus 165).

Ursodeoxycholic acid (UDCA) is currently the only drug approved by the U.S. food and drug administration for widespread use in the treatment of cholestasis, early treatment can alleviate symptoms, improve liver enzyme abnormalities and reduce mortality and liver transplantation rates in patients with Primary Biliary Cirrhosis (PBC). Although UDCA can improve biochemical indicators of liver function, it cannot improve symptoms; and long-term use of UDCA for treatment of PBC patients does not prolong the survival of patients (bin et al, systematic evaluation of ursodeoxycholic acid for treatment of primary biliary cirrhosis, guangxi medicine, 2009, 31(2), 157-. In addition, UDCA is expensive, has a long treatment period, and even needs lifelong treatment. Therefore, the development of safe, effective and cheap new medicaments is urgent.

Gentamicin (also known as Gentamicin, trademark Garamycin) is an antibiotic extracted from micromonospora purpurea, was first discovered in 1963, and is mainly used for treating bacterial infections, especially infections caused by gram-negative bacteria. However, no report has been found on the application of gentamicin in the treatment of cholestasis.

Disclosure of Invention

The invention aims to provide application of gentamicin in treating cholestasis. After oral administration of gentamicin, the concentration of cholate in blood can be obviously reduced, the concentration of toxic cholate in liver and ileum tissues can be reduced, and no kidney toxicity or intestinal toxicity exists.

In one aspect, the invention provides the use of gentamicin in the manufacture of a medicament for the treatment of cholestasis.

In some embodiments, the use of the invention, wherein the medicament for the treatment of cholestasis is capable of reducing the level of cholate.

In another aspect, the invention provides the use of gentamicin in the manufacture of a medicament for the treatment of cholestatic liver disease.

In some embodiments, the use according to the invention, wherein the cholestatic liver disease is a chemical or pharmaceutical or primary cholestatic liver disease.

In some embodiments, the use of the invention, wherein the cholestatic liver disease is intrahepatic cholestasis of pregnancy.

The present invention relates to the treatment of cholestasis and its related diseases using gentamicin. After oral administration of gentamicin, the concentration of cholate in blood can be obviously reduced, the concentration of toxic cholate in liver and ileum tissues can be reduced, the composition of cholate is changed, the proportion of hydrophilic cholate is increased, liver cells and cholate cells are protected from being poisoned by toxic cholic acid, the interference of hydrophobic cholate on a mitochondrial membrane is prevented, the apoptosis of liver cells is inhibited, and the liver function is improved. Particularly, when the gentamicin is used for treating rats of a chronic endogenous cholestasis model, the total cholate level in blood can be obviously reduced and the secondary cholate content in blood and liver can be reduced under the dosage of 25mg/Kg to 50mg/Kg (corresponding to the dosage of 4.17mg/Kg to 8.33mg/Kg in a human body).

Drawings

FIG. 1 shows the effect of oral administration of gentamicin on various biochemical indicators in serum of cholestatic rats according to an embodiment of the present invention; wherein P is <0.05 compared to control; # is P <0.05 compared to model group.

Fig. 2 shows a graph of the concentration of individual cholate in the blood of cholestatic rats after oral administration of gentamicin according to an embodiment of the present invention; wherein P is <0.05 compared to control; # is P <0.05 compared to model group.

Fig. 3 shows a graph of the concentration of individual cholate in the liver of cholestatic rats after oral administration of gentamicin according to an embodiment of the present invention. Wherein P is <0.05 compared to control; # is P <0.05 compared to model group.

Fig. 4 shows a pathological section of liver tissue from cholestatic rats after oral administration of gentamicin according to an embodiment of the present invention. A. B, C, D, E represent control, model, UDCA, 25 mg/Kg-gentamicin and 50 mg/Kg-gentamicin groups, respectively.

Fig. 5 shows a pathological section of kidney tissue of cholestatic rats after oral administration of gentamicin according to an embodiment of the present invention. A. B, C, D, E represent control, model, UDCA, 25 mg/Kg-gentamicin and 50 mg/Kg-gentamicin groups, respectively.

Fig. 6 shows a pathological section of ileum tissue of cholestatic rats after oral administration of gentamicin according to an embodiment of the present invention. A. B, C, D, E represent control, model, UDCA, 25 mg/Kg-gentamicin and 50 mg/Kg-gentamicin groups, respectively.

Figure 7 shows a pathological section of the ileum tissue of normal rats after oral administration of gentamicin according to an embodiment of the present invention. A. B, C represent the control group, 25 mg/Kg-gentamicin group and 50 mg/Kg-gentamicin group, respectively.

Fig. 8 is a diagram showing a pathological section of kidney tissue of a normal rat after oral administration of gentamicin according to an embodiment of the present invention. A. B, C represent the control group, 25 mg/Kg-gentamicin group and 50 mg/Kg-gentamicin group, respectively.

Detailed Description

The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. Unless otherwise indicated, the reagents and methods referred to in the examples are those commonly used in the art.