CN112755028A

CN112755028A - Application of roxasistat in preparation of drugs for preventing and/or treating drug addiction

Info

Publication number: CN112755028A
Application number: CN202110119614.1A
Authority: CN
Inventors: 镇学初; 颜鹏举; 马明
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2021-01-28
Filing date: 2021-01-28
Publication date: 2021-05-07
Anticipated expiration: 2041-01-28
Also published as: CN112755028B

Abstract

The invention relates to application of roxasistat in preparation of drugs for preventing and/or treating drug addiction. The invention discloses a roxasistat which can prevent the formation of drug or drug addiction after being applied and can promote the regression of drug or drug addiction so as to realize the prevention and treatment of drug or drug addiction or dependence.

Description

Application of roxasistat in preparation of drugs for preventing and/or treating drug addiction

Technical Field

The invention relates to the technical field of medicinal application, in particular to application of roxasistat in preparation of a medicament for preventing and/or treating drug addiction.

Background

Drugs are natural, semi-synthetic or synthetic substances that cause dependency, excite or inhibit the central nervous system of animals, thereby causing hallucinations or damage to the animal's motor function, thought, behavior, sensation, or mood. Wherein the natural drugs include opium, morphine, etc.; semi-synthetic drugs including cocaine and the like; the synthetic drugs include amphetamine, methamphetamine (methamphetamine), etc. Drug addiction is a chronic recurrent brain disease, is a series of chronic diseases with morphological structure and function changes of brain nerve cells caused by long-term drug abuse, and is accompanied with obvious psychological, behavioral disorders, mental diseases, social and legal problems and other problems. Drug addiction not only harms physical health, but also imposes a heavy burden on families and society, and has become a serious social problem. Therefore, research on drugs for preventing and/or treating drug addiction is receiving a great deal of attention.

At present, the clinical drug rehabilitation method mainly comprises a drug withdrawal method and a natural withdrawal method. The drug withdrawal method is a main means for treating drug addiction, and the drugs used in the drug withdrawal method are opioid drugs represented by methadone and non-opioid drugs represented by clonidine. Wherein, the opioid drugs have better symptom control, but have addiction, and the improper use can cause drug use dependence; although non-opioid drugs have no addiction, after long-term use or overdose, rebound blood pressure increase, headache, nausea, postural hypotension, dizziness or syncope, slow heartbeat and other serious adverse reactions can occur, and the withdrawal symptoms are obvious and the side effects are large. Natural withdrawal is by hard cessation of drug use, which is associated with intense discomfort and pain and a high likelihood of relapse. Therefore, there is an urgent need for the development of novel drugs that can prevent drug addiction, effectively control withdrawal symptoms, effectively prevent relapse, and have few side effects.

Roxadustat (FG-4592/ASP 1517/rasostat, the domestic trade name of Ehreplaque) is a novel oral hypoxia inducible factor prolyl hydroxylase inhibitor, can induce erythropoietin to produce, is clinically used for treating renal anemia, has a half-life period of about 12 hours, and can permeate blood brain barrier. In recent years, pharmacological experiments prove that the roxasistat has a treatment or protection effect on peripheral diseases such as muscle injury, obesity-related inflammation and metabolic diseases and central neuropsychiatric diseases such as spinal cord injury, Parkinson's disease and depression, but the effect on drug addiction or dependence is not reported.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide the application of the roxasistat in preparing the drugs for preventing and/or treating drug addiction, and the direction is indicated for providing the drugs for preventing and/or treating drug addiction.

One of the schemes of the invention discloses application of a compound shown in formula I, a derivative thereof or a pharmaceutically acceptable salt thereof in preparing a medicament or food for preventing and/or treating drug addiction or dependence, wherein the formula I is as follows:

in the present invention, the compound represented by formula I is roxadestat (Roxadustat).

Further, the derivative is an acetylated or esterified compound of the compound represented by formula I.

Further, the pharmaceutically acceptable salt is a sodium salt or a potassium salt of the compound represented by formula I.

Further, drug addiction includes one or more of opiate, morphine, cocaine, marijuana, heroin, amphetamine, and methamphetamine drug addiction.

The second scheme of the invention discloses application of a compound shown in the formula I, a derivative thereof or a pharmaceutically acceptable salt thereof in preparing a medicament or food for preventing and/or treating drug addiction or dependence, wherein the formula I is as follows:

Furthermore, the drug addiction is the general anesthesia, analgesia, antianxiety and antidepressant drugs in clinic, such as barbiturates, opioids, benzodiazepines, amphetamines, ketamine and other drugs.

Clinically, the maximum recommended dose for treating anemia caused by chronic kidney disease is 2.5 mg/kg. In specific use, the experimental data of the invention on mice show that the dosage of the compound shown in the formula I is 5-10mg/kg, and the corresponding dosage converted into a human body is 0.55-1.1 mg/kg.

In the invention, the compound shown in the formula I, the derivative thereof or the pharmaceutically acceptable salt thereof can be used for preparing foods including beverages, health-care products and the like for preventing and/or treating drugs or drug addiction.

According to the invention, the mice are subjected to abdominal cavity injection of roxasistat (10 mg/kg/day) every day, and after 6 hours, the mice are subjected to abdominal cavity injection of methamphetamine (2 mg/kg/day) for 4 days, so that a drug addiction model is constructed, and after the training is finished, the preference score of the mice staying at the side of methamphetamine concomitant drug is detected, and the result shows that the preference score of the mice at the side of methamphetamine concomitant drug can be obviously reduced by the administration of the roxasistat.

According to the invention, the mice are subjected to morphine condition position preference training for 7 days by intraperitoneal injection of roxasistat (10 mg/kg/day) to the mice every day and 6 hours later and then intraperitoneal injection of morphine (20 mg/kg/day) to the mice to construct a drug addiction model, and the preference scores of the mice staying at the morphine concomitant drug side are detected after training is finished, so that the results show that the preference scores of the mice at the morphine concomitant drug side can be obviously reduced by administration of the roxasistat.

According to the method, a morphine addiction model is constructed by giving morphine (20 mg/kg/day) to the abdominal cavity of a mouse every day to perform condition position preference training for 7 days, the mouse is given roxamastat (10 mg/kg/day) to the abdominal cavity of the mouse to replace the morphine for training on the 8 th day, training is performed for 2 days as one cycle, three cycles are trained in total, preference scores of the mouse staying at the side of morphine concomitant drug are detected after each cycle is finished, and the result shows that the administration of the roxamastat can obviously reduce the preference scores of the mouse on the side of morphine concomitant drug and promote the regression of addiction behaviors.

By the scheme, the invention at least has the following advantages:

(1) aiming at the current situation that drugs for clinically preventing and treating drug addiction are lack, the invention provides a new application of roxasistat and derivatives thereof in preparing drugs for preventing and/or treating drug addiction. The invention provides that the roxasistat can prevent the formation of drug or drug addiction behaviors after being applied and can promote the regression of the drug or drug addiction behaviors, and proves that the roxasistat has a remarkable effect in the prevention and/or treatment of drug addiction or dependence.

(2) The rosxastat drug can prevent the formation of morphine and methamphetamine addiction after administration (for example, 10 mg/kg/day of rosxastat can significantly reduce morphine and methamphetamine induced conditional locus preference scores); and the roxasistat drug does not cause the dependence of users on the roxasistat in the process of preventing or treating drug addiction.

(3) The roxasistat has good tolerance and few adverse reactions, most of the adverse reactions are slight in clinical research, and headache, backache, fatigue, diarrhea and the like are common.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following description is made with reference to the preferred embodiments of the present invention and the accompanying detailed drawings.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

Drawings

FIG. 1 is a graph of the effect of rasagiline on the prevention of methamphetamine addiction;

FIG. 2 is a graph of the effect of rasagiline on the prevention of addiction to morphine;

FIG. 3 is a graph of the effect of dose prevention of addiction to morphine by rasagiline;

FIG. 4 is a graph of the effect of rasagile on the enhancement of regression of morphine addiction behavior;

figure 5 is a graph of the effect of rasagiline on the suppression of morphine relapse after withdrawal.

Detailed Description

The present inventors have conducted extensive and intensive studies and found that rosisasetat can be used for the preparation of a medicament for the prevention and/or treatment of drug addiction or dependence, and a specific embodiment of the present invention will be described in further detail with reference to examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight and the mode of administration in mice is all intraperitoneal.

Example 1 prevention of addiction to methamphetamine by Rosxastat

The C57BL/6J mice used in the present invention were purchased from Shanghai Si Laike laboratory animals, Inc., and the Rosemat He used in the present invention was purchased from Selleck.

The administration method for mice is as follows:

36 male C57BL/6J mice (8 weeks old, 22-25g in weight) were housed in SPF-grade animal rooms and were randomly divided into a control group (11), a methamphetamine group (10), and a methamphetamine + rospase group (15) after 1 week of adaptive housing. Normal saline is injected into the abdominal cavity of a control group mouse, methamphetamine (2 mg/kg/day) is injected into the abdominal cavity of a methamphetamine group mouse, the methamphetamine + roxasistat group mouse is injected with roxasistat (10 mg/kg/day) into the abdominal cavity firstly, and methamphetamine (2 mg/kg/day) is injected into the abdominal cavity after 6 hours and is continuously injected for 4 days.

Mice were subjected to conditional site preference experiments and scored as follows:

a conditional place preference box (laboratory instrument) of Shanghai Ji Mass software technology Co., Ltd is used as a behavioural training and detecting instrument. The experimental instrument is divided into two boxes, namely a medicine accompanying box (a black box) and a non-medicine accompanying box (a white box), wherein the two boxes can be sealed and communicated. On the first day, the mice were placed in the laboratory apparatus (connected state) and freely moved for 900 seconds and the moving time of the mice in the concomitant drug box was recorded and analyzed as a baseline value. Drug addiction training is performed the next day, and after drug administration according to grouping requirements, mice are restricted in a drug accompanying box (closed state) for training for 60 minutes/day for four days. After training, the mice are placed in the experimental instrument for 900 seconds in a free movement (connected state) on the sixth day, and the movement time of the mice in the medicine accompanying box is recorded and analyzed. And subtracting the activity time (base line) of the mouse in the medicine accompanying box on the first day from the activity time of the mouse in the medicine accompanying box on the sixth day to obtain a difference value, wherein the difference value is the preference score.

As shown in FIG. 1, there was a significant difference in preference score between the control group and the methamphetamine group, indicating that an addiction model could be successfully established with the injection of methamphetamine at 2 mg/kg/day. The preference scores of the methamphetamine group and the methamphetamine + rospasol group are obviously different, which indicates that the rospasol injection at 10 mg/kg/day has a prevention effect on the addiction of the methamphetamine.

Example 2 prevention of addiction to morphine by Rosxastat

The administration method for mice is as follows:

36 male C57BL/6J mice (8 weeks old, 22-25g in weight) were housed in SPF-grade animal chambers and were randomly divided into a control group (14), a morphine group (13) and a morphine + rosomastat group (14) after 1 week of acclimation. The normal saline is injected into the abdominal cavity of a control group mouse, the morphine group mouse is injected into the abdominal cavity of the morphine group mouse (20 mg/kg/day), the morphine + Rosesarta group mouse is injected into the abdominal cavity of the Rosesarta (10 mg/kg/day), the morphine (20 mg/kg/day) is injected into the abdominal cavity after 6 hours, and the injection is continuously carried out for 7 days.

a conditional place preference box (laboratory instrument) of Shanghai Ji Mass software technology Co., Ltd is used as a behavioural training and detecting instrument. The experimental instrument is divided into two boxes, namely a medicine accompanying box (a black box) and a non-medicine accompanying box (a white box), wherein the two boxes can be sealed and communicated. On the first day, the mice were placed in the laboratory apparatus (connected state) and freely moved for 900 seconds and the moving time of the mice in the concomitant drug box was recorded and analyzed as a baseline value. Drug addiction training is carried out the next day, and after the drug administration is carried out according to grouping requirements, the mice are limited in a drug accompanying box (in a closed state) for training for 30 minutes/day, and training lasts for seven days. After training, the mice are placed into the experimental instrument for 900 seconds in a free movement (connected state) manner on the ninth day, and the movement time of the mice in the medicine accompanying box is recorded and analyzed. And subtracting the activity time (base line) of the mice in the medicine accompanying box on the ninth day from the activity time of the mice in the medicine accompanying box on the first day to obtain a difference value, wherein the difference value is the preference score.

As shown in fig. 2, there was a significant difference in preference score between the control group and the morphine group, indicating that 20 mg/kg/day morphine injection was successful in establishing an addiction model. The preference scores between the morphine group and the morphine + rospastat group were significantly different, indicating that injection of rospastat at 10 mg/kg/day had a preventive effect on addiction to morphine.

Example 3 dose-response relationship of Roxastat's preventive effect on addiction to morphine

The administration method for mice is as follows:

36 male C57BL/6J mice (8 weeks old, 22-25g in weight) were housed in SPF-grade animal rooms, and were randomly divided into a control group (8), a morphine group (15), a morphine + rosomastat 2.5mg/kg group (14), a morphine + rosomastat 5mg/kg group (14), a morphine + rosomastat 10mg/kg group (13), and a morphine + rosomastat 20mg/kg group (14) after 1 week of acclimation. The normal saline is injected into the abdominal cavity of a control group mouse, the morphine group mouse is injected into the abdominal cavity of the morphine group mouse (20 mg/kg/day), the morphine + Rosesarta group mouse is injected into the abdominal cavity of the Rosesarta (2.5, 5, 10, 20 mg/kg/day), the morphine is injected into the abdominal cavity of the control group mouse after 6 hours (20 mg/kg/day), and the injection is continuously carried out for 7 days.

As shown in fig. 3, there was a significant difference in preference score between the control group and the morphine group, indicating that 20 mg/kg/day morphine injection was successful in establishing an addiction model. The preference score between the morphine group and the morphine +10 mg/kg/day rosisoxostat group is significantly different, which indicates that the 10 mg/kg/day injection of the roxasistat is the most effective dose for preventing morphine addiction.

Example 4 Rosemastat promotes regression of morphine addiction behavior

The administration method for mice is as follows:

36 male C57BL/6J mice (8 weeks old, 22-25g in weight) were housed in SPF-grade animal chambers and were randomly assigned to control (10), morphine (8) and morphine + rosomastat (7) groups after 1 week of acclimation.

The experimental method for establishing the addiction behavior comprises the following steps:

the normal saline is injected into the abdominal cavity of a control group mouse, the morphine (20 mg/kg/day) is injected into the abdominal cavity of a morphine group mouse, and the morphine (20 mg/kg/day) is injected into the abdominal cavity of a morphine + Rosesarta group mouse for 7 days continuously.

The experimental method for the regression of addictive behaviors comprises the following steps:

after the addiction behavior is established, the mice in the control group continue to inject normal saline into the abdominal cavity, the mice in the morphine + Rosemastat group firstly inject Rosemastat (10 mg/kg/day) into the abdominal cavity, the mice in the morphine + Rosemastat group inject normal saline into the abdominal cavity after 6 hours to perform regression training, one cycle is formed every two days of training, and three cycles are formed in total.

a conditional place preference box (laboratory instrument) of Shanghai Ji Mass software technology Co., Ltd is used as a behavioural training and detecting instrument. The experimental instrument is divided into two boxes, namely a medicine accompanying box (a black box) and a non-medicine accompanying box (a white box), wherein the two boxes can be sealed and communicated. On the first day, the mice were placed in the laboratory apparatus (connected state) and freely moved for 900 seconds and the moving time of the mice in the concomitant drug box was recorded and analyzed as a baseline value. Drug addiction training is carried out the next day, and after the drug administration is carried out according to grouping requirements, the mice are limited in a drug accompanying box (in a closed state) for training for 30 minutes/day, and training lasts for seven days. After training, the mice are placed into the experimental instrument for 900 seconds in a free movement (connected state) manner on the ninth day, and the movement time of the mice in the medicine accompanying box is recorded and analyzed. And subtracting the activity time (base line) of the mice in the medicine accompanying box on the ninth day from the activity time of the mice in the medicine accompanying box on the first day to obtain a difference value, wherein the difference value is the preference score of the test.

the dosing training was performed in groups as above, with one cycle every two days, for three cycles, and each cycle was sequentially recorded as regression 1, regression 2, and regression 3. The preference score was determined by the time the mice stayed on the morphine-agonist side after each cycle was completed.

As shown in fig. 4, in the experimental phase of establishing addiction behavior, there was a significant difference in preference scores between the control group and the morphine group, as well as between the morphine and rospasmostat groups, indicating that 20 mg/kg/day morphine injection successfully established an addiction model. In the experimental stage of regression of addiction behaviors, the significant difference of the preference scores between the morphine + rospastat group and the control group disappears in the first regression cycle (regression 1), and the significant difference of the preference scores between the morphine group and the control group disappears in the second regression cycle (regression 2), which indicates that the 10 mg/kg/day injection of rospastat can promote the regression of morphine addiction behaviors and has the effect of treating morphine addiction.

Example 5 inhibition of Re-absorption of morphine by Rosemastat

The administration method for mice is as follows:

36 male C57BL/6J mice (8 weeks old, 22-25g in weight) were housed in SPF-grade animals and were randomly assigned to control (15), morphine (7) and morphine + rosomastat (4) groups after 1 week of acclimation.

The experimental method for establishing and relieving the addictive behaviors comprises the following steps:

the normal saline is injected into the abdominal cavity of a control group mouse, the morphine (20 mg/kg/day) is injected into the abdominal cavity of a morphine group mouse, and the morphine (20 mg/kg/day) is injected into the abdominal cavity of a morphine + Rosesarta group mouse for 7 days continuously. After the addiction behavior is established, mice in a control group, a morphine group and a morphine + rospastat group are subjected to withdrawal training by injecting normal saline into the abdominal cavity, one cycle is formed every two days of training, and three cycles are trained in total.

The experimental method for the reconstruction of the addiction behavior comprises the following steps:

after one week of regression experiment, the mice were re-habituated with low dose (5 mg/kg/day) morphine, the mice in the control group were intraperitoneally injected with normal saline, the mice in the morphine group were intraperitoneally injected with 5mg/kg morphine, the mice in the morphine + rosloxatase group were intraperitoneally injected with rosomastat (10 mg/kg/day), and the mice in the 6 hour post-intraperitoneally injected with low dose morphine (5 mg/kg/day) with the position preference for the re-establishment condition.

The experimental methods for regression and reconstitution of addictive behaviors are as follows:

the physiological saline administration training is carried out on all groups, one cycle is carried out every two days, and three cycles are trained. The preference score for mice staying on the morphine-concomitant side was examined after the third cycle was completed. After the regression experiment is finished for one week, the addiction behavior of the mice is reconstructed by using morphine, the drugs are administered according to the addiction behavior reconstruction experiment groups, the mice are placed into an experimental instrument to freely move (in a connected state) for 900 seconds after the administration, the moving time of the mice in a concomitant drug box is recorded and analyzed, and the time is the tested preference score.

As shown in fig. 5, there was a significant difference in preference score between the control group and the morphine group during the reconstitution phase of addictive behavior, indicating that morphine injection at 5 mg/kg/day was able to reconstitute morphine addiction. In the addiction behavior reestablishment stage, the preference scores of the morphine group and the morphine + rosette group are obviously different, which shows that the rosette injection of 10 mg/kg/day can inhibit the reestablishment of morphine addiction, namely relapse, and the results show that the rosette has the function of preventing the relapse after morphine withdrawal.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims

1. The application of the compound shown as the formula I, the derivative thereof or the pharmaceutically acceptable salt thereof in preparing the medicine or food for preventing and/or treating drug addiction or dependence is disclosed, wherein the formula I is as follows:

2. use according to claim 1, characterized in that: the derivative is an acetylate or an esterified compound of the compound shown in the formula I.

3. Use according to claim 1, characterized in that: the pharmaceutically acceptable salt is a sodium salt or a potassium salt of the compound shown in the formula I.

4. Use according to claim 1, characterized in that: the drug addiction comprises one or more of opium, morphine, cocaine, marijuana, heroin, amphetamine and methamphetamine drug addiction.

5. The application of the compound shown as the formula I, the derivative thereof or the pharmaceutically acceptable salt thereof in preparing the medicine or food for preventing and/or treating drug addiction or dependence is disclosed, wherein the formula I is as follows:

6. use according to claim 5, characterized in that: the derivative is an acetylate or an esterified compound of the compound shown in the formula I.

7. Use according to claim 5, characterized in that: the pharmaceutically acceptable salt is a sodium salt or a potassium salt of the compound shown in the formula I.

8. Use according to claim 5, characterized in that: the drug addiction comprises barbiturates, opioids, benzodiazepines or amphetamine drug addiction.