CN113827603B

CN113827603B - Application of adefovir in preparing medicine for treating glioma

Info

Publication number: CN113827603B
Application number: CN202010577726.7A
Authority: CN
Inventors: 崔庆华; 张宏伟; 郭玉铎
Original assignee: Beijing Jianmu Technology Co ltd
Current assignee: Beijing Jianmu Technology Co ltd
Priority date: 2020-06-23
Filing date: 2020-06-23
Publication date: 2023-05-23
Anticipated expiration: 2040-06-23
Also published as: CN113827603A

Abstract

The invention discloses an application of Remdesivir (Remdesivir) in preparing a medicine for treating glioma. The invention proves the great potential of the Ruidexivir as a glioma therapeutic drug, discloses the good curative effect of the Ruidexivir on glioma for the first time, provides an effective novel potential alternative drug for glioma therapy, expands the indication of the Ruidexivir, and improves the application potential and market prospect of the Ruidexivir.

Description

Application of adefovir in preparing medicine for treating glioma

Technical Field

The invention relates to the field of biological medicine, in particular to application of Ruidexi Wei Zairui Texiwei in preparing a medicine for treating glioma.

Background

Remdesivir (RDV, GS-5734) is a nucleoside analog antiviral developed by Gilled sciences (GILD) that acts by inhibiting viral nucleic acid synthesis.

The general formula of the structure of Remdesivir (Remdesivir) compounds is proposed for the first time in patent WO2009132123A1 and is used for treating hepatitis C virus infection, dengue and other flaviviridae virus infection diseases. Patent WO2012012776A1 proposes the effect of adefovir in the treatment of diseases infected with viruses of the paramyxoviridae family. RDV is also proposed in subsequent patents as an anti-filovirus, anti-arenavirus, and anti-coronavirus drug. According to literature information, the treatment effect of the Rede-Sivir on glioma is not disclosed in domestic and foreign literature at present.

According to the 2015 statistics of the world health organization, cancer is the leading cause of death before 70 years in 48 countries including developed countries in europe and america, cancer is the second largest cause of death in 43 countries including china, and the third or fourth among the other 22 countries is ranked.

Brain tumors are one of the most difficult diseases to diagnose. One article published in the journal of salix-leaf, neurology, 2016 mentions that chinese morbidity and mortality are the first worldwide through global maximum-scale brain tumor statistics.

The brain glioma is the most common malignant brain tumor, the incidence rate is about 45 percent of that of intracranial tumor, and the brain glioma has the characteristics of high incidence rate, strong invasiveness, easy recurrence, high death rate and low cure rate. World health organization statistics, ranked in order of mortality, glioblastoma is the 2 nd cause of death in tumor patients under 34 years old, and the 3 rd cause of death in patients between 35 and 54 years old.

Gliomas are considered as one of the most troublesome refractory tumors in neurosurgical treatment, and the current standard treatment mode is still comprehensive treatment mainly comprising surgery, radiotherapy and chemotherapy, but the recurrence rate is close to 100%, and the five-year survival rate is less than 10%.

The new glioma treatment method and the new glioma treatment medicine have great positive significance for the treatment of glioma patients, and the commercial potential is also huge.

Disclosure of Invention

The invention aims to provide a new indication of a RedeSieve drug. And the adefovir is used as an anti-tumor drug to effectively treat glioma, and provides a new alternative drug for cancer treatment.

In order to achieve the above purpose, the invention adopts the following technical scheme:

the inventors of the present invention have predicted the inhibition of glioma growth and metastasis by adefovir using a self-host computer program.

The invention firstly provides application of the adefovir in preparing a medicament for treating glioma, wherein the adefovir has an inhibition effect on tumor growth or metastasis.

Further, the medicament comprises adefovir, which is present in free form or in the form of a pharmaceutically acceptable compound.

In the above-described use of the invention, the medicament contains an effective dose of adefovir. An effective dose is a unit dosage form (e.g., a tablet, a needle, a pill, or a dose of drug) or a unit dose (e.g., a unit body weight dose) of a treated patient. In the present invention, the scope of the subject to be treated with the drug is mammalian, including human, canine, rodent, etc. The effective dose conversion of different animals can be based on equivalent dose conversion relation of experimental animals and human in the field (generally, the guidance of drug administration such as FDA, SFDA and the like can be seen, and the like can also be seen in Huang Jihan, etc. the equivalent dose conversion between animals and human bodies in pharmacological tests, chinese clinical pharmacology and therapeutics, 2004Sep, 9 (9): 1069-1072 "), and the unit weight dose of human can be deduced from the dose of experimental animals. For example, in a conventional laboratory animal mouse, the conversion relationship with an adult is about 12:1 according to the above-mentioned document.

In the present invention, the effective dose (in terms of content) for significantly inhibiting glioma growth in 8-week-old C57BL mice is 2.5 to 100mg/kg, preferably 40 to 80mg/kg.

Preferably, the adult effective dose is 12.5-500 mg, preferably 200-400 mg, every 2 days when the adult weight standard is set to 60kg according to the conversion relation between the effective dose of the mice and the adult.

Preferably, the medicament further comprises other anticancer drugs.

Preferably, the medicament further comprises a pharmaceutically acceptable carrier.

The carrier provided by the invention is a pharmaceutically acceptable carrier, and is characterized in that: one or more compatible solid or liquid filler or gel materials. They are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.

Preferably, the carrier includes, but is not limited to: diluents, buffers, suspensions, emulsions, granules, encapsulates, excipients, fillers, binders, sprays, transdermal absorbents, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavoring agents or adsorption carriers.

The medicament can be prepared into any pharmaceutically usable dosage form according to the requirement, and preferably, the dosage form of the medicament is suitable for oral administration or injection; preferably, the dosage forms comprise oral liquid, injection, tablets, capsules and the like.

The beneficial effects are that:

the invention proves the great potential of the Ruidexivir as a medicament for treating glioma, discloses the good curative effect of the Ruidexivir on glioma for the first time, provides an effective novel potential alternative medicament for glioma treatment, expands the indication of the Ruidexivir, and improves the application potential and market prospect of the Ruidexivir.

Drawings

Fig. 1 glioblastoma tumor tissue after 8 times oral administration of different doses of adefovir, n=8.

After adefovir treatment in fig. 2, tumor tissue weight statistics were generated with n=8, p <0.05, p <0.01, p <0.001.

Fig. 3 mice body weight record, n=8.

Detailed Description

The following examples are illustrative of the invention and are not intended to limit the scope of the invention. Unless otherwise indicated, the technical means used in the examples are conventional means well known to those skilled in the art, and the reagents used are commercially available.

EXAMPLE 1 Studies of the efficacy of Rede-Sivir in the treatment of glioblastoma

1. Experimental materials

1. Adefovir: purchased from Shanghai Tao Su Biochemical technology Co., ltd., protected from light, sealed, dried and stored at 4 ℃.

2. Experimental animals: immunodeficient mice (BALB/c-nude, 16-18g, female) were supplied by Peking Vitrendy laboratory animal technologies Co.

3. Glioblastoma cells (U87-MG): is provided by basic medical research institute of China medical science.

4. Solvent: dimethyl sulfoxide (DMSO), corn Oil (Corn Oil).

2. Experimental method

1. Molding and grouping:

will be at 8 x 10 under aseptic conditions ⁶ Glioblastoma cells (U87-MG) in the log phase of growth were inoculated into immunodeficient mice by subcutaneous injection. After 6 days, the tumorigenic condition was observed, 24 mice having been tumorigenic and having a similar size were selected, and randomly divided into 3 groups, namely, a control group (Normal control, NC), a low dose group (C1-low), a high dose group (C1-low), a low dose of 40mg/kg, a high dose of 80mg/kg, and 8 mice each (n=8), and experiments were performed.

2. Preparing the medicine:

the Ruidexiwei drug is firstly dissolved in dimethyl sulfoxide (DMSO) to prepare a storage solution with the concentration of 320mg/ml, and can be stored at the temperature of minus 20 ℃. The preparation was diluted 20-fold or 40-fold with Corn Oil (Corn Oil) before administration, and formulated into 16mg/ml or 8mg/ml preparation.

3. And (3) processing and observing:

the administration was started the following day after grouping, and was performed every other day for eight times. The mode of administration is as follows in table 1:

table 1 animal mode of administration

The third day after the end of the administration, mice were sacrificed, tumors were dissected and fixed with 4% paraformaldehyde for 24 hours, photographed, weighed, and the results were counted.

3. Experimental results and conclusions

Compared to the control group (NC), the adefovir treatment significantly inhibited tumor growth, both tumor volume and weight were smaller than the control group (fig. 1, fig. 2). In the mouse glioma model, administration of adefovir Wei Ruide (40 mg/kg, po) and treatment with adefovir (80 mg/kg, po) all had an inhibitory effect on tumor growth. And the high-dose adefovir has stronger inhibition on tumors.

Table 2 is a statistical table of the efficacy of adefovir against glioma inhibition, and the data in the table also shows that the differences in tumor weight compared to the control group have statistical significance of p <0.05, p <0.01, p <0.001. From the data in the table, the obtained Ruidexivir has the best cancer inhibition effect at the dosage of 80mg/kg, and the inhibition rate is 52.71%. But does not exclude the inhibition of tumors by doses <40mg/kg/d (e.g., 2.5-40 mg/kg), nor the inhibition of tumors by doses >80mg/kg/d, e.g., 80-100 mg/kg.

Furthermore, the body weight of mice in the treated group was not significantly reduced compared to the control group, demonstrating to some extent the biosafety of adefovir.

Table 2 shows statistical table of the effects of Rede-Sivir on glioma inhibition

Average inhibition = (average tumor weight of 1-treatment group/average tumor weight of control group) ×100%

While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims

1. Application of adefovir in preparing medicine for treating glioma is characterized in that the medicine

The preparation is oral or injection.

2. The use according to claim 1, wherein the adefovir inhibits glioma growth.

3. The use according to claim 1, wherein the adefovir in the medicament is in free form or in the form of a pharmaceutically acceptable compound.

4. The use according to claim 1, wherein the effective dose of adefovir in medicine is: the adult weight standard is set to 60kg, and the effective dose of the adult is 12.5-500 mg every 2 days.

5. The use according to claim 4, wherein the effective dose of adefovir in medicine is: the weight standard of the adult is set to 60kg, and the effective dose of the adult is 200 mg-400 mg every 2 days.

6. The use according to claim 1, wherein the oral dosage form comprises a powder, a tablet, a granule, a capsule, an oral liquid, an emulsion or a suspension.

7. The use according to claim 1, wherein the medicament further comprises other adjuvants or anticancer drugs.

8. The use according to claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier, the carrier comprising diluents, buffers, suspending agents, encapsulating agents, binders, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavoring agents.

9. The use according to claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier, the carrier comprising fillers, buffers, suspensions, encapsulates, binders, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavoring agents.