CN113827603A

CN113827603A - Application of Rudesiwei in preparation of drug for treating glioma

Info

Publication number: CN113827603A
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: 2021-12-24
Anticipated expiration: 2040-06-23
Also published as: CN113827603B

Abstract

The invention discloses an application of Remdesivir (Remdesivir) in preparation of a medicament for treating glioma. The invention proves the great potential of the Reidesciclovir as a glioma treatment drug, firstly discloses the good curative effect of the Reidesciclovir on glioma, provides an effective novel potential alternative drug for glioma treatment, expands the adaptation symptoms of the Reidesciclovir, and improves the application potential and market prospect of the Reidesciclovir.

Description

Application of Rudesiwei in preparation of drug for treating glioma

Technical Field

The invention relates to the field of biological medicines, in particular to application of ridiflower in preparation of a glioma treatment drug.

Background

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

The general formula of the structure of the Remdesivir (Remdesivir) compound is proposed for the first time in the patent WO2009132123A1, and the Remdesivir compound is used for treating flaviviridae virus infection diseases such as hepatitis C virus infection, dengue fever and the like. Patent WO2012012776a1 suggests the effect of resisitivir in the treatment of diseases infected with viruses of the paramyxoviridae family. RDV has also been proposed in subsequent patents as anti-filovirus, anti-arenavirus and anti-coronavirus agents. According to literature information, the therapeutic effect of the Reidesciclovir on glioma is not disclosed in domestic and foreign documents at present.

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

Brain tumors have been one of the most difficult diseases to diagnose. A paper published in the Neurology of lancet, 2016, mentions that chinese morbidity and mortality are first worldwide as statistically found by the largest-scale brain tumors worldwide.

The brain glioma is the most common malignant brain tumor, has the morbidity accounting for about 45 percent of the intracranial tumor, and has the characteristics of high morbidity, strong invasiveness, easy relapse, high death rate and low cure rate. According to the statistics of the world health organization, the malignant glioma is the 2 nd cause of death of patients with tumors under the age of 34 years and the 3 rd cause of death of patients between the age of 35-54 years.

Brain glioma is considered to be one of the most difficult 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 drug have great positive significance for the treatment of glioma patients all over the world, and the commercial potential of the glioma treatment method and the drug is also very huge.

Disclosure of Invention

The invention aims to provide a new indication of a Reidesvir medicament. The Rudesavir 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 purpose, the invention adopts the following technical scheme:

the inventor of the invention predicts the inhibition effect of redexivir on glioma growth and metastasis by using an autonomous computer program.

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

Further, the medicament comprises redciclovir in free form or in the form of a pharmaceutically acceptable compound.

In the above-mentioned use of the present invention, the medicament contains an effective dose of redexivir. An effective dose is a unit dosage form (e.g., content of a tablet, a needle, a pill, or a dose of a drug) or unit dose (e.g., unit weight dose) of the patient to be treated. In the present invention, the subject of drug treatment is mammalian, including human, canine, rodent, etc. The effective dose conversion of different animals can be based on the equivalent dose conversion relationship between experimental animals and human in the field (usually refer to the guidance of drug administration such as FDA, SFDA, etc., and also refer to the "Huang-Ji-Han, etc.. equivalent dose conversion between animals and human in pharmacological test. Chinese clinical pharmacology and therapeutics, 2004 Sep; 9 (9): 1069 and 1072), that is, the unit weight dose of human can be deduced from the dose of experimental animals. For example, the conversion relationship between the mouse and the adult is about 12:1 for a commonly used experimental animal mouse according to the above-mentioned document.

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

Preferably, the effective dose of the adult is 12.5-500 mg, preferably 200-400 mg every 2 days by setting the adult weight standard to 60kg according to the conversion relation of the effective doses of the mouse and the adult.

Preferably, the medicament further comprises other anti-cancer drugs.

Preferably, the medicament further comprises a pharmaceutically acceptable carrier.

The carrier provided by the invention is a pharmaceutically acceptable carrier, and refers to: one or more compatible solid or liquid fillers or gel substances. They are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient.

Preferably, the vectors include, but are not limited to: diluents, buffers, suspensions, emulsions, granules, encapsulating agents, excipients, fillers, adhesives, sprays, transdermal absorbents, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavors, or adsorptive carriers.

The medicine can be prepared into any available dosage form in medicine according to the requirement, and preferably, the dosage form of the medicine is suitable for oral administration or injection; preferably, the dosage form includes oral liquid, injection, tablet, capsule, etc.

Has the advantages that:

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

Drawings

Fig. 1 glioblastoma tumor tissue after 8 oral doses of different doses of reidecivir, n-8.

Figure 2 generates tumor tissue weight statistics after ridciclovir treatment, n-8, p <0.05, p <0.01, p < 0.001.

Fig. 3 mice body weights recorded, n-8.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the reagents used may be normally purchased from commercial sources.

Example 1 study of the drug efficacy of Reidesvir in the treatment of glioblastoma

First, experimental material

1. Reidesciclovir: purchased from Shanghai pottery 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 provided by the laboratory animal technology, Inc., Viton, Beijing.

3. Glioblastoma cell (U87-MG): provided by the institute of basic medicine of Chinese academy of medical sciences.

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

Second, Experimental methods

1. Molding and grouping:

will be at 8 x 10 under sterile conditions⁶Several glioblastoma cells (U87-MG) in log phase of growth were inoculated subcutaneously into immunodeficient mice. After 6 days, the tumor formation was observed, and 24 mice with similar tumor formation size were selected and randomly divided into 3 groups, namely a control group (Normal control, NC), a low dose group (C1-low), and a high dose group (C1-low), wherein the low dose is 40mg/kg, the high dose is 80mg/kg, and each group contains 8 mice (n is 8), and experiments were performed.

2. Preparing the medicine:

the RudeSewei drug is firstly dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution with the concentration of 320mg/ml, and the stock solution can be stored at the temperature of-20 ℃. Diluting with Corn Oil (Corn Oil) 20 times or 40 times before administration, respectively, and making into 16mg/ml or 8mg/ml preparation.

3. And (3) processing and observing:

the administration was started the second day after the group, and every other day for a total of eight administrations. The administration is as follows in table 1:

TABLE 1 animal modes of administration

On the third day after the administration, the mice were sacrificed, tumors were dissected and removed, and after 24 hours of fixation with 4% paraformaldehyde, the mice were photographed, weighed, and the results were counted.

Third, experimental results and conclusions

Compared to the control group (NC), the ridciclovir treatment significantly inhibited the growth of tumors, both in volume and weight, which were smaller than the control group (fig. 1, fig. 2). In a mouse glioma model, the administration of Darcy-Werdciclovir (40mg/kg, po) has an inhibitory effect on tumor growth after being treated by Darcy-Werdciclovir (80mg/kg, po). And the high dose of the Redexilvir has stronger inhibition on tumors.

Table 2 is a pharmacodynamic table of the inhibition effect of resiscivir on glioma, and the data in the table also show that the difference in tumor weight is statistically significant p <0.05, p <0.01, p <0.001, compared to the control group. The data in the table show that the Reidesciclovir has the best cancer inhibition effect at the dosage of 80mg/kg, and the inhibition rate is 52.71%. However, the inhibition of a dose of <40mg/kg/d (e.g., 2.5-40 mg/kg) on tumors is not excluded, and the inhibition of a dose of >80mg/kg/d, e.g., 80-100 mg/kg, on tumors is not excluded.

In addition, the body weight of the mice in the treatment group is not significantly reduced compared with that in the control group, and the biological safety of the Reidesciclovir is proved to a certain extent.

Table 2 shows the drug effect statistics of Reidesciclovir on glioma inhibition

Mean inhibition ═ 100% (1-mean tumor weight in treatment group/mean tumor weight in control group)%

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. Application of Rudesiwei in preparing medicine for treating glioma is provided.

2. The use according to claim 1, wherein the Reidesciclovir inhibits glioma growth or metastasis.

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

4. The use according to claim 1, wherein the effective dose of Reidesciclovir in the medicament is: the weight standard of an adult is set as 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 Reidesciclovir in the medicament is: the adult weight standard is set to be 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 medicament is in a form for oral or injectable administration, including powders, tablets, granules, capsules, oral liquids, emulsions or suspensions.

7. The use of claim 1, wherein the medicament further comprises other excipients or anticancer drugs.

8. The use of claim 6, wherein the medicament further comprises a pharmaceutically acceptable carrier comprising a diluent, buffer, suspension, emulsion, granule, encapsulating agent, excipient, filler, adhesive, spray, transdermal absorbent, wetting agent, disintegrant, absorption enhancer, surfactant, colorant, flavoring agent, or adsorbent carrier.