CN112353804B - Application of YL-0919 in preparation of medicine for resisting infection or infection-related diseases - Google Patents

Abstract

The invention discloses application of YL-0919 in preparation of a medicament for resisting infection or infection-related diseases. Animal experiments prove that YL-0919 has a better anti-infection effect. The research result of the invention provides a new method and thought for clinical treatment.

Description

Application of YL-0919 in preparation of medicine for resisting infection or infection-related diseases

Technical Field

The invention belongs to the field of biological medicine, and relates to application of YL-0919 in preparation of a medicine for resisting infection or infection-related diseases.

Background

Infectious diseases are diseases caused by pathogenic microorganisms such as viruses, chlamydia, mycoplasma, rickettsia, bacteria, spirochetes, fungi, worms, and the like. To date, infection remains one of the leading causes of death and disability in humans, and is a major problem facing the medical community today. The occurrence of known or unknown infectious diseases seriously endanger the life health of human beings, such as novel coronavirus pneumonia (SARS-CoV-2), meningitis, viral hepatitis, avian influenza, AIDS and the like.

The anti-infective drug refers to various antibiotics, sulfonamides, quinolones and other chemical synthetic drugs which have the function of killing or inhibiting various pathogenic microorganisms and can be applied to the whole body by oral administration, intramuscular injection, intravenous injection and the like. Among various medical products at home and abroad, the anti-infective drug has the highest occurrence rate in the prescription. The global data of Evaluate Pharma shows that the global anti-infection related disease drug market reaches $ 951.99 billion in 2018, and becomes the second largest global drug application field to anti-tumor. Currently, the most studied anti-infective drugs are antibacterial and antiviral drugs.

Antibacterial agents, also known as "antibacterial agents," are a class of drugs used to inhibit the growth of or kill bacteria. Without being ambiguous, an antibacterial may also be referred to simply as an "antibacterial". The currently clinically used antibacterial drug is an antibiotic, which refers to a class of secondary metabolites with anti-pathogen or other activities generated by microorganisms or higher animals and plants in the life process and chemical substances capable of interfering with the development functions of other living cells. Antibiotics are by definition a broad concept and include antibacterial antibiotics, antifungal antibiotics, and antibiotics against other micro-pathogens; in clinical practice, however, antibiotics are often referred to as antibacterial antibiotics. There are several major classes of antibacterial antibiotics: penicillin, cephalosporin, aminoglycoside antibiotics, macrolide antibiotics, tetracycline antibiotics, chloramphenicol. During the use of the medicines, penicillin easily causes gastrointestinal discomfort and diarrhea, severe allergy and occasional occurrence of brain and kidney toxicity; cephalosporin is easy to cause discomfort and diarrhea of digestive tract, and if the cephalosporin is taken together with alcohol, nausea can be caused, and the cephalosporin can also cause an allergic phenomenon; aminoglycoside antibiotics are easy to cause damage to hearing, can also cause dizziness and even cause renal toxicity; when the macrolide antibiotics are used in large dose, nausea, vomiting and diarrhea are common, and jaundice can also occur; tetracycline antibiotics are easy to cause gastrointestinal discomfort, photophobia, tetracycline teeth and potential toxicity of pregnant mothers and babies; chloramphenicol is a fully synthetic antibiotic, mainly aiming at various sensitive bacteria, but can cause granulocytopenia, thrombocytopenia, aplastic anemia and the like, can cause optic neuritis, ataxia, superinfection and the like after long-term use, can cause gray infant syndrome for newborns, can cause serious reaction for mental patients, and can cause serious reaction easily due to intramuscular injection, so the chloramphenicol is forbidden to be used. Quinolones and sulfonamides are artificially fully synthetic antibacterial agents that are neither microbial secretions nor analogs thereof. In the process of using the two medicines, the quinolone can cause phenomena of nausea and tendon degeneration; sulfonamides are prone to symptoms of nausea, vomiting, diarrhea, allergic rash, urinary crystals, renal failure, decreased white blood cell count, and photophobia. Therefore, the current or used commonly used antibacterial agents have more or less side effects in the using process and have larger influence on physical and psychological health of patients, and no ideal antibacterial agent with reliable and safe curative effect exists at present.

The main clinical approach to treating viral infections is the use of broad-spectrum antiviral drugs and immunomodulators, such as acyclovir and ribavirin. Most antiviral drugs are viral polymerase inhibitors, which inhibit the growth and reproduction of the virus, primarily by inhibiting or interfering with the synthesis of viral DNA during the lytic phase. However, the virus has a simple structure and a small protein content, and after long-term use of antiviral drugs, the virus has high drug resistance, so that the effect of the current antiviral drugs commonly used in clinic is not very ideal. Therefore, the development of new effective antiviral therapeutic drugs is urgently needed.

Hydroxypiperone hydrochloride YL-0919 is a powerful new antidepressant drug developed by the institute of poisonous drugs of military medical institute of military academy of sciences. Earlier stage researches show that the medicine has quick effect on resisting depression, the depression resisting effect can be generated by intragastric administration for 3 days in a chronic stress rat model, and the hippocampal neural plasticity is quickly enhanced within 7 days. The YL-0919 has the advantages of simple synthesis process, low cost, controllable quality, stable metabolism, lower toxicity, clear effect and target characteristics and stronger application prospect. The preparation method and the application of YL-0919 and the function of the YL-0919 in resisting depression and post-traumatic stress disorder are patented in China. The application of YL-0919 in the preparation of the anti-infective medicament is disclosed for the first time, belongs to a brand new skeleton type, has good anti-infective effect, does not have the possibility of giving any revelation by other compounds, has outstanding substantive characteristics, and obviously has remarkable progress when being used for preventing and treating infectious diseases.

Disclosure of Invention

The invention aims to provide a new direction for developing a new anti-infective medicament by applying YL-0919 to the preparation of the medicament for resisting infection or infection-related diseases.

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

according to one aspect of the present invention, there is provided an anti-infective medicament comprising an effective amount of YL-0919, or a pharmaceutically acceptable salt thereof.

Furthermore, the dosage forms of the medicine comprise tablets, capsules, granules, pills, dripping pills, syrups, powders, suppositories, drops, emulsions, injections, solutions or suspensions.

Furthermore, the dosage form of the medicine is injection.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention. Suitable pharmaceutically acceptable salts include acid addition salts which may be formed, for example, by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Further, where the compound carries an acidic group, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts with suitable organic ligands (e.g., ammonium salts, quaternary ammonium salts, and amine cations formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates, and aryl sulfonates). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium ethylenediaminetetraacetate (calcium edetate), camphorate, camphorsulfonate, carbonate, chloride, citrate, clavulanate (clavulanate), cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, etonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsoninate (glycoarylanilate), hemisulfate, heptanoate, hexanoate, heptanoate, glucose heptanoate, gluconate, glutamate, glycerophosphate, glycolylargonate (glycopyrrolate), hemisulfate, heptanoate, hexanoate, and mixtures thereof, Hexylisophthalate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (pamoate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate (subacetate), Succinate, tannate, tartrate, theachlorate, tosylate, triethiodide, undecanoate, valerate, and the like.

The medicine is prepared by taking YL-0919 as an active ingredient and adding a pharmaceutically acceptable carrier or auxiliary material.

The "pharmaceutically acceptable carrier or adjuvant" as used herein refers to any carrier or adjuvant which can be administered to a patient together with a pharmaceutically active ingredient, without destroying the pharmacological activity of the pharmaceutically active ingredient.

Pharmaceutically acceptable carriers or excipients for use in the medicaments of the invention include, but are not limited to, ion exchangers, alumina, aluminium stearate, lecithin, galactinized drug delivery systems (SEDDS) such as da-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, clorsop, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as potassium sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol and lanolin. Cyclodextrins, such as a-cyclodextrin, β -cyclodextrin, and γ -cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl- β -cyclodextrin, or other solubilizing derivatives may also be used to facilitate the delivery of the drugs of the present invention.

The medicaments of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Administration by injection is preferred. In some cases, pharmaceutically acceptable acids, bases or buffers may be used to adjust the pH of the drug to improve the stability of the formulated drug dosage form. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intracolic, intralesional, and intracranial injection or infusion techniques.

The medicaments of the invention may be in the form of sterile injectable preparations, for example sterile injectable aqueous or oleaginous suspensions. The suspension may be formulated according to the techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable excipients and solvents that may be used are mannitol, water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For example, bland fixed oils may be employed including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils such as olive oil or castor oil, especially the polyoxyethylated versions thereof. These oil solutions or suspensions may also contain a long chain alcohol diluent, or dispersant, or similar alcohol, or carboxymethyl cellulose, or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions or suspensions. Other commonly used surfactants such as tween or span and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

The pharmaceutically active ingredients of the present invention and pharmaceutically acceptable salts thereof and drugs may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The medicaments of the invention, alone and/or in combination, can be used for the treatment of infectious diseases. The amount to be treated will depend upon a variety of factors, such as the intended use, the mode of administration, the recipient, the type and severity of the condition or disease being treated, and ultimately the judgment of the physician or veterinarian.

The effective dose described in the present invention is the correct dose that is not toxic to the patient, but does not exclude that in some cases it is forced to administer larger doses that may lead to signs of toxicity, depending on the severity of the disease.

To improve the condition of the patient, a maintenance dose of the medicament of the invention may be administered, if necessary. The dosage or frequency of administration, or both, can then be reduced to a level that maintains the improved condition, depending on the symptoms, and treatment is discontinued when the symptoms have alleviated to the desired level. However, patients may require long-term intermittent treatment due to recurrence of disease symptoms.

One skilled in the art will appreciate that lower or higher doses than those described above may be required. The specific dosage and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the drug employed, the age, body weight, general health, sex, diet, time of administration, rate of secretion, drug combination, the severity and course of the disease, the patient's predisposition to the disease, and the judgment of the treating physician.

According to another aspect of the present invention, there is provided the use of YL-0919 in the manufacture of a medicament for combating infection or infection-related disease, said infection being a viral, chlamydial, mycoplasma, rickettsial, bacterial, spirochete, fungal, helminth infection.

The medicament of the invention can be used for resisting bacterial infection. The type of the bacterium is not particularly limited. Examples of possible bacteria include, but are not limited to, the following: haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, Chlamydia trachomatis, Actinobacillus hemolyticus, Pasteurella koreana, Haemophilus ducreyi, Treponema pallidum, Diplococcus gonorrhoeae, helicobacter pylori, Leptospira rouxii, Borrelia burgdorferi, Campylobacter jejuni, Bacteroides, Bordetella pertussis, Staphylococcus aureus, coagulase-negative staphylococci, enterococcus faecalis, enterococcus faecium, enterococcus casseliflavus, enterococcus durans, Peptostreptococcus, Streptococcus pneumoniae, Streptococcus pyogenes, group A to G streptococci, Streptococcus agalactiae, Streptococcus viridis, Corynebacterium parvum, Mycobacterium microtuberculi, Mycobacterium urealyticum, Listeria, Mycoplasma pneumoniae, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium paratuberculosis, Mycobacterium vaccae, Mycobacterium sakei, Mycobacterium saxiella, Mycobacterium phlei, Mycosphaeophilum, Mycobacterium sarmentum, and Mycosphacoenobilis, and combinations thereof, Mycobacterium tuberculosis, Cryptosporidium, Clostridium and/or Clostridium perfringens of Testudinis.

In a specific embodiment of the invention, the bacterium is listeria.

The medicine of the present invention may be used in resisting viral infection. There is no particular limitation on the type of virus. Examples of possible viruses include, but are not limited to, viruses consisting of: poxviridae, herpesviridae, adenoviridae, Papilomaviridae (Papilomaviridae), Polyomaviridae (Polyomaviridae), parvoviridae, hepadnaviridae, retroviridae, reoviridae, filoviridae, paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Orthoviridae, arenaviridae, Coronaviridae, picornaviridae, Hepeviridae, mosaic viridae, Astroviridae (Astroviridae), Togaviridae, Flaviviridae, Deltaviridae (Deltavirus), Bornaviridae (Bornaveridae) and prions.

In a particular embodiment of the invention, the virus is of the Rhabdoviridae family.

Further, the virus is vesicular stomatitis virus.

Infection-related diseases described in the present invention include, but are not limited to, the following diseases: respiratory system infection diseases, urinary system infection diseases, digestive system infection diseases, bone joint infection diseases, central nervous system infection diseases, cardiovascular system infection diseases, blood infection diseases, reproductive system infection diseases, skin and soft tissue infection diseases, operation site infection diseases, five sense organs and oral system infection diseases, and systemic infection diseases.

Further, the respiratory infectious diseases include, but are not limited to, middle respiratory tract infection, tracheitis, bronchitis, pneumonia, other respiratory infections; urinary system infectious diseases include, but are not limited to, symptomatic urinary tract infections, asymptomatic bacteriuria, urinary system other infections (kidney, ureter, bladder, urethra); digestive infectious diseases include, but are not limited to, gastroenteritis, gastrointestinal infections (esophagus, stomach, large and small intestine, rectum), hepatitis, intra-abdominal infections (gallbladder, biliary tract, liver, spleen, peritoneum, subphragmatic tissue or other abdominal tissues), necrotic enteritis in infants; joint infectious diseases of the bone include, but are not limited to, osteomyelitis, joint or synovial infection, disc infection; central nervous system infectious diseases include, but are not limited to, intracranial infections (brain abscesses, subdural/external infections, encephalitis), meningitis, meningoencephalitis, ventriculitis, meningoencephalic inflammatory intraspinal abscesses; cardiovascular system infectious diseases include, but are not limited to, arteriovenous infections, endocarditis, myocarditis, pericarditis, mediastinal infections; blood-borne infectious diseases include, but are not limited to, laboratory-proven blood infections, clinical sepsis; reproductive system infectious diseases include, but are not limited to, uterine infections, adnexal infections, pelvic infections, vulvar incision infections, vaginal wall infections, other infections of the reproductive tract (epididymis, testis, prostate); skin and soft tissue infectious diseases include, but are not limited to, soft tissue infections (necrotizing fasciitis, infectious gangrene, necrotizing cellulitis, lymphadenitis/canalitis, infectious myositis), bedsores (superficial and deep tissue infections), burn tissue infections, breast abscesses or mastitis, umbilicitis, infant impetigo; surgical site infections include, but are not limited to, surgical incision infections, deep tissue infections of surgical incisions; infectious diseases of the five sense organs and oral system include, but are not limited to, ear infections (otitis externa, otitis media, otitis interna, mastoiditis), sinusitis, pharyngitis, laryngitis, infections of the oral cavity, conjunctivitis, keratitis, intrabulbar infections; systemic infectious diseases are infections of multiple systems or organs.

In a specific embodiment of the present invention, the infection-related disease is a central nervous system infectious disease.

Further, the central nervous system infectious diseases include encephalitis, meningitis, meningoencephalitis.

Further, the meningitis includes bacterial meningitis, viral meningitis, tubercular meningitis, cryptococcal meningitis.

Further, the meningitis is bacterial meningitis.

Further, the bacterial meningitis includes purulent meningitis and non-purulent meningitis.

Further, the bacterial meningitis is purulent meningitis. In a specific embodiment of the invention, the pyogenic meningitis is listerial meningitis.

Further, the encephalitis includes bacterial encephalitis, viral encephalitis, rickettsial encephalitis, and parasitic encephalitis.

Further, the encephalitis is a viral encephalitis. In a specific embodiment of the invention, the viral encephalitis is a vesicular stomatitis virus encephalitis.

The invention has the advantages and beneficial effects that:

the invention discovers that YL-0919 can be used for resisting infection for the first time, and provides a new angle and a new method for treating clinical infection.

The invention researches the new function of YL-0919 by using a mouse model, so the experimental result is credible and a favorable support is provided for clinical application.

Drawings

FIG. 1 is a graph of the body weight measurement assay after YL-0919 treatment of bacterial meningitis mice;

FIG. 2 is a graph of the clinical score analysis after YL-0919 treatment of bacterial meningitis mice;

FIG. 3 is a graph of survival analysis of YL-0919 treated mice with bacterial meningitis;

FIG. 4 is a graph of survival analysis after YL-0919 treatment of mice infected with VSV (vesicular stomatitis virus).

Detailed Description

The present invention is further illustrated below with reference to specific examples, which are intended to be illustrative only and are not to be construed as limiting the invention. Those of ordinary skill in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents. The following examples are examples of experimental methods not indicating specific conditions, and the detection is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturers.

Example 1 investigation of the Effect of YL-0919 against bacterial infection

Firstly, experimental materials:

(1) the instrument comprises the following steps: 25 μ L microsyrinths (Shanghai Tingn microsyrinths), 5ml syringes, foam boards, electronic weight scales (Beijing Kaiyouchun Biotech Co., Ltd.), constant temperature shaker THZ-C (Suzhou peying laboratory instruments Co., Ltd.), low speed centrifuge (Thermo Co.), clean bench (Qingdao Haier Co., Ltd.), biosafety cabinet (Qingdao Haier Co., Ltd.), CO2 incubator (Thermo Co., Ltd.).

(2) Bacteria: listeria (l. monocytogenes-OVA) (gifted by professor of the military cognition and brain science institute, zhanji rock, military medical institute, academy of military science).

(3) Drugs and major agents: brain Heart Infusion Agar (BHIA) (Beijing Karnuochun spring Biotechnology Co., Ltd.), normal saline for injection (national drug chemical Co., Ltd.), hydroxypiprepin hydrochloride (YL-0919) (provided by professor Liyunfeng, institute of military cognition and Brain science).

(4) Animals: male C57BL/6 mice were purchased from Spbefu (Beijing) Biotechnology, Inc., SPF grade, weighing 19-22 g, for 6-8 weeks, placed in a 12-hour light/dark cycle, provided with freely accessible food and water, and acclimatized for 5 days.

Second, Experimental methods

(1) Preparation of bacterial suspensions

Listeria monocytogenes was inoculated into Brain Heart Infusion Agar (BHIA) medium at 37 deg.C with 5% CO₂Culturing overnight in a constant temperature incubator, inoculating single colony into 5ml brain heart lipid extract at 220r/min and 37 deg.C, shaking for 18.5 hr, taking out 1ml bacterial solution, adding 4ml brain heart lipid extract at 220r/min and 37 deg.C, and shaking for 18.5 hr. Centrifuging 1ml bacterial solution (1000r/min), washing with physiological saline, centrifuging, and diluting bacterial solution to 10 times⁵CFU/ml。

(2) Bacterial meningitis model construction

A mouse fixing plate is manufactured by self, a 10ml injector is fixed on the plate, the head and the trunk of a mouse can form 120 degrees, macropores of an occipital bone are exposed, and a proper Listeria meningitis mouse model is constructed by a method of injecting Listeria bacteria through a medulla oblongata pool. Mice were evaluated for clinical score (according to evaluation criteria 1 of Diederik van de Beek), survival curve, and weight change.

(3) Design of experiments

a. Study if YL-0919 has an anti-bacterial effect: after the bacterial meningitis model was constructed, the experimental mice were divided into 3 groups (NaCl, Anti-Tim-3-Ab, YL-09195 mg/kg). Intraperitoneal injections of 200 μ L Nacl, Anti-Tim-3-Ab, YL-0919 were given every 24h after modeling for 7 days, and then the endpoints were observed.

b. Study of treatment dose of YL-0919: after the bacterial meningitis model was constructed, the experimental mice were divided into 4 groups (NaCl, YL-09192.5mg/kg, 5mg/kg, 10 mg/kg). Intraperitoneal injection of 200 μ LNacl, YL-0919 at three doses, was given every 24h after modeling, and dosing continued for 7 days to the observed endpoint.

(4) Mouse survival curve, observation of body constitution

Body mass and time to death were recorded daily after cisterna bulbifera injection.

(5) Mouse clinical scoring index

The clinical course is divided into prophase (from inoculation time to clinical score of less than or equal to 10 points) and symptomatic phase (from clinical score of 10-15 points until death).

TABLE 1 mouse clinical Scoring criteria

(6) Statistical analysis

The difference is statistically significant by adopting Graphpadvarim 8 software for mapping and using one-factor anova to test the level P < 0.05.

(7) Results of the experiment

As shown in fig. 1-3, mice in the group given YL-0919 had significantly higher body weight, significantly lower clinical score, and significantly higher survival rate compared to the NaCl control group, indicating that YL-0919 had a clear effect against bacterial infection, and that YL-0919(10mg/kg) was the most significant against bacterial infection.

Example 2 investigation of the Effect of YL-0919 against viral infection

First, experimental materials and instruments: VSV (Beijing coordination Hospital), C57BL/6 female 6-8 week mouse, microinjector, sodium pentobarbital, drill needle, brain stereotaxic apparatus, MC-5 micromanipulator.

Second, Experimental methods

(1) VSV viral encephalitis model establishment

Anesthetizing the mouse with 1% sodium pentobarbital (8 μ L/g), 3-5 min later, cutting off the head skin, exposing the skull, fixing the mouse in a cerebral stereotaxic apparatus with bregma as the center zero point, 1.2mm lateral opening, 0.7mm posterior bregma, and a depth of 2mm, drilling the location with an electric drill, and injecting VSV virus (1 × 10) with a microinjector⁶pfu/g), 2 mu L/8 min/piece is injected, and after the injection is finished, the injector stays for 5min and is taken out.

a. Animal anesthesia: c57BL/6 mice, females, weighing 18-20g, were slowly injected with 1% sodium pentobarbital as an intraperitoneal anesthetic, and the status of the animals was noted at any time.

b. Fixing the head of the mouse: the incisor teeth of the mouse are fixed on the upper jaw fixer of the brain locator, and then the ear rod at one side is pushed into the outer channel of the animal, so that the head of the animal is positioned in the middle of the two slide ways. The other ear rod is pushed into the external auditory canal on the other side. At this moment, after the scales of the two ear rods are observed to be consistent, the fixing screws on the two ear rods are screwed tightly, the nose ring is pressed down on the tooth fixer and then screwed tightly (the tightness of the nose ring and the ear rods is adjusted to be good), and the head of the animal is pushed and pressed from all directions at this moment without moving.

c. Skin preparation before craniotomy and drilling: the hair of the animal head was cut off, the skin of the head was sterilized with a 75% alcohol cotton swab, a 3cm long skin incision was made along the sagittal suture, the subcutaneous tissue was separated, and the bregma, the herringbone suture and the sagittal suture were exposed.

d. Determining a standard centerline: the metal positioning needle is moved downwards to the upper part of the sagittal suture, and then the positioning needle is moved forwards and backwards to position the positioning needle to the bregma.

e. Mouse ventricle localization: a point is positioned at 0.7mm behind bregma and 1.2mm beside the sagittal suture by using a positioning needle, namely the plane position of the ventricles of brain, and then a small round hole is drilled on the skull by using a drilling needle at the point.

f. And (3) virus injection: the mouse ventricle is 2mm below the round hole, a 2 μ L syringe is sucked into the VSV and placed on the MC-5 micromanipulator, the injection of the VSV is completed when the syringe needle is lowered 2mm from the mouse brain bore, and the VSV virus (1X 10 VSV) is injected⁶pfu/g), 2 muL/8 min/piece, after the injection is finished, the injector stays for 5min and then is taken out.

(2) Design of experiments

Establishing a viral encephalitis model by intracerebral infection of VSV virus in C57BL/6 mice at 6-8 weeks with an infection dose of 1 × 10⁶pfu/g; treatment was given by intraperitoneal injection of YL-0919(10mg/kg) at the same time as infection, and administration was continued daily for 7 days, and the survival rate of mice was observed.

Third, experimental results

The experimental results are shown in FIG. 4, and compared with the NaCl control group, the YL-0919(10mg/kg) group remarkably improves the survival rate of the mice, which indicates that the YL-0919 has a definite action of resisting VSV virus infection.

The above description of the embodiments is only intended to illustrate the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications will also fall into the protection scope of the claims of the present invention.

Claims (3)

1. Use of YL-0919 in the manufacture of a medicament for treating a cns infection selected from the group consisting of viral encephalitis and bacterial meningitis, wherein:

   said bacterial meningitis is caused by listeria infection;

   the viral encephalitis is caused by vesicular stomatitis virus infection.
2. 2. The use as claimed in claim 1, wherein the medicament is in the form of tablets, capsules, granules, pills, drop pills, syrups, powders, suppositories, drops, emulsions, injections, solutions or suspensions.
3. 3. The use according to claim 1 or 2, wherein the medicament is in the form of an injection.

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