Pharmaceutical composition for co-treatment with ldrt for treating respiratory viral infection symptoms and method for treating respiratory viral infection symptoms by the co-treatment usin the same

Abstract

The present invention relates to a pharmaceutical composition for treating respiratory viral infections for combination therapy with low-dose radiation therapy and a method for combination therapy of respiratory viral infections using the same. More specifically, the invention relates to a pharmaceutical composition for treating respiratory viral infections for combination therapy with low-dose radiation therapy, comprising a flavonoid compound represented by the following chemical formula (Ia); and a method for combination therapy of respiratory viral infections comprising the steps of: administering the pharmaceutical composition for treating respiratory viral infections, comprising the flavonoid compound represented by the following chemical formula (Ia), to a patient in need thereof; and irradiating a lesion where respiratory viral infection has occurred with a low dose of radiation. Chemical formula (Ia)

Description

Technology Field

[0001] The present invention relates to a pharmaceutical composition for treating respiratory viral infections for combination therapy with low-dose radiation therapy and a method for combination therapy of respiratory viral infections using the same. More specifically, the invention relates to a pharmaceutical composition for treating respiratory viral infections having synergistic anti-inflammatory and viral infection treatment effects when combined with low-dose radiation therapy, and a method for combination therapy of respiratory viral infections using the same. Background Technology

[0002] Inflammatory response is a series of immune responses that inevitably occur due to activated immune cells. When immune cells are exposed to foreign substances, such as microorganisms including bacteria and viruses, or foreign substances, the immune cells become activated and accelerate the inflammatory response. When an inflammatory response occurs due to lipopolysaccharide (LPS), a bacterial inflammatory agent, various pro-inflammatory mediators are produced. These mediators include nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), and prostaglandin E2 (PGE2), produced by cyclooxygenase (COX-2).

[0003] Meanwhile, inflammatory responses to inhaled or endogenous irritants are characterized by a nonspecific increase in vascular permeability and the release of inflammatory inducing factors and chemotactic factors, including histamine, eicosanoids, prostaglandins, cytokines, and chemokines. These factors control the expression and binding of leukocyte-endothelial cell adhesion molecules, thereby increasing the presence of inflammatory cells in the blood.

[0004] Although corticosteroids are widely used to treat such inflammatory diseases, long-term use can cause side effects such as tolerance, cardiovascular disease, and musculoskeletal disorders. Furthermore, the UK National Institute for Health and Clinical Excellence (NICE) has recommended against the use of corticosteroids for pneumonia caused by COVID-19 unless the patient exhibits other symptoms such as asthma or COPD. Consequently, there is a growing demand for more effective new treatments for inflammatory diseases.

[0005] Recently, research is underway to alter the physical, chemical, and physiological properties of natural products by applying radiation technology. While studies have reported increasing the activity, structural changes, or content of specific substances through radiation (Korean Patent No. 2009-0043706), there has not yet been much research regarding the ability to achieve effective anti-inflammatory effects with only small amounts of use. Furthermore, there is a lack of research on combination therapy with radiation. Meanwhile, it has been reported that low-dose radiation therapy (LDRT) for the whole lung is not effective in critically ill patients requiring mechanical ventilation due to pneumonia caused by COVID-19 infection (COVID-19 SCIENTIFIC COMMUNICATION| VOLUME 110, ISSUE 5, P1274-1282, AUGUST 01, 2021, DOI:https: / / doi.org / 10.1016 / j.ijrobp.2021.02.054).

[0006] Therefore, it is expected that a pharmaceutical composition for treating inflammation and a method for treating inflammation using the same, which can achieve more effective anti-inflammatory activity while using a compound with excellent anti-inflammatory effects at a dose below the level at which toxicity occurs, will be usefully applied in related fields. The problem to be solved

[0007] Accordingly, one aspect of the present invention is to provide a pharmaceutical composition for treating respiratory viral infections that exhibits a synergistic effect when combined with low-dose radiation therapy.

[0008] Another aspect of the present invention is to provide a method for the combined treatment of respiratory viral infections using such a pharmaceutical composition for treating respiratory viral infections. means of solving the problem

[0009] According to one aspect of the present invention, a pharmaceutical composition for treating respiratory viral infections is provided, comprising a flavonoid compound represented by the following chemical formula (Ia), for combined treatment with low-dose radiation therapy.

[0010] Chemical formula (Ia)

[0011] According to another aspect of the present invention, a method for the combined treatment of a respiratory viral infection is provided, comprising the steps of: administering a pharmaceutical composition for treating a respiratory viral infection comprising a flavonoid compound represented by the chemical formula (Ia) to a patient in need thereof; and irradiating a lesion where a respiratory viral infection has occurred with a low dose of radiation. Effects of the invention

[0012] According to the pharmaceutical composition for treating respiratory viral infections for combination therapy with low-dose radiation therapy and the method for combination therapy for respiratory viral infections based thereon, more effective anti-inflammatory activity can be obtained while using the flavonoid of the present invention at a dose below the level at which toxicity is expressed, and in particular, since cytokines and chemokines, which are inflammatory mediators that increase due to viral infections, can be effectively suppressed, the hyperinflammatory response caused by viral infections can be effectively controlled. Brief explanation of the drawing

[0013] Figure 1 shows the results of an experiment to confirm the potential to inhibit viral infection when CM1 and CM2 are treated individually. Figure 1(a) shows a representative figure (histogram) of viral nucleoprotein expression analyzed using a flow cytometer, Figure 1(b) shows the results in %, and Figure 1(c) shows the results in MFI (mean fluorescence intensity). Figure 2 shows the results confirming the excellent anti-inflammatory effect of the combination therapy of the present invention in influenza A-infected mice. (Statistical analysis: *p < 0.05, **p < 0.01, and ***p < 0.001) Specific details for implementing the invention

[0014] Hereinafter, preferred embodiments of the present invention will be described with reference to the attached drawings. However, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.

[0015] According to the present invention, a pharmaceutical composition for treating respiratory viral infections for combination therapy with low-dose radiation therapy and a method for combination therapy of respiratory viral infections using the same are provided.

[0016] More specifically, the pharmaceutical composition for treating respiratory viral infections of the present invention is intended for combined treatment with low-dose radiation therapy and comprises a flavonoid compound represented by the following chemical formula (Ia).

[0017] Chemical formula (Ia)

[0018] The flavonoid compound represented by the above chemical formula (Ia) may be included in a pharmaceutically effective amount in a pharmaceutical composition for treating respiratory viral infections.

[0019] The flavonoid compound represented by the formula (Ia) of the present invention may be in the form of a pharmaceutically acceptable salt, and the term "pharmaceutically acceptable salt" as used herein refers to a formulation of the compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The above pharmaceutical salt includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide (bromic acid), hydroiodide (iodic acid), perchloric acid, tartaric acid, etc., organic carboxylic acids like succinic acid, oxalic acid, tartaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc. A compound according to the present invention can be converted into its salt by conventional methods.

[0020] The compound of formula (Ia) of the present invention can be synthesized by any synthesis process widely known in the art. For example, the compound represented by formula (Ia) can be obtained as a product of irradiation of chrysin by irradiating chrysin, by separating it through processes such as liquid chromatography, preparative-HPLC, LC-MS, and NMR after irradiation of chrysin.

[0021] In the present invention, 'low-dose radiation (LDR)' in 'low-dose radiation therapy (LDRT)' is understood to mean radiation with a dose of 0.1 to 5 Gy, and in the present invention, respiratory viral infections can be effectively treated by irradiating LDR together with the administration of a compound of formula (Ia).

[0022] At this time, the radiation that can be used in the present invention may be high-energy X-rays, electron beams, or gamma rays generated in a linear accelerator widely used in external irradiation therapy, and preferably, it is gamma rays. The gamma rays may be emitted from any one radioactive isotope selected from the group consisting of Cobalt (Co)-60, Krypton (Kr)-85, Strontium (Sr)-90, and Cesium (Cs)-137, and preferably, the gamma rays may be Cobalt (Co)-60, but are not limited thereto.

[0023] The above pharmaceutical composition for treating inflammation may be administered together with, before, or after low-dose radiation therapy, for example, the above pharmaceutical composition for treating inflammation may be administered, for example, around 1 hour before or after the time of low-dose radiation irradiation, or administered at least once during a period of more than 1 hour to within 24 hours before low-dose radiation irradiation, or more than 1 hour to within 24 hours after low-dose radiation irradiation.

[0024] In the present invention, "administration" means providing a specific substance to a patient by any appropriate method, and the route of administration of the composition of the present invention may be oral or parenteral through any general route that can reach the target tissue, and preferably parenteral.

[0025] In the present invention, "patient" refers to a human and all other animals having a disease whose symptoms can be improved by administering the composition of the present invention. The composition according to the present invention may be applied not only to humans (for treatment, suppression, or prevention) but also to other commercially useful animals, for example, animals other than humans.

[0026] In the present invention, "pharmaceuticalally effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the level of the effective amount may be determined according to factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0027] The above composition for improving respiratory viral infections comprises a pharmaceutically effective amount of the flavonoid compound of the present invention, and optionally may comprise a pharmaceutically acceptable salt thereof, and by administering such a pharmaceutical composition to a patient, inhibitory, preventive, and therapeutic effects of respiratory viral infectious diseases can be obtained.

[0028] The above composition for improving respiratory viral infections may include a flavonoid compound of formula (Ia) of the present invention in an amount of more than 0.001 weight% and less than or equal to 10 weight% based on the weight of the total composition, for example, 0.01 to 5 weight%, preferably 0.02 to 1 weight%. If the compound of formula (Ia) is less than the above range, the effect of improving viral infections may be negligible, and if it exceeds the above range, there is a possibility of causing toxicity.

[0029] The above respiratory viral infection may be caused by at least one virus selected from metapneumovirus, coronavirus, enterovirus, respiratory syncytial virus, adenovirus, bocavirus, rhinovirus, and influenza virus.

[0030] Meanwhile, the respiratory virus infection of the present invention includes symptoms such as fever, redness, loss of at least one of taste and smell, sputum, cough, sore throat, headache, diarrhea, abdominal pain, abdominal discomfort, hemoptysis, nausea, and shortness of breath caused by these viruses, and may be a respiratory inflammatory disease selected from the group consisting of, for example, asthma, bronchitis, pneumonia, bronchiectasis, tonsillitis, pharyngitis, chronic obstructive pulmonary disease, cystic fibrosis, and pulmonary fibrosis, and may include, for example, pneumonia caused by a virus such as a coronavirus.

[0031] Furthermore, the above pharmaceutical composition for treating respiratory viral infections can be formulated and used in various forms according to conventional methods to suit the intended use, such as oral formulations like powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, or in the form of sterile injectable solutions. It can be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, intramuscular, intradural, rectal, and local administration. Preferably, it is formulated as an injectable preparation administered through a route selected from the group consisting of intravenous, intraperitoneal, subcutaneous, intramuscular, and intradural, so as to be administered via an injection route selected from the group consisting of intravenous, intraperitoneal, subcutaneous, intramuscular, and intradural.

[0032] Examples of suitable carriers, excipients, and diluents that may be included in pharmaceutical compositions for treating such inflammatory diseases include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0033] In addition, the pharmaceutical composition for treating inflammatory diseases may further include fillers, anticoagulants, lubricants, humectants, fragrances, emulsifiers, preservatives, etc.

[0034] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms can be formulated by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., with the pharmaceutical composition for treating inflammatory diseases. In addition, lubricants such as magnesium stearate and talc may also be used in addition to simple excipients. Liquid dosage forms for oral administration include suspensions, liquid formulations, emulsions, syrups, etc., and may include various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.

[0035] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for injectables, conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives may be included.

[0036] By administering the composition of the present invention to a patient along with low-dose radiation, respiratory viral infections, particularly inflammatory diseases caused by respiratory viruses, can be suppressed, prevented, and treated, and the pharmaceutical composition for treating inflammatory diseases of the present invention is administered in a pharmaceutically effective amount.

[0037] The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents or treatment methods, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by taking all of the above-mentioned factors into consideration, and this can be easily determined by a person skilled in the art.

[0038] The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition and weight, age, degree of disease, drug form, route of administration, and duration, and may be appropriately selected by those skilled in the art.

[0039] However, since the dosage may be increased or decreased depending on the route of administration, severity of the disease, gender, body weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0040] According to another aspect of the present invention, a method for the combined treatment of a respiratory viral infection is provided, said method for the combined treatment of a respiratory viral infection comprises the steps of: administering a pharmaceutical composition for treating a respiratory viral infection comprising a flavonoid compound represented by the following chemical formula (Ia) to a patient in need thereof; and irradiating a lesion where a respiratory viral infection has occurred with a low dose of radiation.

[0041] Chemical formula (Ia); and

[0042] The contents described above in relation to the pharmaceutical composition for treating respiratory viral infections apply equally to the combination treatment method for respiratory viral infections.

[0043] In the combination treatment method for respiratory viral infections according to the present invention, the lesion where the respiratory viral infection has occurred and to which low-dose radiation is irradiated refers to a site of tissue and / or organ where symptoms have manifested due to a respiratory virus; however, the site and number of lesions are not particularly limited and may be applied to one lesion or two or more lesions, and the size of the lesion site is also not particularly limited.

[0044] The combination therapy method of the present invention exhibits excellent therapeutic effects on viral infections and anti-inflammatory activity, while significantly reducing cytotoxicity to patients, so it can be effectively applied to the treatment of related diseases; furthermore, it is expected that the development of treatment methods for various viral infections and inflammatory diseases based on the present invention will be possible.

[0045] The present invention will be explained in more detail below through specific embodiments. The following embodiments are merely examples to aid in understanding the present invention and do not limit the scope of the present invention.

[0046] Examples

[0047] 1. Preparation of flavonoid compounds

[0048] (1) Chemical formula (Ia) Compound (CM1)

[0049] Chrysine was dissolved in DMSO at a concentration of 25 mg / mL, diluted in methanol to a concentration of 1 mg / mL, and irradiated in a Cobalt-60 gamma irradiation facility at a total absorbed dose of 50 kGy (10 kGy per hour). Subsequently, the flavonoid compound represented by the following chemical formula (Ia) was separated and purified using Prep-HPLC (preparative-high performance liquid chromatography). For separation and purification, an Agilent Eclipse XDB-C18 (7 μM pore, inner diameter 21.2 mm x length 150 mm) column and solvent A (distilled water containing 0.1% formic acid) and solvent B (methanol) were used. Purification was performed after adjusting the solvent gradient conditions based on solvent B to 0 min (20%), 5 min (20%), 12 min (40%), 25 min (55%), 30 min (80%), and 38 min (80%). Compound of chemical formula (Ia) was obtained under solvent gradient conditions of approximately 17-19 minutes. After removing methanol from the obtained compound (Ia) using a rotary evaporator, it was freeze-dried to produce a powder.

[0050] Chemical formula (Ia)

[0051] The chemical formula of the above compound is C 17 H 16 It is represented as O5, and its chemical name is 5,7-dihydroxy-3-(2-hydroxyethyl)-2-phenylchroman-4-one. In this specification, the compound is also referred to as CM1, the compound of chemical formula (Ia), or the compound of the present invention.

[0052] After dissolving the compound of chemical formula (Ia) above in PBS containing 1% DMSO and 0.5% Tween 20, CM1 was administered at a concentration of 3 mg / kg in the combination therapy experiment of 2. below.

[0053] (2) Comparative example compound (CM2)

[0054] A chrysin solution was prepared by dissolving chrysin powder in methanol at a concentration of 1 mg / mL. The chrysin was then irradiated with gamma rays at 50 kGy at room temperature in the Cobalt-60 gamma irradiation facility installed at the Advanced Radiation Research Institute of the Korea Atomic Energy Research Institute. Subsequently, a flavonoid compound represented by the following chemical formula (Ib) was separated and purified using Prep-HPLC (preparative-high performance liquid chromatography). For the separation and purification, an Agilent Eclipse XDB-C18 (7 μM pore, inner diameter 21.2 mm x length 150 mm) column, solvent A (distilled water containing 0.1% formic acid), and solvent B (methanol) were used. Purification was performed after adjusting the solvent gradient conditions based on solvent B to 0 min (20%), 5 min (20%), 12 min (40%), 25 min (55%), 30 min (80%), and 38 min (80%). A compound with the chemical formula (Ib) was obtained under solvent gradient conditions of approximately 22-23 min. The obtained (Ib) compound was prepared in powder form by removing methanol using a rotary evaporator and then freeze-drying.

[0055] Chemical formula (Ib)

[0056] The chemical formula of the above compound is C 17 H 16 It is represented as O5, and its chemical name is 4-(hydroxymethoxy)-2-phenyl-4H-cromen-5,7-diol (4-(hydroxymethoxy)-2-phenyl-4H-cromen-5,7-diol), and in this specification, the compound is also referred to as CM2, the comparative example compound, or the compound of chemical formula (Ib).

[0057] After dissolving the compound of chemical formula (Ib) above in PBS containing 1% DMSO and 0.5% Tween 20, CM2 was administered at a concentration of 20 mg / kg in the combination therapy experiment of 2. below.

[0058] 2. Confirmation of viral inhibitory ability upon treatment with flavonoid compounds alone

[0059] Experiments were conducted to confirm the possibility of inhibiting viral infection when CM1 and CM2 obtained in 1. above were treated individually.

[0060] Human bronchial epithelial cells, A549, were infected at a concentration of 5 MOI (multiplicity of infection) and then treated with compounds of chemical formulas (Ia) and (Ib), respectively, and cultured for 24 hours. At this time, chemical formulas (Ia) and (Ib) were dissolved in DMSO at 10 mg / mL and then diluted in PBS (phosphate buffered saline) to treat at each concentration. Subsequently, each treated cell was harvested, fixed with 4% paraformaldehyde for 30 minutes, and permeated with 0.1% Triton-X100 for 5 minutes. After blocking with 2% BSA (bovine serum albumin) for 30 minutes, the cells were stained at room temperature for 30 minutes using FITC-conjugated anti-influenza A virus nucleoprotein (NP) antibody. Afterward, the degree of inhibition of the intracellular influenza virus and the expression rate of the viral nucleoprotein (NP) were analyzed using a flow cytometer.

[0061] As a result, in the group treated with compound (CM1) of formula (Ia), no reduction in intracellular viral NP protein occurred, while in the group treated with compound (CM2) of formula (Ib), it was confirmed that the intracellular NP expression rate was effectively reduced (Fig. 1). Fig. 1(a) shows a representative figure (histogram) representing the NP protein expression levels of each group, where 'Con' represents the untreated group and 'Vechicle' represents the 0.5% DMSO control group; in contrast, CM1 represents the groups treated with CM1 and the virus at each concentration, and CM2 represents the groups treated with CM2 and the virus at each concentration. At this time, CM1 and CM2 were dissolved in DMSO, and to prevent DMSO-induced cytotoxicity, they were diluted in PBS to ensure the DMSO concentration was 0.5% or less. Fig. 1(b) shows the results in %, and Fig. 1(c) shows the results in MFI (mean fluorescence intensity).

[0062] The results of this experiment indicate that while compound Ia has no inhibitory effect on viral infection when treated alone, compound Ib demonstrates excellent inhibitory ability against the influenza virus when treated alone.

[0063] 3. Combination therapy for inflammation

[0064] 8-week-old female BALB / c mice were anesthetized by intraperitoneal administration of 2,2,2-tribromoethanol, and then 30 HAU (hemagglutination units) of influenza A virus were administered intranasally.

[0065] Low-dose radiation therapy (LDRT) was administered 24 hours after infection in mice. After anesthetizing mice by intraperitoneal administration of a mixture of 100 mg / kg ketamine and 10 mg / kg xylazine, the chest was locally irradiated using a lead block 3.5 cm in diameter and 2.5 cm in thickness. Mouse irradiation was 137 The procedure was performed using a Cs gamma irradiator (Gamma cell-40) at a dose of 1.8 Gy.

[0066] The CM1 and CM2 obtained in 1. above were administered intraperitoneally a total of three times, 4 hours (1 time), 26 hours (2 times), and 48 hours (3 times) after mouse influenza infection, respectively, and LDRT was administered 2 hours before the 2nd time, that is, 24 hours after influenza infection.

[0067] 4. Confirmation of the efficacy of combination therapy for inflammation

[0068] Three days after mouse infection, mice were sacrificed to obtain bronchoalveolar lavage fluid (BALF). After connecting an SCM IV catheter to the airway, BALF was obtained by washing twice with 500 μL of PBS (phosphate buffered saline). Subsequently, the supernatant was separated by centrifugation at 400 xg at 4 ℃ for 5 minutes.

[0069] To analyze cytokines and chemokines in BALF, levels of interleukin 6 (IL-6), interleukin 10 (IL-10), TNF (tumor necrosis factor)-α, KC (keratinocyte-derived chemokine), MCP (monocyte chemoattractant protein)-1, and RANTES in mouse BALF were analyzed using a cytometric bead assay kit.

[0070] 1 μL of each capture bead and 24 μL of capture bead buffer from the Mouse / Rat Soluble Protein Master Buffer Kit were mixed into 50 μL of the BALF supernatant and incubated in a dark room for 1 hour. Afterward, PE-fluorescent beads were added and incubated in a dark room for 1 hour. After washing twice with wash buffer, the results were measured using a flow cytometer. TGF (Transforming growth factor)-β was analyzed using an ELISA kit (Sandiwich ELISA method).

[0071] As a result, it was confirmed that the levels of early inflammatory cytokines (IL-6 and TNF-α) and chemokines (KC, MCP-1, and RANTES) in the BALF of mice infected with influenza A were observed to be low in the CM1 and LDRT combination treatment group. In addition, the levels of the anti-inflammatory cytokines IL-10 and TGF-β were observed to be highest in the CM1 and LDRT combination treatment group. These results indicate that the inflammatory response caused by respiratory viral infection can be controlled synergistically in the CM1 and LDRT combination treatment group compared to the CM1 and LDRT monotherapy groups. Furthermore, it was confirmed that the combination showed superior efficacy compared to the case where Tamiflu, a widely known treatment for influenza virus infection, was dissolved in mouse drinking water and administered orally at a dose of 100 mg / kg as a positive control (Fig. 2).

[0072] Meanwhile, in the case of the CM2 compound, it was confirmed that the pneumonia relief effect was reduced in the CM2 and LDRT combined treatment group compared to the CM2 alone treatment group, so it was possible to conclude that when low-dose radiation is combined with a compound that has an anti-inflammatory effect, the effect may actually be reduced.

[0073] As such, although CM1 and CM2 are compounds known to have anti-inflammatory effects, the effects when combined with LDRT are completely different, confirming that the combined administration of the present invention exhibits an unexpected synergistic anti-inflammatory effect.

[0074] Although embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and it will be obvious to those skilled in the art that various modifications and variations are possible within the scope of the technical concept of the present invention as described in the claims.

Claims

Claim 1 It includes a flavonoid compound represented by the following chemical formula (Ia), and Chemical formula (Ia) Pharmaceutical composition for treating influenza A virus-induced bronchitis for use in combination with low-dose radiation therapy. Claim 2 A pharmaceutical composition for treating influenza A virus-induced bronchitis, wherein, in claim 1, the pharmaceutical composition is administered together with, before, or after low-dose radiation therapy. Claim 3 A pharmaceutical composition for treating influenza A virus-induced bronchitis according to claim 1, wherein the low-dose radiation therapy is performed at a dose of 0.1 to 5 Gy. Claim 4 In claim 1, the pharmaceutical composition for treating influenza A virus-induced bronchitis is formulated as an injectable preparation administered via a route selected from the group consisting of intravenous, intraperitoneal, subcutaneous, intramuscular, and intradural. Claim 5 delete Claim 6 delete Claim 7 A step of administering a pharmaceutical composition for treating influenza A virus-induced bronchitis comprising a flavonoid compound represented by the following chemical formula (Ia) to a patient in need thereof: A method for the combined treatment of influenza A virus-induced bronchitis, comprising: a chemical formula (Ia); and a step of irradiating a lesion where influenza A virus-induced bronchitis has occurred with a low dose of radiation, wherein the patient is an animal other than a human. Claim 8 delete Claim 9 A method for the combined treatment of influenza A virus-induced bronchitis according to claim 7, wherein the administering step is performed together with, before, or after the step of irradiating with a low dose of radiation. Claim 10 A method for the combined treatment of influenza A virus-induced bronchitis, wherein, in claim 7, the step of irradiating with radiation is performed with a dose of 0.1 to 5 Gy. Claim 11 A method for the combined treatment of influenza A virus-induced bronchitis according to claim 7, wherein the pharmaceutical composition is administered by injection via a route selected from the group consisting of intravenous, intraperitoneal, subcutaneous, intramuscular, and intradural. Claim 12 delete Claim 13 delete

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