WO2014013664A1 - インフルエンザウイルス感染症の予防・治療剤 - Google Patents
インフルエンザウイルス感染症の予防・治療剤 Download PDFInfo
- Publication number
- WO2014013664A1 WO2014013664A1 PCT/JP2013/003486 JP2013003486W WO2014013664A1 WO 2014013664 A1 WO2014013664 A1 WO 2014013664A1 JP 2013003486 W JP2013003486 W JP 2013003486W WO 2014013664 A1 WO2014013664 A1 WO 2014013664A1
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- WO
- WIPO (PCT)
- Prior art keywords
- iron
- influenza virus
- group
- virus infection
- therapeutic agent
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- 241000712461 unidentified influenza virus Species 0.000 title claims abstract description 79
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- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 44
- 230000000069 prophylactic effect Effects 0.000 title claims abstract description 15
- 239000008280 blood Substances 0.000 claims abstract description 47
- 210000004369 blood Anatomy 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 31
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- 150000002506 iron compounds Chemical class 0.000 claims abstract description 27
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 47
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
- 235000012631 food intake Nutrition 0.000 claims description 18
- 229910052742 iron Inorganic materials 0.000 claims description 18
- 230000037406 food intake Effects 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- JHYAVWJELFKHLM-UHFFFAOYSA-H tetrasodium;2-hydroxypropane-1,2,3-tricarboxylate;iron(2+) Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O JHYAVWJELFKHLM-UHFFFAOYSA-H 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
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- MDXRFOWKIZPNTA-UHFFFAOYSA-L butanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)CCC([O-])=O MDXRFOWKIZPNTA-UHFFFAOYSA-L 0.000 claims description 3
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a preventive and / or therapeutic agent for influenza virus infection, and more particularly, prevention of influenza virus infection comprising 5-aminolevulinic acid (5-ALA) or a derivative thereof or a salt thereof and an iron compound. And / or a therapeutic agent.
- 5-ALA 5-aminolevulinic acid
- Influenza virus infection that causes a global epidemic every year causes mass infection with deaths. Although the effectiveness of anti-influenza virus drug administration has been shown in the early days of virus infection, the effect is halved if the administration time is misjudged.
- therapeutic agents for influenza virus infections clinically used for treating influenza include oseltamivir and zanamivir that inhibit the action of the enzyme neuraminidase present on the surface of influenza virus, amantadine that inhibits M2 protein of influenza virus,
- ribavirin which is a nucleotide drug
- influenza vaccines using immunity are known. There are few effective and safe drugs for influenza virus infections, and the emergence of resistant viruses against them has started to be regarded as a problem, and the development of new preventive and therapeutic drugs for influenza virus infections is expected.
- 5-ALA is known as an intermediate of the tetrapyrrole biosynthetic pathway widely present in animals, plants and fungi, and is usually biosynthesized from succinyl CoA and glycine by 5-aminolevulinic acid synthase.
- Photodynamic therapy or photodynamic therapy using 5-ALA (hereinafter also referred to as “ALA-PDT”) has been developed, and is attracting attention as a treatment method that is low in invasiveness and maintains QOL.
- the tumor diagnosis / treatment agents used have been reported.
- 5-ALA is also known to be useful as an agent for preventing or improving adult diseases, cancer and male infertility (see, for example, Patent Documents 1 to 3).
- An object of the present invention is to provide a prophylactic / therapeutic agent for influenza virus infection that is highly safe for humans, which is effective not only during influenza virus infection but also early infection as well as late infection.
- influenza virus infections The most common treatment for influenza virus infections today is the administration of anti-influenza virus drugs that inhibit viral growth in the body, but unless early administration is performed within 48 hours after infection. Does not respond.
- anti-influenza virus drugs that inhibit viral growth in the body, but unless early administration is performed within 48 hours after infection. Does not respond.
- severe cases such as severe ketosis due to multiple organ failure in addition to influenza encephalopathy.
- Recent studies have shown that the energy metabolism of vascular endothelial cells is a factor of this severity, and along with this, the progression from peripheral circulatory failure to multiple organ failure has become clear.
- the currently effective treatment is only the administration of an anti-influenza virus drug at an early stage of infection, and there is no safe therapeutic drug that prevents energy metabolism deficiency at the late stage of infection.
- the present inventors have conceived that administration of 5-ALA and an iron compound can prevent severe influenza caused by the breakdown of internal energy metabolism, and using influenza model mice, As a result of being able to prevent the decrease in food intake, water intake, body weight and body temperature due to the above, and avoiding the seriousness of influenza, it can improve the increase in the amount of ketone body in the blood and decrease the amount of ATP in the blood It has been found that improving the survival rate, improving the survival rate, and improving the abnormal body surface temperature, and has completed the present invention.
- the present invention provides [1] a prophylactic and / or therapeutic agent for influenza virus infection comprising a compound represented by the following formula (I) or a salt thereof: (Wherein R 1 represents a hydrogen atom or an acyl group, and R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group) or [2] R 1 And R 2 is a hydrogen atom, the preventive and / or therapeutic agent for influenza virus infection according to the above [1], and [3] further containing an iron compound [ 1) or [2] preventive and / or therapeutic agent for influenza virus infection, and [4] iron compound is ferric chloride, iron sesquioxide, iron sulfate, ferrous pyrophosphate, ferrous citrate Iron, sodium iron citrate, sodium ferrous citrate, ammonium iron citrate, ferric pyrophosphate, iron lactate, ferrous gluconate, sodium iron diethylenetri
- the present invention relates to a preventive and / or therapeutic agent for influenza virus infection according to any one of [7].
- Other aspects of the invention relating to the preventive and / or therapeutic agent for influenza virus infection include compounds represented by the above formula (I) or salts thereof for preventing and / or treating influenza virus infection, A compound represented by the above formula (I) or a salt thereof for use in the prevention and / or treatment of infectious diseases can be exemplified.
- the present invention also provides [9] a method for preventing and / or treating an influenza virus infection, comprising administering to the subject the preventive and / or therapeutic agent according to any one of [1] to [8], [10] a) Compound represented by the above formula (I) or a salt thereof (wherein R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a linear or branched alkyl group, cycloalkyl) A kit for the prophylaxis and / or treatment of influenza virus infections comprising: a group, an aryl group or an aralkyl group); b) an iron compound; or [11] a) a compound represented by the above formula (I) or a compound thereof Salt (wherein R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group); b
- the present invention also provides [12] a) a preventive and / or therapeutic agent for influenza virus infection according to any one of [1] to [8] above; and b) an anti-influenza agent.
- the present invention relates to [14] a compound represented by the above formula (I), wherein R 1 represents a hydrogen atom or an acyl group, R 2 represents a hydrogen atom, a linear or branched alkyl group, cycloalkyl Group, an aryl group, or an aralkyl group) or a salt thereof.
- R 1 represents a hydrogen atom or an acyl group
- R 2 represents a hydrogen atom, a linear or branched alkyl group, cycloalkyl Group, an aryl group, or an aralkyl group
- a salt thereof which comprises administering to the subject a compound represented by the above formula (I) or a salt thereof. Examples thereof include compounds represented by the above formula (I) or salts thereof.
- a highly safe preventive and / or therapeutic agent for influenza virus infection that prevents a decrease in food intake, water intake, body weight, and body temperature in a subject, avoids severe influenza, and improves survival rate.
- the compound represented by the above formula (I) or a salt thereof (hereinafter sometimes collectively referred to as “ALAs”) is used as an active ingredient. It is not particularly limited as long as it contains, but preferably contains an iron compound in addition to ALAs, and further improves (prevents) reduction in food intake, water intake and / or body weight, and causes ketosis. To improve (decrease) the increase in blood ketone body level, improve (prevent) the decrease in blood ATP level, or improve (increase) abnormalities in survival rate and / or body surface temperature For this purpose, those that can be used are preferred.
- the method for preventing and / or treating influenza virus infection of the present invention comprises administering the agent for preventing and / or treating influenza virus infection of the present invention to subjects such as livestock, poultry and pets in addition to humans. It is characterized by.
- the kit for preventing and / or treating influenza virus infection of the present invention is not particularly limited as long as it is a kit that individually contains ALAs and an iron compound as active ingredients.
- ALAs and an iron compound as active ingredients.
- the kit of the present invention is limited to use as a kit for prevention and / or treatment of influenza virus infection.
- the kit for prevention and / or treatment of influenza virus infection of the present invention generally includes components used in this type of prevention and / or treatment kit, such as carriers, pH buffers and stabilizers, as well as handling. Attached documents such as instructions are usually included.
- the method for preventing and / or treating influenza virus infection according to the present invention using the kit for preventing and / or treating influenza virus infection according to the present invention comprises the steps of: In addition, it is administered to subjects such as livestock, poultry and pets.
- the combination of the preventive and / or therapeutic agent of the present invention includes a combination of a prophylactic / therapeutic agent of the above-mentioned preventive and / or therapeutic agent for influenza virus infection of the present invention and an anti-influenza drug, ALA If it is a combination of a prophylactic / therapeutic drug of a class, an iron compound, and an anti-influenza drug, it is not particularly limited, and it is also possible to prevent and / or prevent influenza virus infection by administering a combination of these prophylactic / therapeutic drugs. Can be treated. Each formulation (component) of these combinations can be administered simultaneously or separately.
- the blood ketone body increase inhibitor of the present invention is not particularly limited as long as it contains ALA as an active ingredient, but preferably contains an iron compound in addition to ALA. Moreover, it can also be set as the kit for suppression of the increase in the amount of ketone bodies in blood which contains ALA and an iron compound as an active ingredient separately. Such kits usually include components used in this type of kit, for example, carriers, pH buffering agents, stabilizers, and package inserts such as instruction manuals.
- the above-mentioned blood ketone body increase inhibitor is administered to the subject, or a kit for suppressing increase in blood ketone body is used. By administering to subjects such as poultry and pets, an increase in blood ketone body mass can be suppressed.
- 5-ALA is one of the amino acids also called ⁇ -aminolevulinic acid.
- R 1 in the formula (I) is a hydrogen atom or an acyl group
- R 2 in the formula (I) is a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group
- compounds other than 5-ALA, which is an aralkyl group can be mentioned.
- acyl group in the formula (I) examples include linear or branched alkanoyl groups having 1 to 8 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, benzylcarbonyl group, etc. And aroyl groups having 7 to 14 carbon atoms such as benzoyl, 1-naphthoyl and 2-naphthoyl groups.
- alkyl group in the formula (I) examples include linear or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl groups. Mention may be made of alkyl groups having 1 to 8 carbon atoms.
- the cycloalkyl group in the formula (I) may have a saturated or partially unsaturated bond such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl group, etc. And a cycloalkyl group having 3 to 8 carbon atoms.
- aryl group in the formula (I) examples include aryl groups having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl, and phenanthryl groups.
- the aryl moiety can be the same as the above aryl group, and the alkyl moiety can be the same as the above alkyl group, specifically, benzyl, phenethyl, phenylpropyl, phenylbutyl, benzhydryl.
- aralkyl groups having 7 to 15 carbon atoms such as trityl, naphthylmethyl, naphthylethyl group, and the like.
- R 1 is formyl, acetyl, propionyl, or butyryl group
- compound said R 2 is methyl, ethyl, propyl, butyl, compound pentyl group
- the R 1 and Preferred examples of the combination of R 2 include formyl and methyl, acetyl and methyl, propionyl and methyl, butyryl and methyl, formyl and ethyl, acetyl and ethyl, propionyl and ethyl, butyryl and ethyl, and the like.
- ALAs only need to act as active ingredients in the state of 5-ALA of formula (I) or a derivative thereof in vivo, and various salts, esters, or biological compounds for increasing solubility depending on the administration form. It can be administered as a prodrug (precursor) that is degraded by enzymes in the body.
- examples of salts of 5-ALA and its derivatives include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and the like.
- acid addition salts include hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, and other inorganic acid salts, formate, acetate, propionate, toluenesulfonic acid Salt, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, malate, etc.
- Organic acid addition salts can be exemplified.
- metal salts include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium and calcium salt, and metal salts such as aluminum and zinc.
- ammonium salts include ammonium salts and alkylammonium salts such as tetramethylammonium salts.
- organic amine salt include salts such as triethylamine salt, piperidine salt, morpholine salt, and toluidine salt. These salts can also be used as a solution at the time of use.
- ALA preferred are various esters such as 5-ALA and 5-ALA methyl ester, 5-ALA ethyl ester, 5-ALA propyl ester, 5-ALA butyl ester, 5-ALA pentyl ester, etc.
- esters such as 5-ALA and 5-ALA methyl ester, 5-ALA ethyl ester, 5-ALA propyl ester, 5-ALA butyl ester, 5-ALA pentyl ester, etc.
- hydrochlorides, phosphates and sulfates can be particularly preferably exemplified.
- the ALAs can be produced by any known method of chemical synthesis, production by microorganisms, or production by enzymes.
- the ALAs may form hydrates or solvates, and any one of them may be used alone or in combination of two or more.
- the iron compound may be an organic salt or an inorganic salt.
- the inorganic salt include ferric chloride, iron sesquioxide, iron sulfate, and ferrous pyrophosphate.
- the organic salt include a carboxylate.
- hydroxycarboxylates such as ferrous citrate, sodium iron citrate, sodium ferrous citrate, ammonium iron citrate, ferric pyrophosphate, iron lactate, gluconic acid
- Ferrous iron sodium diethylenetriaminepentaacetate, ammonium diethylenetriaminepentaacetate, sodium iron ethylenediaminetetraacetate, ammonium irondiaminediaminetetraacetate, sodium iron dicarboxymethylglutamate, ammonium dicarboxymethylglutamate, ferrous fumarate, iron acetate, Iron oxalate, ferrous succinate, iron citrate
- organic acid salts such as lithium, heme iron, dextran iron, triethylenetetraamine iron, lactoferrin iron
- the above iron compounds may be used alone or in admixture of two or more.
- the dose of the iron compound may be 0.01 to 100 times in molar ratio with respect to the dose of ALA (5-ALA conversion), preferably 0.05 to 10 times, preferably 0.1 times. ⁇ 8 times is more desirable.
- influenza virus infection in the method for preventing and / or treating influenza virus infection according to the present invention, it can be administered as a composition containing ALAs and an iron compound, or each can be administered alone or simultaneously.
- each when each is administered alone, it is preferable to administer at the same time.
- administration of ALAs and an iron compound can exert an additive effect, preferably a synergistic effect.
- it is preferable to administer without a considerable interval between the two.
- Anti-influenza drugs such as oseltamivir, zanamivir, amantadine, peramivir, laninamivir, favipiravir and the like for the prevention and / or treatment of influenza virus infection of the present invention and kits for prevention and / or treatment of influenza virus infection
- One type or two or more types can be used in combination. Since the preventive and / or therapeutic agent for influenza virus infection of the present invention and the kit for prevention and / or treatment of influenza virus infection differ from these existing anti-influenza drugs, the influenza of the present invention With the combination of preventive and / or therapeutic agents for viral infections, an additive and possibly synergistic effect can be expected.
- Examples of the method for suppressing the suppression of the increase in the amount of ketone body in blood include a method of administering as a composition containing ALAs and an iron compound, or each of them alone or simultaneously. When each is administered alone, it is preferable to administer at the same time. However, when each is administered alone, administration of ALAs and an iron compound can exert an additive effect, preferably a synergistic effect. Thus, it is preferable to administer without a considerable interval between the two.
- each component of the kit for prevention and / or treatment each component of the combination of prophylactic and therapeutic agents, or the amount of ketone body in the blood
- the route of administration of each component of the increase inhibitor and the increase inhibitor kit includes oral administration including sublingual administration, nasal administration, inhalation administration, intravenous administration including infusion, transdermal administration using a cataplasm, etc., suppository Or parenteral administration such as administration by forced enteral nutrition using a nasogastric tube, nasal intestinal tract, gastric leak tube or enteral leak tube.
- Each of the preventive and / or therapeutic agent for influenza virus infection of the present invention, the dosage form of each component of the kit for prevention and / or treatment, the increase inhibitor of blood ketone body, and the increase suppression kit The dosage form of the component can be appropriately determined according to the administration route described above, but water dissolved in injections, nasal drops, drops, tablets, capsules, fine granules, scattered, liquids, syrups, etc. Agents, poultices, suppositories and the like.
- the agent for preventing and / or treating influenza virus infection of the present invention, each component of the kit for prevention and / or treatment, or each component of the increase inhibitor of blood ketone body and each component of the increase suppression kit are for pharmaceutical use.
- a disintegrating tablet form that rapidly disintegrates in the mouth and a liquid form suitable for nasogastric tube administration are preferable.
- kits for prevention and / or treatment In order to prepare the preventive and / or therapeutic agent for influenza virus infection of the present invention, a kit for prevention and / or treatment, an increase inhibitor of blood ketone body amount, and an increase suppression kit, as necessary.
- Pharmacologically acceptable carriers excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, lubricants, lubricants, flavoring agents, sweeteners, solubilizers, Solvents, gelling agents, nutrients, etc.
- influenza virus infection prevention agent of this invention can be added, specifically water, saline, animal fats and oils, vegetable oils, lactose, starch, gelatin, crystalline cellulose, gum, talc, stearin Examples thereof include magnesium acid, hydroxypropyl cellulose, polyalkylene glycol, polyvinyl alcohol, and glycerin.
- aqueous solution may not become alkaline.
- the decomposition can also be prevented by removing.
- the preventive and / or therapeutic agent for influenza virus infection of the present invention includes humans, It can also be used in veterinary fields such as livestock, poultry and pets.
- the amount, frequency, and duration of administration of such preventive and / or therapeutic agents vary depending on the age, weight, symptom, etc. of the influenza virus infection patient when the subject is a human.
- 0.01 mmol to 25 mmol / day preferably 0.025 mmol to 7.5 mmol / day, more preferably 0.075 mmol to 5.5 mmol / day, and further preferably 0.2 mmol to 2 mmol / day, per adult.
- Day especially 0.45 mmol to 1.3 mmol / day can be mentioned, and the administration frequency can be exemplified by administration once to several times a day or continuous administration by infusion or the like.
- the administration period can be determined by a pharmacologist or clinician in the technical field by a known method, and at that time, the blood ketone body amount or the blood ATP amount can be used as an index.
- mice with severe influenza flu The effect of 5-ALA hydrochloride and ferrous sodium citrate administration on body weight, food intake, water intake, and biochemical parameters in mice with severe influenza flu was investigated. That is, the inhibitory effect of ALA + Fe administration on the phenomenon of water intake, decrease in food intake, and shift from glucose metabolism to lipid metabolism caused by the progression of the pathology of influenza virus-infected / onset mice was examined.
- mice Females of C57BL / 6J mice were purchased from Japan SLC Co., Ltd. at the age of 4 weeks, and visually healthy mice were used for the test on the day of arrival. On the next day of arrival, the group was divided into 3 groups as 10 animals per group by random extraction based on body weight, and further, 1 group was divided into 3 animals, 3 animals, and 4 animals per cage.
- Basic feed MF manufactured by Oriental Yeast Co., Ltd. was freely ingested together with tap water, and was raised in a breeding room with a room temperature of 23 to 24 ° C., a humidity of 30 to 40% and a fluorescent lamp illumination for 12 hours.
- Test group As shown below, it was divided into three groups 1) -3) with or without virus infection or different administration drugs. 1) group; virus non-infected group (CMC oral administration) 10 mice 2) group; virus infection group (CMC oral administration) 10 mice 3) group; virus infection + ALA + Fe administration group 10 mice
- influenza virus PR8 strain solution was administered into the lungs from both nasal passages.
- the viral load was 100 PFU per animal.
- the day of virus infection was Day-0.
- FIG. 4 shows the change in the amount of ketone body in blood in the test group used for the test.
- the value of Day-7 was not changed in 1) non-virus-infected group compared with Day-4, and 3) increased only 25% in the virus-infected and ALA + Fe-treated groups.
- the value of the virus-infected group showed a remarkable increase with an increase of 242%.
- the effect on the survival rate and body surface temperature of 5-ALA hydrochloride and ferrous sodium citrate administration using influenza severe mouse models was investigated. That is, the inhibitory effect by administration of ALA + Fe on the events such as decrease in water intake, food intake and body weight, and increase in blood ketone amount caused in the influenza severe mouse model mice seen in Example 1 above is the survival rate of mice. In addition to body temperature and body temperature, it was verified whether it affected blood ATP levels.
- FIG. 7 shows changes in Day-4 and Day-7 in the blood ATP level of the test group used in the test. 2) The value of Day-7 blood ATP in the virus-infected group was 1) lower than that in the virus-uninfected group. On the other hand, in the case of 3) virus infection and ALA + Fe administration group, Day-7 blood ATP level did not decrease even in Day-7, and showed a high value. In addition, the ATP level in the blood increased compared to Day-4.
- influenza seriousness model mouse infected with influenza virus PR8 strain with low pathogenicity was investigated.
- influenza virus PR8 strain of Example 2 which is a fresh virus immediately after hen egg culture and shows a strong lethality
- influenza which has been stored for 3 to 6 months after culturing at ⁇ 80 ° C. and no longer exhibits a strong lethality was examined using the virus PR8 strain.
- test groups were 1) non-virus-infected group and 2) virus-infected group, except that the influenza virus PR8 strain which does not show a strong lethality compared to the influenza virus PR8 strain of Example 2 was used.
- Viral infection and drug administration were performed in the same manner as in Example 2. In addition, each cage was observed every day, and the ratio of the number of surviving individuals to all individuals was regarded as the survival rate.
- the transition of the survival rate is shown in FIG.
- 2 death cases appeared in Day-8 in the virus-infected group, but after that, the survival rate was maintained at 80%.
- Results of survival rate in this reference example Day-14, survival rate 80%
- survival rate results using the influenza virus PR8 strain of Example 2 Day-14, survival rate 0%; see FIG. 5)
- the influenza virus PR8 strain of Example 2 shows a stronger lethality. From this, even when the influenza virus PR8 strain of Example 2 showing a strong lethality was used, 3) In the virus infection (100 PFU) and ALA + Fe administration groups, the survival rate recovered to 30%. (See FIG. 5).
- influenza virus infection preventive / therapeutic agent of the present invention can be advantageously used in the medical field.
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Abstract
Description
(式中、R1は、水素原子又はアシル基を表し、R2は、水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基又はアラルキル基を表す)や、[2]R1及びR2が、水素原子であることを特徴とする上記[1]記載のインフルエンザウイルス感染症の予防及び/又は治療剤や、[3]さらに、鉄化合物を含有することを特徴とする上記[1]又は[2]記載のインフルエンザウイルス感染症の予防及び/又は治療剤や、[4]鉄化合物が、塩化第二鉄、三二酸化鉄、硫酸鉄、ピロリン酸第一鉄、クエン酸第一鉄、クエン酸鉄ナトリウム、クエン酸第一鉄ナトリウム、クエン酸鉄アンモニウム、ピロリン酸第二鉄、乳酸鉄、グルコン酸第一鉄、ジエチレントリアミン五酢酸鉄ナトリウム、ジエチレントリアミン五酢酸鉄アンモニウム、エチレンジアミン四酢酸鉄ナトリウム、エチレンジアミン四酢酸鉄アンモニウム、ジカルボキシメチルグルタミン酸鉄ナトリウム、ジカルボキシメチルグルタミン酸鉄アンモニウム、フマル酸第一鉄、酢酸鉄、シュウ酸鉄、コハク酸第一鉄、コハク酸クエン酸鉄ナトリウム、ヘム鉄、デキストラン鉄、トリエチレンテトラアミン鉄、ラクトフェリン鉄、トランスフェリン鉄、鉄クロロフィリンナトリウム、フェリチン鉄、含糖酸化鉄、及び硫化グリシン鉄から選ばれる1種又は2種以上の化合物であることを特徴とする上記[3]記載のインフルエンザウイルス感染症の予防及び/又は治療剤や、[5]鉄化合物が、クエン酸第一鉄ナトリウムであることを特徴とする上記[3]記載のインフルエンザウイルス感染症の予防及び/又は治療剤や、[6]摂食量、摂水量、及び/又は体重の低下を改善するために使用することを特徴とする上記[1]~[5]のいずれか記載のインフルエンザウイルス感染症の予防及び/又は治療剤や、[7]血中ケトン体量の増加、及び/又は血中ATP量の低下を改善するために使用することを特徴とする上記[1]~[6]のいずれか記載のインフルエンザウイルス感染症の予防及び/又は治療剤や、[8]生存率の低下及び/又は体表面温度の異常を改善するために使用することを特徴とする上記[1]~[7]のいずれか記載のインフルエンザウイルス感染症の予防及び/又は治療剤に関する。これらインフルエンザウイルス感染症の予防及び/又は治療剤に関する発明の他の態様としては、インフルエンザウイルス感染症の予防及び/又は治療のための上記式(I)で示される化合物又はその塩や、インフルエンザウイルス感染症の予防及び/又は治療に用いるための上記式(I)で示される化合物又はその塩を例示することができる。
(1)動物及び飼育条件
日本SLC株式会社よりC57BL/6Jマウスの雌を4週齢で購入し、入荷当日に視診上健康なマウスを試験に供した。入荷翌日、体重を基に無作為抽出により1群10匹として3群に分け、更に1群を1ケージ当たり3匹、3匹、4匹となるように分けた。オリエンタル酵母株式会社製の基礎飼料MFを、水道水と共に自由に摂取させ、室温23~24℃、湿度30~40%、12時間蛍光灯照明の飼育室において飼育した。
以下に示すとおり、ウイルス感染の有無又は投与薬剤の異なる1)-3)の3群に分けた。
1)群;ウイルス非感染群(CMC経口投与) 10匹
2)群;ウイルス感染群(CMC経口投与) 10匹
3)群;ウイルス感染+ALA+Fe投与群 10匹
ケタラール及びセラクタールによる麻酔下において、インフルエンザウイルスPR8株溶液を両鼻腔より肺へ投与した。ウイルス量は、1匹あたり100PFUとした。本ウイルス感染日をDay-0とした。
各日、AM10:00及びPM17:00に、上記1)群及び2)群には、メチルセルロース溶液(0.5w/v% Methyl Cellulose 400cP Solution,Sterilized:和光純薬)を0.1mL、3)群には5-ALA塩酸塩、クエン酸第一鉄ナトリウムを投与直前にメチルセルロース溶液に溶解調製して、0.1mLをゾンデを用いて胃内に強制投与した。3)群における5-ALA塩酸塩の投与量は、体重1kg当たり15mgを1回量とし、1日あたり体重1kg当たり30mg量とした。また、クエン酸第一鉄ナトリウムの投与量はモル比で5-ALA塩酸塩の0.5倍量となる、体重1kg当たり23.54mgを1回量とし、体重1kg当たり47.08mgを1日量とした。
各ケージを毎日観察し、AM10:00の薬剤投与前に各個体の体重、各ケージあたりの摂食量及び摂水量を測定した。
Day.4及びDay.7に5匹ずつ解剖した。マウスの無麻酔下での断頭により採血し、血液生化学的検査(ケトン体量)を実施した。血中ケトン体量の測定には、「プレシジョンエクシード 3-ヒドロキシ酪酸キット(アボット社)」の測定キットを用いた。
(1)体重の変化
検査に用いた試験群の体重変化を図1に示す。1)ウイルス非感染群、2)ウイルス感染群、3)ウイルス感染、ALA+Fe投与群共に、Day-3までは同様の体重増加が見られた。ところが、2)ウイルス感染群については、Day-4から急激な体重の減少が観察され、観察最終日のDay-7においては、Day-3に比べ約20%の体重減少が見られた。一方、1)ウイルス非感染群においては、Day-5まで体重増加がみられ、その後観察最終日のDay-7まで維持された。3)ウイルス感染、ALA+Fe投与群においては、Day-4まで体重増加が見られ、その後Day-7まで緩やかな減少がみられた。しかしながら、観察最終日のDay-7における体重減少はDay-4に比べ約6%にとどまった。
検査に用いた試験群の摂食量の変化を図2に示す。1)ウイルス非感染群、2)ウイルス感染群、3)ウイルス感染、ALA+Fe投与群共に、Day-2までは同様の摂食量増加が見られた。しかし2)ウイルス感染群については、Day-3でその増加率が他2群に比べ停滞傾向を示し、Day-4から急激な摂食量減少が観察された。観察最終日のDay-7においては、Day-3に比べ約90%の摂食量減少がみられた。一方、1)ウイルス非感染群においては、Day-5まで増加がみられた。3)ウイルス感染、ALA+Fe投与群においては、Day-4まで摂食量増加が見られ、その後Day-7まで緩やかな減少がみられた。しかしながら観察最終日のDay-7における摂食量減少はDay-4に比べ約35%の減少にとどまった。
検査に用いた試験群の摂水量の変化を図3に示す。2)ウイルス感染群については、Day-2までに摂水量の増加は止まり、Day-4には一旦減少した。Day-5では一旦回復したものの、その後急激な減少が見られた。観察最終日のDay-7においては、Day-3に比べ約60%の摂水量減少がみられた。3)ウイルス感染、ALA+Fe投与群においては、Day-6まで摂水量増加が見られ、Day-7で緩やかな減少がみられたが、Day-6に比べ約12%の減少にとどまった。
検査に用いた試験群の血中ケトン体量の変化を図4に示す。血中ケトン体量について、Day-7の値は、Day-4に比べ、1)ウイルス非感染群では変化が無く、3)ウイルス感染、ALA+Fe与群では25%の増加にとどまったが、2)ウイルス感染群の値は、242%の増加と著しい上昇がみられた。
(1)動物及び飼育条件、試験群及び薬剤の投与
動物及び飼育条件、試験群並びに薬剤の投与については実施例1と同様に行った。
ケタラール及びセラクタールによる麻酔下において、鶏卵培養直後の新鮮ウイルスで強い致死率を示すインフルエンザウイルスPR8株溶液を両鼻腔より肺へ投与した(ウイルス実験株の中でもPR8株は最も致死性の高いウイルス株であるが、その中でも培養直後のウイルス株は強い病原性を示す)。ウイルス量は、1匹あたり100PFU又は150PFUとした。本ウイルス感染日をDay-0とした。
各ケージを毎日観察し、全個体に対する生存個体数の割合を生存率とした。また、Day-6以降の、17:00における生存個体の体表面温を測定した。
Day.4及びDay.7に5匹ずつ解剖した。マウスの無麻酔下での断頭により採血し、血液生化学的検査(ATP量)を実施した。血中ATP量の測定には、「XL-ATP kit(アプロサイエンス社)」の測定キットを用いた。
(1)生存率の推移
生存率の推移を図5に示す。ウイルス量150PFUにて感染させると、ALA非投与の2)ウイルス感染群においてはDay-9で、3)ウイルス感染、ALA+Fe投与群においてはDay-10で、全頭死亡した。ウイルス量100PFUにて感染させた場合については、ALA投与の有無でDay-9より生存率に差が発生し、ALA非投与の2)ウイルス感染群はDay-13までに全頭死亡したが、3)ウイルス感染、ALA+Fe投与群は試験期間内に3頭生存した。この結果から、強い致死率を示すインフルエンザウイルスPR8株を用いた場合であっても、生存率が向上することがわかる。
生存しているマウス体表面温の推移を図6に示す。ALA非投与の2)ウイルス感染群においては感染後継続して体温は低下した。死亡個体については24℃台となった翌日に死亡していた。一方、3)ウイルス感染、ALA+Fe投与群においてはDay-9以降、緩やかに回復した。このように、ALA+Feを投与した場合、体表面温度の異常を改善できることがわかる。
検査に用いた試験群の血液中ATP量のDay-4及びDay-7の変化を図7に示す。2)ウイルス感染群のDay-7の血液中ATP量の値は、1)ウイルス非感染群に比べて低い値を示した。一方、3)ウイルス感染、ALA+Fe投与群のDay-7の血液中ATP量の値はDay-7においても低下せず、高い値を示した。また、Day-4に比べても血液中ATP量の値が増加していた。
次に、病原性の低いインフルエンザウイルスPR8株を感染させたインフルエンザ重症化モデルマウスにおける生存率を調べた。すなわち、鶏卵培養直後の新鮮ウイルスで強い致死率を示す実施例2のインフルエンザウイルスPR8株に代えて、培養後-80℃条件下に3~6ヶ月保存経過して強い致死率を示さなくなったインフルエンザウイルスPR8株を用いて生存率を検討した。
Claims (14)
- R1及びR2が、水素原子であることを特徴とする請求項1記載のインフルエンザウイルス感染症の予防及び/又は治療剤。
- さらに、鉄化合物を含有することを特徴とする請求項1又は2記載のインフルエンザウイルス感染症の予防及び/又は治療剤。
- 鉄化合物が、塩化第二鉄、三二酸化鉄、硫酸鉄、ピロリン酸第一鉄、クエン酸第一鉄、クエン酸鉄ナトリウム、クエン酸第一鉄ナトリウム、クエン酸鉄アンモニウム、ピロリン酸第二鉄、乳酸鉄、グルコン酸第一鉄、ジエチレントリアミン五酢酸鉄ナトリウム、ジエチレントリアミン五酢酸鉄アンモニウム、エチレンジアミン四酢酸鉄ナトリウム、エチレンジアミン四酢酸鉄アンモニウム、ジカルボキシメチルグルタミン酸鉄ナトリウム、ジカルボキシメチルグルタミン酸鉄アンモニウム、フマル酸第一鉄、酢酸鉄、シュウ酸鉄、コハク酸第一鉄、コハク酸クエン酸鉄ナトリウム、ヘム鉄、デキストラン鉄、トリエチレンテトラアミン鉄、ラクトフェリン鉄、トランスフェリン鉄、鉄クロロフィリンナトリウム、フェリチン鉄、含糖酸化鉄、及び硫化グリシン鉄から選ばれる1種又は2種以上の化合物であることを特徴とする請求項3記載のインフルエンザウイルス感染症の予防及び/又は治療剤。
- 鉄化合物が、クエン酸第一鉄ナトリウムであることを特徴とする請求項3記載のインフルエンザウイルス感染症の予防及び/又は治療剤。
- 摂食量、摂水量、及び/又は体重の低下を改善するために使用することを特徴とする請求項1~5のいずれか記載のインフルエンザウイルス感染症の予防及び/又は治療剤。
- 血中ケトン体量の増加、及び/又は血中ATP量の低下を改善するために使用することを特徴とする請求項1~6のいずれか記載のインフルエンザウイルス感染症の予防及び/又は治療剤。
- 生存率及び/又は体表面温度の異常を改善するために使用することを特徴とする請求項1~7のいずれか記載のインフルエンザウイルス感染症の予防及び/又は治療剤。
- 請求項1~8のいずれか記載の予防及び/又は治療剤を対象に投与することを特徴とするインフルエンザウイルス感染症の予防及び/又は治療方法。
- a)請求項1~8のいずれか記載のインフルエンザウイルス感染症の予防及び/又は治療剤;
b)抗インフルエンザ薬剤;
を含む予防及び/又は治療剤の組合せ。
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WO2016163082A1 (ja) * | 2015-04-10 | 2016-10-13 | Sbiファーマ株式会社 | Ala類を含むウイルス感染症予防/治療剤 |
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WO2020218577A1 (ja) | 2019-04-26 | 2020-10-29 | ネオファーマジャパン株式会社 | フラビウイルス感染症治療剤 |
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WO2021215517A1 (ja) * | 2020-04-22 | 2021-10-28 | ネオファーマジャパン株式会社 | 新型コロナウイルス感染症(covid-19)の治療及び/又は予防剤 |
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WO2022014654A1 (ja) * | 2020-07-15 | 2022-01-20 | ネオファーマジャパン株式会社 | アフリカ豚熱(African Swine Fever:ASF)の治療及び/又は予防剤 |
WO2022201644A1 (ja) * | 2021-03-26 | 2022-09-29 | 国立大学法人東京工業大学 | Tmprss2発現抑制用医薬組成物 |
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EP2875813B1 (en) | 2018-04-18 |
CN104487067B (zh) | 2017-09-01 |
HK1205688A1 (en) | 2015-12-24 |
AU2013291455A1 (en) | 2015-01-29 |
US9351949B2 (en) | 2016-05-31 |
AU2013291455B2 (en) | 2016-07-21 |
TW201412306A (zh) | 2014-04-01 |
CN104487067A (zh) | 2015-04-01 |
EP2875813A1 (en) | 2015-05-27 |
US20150164838A1 (en) | 2015-06-18 |
CA2877232A1 (en) | 2014-01-23 |
CA2877232C (en) | 2017-08-22 |
HK1206986A1 (en) | 2016-01-22 |
TWI584805B (zh) | 2017-06-01 |
JPWO2014013664A1 (ja) | 2016-06-30 |
EP2875813A4 (en) | 2016-04-20 |
JP5920901B2 (ja) | 2016-05-18 |
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