WO2022014654A1 - Therapeutic and/or prophylactic agent for african swine fever (asf) - Google Patents
Therapeutic and/or prophylactic agent for african swine fever (asf) Download PDFInfo
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- WO2022014654A1 WO2022014654A1 PCT/JP2021/026527 JP2021026527W WO2022014654A1 WO 2022014654 A1 WO2022014654 A1 WO 2022014654A1 JP 2021026527 W JP2021026527 W JP 2021026527W WO 2022014654 A1 WO2022014654 A1 WO 2022014654A1
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
Definitions
- the present invention relates to a therapeutic and / or prophylactic agent for African swine fever (ASF), and more particularly to African swine fever (ASF) containing 5-aminolevulinic acid (5-ALA) or a derivative thereof or a salt thereof. ) And / or prophylactic agents and treatment and / or prevention of African swine fever (ASF) using them.
- ASF African swine fever
- African swine fever is a febrile infectious disease of pigs and wild boars caused by the African swine fever virus (ASFV), characterized by strong infectivity and high lethality.
- ASFV spreads rapidly within the herd of pigs through direct or indirect contact with pigs and wild boars affected by the disease, causing serious damage to the pig farming industry.
- the countermeasures may be delayed only by the epidemic prevention measures limited to the place of occurrence. In resident and endemic areas, transmission between wild boars and the formation of an infection ring through the genus Argasidae complicates epidemic prevention.
- African swine fever virus is the only virus classified in the genus Asfarviridae Asfarviridae, which has a double-stranded DNA in the genome and a linear genomic DNA in the inner membrane. It has a structure that is surrounded by three layers of a hedron capsid and a cell membrane-derived envelope. Genome size varies between 170-190 kbp and virus strains, but approximately 125 kbp in the center is relatively well conserved. While the serotype (antigenicity) of a virus is considered to be single, genotyping based on the difference in base sequence is possible, and 22 genotypes are currently known (Non-Patent Document 1). ).
- Clinical symptoms vary depending on the pathogenicity of each virus strain, host factors (animal species, age, health status, etc.) and infection route, and are extremely acute, acute, subacute, chronic and subclinical. Shows type and various pathological conditions. Lactating and pregnant pigs show more severe symptoms and have a higher case fatality rate. The extremely acute type may present with fever of 41 ° C or higher, loss of energy, and loss of appetite. Congestion of the skin and erythema may be strongly observed, but most of them die suddenly within 4 days after infection without showing clinically significant changes. Case fatality rate reaches 100%. In the acute form, clinical symptoms are most common, with fever at 40-42 ° C, loss of energy, and loss of appetite. Symptoms of fever are seen 3 to 6 days after infection.
- Miscarriage is also seen in mother pigs. Infected pigs die within a week after fever, with a case fatality rate of approximately 100%. The subacute type shows the same symptoms as the acute type, but progresses more slowly and dies 7 to 20 days after infection. Case fatality rate is less than 70%, and surviving pigs recover in 3-4 weeks. It may be caught in the wake of a miscarriage. Chronic type refers to those who do not show significant symptoms. There are reports of respiratory symptoms, diarrhea, swelling of joints, dermatitis with ulcers, etc., but these symptoms are thought to be due to secondary bacterial infection.
- Non-Patent Document 1 National Research and Development Corporation National Institute of Animal Health, Animal Health Research Division Home Page, URL: http: // www. naro. affrc. go. jp / laboratory / niah / asf /, Access date: May 20, 2020
- 5-ALA is a common precursor of heme compounds produced in intracellular mitochondria. It has been reported that 5-ALA is absorbed into the body and then metabolized intracellularly to protoporphyrin, heme, and biliverdin, and each of these 5-ALA metabolites exhibits various physiological actions. It has been known that administration of 5-ALA has an anti-inflammatory effect against specific inflammatory diseases, but 5-ALA and its derivatives are infected with African swine fever (ASF) and / or. It was not known that it could suppress symptoms and treat or prevent African swine fever (ASF). INDUSTRIAL APPLICABILITY The present invention provides a medicine containing 5-ALA and its derivatives and its use for treating or preventing African swine fever (ASF).
- the present inventors have excellent treatment or prevention of African swine fever (ASF) by using a combination of 5-ALA and a metal-containing compound such as sodium ferrous citrate (SFC). We also found that it was effective.
- ASF African swine fever
- SFC sodium ferrous citrate
- the present invention provides the following.
- a therapeutic and / or prophylactic agent for African swine fever (ASF) which comprises the compound indicated by or a salt thereof.
- a therapeutic and / or prophylactic agent for African swine fever (ASF) according to item 1, wherein R1 and R2 are hydrogen atoms.
- AAF African swine fever
- AMF African swine fever
- the metal-containing compound is a compound containing iron, magnesium, zinc, nickel, vanadium, copper, chromium, molybdenum or cobalt.
- Agent is a compound containing iron, magnesium or zinc.
- a therapeutic and / or prophylactic agent for African swine fever according to item 3, wherein the metal-containing compound is an iron-containing compound.
- 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.
- a method for treating and / or preventing African swine fever (ASF) which comprises administering the compound represented by the above or a salt thereof together with a pharmaceutically acceptable excipient.
- the treatment and / or preventive agent for African swine fever (ASF) of the present invention is excellent in treating and / or treating African swine fever (ASF) by strongly suppressing virus infection or proliferation, impaired biological function due to virus, and the like. / Or has a preventive effect.
- FIG. 1 is a diagram showing a table recording the test results of Example 1.
- FIG. 2 is a diagram showing a table recording a part of the test results of Example 2.
- High-dose combination administration group A1 (5-ALA: 30 mg / kg / day, SFC: 34.5 mg / kg / day)
- high-dose single administration group A2 (5-ALA: 30 mg / kg / day)
- medium-dose combination administration The results of group B2 (10 mg / kg / day, SFC: 11.5 mg / kg / day) and medium-dose single-dose group B2 (5-ALA: 10 mg / kg / day) are shown.
- FIG. 3 is a diagram showing a table recording a part of the test results of Example 2.
- the compound used as an active ingredient of the therapeutic and / or preventive agent for African swine fever (ASF) of the present invention is a compound represented by the formula (I) or a salt thereof (hereinafter, these are collectively referred to as "ALAs". There is also).
- 5-ALA also called ⁇ -aminolevulinic acid, is a case where both R 1 and R 2 of the formula (I) are hydrogen atoms, and is one of the amino acids.
- R 1 of the formula (I) is a hydrogen atom or an acyl group
- R 2 of the formula (I) is a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl.
- Compounds other than the underlying 5-ALA 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 and benzylcarbonyl groups. , Benzoyl, 1-naphthoyl, 2-naphthoyl group and other aloyl groups having 7 to 14 carbon atoms can be mentioned.
- the alkyl group in the formula (I) may be a linear or branched group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl groups.
- Alkyl groups having 1 to 8 carbon atoms can be mentioned.
- cycloalkyl group in the formula (I) a saturated or partially unsaturated bond such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl group may be present.
- Cycloalkyl groups having 3 to 8 carbon atoms can be mentioned.
- 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 exemplified in the same manner as the above aryl group
- the alkyl moiety can be exemplified in the same manner as the above alkyl group, specifically, benzyl, phenethyl, phenylpropyl, phenylbutyl, benzhydryl.
- Trityl, naphthylmethyl, naphthylethyl group and other aralkyl groups having 7 to 15 carbon atoms can be mentioned.
- a compound in which R 1 is a formyl, acetyl, propionyl, butyryl group or the like, or a compound in which R 2 is a methyl, ethyl, propyl, butyl, pentyl group or the like is preferable. It is preferable to mention compounds in which the combination of 1 and R 2 is a combination of formyl and methyl, acetyl and methyl, propionyl and methyl, butyryl and methyl, formyl and ethyl, acetyl and ethyl, propionyl and ethyl, butyryl and ethyl. can.
- the 5-ALAs may act as an active ingredient in the state of 5-ALA of the formula (I) or a derivative thereof in vivo, and various salts, esters, etc. for increasing solubility may be used depending on the form to be administered. Alternatively, it may be administered as a prodrug (precursor) that is decomposed by an enzyme in the living body.
- the salt of 5-ALA and its derivative include a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt and the like.
- Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and other inorganic acid salts, formate, acetate, propionate and toluenesulfonic acid. Salt, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, malate, etc.
- An organic acid addition salt can be exemplified.
- Examples of the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, and metal salts such as aluminum and zinc.
- ammonium salt examples include an alkylammonium salt such as an ammonium salt and a tetramethylammonium salt.
- organic amine salt examples include triethylamine salt, piperidine salt, morpholine salt, toluidine salt and the like. These salts can also be used as a solution at the time of use.
- 5-ALA and various esters such as 5-ALA methyl ester, 5-ALA ethyl ester, 5-ALA propyl ester, 5-ALA butyl ester and 5-ALA pentyl ester.
- these hydrochlorides, phosphates, sulfates, and ALA hydrochlorides, 5-ALA phosphates can be particularly preferably exemplified.
- the above ALAs can be produced by any known method of chemical synthesis, production by microorganisms, and production by enzymes.
- the above ALAs may form a hydrate or a solvate, and either of them may be used alone or in combination of two or more.
- the therapeutic and / or preventive agent for African pig fever (ASF) of the present invention preferably contains a metal-containing compound as long as it does not cause excess disease, and the metal portion of the metal-containing compound includes iron and magnesium.
- the metal portion of the metal-containing compound includes iron and magnesium.
- Zinc, nickel, vanadium, cobalt, copper, chromium, molybdenum can be mentioned, but iron, magnesium and zinc are preferable, and iron can be preferably exemplified.
- the iron compound may be an organic salt or an inorganic salt
- examples of the inorganic salt include ferric chloride, iron sesquioxide, iron sulfate, and ferrous pyrophosphate
- examples of the organic salt are carboxylates.
- citrates such as ferrous citrate, sodium iron citrate, sodium ferrous citrate (Sodium Ferrous Citrate, SFC), ammonium iron citrate, which are hydroxycarboxylates, and ferric pyrophosphate.
- magnesium compound examples include magnesium citrate, magnesium benzoate, magnesium acetate, magnesium oxide, magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium sulfate, magnesium silicate, magnesium nitrate, diethylenetriamine pentamagnesium diammonate, and ethylenediamine tetraacetate.
- magnesium disodium and magnesium protoporphyrin examples include magnesium disodium and magnesium protoporphyrin.
- Examples of the zinc compound include zinc chloride, zinc oxide, zinc nitrate, zinc carbonate, zinc sulfate, diethylenetriamine diammonium pentaacetate, disodium ethylenediamine tetraacetate, zinc protoporphyllin, and zinc-containing yeast.
- One type or two or more types of the metal-containing compound can be used, respectively, and the dose of the metal-containing compound may be 0 to 100 times the molar ratio of the dose of 5-ALA, which is 0. It is preferably 0.01 to 10 times, more preferably 0.1 to 8 times.
- the therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention can be used in combination with other antiviral agents and other disease therapeutic agents as long as it does not cause excess disease.
- the dose of these other agents and the ratio to the dose of 5-ALA can be appropriately adjusted by those skilled in the art.
- the dosing intervals are 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour. It can be set to, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc., but is not limited thereto.
- the route of administration of the therapeutic and / or prophylactic agent for African pig fever (ASF) of the present invention is not particularly limited, but is oral administration, inhalation administration, nasal administration, injection, intravenous administration by infusion, transdermal administration, suppository, etc.
- parenteral administration such as administration by forced enteral feeding using a nasal gastrointestinal tract, a nasal intestinal tract, a gastric fistula tube, or an intestinal fistula tube can be used.
- the dosage form of the therapeutic and / or preventive agent of the present invention can be appropriately determined according to the above-mentioned administration route, but is an injection, a drip, a tablet, a capsule, or a fine granule. , Powders, liquids, liquids dissolved in syrups, paps, capsules and the like.
- Agents, coatings, lubricants, lubricants, lubricants, flavoring agents, sweeteners, solubilizers, solvents, gelling agents, nutrients, etc. can be added, and those skilled in the art can add each specific ingredient. It can be selected according to the purpose.
- the amount, frequency, and duration of administration of the treatment and / or preventive agent for African swine fever (ASF) and the virus protein expression inhibitor of the present invention include the types of animals for which treatment or prevention of African swine fever (ASF) is to be performed. Although it depends on age, body weight, symptoms, etc., for example, when administered to pigs, the dose of ALA is 0.1-1000 mg / kg body weight / day, preferably 0.1-1000 mg / kg body weight / day in terms of 5-ALA weight.
- the dose is 0.1-30 mg / kg body weight / day, preferably 0.3 to 10 mg / kg body weight / day, more preferably 1 to 3 mg / kg body weight / day. It can also be administered.
- the frequency of administration may be exemplified by administration once to a plurality of times a day or continuous administration by infusion or the like.
- the duration of administration as a therapeutic or prophylactic agent can be determined by a method known by a veterinarian or other expert in the art.
- the treatment and / or prophylaxis of African swine fever (ASF) of the present invention may be applied to the treatment and prevention of various symptoms and disorders caused by the infection of ASFV and / or the onset of African swine fever (ASF). It can suppress, delay, etc. the development of these symptoms in animals exposed to ASFV.
- Such symptoms can include, but are not limited to, fever, loss of energy, loss of appetite, congestion, erythema and miscarriage, and death.
- the therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention can be administered to Suidae animals such as pigs and wild boars and related animals thereof.
- 5-ALA and SFC-containing feed 100 mg / kg body weight / day 5-ALA dose and 115 mg / kg body weight / day SFC dose (5-ALA to SFC molar ratio 1: 0.5) 5-ALA phosphate aqueous solution and SFC aqueous solution were mixed with the pig feeding feed and fed so as to be.
- No-treatment feed As a negative control, a pig feed for pigs not mixed with 5-ALA phosphate or 5-ALA phosphate and SFC was fed.
- Test method Ten test pigs were assigned to different pig sheds (pig houses A and B), five each. Every morning at 10 o'clock, 3 out of 5 test pigs (A1, A2, A3) in Pighouse A were orally administered 5-ALA-containing feed at a dose of 100 mg / kg body weight / day for 7 days (2). B1, B2) were orally administered untreated feed for 7 days. At 10 o'clock every morning, 3 out of 5 test pigs (C1, C2, C3) in Pighouse B were fed 5-ALA and SFC-containing feed at 100 mg / kg / day 5-ALA and 115 mg / kg / day.
- the dose of SFC was orally administered for 7 days, and the untreated feed was orally administered to 2 animals (C4 and C5) for 7 days.
- Table 1 Assignment of treatment groups On the 7th day after the start of feed administration, 10 2 HAD 50 / mL ASFV was orally inoculated to all test pigs. After inoculation with ASFV, administration of 5-ALA, 5ALA + SFC or untreated feed was continued, body temperature (rectal temperature) was measured daily for each test pig, and blood virus concentration was 0, 4, 6, after ASFV inoculation. The test was performed at 8, 10, 12, 14, 18, and 21 days later, and if the test pig died, the date of death was recorded.
- test pig B1 continued to be positive for blood virus 14 days after the fever of 40 ° C. or higher from 8 days after the ASFV inoculation. Died.
- the test pig B2 also showed intermittent fever after 10 days, and showed blood virus positive with continuous fever after 14 days.
- Test pig C1 showed no fever until 21 days after inoculation and was also negative for blood virus.
- the test pig C2 showed a fever of 40 ° C. or higher over 10 to 11 days, but no fever thereafter, and the blood virus was negative until 21 days later.
- the test pig C3 showed no fever until 21 days after inoculation, and only the blood virus was positive 21 days later.
- the untreated test pigs (D1 and D2) in the same piggery B all died before 21 days later.
- the test pig D1 continued to have a fever of 40 ° C. or higher after 11 days, continued to be positive for blood virus after 12 days, and died 19 days later.
- the test pig D2 showed continuous fever and positive blood virus after 12 days, and died 18 days later.
- Example 1 Similar tests as in Example 1 were performed with higher viral load and lower 5-ALA dose. (Materials and methods) 1. 1. Animals: Pigs 6-7 weeks old (weighing about 20 kg) were used. 2. 2. Virus strain: ASFV strain (genotype 2 P252) clinically isolated in Vietnam used in Example 1 was subjected to a virus solution in 10 3 HAD 50 / mL EMEM, which was 10 times the concentration of Example 1. Prepared and used.
- Table 6 The results are shown in Table 6 below and Tables 7 and 8 of FIGS.
- the "elapsed days” in Tables 7 and 8 indicate the number of days after inoculation with the ASFV virus.
- Table 6 Fever, positive blood virus, and presence or absence of death
- Table 6 in the untreated group, all the test pigs died by 21 days after the virus inoculation, and the survival rate at 28 days after the virus inoculation was 0%, whereas the high dose combination was used.
- Administration group A1 (5-ALA: 30 mg / kg / day, SFC: 34.5 mg / kg / day), medium-dose combination administration group B2 (10 mg / kg / day, SFC: 11.5 mg / kg / day), low In the combined dose group C2 (3 mg / kg / day, SFC: 3.45 mg / kg / day), the survival rates were 67%, 100%, and 67% at the same time, respectively, and the high-dose single-dose group A2 (5-ALA). : 30 mg / kg / day), medium-dose single-administration group B2 (5-ALA: 10 mg / kg / day), low-dose single-administration group C2 (5-ALA: 3 mg / kg / day), 100 at the same time.
- test pigs identification number 3 in the high-dose combination administration group A1 showed fever and a positive blood virus test 6 days after the virus infection treatment, and died 13 days after the infection treatment. It has been confirmed that the nose of pigs was injured during the virus infection treatment, and it is suspected that the virus that invaded from the injured part may have caused an explosive spread of infection.
- test pigs in the low-dose combination administration group C1 died 25 days after the virus infection treatment, but the test pig was found in the blood virus test 14 days after the virus infection treatment. Although they were moved to a cage dedicated to infected pigs because they showed positive results, negative results were confirmed in subsequent blood virus tests (15 and 17 days after virus infection treatment), and 14 days after virus infection treatment. It is suspected that the results of the blood virus test may have been false positives. In the cage dedicated to infected pigs, cohabitation infection from other positive pigs carrying a high concentration of virus is easy, so the subject pig was infected in the cage dedicated to infected pigs and died 25 days after the virus infection treatment. It is probable that it was done. This study showed that 5-ALA provides protection against ASFV virus infection at low doses, while the combination of 5-ALA and SFC provides even better protection at low doses.
- 5-ALA or 5-ALA and SFC combined administration suppresses ASFV infection and / or ASF onset after infection.
- administration of 5-ALA can suppress African swine fever (ASF) infection and / or symptoms and treat or prevent African swine fever (ASF).
- ASF African swine fever
Abstract
The present invention provides: a therapeutic and/or prophylactic agent for African swine fever (ASF) that contains 5-aminolevulinic acid (ALA), a derivative thereof or a salt of the same; and a therapeutic and/or prophylactic method for ASF by using the aforesaid agent.
Description
本発明は、アフリカ豚熱（Ａｆｒｉｃａｎ Ｓｗｉｎｅ Ｆｅｖｅｒ：ＡＳＦ）の治療及び／又は予防剤に関し、さらに詳しくは、５－アミノレブリン酸（５－ＡＬＡ）若しくはその誘導体又はそれらの塩を含むアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤およびこれを用いたアフリカ豚熱（ＡＳＦ）の治療及び／又は予防に関する。
The present invention relates to a therapeutic and / or prophylactic agent for African swine fever (ASF), and more particularly to African swine fever (ASF) containing 5-aminolevulinic acid (5-ALA) or a derivative thereof or a salt thereof. ) And / or prophylactic agents and treatment and / or prevention of African swine fever (ASF) using them.
アフリカ豚熱（ＡＳＦ）はアフリカ豚熱ウイルス（Ａｆｒｉｃａｎ Ｓｗｉｎｅ Ｆｅｖｅｒ Ｖｉｒｕｓ：ＡＳＦＶ）による豚およびイノシシの熱性伝染病で、強い伝染性と高い致死率を特徴とする。ＡＳＦＶは本病に罹患した豚やイノシシとの直接的または間接的な接触により豚群内で急速に広がり、養豚業に深刻な打撃を与える。また汚染した豚肉中で長期間感染力を維持するため、精肉や非加熱の豚肉加工品を介して遠隔地に持ち込まれ、食品残渣の給与等を通じて未発生地域に侵入する。そのため発生地に限局した防疫措置のみでは対策が後手に回る場合がある。常在地や流行地では野生のイノシシ間の伝播やヒメダニ属を介した感染環が形成され、防疫を複雑にしている。
African swine fever (ASF) is a febrile infectious disease of pigs and wild boars caused by the African swine fever virus (ASFV), characterized by strong infectivity and high lethality. ASFV spreads rapidly within the herd of pigs through direct or indirect contact with pigs and wild boars affected by the disease, causing serious damage to the pig farming industry. In addition, in order to maintain infectivity in contaminated pork for a long period of time, it is brought to remote areas via meat and unheated processed pork products, and invades unoccurred areas through feeding of food residues. Therefore, the countermeasures may be delayed only by the epidemic prevention measures limited to the place of occurrence. In resident and endemic areas, transmission between wild boars and the formation of an infection ring through the genus Argasidae complicates epidemic prevention.
アフリカ豚熱ウイルス（ＡＳＦＶ）はアスファウイルス科アスフィウイルス属（Ａｓｆａｒｖｉｒｉｄａｅ Ａｓｆｉｖｉｒｕｓ）に分類される唯一のウイルスで、２本鎖ＤＮＡをゲノムにもち、直鎖状のゲノムＤＮＡを、内膜、正２０面体のキャプシドおよび細胞膜由来のエンベローブの３層で包みこむ構造を有している。ゲノムサイズは１７０～１９０ｋｂｐとウイルスの株間で差がみられるが、中央部のおよそ１２５ｋｂｐは比較的よく保存されている。ウイルスの血清型（抗原性）は単一と考えられている一方で、塩基配列の違いに基づいた遺伝子型別が可能であり、現在２２種の遺伝子型が知られている（非特許文献１）。
African swine fever virus (ASFV) is the only virus classified in the genus Asfarviridae Asfarviridae, which has a double-stranded DNA in the genome and a linear genomic DNA in the inner membrane. It has a structure that is surrounded by three layers of a hedron capsid and a cell membrane-derived envelope. Genome size varies between 170-190 kbp and virus strains, but approximately 125 kbp in the center is relatively well conserved. While the serotype (antigenicity) of a virus is considered to be single, genotyping based on the difference in base sequence is possible, and 22 genotypes are currently known (Non-Patent Document 1). ).
臨床症状は、ウイルス株ごとの病原性の違い、宿主側の要因（動物種、年齢、健康状態等）ならびに感染経路によって異なり、甚急性型、急性型、亜急性型、慢性型および不顕性型と多様な病態を示す。哺乳豚や妊娠豚はより重篤な症状を示し、致死率も高い。甚急性型では４１°Ｃ以上の発熱、元気消失、食欲不振を呈することがある。皮膚のうっ血、紅斑が強く見られる場合もあるが、多くは臨床的に著変を示すことなく感染後４日以内に突然死する。致死率は１００％に達する。急性型では臨床症状が最もよく認められ、４０～４２°Ｃの発熱、元気消失、食欲不振を呈する。発熱の症状は感染３～６日後にみられる。母豚では流産もみられる。感染した豚は発熱後１週間以内に死亡し、致死率は概ね１００％である。亜急性型では急性型と同様の症状を示すが、より進行が緩やかで感染後７～２０日に死亡する。致死率は７０％以下で、生き残った豚は３～４週間で回復する。流産をきっかけにして摘発されることもある。慢性型は顕著な症状を示さないものをいう。呼吸器症状や下痢、関節の腫脹、潰瘍を伴う皮膚炎等の報告があるが、これらの症状は細菌の二次感染によるものと思われる。不顕性型はアフリカのイボイノシシやカワイノシシ類に見られるもので、無症状で感染が長期間持続する。ＡＳＦＶが未発生地域へ侵入した場合には、特別な症状を示さないまま突然死が続くことで発生が確認される。ＡＳＦＶは伝染性が非常に強いため、豚房内で少頭数のみが発症するような事例は考え難く、ひとたび侵入すると同居豚はすべて感染して発症するといった状況が想定される。現在のところ、アフリカ豚熱（ＡＳＦ）に対するワクチンや治療薬は存在していない（非特許文献１）。したがって、アフリカ豚熱（ＡＳＦ）に対して有効な治療薬の開発が急務となっている。
Clinical symptoms vary depending on the pathogenicity of each virus strain, host factors (animal species, age, health status, etc.) and infection route, and are extremely acute, acute, subacute, chronic and subclinical. Shows type and various pathological conditions. Lactating and pregnant pigs show more severe symptoms and have a higher case fatality rate. The extremely acute type may present with fever of 41 ° C or higher, loss of energy, and loss of appetite. Congestion of the skin and erythema may be strongly observed, but most of them die suddenly within 4 days after infection without showing clinically significant changes. Case fatality rate reaches 100%. In the acute form, clinical symptoms are most common, with fever at 40-42 ° C, loss of energy, and loss of appetite. Symptoms of fever are seen 3 to 6 days after infection. Miscarriage is also seen in mother pigs. Infected pigs die within a week after fever, with a case fatality rate of approximately 100%. The subacute type shows the same symptoms as the acute type, but progresses more slowly and dies 7 to 20 days after infection. Case fatality rate is less than 70%, and surviving pigs recover in 3-4 weeks. It may be caught in the wake of a miscarriage. Chronic type refers to those who do not show significant symptoms. There are reports of respiratory symptoms, diarrhea, swelling of joints, dermatitis with ulcers, etc., but these symptoms are thought to be due to secondary bacterial infection. The subclinical type is found in African wild boars and bus-synching, and is asymptomatic and the infection persists for a long time. When ASFV invades an area where it has not occurred, the outbreak is confirmed by sudden death without showing any special symptoms. Since ASFV is extremely contagious, it is unlikely that only a small number of pigs will develop in the pig cell, and once invaded, all pigs living together will be infected and develop. At present, there is no vaccine or therapeutic agent for African swine fever (ASF) (Non-Patent Document 1). Therefore, there is an urgent need to develop effective therapeutic agents for African swine fever (ASF).
非特許文献１：国立研究開発法人 農業・食品産業技術総合研究機構、動物衛生研究部門ホームページ、ＵＲＬ：ｈｔｔｐ：／／ｗｗｗ．ｎａｒｏ．ａｆｆｒｃ．ｇｏ．ｊｐ／ｌａｂｏｒａｔｏｒｙ／ｎｉａｈ／ａｓｆ／、アクセス日：２０２０年５月２０日
Non-Patent Document 1: National Research and Development Corporation National Institute of Animal Health, Animal Health Research Division Home Page, URL: http: // www. naro. affrc. go. jp / laboratory / niah / asf /, Access date: May 20, 2020
本発明の課題は、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤を提供することである。より詳細には、５－ＡＬＡ若しくはその誘導体又はそれらの塩を含むアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤を提供することである。また、別の態様において、５－ＡＬＡ若しくはその誘導体又はそれらの塩を用いたアフリカ豚熱（ＡＳＦ）の治療及び／又は予防方法を提供することである。
An object of the present invention is to provide a therapeutic and / or preventive agent for African swine fever (ASF). More specifically, it is to provide a therapeutic and / or prophylactic agent for African swine fever (ASF), which comprises 5-ALA or a derivative thereof or a salt thereof. Further, in another embodiment, it is to provide a method for treating and / or preventing African swine fever (ASF) using 5-ALA or a derivative thereof or a salt thereof.
本発明者等は、上記課題解決に向けて鋭意研究を重ねた結果、全く意外にも５－ＡＬＡがアフリカ豚熱（ＡＳＦ）の感染および／または症状を抑制し、アフリカ豚熱（ＡＳＦ）を治療または予防することを見いだして本発明を完成した。
As a result of diligent research aimed at solving the above problems, the present inventors, surprisingly, 5-ALA suppressed African swine fever (ASF) infection and / or symptoms, and African swine fever (ASF) was developed. The present invention has been completed by finding treatment or prevention.
５－ＡＬＡは、細胞内のミトコンドリア内で産生されるヘム系化合物の共通前駆体である。５－ＡＬＡは体内に吸収された後、細胞内で、プロトポルフィリン、ヘム、ビリベルジンへと代謝され、これらの５－ＡＬＡ代謝産物はそれぞれ様々な生理作用を示すことが報告されている。５－ＡＬＡを投与することで、特定の炎症性疾患に対して抗炎症作用が得られることなどが知られていたが、５－ＡＬＡおよびその誘導体がアフリカ豚熱（ＡＳＦ）の感染および／または症状を抑制し、アフリカ豚熱（ＡＳＦ）を治療または予防し得ることは知られていなかった。本発明は新たに、アフリカ豚熱（ＡＳＦ）を治療または予防するための、５－ＡＬＡおよびその誘導体を含有する医薬およびその使用を提供するものである。
5-ALA is a common precursor of heme compounds produced in intracellular mitochondria. It has been reported that 5-ALA is absorbed into the body and then metabolized intracellularly to protoporphyrin, heme, and biliverdin, and each of these 5-ALA metabolites exhibits various physiological actions. It has been known that administration of 5-ALA has an anti-inflammatory effect against specific inflammatory diseases, but 5-ALA and its derivatives are infected with African swine fever (ASF) and / or. It was not known that it could suppress symptoms and treat or prevent African swine fever (ASF). INDUSTRIAL APPLICABILITY The present invention provides a medicine containing 5-ALA and its derivatives and its use for treating or preventing African swine fever (ASF).
さらに、本発明者等は、５－ＡＬＡとクエン酸第一鉄ナトリウム（Ｓｏｄｉｕｍ Ｆｅｒｒｏｕｓ Ｃｉｔｒａｔｅ、ＳＦＣ）などの金属含有化合物を組み合わせて用いることにより、極めて優れたアフリカ豚熱（ＡＳＦ）の治療または予防効果が得られることも見出した。
Furthermore, the present inventors have excellent treatment or prevention of African swine fever (ASF) by using a combination of 5-ALA and a metal-containing compound such as sodium ferrous citrate (SFC). We also found that it was effective.
すなわち、本発明は以下を提供する。
［項目１］
下記式（Ｉ）
（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。）
で示される化合物又はその塩を含有する、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目２］
Ｒ１及びＲ２が水素原子であることを特徴とする、項目１に記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目３］
さらに、一種又は二種以上の金属含有化合物を含有することを特徴とする、項目１又は２記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目４］
金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデン又はコバルトを含有する化合物であることを特徴とする、項目３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目５］
金属含有化合物が、鉄、マグネシウム又は亜鉛を含有する化合物であることを特徴とする、項目３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目６］
金属含有化合物が、鉄を含有する化合物であることを特徴とする、項目３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目７］
下記式（Ｉ）
（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。）
で示される化合物又はその塩を、薬学的許容される賦形剤と共に投与することを含む、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防方法。
［項目８］
下記式（Ｉ）
（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。）
で示される化合物又はその塩の、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防における使用。 That is, the present invention provides the following.
[Item 1]
The following formula (I)
(In the formula, R1 represents a hydrogen atom or an acyl group, and R2 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.)
A therapeutic and / or prophylactic agent for African swine fever (ASF), which comprises the compound indicated by or a salt thereof.
[Item 2]
The therapeutic and / or prophylactic agent for African swine fever (ASF) according toitem 1, wherein R1 and R2 are hydrogen atoms.
[Item 3]
The therapeutic and / or prophylactic agent for African swine fever (ASF) according to item 1 or 2, characterized in that it contains one or more metal-containing compounds.
[Item 4]
The treatment and / or prevention of African swine fever (ASF) according toitem 3, wherein the metal-containing compound is a compound containing iron, magnesium, zinc, nickel, vanadium, copper, chromium, molybdenum or cobalt. Agent.
[Item 5]
The therapeutic and / or preventive agent for African swine fever (ASF) according toitem 3, wherein the metal-containing compound is a compound containing iron, magnesium or zinc.
[Item 6]
The therapeutic and / or prophylactic agent for African swine fever (ASF) according toitem 3, wherein the metal-containing compound is an iron-containing compound.
[Item 7]
The following formula (I)
(In the formula, 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.)
A method for treating and / or preventing African swine fever (ASF), which comprises administering the compound represented by the above or a salt thereof together with a pharmaceutically acceptable excipient.
[Item 8]
The following formula (I)
(In the formula, 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.)
Use of the compounds indicated by, or salts thereof, in the treatment and / or prevention of African swine fever (ASF).
［項目１］
下記式（Ｉ）
で示される化合物又はその塩を含有する、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目２］
Ｒ１及びＲ２が水素原子であることを特徴とする、項目１に記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目３］
さらに、一種又は二種以上の金属含有化合物を含有することを特徴とする、項目１又は２記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目４］
金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデン又はコバルトを含有する化合物であることを特徴とする、項目３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目５］
金属含有化合物が、鉄、マグネシウム又は亜鉛を含有する化合物であることを特徴とする、項目３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目６］
金属含有化合物が、鉄を含有する化合物であることを特徴とする、項目３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。
［項目７］
下記式（Ｉ）
で示される化合物又はその塩を、薬学的許容される賦形剤と共に投与することを含む、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防方法。
［項目８］
下記式（Ｉ）
で示される化合物又はその塩の、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防における使用。 That is, the present invention provides the following.
[Item 1]
The following formula (I)
A therapeutic and / or prophylactic agent for African swine fever (ASF), which comprises the compound indicated by or a salt thereof.
[Item 2]
The therapeutic and / or prophylactic agent for African swine fever (ASF) according to
[Item 3]
The therapeutic and / or prophylactic agent for African swine fever (ASF) according to
[Item 4]
The treatment and / or prevention of African swine fever (ASF) according to
[Item 5]
The therapeutic and / or preventive agent for African swine fever (ASF) according to
[Item 6]
The therapeutic and / or prophylactic agent for African swine fever (ASF) according to
[Item 7]
The following formula (I)
A method for treating and / or preventing African swine fever (ASF), which comprises administering the compound represented by the above or a salt thereof together with a pharmaceutically acceptable excipient.
[Item 8]
The following formula (I)
Use of the compounds indicated by, or salts thereof, in the treatment and / or prevention of African swine fever (ASF).
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤は、特にウイルスの感染もしくは増殖、ウイルスによる生体機能の障害等を強力に抑制することにより、優れたフリカ豚熱（ＡＳＦ）治療及び／または予防効果を奏する。
The treatment and / or preventive agent for African swine fever (ASF) of the present invention is excellent in treating and / or treating African swine fever (ASF) by strongly suppressing virus infection or proliferation, impaired biological function due to virus, and the like. / Or has a preventive effect.
（定義）
本明細書において、複数の数値の範囲が示された場合、それら複数の範囲の任意の下限値および上限値の組み合わせからなる範囲も同様に意味する。 (Definition)
In the present specification, when a range of a plurality of numerical values is shown, a range consisting of any combination of a lower limit value and an upper limit value of the plurality of ranges is also meant.
本明細書において、複数の数値の範囲が示された場合、それら複数の範囲の任意の下限値および上限値の組み合わせからなる範囲も同様に意味する。 (Definition)
In the present specification, when a range of a plurality of numerical values is shown, a range consisting of any combination of a lower limit value and an upper limit value of the plurality of ranges is also meant.
（本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤の有効成分）
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤の有効成分として用いられる化合物は、式（Ｉ）で示される化合物又はその塩（以下、これらを総称して「ＡＬＡ類」ということもある）として例示することができる。δ－アミノレブリン酸とも呼ばれる５－ＡＬＡは、式（Ｉ）のＲ１及びＲ２が共に水素原子の場合であり、アミノ酸の１種である。５－ＡＬＡ誘導体としては、式（Ｉ）のＲ１が水素原子又はアシル基であり、式（Ｉ）のＲ２が水素原子、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である、５－ＡＬＡ以外の化合物を挙げることができる。 (Active ingredient of therapeutic and / or preventive agent for African swine fever (ASF) of the present invention)
The compound used as an active ingredient of the therapeutic and / or preventive agent for African swine fever (ASF) of the present invention is a compound represented by the formula (I) or a salt thereof (hereinafter, these are collectively referred to as "ALAs". There is also). 5-ALA, also called δ-aminolevulinic acid, is a case where both R 1 and R 2 of the formula (I) are hydrogen atoms, and is one of the amino acids. As the 5-ALA derivative, R 1 of the formula (I) is a hydrogen atom or an acyl group, and R 2 of the formula (I) is a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl. Compounds other than the underlying 5-ALA can be mentioned.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤の有効成分として用いられる化合物は、式（Ｉ）で示される化合物又はその塩（以下、これらを総称して「ＡＬＡ類」ということもある）として例示することができる。δ－アミノレブリン酸とも呼ばれる５－ＡＬＡは、式（Ｉ）のＲ１及びＲ２が共に水素原子の場合であり、アミノ酸の１種である。５－ＡＬＡ誘導体としては、式（Ｉ）のＲ１が水素原子又はアシル基であり、式（Ｉ）のＲ２が水素原子、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である、５－ＡＬＡ以外の化合物を挙げることができる。 (Active ingredient of therapeutic and / or preventive agent for African swine fever (ASF) of the present invention)
The compound used as an active ingredient of the therapeutic and / or preventive agent for African swine fever (ASF) of the present invention is a compound represented by the formula (I) or a salt thereof (hereinafter, these are collectively referred to as "ALAs". There is also). 5-ALA, also called δ-aminolevulinic acid, is a case where both R 1 and R 2 of the formula (I) are hydrogen atoms, and is one of the amino acids. As the 5-ALA derivative, R 1 of the formula (I) is a hydrogen atom or an acyl group, and R 2 of the formula (I) is a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group or an aralkyl. Compounds other than the underlying 5-ALA can be mentioned.
式（Ｉ）におけるアシル基としては、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ヘキサノイル、オクタノイル、ベンジルカルボニル基等の直鎖又は分岐状の炭素数１～８のアルカノイル基や、ベンゾイル、１－ナフトイル、２－ナフトイル基等の炭素数７～１４のアロイル基を挙げることができる。
Examples of the acyl group in the formula (I) include linear or branched alkanoyl groups having 1 to 8 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl and benzylcarbonyl groups. , Benzoyl, 1-naphthoyl, 2-naphthoyl group and other aloyl groups having 7 to 14 carbon atoms can be mentioned.
式（Ｉ）におけるアルキル基としては、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、ヘプチル、オクチル基等の直鎖又は分岐状の炭素数１～８のアルキル基を挙げることができる。
The alkyl group in the formula (I) may be a linear or branched group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl groups. Alkyl groups having 1 to 8 carbon atoms can be mentioned.
式（Ｉ）におけるシクロアルキル基としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロドデシル、１－シクロヘキセニル基等の飽和、又は一部不飽和結合が存在してもよい、炭素数３～８のシクロアルキル基を挙げることができる。
As the cycloalkyl group in the formula (I), a saturated or partially unsaturated bond such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl group may be present. , Cycloalkyl groups having 3 to 8 carbon atoms can be mentioned.
式（Ｉ）におけるアリール基としては、フェニル、ナフチル、アントリル、フェナントリル基等の炭素数６～１４のアリール基を挙げることができる。
Examples of the aryl group in the formula (I) include aryl groups having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl, and phenanthryl groups.
式（Ｉ）におけるアラルキル基としては、アリール部分は上記アリール基と同じ例示ができ、アルキル部分は上記アルキル基と同じ例示ができ、具体的には、ベンジル、フェネチル、フェニルプロピル、フェニルブチル、ベンズヒドリル、トリチル、ナフチルメチル、ナフチルエチル基等の炭素数７～１５のアラルキル基を挙げることができる。
As the aralkyl group in the formula (I), the aryl moiety can be exemplified in the same manner as the above aryl group, and the alkyl moiety can be exemplified in the same manner as the above alkyl group, specifically, benzyl, phenethyl, phenylpropyl, phenylbutyl, benzhydryl. , Trityl, naphthylmethyl, naphthylethyl group and other aralkyl groups having 7 to 15 carbon atoms can be mentioned.
上記５－ＡＬＡ誘導体としては、Ｒ１が、ホルミル、アセチル、プロピオニル、ブチリル基等である化合物や、上記Ｒ２が、メチル、エチル、プロピル、ブチル、ペンチル基等である化合物が好ましく、上記Ｒ１とＲ２の組合せが、ホルミルとメチル、アセチルとメチル、プロピオニルとメチル、ブチリルとメチル、ホルミルとエチル、アセチルとエチル、プロピオニルとエチル、ブチリルとエチルの組合せである化合物などを好ましく挙げることができる。
As the 5-ALA derivative , a compound in which R 1 is a formyl, acetyl, propionyl, butyryl group or the like, or a compound in which R 2 is a methyl, ethyl, propyl, butyl, pentyl group or the like is preferable. It is preferable to mention compounds in which the combination of 1 and R 2 is a combination of formyl and methyl, acetyl and methyl, propionyl and methyl, butyryl and methyl, formyl and ethyl, acetyl and ethyl, propionyl and ethyl, butyryl and ethyl. can.
５－ＡＬＡ類は、生体内で式（Ｉ）の５－ＡＬＡ又はその誘導体の状態で有効成分として作用すればよく、投与する形態に応じて、溶解性を上げるための各種の塩、エステル、または生体内の酵素で分解されるプロドラッグ（前駆体）として投与すればよい。例えば、５－ＡＬＡ及びその誘導体の塩としては、薬理学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩等を挙げることができる。酸付加塩としては、例えば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩、硝酸塩、硫酸塩等の各無機酸塩、ギ酸塩、酢酸塩、プロピオン酸塩、トルエンスルホン酸塩、コハク酸塩、シュウ酸塩、乳酸塩、酒石酸塩、グリコール酸塩、メタンスルホン酸塩、酪酸塩、吉草酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、リンゴ酸塩等の各有機酸付加塩を例示することができる。金属塩としては、リチウム塩、ナトリウム塩、カリウム塩等の各アルカリ金属塩、マグネシウム塩、カルシウム塩等の各アルカリ土類金属塩、アルミニウム、亜鉛等の各金属塩を例示することができる。アンモニウム塩としては、アンモニウム塩、テトラメチルアンモニウム塩等のアルキルアンモニウム塩等を例示することができる。有機アミン塩としては、トリエチルアミン塩、ピペリジン塩、モルホリン塩、トルイジン塩等の各塩を例示することができる。なお、これらの塩は使用時において溶液としても用いることができる。
The 5-ALAs may act as an active ingredient in the state of 5-ALA of the formula (I) or a derivative thereof in vivo, and various salts, esters, etc. for increasing solubility may be used depending on the form to be administered. Alternatively, it may be administered as a prodrug (precursor) that is decomposed by an enzyme in the living body. For example, examples of the salt of 5-ALA and its derivative include a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt and the like. Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and other inorganic acid salts, formate, acetate, propionate and toluenesulfonic acid. Salt, succinate, oxalate, lactate, tartrate, glycolate, methanesulfonate, butyrate, valerate, citrate, fumarate, maleate, malate, etc. An organic acid addition salt can be exemplified. Examples of the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, and metal salts such as aluminum and zinc. Examples of the ammonium salt include an alkylammonium salt such as an ammonium salt and a tetramethylammonium salt. Examples of the organic amine salt include triethylamine salt, piperidine salt, morpholine salt, toluidine salt and the like. These salts can also be used as a solution at the time of use.
以上のＡＬＡ類のうち、望ましいものは、５－ＡＬＡ、及び５－ＡＬＡメチルエステル、５－ＡＬＡエチルエステル、５－ＡＬＡプロピルエステル、５－ＡＬＡブチルエステル、５－ＡＬＡペンチルエステル等の各種エステル類、並びに、これらの塩酸塩、リン酸塩、硫酸塩であり、ＡＬＡ塩酸塩、５－ＡＬＡリン酸塩を特に好適に例示することができる。
Among the above ALAs, desirable ones are 5-ALA and various esters such as 5-ALA methyl ester, 5-ALA ethyl ester, 5-ALA propyl ester, 5-ALA butyl ester and 5-ALA pentyl ester. , And these hydrochlorides, phosphates, sulfates, and ALA hydrochlorides, 5-ALA phosphates can be particularly preferably exemplified.
上記ＡＬＡ類は、化学合成、微生物による生産、酵素による生産のいずれの公知の方法によって製造することができる。また、上記ＡＬＡ類は、水和物又は溶媒和物を形成していてもよく、またいずれかを単独で又は２種以上を適宜組み合わせて用いることができる。
The above ALAs can be produced by any known method of chemical synthesis, production by microorganisms, and production by enzymes. In addition, the above ALAs may form a hydrate or a solvate, and either of them may be used alone or in combination of two or more.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤は、過剰症を生じない範囲で、さらに金属含有化合物を含有するものが好ましく、かかる金属含有化合物の金属部分としては、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、コバルト、銅、クロム、モリブデンを挙げることができるが、鉄、マグネシウム、亜鉛が好ましく、中でも鉄を好適に例示することができる。
The therapeutic and / or preventive agent for African pig fever (ASF) of the present invention preferably contains a metal-containing compound as long as it does not cause excess disease, and the metal portion of the metal-containing compound includes iron and magnesium. , Zinc, nickel, vanadium, cobalt, copper, chromium, molybdenum can be mentioned, but iron, magnesium and zinc are preferable, and iron can be preferably exemplified.
上記ＡＬＡ類と金属含有化合物を併用することで、より低濃度のＡＬＡ類の使用でも、優れたアフリカ豚熱（ＡＳＦ）の治療及び／又は予防効果を得ることができる。
By using the above ALAs in combination with a metal-containing compound, an excellent therapeutic and / or preventive effect on African swine fever (ASF) can be obtained even when a lower concentration of ALAs is used.
上記鉄化合物としては、有機塩でも無機塩でもよく、無機塩としては、塩化第二鉄、三二酸化鉄、硫酸鉄、ピロリン酸第一鉄を挙げることができ、有機塩としては、カルボン酸塩、例えばヒドロキシカルボン酸塩である、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（Ｓｏｄｉｕｍ Ｆｅｒｒｏｕｓ Ｃｉｔｒａｔｅ、ＳＦＣ）、クエン酸鉄アンモニウム等のクエン酸塩や、ピロリン酸第二鉄、ヘム鉄、デキストラン鉄、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、エチレンジアミン五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等の有機酸塩や、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、グリシン第一鉄硫酸塩を挙げることができる。
The iron compound may be an organic salt or an inorganic salt, and examples of the inorganic salt include ferric chloride, iron sesquioxide, iron sulfate, and ferrous pyrophosphate, and examples of the organic salt are carboxylates. For example, citrates such as ferrous citrate, sodium iron citrate, sodium ferrous citrate (Sodium Ferrous Citrate, SFC), ammonium iron citrate, which are hydroxycarboxylates, and ferric pyrophosphate. , Hem iron, iron dextran, iron lactate, ferrous gluconate, sodium diethylenetriamine pentaacetate, ammonium diethylenetriamine pentaacetate, sodium ethylenediamine tetraacetate, ammonium ethylenediamine pentaacetate, sodium dicarboxymethylglutamate, dicarboxymethyl Organic acid salts such as ammonium iron glutamate, ferrous fumarate, iron acetate, iron oxalate, ferrous succinate, and sodium iron citrate succinate, triethylenetetraamine iron, lactoferrin iron, transferase iron, and iron chlorophyllin. Examples thereof include sodium, ferritin iron, sugar-containing iron oxide, and ferric glycine sulfate.
上記マグネシウム化合物としては、クエン酸マグネシウム、安息香酸マグネシウム、酢酸マグネシウム、酸化マグネシウム、塩化マグネシウム、水酸化マグネシウム、炭酸マグネシウム、硫酸マグネシウム、ケイ酸マグネシウム、硝酸マグネシウム、ジエチレントリアミン五酢酸マグネシウムジアンモニウム、エチレンジアミン四酢酸マグネシウムジナトリウム、マグネシウムプロトポルフィリンを挙げることができる。
Examples of the magnesium compound include magnesium citrate, magnesium benzoate, magnesium acetate, magnesium oxide, magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium sulfate, magnesium silicate, magnesium nitrate, diethylenetriamine pentamagnesium diammonate, and ethylenediamine tetraacetate. Examples include magnesium disodium and magnesium protoporphyrin.
上記亜鉛化合物としては、塩化亜鉛、酸化亜鉛、硝酸亜鉛、炭酸亜鉛、硫酸亜鉛、ジエチレントリアミン五酢酸亜鉛ジアンモニウム、エチレンジアミン四酢酸亜鉛ジナトリウム、亜鉛プロトポルフィリン、亜鉛含有酵母を挙げることができる。
Examples of the zinc compound include zinc chloride, zinc oxide, zinc nitrate, zinc carbonate, zinc sulfate, diethylenetriamine diammonium pentaacetate, disodium ethylenediamine tetraacetate, zinc protoporphyllin, and zinc-containing yeast.
上記金属含有化合物は、それぞれ１種類又は２種類以上を用いることができ、金属含有化合物の投与量としては、５－ＡＬＡの投与量に対してモル比で０～１００倍であればよく、０．０１倍～１０倍が望ましく、０．１倍～８倍がより望ましい。
One type or two or more types of the metal-containing compound can be used, respectively, and the dose of the metal-containing compound may be 0 to 100 times the molar ratio of the dose of 5-ALA, which is 0. It is preferably 0.01 to 10 times, more preferably 0.1 to 8 times.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤は、過剰症を生じない範囲で、さらに他の抗ウイルス剤や、他の疾患治療薬と併用することができる。これら他の薬剤の投与量、および５－ＡＬＡの投与量との比率は、当業者が適宜調整することができる。
The therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention can be used in combination with other antiviral agents and other disease therapeutic agents as long as it does not cause excess disease. The dose of these other agents and the ratio to the dose of 5-ALA can be appropriately adjusted by those skilled in the art.
（本発明の治療及び／又は予防剤の投与方法）
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤に含有されるＡＬＡ類と金属含有化合物または他の薬剤は、これらのうちのいずれか２つ以上を含む組成物としても、あるいは、それぞれを単独で含む組成物としても投与することできる。ＡＬＡ類と金属含有化合物または他の薬剤とを、それぞれ単独で含む組成物を用いる場合、これらを同時に投与してもよく、また、別々に投与してもよい。好ましくは、ＡＬＡ類と金属含有化合物または他の薬剤との投与が相加的効果、好ましくは相乗的効果を奏することができるように組み合わせて投与することができる。ＡＬＡ類と金属含有化合物または他の薬剤をそれぞれ単独で含む組成物を別々に投与する場合、それらの投与間隔は、５分、１０分、１５分、２０分、３０分、４５分、１時間、２時間、３時間、４時間、５時間、６時間、７時間、８時間、９時間、１０時間、１１時間、１２時間等に設定できるが、これらに限定されない。 (Method of administration of therapeutic and / or prophylactic agent of the present invention)
The ALAs and metal-containing compounds or other agents contained in the therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention may be a composition containing any two or more of them, or may be used. It can also be administered as a composition containing each alone. When a composition containing ALAs and a metal-containing compound or another drug is used alone, these may be administered simultaneously or separately. Preferably, the ALAs and the metal-containing compound or other agents can be administered in combination so as to have an additive effect, preferably a synergistic effect. When the compositions containing ALAs and metal-containing compounds or other drugs alone are administered separately, the dosing intervals are 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour. It can be set to, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc., but is not limited thereto.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤に含有されるＡＬＡ類と金属含有化合物または他の薬剤は、これらのうちのいずれか２つ以上を含む組成物としても、あるいは、それぞれを単独で含む組成物としても投与することできる。ＡＬＡ類と金属含有化合物または他の薬剤とを、それぞれ単独で含む組成物を用いる場合、これらを同時に投与してもよく、また、別々に投与してもよい。好ましくは、ＡＬＡ類と金属含有化合物または他の薬剤との投与が相加的効果、好ましくは相乗的効果を奏することができるように組み合わせて投与することができる。ＡＬＡ類と金属含有化合物または他の薬剤をそれぞれ単独で含む組成物を別々に投与する場合、それらの投与間隔は、５分、１０分、１５分、２０分、３０分、４５分、１時間、２時間、３時間、４時間、５時間、６時間、７時間、８時間、９時間、１０時間、１１時間、１２時間等に設定できるが、これらに限定されない。 (Method of administration of therapeutic and / or prophylactic agent of the present invention)
The ALAs and metal-containing compounds or other agents contained in the therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention may be a composition containing any two or more of them, or may be used. It can also be administered as a composition containing each alone. When a composition containing ALAs and a metal-containing compound or another drug is used alone, these may be administered simultaneously or separately. Preferably, the ALAs and the metal-containing compound or other agents can be administered in combination so as to have an additive effect, preferably a synergistic effect. When the compositions containing ALAs and metal-containing compounds or other drugs alone are administered separately, the dosing intervals are 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour. It can be set to, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc., but is not limited thereto.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤の投与経路としては特に限定されないが、経口投与、吸入投与、経鼻投与、注射、点滴等による静脈内投与、経皮投与、座薬、又は経鼻胃管、経鼻腸管、胃ろうチューブ若しくは腸ろうチューブを用いる強制的経腸栄養法による投与等の非経口投与などを使用することができる。
The route of administration of the therapeutic and / or prophylactic agent for African pig fever (ASF) of the present invention is not particularly limited, but is oral administration, inhalation administration, nasal administration, injection, intravenous administration by infusion, transdermal administration, suppository, etc. Or, parenteral administration such as administration by forced enteral feeding using a nasal gastrointestinal tract, a nasal intestinal tract, a gastric fistula tube, or an intestinal fistula tube can be used.
（本発明の治療及び／又は予防剤の剤型）
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤の剤型としては、上記投与経路に応じて適宜決定することができるが、注射剤、点滴剤、錠剤、カプセル剤、細粒剤、散剤、液剤、シロップ等に溶解した水剤、パップ剤、座薬剤等を挙げることができる。 (Dosage form of therapeutic and / or preventive agent of the present invention)
The dosage form of the therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention can be appropriately determined according to the above-mentioned administration route, but is an injection, a drip, a tablet, a capsule, or a fine granule. , Powders, liquids, liquids dissolved in syrups, paps, capsules and the like.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤の剤型としては、上記投与経路に応じて適宜決定することができるが、注射剤、点滴剤、錠剤、カプセル剤、細粒剤、散剤、液剤、シロップ等に溶解した水剤、パップ剤、座薬剤等を挙げることができる。 (Dosage form of therapeutic and / or preventive agent of the present invention)
The dosage form of the therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention can be appropriately determined according to the above-mentioned administration route, but is an injection, a drip, a tablet, a capsule, or a fine granule. , Powders, liquids, liquids dissolved in syrups, paps, capsules and the like.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤を調製するために、必要に応じて、薬理学的に許容し得る担体、賦形剤、希釈剤、添加剤、崩壊剤、結合剤、被覆剤、潤滑剤、滑走剤、滑沢剤、風味剤、甘味剤、可溶化剤、溶剤、ゲル化剤、栄養剤等を添加することができ、当業者は各具体的な成分を目的に応じて選択することができる。
Pharmacologically acceptable carriers, excipients, diluents, additives, disintegrants, binders, as needed, to prepare therapeutic and / or prophylactic agents for African pig fever (ASF) of the invention. Agents, coatings, lubricants, lubricants, lubricants, flavoring agents, sweeteners, solubilizers, solvents, gelling agents, nutrients, etc. can be added, and those skilled in the art can add each specific ingredient. It can be selected according to the purpose.
（本発明の治療及び／又は予防剤の投与量）
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤並びにウイルスタンパク質発現抑制剤の投与の量・頻度・期間としては、アフリカ豚熱（ＡＳＦ）を治療又は予防しようとする動物の種類、年齢、体重、症状等により異なるが、例えば豚に投与する場合、ＡＬＡ類の投与量としては、５－ＡＬＡ重量換算で、動物１頭当たり、０．１－１０００ｍｇ／体重ｋｇ／日、好ましくは０．３－３００ｍｇ／体重ｋｇ／日、より好ましくは１－３０ｍｇ／体重ｋｇ／日、さらに好ましくは３－３０ｍｇ／体重ｋｇ／日を挙げることができ、特に予防剤として用いる場合は、低用量を継続して摂取することが望ましい。例えば予防サプリメントとして投与する場合には、０．１－３０ｍｇ／体重ｋｇ／日、好ましくは０．３～１０ｍｇ／体重ｋｇ／日、より好ましくは１～３ｍｇ／体重ｋｇ／日などの投与量で投与することもできる。投与頻度としては、一日一回～複数回の投与又は点滴等による連続的投与を例示することができる。治療剤または予防剤としての投与期間は、獣医等当該技術分野の専門家が既知の方法により決定することができる。 (Dose of therapeutic and / or prophylactic agent of the present invention)
The amount, frequency, and duration of administration of the treatment and / or preventive agent for African swine fever (ASF) and the virus protein expression inhibitor of the present invention include the types of animals for which treatment or prevention of African swine fever (ASF) is to be performed. Although it depends on age, body weight, symptoms, etc., for example, when administered to pigs, the dose of ALA is 0.1-1000 mg / kg body weight / day, preferably 0.1-1000 mg / kg body weight / day in terms of 5-ALA weight. 0.3-300 mg / kg body weight / day, more preferably 1-30 mg / kg body weight / day, even more preferably 3-30 mg / kg body weight / day, especially when used as a prophylactic agent, at low doses. It is desirable to continue to take. For example, when administered as a prophylactic supplement, the dose is 0.1-30 mg / kg body weight / day, preferably 0.3 to 10 mg / kg body weight / day, more preferably 1 to 3 mg / kg body weight / day. It can also be administered. The frequency of administration may be exemplified by administration once to a plurality of times a day or continuous administration by infusion or the like. The duration of administration as a therapeutic or prophylactic agent can be determined by a method known by a veterinarian or other expert in the art.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤並びにウイルスタンパク質発現抑制剤の投与の量・頻度・期間としては、アフリカ豚熱（ＡＳＦ）を治療又は予防しようとする動物の種類、年齢、体重、症状等により異なるが、例えば豚に投与する場合、ＡＬＡ類の投与量としては、５－ＡＬＡ重量換算で、動物１頭当たり、０．１－１０００ｍｇ／体重ｋｇ／日、好ましくは０．３－３００ｍｇ／体重ｋｇ／日、より好ましくは１－３０ｍｇ／体重ｋｇ／日、さらに好ましくは３－３０ｍｇ／体重ｋｇ／日を挙げることができ、特に予防剤として用いる場合は、低用量を継続して摂取することが望ましい。例えば予防サプリメントとして投与する場合には、０．１－３０ｍｇ／体重ｋｇ／日、好ましくは０．３～１０ｍｇ／体重ｋｇ／日、より好ましくは１～３ｍｇ／体重ｋｇ／日などの投与量で投与することもできる。投与頻度としては、一日一回～複数回の投与又は点滴等による連続的投与を例示することができる。治療剤または予防剤としての投与期間は、獣医等当該技術分野の専門家が既知の方法により決定することができる。 (Dose of therapeutic and / or prophylactic agent of the present invention)
The amount, frequency, and duration of administration of the treatment and / or preventive agent for African swine fever (ASF) and the virus protein expression inhibitor of the present invention include the types of animals for which treatment or prevention of African swine fever (ASF) is to be performed. Although it depends on age, body weight, symptoms, etc., for example, when administered to pigs, the dose of ALA is 0.1-1000 mg / kg body weight / day, preferably 0.1-1000 mg / kg body weight / day in terms of 5-ALA weight. 0.3-300 mg / kg body weight / day, more preferably 1-30 mg / kg body weight / day, even more preferably 3-30 mg / kg body weight / day, especially when used as a prophylactic agent, at low doses. It is desirable to continue to take. For example, when administered as a prophylactic supplement, the dose is 0.1-30 mg / kg body weight / day, preferably 0.3 to 10 mg / kg body weight / day, more preferably 1 to 3 mg / kg body weight / day. It can also be administered. The frequency of administration may be exemplified by administration once to a plurality of times a day or continuous administration by infusion or the like. The duration of administration as a therapeutic or prophylactic agent can be determined by a method known by a veterinarian or other expert in the art.
（本発明の治療及び／又は予防剤の適用症状）
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤は、ＡＳＦＶの感染および／またはアフリカ豚熱（ＡＳＦ）発症を原因として生じる様々な症状および障害の、治療および予防に適用することができ、ＡＳＦＶに接した動物のこれら症状の発生の抑制、遅延などをもたらすことができる。そのような症状として、発熱、元気消失、食欲不振、うっ血、紅斑および流産、死亡を例示することができるが、これらに限定されない。 (Applicable symptoms of the therapeutic and / or prophylactic agent of the present invention)
The treatment and / or prophylaxis of African swine fever (ASF) of the present invention may be applied to the treatment and prevention of various symptoms and disorders caused by the infection of ASFV and / or the onset of African swine fever (ASF). It can suppress, delay, etc. the development of these symptoms in animals exposed to ASFV. Such symptoms can include, but are not limited to, fever, loss of energy, loss of appetite, congestion, erythema and miscarriage, and death.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤は、ＡＳＦＶの感染および／またはアフリカ豚熱（ＡＳＦ）発症を原因として生じる様々な症状および障害の、治療および予防に適用することができ、ＡＳＦＶに接した動物のこれら症状の発生の抑制、遅延などをもたらすことができる。そのような症状として、発熱、元気消失、食欲不振、うっ血、紅斑および流産、死亡を例示することができるが、これらに限定されない。 (Applicable symptoms of the therapeutic and / or prophylactic agent of the present invention)
The treatment and / or prophylaxis of African swine fever (ASF) of the present invention may be applied to the treatment and prevention of various symptoms and disorders caused by the infection of ASFV and / or the onset of African swine fever (ASF). It can suppress, delay, etc. the development of these symptoms in animals exposed to ASFV. Such symptoms can include, but are not limited to, fever, loss of energy, loss of appetite, congestion, erythema and miscarriage, and death.
（本発明の治療及び／又は予防剤の適用動物）
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤は、豚、イノシシなどのイノシシ科動物およびこれらの近縁動物等に投与することができる。 (Animal to which the therapeutic and / or prophylactic agent of the present invention is applied)
The therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention can be administered to Suidae animals such as pigs and wild boars and related animals thereof.
本発明のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤は、豚、イノシシなどのイノシシ科動物およびこれらの近縁動物等に投与することができる。 (Animal to which the therapeutic and / or prophylactic agent of the present invention is applied)
The therapeutic and / or prophylactic agent for African swine fever (ASF) of the present invention can be administered to Suidae animals such as pigs and wild boars and related animals thereof.
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれらによって限定されるものではない。
Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.
（材料と方法）
１．動物：ディロック種もしくはランドレース種の４～５週齢の豚（体重約１０ｋｇ、雌または雄）を使用した。
２．ウイルス株：ベトナムにおいて臨床的に単離されたＡＳＦＶ株（遺伝子型２ Ｐ２５２）を使用した。当該ウイルス株は、接触感染および飲用水を通じた感染が確認されている。１０２ＨＡＤ５０／ｍＬ ＥＭＥＭ中のウイルス溶液を調製して使用した。
３．５－ＡＬＡおよびＳＦＣの調製
（１）５－ＡＬＡ含有飼料：１００ｍｇ／体重ｋｇ／日（体重は実験開始時点）の５－ＡＬＡ用量となるように、５－ＡＬＡリン酸塩水溶液を養豚用飼料と混合して給餌した。
（２）５－ＡＬＡおよびＳＦＣ含有飼料：１００ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および１１５ｍｇ／体重ｋｇ／日のＳＦＣ投与量（５－ＡＬＡとＳＦＣのモル比は１：０．５）となるように、５－ＡＬＡリン酸塩水溶液およびＳＦＣ水溶液を養豚用飼料と混合して給餌した。
（３）無処置用飼料：陰性対照として、５－ＡＬＡリン酸塩もしくは５－ＡＬＡリン酸塩およびＳＦＣを混合しない養豚用飼料を給餌した。 (Materials and methods)
1. 1. Animals: 4-5 week old pigs of Dylock or Landrace (weighing about 10 kg, female or male) were used.
2. 2. Virus strain: ASFV strain (genotype 2 P252) clinically isolated in Vietnam was used. The virus strain has been confirmed to be transmitted by contact and through drinking water. 10 2 HAD 50 / mL A virus solution in EMEM was prepared and used.
Preparation of 3.5-ALA and SFC (1) 5-ALA-containing feed: 100 mg / kg of body weight / day (body weight is at the start of the experiment) 5-ALA aqueous solution is used to raise pigs so that the dose is 5-ALA. It was mixed with feed and fed.
(2) 5-ALA and SFC-containing feed: 100 mg / kg body weight / day 5-ALA dose and 115 mg / kg body weight / day SFC dose (5-ALA to SFC molar ratio 1: 0.5) 5-ALA phosphate aqueous solution and SFC aqueous solution were mixed with the pig feeding feed and fed so as to be.
(3) No-treatment feed: As a negative control, a pig feed for pigs not mixed with 5-ALA phosphate or 5-ALA phosphate and SFC was fed.
１．動物：ディロック種もしくはランドレース種の４～５週齢の豚（体重約１０ｋｇ、雌または雄）を使用した。
２．ウイルス株：ベトナムにおいて臨床的に単離されたＡＳＦＶ株（遺伝子型２ Ｐ２５２）を使用した。当該ウイルス株は、接触感染および飲用水を通じた感染が確認されている。１０２ＨＡＤ５０／ｍＬ ＥＭＥＭ中のウイルス溶液を調製して使用した。
３．５－ＡＬＡおよびＳＦＣの調製
（１）５－ＡＬＡ含有飼料：１００ｍｇ／体重ｋｇ／日（体重は実験開始時点）の５－ＡＬＡ用量となるように、５－ＡＬＡリン酸塩水溶液を養豚用飼料と混合して給餌した。
（２）５－ＡＬＡおよびＳＦＣ含有飼料：１００ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および１１５ｍｇ／体重ｋｇ／日のＳＦＣ投与量（５－ＡＬＡとＳＦＣのモル比は１：０．５）となるように、５－ＡＬＡリン酸塩水溶液およびＳＦＣ水溶液を養豚用飼料と混合して給餌した。
（３）無処置用飼料：陰性対照として、５－ＡＬＡリン酸塩もしくは５－ＡＬＡリン酸塩およびＳＦＣを混合しない養豚用飼料を給餌した。 (Materials and methods)
1. 1. Animals: 4-5 week old pigs of Dylock or Landrace (weighing about 10 kg, female or male) were used.
2. 2. Virus strain: ASFV strain (
Preparation of 3.5-ALA and SFC (1) 5-ALA-containing feed: 100 mg / kg of body weight / day (body weight is at the start of the experiment) 5-ALA aqueous solution is used to raise pigs so that the dose is 5-ALA. It was mixed with feed and fed.
(2) 5-ALA and SFC-containing feed: 100 mg / kg body weight / day 5-ALA dose and 115 mg / kg body weight / day SFC dose (5-ALA to SFC molar ratio 1: 0.5) 5-ALA phosphate aqueous solution and SFC aqueous solution were mixed with the pig feeding feed and fed so as to be.
(3) No-treatment feed: As a negative control, a pig feed for pigs not mixed with 5-ALA phosphate or 5-ALA phosphate and SFC was fed.
４．試験方法：
１０匹の被験豚を５匹ずつ別の豚舎（豚舎ＡおよびＢ）に割り当てた。毎朝１０時に豚舎Ａの５匹の被験豚のうち３匹（Ａ１、Ａ２、Ａ３）に５－ＡＬＡ含有飼料を１００ｍｇ／体重ｋｇ／日の５－ＡＬＡ用量で７日間経口投与し、２匹（Ｂ１、Ｂ２）に無処置用飼料を７日間経口投与した。毎朝１０時に豚舎Ｂの５匹の被験豚のうち３匹（Ｃ１、Ｃ２、Ｃ３）に５－ＡＬＡおよびＳＦＣ含有飼料を、１００ｍｇ／体重ｋｇ／日の５－ＡＬＡおよび１１５ｍｇ／体重ｋｇ／日のＳＦＣの投与量で７日間経口投与し、２匹（Ｃ４、Ｃ５）に無処置用飼料を７日間経口投与した。
（表１）処置群の割り当て
飼料の投与開始後７日目に、１０２ＨＡＤ５０／ｍＬのＡＳＦＶをすべての被験豚に経口接種した。ＡＳＦＶ接種後、５－ＡＬＡ、５ＡＬＡ＋ＳＦＣまたは無処置用飼料の投与を継続し、各被験豚について、体温（直腸内温度）を毎日測定し、血中ウイルス濃度をＡＳＦＶ接種後０、４、６、８、１０、１２、１４、１８、２１日後の時点で検査するとともに、被検豚が死亡した場合には死亡日を記録した。
4. Test method:
Ten test pigs were assigned to different pig sheds (pig houses A and B), five each. Every morning at 10 o'clock, 3 out of 5 test pigs (A1, A2, A3) in Pighouse A were orally administered 5-ALA-containing feed at a dose of 100 mg / kg body weight / day for 7 days (2). B1, B2) were orally administered untreated feed for 7 days. At 10 o'clock every morning, 3 out of 5 test pigs (C1, C2, C3) in Pighouse B were fed 5-ALA and SFC-containing feed at 100 mg / kg / day 5-ALA and 115 mg / kg / day. The dose of SFC was orally administered for 7 days, and the untreated feed was orally administered to 2 animals (C4 and C5) for 7 days.
(Table 1) Assignment of treatment groups
On the 7th day after the start of feed administration, 10 2 HAD 50 / mL ASFV was orally inoculated to all test pigs. After inoculation with ASFV, administration of 5-ALA, 5ALA + SFC or untreated feed was continued, body temperature (rectal temperature) was measured daily for each test pig, and blood virus concentration was 0, 4, 6, after ASFV inoculation. The test was performed at 8, 10, 12, 14, 18, and 21 days later, and if the test pig died, the date of death was recorded.
１０匹の被験豚を５匹ずつ別の豚舎（豚舎ＡおよびＢ）に割り当てた。毎朝１０時に豚舎Ａの５匹の被験豚のうち３匹（Ａ１、Ａ２、Ａ３）に５－ＡＬＡ含有飼料を１００ｍｇ／体重ｋｇ／日の５－ＡＬＡ用量で７日間経口投与し、２匹（Ｂ１、Ｂ２）に無処置用飼料を７日間経口投与した。毎朝１０時に豚舎Ｂの５匹の被験豚のうち３匹（Ｃ１、Ｃ２、Ｃ３）に５－ＡＬＡおよびＳＦＣ含有飼料を、１００ｍｇ／体重ｋｇ／日の５－ＡＬＡおよび１１５ｍｇ／体重ｋｇ／日のＳＦＣの投与量で７日間経口投与し、２匹（Ｃ４、Ｃ５）に無処置用飼料を７日間経口投与した。
（表１）処置群の割り当て
Ten test pigs were assigned to different pig sheds (pig houses A and B), five each. Every morning at 10 o'clock, 3 out of 5 test pigs (A1, A2, A3) in Pighouse A were orally administered 5-ALA-containing feed at a dose of 100 mg / kg body weight / day for 7 days (2). B1, B2) were orally administered untreated feed for 7 days. At 10 o'clock every morning, 3 out of 5 test pigs (C1, C2, C3) in Pighouse B were fed 5-ALA and SFC-containing feed at 100 mg / kg / day 5-ALA and 115 mg / kg / day. The dose of SFC was orally administered for 7 days, and the untreated feed was orally administered to 2 animals (C4 and C5) for 7 days.
(Table 1) Assignment of treatment groups
（結果）
結果を図１の表２および下記表３、４に示す。
（表３）発熱、血中ウイルス陽性および死亡の有無
（表４)継続的な発熱および血中ウイルス陽性の開始日並びに死亡日
５－ＡＬＡ＋ＳＦＣを併用投与した被験豚（Ａ１、Ａ２、Ａ３）は、ＡＳＦＶ接種の２１日後まで全匹生存した。被験豚Ａ１およびＡ３は、接種の２１日後まで発熱を示さず、血中ウイルスについても陰性であった。被験豚Ａ２のみ、２０～２１日後にかけて４０℃以上の発熱を示し、２１日後に血中ウイルスが陽性となった。一方、同一豚舎Ａ内の無処置被験豚（Ｂ１、Ｂ２）のうち、被験豚Ｂ１はＡＳＦＶ接種の８日後から４０℃以上の発熱とともに、血中ウイルスが陽性の状態が継続し、１４日後に死亡した。被験豚Ｂ２も１０日後以降断続的に発熱を示し、１４日後以降は継続的な発熱と共に血中ウイルス陽性を示した。
５－ＡＬＡを単独投与した被験豚（Ｃ１、Ｃ２、Ｃ３）も、ＡＳＦＶ接種の２１日後まで全匹生存した。被験豚Ｃ１は、接種の２１日後まで発熱を示さず、血中ウイルスについても陰性であった。被験豚Ｃ２は、１０～１１日後にかけて４０℃以上の発熱を示したものの、その後発熱はなく、２１日後まで血中ウイルスは陰性であった。被験豚Ｃ３は、接種の２１日後まで発熱を示さず、２１日後に血中ウイルスのみ陽性を示した。一方、同一豚舎Ｂ内の無処置被験豚（Ｄ１、Ｄ２）はいずれも２１日後以前に死亡した。被験豚Ｄ１は１１日後から４０℃以上の発熱が継続し、１２日後以降血中ウイルスが陽性の状態が継続し、１９日後に死亡した。被験豚Ｄ２は１２日後以降継続的に発熱と共に血中ウイルス陽性を示し、１８日後に死亡した。 (result)
The results are shown in Table 2 of FIG. 1 and Tables 3 and 4 below.
(Table 3) Fever, positive blood virus, and presence or absence of death
(Table 4) Start date and death date of continuous fever and blood virus positive
All the test pigs (A1, A2, A3) to which 5-ALA + SFC was co-administered survived until 21 days after the ASFV inoculation. Test pigs A1 and A3 showed no fever until 21 days after inoculation and were also negative for blood virus. Only the test pig A2 showed a fever of 40 ° C. or higher over 20 to 21 days, and the blood virus became positive 21 days later. On the other hand, among the untreated test pigs (B1, B2) in the same piggery A, the test pig B1 continued to be positive for blood virus 14 days after the fever of 40 ° C. or higher from 8 days after the ASFV inoculation. Died. The test pig B2 also showed intermittent fever after 10 days, and showed blood virus positive with continuous fever after 14 days.
All the test pigs (C1, C2, C3) to which 5-ALA was administered alone survived until 21 days after the ASFV inoculation. Test pig C1 showed no fever until 21 days after inoculation and was also negative for blood virus. The test pig C2 showed a fever of 40 ° C. or higher over 10 to 11 days, but no fever thereafter, and the blood virus was negative until 21 days later. The test pig C3 showed no fever until 21 days after inoculation, and only the blood virus was positive 21 days later. On the other hand, the untreated test pigs (D1 and D2) in the same piggery B all died before 21 days later. The test pig D1 continued to have a fever of 40 ° C. or higher after 11 days, continued to be positive for blood virus after 12 days, and died 19 days later. The test pig D2 showed continuous fever and positive blood virus after 12 days, and died 18 days later.
結果を図１の表２および下記表３、４に示す。
（表３）発熱、血中ウイルス陽性および死亡の有無
５－ＡＬＡを単独投与した被験豚（Ｃ１、Ｃ２、Ｃ３）も、ＡＳＦＶ接種の２１日後まで全匹生存した。被験豚Ｃ１は、接種の２１日後まで発熱を示さず、血中ウイルスについても陰性であった。被験豚Ｃ２は、１０～１１日後にかけて４０℃以上の発熱を示したものの、その後発熱はなく、２１日後まで血中ウイルスは陰性であった。被験豚Ｃ３は、接種の２１日後まで発熱を示さず、２１日後に血中ウイルスのみ陽性を示した。一方、同一豚舎Ｂ内の無処置被験豚（Ｄ１、Ｄ２）はいずれも２１日後以前に死亡した。被験豚Ｄ１は１１日後から４０℃以上の発熱が継続し、１２日後以降血中ウイルスが陽性の状態が継続し、１９日後に死亡した。被験豚Ｄ２は１２日後以降継続的に発熱と共に血中ウイルス陽性を示し、１８日後に死亡した。 (result)
The results are shown in Table 2 of FIG. 1 and Tables 3 and 4 below.
(Table 3) Fever, positive blood virus, and presence or absence of death
All the test pigs (C1, C2, C3) to which 5-ALA was administered alone survived until 21 days after the ASFV inoculation. Test pig C1 showed no fever until 21 days after inoculation and was also negative for blood virus. The test pig C2 showed a fever of 40 ° C. or higher over 10 to 11 days, but no fever thereafter, and the blood virus was negative until 21 days later. The test pig C3 showed no fever until 21 days after inoculation, and only the blood virus was positive 21 days later. On the other hand, the untreated test pigs (D1 and D2) in the same piggery B all died before 21 days later. The test pig D1 continued to have a fever of 40 ° C. or higher after 11 days, continued to be positive for blood virus after 12 days, and died 19 days later. The test pig D2 showed continuous fever and positive blood virus after 12 days, and died 18 days later.
実施例１と同様の試験を、よりウイルス高いウイルス負荷およびより低い５－ＡＬＡ投与量で行った。
（材料と方法）
１．動物：６～７週齢の豚（体重約２０ｋｇ）を使用した。
２．ウイルス株：実施例１で用いたベトナムにおいて臨床的に単離されたＡＳＦＶ株（遺伝子型２ Ｐ２５２）を、実施例１の１０倍の濃度である１０３ＨＡＤ５０／ｍＬ ＥＭＥＭ中のウイルス溶液を調製して使用した。
３．５－ＡＬＡおよびＳＦＣの調製
（１）５－ＡＬＡ含有飼料：３ｍｇ／体重ｋｇ／日、１０ｍｇ／体重ｋｇ／日および３０ｍｇ／体重ｋｇ／日（体重は実験開始時点）の５－ＡＬＡ用量となるように、５－ＡＬＡリン酸塩水溶液を養豚用飼料と混合して給餌した。
（２）５－ＡＬＡおよびＳＦＣ含有飼料：３ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および３．４５ｍｇ／体重ｋｇ／日のＳＦＣ投与量、１０ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および１１．５ｍｇ／体重ｋｇ／日のＳＦＣ投与量、３０ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および３４．５ｍｇ／体重ｋｇ／日のＳＦＣ投与量（いずれも５－ＡＬＡとＳＦＣのモル比は１：０．５）となるように、５－ＡＬＡリン酸塩水溶液およびＳＦＣ水溶液を養豚用飼料と混合して給餌した。
（３）無処置用飼料：陰性対照として、５－ＡＬＡリン酸塩もしくは５－ＡＬＡリン酸塩およびＳＦＣを混合しない養豚用飼料を給餌した。 Similar tests as in Example 1 were performed with higher viral load and lower 5-ALA dose.
(Materials and methods)
1. 1. Animals: Pigs 6-7 weeks old (weighing about 20 kg) were used.
2. 2. Virus strain: ASFV strain (genotype 2 P252) clinically isolated in Vietnam used in Example 1 was subjected to a virus solution in 10 3 HAD 50 / mL EMEM, which was 10 times the concentration of Example 1. Prepared and used.
Preparation of 3.5-ALA and SFC (1) 5-ALA-containing feed: 5-ALA dose of 3 mg / kg body weight / day, 10 mg / kg body weight / day and 30 mg / kg body weight / day (body weight at the start of the experiment) A 5-ALA phosphate aqueous solution was mixed with a pig feed for feeding so as to be.
(2) 5-ALA and SFC-containing feed: 3 mg / kg body weight / day 5-ALA dose and 3.45 mg / body weight kg / day SFC dose, 10 mg / body weight kg / day 5-ALA dose and 11.5 mg / kg body weight / day SFC dose, 30 mg / kg body weight / day 5-ALA dose and 34.5 mg / kg body weight / day SFC dose (both the molar ratio of 5-ALA to SFC is The 5-ALA phosphate aqueous solution and the SFC aqueous solution were mixed with the pig-rearing feed and fed so as to be 1: 0.5).
(3) No-treatment feed: As a negative control, a pig feed for pigs not mixed with 5-ALA phosphate or 5-ALA phosphate and SFC was fed.
（材料と方法）
１．動物：６～７週齢の豚（体重約２０ｋｇ）を使用した。
２．ウイルス株：実施例１で用いたベトナムにおいて臨床的に単離されたＡＳＦＶ株（遺伝子型２ Ｐ２５２）を、実施例１の１０倍の濃度である１０３ＨＡＤ５０／ｍＬ ＥＭＥＭ中のウイルス溶液を調製して使用した。
３．５－ＡＬＡおよびＳＦＣの調製
（１）５－ＡＬＡ含有飼料：３ｍｇ／体重ｋｇ／日、１０ｍｇ／体重ｋｇ／日および３０ｍｇ／体重ｋｇ／日（体重は実験開始時点）の５－ＡＬＡ用量となるように、５－ＡＬＡリン酸塩水溶液を養豚用飼料と混合して給餌した。
（２）５－ＡＬＡおよびＳＦＣ含有飼料：３ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および３．４５ｍｇ／体重ｋｇ／日のＳＦＣ投与量、１０ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および１１．５ｍｇ／体重ｋｇ／日のＳＦＣ投与量、３０ｍｇ／体重ｋｇ／日の５－ＡＬＡ投与量および３４．５ｍｇ／体重ｋｇ／日のＳＦＣ投与量（いずれも５－ＡＬＡとＳＦＣのモル比は１：０．５）となるように、５－ＡＬＡリン酸塩水溶液およびＳＦＣ水溶液を養豚用飼料と混合して給餌した。
（３）無処置用飼料：陰性対照として、５－ＡＬＡリン酸塩もしくは５－ＡＬＡリン酸塩およびＳＦＣを混合しない養豚用飼料を給餌した。 Similar tests as in Example 1 were performed with higher viral load and lower 5-ALA dose.
(Materials and methods)
1. 1. Animals: Pigs 6-7 weeks old (weighing about 20 kg) were used.
2. 2. Virus strain: ASFV strain (
Preparation of 3.5-ALA and SFC (1) 5-ALA-containing feed: 5-ALA dose of 3 mg / kg body weight / day, 10 mg / kg body weight / day and 30 mg / kg body weight / day (body weight at the start of the experiment) A 5-ALA phosphate aqueous solution was mixed with a pig feed for feeding so as to be.
(2) 5-ALA and SFC-containing feed: 3 mg / kg body weight / day 5-ALA dose and 3.45 mg / body weight kg / day SFC dose, 10 mg / body weight kg / day 5-ALA dose and 11.5 mg / kg body weight / day SFC dose, 30 mg / kg body weight / day 5-ALA dose and 34.5 mg / kg body weight / day SFC dose (both the molar ratio of 5-ALA to SFC is The 5-ALA phosphate aqueous solution and the SFC aqueous solution were mixed with the pig-rearing feed and fed so as to be 1: 0.5).
(3) No-treatment feed: As a negative control, a pig feed for pigs not mixed with 5-ALA phosphate or 5-ALA phosphate and SFC was fed.
４．試験方法：
下記表に示すように、３０ｍｇ／ｋｇ／日の５－ＡＬＡおよび３４．５ｍｇ／ｋｇ／日のＳＦＣを併用投与する群（Ａ１）、１０ｍｇ／ｋｇ／日および１１．５ｍｇ／ｋｇ／日のＳＦＣを併用投与する群（Ｂ１）、３ｍｇ／ｋｇ／日および３，４５ｍｇ／ｋｇ／日のＳＦＣを併用投与する群（Ｃ１）、３０ｍｇ／ｋｇ／日の５－ＡＬＡを単独投与する群（Ａ２）、１０ｍｇ／ｋｇ／日の５－ＡＬＡを単独投与する群（Ｂ２）、３ｍｇ／ｋｇ／日の５－ＡＬＡを単独投与する群（Ｃ２）、および無処置の群（Ｄ）に各３匹の動物を割り当て、各薬剤を７日間経口投与した。
（表５）処置群の割り当て
飼料の投与開始後７日目に、１０３ＨＡＤ５０／ｍＬのＡＳＦＶをすべての被験豚に経鼻接種した。ＡＳＦＶ接種後、５－ＡＬＡ、５ＡＬＡ＋ＳＦＣまたは無処置用飼料の投与を継続し、各被験豚について、体温（直腸内温度）を毎日測定し、血中ウイルス濃度をＡＳＦＶ接種後０、４、７、１０、１４、１７、２１、２８日後の時点、および、体温が４０℃を超えた場合に追加的に検査するとともに、被検豚が死亡した場合には死亡日を記録した。血中ウイルス濃度はリアルタイムＰＣＲを用いて測定した。
なお、血中ウイルス濃度について陽性を示した豚は、一般的に豚飼育時にウイルス感染が疑われる場合に行われる処置にしたがって、同一豚舎内の感染豚専用の檻へ隔離した。 4. Test method:
As shown in the table below, the group (A1) in which 5-ALA of 30 mg / kg / day and SFC of 34.5 mg / kg / day are co-administered (A1) and SFC of 10 mg / kg / day and 11.5 mg / kg / day. (B1), 3 mg / kg / day and 3,45 mg / kg / day SFC combined administration (C1), 30 mg / kg / day 5-ALA alone (A2) Three animals each in the group receiving 10 mg / kg / day 5-ALA alone (B2), the group receiving 3 mg / kg / day 5-ALA alone (C2), and the untreated group (D). Animals were assigned and each drug was orally administered for 7 days.
(Table 5) Assignment of treatment groups
7 days after initiation of administration of feed, nasally inoculated with ASFV of 10 3 HAD 50 / mL in all tested pigs. After inoculation with ASFV, administration of 5-ALA, 5ALA + SFC or untreated feed was continued, body temperature (rectal temperature) was measured daily for each test pig, and blood virus concentration was 0, 4, 7, after ASFV inoculation. At 10, 14, 17, 21, 28 days later, and when the body temperature exceeded 40 ° C., additional tests were performed, and when the test pig died, the date of death was recorded. Blood virus concentration was measured using real-time PCR.
Pigs that showed a positive blood virus concentration were isolated in a cage dedicated to infected pigs in the same piggery according to the treatment generally performed when virus infection was suspected during pig breeding.
下記表に示すように、３０ｍｇ／ｋｇ／日の５－ＡＬＡおよび３４．５ｍｇ／ｋｇ／日のＳＦＣを併用投与する群（Ａ１）、１０ｍｇ／ｋｇ／日および１１．５ｍｇ／ｋｇ／日のＳＦＣを併用投与する群（Ｂ１）、３ｍｇ／ｋｇ／日および３，４５ｍｇ／ｋｇ／日のＳＦＣを併用投与する群（Ｃ１）、３０ｍｇ／ｋｇ／日の５－ＡＬＡを単独投与する群（Ａ２）、１０ｍｇ／ｋｇ／日の５－ＡＬＡを単独投与する群（Ｂ２）、３ｍｇ／ｋｇ／日の５－ＡＬＡを単独投与する群（Ｃ２）、および無処置の群（Ｄ）に各３匹の動物を割り当て、各薬剤を７日間経口投与した。
（表５）処置群の割り当て
なお、血中ウイルス濃度について陽性を示した豚は、一般的に豚飼育時にウイルス感染が疑われる場合に行われる処置にしたがって、同一豚舎内の感染豚専用の檻へ隔離した。 4. Test method:
As shown in the table below, the group (A1) in which 5-ALA of 30 mg / kg / day and SFC of 34.5 mg / kg / day are co-administered (A1) and SFC of 10 mg / kg / day and 11.5 mg / kg / day. (B1), 3 mg / kg / day and 3,45 mg / kg / day SFC combined administration (C1), 30 mg / kg / day 5-ALA alone (A2) Three animals each in the group receiving 10 mg / kg / day 5-ALA alone (B2), the group receiving 3 mg / kg / day 5-ALA alone (C2), and the untreated group (D). Animals were assigned and each drug was orally administered for 7 days.
(Table 5) Assignment of treatment groups
Pigs that showed a positive blood virus concentration were isolated in a cage dedicated to infected pigs in the same piggery according to the treatment generally performed when virus infection was suspected during pig breeding.
（結果）
結果を下記表６および図２～３の表７、８に示す。なお、表７、８の「経過日数」は、ＡＳＦＶウイルス接種後の日数を示す。
（表６）発熱、血中ウイルス陽性および死亡の有無
表６に示すように、無処置群ではすべての被験豚がウイルス接種後２１日後までに死亡し、ウイルス接種後２８日時点での生存率が０％であったのに対して、高用量併用投与群Ａ１（５－ＡＬＡ：３０ｍｇ／ｋｇ／日、ＳＦＣ：３４．５ｍｇ／ｋｇ／日）、中用量併用投与群Ｂ２（１０ｍｇ／ｋｇ／日、ＳＦＣ：１１．５ｍｇ／ｋｇ／日）、低用量併用投与群Ｃ２（３ｍｇ／ｋｇ／日、ＳＦＣ：３．４５ｍｇ／ｋｇ／日）では、同時点でそれぞれ６７％、１００％、６７％の生存率、高用量単独投与群Ａ２（５－ＡＬＡ：３０ｍｇ／ｋｇ／日）、中用量単独投与群Ｂ２（５－ＡＬＡ：１０ｍｇ／ｋｇ／日）、低用量単独投与群Ｃ２（５－ＡＬＡ：３ｍｇ／ｋｇ／日）では、同時点でそれぞれ１００％、１００％、３３％の生存率を示し、感染および発症に対する防御を示した。
表７、８でさらに詳細に示すように、５ＡＬＡの低～高用量単独投与および５ＡＬＡとＳＦＣの低～高用量併用投与は、発熱および血中ウイルス試験においても、感染抑制を示す結果を示した。
なお、高用量併用投与群Ａ１の被験豚の１匹（識別番号３）は、ウイルス感染処置後６日後から発熱および血中ウイルス試験陽性を示し、感染処置後１３日で死亡したが、当該被験豚についてはウイルス感染処置の際に、鼻部を傷害したことが確認されており、傷害部から侵入したウイルスによる爆発的な感染拡大が生じた可能性が疑われる。
また、低用量併用投与群Ｃ１の被験豚の１匹（識別番号１４）は、ウイルス感染処置後２５日で死亡したが、当該被験豚はウイルス感染処置後１４日の時点で血中ウイルス試験において陽性を示したために、感染豚専用の檻へ移動したものの、その後の血中ウイルス試験（ウイルス感染処置後１５日および１７日後）において陰性が確認されており、ウイルス感染処置後１４日の時点の血中ウイルス試験の結果は擬陽性であった可能性が疑われる。感染豚専用の檻では濃度の高いウイルスを保有している他の陽性豚からの同居感染が容易となるため、当該被験豚は感染豚専用檻内で感染し、ウイルス感染処置後２５日で死亡したものと考えられる。
本試験により、５－ＡＬＡが低用量でもＡＳＦＶウイルス感染に対する防御を提供するともに、低用量においても、５－ＡＬＡとＳＦＣの併用がさらに優れた防御を示すことが示された。 (result)
The results are shown in Table 6 below and Tables 7 and 8 of FIGS. The "elapsed days" in Tables 7 and 8 indicate the number of days after inoculation with the ASFV virus.
(Table 6) Fever, positive blood virus, and presence or absence of death
As shown in Table 6, in the untreated group, all the test pigs died by 21 days after the virus inoculation, and the survival rate at 28 days after the virus inoculation was 0%, whereas the high dose combination was used. Administration group A1 (5-ALA: 30 mg / kg / day, SFC: 34.5 mg / kg / day), medium-dose combination administration group B2 (10 mg / kg / day, SFC: 11.5 mg / kg / day), low In the combined dose group C2 (3 mg / kg / day, SFC: 3.45 mg / kg / day), the survival rates were 67%, 100%, and 67% at the same time, respectively, and the high-dose single-dose group A2 (5-ALA). : 30 mg / kg / day), medium-dose single-administration group B2 (5-ALA: 10 mg / kg / day), low-dose single-administration group C2 (5-ALA: 3 mg / kg / day), 100 at the same time. They showed a survival rate of%, 100%, and 33%, and showed protection against infection and onset.
As shown in more detail in Tables 7 and 8, low to high dose single doses of 5ALA and low to high dose combined doses of 5ALA and SFC also showed results showing infection suppression in fever and blood virus tests. ..
One of the test pigs (identification number 3) in the high-dose combination administration group A1 showed fever and a positiveblood virus test 6 days after the virus infection treatment, and died 13 days after the infection treatment. It has been confirmed that the nose of pigs was injured during the virus infection treatment, and it is suspected that the virus that invaded from the injured part may have caused an explosive spread of infection.
In addition, one of the test pigs (identification number 14) in the low-dose combination administration group C1 died 25 days after the virus infection treatment, but the test pig was found in theblood virus test 14 days after the virus infection treatment. Although they were moved to a cage dedicated to infected pigs because they showed positive results, negative results were confirmed in subsequent blood virus tests (15 and 17 days after virus infection treatment), and 14 days after virus infection treatment. It is suspected that the results of the blood virus test may have been false positives. In the cage dedicated to infected pigs, cohabitation infection from other positive pigs carrying a high concentration of virus is easy, so the subject pig was infected in the cage dedicated to infected pigs and died 25 days after the virus infection treatment. It is probable that it was done.
This study showed that 5-ALA provides protection against ASFV virus infection at low doses, while the combination of 5-ALA and SFC provides even better protection at low doses.
結果を下記表６および図２～３の表７、８に示す。なお、表７、８の「経過日数」は、ＡＳＦＶウイルス接種後の日数を示す。
（表６）発熱、血中ウイルス陽性および死亡の有無
表７、８でさらに詳細に示すように、５ＡＬＡの低～高用量単独投与および５ＡＬＡとＳＦＣの低～高用量併用投与は、発熱および血中ウイルス試験においても、感染抑制を示す結果を示した。
なお、高用量併用投与群Ａ１の被験豚の１匹（識別番号３）は、ウイルス感染処置後６日後から発熱および血中ウイルス試験陽性を示し、感染処置後１３日で死亡したが、当該被験豚についてはウイルス感染処置の際に、鼻部を傷害したことが確認されており、傷害部から侵入したウイルスによる爆発的な感染拡大が生じた可能性が疑われる。
また、低用量併用投与群Ｃ１の被験豚の１匹（識別番号１４）は、ウイルス感染処置後２５日で死亡したが、当該被験豚はウイルス感染処置後１４日の時点で血中ウイルス試験において陽性を示したために、感染豚専用の檻へ移動したものの、その後の血中ウイルス試験（ウイルス感染処置後１５日および１７日後）において陰性が確認されており、ウイルス感染処置後１４日の時点の血中ウイルス試験の結果は擬陽性であった可能性が疑われる。感染豚専用の檻では濃度の高いウイルスを保有している他の陽性豚からの同居感染が容易となるため、当該被験豚は感染豚専用檻内で感染し、ウイルス感染処置後２５日で死亡したものと考えられる。
本試験により、５－ＡＬＡが低用量でもＡＳＦＶウイルス感染に対する防御を提供するともに、低用量においても、５－ＡＬＡとＳＦＣの併用がさらに優れた防御を示すことが示された。 (result)
The results are shown in Table 6 below and Tables 7 and 8 of FIGS. The "elapsed days" in Tables 7 and 8 indicate the number of days after inoculation with the ASFV virus.
(Table 6) Fever, positive blood virus, and presence or absence of death
As shown in more detail in Tables 7 and 8, low to high dose single doses of 5ALA and low to high dose combined doses of 5ALA and SFC also showed results showing infection suppression in fever and blood virus tests. ..
One of the test pigs (identification number 3) in the high-dose combination administration group A1 showed fever and a positive
In addition, one of the test pigs (identification number 14) in the low-dose combination administration group C1 died 25 days after the virus infection treatment, but the test pig was found in the
This study showed that 5-ALA provides protection against ASFV virus infection at low doses, while the combination of 5-ALA and SFC provides even better protection at low doses.
以上の結果から、５－ＡＬＡまたは５－ＡＬＡとＳＦＣの併用投与により、ＡＳＦＶの感染および／または感染後のＡＳＦ発症が抑制されることを示している。上記試験で示したように、５－ＡＬＡの投与によって、アフリカ豚熱（ＡＳＦ）の感染および／または症状を抑制し、アフリカ豚熱（ＡＳＦ）を治療または予防し得ることができる。
From the above results, it is shown that 5-ALA or 5-ALA and SFC combined administration suppresses ASFV infection and / or ASF onset after infection. As shown in the above studies, administration of 5-ALA can suppress African swine fever (ASF) infection and / or symptoms and treat or prevent African swine fever (ASF).
Claims (6)
- 下記式（Ｉ）
で示される化合物又はその塩を含有する、アフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。 The following formula (I)
A therapeutic and / or prophylactic agent for African swine fever (ASF), which comprises the compound indicated by or a salt thereof. - Ｒ１及びＲ２が水素原子であることを特徴とする、請求項１に記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。 The therapeutic and / or prophylactic agent for African swine fever (ASF) according to claim 1, wherein R 1 and R 2 are hydrogen atoms.
- さらに、一種又は二種以上の金属含有化合物を含有することを特徴とする、請求項１又は２記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。 The therapeutic and / or prophylactic agent for African swine fever (ASF) according to claim 1 or 2, further comprising one or more metal-containing compounds.
- 金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデン又はコバルトを含有する化合物であることを特徴とする、請求項３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。 The treatment and / or treatment for African swine fever (ASF) according to claim 3, wherein the metal-containing compound is a compound containing iron, magnesium, zinc, nickel, vanadium, copper, chromium, molybdenum or cobalt. Prophylactic agent.
- 金属含有化合物が、鉄、マグネシウム又は亜鉛を含有する化合物であることを特徴とする、請求項３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。 The therapeutic and / or preventive agent for African swine fever (ASF) according to claim 3, wherein the metal-containing compound is a compound containing iron, magnesium or zinc.
- 金属含有化合物が、鉄を含有する化合物であることを特徴とする、請求項３記載のアフリカ豚熱（ＡＳＦ）の治療及び／又は予防剤。 The therapeutic and / or preventive agent for African swine fever (ASF) according to claim 3, wherein the metal-containing compound is an iron-containing compound.
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| CN116549429A (en) * | 2023-07-06 | 2023-08-08 | 北京挑战生物技术有限公司 | Application of 5-aminolevulinic acid in preparation of products for preventing and treating porcine reproductive and respiratory syndrome |
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| CN116549429A (en) * | 2023-07-06 | 2023-08-08 | 北京挑战生物技术有限公司 | Application of 5-aminolevulinic acid in preparation of products for preventing and treating porcine reproductive and respiratory syndrome |
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