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WO2017170970A1 - Composition de lutte contre les microsporidies chez des poissons et procédé de lutte contre les microsporidies chez des poissons utilisant celle-ci - Google Patents

Composition de lutte contre les microsporidies chez des poissons et procédé de lutte contre les microsporidies chez des poissons utilisant celle-ci Download PDF

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Publication number
WO2017170970A1
WO2017170970A1 PCT/JP2017/013489 JP2017013489W WO2017170970A1 WO 2017170970 A1 WO2017170970 A1 WO 2017170970A1 JP 2017013489 W JP2017013489 W JP 2017013489W WO 2017170970 A1 WO2017170970 A1 WO 2017170970A1
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WIPO (PCT)
Prior art keywords
group
substituted
seafood
fish
controlling
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PCT/JP2017/013489
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English (en)
Japanese (ja)
Inventor
幸辰 藤田
博 横山
大樹 小川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Tokyo NUC
Maruha Nichiro Corp
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University of Tokyo NUC
Maruha Nichiro Corp
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Priority claimed from JP2017047531A external-priority patent/JP6343796B2/ja
Application filed by University of Tokyo NUC, Maruha Nichiro Corp filed Critical University of Tokyo NUC
Priority to KR1020187030805A priority Critical patent/KR20180125565A/ko
Priority to US16/089,226 priority patent/US10813914B2/en
Priority to CN201780021272.1A priority patent/CN108883095B/zh
Priority to EP17775503.0A priority patent/EP3437642A4/fr
Priority to MX2018011974A priority patent/MX2018011974A/es
Priority to AU2017239880A priority patent/AU2017239880B2/en
Publication of WO2017170970A1 publication Critical patent/WO2017170970A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A01N43/52—1,3-Diazoles; Hydrogenated 1,3-diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a composition for controlling microspores of seafood and a method for controlling microspores of seafood using the same.
  • Microsporidia are a group of unicellular eukaryotes that parasitize the cells of various animals such as insects, crustaceans, seafood, and mammals, and many of them are pathogenic to these animals.
  • microsporeworms that are pathogenic to seafood, (1) Amberjack, Hamachi encephalomyelitis-causing microsporidia, (2) Heterosporis anguillarum, which causes downy mildew in cultured eels (3) Glugea plecoglossi, etc.
  • Buko becosis is an infectious disease of mojaco (brass fry) caused by the microsporidia Microsporidium seriolae, which is currently confirmed in Japan and Taiwan.
  • Mojaco is infected with Microsporidium seriolae
  • a cheese mass cyst (spore sac) that can be seen with the naked eye is formed in the muscle.
  • the fish body becomes uneven as the surrounding muscle tissue melts.
  • Beco's disease generally disappears with age, but part of it remains in the muscle at the time of shipment, which can greatly reduce the commercial value. For this reason, farmers have suffered significant economic losses.
  • even in cultured amberjack although the types of microsporidia that cause it are different, the occurrence of downy mildew has become a problem and the damage is on the rise.
  • Benzimidazole drugs are examples of drugs that have a high therapeutic effect on microsporidia in terrestrial animals including humans. For example, in an antibacterial activity test in a culture test, it has been reported that high antibacterial activity is observed for benzimidazole drugs or fumagillin against some microsporidia. In particular, albendazole (see the following formula) has been reported to exhibit high antibacterial activity against many microsporeworms (see Non-Patent Documents 3 to 7).
  • benzimidazole-containing drugs including albendazole have become the first choice for encephalistosis in rabbits caused by human microsporidia and microsporidia as the causative agent (see Non-Patent Document 8). ).
  • fumagillin which is an antibiotic against amoeba
  • Ayu gulgeosis causal pathogen is a kind of microsporidia belonging to the subfamily of Apansporoblast.
  • Glugea plecoglossi see Non-Patent Document 1
  • eel beko disease a high therapeutic effect was observed. Has been reported.
  • Benzimidazole drugs are approved in many countries as animal husbandry and human medicines for parasitic diseases. In Japan as well, as human body drugs, echinococcus control agent, escazole (main component: albendazole), as livestock medicine, facinex (main component: triclabendazole), roundworm, roundworm, whipworm Marine bantel (main component: fenbendazole (see the formula below) for trough puffer's aphids (heterobotulosis) as an insecticide, flumoxal (main component: fulbendazole), Maypol (main component: fenbendazole), and a marine product )) Is commercially available.
  • fumagillin is not approved as a human body medicine or animal husbandry because of its low safety against animals.
  • benzimidazole derivatives only changes in the protozoa morphology under a microscope after drug sensitization to the spiderfish gulgea disease have been confirmed.
  • glugea anomala is a microsporidia with a pathological condition that is distinctly different from the genus Microsporidium, which is susceptible to the action of drugs in the bath because it makes cysts mainly on the body surface of fish, and forms cysts in the muscles. For this reason, it is not an exaggeration to say that there is no information on the control effect against the genus Microspodium, which is the most important from the viewpoint of productivity for aquaculture business.
  • the present invention has been made in view of the above circumstances, and prevents the infection of sea urchin muscles or organs by microsporidia and / or suppresses the growth of microspores in seafood muscles or organs. And / or a composition for controlling microspores of seafood that is highly effective in controlling microsporeworms from the body of seafood and is excellent in safety, and control of microsporeworms of seafood using the same
  • the purpose is to provide a method that can be effectively used in industry.
  • a first aspect of the present invention that meets the above-described object is represented by the following general formula (I), prevents infection of microspores to muscles or organs of seafood and / or muscles or organs of seafood
  • An object of the present invention is to provide a composition for controlling microspores of fish and shellfish containing one or more selected from the group consisting of compounds that produce a compound represented by formula (I) as an active ingredient. It is.
  • R 2 represents an amino group, a functional group represented by the formula —NH—COOR 8 , a functional group represented by the formula —N ⁇ CHR 9 , a functional group represented by the formula —N ⁇ CR 10 (R 11 ),
  • a functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group, R 4 , R 6 and R 7 are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected
  • the second aspect of the present invention is represented by the above general formula (I), prevents infection of microsporeworms to the muscles or organs of seafood and / or microscopically in the muscles or organs of seafood.
  • a compound having an activity of inhibiting the growth of spores and / or eliminating microsporeworms from the body of fish and shellfish, a pharmaceutically acceptable salt thereof, and metabolism in the body of fish and shellfish, the above general formula (I) By providing a method for controlling microsporeworms in fish and shellfish, comprising the step of administering to the fish and shellfish a composition comprising one or more selected from the group consisting of compounds that produce the compound represented by It solves the problem.
  • the composition is represented by the general formula (I).
  • the compound that produces the compound represented by the general formula (I) is represented by the following formula (8): )
  • the seafood is, for example, perch It may be a fish belonging to (Perciformes) or the flounder (Pleuronectiformes).
  • the fish and shellfish are periwinkle.
  • Tuna genus Thunnus
  • Persimmonidae Carangidae
  • Buri Buri
  • Persimmonidae Sparidae
  • Red sea bream Chorysophrys
  • Lepidoptera Paralichthyidae
  • Flatfish Paralichthys
  • flounder It may be a fish belonging to the genus Pleuronectidae (Verasper).
  • the microsporeworm is, for example, Microsporidium. It may be a microsporeworm belonging to the genus.
  • the microsporeworm is Microsporidium seriolae. There may be.
  • the composition may be, for example, an oral administration agent, a feed for fish farming, an injection, or a bath powder. Good.
  • control of microsporeworms means prevention of infection of microsporeworms, prevention of growth of microsporeworms that have entered (infected) the body of seafood, extermination and other muscles of A seafood Or it refers to the prevention of microspore invasion into organs and the management of the population (including extermination and killing).
  • the administration to the seafood may be oral administration.
  • the first of the present invention is an oral preparation.
  • the composition for controlling microspores of fish and shellfish according to the embodiment is applied once or a plurality of times at intervals of 1 day or more and 180 days or less so that the dose of the active ingredient is 0.1 mg / kg or more and 100 mg / kg or less.
  • the composition for controlling microsporeworms of fish and shellfish according to the first aspect of the present invention, which is an oral preparation may be effective for preventing the infection of fish and shellfish by oral administration.
  • the microsporeworms of fish and shellfish may be controlled by oral administration once or multiple times at intervals of 6 hours or more and 180 days or less so that the dose of the component is 20 mg / kg or more and 400 mg / kg or less. .
  • the composition for controlling microsporeworms of seafood according to the first aspect of the present invention which is an oral agent, is used as an active ingredient thereof. Even if the dose is 20 mg / kg or more and 400 mg / kg or less, it is administered orally several times at intervals of 3 days or more and 180 days or less to control the microsporidia of seafood and prevent reinfection. Good.
  • oral administration may be performed at intervals of 5 days or more and 21 days or less, and the plurality of oral administrations may be defined as one cycle, and the cycle may be repeated at intervals of 3 days or more and 180 days or less.
  • the administration to the seafood may be intramuscular injection or intraperitoneal injection.
  • the administration to the fish and shellfish may be immersion in a medicine bath, and in this case, it is a medicine bath.
  • Immersion in fish and shellfish in a medicinal bath solution containing the composition for controlling microspores of fish and shellfish according to the first aspect of the present invention in an amount such that the concentration of the active ingredient is 1 to 1000 ppm. Administration may be performed.
  • the present invention it is possible to prevent infection of microsporeworms in muscles or organs of seafood and / or suppress the growth of microsporeworms in muscles or organs of seafood, and / or the body of seafood.
  • the present invention provides a composition for controlling microspores of seafood that is highly effective in controlling microsporeworms and is excellent in safety, and a method for controlling microspores of seafood using the same.
  • composition for controlling microspores of seafood according to the first embodiment of the present invention (hereinafter sometimes referred to as “composition for controlling microspores of seafood” or simply “composition”) .) Is represented by the following general formula (I), and prevents the infection of fish and muscles or organs with microsporeworms and / or the growth of microspores in fish and shellfish muscles or organs: It is represented by the following general formula (I) by a compound having an activity of inhibiting and / or eliminating microsporeworms from the body of fish and shellfish, a pharmaceutically acceptable salt thereof, and metabolism in the body of fish and shellfish One or more selected from the group consisting of compounds that produce compounds (prodrugs) are included as active ingredients.
  • R 2 represents an amino group, a functional group represented by the formula —NH—COOR 8 , a functional group represented by the formula —N ⁇ CHR 9 , a functional group represented by the formula —N ⁇ CR 10 (R 11 ),
  • a functional group selected from the group consisting of a 2-thiazolyl group and an alkylthio group, R 4 , R 6 and R 7 are each independently a hydrogen atom, halogen atom, nitro group, sulfonic acid group, carboxyl group, cyano group, acyl group, alkyl group, cycloalkyl group, alkoxyl group, aryl group, From heteroaryl group, aryloxy group, heteroaryloxy group, substituted acyl group, substituted alkyl group, substituted cycloalkyl group, substituted alkoxyl group, substituted aryl group, substituted heteroaryl group, substituted aryloxy group, substituted heteroaryloxy group An atom or functional group selected
  • the substituted or unsubstituted alkyl group in the general formula (I) is preferably an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. Included in the above general formula (I) are a substituted or unsubstituted alkylthio group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxyl group, and a substituted or unsubstituted alkyl sulfoxide group (alkylsulfinyl group).
  • the alkyl groups are each independently an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms.
  • the substituted or unsubstituted cycloalkyl group is preferably a cycloalkyl having 3 to 7 carbon atoms.
  • the substituted or unsubstituted aryl group in the above general formula is preferably a phenyl group.
  • a phenyl group is preferred.
  • a halogen atom can be mentioned as a substituent of an aryl group.
  • Examples of the substituted phenyl group include a 4-fluorophenyl group and a 2,3-dichlorophenyl group.
  • Examples of the acyl group having a substituted or unsubstituted aryl group include a phenylcarbonyl group and a 4-fluorophenylcarbonyl group.
  • An example of a substituted aryloxy group is a 2,3-dichlorophenyloxy group.
  • Examples of the alkylthio group include a methylsulfanyl group, an ethylsulfanyl group, and a propylsulfanyl group.
  • Examples of the arylthio group include a phenylthio group.
  • alkyl sulfoxide group examples include a methylsulfinyl group, an ethylsulfinyl group, and a propylsulfinyl group.
  • aryl sulfoxide group examples include a phenylsulfinyl group.
  • Benzimidazole is a compound composed of a complex ring of benzene and imidazole (benzimidazole ring) as shown in the general formula (I), and this skeleton is strong against tubulin in nematode and microsporidia cells. By binding, it is thought to exert an anthelmintic action by inhibiting the polymerization action of intracellular microtubules. Moreover, the difference in antibacterial activity is recognized by the difference in the functional group of a side chain (reference literature: E.Lacey. Mode of action of benzimidazoles. Parasitology Today 1990, 6, p112-115.).
  • the active ingredient of the control composition is a benzimidazole derivative, and the benzimidazole derivative containing a basic functional group such as an amino group or an acidic functional group such as a carboxylic acid group or a sulfonic acid group as a substituent.
  • Pharmaceutically acceptable salts and compounds that produce benzimidazole derivatives or pharmaceutically acceptable salts thereof by metabolism in the body of fish and shellfish (not necessarily containing a benzimidazole ring).
  • the active ingredient may be one of these, or a mixture containing any two or more of them in any proportion.
  • compositions include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, acetate salt, propionate salt, butyrate salt, Organic acid salts such as lactate, tartrate, citrate, succinate, fumarate and maleate, inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrogensulfate, carbonate, bicarbonate Is mentioned.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as magnesium salt and calcium salt
  • ammonium salt such as acetate salt, propionate salt, butyrate salt
  • Organic acid salts such as lactate, tartrate, citrate, succinate, fumarate and maleate
  • inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrogensulfate, carbonate, bicarbonate Is mentioned.
  • the prodrug of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a compound that generates the compound represented by the general formula (I) include the following formula (1) ) To (10).
  • the compound of the formula (8) is an albendazole prodrug
  • the compound of the formula (9) is a fenbendazole prodrug.
  • fenbendazole represented by formula (1) albendazole represented by formula (3)
  • flubendazole represented by formula (6) and formula (10) are particularly preferable.
  • the target seafood is not particularly limited.
  • fish belonging to the order Perciformes or Pleuronectiformes and particularly belonging to the genus Scombridae, Thunnus, bluefin tuna, southern bluefin tuna , Bigeye, yellowfin, etc.
  • target microsporidia is not particularly limited, for example, it belongs to the genus Microsporidium, and in particular, Microsporidium seriolae, which is a causative agent of yellowtail rot.
  • composition for controlling microspores of seafood may take any form suitable for administration to seafood, and specific examples include oral preparations, injections, and bath preparations. .
  • These compositions may contain components other than at least one active ingredient selected from any pharmaceutically acceptable carrier, solvent, excipient, spreading agent and other additives.
  • Known or conventionally used carriers, solvents, excipients, spreading agents and other additives can be used.
  • it comprises a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof, and a compound that generates a compound represented by general formula (I) by metabolism in the body of fish and shellfish. At least one selected from the group can be used as an active ingredient of the composition for controlling microsporeworms.
  • a compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof and a compound that produces a compound represented by the general formula (I) by metabolism in the body of fish and shellfish.
  • At least one selected can be used as an active ingredient in the production of a composition for controlling microsporeworms.
  • the composition for controlling microsporidia at least one active ingredient selected from any of the above-mentioned pharmaceutically acceptable carriers, solvents, excipients, spreading agents and other additives. These ingredients may be blended. Therefore, this invention includes the usage method in manufacture of the composition for microspore insect control of such an active ingredient.
  • control method of microspores of fish and shellfish The method for controlling microspores of fish and shellfish according to the second embodiment of the present invention (hereinafter sometimes referred to as “control method of microspores of fish and shellfish” or simply “control method”).
  • control method of microspores of fish and shellfish Represented by the above general formula (I), preventing the infection of seafood muscles or organs with microsporeworms and / or suppressing the growth of microspores in seafood muscles or organs, and / or Or from a compound that has the activity of controlling microsporidia from the body of fish and shellfish, a pharmaceutically acceptable salt thereof, and a compound that generates the compound represented by the general formula (I) by metabolism in the body of fish and shellfish
  • description is abbreviate
  • any administration method is particularly applicable as long as it can be applied to the seafood.
  • the administration method include oral administration, injection (intramuscular injection, intraperitoneal injection), and immersion administration in a drug bath.
  • administration in any form suitable for oral administration is possible, but it is convenient and preferable to ingest with feed in the form of inclusion in feed during feeding.
  • the dose, administration interval, and administration period are appropriately adjusted according to the target seafood, the type of microsporeworm to be controlled, and the purpose of administration (for example, prevention (infection prevention), extermination, etc.).
  • prevention prevention
  • extermination etc.
  • the composition is administered orally multiple times. By administering the composition for controlling microspores of fish and shellfish at such doses and intervals, the effect of preventing microspore infections is maintained for at least about 4 weeks after the end of the administration.
  • control of microsporidia it is orally administered once or multiple times at intervals of 6 hours or more and 180 days or less so that the dose of the active ingredient is 20 mg / kg or more and 400 mg / kg or less.
  • the dose for each administration may be changed, and the administration interval may not be constant.
  • the dose of the active ingredient is 20 mg / kg or more and 400 mg / kg or less, preferably 3 days or more and 180 days or less, more preferably 5 days or more and 21 days or less
  • the composition for controlling microspores of seafood may be orally administered multiple times.
  • the composition for controlling microspores of fish and shellfish is administered at such doses and intervals, the composition for controlling microspores of fish and shellfish per time increases, but between each time of administration
  • fish and shellfish will acquire immunity to microsporidia and the reinfection prevention effect of microsporidia will last for a long period of time, and the total dose of the composition for controlling microspores of seafood Can be reduced.
  • the plurality of oral administrations described above may be one cycle, and this administration cycle may be repeated at intervals of 3 days or more and 180 days or less.
  • the concentration of the active ingredient in the chemical bath solution is, for example, 0.1 to 1000 ppm.
  • the most preferable concentration and time are 10 mg / kg and 2 hours, but since the effect and toxicity differ depending on the water temperature, it is necessary to adjust while observing the state of the fish.
  • Administration may be single or multiple.
  • the concentration of the active ingredient in the chemical bath, the soaking time for each time, and the administration interval are appropriately adjusted according to the drug metabolism status of the target fish.
  • the administration interval may be constant as in the case of oral administration, or may be changed every time.
  • the concentration of the active ingredient in the injection solution is, for example, 1 mg to 300 mg / kg.
  • Administration may be single or multiple.
  • the most preferred concentration is 10 to 100 mg / kg, and the concentration of active ingredient and the administration interval may be constant as in the case of oral administration, or may be changed each time.
  • test group control group (test was conducted under the same conditions as described above except that the feed fed did not contain fenbendazole), fenbendazole group)
  • 10 mojakos were taken out from each of them and dropped into 3 pieces, and it was visually inspected for microsporeworm cysts (becocysts) in one body. If becocyst was observed, it was determined as positive and counted. The number of becocysts confirmed with the naked eye was confirmed, and the average number of infections per fish was determined.
  • Table 1 shows the inspection results.
  • the number of positives in the control group was 8 out of 10
  • the number of positives in the fenbendazole group was 6 out of 10 animals, and no significant difference was observed.
  • the average number of becocysts per fish is 8.0 ⁇ 5.20 for the control group, while it is 3.5 ⁇ 3.83 for the fenbendazole group. Significant differences were observed within 5%.
  • Table 2 shows the inspection results.
  • the prevention test was conducted according to the following procedure. ⁇ Test cage 5m ⁇ 5m ⁇ 5m ⁇ Number of test fish 1000 (starting weight 7g) ⁇ Administration method Oral administration (feeding with spreading agent) Test period 2 months Drug Albendazole (compound represented by the above formula (3)) ⁇ Dose 20mg / kg Bw (20mg per kg fish weight) ⁇ Dose interval 6 times / week
  • Sampling inspection was performed according to the following procedure. Every 2 weeks from the start of administration, 20 mojaco (100 fish in the 8th week after the start of administration) are picked up from each test group, dropped into 3 pieces, and microsporeworm cysts (becocysts) are observed on one side Inspect visually. If becocyst is found, it is determined as positive and counted. The number of becocysts confirmed with the naked eye is confirmed, and the average number of infections per animal is determined.
  • Table 4 shows the changes in the weight of Mojaco subjected to the test.
  • the dose and administration interval of albendazole per time are as described in 1-1.
  • the prevention of becopathic infection did not continue until 8 weeks after the end of the administration of albendazole, and the occurrence of becocysts was confirmed.
  • the end of the administration of albendazole It was confirmed that the occurrence of becocysts was greatly suppressed even after the lapse of 8 weeks (24 weeks after the start of administration).
  • the becocysts confirmed in Test Zone 2 are old and hardened and are not considered to have newly occurred after the administration of albendazole. From these results, it was suggested that the resistance to reinfection of Beco's disease was acquired in Test Group 2 by administering albendazole by a different administration method from Test Group 1.
  • the microsporeworm ⁇ -tubulin gene which is a pathogen of seafood shows a high homology with the microsporeworm ⁇ -tubulin gene sensitive to benzimidazole drugs, Furthermore, it can be presumed that a benzimidazole drug is highly likely to be a microsporeworm control drug for those whose codon 198 is glutamic acid. Therefore, the ⁇ -tubulin gene was isolated from microsporidia that were infectious to various fish and shellfish, amplified by PCR, sequencing and amino acid sequence confirmation. The results are shown in Table 10 below.
  • the amino acid sequence of ⁇ -tubulin from rabbit-derived microsporidia that is sensitive to benzimidazole drugs is highly homologous to the amino acid sequence of ⁇ -tubulin from yellowtail, amberjack, bluefin tuna, red sea bream, and flounder It was. Furthermore, the microsporeworm ⁇ -tubulin gene codon 198 derived from these fish was all glutamic acid (E). From the above test results, it was suggested that the microspores derived from red sea bream, hoshigarei and bluefin tuna may be sensitive to benzimidazole.
  • Example 2 Treatment test 2-1. Therapeutic test of downy mildew-infected mojaco using albendazole The therapeutic test was performed according to the following procedure. ⁇ Test cage 5m ⁇ 5m ⁇ 5m ⁇ Number of test fish: 100 (tests were conducted by selecting fish that were clearly infected with downy mildew by visual inspection at the time of vaccination) ⁇ Administration method Oral administration (feeding with spreading agent) Test period 2 months Drug Albendazole (compound represented by the above formula (3)) ⁇ Dose 50mg / kg Bw (50mg / kg fish weight) ⁇ Dose interval 6 times / week

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Abstract

La présente invention concerne une composition pour lutter contre les microsporidies chez des poissons qui est préparée en utilisant, en tant que substance active, au moins un type de composé choisi dans le groupe constitué d'un composé représenté par la formule générale (I) [dans laquelle R2, R4, R5, R6 et R7 représentent indépendamment un substituant spécifique], un sel pharmaceutiquement acceptable de celui-ci, et un composé capable de former un composé représenté par la formule générale (I) lorsqu'il est métabolisé dans le corps d'un poisson. L'invention concerne un procédé de lutte contre les microsporidies chez des poissons, ledit procédé comprenant l'utilisation de ladite composition pour lutter contre les microsporidies chez des poissons de façon à exercer d'excellents effets de prévention d'une infection par des microsporidies dans les muscles ou les organes de poissons, et/ou l'inhibition de la prolifération de microsporidies dans des muscles ou des organes de poisson, et/ou l'extermination de microsporidies dans des corps de poisson, et ayant une sécurité élevée.
PCT/JP2017/013489 2016-03-31 2017-03-30 Composition de lutte contre les microsporidies chez des poissons et procédé de lutte contre les microsporidies chez des poissons utilisant celle-ci Ceased WO2017170970A1 (fr)

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KR1020187030805A KR20180125565A (ko) 2016-03-31 2017-03-30 어개류의 미포자충의 방제용 조성물 및 그것을 사용한 어개류의 미포자충의 방제 방법
US16/089,226 US10813914B2 (en) 2016-03-31 2017-03-30 Composition for controlling microsporidia in fishes and method for controlling microsporidia in fishes using same
CN201780021272.1A CN108883095B (zh) 2016-03-31 2017-03-30 鳞介类的微孢子虫的防除用组合物、及使用了该组合物的鳞介类的微孢子虫的防除方法
EP17775503.0A EP3437642A4 (fr) 2016-03-31 2017-03-30 Composition de lutte contre les microsporidies chez des poissons et procédé de lutte contre les microsporidies chez des poissons utilisant celle-ci
MX2018011974A MX2018011974A (es) 2016-03-31 2017-03-30 Composicion para controlar microsporidia en peces y metodo para controlar microsporidia en peces utilizando la misma.
AU2017239880A AU2017239880B2 (en) 2016-03-31 2017-03-30 Composition for controlling microsporidia in fishes and method for controlling microsporidia in fishes using same

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JP2017047531A JP6343796B2 (ja) 2016-03-31 2017-03-13 魚介類の微胞子虫の防除用組成物及びそれを用いた魚介類の微胞子虫の防除方法

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57106621A (en) * 1980-12-24 1982-07-02 Takeda Chem Ind Ltd Preventing agent and remedy for fish disease
JP2002220309A (ja) * 2001-01-29 2002-08-09 Kyowa Hakko Kogyo Co Ltd 魚類はだむしの駆除剤及び駆除方法
JP2004511471A (ja) * 2000-10-06 2004-04-15 バイエル　アクチェンゲゼルシャフト Ｎ−アルコキシアルキル−置換ベンズイミダゾール及び寄生性原虫類に対する薬剤としてのそれらの使用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57106621A (en) * 1980-12-24 1982-07-02 Takeda Chem Ind Ltd Preventing agent and remedy for fish disease
JP2004511471A (ja) * 2000-10-06 2004-04-15 バイエル　アクチェンゲゼルシャフト Ｎ−アルコキシアルキル−置換ベンズイミダゾール及び寄生性原虫類に対する薬剤としてのそれらの使用
JP2002220309A (ja) * 2001-01-29 2002-08-09 Kyowa Hakko Kogyo Co Ltd 魚類はだむしの駆除剤及び駆除方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SCHMAHL G. ET AL.: "Treatment of fish parasites. 11. Effects of different benzimidazole derivatives (albendazole, mebendazole, fenbendazole) on Glugea anomala, Moniez, 1887 (Microsporidia): Ultrastructural aspects and efficacy studies", PARASITOLOGY RESEARCH, vol. 84, no. 1, 1 February 1998 (1998-02-01), pages 41 - 49, XP055578950 *
See also references of EP3437642A4 *

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