CN101657197A - 杀真菌剂用于治疗鱼类真菌病 - Google Patents
杀真菌剂用于治疗鱼类真菌病 Download PDFInfo
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- CN101657197A CN101657197A CN200880012238A CN200880012238A CN101657197A CN 101657197 A CN101657197 A CN 101657197A CN 200880012238 A CN200880012238 A CN 200880012238A CN 200880012238 A CN200880012238 A CN 200880012238A CN 101657197 A CN101657197 A CN 101657197A
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- fish
- antifungal
- methyl
- agent
- fenamidone
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/539—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more oxygen atoms in the same ring, e.g. dioxazines
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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
- A61K31/33—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
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Farming Of Fish And Shellfish (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及一种通过使用至少一种选自2－[[[[[1－[3－(1－氟－2－苯乙基)氧基]苯基]亚乙基]氨基]氧基]甲基]α－(甲氧基亚氨基)－N－甲基－αE－苯乙酰胺、吲唑磺菌胺、氰霜唑、烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺、啶氧菌酯和pyribencarb的杀真菌剂来保护鱼类和无脊椎动物及其所有发育阶段、和治疗由水霉属、丝囊霉属、鞭绵霉属及水产养殖中的其他重要种属的真菌引起的真菌病的方法。所述使用可抑制或杀死致病真菌。含有至少一种选自上述杀真菌剂的用于鱼类养殖和培育的试剂适于预防和治疗水产养殖中、培育塘、培育罐、培养缸、天然供垂钓水域、池塘和海洋渔场中的鱼类疾病。相关应用形式为将所述杀真菌剂添加到水中和喂养，以及直接施用。向水中添加本发明试剂可减少卵和鱼的真菌感染。
Description
本发明涉及一种通过使用至少一种杀真菌剂来预防和治疗由水霉属(Saprolegnia)、绵霉属(Achlya)、丝囊霉属(Aphanomyces)和水产养殖中的其他重要种属的真菌(以下称为致病真菌)引起的鱼类和无脊椎动物及其所有发育阶段的真菌病的方法，所述杀真菌剂选自2-[[[[1-[3-(1-氟-2-苯乙基)氧基]苯基]亚乙基]氨基]氧基]甲基]α-(甲氧基亚氨基)-N-甲基-αE-苯乙酰胺、吲唑磺菌胺(amisulbrom)、氰霜唑(cyazofamid)、烯肟菌酯(enestrobin)、噁唑菌酮(famoxadone)、咪唑菌酮(fenamidone)、氟嘧菌酯(fluoxastrobin)、肟醚菌胺(orysastrobin)、啶氧菌酯(picoxystrobin)和pyribencarb。
本发明还涉及用于预防和治疗由水霉属、绵霉属、丝囊霉属和水产养殖中的其他重要种类真菌(以下称为致病真菌)引起的鱼类和无脊椎动物及其所有发育阶段的真菌病的组合物，其含有至少一种选自2-[[[[1-[3-(1-氟-2-苯乙基)氧基]苯基]亚乙基]氨基]氧基]甲基]α-(甲氧基亚氨基)-N-甲基-αE-苯乙酰胺、吲唑磺菌胺、氰霜唑、烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺、啶氧菌酯和pyribencarb的杀真菌剂。该组合物用于鱼类养殖和鱼类培育的所有发育阶段中，尤其是预防和治疗性地用在患病和受胁迫的鱼类中。
本发明还涉及组合物用于鱼卵的抗真菌处理的用途。
由于全球对鱼类需求的增加，使得水产养殖日益增多。可作为实例但非限制性地提及以下与水产养殖有关的鱼类：鲶鱼、鳟鱼、鲑鱼、
鲶鱼(Pangasius)和鲈鱼。由于鱼类的相互接近，这种类型的水产养殖极易感染病原体，特别是致病真菌。侵袭鱼和鱼卵及其他发育阶段的致病真菌属于以下属：Saprolegnia hypogyna，多子水霉(S.ferax)、澳大利亚水霉(S.australis)、异丝水霉(S.declina)、S.longicaulis，混生水霉(S.mixta)、寄生水霉(S.parasitica)、孢子囊水霉(S.sporangium)、可变水霉(S.variabilis)、丝囊霉(Aphanomyces invadans)和鞭绵霉属(Achlyaflagellata spp.)。
真菌病对生产性鱼和观赏鱼以及甲壳类和其他无脊椎动物的养殖和培育造成高额经济损失(Bruno，D.W.，Wood，B.P.，1999：Saprolegnia and other Oomycetes：Woo，P.T.K.，Bruno，D.W.(Ed)：FishDiseases and Disorder.Vol.3 Viral，Bacterial and fungal infections.CAB International，Wallingford)。
但是，迄今只已知较少的物质适于防治鱼类真菌病。
过去，通常使用孔雀石绿作为预防和治疗真菌病的活性物质。但是，由于其致癌性、诱变性和致畸性，该物质仅在德国允许用于处理鱼卵，但不允许用于处理鱼(Meyer，F.P.；Jorgenson.T.A.，1983：Teratological and other effects of malachite green on development ofrainbow trout and rabbits.Trans.Am.Fish.Soc.112，818-824，(Bundesinstitut fur gesundheitlichen Verbraucherschutz and
[Federal Institute for Consumer Protection of Healthand Veterinary Medicine]，2002)。由于孔雀石绿是一种染料，其可导致水及被处理的鱼变色。此外，孔雀石绿具有较长的半衰期，因此其可导致在之后被食用的鱼类中残留(D.J.Alderman在Journal of FishDiseases 8.(1985)289-298中所述)。
现在，还使用福尔马林，福尔马林对致病真菌具有一定的杀菌作用，但是在实际使用中不令人满意，其还引起职业性的安全问题，特别是在封闭系统中。
在DE 10237740中，描述了天然及合成腐殖质在鱼类养殖中的用途。
由DE 2037610中还已知某些苄基咪唑(benzylimidazole)能在体外作用于寄生水霉(Saprolegnia parasitica)。但是，未提及任何关于在鱼类养殖中的潜在应用。
在CN 1472448中，描述了具有杀真菌活性的中药制剂用作抵抗鱼类、虾类和蟹类的水霉病的试剂。该制剂含有40-70重量％的五倍子(Galla Chinensis)、10-30重量％的黄柏(Cortex Phellodendri)(川黄柏(Phellodendron chinense)和/或关黄柏(Phellodendronamurense))、10-30重量％的牡丹皮(Paeonia suffruticosa bark)和10-30重量％的鱼腥草(Houttuynia cordata)。
还可使用含多种多酚的茶叶提取物(JP 3698745)。
在WO 04002574中，描述了将含葡聚糖酶的酶混合物用于预防和治疗鱼类及其发育阶段(卵)的真菌病。
在WO 9805311中，溴硝醇(溴-2-硝基丙-1，3-二醇)被用于防治水生有机体、特别是鲑鱼及其卵的多种疾病。
此外，已知可使用二氧化氯(WO 9518534)、3-苯氧基羰基甲氧基-1，1，2-三碘代-1-丙烯(JP 57116012)和2-吡啶硫醇1-氧化物(JP47019191)抵抗水霉属疾病。
醚菌酯(kresoxim-methyl)用于防治鱼类真菌病的用途已知于WO 97006690。
但是，一方面，这些物质的药效、尤其是在低剂量时常常不足够。另一方面，由于对鱼的毒性(piscotoxic properties)，可出现对处理相容性的限制，从而无法充分地使用有效剂量。而且，精确剂量、特别是中药或茶叶提取物或酶混合物的精确剂量由于其变化的活性物质含量而难于控制。此外，这些制剂的使用仅适于防治个别鱼种和个别疾病。而且，由于这些制剂的毒性，在其使用和被鱼类消耗之间需要很长的等待时间，因此其常常限于在捕鱼(“收获”)之前的很长一段时间时使用。
由于对现今抗真菌药的生态和经济要求不断提高，例如在作用谱、毒性、选择性、施用率、残留物生成和便利的生产性方面，因此持续地需要开发新的与已知抗真菌药相比至少在部分方面更有利的抗真菌药。
此外，这些物质具有毒副效应。例如，福尔马林、氯胺T和草酸孔雀石绿的使用通常伴随许多副作用和风险，例如，其具有致癌、诱变、损害染色体和致畸的可能性，起呼吸毒剂的作用，此外还会发生组织病理学后遗症和多器官损害及显著的生化血液参数的改变(Sanchez等人，1998；Srivastava等人，2004；St.Heidrich的论文，2005)。
除纯的杀菌剂外，还使用其他物质。所述物质包括乙酸(用于浸渍处理)、氯化钠和氯化钙(用于渗透调节处理)、碳酸钠和二氧化碳(用于对鱼进行麻醉)和亚硫酸钠(用于改良产卵)和聚乙烯吡酮碘(povidone iodine)(用于对鱼卵的表面进行杀菌)。
常规预防剂和治疗剂缺点产生的原因源于为了消除细菌性、寄生虫性及环境相关的疾病和增加产率而对抗生素、化学治疗剂和三苯基染料等活性物质的长期广泛使用以及在某些情况下不慎使用。在某些情况下，这类使用引发了对治疗动物和人类疾病的不利的抗性环境。此外，常规组合物的使用通常伴随严重的副作用、危险性和环境破坏性。
因此，在水产养殖领域中，亟需有效防治那些降低商品鱼类生产产率的病原体的方法。在鱼类发生疾病的情况下，主要具有预防特性的且能够避免和减轻诱病因素的早期干预可发挥较大作用。为此，寻找可行的替代处理方法非常重要。可用方法应该能够防治广谱病原菌并满足目前的安全准则。本发明满足这些标准并具有其他优点。
令人惊讶的是，现已发现，至少一种选自2[[[[1-[3-(1-氟-2-苯乙基)氧基]苯基]亚乙基]氨基]氧基]甲基]α-(甲氧基亚氨基)-N-甲基-αE-苯乙酰胺、吲唑磺菌胺、氰霜唑、烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺、啶氧菌酯和pyribencarb的杀真菌剂非常适于预防和治疗鱼、虾、蟹和其他无脊椎动物及它们的所有发育阶段的真菌病，所述真菌病由水霉属、绵霉属、丝囊霉属真菌引起，特别是由水霉属种引起的真菌性疾病。本发明组合物适于防治由水霉属和/或绵霉属和/或丝囊霉属属种引起的真菌病。
同现有技术已知的物质或处理方法相比，在处理中使用所述杀真菌剂具有以下优点：它们显示出良好的药效并且不会在鱼体内累积至不希望的程度，它们具有有利的生态学特性及其他毒理学特性并且不具有任何不能被生物群落接受的作用。
因此，本发明涉及至少一种选自2-[[[[1-[3-(1-氟-2-苯乙基)氧基]苯基]亚乙基]氨基]氧基]甲基]α-(甲氧基亚氨基)-N-甲基-αE-苯乙酰胺、吲唑磺菌胺、氰霜唑、烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺、啶氧菌酯和pyribencarb的杀真菌剂在防治所有鱼种群及其发育阶段的鱼类真菌病、特别是由水霉属病原体引起的鱼类真菌病的用途。
在本发明方法中使用的杀真菌剂已知为农化活性物质(参见例如农药手册，第13版)。
鱼类疾病会影响鱼类养殖和水产养殖、水族养殖(aquaristics)和野生鱼种群。此处可将疾病划分为多种类型，例如遗传性疾病、感染性疾病和寄生性疾病、损伤、与水相关的损害和在养殖条件下由于胁近因素而导致的损害。防御能力、病原体和生活条件之间存在复杂的相互关系，这最终决定了感染性疾病的爆发。许多传播广泛的鱼类疾病由寄生虫的侵袭引起。寄生虫还是约50％的水生幼小动物死亡的原因。根据病原体的类型，寄生虫的侵袭可隐匿地发生或爆发性地发生并且必定会导致池塘中的许多甚至全部动物均被疾病侵袭。真菌、细菌和病毒也可造成鱼类疾病。
由真菌引起的疾病称真菌病。此处真菌病可以是继发性感染，即在真菌病之前，其他疾病已经侵袭鱼类或池塘。真菌也可初级寄生存活。由于真菌还具有一个壁围成的边界，因此已渗入皮肤中的真菌病的治疗较为困难。
水霉属属于卵菌(Oomycetes)纲。患病的鱼具有以下症状：它们呈现白色、类似棉絮的、灰白色真菌感染表面。如果保护性粘膜层或表皮受损，这些真菌通常可随之移生在鱼上。所述真菌的增殖可由其他有机体刺伤或咬伤的伤口而产生或由机械损伤而产生，而且可由于温度或废水的影响而产生。但是，鱼卵也受到危害。上述真菌天然存在于所有淡水水域中并侵袭衰弱的鱼。特别是老龄的雄性鳟鱼常常被严重侵袭。水霉属既是一种较弱的二重寄生物，也是一种能够直接侵袭鱼类及其卵的初寄生物。某些情形下其也可侵袭所有类型的鱼。
本发明的目标是表明在避免和处理在捕鱼、运输和保存中产生的鱼损害方面的应用，从而改进在饲养鱼和卵处理方面的结果，和保证水产养殖设备和水族箱设备的无故障运行。
所述杀真菌剂既可以纯的形式存在也可作为多种可能异构形式的混合物而存在，特别是立体异构体，例如E和Z型、苏式和赤式、以及旋光异构体如R和S异构体或阻转异构体，但是如果合适，也可以是互变异构体。本发明包含纯的异构体及它们的混合物。
根据以上定义的取代基的类型，上述杀真菌剂具有酸性或碱性并且可形成盐，也可任选地形成内盐。如果杀真菌剂带有羟基、羧基或其他产生酸性的基团，则这些化合物可与碱反应得到盐。适宜的碱有例如，碱金属和碱土金属特别是钠、钾、镁和钙的氢氧化物、碳酸盐、碳酸氢盐，以及氨和具有(C1-C4)烷基基团的伯胺、仲胺和叔胺、(C1-C4)烷醇的单烷醇胺、二烷醇胺和三烷醇胺，胆碱和氯胆碱。如果杀真菌剂带有氨基、烷基氨基或其他产生碱性的基团，则这些化合物可与酸反应得到盐。适宜的酸有例如，无机酸，如盐酸、硫酸和磷酸；有机酸如乙酸或草酸；和酸式盐例如NaHSO4和KHSO4。以该方式获得的盐同样具有杀真菌特性。
在本发明中待使用的杀真菌剂在上文已提及。
优选选自吲唑磺菌胺、氰霜唑、烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺、啶氧菌酯和pyribencarb的杀真菌剂。
特别优选选自烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺和啶氧菌酯的杀真菌剂。
非常特别优选选自咪唑菌酮和噁唑菌酮的杀真菌剂。
还非常特别优选选自烯肟菌酯、肟醚菌胺和氟嘧菌酯的杀真菌剂。
特别是优选选自咪唑菌酮和氟嘧菌酯的杀真菌剂。
在本发明的方法、用途和组合物中，可选择单个的杀真菌剂和两种或多种杀真菌剂的结合。
根据本发明，将杀真菌剂添加至水产养殖设备中的水中，所述设备例如孵化设备、培育池、培育罐、圆形游泳池、育肥池(fatteningpool)、水族箱、天然的供垂钓水域和海洋鱼场；通过杀真菌剂的作用抑制或破坏致病真菌的生长。此意义上的水产养殖设备为用于在淡水、微咸水或咸水中养殖鱼类或无脊椎动物的设备。所述杀菌剂被加入水中。剂量基于水产养殖设备中水的状况(有机物污染)、杀真菌剂的活性和待处理的鱼类的发育阶段。活性水平通过连续或间歇添加杀真菌剂来维持，这可抑制已有的真菌病和预防新感染的发生。
根据鱼的种类和发育阶段及杀真菌剂的类型，施用率为0.1μg/l-1g/l、优选1μg/l-100mg/l、尤其优选5μg/l-1mg/l的活性物质。通常无需较高的浓度，但处理卵、幼虫及其幼年阶段时可使用更高的浓度，这取决于化合物类型或施用类型，特别是在人工体系中，例如培育罐或水族箱中。
抗真菌病的作用的实现还在于，杀真菌剂不仅以游离形式施用于水产养殖设备的含水介质中，并且还粘附于待保护的有机体表面(粘膜)或其卵表面。当感染的危险性较高使得需要较高的杀真菌剂含量，或者水产养殖设备中的水处理量较大而不可能连续添加杀真菌剂混合物时，上述方式是优选的。除优选施用可提高杀真菌剂粘附的杀真菌剂混合物外，所述粘附还可通过以提高的杀真菌剂浓度暂时性预培育来处理动物或它们的卵而实现。
对于鱼类而言，杀真菌剂的有效量示例性地包括约为1μg-10mg/kg/天的剂量率，其可以以单剂量或单独的分剂量——例如每天1-4次——进行给药。优选地，化合物以小于10mg/kg/天的剂量给药，给药为单剂量或2-4次分剂量。
活性物质可直接给药或在使用前与常规惰性载体混合而给药。基本上，那些便于或确保活性物质在水中或待保护的有机体表面(粘膜)或其卵表面均匀分布的物质都适宜作为惰性载体。
根据活性物质各自的物理和/或化学性质，可将它们转化为常规制剂，例如溶液剂、乳剂、悬浮剂、粉剂、泡沫剂、糊剂、颗粒剂、气雾剂、聚合物中的微胶囊剂和种子包衣组合物，及ULV冷雾剂和热雾剂。
这些制剂以已知方式制备，例如通过将活性物质与填充剂，即与液体溶剂、加压液化气和/或固体载体混合而制得，如果合适，可使用表面活性剂，即乳化剂和/或分散剂和/或发泡剂。在使用水作填充剂的情况下，还可使用例如有机溶剂作助溶剂。适宜的液体溶剂主要有：芳香族化合物，例如二甲苯、甲苯或烷基萘；氯化芳香族化合物或氯化脂族烃，例如氯苯、氯乙烯或二氯甲烷；脂族烃，例如环己烷或石蜡，如石油馏分；醇，例如丁醇或乙二醇及它们的醚及酯；酮，例如丙酮、甲基乙基酮、甲基异丁基酮或环己酮；强极性溶剂，例如二甲基甲酰胺或二甲基亚砜；和水。对于液化气填充剂或载体，所述液体意指在常温和常压下为气态的液体，例如气溶胶喷雾剂，如卤代烃，及丁烷、丙烷、氮气和二氧化碳。适宜的固体载体有：例如粉碎的天然矿物，例如高岭土、粘土、滑石、白垩、石英、绿坡缕石、蒙脱石或硅藻土；以及粉碎的合成矿物，例如细分散二氧化硅、氧化铝及硅酸盐。适用于颗粒剂的固体载体有：例如粉碎并分级的天然岩石，如方解石、浮石、大理石、海泡石及白云石；和合成的无机及有机粉颗粒，以及有机物颗粒，所述有机物例如锯屑、椰壳、玉米穗轴和烟草茎。适宜的乳化剂和/或发泡剂有：例如非离子及阴离子乳化剂，例如聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚如烷基芳基聚乙二醇醚、烷基磺酸盐、烷基硫酸盐、芳基磺酸盐，及蛋白质水解产物。适宜的分散剂有：例如木素亚硫酸盐废液及甲基纤维素。
可在制剂中使用粘合剂，例如羧甲基纤维素，天然及合成的粉状、颗粒状或胶乳样聚合物，例如阿拉伯树胶、聚乙烯醇及聚乙酸乙烯酯；和天然磷脂，例如脑磷脂和卵磷脂，及合成磷脂。其它添加剂可为矿物油和植物油。
可使用色料，例如无机颜料，如氧化铁、氧化钛及普鲁士蓝；以及有机染料，如茜素染料、偶氮染料及金属酞菁染料；以及微量营养物，如铁盐、锰盐、硼盐、铜盐、钴盐、钼盐及锌盐。
制剂通常含有0.1至95重量％的活性物质，优选0.5至90％。
本发明涉及用有效杀真菌剂来处理患真菌病的鱼及其所有发育阶段的方法。
显而易见的是，具体剂量和用药频率可以针对某些鱼类、根据其发育阶段而改变，其取决于许多因素，包括所用具体化合物的药效、代谢稳定性和该化合物的作用期、鱼的种类、年龄、重量、总体健康状况、性别和食物、给药方式和给药时间、排泄率和具体病情的严重程度。
因此本发明提供了一种兽医药剂，该药剂含有至少一种有效量的可治疗水霉属疾病或其他鱼类疾病的杀真菌剂、和一种药学上可接受的载体或一种药学上可接受的稀释剂。本发明组合物可含有如下所述的其他治疗剂并可使用例如常规的固体或液体载体或稀释剂进行配制：例如根据药学盖仑制剂(galenics)领域公知的技术或已认可的药学实践所需要的技术适于进行所需给药的一类药物添加剂(例如赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)。
上述有效杀真菌剂可通过任何所需的适宜方式进行给药，所述方式例如口服，如以片剂、胶囊剂、颗粒剂或粉剂形式；舌下给药；口腔给药；肠胃外给药，如通过皮下、静脉内、肌内或膜内注射，或灌注技术(例如灭菌可注射的水性或非水性溶液或悬浮液)；局部给药，例如以乳膏剂或软膏剂的形式，或以含有无毒的、药学上可接受的载体或稀释剂的单位剂量制剂形式给药。杀真菌剂可以例如适于速释或缓释的形式进行给药。所述速释或缓释可通过使用含上述有效杀真菌剂的适宜药剂、或者尤其是对于缓释而言，通过使用诸如皮下植入物或渗透泵等装置来实现。所述化合物也可以以脂质体的方式给药。例如，活性物质可在一种每单位剂量含约5至约500mg上文所列杀真菌剂化合物或化合物混合物的组合物例如片剂、胶囊、溶液或悬浮剂中使用，或以局部方式使用(0.01-5％杀真菌剂，每天处理1-5次)。所述活性物质可以常规方式与生理学上可接受的载体、赋形剂、粘合剂、防腐剂、稳定剂、调味剂等混合，或与一种局部给药用载体混合。也可将所述化合物配制为诸如用于肠胃外给药的灭菌溶液或悬浮液等组合物。按照已认可的药学实践要求，可将约0.1至500mg杀真菌剂与生理上可接受的载体、赋形剂、粘合剂、防腐剂、稳定剂等混合成单位剂量的形式。这些组合物或制剂中活性物质的量优选为可得到所指明范围内的适宜剂量的量。
口服给药的示例性组合物包括：悬浮剂，所述悬浮剂可含有例如工业中已知的用来构成主要部分的微晶纤维素，作为悬浮剂的藻酸或藻酸钠，作为粘度增强剂的甲基纤维素和甜味剂或调味剂；和速释片剂，所述片剂可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或其他工业中已知的赋形剂、粘合剂、填充剂、崩解剂、稀释剂和润滑剂。模制片剂、压制片剂或冻干片剂为可使用的示例形式。示例性组合物包括杀菌活性物质与可快速溶解的溶剂所配制的那些组合物，所述可快速溶解的溶剂例如甘露糖醇、乳糖、蔗糖和/或环糊精。在该类型的制剂中，也可存在高分子量的赋形剂，例如纤维素(微晶纤维素(Avicel))或聚乙二醇(PEG)。为促进粘膜粘附，该类型的制剂还可合有一种赋形剂，例如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)、马来酸酐共聚物(例如Gantrez)；和控制释放用的物质，例如聚丙烯酸共聚物(例如Carbopol 934)。为使制备和使用更简易，还可添加润滑剂、助流剂、调味剂、着色剂和稳定剂。
上述杀真菌剂可以其本身给药，或与其他杀真菌剂结合给药。尤其可使用杀真菌剂的组合物，其对鱼类真菌病同样具有活性，从而相应地和有效地维护活性以防止真菌病原体对活性物质抗性的形成。
可通过实验室试验或通过实验动物的实验对处理剂的药效进行检查确认。实验室试验可根据化合物的作用能力精确表征其药效。为此，将活性物质添加到人工培养基中并在培养期之后测定真菌生长情况。在动物实验中，对例如养殖鱼的卵进行处理。为此，向存在鱼卵的水罐中添加适宜浓度的处理剂。这可借助于例如在鱼类养殖过程中向培育罐连续添加水流而实现。供给处理剂后，水的更换停止一定的时间，从而使处理剂可开始起作用。该处理可进行一次或连续进行多天，或者每隔一天或数天进行数分钟至几小时。其后，处理剂通过更换水而从培育罐中除去。该处理的药效和耐受性通过存活的且未被真菌感染的卵的数目确定。在已孵化、发育的鱼或成体动物中的药效和耐受性在培育鱼的水罐中进行测定。为此，向鱼罐中添加处理剂。供给处理剂后，水的更换停止一定的时间，从而使处理剂可开始起作用。该处理可进行一次或连续进行多天，或者每隔一天或数天进行数分钟至几小时。该处理的药效和耐受性通过存活的鱼的数目和真菌感染的程度来确定。
通过以下实施例对本发明进行更详细地说明。
实施例
实施例1：测定物质抗鱼类寄生真菌例如水霉属属种的药效。
使寄生水霉(CBS 540.67，Centraalbureau voor Schimmelcultures，Baarn，Netherlands)隔离群在20℃黑暗中在PD琼脂上(39g/l终浓度)生长和繁殖。为测定ED50值，用0-0.03-0.1-0.3-1-3-10-30ppm浓度系列的待测试的杀真菌剂对PD琼脂板进行处理。对于每一种情况，将含寄生水霉的接种片放在经所述多种浓度的杀真菌剂处理过的培养皿的中心。
将所述琼脂板在20℃黑暗中培育三天，然后测量该琼脂板上真菌的生长情况，并通过与未经处理的对照组相比较计算ED50值。
在该试验中，杀真菌剂例如氟嘧菌酯、咪唑菌酮、氰霜唑、噁唑菌酮和pyribencarb显示出5ppm或更小的ED50值。
Claims (4)
1.用于治疗由水霉属、绵霉属、丝囊霉属真菌引起的鱼类和无脊椎动物及其所有发育阶段的真菌病的组合物，其特征在于所述组合物含有至少一种选自以下的杀真菌剂：2-[[[[1-[3-(1-氟-2-苯乙基)氧基]苯基]亚乙基]氨基]氧基]甲基]α-(甲氧基亚氨基)-N-甲基-αE-苯乙酰胺、吲唑磺菌胺、氰霜唑、烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺、啶氧菌酯和pyribencarb。
2.权利要求1的组合物，其特征在于所述组合物含有至少一种选自以下的杀真菌剂：咪唑菌酮和氟嘧菌酯。
3.至少一种选自以下的杀真菌剂用于制备抵抗由水霉属、绵霉属、丝囊霉属真菌引起的鱼类和无脊椎动物及其所有发育阶段的真菌病的组合物的用途：2-[[[[1-[3-(1-氟-2-苯乙基)氧基]苯基]亚乙基]氨基]氧基]甲基]α-(甲氧基亚氨基)-N-甲基-αE-苯乙酰胺、吲唑磺菌胺、氰霜唑、烯肟菌酯、噁唑菌酮、咪唑菌酮、氟嘧菌酯、肟醚菌胺、啶氧菌酯和pyribencarb。
4.至少一种选自以下的杀真菌剂用于制备抵抗由水霉属、绵霉属、丝囊霉属真菌引起的鱼类和无脊椎动物及其所有发育阶段的真菌病的组合物的用途：咪唑菌酮和氟嘧菌酯。
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| CN103561577A (zh) * | 2011-06-01 | 2014-02-05 | 住友化学株式会社 | 害虫防治组合物和用于防治害虫的方法 |
| CN103936678A (zh) * | 2014-04-23 | 2014-07-23 | 西安近代化学研究所 | 一种4-氯-2-氰基-n,n-二甲基-5-(4-甲基苯基)-1h-咪唑-1-磺酰胺的合成方法 |
| CN114007414A (zh) * | 2019-06-05 | 2022-02-01 | V·斯利瓦斯塔瓦 | 水霉病的治疗 |
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| DE102004045242A1 (de) | 2004-09-17 | 2006-03-23 | Bayer Cropscience Ag | Synergistische fungizide Wirkstoffkombinationen |
| EP1982715A1 (de) | 2007-04-20 | 2008-10-22 | Bayer CropScience AG | Verwendung von Fungiziden zur Behandlung von Fischmykosen |
| EP1982717A1 (de) * | 2007-04-20 | 2008-10-22 | Bayer CropScience AG | Verwendung von Fungiziden zur Behandlung von Fischmykosen |
| RU2421987C1 (ru) * | 2010-01-11 | 2011-06-27 | Федеральное государственное научное учреждение "ГОСУДАРСТВЕННЫЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ОЗЕРНОГО И РЕЧНОГО РЫБНОГО ХОЗЯЙСТВА" (ФГНУ "ГосНИОРХ") | Способ повышения сопротивляемости икры к заболеваниям |
| CN104255607A (zh) * | 2014-09-25 | 2015-01-07 | 广东省昆虫研究所 | 一种简单快速清除侵入养殖池塘中的罗非鱼的方法 |
| US20200267989A1 (en) * | 2017-09-12 | 2020-08-27 | University Of Maine System Board Of Trustees | Parasite treatment compound |
| CN114223586A (zh) * | 2021-12-01 | 2022-03-25 | 天津市金水族水产养殖有限公司 | 一种鱼卵水霉病的防治方法 |
| CN115067246B (zh) * | 2022-07-14 | 2023-06-27 | 淮北聚源渔业有限公司 | 一种鲈鱼孵化卵收集设备 |
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- 2008-04-08 CN CN200880012238.9A patent/CN101657197B/zh not_active Expired - Fee Related
- 2008-04-08 RU RU2009142557/15A patent/RU2482845C2/ru not_active IP Right Cessation
- 2008-04-08 US US12/595,034 patent/US8076328B2/en not_active Expired - Fee Related
- 2008-04-08 JP JP2010503379A patent/JP5361860B2/ja not_active Expired - Fee Related
- 2008-04-08 WO PCT/EP2008/002758 patent/WO2008128640A1/de active Application Filing
- 2008-04-08 CN CN2013102770957A patent/CN103393677A/zh active Pending
- 2008-04-08 CA CA2684342A patent/CA2684342C/en not_active Expired - Fee Related
- 2008-04-14 UY UY31021A patent/UY31021A1/es not_active Application Discontinuation
- 2008-04-14 CL CL2008001056A patent/CL2008001056A1/es unknown
- 2008-04-14 PE PE2008000646A patent/PE20090697A1/es not_active Application Discontinuation
- 2008-04-18 TW TW102125866A patent/TWI488625B/zh not_active IP Right Cessation
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- 2008-04-18 TW TW097114045A patent/TWI419688B/zh not_active IP Right Cessation
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2011
- 2011-11-22 US US13/302,946 patent/US20120071531A1/en not_active Abandoned
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2012
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2013
- 2013-07-05 JP JP2013141314A patent/JP5806708B2/ja not_active Expired - Fee Related
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1193257A (zh) * | 1995-08-17 | 1998-09-16 | 巴斯福股份公司 | 抗鱼真菌病和单细胞寄生物的方法 |
| CN1909784A (zh) * | 2004-01-20 | 2007-02-07 | 巴斯福股份公司 | 杀真菌混合物 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103561577A (zh) * | 2011-06-01 | 2014-02-05 | 住友化学株式会社 | 害虫防治组合物和用于防治害虫的方法 |
| CN103561577B (zh) * | 2011-06-01 | 2015-10-14 | 住友化学株式会社 | 害虫防治组合物和用于防治害虫的方法 |
| CN103936678A (zh) * | 2014-04-23 | 2014-07-23 | 西安近代化学研究所 | 一种4-氯-2-氰基-n,n-二甲基-5-(4-甲基苯基)-1h-咪唑-1-磺酰胺的合成方法 |
| CN103936678B (zh) * | 2014-04-23 | 2016-04-27 | 西安近代化学研究所 | 一种4-氯-2-氰基-n,n-二甲基-5-(4’-甲基苯基)-1h-咪唑-1-磺酰胺的合成方法 |
| CN114007414A (zh) * | 2019-06-05 | 2022-02-01 | V·斯利瓦斯塔瓦 | 水霉病的治疗 |
Also Published As
| Publication number | Publication date |
|---|---|
| CL2013003307A1 (es) | 2014-07-04 |
| JP5361860B2 (ja) | 2013-12-04 |
| TW201345522A (zh) | 2013-11-16 |
| US20120071531A1 (en) | 2012-03-22 |
| EP2148671B1 (de) | 2016-04-06 |
| CL2008001056A1 (es) | 2008-11-03 |
| US20100063039A1 (en) | 2010-03-11 |
| UY31021A1 (es) | 2008-11-28 |
| JP5806708B2 (ja) | 2015-11-10 |
| CN103393677A (zh) | 2013-11-20 |
| EP2148671A1 (de) | 2010-02-03 |
| RU2482845C2 (ru) | 2013-05-27 |
| WO2008128640A1 (de) | 2008-10-30 |
| EP1982715A1 (de) | 2008-10-22 |
| US8455481B2 (en) | 2013-06-04 |
| US20130012558A1 (en) | 2013-01-10 |
| JP2010526032A (ja) | 2010-07-29 |
| TW200908965A (en) | 2009-03-01 |
| TWI488625B (zh) | 2015-06-21 |
| US8076328B2 (en) | 2011-12-13 |
| ES2567073T3 (es) | 2016-04-19 |
| RU2009142557A (ru) | 2011-05-27 |
| CA2684342C (en) | 2017-07-18 |
| TWI419688B (zh) | 2013-12-21 |
| PE20090697A1 (es) | 2009-07-17 |
| CA2684342A1 (en) | 2008-10-30 |
| JP2013237679A (ja) | 2013-11-28 |
| AR066119A1 (es) | 2009-07-22 |
| CN101657197B (zh) | 2016-04-13 |
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