CN115916178A - 非洲猪瘟(African Swine Fever:ASF)的治疗剂和/或预防剂 - Google Patents
非洲猪瘟(African Swine Fever:ASF)的治疗剂和/或预防剂 Download PDFInfo
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- CN115916178A CN115916178A CN202180048004.5A CN202180048004A CN115916178A CN 115916178 A CN115916178 A CN 115916178A CN 202180048004 A CN202180048004 A CN 202180048004A CN 115916178 A CN115916178 A CN 115916178A
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- african swine
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- swine fever
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- YUMLNTJCWGYGQU-UHFFFAOYSA-N zinc azane Chemical compound N.N.[Zn+2] YUMLNTJCWGYGQU-UHFFFAOYSA-N 0.000 description 1
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- 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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- 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 or pantothenic acid
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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
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- Reproductive Health (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供一种非洲猪瘟(ASF)的治疗剂和/或预防剂、以及使用其的非洲猪瘟(ASF)的治疗方法和/或预防方法,所述治疗剂和/或预防剂含有5‑氨基乙酰丙酸(ALA)或其衍生物或其盐。
Description
技术领域
本发明涉及非洲猪瘟(African Swine Fever:ASF)的治疗剂和/或预防剂,更详细而言,涉及含有5-氨基乙酰丙酸(5-ALA)或其衍生物或它们的盐的非洲猪瘟(ASF)的治疗剂和/或预防剂、以及涉及使用该治疗剂和/或预防剂的非洲猪瘟(ASF)的治疗和/或预防。
背景技术
非洲猪瘟(ASF)是由非洲猪瘟病毒(African Swine Fever Virus:ASFV)产生的猪和野猪的热性传染病,其特征在于强传染性和高致死率。ASFV通过与患有本病的猪或野猪的直接或间接接触而在猪群内快速传播,给养猪业带来沉重的打击。另外,由于在污染的猪肉中长时间维持感染力,会经由精肉或非加热的猪肉加工品带入远方,通过食品残渣的流通等侵入到未发病地域。因此,仅通过局限在发病地的防疫措施,有时对策会落后。在常驻地或流行地,形成了野生野猪间的传播、经由软蜱属的感染环,使防疫变复杂。
非洲猪瘟病毒(ASFV)是唯一被分类非洲猪瘟病毒科非洲猪瘟病毒属(Asfarviridae Asfivirus)的病毒,在基因组中具有双链DNA,具有将直链状的基因组DNA用内膜、正二十面体的衣壳蛋白以及源自细胞膜的包膜这3层包裹的结构。基因组大小为170~190kbp,病毒株之间有差异,但中央部的约125kbp比较良好地保存。认为病毒的血清型(抗原性)是单一的,另一方面,能够根据碱基序列的不同而区分基因型,目前已知有22种基因型(非专利文献1)。
临床症状根据每个病毒株的病原性的不同、宿主侧的因素(动物种类、年龄、健康状态等)以及感染路径而不同,显示出特急性型、急性型、亚急性型、慢性型和非显性型等多样的病态。哺乳猪或妊娠猪表现出更严重的症状,致死率也高。在特急性型中,有时呈现41℃以上的发热、没有精神、食欲不振。虽然有时也有看到严重的皮肤淤血、红斑的情况,但多数情况下在临床上不显示出显著变化而在感染后4天以内突然死亡。致死率达到100%。急性型的情况下临床症状最常见,呈现40~42℃的发热、没有精神、食欲不振。可以在感染3~6天后看到发热的症状。母猪中也发现了流产。感染的猪在发热后1周以内死亡,致死率大致为100%。亚急性型表现出与急性型同样的症状,但更缓慢地发展而在感染后7~20天死亡。致死率在70%以下,幸存的猪在3~4周恢复。也有以流产为契机而发现的情况。慢性型是指不显示显著的症状。虽然有呼吸道症状、腹泻、关节的肿胀、伴有溃疡的皮炎等报告,但认为这些症状是因细菌的二次感染而引起的。非显性型是在非洲的荒漠疣猪或红河猪中发现的,无症状且感染长时间持续。在ASFV侵入到未发病地域的情况下,在不显示特别的症状的状态下持续突然死亡,由此确认发病。由于ASFV的传染性非常强,因此很难想象在猪圈内仅出现少量发病这样的事例,而是设想一旦侵入则同居的猪全部感染而发病的状况。目前,不存在针对非洲猪瘟(ASF)的疫苗或治疗药物(非专利文献1)。因此,针对非洲猪瘟(ASF)有效的治疗药物的开发成为当务之急。
现有技术文献
非专利文献
非专利文献1:国立研究开发法人农业·食品工业技术综合研究机构,动物卫生研究部门主页,URL:http://www.naro.affrc.go.jp/laboratory/niah/asf/,访问日:2020年5月20日
发明内容
发明所要解决的课题
本发明的课题在于提供非洲猪瘟(ASF)的治疗剂和/或预防剂。更详细而言,提供一种含有5-ALA或其衍生物或它们的盐的非洲猪瘟(ASF)的治疗剂和/或预防剂。另外,在另一方式中,提供一种使用5-ALA或其衍生物或它们的盐的非洲猪瘟(ASF)的治疗方法和/或预防方法。
解决课题的手段
本发明人等为了解决上述课题反复进行了深入研究,结果完全意外地发现5-ALA会抑制非洲猪瘟(ASF)的感染和/或症状,治疗或预防非洲猪瘟(ASF),从而完成了本发明。
5-ALA是在细胞内的线粒体内产生的血红素系化合物的共同前体。有报道5-ALA在体内被吸收后,在细胞内被代谢为原卟啉、血红素、胆绿素,这些5-ALA代谢产物分别显示各种生理作用。虽然已知通过给药5-ALA,可以针对特定的炎症性疾病获得抗炎作用等,但不知道5-ALA及其衍生物能够抑制非洲猪瘟(ASF)的感染和/或症状,能够治疗或预防非洲猪瘟(ASF)。本发明新提供一种用于治疗或预防非洲猪瘟(ASF)的含有5-ALA及其衍生物的药物及其应用。
进而,本发明人等还发现,通过组合使用5-ALA和柠檬酸亚铁钠(Sodium FerrousCitrate,SFC)等含金属化合物,可以得到极其优异的非洲猪瘟(ASF)的治疗或预防效果。
即,本发明提供以下方案。
[项目1]
一种非洲猪瘟(ASF)的治疗剂和/或预防剂,其含有下述式(I)所示的化合物或其盐。
[化1]
(式中,R1表示氢原子或酰基,R2表示氢原子、直链或支链状烷基、环烷基、芳基或芳烷基。)
[项目2]
根据项目1所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,R1和R2为氢原子。
[项目3]
根据项目1或2所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,其还含有一种或两种以上的含金属化合物。
[项目4]
根据项目3所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,含金属化合物是含有铁、镁、锌、镍、钒、铜、铬、钼或钴的化合物。
[项目5]
根据项目3所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,含金属化合物是含有铁、镁或锌的化合物。
[项目6]
根据项目3所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,含金属化合物是含有铁的化合物。
[项目7]
一种非洲猪瘟(ASF)的治疗方法和/或预防方法,其包括将下述式(I)所示的化合物或其盐与药学上可接受的赋形剂一起给药。
[化2]
(式中,R1表示氢原子或酰基,R2表示氢原子、直链或支链状烷基、环烷基、芳基或芳烷基。)
[项目8]
一种下述式(I)所示的化合物或其盐在非洲猪瘟(ASF)的治疗和/或预防中的应用。
[化3]
(式中,R1表示氢原子或酰基,R2表示氢原子、直链或支链状烷基、环烷基、芳基或芳烷基。)
发明效果
本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂特别是通过强力地抑制病毒的感染或复制、病毒对生物体功能的损害等,从而发挥优异的非洲猪瘟(ASF)治疗和/或预防效果。
附图说明
图1是表示记录了实施例1的试验结果的表的图。
图2是表示记录了实施例2的试验结果的一部分的表的图。示出高剂量联合给药组A1(5-ALA:30mg/kg/日、SFC:34.5mg/kg/日)、高剂量单独给药组A2(5-ALA:30mg/kg/日)、中剂量联合给药组B1(10mg/kg/日、SFC:11.5mg/kg/日)和中剂量单独给药组B2(5-ALA:10mg/kg/日)的结果。
图3是表示记录了实施例2的试验结果的一部分的表的图。示出低剂量联合给药组C2(3mg/kg/日、SFC:3.45mg/kg/日)、低剂量单独给药组C2(5-ALA:3mg/kg/日)、以及无处置组的结果。
具体实施方式
(定义)
在本说明书中,在示出多个数值的范围的情况下,也同样意味着由这些多个范围的任意的下限值和上限值的组合构成的范围。
(本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂的有效成分)
作为本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂的有效成分使用的化合物可以例示出式(I)所示的化合物或其盐(以下,有时也将它们总称为“ALA类”)。也称为δ-氨基乙酰丙酸的5-ALA是式(I)的R1和R2均为氢原子的情况,是氨基酸的一种。作为5-ALA衍生物,可以举出式(I)的R1为氢原子或酰基、式(I)的R2为氢原子、直链或支链状烷基、环烷基、芳基或芳烷基的5-ALA以外的化合物。
作为式(I)中的酰基,可以举出甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、辛酰基、苄基羰基等直链或支链状的碳原子数1~8的烷酰基、或苯甲酰基、1-萘甲酰基、2-萘甲酰基等碳原子数7~14的芳酰基。
作为式(I)中的烷基,可以举出甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基等直链或支链状的碳原子数为1~8的烷基。
作为式(I)中的环烷基,可以举出环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环十二烷基、1-环己烯基等饱和、或可以存在部分不饱和键的碳原子数3~8的环烷基。
作为式(I)中的芳基,可以举出苯基、萘基、蒽基、菲基等碳原子数6~14的芳基。
作为式(I)中的芳烷基,芳基部分可以与上述芳基的例示相同,烷基部分可以与上述烷基的例示相同,具体而言,可以举出苄基、苯乙基、苯基丙基、苯基丁基、二苯甲基、三苯甲基、萘基甲基、萘基乙基等碳原子数为7~15的芳烷基。
作为上述5-ALA衍生物,优选R1为甲酰基、乙酰基、丙酰基、丁酰基等的化合物,或上述R2为甲基、乙基、丙基、丁基、戊基等的化合物,可以优选举出上述R1和R2的组合为甲酰基和甲基、乙酰基和甲基、丙酰基和甲基、丁酰基和甲基、甲酰基和乙基、乙酰基和乙基、丙酰基和乙基、丁酰基和乙基的组合的化合物等。
5-ALA类只要在生物体内在式(I)的5-ALA或其衍生物的状态下作为有效成分发挥作用即可,根据给药的形态,作为用于提高溶解性的各种盐、酯或由生物体内的酶分解的前药(前体)给药即可。例如,作为5-ALA及其衍生物的盐,可以举出药学上可接受的酸加成盐、金属盐、铵盐、有机胺加成盐等。作为酸加成盐,可以例示出例如盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硝酸盐、硫酸盐等各无机酸盐,甲酸盐、乙酸盐、丙酸盐、甲苯磺酸盐、琥珀酸盐、草酸盐、乳酸盐、酒石酸盐、乙醇酸盐、甲磺酸盐、丁酸盐、戊酸盐、柠檬酸盐、富马酸盐、马来酸盐、苹果酸盐等各有机酸加成盐。作为金属盐,可以例示出锂盐、钠盐、钾盐等各碱金属盐,镁盐、钙盐等各碱土金属盐,铝、锌等各金属盐。作为铵盐,可以例示出铵盐、四甲基铵盐等烷基铵盐等。作为有机胺盐,可以例示出三乙胺盐、哌啶盐、吗啉盐、甲苯胺盐等各盐。需要说明的是,这些盐在使用时也可以作为溶液使用。
以上的ALA类中,优选5-ALA、以及5-ALA甲酯、5-ALA乙酯、5-ALA丙酯、5-ALA丁酯、5-ALA戊酯等各种酯类、以及它们的盐酸盐、磷酸盐、硫酸盐,特别优选例示出ALA盐酸盐、5-ALA磷酸盐。
上述ALA类可以通过化学合成、利用微生物的生产、利用酶的生产中的任一种公知的方法来制造。另外,上述ALA类可以形成水合物或溶剂化物,另外可以单独使用任意一种或将2种以上适当组合使用。
本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂优选在不产生过剩症的范围内进一步含有含金属化合物,作为该含金属化合物的金属部分,可以举出铁、镁、锌、镍、钒、钴、铜、铬、钼,优选铁、镁、锌,其中可以优选例示出铁。
通过联合使用上述ALA类和含金属化合物,即使使用更低浓度的ALA类,也能够得到优异的非洲猪瘟(ASF)的治疗和/或预防效果。
作为上述铁化合物,可以是有机盐也可以是无机盐,作为无机盐,可以举出氯化铁(III)、三氧化二铁、硫酸铁、焦磷酸亚铁。作为有机盐,可以举出羧酸盐、例如羟基羧酸盐、柠檬酸亚铁、柠檬酸铁钠、柠檬酸亚铁钠(Sodium Ferrous Citrate,SFC)、柠檬酸铁铵等柠檬酸盐,焦磷酸铁(III)、血红素铁、右旋糖苷铁、乳酸铁、葡萄糖酸亚铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺五乙酸铁铵、二羧基甲基谷氨酸铁钠、二羧基甲基谷氨酸铁胺、富马酸亚铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠等有机酸盐、三亚乙基四胺铁、乳铁蛋白铁、转铁蛋白铁、铁叶绿酸钠、铁蛋白铁、含糖氧化铁、甘氨酸亚铁硫酸盐。
作为上述镁化合物,可以举出柠檬酸镁、苯甲酸镁、乙酸镁、氧化镁、氯化镁、氢氧化镁、碳酸镁、硫酸镁、硅酸镁、硝酸镁、二亚乙基三胺五乙酸镁二铵、乙二胺四乙酸镁二钠、镁原卟啉。
作为上述锌化合物,可以举出氯化锌、氧化锌、硝酸锌、碳酸锌、硫酸锌、二亚乙基三胺五乙酸锌二铵、乙二胺四乙酸锌二钠、锌原卟啉、含锌酵母。
上述含金属化合物可以分别使用1种或2种以上,作为含金属化合物的给药量,相对于5-ALA的给药量以摩尔比计为0~100倍即可,优选为0.01倍~10倍,更优选为0.1倍~8倍。
在不产生过剩症的范围内,本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂可以进一步与其他抗病毒剂、其他疾病治疗药物联合使用。本领域技术人员可以适当调整这些其他药剂的给药量和5-ALA的给药量的比率。
(本发明的治疗剂和/或预防剂的给药方法)
本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂中含有的ALA类和含金属化合物或其他药剂可以以如下方式给药:作为含有它们中的任意2种以上的组合物,或者也可以作为单独含有它们的组合物。在使用分别单独含有ALA类和含金属化合物或其他药剂的组合物的情况下,可以将它们同时给药,或者也可以分别进行给药。优选的是,ALA类与含金属化合物或其他药剂的给药可以以能够发挥叠加效果、优选协同效果的方式组合给药。在分别给药单独含有ALA类和含金属化合物或其他药剂的组合物的情况下,它们的给药间隔可以设定为5分钟、10分钟、15分钟、20分钟、30分钟、45分钟、1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时等,但并不限定于这些。
作为本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂的给药途径,没有特别限定,可以使用口服给药、吸入给药、经鼻给药、注射、利用输液等的静脉内给药、经皮给药、栓剂、或者基于使用经鼻胃管、经鼻肠管、胃瘘管或肠瘘管的强制经肠营养法的给药等非经口给药等。
(本发明的治疗剂和/或预防剂的剂型)
作为本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂的剂型,可以根据上述给药途径适当确定,可以举出:注射剂、输液剂、片剂、胶囊剂、细粒剂、散剂、液剂、溶解于糖浆等中的水剂、膏剂、栓剂等。
为了制备本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂,可以根据需要添加药学上可接受的载体、赋形剂、稀释剂、添加剂、崩解剂、结合剂、包覆剂、润滑剂、滑行剂、润滑光泽剂、风味剂、甜味剂、增溶剂、溶剂、凝胶化剂、营养剂等,本领域技术人员可以根据目的选择各具体的成分。
(本发明的治疗剂和/或预防剂的给药量)
作为本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂以及病毒蛋白表达抑制剂的给药的量、频率、期间,根据要治疗或预防非洲猪瘟(ASF)的动物的种类、年龄、体重、症状等而不同,例如在对猪给药的情况下,作为ALA类的给药量,可以举出以5-ALA重量换算计每1头动物0.1-1000mg/kg体重/日、优选0.3-300mg/kg体重/日、更优选1-30mg/kg体重/日、进一步优选3-30mg/kg体重/日,特别是作为预防剂使用的情况下,优选持续摄取低剂量。例如在作为预防补品给药的情况下,也可以以0.1-30mg/kg体重/日、优选0.3~10mg/kg体重/日、更优选1~3mg/kg体重/日等给药量进行给药。作为给药频率,可以例示出一天一次~多次的给药或通过输液等连续给药。作为治疗剂或预防剂的给药期间,可以通过兽医等该技术领域的专家已知的方法来决定。
(本发明的治疗剂和/或预防剂的适用症状)
本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂能够适用于以ASFV的感染和/或非洲猪瘟(ASF)发病为原因而产生的各种症状和损害的治疗和预防,能够抑制、延迟与ASFV接触的动物产生这些症状等。作为这样的症状,可以例示出发热、没有精神、食欲不振、淤血、红斑和流产、死亡,但并不限定于这些。
(本发明的治疗剂和/或预防剂的适用动物)
本发明的非洲猪瘟(ASF)的治疗剂和/或预防剂可以对猪、野猪等野猪科动物以及它们的近亲动物等给药。
以下,通过实施例对本发明进行更详细的说明,但本发明并不限定于此。
[实施例1]
(材料和方法)
1.动物:使用杜洛克猪种或长白猪种的4~5周龄的猪(体重约10kg、雌或雄)。
2.病毒株:使用在越南在临床上分离的ASFV株(基因型2P252)。该病毒株确认了接触感染和通过饮用水的感染。制备102HAD50/mL EMEM中的病毒溶液并使用。
3.5-ALA以及SFC的制备
(1)含5-ALA的饲料:以100mg/kg体重/日(体重为实验开始时刻)的5-ALA剂量的方式,将5-ALA磷酸盐水溶液与猪用饲料混合并投喂。
(2)含5-ALA和SFC的饲料:以100mg/kg体重/日的5-ALA给药量、115mg/kg体重/日的SFC给药量(5-ALA和SFC的摩尔比为1:0.5)的方式,将5-ALA磷酸盐水溶液和SFC水溶液与猪用饲料混合并投喂。
(3)无处置用饲料:作为阴性对照,投喂不混合5-ALA磷酸盐或5-ALA磷酸盐和SFC的猪用饲料。
4.试验方法:
将10头受试猪按每5头一个猪舍分配(猪舍A和B)。每早10点,对猪舍A的5头受试猪中的3头(A1、A2、A3)将含5-ALA的饲料口服给药7天,其中5-ALA剂量为100mg/kg体重/日;对2头(B1、B2)将无处置用饲料口服给药7天。每早10点,对猪舍B的5头受试猪中的3头(C1、C2、C3)将含5-ALA和SFC的饲料口服给药7天,其中5-ALA的给药量为100mg/kg体重/日、SFC的给药量为115mg/kg体重/日;对2头(C4、C5)将无处置用饲料口服给药7天。
(表1)处置组的分配
在饲料的投喂开始后第7天,将102HAD50/mL的ASFV经口接种于所有的受试猪。ASFV接种后,继续5-ALA、5ALA+SFC或无处置用饲料的给药。对各受试猪,每天测定体温(直肠内温度),在ASFV接种后0、4、6、8、10、12、14、18、21天后的时间点检查血中病毒浓度,并且在受试猪死亡的情况下记录死亡日。
(结果)
将结果示于图1的表2和下述表3、4。
(表3)发热、血中病毒阳性以及有无死亡
(表4)持续的发热和血中病毒阳性的开始日以及死亡日
5-ALA+SFC联合给药的受试猪(A1、A2、A3)直到ASFV接种的21天后全部存活。受试猪A1和A3直到接种的21天后不显示发热,血中病毒也为阴性。只有受试猪A2在20~21天后显示40℃以上的发热,21天后血中病毒为阳性。另一方面,在同一猪舍A内的无处置受试猪(B1、B2)中,受试猪B1在从ASFV接种的8天后起有40℃以上的发热,并且血中病毒持续阳性的状态,14天后死亡。受试猪B2也在10天后断续地显示发热,在14天后持续发热,并且显示血中病毒阳性。
5-ALA单独给药后的受试猪(C1、C2、C3)也直到ASFV接种的21天后全部存活。受试猪C1在接种的21天后不显示发热,血中病毒也为阴性。受试猪C2虽然在10~11天后显示40℃以上的发热,但之后没有发热,到21天后血中病毒为阴性。受试猪C3直到接种的21天后不显示发热,在21天后只示出血中病毒阳性。另一方面,同一猪舍B内的无处置受试猪(D1、D2)均在21天内死亡。受试猪D1从11天后起持续40℃以上的发热,12天后的血中病毒持续阳性的状态,19天后死亡。受试猪D2在12天后继续发热,并且显示血中病毒阳性,在18天后死亡。
[实施例2]
以更高病毒的病毒负荷和更低的5-ALA给药量进行与实施例1同样的试验。
(材料和方法)
1.动物:使用6~7周龄的猪(体重约20kg)。
2.病毒株:使用在实施例1中使用的在越南在临床上分离的ASFV株(基因型2P252),制备实施例1的10倍浓度即103HAD50/mL EMEM中的病毒溶液。
3.5-ALA以及SFC的制备
(1)含5-ALA的饲料:以3mg/kg体重/日、10mg/kg体重/日和30mg/kg体重/日(体重为实验开始时刻)的5-ALA剂量的方式,将5-ALA磷酸盐水溶液与猪用饲料混合并投喂。
(2)含5-ALA和SFC的饲料:以3mg/kg体重/日的5-ALA给药量和3.45mg/kg体重/日的SFC给药量、10mg/kg体重/日的5-ALA给药量和11.5mg/kg体重/日的SFC给药量、30mg/kg体重/日的5-ALA给药量和34.5mg/kg体重/日的SFC给药量(5-ALA和SFC的摩尔比均为1:0.5)的方式,将5-ALA磷酸盐水溶液和SFC水溶液与猪用饲料混合并投喂。
(3)无处置用饲料:作为阴性对照,投喂不混合5-ALA磷酸盐或5-ALA磷酸盐和SFC的猪用饲料。
4.试验方法:
如下述表所示,对联合给药30mg/kg/日的5-ALA和34.5mg/kg/日的SFC的组(A1)、联合给药10mg/kg/日和11.5mg/kg/日的SFC的组(B1)、联合给药3mg/kg/日和3.45mg/kg/日的SFC的组(C1)、单独给药30mg/kg/日的5-ALA的组(A2)、单独给药10mg/kg/日的5-ALA的组(B2)、单独给药3mg/kg/日的5-ALA的组(C2)、以及对无处置的组(D)各分配3头动物,将各药剂口服给药7天。
(表5)处置组的分配
在饲料的投喂开始后第七天,将103HAD50/mL的ASFV对所有的受试猪进行经鼻接种。ASFV接种后,继续进行5-ALA、5ALA+SFC或无处置用饲料的给药。对于各受试猪,每天测定体温(直肠内温度),在ASFV接种后0、4、7、10、14、17、21、28天后的时间点检查血中病毒浓度、以及体温超过40℃的情况下追加检查,并且在受试猪死亡的情况下记录死亡日。血中病毒浓度采用实时PCR进行测定。
需要说明的是,对于血中病毒浓度显示阳性的猪,一般根据在饲养猪时怀疑病毒感染的情况下进行的处置,在同一猪舍内的感染猪专用的笼子隔离。
(结果)
将结果示于下述表6和图2~3的表7、8。需要说明的是,表7、8的“经过天数”表示ASFV病毒接种后的天数。
(表6)发热、血中病毒阳性和有无死亡
如表6所示,在无处置组中,所有的受试猪在病毒接种后21天后死亡,在病毒接种后28天时间点的存活率为0%,与此相对,在高剂量联合给药组A1(5-ALA:30mg/kg/日、SFC:34.5mg/kg/日)、中剂量联合给药组B2(10mg/kg/日、SFC:11.5mg/kg/日)、低剂量联合给药组C2(3mg/kg/日、SFC:3.45mg/kg/日)中,在同一时间点分别示出67%、100%、67%的存活率;在高剂量单独给药组A2(5-ALA:30mg/kg/日)、中剂量单独给药组B2(5-ALA:10mg/kg/日)、低剂量单独给药组C2(5-ALA:3mg/kg/日)中,在同一时间点分别示出100%、100%、33%的存活率,显示出对感染和发病的防御。
如表7、8更详细地示出的,5ALA的低~高剂量单独给药以及5ALA和SFC的低~高剂量联合给药在发热和血中病毒试验中也显示了表示抑制感染的结果。
需要说明的是,高剂量联合给药组A1的受试猪中的1头(识别编号3)从病毒感染处置后6天后起显示出发热及血中病毒试验阳性,在感染处置后13天死亡,但关于该受试猪,在病毒感染处置时,确认到对鼻部造成了伤害,怀疑有可能从伤害部位侵入的病毒引起爆发性的感染扩大。
另外,低剂量联合给药组C1的受试猪中的1头(识别编号14)在病毒感染处置后25天死亡,由于该受试猪在病毒感染处置后14天的时刻在血中病毒试验中显示阳性,因此转移到感染猪专用的笼子,但在其后的血中病毒试验(病毒感染处置后15天和17天后)确认为阴性,怀疑有可能病毒感染处置后14天的时刻的血中病毒试验的结果为假阳性。在感染猪专用的笼子中,来自具有高浓度的病毒的其他阳性猪的同居感染变得容易,因此认为该受试猪在感染猪专用笼内感染,在病毒感染处置后25天死亡。
通过本试验,显示出即使5-ALA为低剂量,也提供对ASFV病毒感染的防御,并且即使在低剂量下,5-ALA和SFC的联合使用也显示出更优异的防御。
以上的结果表示,通过5-ALA或5-ALA和SFC的联合给药,抑制了ASFV的感染和/或感染后的ASF发病。如上述试验所示,通过5-ALA的给药,能够抑制非洲猪瘟(ASF)的感染和/或症状,能够治疗或预防非洲猪瘟(ASF)。
Claims (6)
2.根据权利要求1所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,R1和R2为氢原子。
3.根据权利要求1或2所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,其还含有一种或两种以上的含金属化合物。
4.根据权利要求3所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,含金属化合物是含有铁、镁、锌、镍、钒、铜、铬、钼或钴的化合物。
5.根据权利要求3所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,含金属化合物是含有铁、镁或锌的化合物。
6.根据权利要求3所述的非洲猪瘟(ASF)的治疗剂和/或预防剂,其特征在于,含金属化合物是含有铁的化合物。
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