WO2017173956A1 - 天维菌素用于防治寄生虫的用途 - Google Patents

天维菌素用于防治寄生虫的用途 Download PDF

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WO2017173956A1
WO2017173956A1 PCT/CN2017/079061 CN2017079061W WO2017173956A1 WO 2017173956 A1 WO2017173956 A1 WO 2017173956A1 CN 2017079061 W CN2017079061 W CN 2017079061W WO 2017173956 A1 WO2017173956 A1 WO 2017173956A1
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avermectin
group
use according
parasite
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PCT/CN2017/079061
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English (en)
French (fr)
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王继栋
黄隽
张辉
林甲壇
李美红
张灵坚
邓爱文
王玲萍
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浙江海正药业股份有限公司
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Priority to US16/091,304 priority Critical patent/US20190151341A1/en
Priority to AU2017247267A priority patent/AU2017247267A1/en
Publication of WO2017173956A1 publication Critical patent/WO2017173956A1/zh

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • 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 invention belongs to the field of medicine, and particularly relates to the use of avermectin for controlling parasites in humans or animals.
  • parasitic diseases As a disease that is very harmful to livestock and poultry, parasitic diseases often endanger animal health in a very hidden way. Most of them are chronic diseases. Most of them have no obvious symptoms in clinical practice, making livestock and poultry in a subclinical state for a long time. Staff neglected. There are many types of animal parasitic diseases, which are widely distributed and easily mixed infection. Once the disease will seriously affect the animal's physical health, damage its reproductive ability, inhibit the growth and development of young animals, weaken the production performance of livestock and poultry, and reduce the quantity of livestock and poultry products. Quality, causing serious economic losses to livestock production. Parasitic diseases not only cause harm to the animal husbandry industry, but also cause serious harm to human health. Parasitic diseases are one of the greatest enemies of human health, and it poses a serious threat to public health.
  • Anti-parasitic diseases traditional drugs for the treatment of ectoparasites, such as trichlorfon, are highly eradicated, and are safe, broad-spectrum, high-efficiency, residue-free or low-residue, with grouped drug delivery.
  • the physicochemical properties and low-cost ideal anti-parasitic drugs are on the stage.
  • the avermectins are a class of natural and semi-synthetic antibiotics produced by fermentation of Streptomyces avermitilis. This class of drugs has a broad spectrum of anti-parasitic activity and can kill mature and immature nematodes and arthropods at very low concentrations. Although this class of drugs is extremely toxic to bacteria, fungi, mites, plants and birds, it has a high toxic effect on certain aquatic organisms. After several weeks of administration, the avermectins have drug residues in the animal feces, and the residual drugs in the agglomerated feces cannot be quickly decomposed. Therefore, it is potentially harmful to aquatic organisms.
  • Patent CN201410208660.9 discloses a new class of macrolide compounds avermectin A and B (the structure of which is shown in Formula 1) produced by genetically engineered bacteria MA220 and its control against cinnabarinus and scutellaria, Plutella xylostella, beet armyworm, Spodoptera litura, cotton bollworm, small tiger, golden worm, armyworm, pine caterpillar, pine wood nematode, rice aphid and other agricultural and forestry crop pests and pests.
  • the invention provides the use of one or both of the compounds of formula (I) below for the manufacture of a medicament for the control of human or animal parasites:
  • R is selected from CH 3 or C 2 H 5 , and when R is CH 3 , it is avermectin A, and when R is C 2 H 5 , it is avermectin B.
  • the animal is selected from the group consisting of pig, cow, dog, sheep, rabbit, chicken, duck or goose.
  • the parasite is selected from the group consisting of: a nematode, an insect, and an arachnid.
  • the parasite is selected from the group consisting of a genus, a scutellaria, a scutellaria, a scutellaria, a snail, a snail, a snail, a pterophyllum, a diptera, a scorpion, a scorpion, a scorpion Eyes or real attention, preferably round Eye, eye, silkworm, whiptail, eye or true eye.
  • the parasite is selected from the group consisting of the genus Ranunculus, the genus Hook, the phylum, the genus, the genus, the genus, the genus, the genus, the genus, the tubular Branch, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, cockroach, cockroach, cockroach, cockroach, cockroach, cockroach, cockroach, cockroach, cockroach Worm, hard carp or carp.
  • the parasite is selected from the group consisting of a nematode, a blood scorpion, a calf, a sheep digestive nematode or a sheep mites.
  • the compound of formula (I) is a mixture of avermectin A and avermectin B.
  • the animal is selected from the group consisting of a fish, a crustacean, a mollusc or an aquatic invertebrate, preferably grass carp, gibel carp, carp, wheat carp, mosquito carp, carp, greenshrimp, river crab, round snail, Matsuura mirror and ornamental fish, etc., more suitable for silver carp, grass carp, Matsuura mirror or ornamental fish.
  • the parasite is selected from the group consisting of a sporozoan, a mites, a nematode, a worm, a paragonimiasis, a schistosomiasis, a ringworm or an anchor.
  • the compound of the formula (I) is a mixture of avermectin A and avermectin B, preferably, the mixture of avermectin A and avermectin B in the mixture
  • the weight ratio is ⁇ 9:1, more preferably ⁇ 19:1.
  • avermectin A and avermectin B are structurally similar to avermectin, ivermectin, milbemycin, and carbaryl salts, but the inventors passed The toxicological experiment of zebrafish unexpectedly found that the toxicity of avermectin A and avermectin B was significantly lower than that of similar products such as avermectin, ivermectin, milbemycin and carbaryl salt. The product is more green and has better market application prospects.
  • the compound of the formula (I) according to the invention can be prepared in the form of a conventional preparation.
  • the conventional preparation forms include, for example, pour-on, tablets, injections, and dry suspensions.
  • Ivermectin, avermectin A and avermectin B are all from Zhejiang Haizheng Pharmaceutical Co., Ltd. As shown in the formula of the formula of Table 1, the drug substance was dissolved in dimethylformamide, stirred in propylene glycol, and uniformly filtered, and 1% ivermectin, 1% avermectin A and 1% were respectively obtained by sterile filtration. Injection of avermectin B.
  • Excipient 1 Active ingredient
  • Excipient 2 1% ivermectin Ivermectin, 1kg Dimethylformamide, 10L Propylene glycol, 90L 1% avermectin A Tianweimycin A, 1kg Dimethylformamide, 10L Propylene glycol, 90L 1% avermectin B Tianweimycin B, 1kg Dimethylformamide, 10L Propylene glycol, 90L
  • Test agent 1% ivermectin injection, 1% avermectin A injection, and 1% avermectin B injection as obtained in Example 1.
  • Test animals and grouping Pigs cultured on the same farm were selected, and 40 pigs naturally infected with digestive tract nematodes were selected for testing by stool examination. The average weight of the test pigs was 30-50 kg. Forty pigs were randomly divided into 4 groups, each of which was 10 rats. The first group was the ivermectin control group, the second group was the avermectin A group, and the third group was the avermectin B group. The drug-administered group was injected subcutaneously in the neck at 0.2 mg/kg.bw. Group 4 was a blank group and was not administered.
  • Test agent 1% ivermectin injection, 1% avermectin A injection, and 1% avermectin B injection as obtained in Example 1.
  • Test animals and grouping Six cattle of natural cattle infected with cattle mites in the same village were selected for testing. Six cows were randomly divided into three groups, each of which was two. The first group was the ivermectin control group, the second group was the avermectin A group, and the third group was the avermectin B group. The drug-administered group was injected subcutaneously at 2 mg/kg.bw.
  • Bovine aphids on each group of cattle were counted 1 day before administration.
  • Bovine aphids on each group of cattle were counted on days 1, 2, 3 and 4 after administration.
  • the avermectin A group, the avermectin B group and the ivermectin group had comparable deworming effects, but the avermectin A group and the avermectin B group were more durable.
  • Test agent 1% ivermectin injection, 1% avermectin A injection, and 1% avermectin B injection as obtained in Example 1.
  • Test animals and grouping Select the sheep grazing under the same conditions, and select 80 sheep from 0.8-2.0 years old naturally infected with digestive tract nematodes through the stool examination for the test.
  • the average weight of the test sheep is 30 kg.
  • Eighty sheep were randomly divided into 4 groups, each of which was 20 rats. The first group was the ivermectin control group, the second group was the avermectin A group, and the third group was the avermectin B group.
  • the drug-administered group was injected subcutaneously in the neck at 0.2 mg/kg.bw. Group 4 was a blank group and was not administered.
  • Test agent 1% ivermectin injection, 1% avermectin A injection, and 1% avermectin B injection as obtained in Example 1.
  • Test animals and grouping Select sheep grazing under the same conditions, and select 40 sheep infected with sheep mites by parasitological examination. Forty sheep were randomly divided into 4 groups of 10 each. The first group was the ivermectin control group, the second group was the avermectin A group, and the third group was the avermectin B group. The drug-administered group was injected subcutaneously in the neck at 0.2 mg/kg.bw. Group 4 was a blank group and was not administered.
  • Test method observe the changes of clinical symptoms, and use the surgical blade with glycerin to scrape the skin to the skin at the junction of the diseased part of the diseased sheep and the healthy skin. Take the dandruff and put it in the dish and bring it back to the laboratory, and place it on the slide. Add a drop of 50% glycerol solution, add a cover slip and check under a low power microscope. It is confirmed to be positive by seeing live sputum. Samples were taken before administration and at 1, 2, 3, and 4 weeks after administration. Under the microscope, it was found that a live aphid was found to be positive based on whether a live aphid was found, and a clinical symptom change was observed as a reference.
  • Test agents avermectin, milbemycin, ivermectin, avermectin A and avermectin B are all from Zhejiang Haizheng Pharmaceutical Co., Ltd.
  • the sample was formulated as a 50 mg/ml mother liquor in DMF.
  • Test fish and water Zebrafish (Brachydanio rerio) was purchased from Zhejiang Academy of Agricultural Sciences, with the same size, average body length 2-3cm, average body weight 0.3g. Domesticated for 7 days indoors before the test. The natural mortality rate is zero. Feeding was stopped 1 day before the test and was not fed during the test. The test water is tap water after removing residual chlorine for more than 24 hours, and the pH is 6.8.
  • Test method semi-static method. Each sample was set to 0.5 ppm, 1.0 ppm and 1.5 ppm, and each step was set to 3 sets of parallel, each group was raised 10 times, and a blank control (one group without drug addition and only solvent addition) was set. The sample was taken to the corresponding volume of the mother liquor according to the concentration, and the volume was adjusted to 150 ⁇ l with DMF, and then added to the test group (containing 1.6 L of water). The temperature was controlled at 22 ⁇ 2 ° C for 96 hours, and the water was changed every 24 hours and the sample was re-added. The fish mortality was recorded for the first 8 hours and at 24, 48, 72, and 96 hours, and the dead fish were harvested in time. Finally, according to the size of the LC 50 , it is divided into three grades: >10ppm is low toxicity, 1.0-10ppm is poisoning, and ⁇ 1.0ppm is highly toxic.
  • Test results The test results are shown in Table 6. It can be seen from Table 6 that the concentration of avermectin A is 1 ppm, and the 96-hour existence rate of zebrafish is more than 50%, indicating that ivermectin A has a 96-hour LC 50 >1 ppm for zebrafish, which is poisonous; Although the bacteriocin B did not reach the level of poisoning, its toxicity to zebrafish was much lower than that of avermectin, ivermectin, milbemycin and carbaryl.
  • the octopus has an 8-hour survival rate of avermectin, ivermectin, milbemycin, and avidin at 0.5 ppm, indicating avermectin, ivermectin, milbemycin and A 96-hour LC 50 of the zebra salt on the zebra is highly toxic.
  • Allogynogenetic crucian carp is one of the main aquaculture species in Jiangsu and Zhejiang provinces. In many areas, the production of silver carp is more than 30% of freshwater fish production. Therefore, to understand the toxic effect of avermectin A on gibel carp, it is of great significance for rational drug use in aquaculture production.
  • Test fish and water The gibel carp was purchased from Taowang Farm in Jiaojiang District, Taizhou City, with a body length of (9.60 ⁇ 0.52) cm and a body weight of (28.22 ⁇ 3.44) g.
  • the healthy and lively fish with the same specifications were selected and kept in the indoor aquarium. They were domesticated for 7 days indoors before the test. The natural mortality rate is zero. Feeding was stopped 1 day before the test and was not fed during the test.
  • the test water is tap water after removing residual chlorine for more than 24 hours, and the pH is 6.8.
  • Tianweimycin (the mass ratio of tianweimycin A / weiweimycin B is 95/5) (Zhejiang Haizheng Pharmaceutical Co., Ltd.);
  • Tianweimycin (the ratio of avermectin A / tianweimycin B is 90/10) (Zhejiang Haizheng Pharmaceutical Co., Ltd.);
  • Tianweimycin (the mass ratio of tianweimycin A / tianweimycin B is 85/15) (Zhejiang Haizheng Pharmaceutical Co., Ltd.);
  • tianweimycin B (the content of tianweimycin A is 0.51%) ((Zhejiang Haizheng Pharmaceutical Co., Ltd.);
  • Emamectin Benzoate (Zhejiang Shenghua Baike Biological Co., Ltd.).
  • the sample was formulated as a 50 mg/ml mother liquor in DMF.
  • the efficacy test was carried out in a laboratory next to the fish pond where the anchor head parasitic disease occurred near the Changtan Reservoir in Huangyan District, Taizhou City.
  • the test water is from the diseased fish pond.
  • the experimental container is a plastic aquarium of 85cm ⁇ 45cm ⁇ 35cm. Each aquarium stores 100L of water, water temperature (27.0 ⁇ 0.5)°C, pH 7.4 ⁇ 7.8, and is continuously inflated.
  • the dosages of 1.8% avermectin emulsifiable concentrates A, B, C and 1.8% avermectin emulsifiable concentrate and 1.8% ivermectin emulsifiable concentrate were 0.01 mg/L, 0.02 mg/L and 0.04 mg/L, respectively. Change the liquid. Two species of sick silver carp were placed in each aquarium, and the number of anchor heads attached to each test fish was counted before being placed. Each test was performed with clear water as a control, and the concentration of each drug solution was repeated 6 times. After the start of the test, the first 6 hours were observed continuously, and then their behavior, symptoms of poisoning and loss of insects were observed from time to time.
  • the number of insects in the heads of each test group was recorded at 6h, 12h, 24h, 48h, and 96h.
  • the survival rate of the insects of the parasitic anchor head of the silver carp body after application was shown in Table 8.
  • the LSD test analyzed the difference significance.
  • Table 8 Insect survival rate of parasitic anchor head mites in silver carp after application

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Abstract

如式(I)的化合物用于防治人或动物中寄生虫的用途，其中R选自-CH 3或-C 2H 5，并且当R为-CH 3时为天维菌素A，当R为-C 2H 5时为天维菌素B，两者对人或动物中的寄生虫，例如线虫及节肢动物具有杀灭效果，而且其毒性低于现有大环内酯类化合物。

Description

[根据细则37.2由ISA制定的发明名称]　天维菌素用于防治寄生虫的用途 发明领域
本发明属于医药领域，具体涉及天维菌素用于防治人或动物中寄生虫的用途。
背景技术
寄生虫病作为一种对畜禽危害十分严重的疾病，常以极隐蔽的方式危害动物健康，其多为慢性疾病，在临床大多无明显症状，使畜禽长期处于亚临床状态，易被养殖人员忽视。动物寄生虫病种类多，散布广泛，易混合感染，一旦发病会严重影响动物的身体健康，损害其繁殖能力，抑制幼畜的生长发育，削弱畜禽的生产性能，降低畜禽产品的数量及质量，给畜牧业生产造成严重的经济损失。寄生虫病不仅对畜牧养殖业带来危害，还对人类健康造成严重危害。人兽共患寄生虫病是人类健康的大敌之一，它对公共卫生构成严重威胁。
随着畜牧业和公共卫生安全的发展需要。对抗寄生虫病，传统的治疗体外寄生虫病的药物，如敌百虫等多为剧毒药物逐渐被淘汰，而具备安全、广谱、高效、无残留或低残留，具有群体化给药的理化性质以及价格低廉的理想抗寄生虫药物走向舞台。
阿维菌素类(Avermectins)药物是由链霉菌(Streptomyces avermitilis)发酵产生的一类天然的及其半合成抗生素。本类药物具有广谱抗寄生虫活性，在极低的浓度条件下能驱杀成熟及未成熟线虫和节肢动物。虽然本类药物对细菌、真菌、蚯蚓、植物和鸟类的毒性极低，但是其对某些水生生物有较高的毒性作用。阿维菌素类药物在用药数周后，动物粪便中还有药物残留，在结块的粪便中的残留药物不能很快分解。因此，其对水生生物具有潜在的危害。
专利CN201410208660.9公开了基因工程菌MA220产生的一类新的大环内酯类化合物天维菌素A和B(其结构如式1所示)及其防治朱砂叶螨、二斑叶螨，小菜蛾、甜菜夜蛾、斜纹夜蛾、棉铃虫，小地老虎、金针虫，粘虫、松毛虫、松材线虫病，水稻螟虫等农林作物害虫和害螨的作用。
Figure PCTCN2017079061-appb-000001
发明内容
本发明提供了如下式(I)的化合物中的一种或二种混合物在制备用于控制人或动物寄生虫的药物中的用途：
Figure PCTCN2017079061-appb-000002
其中R选自CH3或C2H5，并且当R为CH3时为天维菌素A，当R为C2H5时为天维菌素B。
在一个优选的实施方案中，所述动物选自猪、牛、狗、羊、兔、鸡、鸭或鹅。
在一个优选的技术方案中，所述寄生虫选自：线虫纲、昆虫纲和蛛形纲。
在一个优选的实施方案中，所述寄生虫选自圆线目，小杆目，蛔目，尖尾目，旋尾目，丝虫目，鞭尾目，双翅目，吸虱目，蚤目，蜱螨目或真螨目，优选圆线 目，蛔目，丝虫目，鞭尾目，蜱螨目或真螨目。
在一个优选的实施方案中，所述寄生虫选自毛圆科，钩口科，结节科，网尾科，类圆科，蛔科，弓首科，禽蛔科，尖尾科，管状科，旋尾科，盖头虫科，毛细科，毛形科，鞭虫科，蚊科，蝇科，虱科，蚤科，硬蜱科或疥螨科，优选蛔科，禽蛔科，鞭虫科，硬蜱科或疥螨科。
在一个优选的技术方案中，所述寄生虫选自猪线虫、血虱、牛蜱虫、绵羊消化道线虫或绵羊疥螨。
在一个优选的技术方案中，所述式(I)的化合物为天维菌素A和天维菌素B的混合物。
在一个优选的技术方案中，所述动物选自鱼、甲壳类动物、软体动物或水生无脊椎动物，优选草鱼、异育银鲫、鲢鱼、麦穗鱼、食蚊鱼、鳙鱼、青虾、河蟹、圆田螺、松浦镜鲤及观赏鱼类等，更优选异育银鲫、草鱼、松浦镜鲤或观赏鱼类。
在一个优选的技术方案中，所述寄生虫选自孢子虫、绦虫、线虫、艾美虫、肺吸虫、血吸虫、指环虫或锚头鲺。
在一个优选的技术方案中，所述式(I)的化合物为天维菌素A和天维菌素B的混合物，优选的，所述混合物中天维菌素A与天维菌素B的重量比≥9:1，更优选≥19:1。
本发明人惊奇的发现，天维菌素A和天维菌素B虽然在结构上与阿维菌素、伊维菌素、米尔贝霉素和甲维盐等很相似，但发明人通过对斑马鱼的毒理实验，意外的发现天维菌素A和天维菌素B的毒性明显低于同类的阿维菌素、伊维菌素、米尔贝霉素和甲维盐等产品，因此该产品更绿色环保，具有更好的市场应用前景。
本发明所述式(I)的化合物可制成常规制剂形式。所述常规制剂形式包括例如，浇泼剂、片剂、注射剂和干混悬剂。
具体实施方式
以下通过实施例对本发明进一步进行说明，必须指出，这些实施例是用于说明本发明，而不应理解为对本发明的限制。
实施例1
1％伊维菌素、1％天维菌素A和1％天维菌素B制剂的制备
伊维菌素、天维菌素A和天维菌素B原料药均来自浙江海正药业股份有限公司。如表1配方所述量比关系，将原料药溶解于二甲基甲酰胺中，加入丙二醇中搅拌均匀，无菌过滤分别得1％伊维菌素、1％天维菌素A和1％天维菌素B的注射剂。
表1
制剂 活性成分 辅料1 辅料2
1％伊维菌素 伊维菌素，1kg 二甲基甲酰胺，10L 丙二醇，90L
1％天维菌素A 天维菌素A，1kg 二甲基甲酰胺，10L 丙二醇，90L
1％天维菌素B 天维菌素B，1kg 二甲基甲酰胺，10L 丙二醇，90L
实施例2
天维菌素A和天维菌素B对猪线虫和血虱的驱除
供试药剂：如实施例1所得1％伊维菌素注射剂、1％天维菌素A注射剂和1％天维菌素B注射剂。
试验动物及分组：选择同一猪场养殖的猪，通过粪便检查，从中挑选出自然感染消化道线虫的猪40只供试验用，试验猪的平均体重30-50kg。将40只猪随机分为4组，每组均为10只。第1组为伊维菌素对照组，第2组为天维菌素A组，第3组为天维菌素B组。给药组均按照0.2mg/kg.bw颈部皮下注射。第4组为空白组，不给药。
试验方法：
1)给药前l天对各组猪逐头采粪检查，用McMaster′s法作虫卵计数，统计每克粪便所含虫卵数(EPG)并观察体表血虱情况。
2)给药后1，2，3，4周均用McMaster′s法对各组猪进行粪检，统计EPG并观察体表血虱的变化情况。
3)按常规方法计算试验猪转阴率和虫卵减少率进行驱除猪线虫的疗效判定。
4)其对猪血虱的杀虫效果，依据给药后第7天猪血虱存活情况进行判定。
试验结果：
1)从表2可见，天维菌素A组、天维菌素B组和伊维菌素组的驱虫效果依次为天维菌素B＞天维菌素A组＞伊维菌素组，天维菌素B组和天维菌素A组的药效更持久；
2)试验组用药至第7天及后续3周观察天维菌素A组、天维菌素B组和伊维菌素组都未发现有活动的血虱，而观察空白组猪群体表血虱数量未见减少。
表2各组试验猪转阴率和虫卵减少率
Figure PCTCN2017079061-appb-000003
实施例3
天维菌素A和天维菌素B对牛蜱虫的杀灭作用
供试药剂：如实施例1所得1％伊维菌素注射剂、1％天维菌素A注射剂和1％天维菌素B注射剂。
试验动物及分组：选择同村自然感染牛蜱虫的黄牛6头供试验用。将6头牛随机分为3组，每组均为2头。第1组为伊维菌素对照组，第2组为天维菌素A组，第3组为天维菌素B组。给药组均按照2mg/kg.bw皮下注射。
试验方法：
1)给药前l天对各组牛身上的牛蜱虫进行计数。
2)给药后第1、2、3和4周后天对各组牛身上的牛蜱虫进行计数。
3)按常规方法计算牛蜱虫数并进行疗效判定。
试验结果：
从表3可见，天维菌素A组、天维菌素B组和伊维菌素组的驱虫效果相当，但是天维菌素A组和天维菌素B组的药效更持久。
表3各组试验牛给药后各周的蜱虫数
Figure PCTCN2017079061-appb-000004
实施例4
天维菌素A和天维菌素B对绵羊消化道线虫的驱虫试验
供试药剂：如实施例1所得1％伊维菌素注射剂、1％天维菌素A注射剂和1％天维菌素B注射剂。
试验动物及分组：选择同一条件下放牧的绵羊，通过粪便检查，从中挑选出0.8-2.0岁龄自然感染消化道线虫的绵羊80只供试验用，试验羊的平均体重30kg。将80只绵羊随机分为4组，每组均为20只。第1组为伊维菌素对照组，第2组为天维菌素A组，第3组为天维菌素B组。给药组均按照0.2mg/kg.bw颈部皮下注射。第4组为空白组，不给药。
试验方法：
1)给药前l天对各组羊逐头采粪检查，用McMaster′s法作虫卵计数，统计每克粪便所含虫卵数(EPG)。
2)给药后第9天用McMaster′s法对各组羊进行粪检，统计EPG。
3)按常规方法计算虫卵转阴率和虫卵减少率进行疗效判定。
试验结果：
试验结果详见表4。从表4可见，天维菌素A组、天维菌素B组和伊维菌素组的驱虫效果相当，其虫卵转阴率和虫卵减少率均为100％。
表4各组试验羊虫卵转阴率和减少率
Figure PCTCN2017079061-appb-000005
实施例5
天维菌素A和天维菌素B对绵羊疥螨病的治疗
供试药剂：如实施例1所得1％伊维菌素注射剂、1％天维菌素A注射剂和1％天维菌素B注射剂。
试验动物及分组：选择同一条件下放牧的绵羊，经寄生虫学检查，挑选己感染绵羊疥螨的绵羊40只。将40只绵羊随机分为4组，每组均为10只。第1组为伊维菌素对照组，第2组为天维菌素A组，第3组为天维菌素B组。给药组均按照0.2mg/kg.bw颈部皮下注射。第4组为空白组，不给药。
试验方法：观察临床症状变化，并在病羊患部与健康皮肤交接处用沾有甘油的外科手术刀片刮至皮肤微见血，取皮屑放于平皿内带回实验室，置载玻片上，加50％甘油水溶液一滴，加盖玻片后在低倍显微镜下检查，见到活的疥螨即可确定为阳性。于给药前与给药后1，2，3，4周采样进行检查。在显微镜下检查，以是否查到活的螨虫作为判定依据，发现1个活的螨虫即可判定为阳性，并观察临床症状变化作为参考。
试验结果：
试验结果见表5。从表5可见，天维菌素A组、天维菌素B组相比伊维菌素组对绵羊疥螨病的治疗效果好，其中天维菌素B效果优势更加明显。
表5各组试验羊转阴数和转阴率
Figure PCTCN2017079061-appb-000006
实施例6
天维菌素对斑马鱼的毒性试验
供试药剂：阿维菌素、米尔贝霉素、伊维菌素、天维菌素A和天维菌素B原料药均来自浙江海正药业股份有限公司。样品以DMF配制成50mg/ml母液。
供试鱼和用水：斑马鱼(Brachydanio rerio)采购于浙江省农业科学院，大小一致，平均体长2-3cm，平均体重0.3g。试验前在室内驯养7天。自然死亡率为0。试验前1天停止喂食，试验期间不喂食。试验用水为经暴晒24小时以上去除余氯后的自来水，pH值为6.8。
试验方法：采用半静态法。每个样品设0.5ppm，1.0ppm和1.5ppm 3个级差，每个级差设3组平行，每组养10尾，并设空白对照(不加药剂和仅加溶剂各1组)。样品按浓度需要取相应体积的母液，并以DMF定容至150μl后，加入试验组(含1.6L水)。室温控制在22±2℃，连续96小时，每24小时换一次水，并重新加样品。记录最初8小时，以及24、48、72、96小时时鱼的死亡率， 及时捞出死鱼。最后按LC50的大小划分为三个等级：>10ppm为低毒，1.0-10ppm为中毒，<1.0ppm为高毒。
试验结果：试验结果见表6。从表6可见，天维菌素A的浓度在1ppm时，斑马鱼的96小时存在率都大于50％，说明天维菌素A对斑马鱼的96小时LC50>1ppm，为中毒；天维菌素B虽然没达到中毒水平，但其对斑马鱼的毒性也远远低于阿维菌素、伊维菌素、米尔贝霉素和甲维盐。阿维菌素、伊维菌素、米尔贝霉素和甲维盐在0.5ppm时，斑马鱼的8小时存活率均为0，说明阿维菌素、伊维菌素、米尔贝霉素和甲维盐对斑马的96小时LC50<0.5ppm，为高毒。
表6不同药剂对斑马鱼的毒性试验
Figure PCTCN2017079061-appb-000007
Figure PCTCN2017079061-appb-000008
实施例7
天维菌素对异育银鲫的毒性试验。
异育银鲫(Allogynogenetic crucian carp)是中国江浙一带主要水产养殖品种之一,许多地区异育银鲫产量占淡水鱼产量的30％以上。因此，弄清天维菌素A对异育银鲫的毒性作用,对养殖生产过程中合理用药具有重要意义。
供试鱼和用水：异育银鲫采购于台州市椒江区陶王农场，体长为(9.60±0.52)cm，体重为(28.22±3.44)g。挑选健康活泼且规格一致的鱼暂养于室内水族箱中，试验前在室内驯养7天。自然死亡率为0。试验前1天停止喂食，试验期间不喂食。试验用水为经暴晒24小时以上去除余氯后的自来水，pH值为6.8。
供试药剂：
99.4％天维菌素A(天维菌素B质量含量为0.02％)(浙江海正药业股份有限公司)；
天维菌素(天维菌素A/天维菌素B质量比为95/5)(浙江海正药业股份有限公司)；
天维菌素(天维菌素A/天维菌素B质量比为90/10)(浙江海正药业股份有限公司)；
天维菌素(天维菌素A/天维菌素B质量比为85/15)(浙江海正药业股份有限公司)；
99.1％天维菌素B(天维菌素A质量含量为0.51％)((浙江海正药业股份有限公司)；
92％阿维菌素(abamectin)(浙江钱江生物化学股份有限公司)；
96％伊维菌素(Ivermectin)(浙江海正药业股份有限公司)；
90％甲氨基阿维菌素苯甲酸盐(甲维盐)(Emamectin Benzoate)(浙江升华拜克生物股份有限公司)。
样品以DMF配制成50mg/ml母液。
方法：采用半静态法。每个样品设0.5ppm，1.0ppm和2.0ppm 3个级差， 每个级差设3组平行，每组养10尾，并设空白对照(不加药剂和仅加溶剂各1组)。样品按浓度需要取相应体积的母液，并以DMF定容至150μl后，加入试验组(含1.6L水)。室温控制在22±2℃，连续96小时，每24小时换一次水，并重新加样品。记录最初8小时，以及24、48、72、96小时时鱼的死亡率，及时捞出死鱼。最后按LC50的大小划分为三个等级：>10ppm为低毒，1.0-10ppm为中毒，<1.0ppm为高毒。试验结果见表7。
表7不同药剂对异育银鲫的毒性试验
Figure PCTCN2017079061-appb-000009
Figure PCTCN2017079061-appb-000010
结果表明：99.4％天维菌素A及天维菌素A:B＝95:5对异育银鲫为低毒，天维菌素A:B＝90:10的浓度在1ppm时，斑马鱼的96小时存活率仍大于50％，说明天维菌素A:B＝90:10对异育银鲫的96小时LC50>1ppm，为中毒；而且天维菌素对异育银鲫的毒性随着A组分比例的提高而降低。而阿维菌素、伊维菌素和甲维盐在0.5ppm时，异育银鲫的8小时存活率均为0，说明阿维菌素、伊维菌素和甲维盐对异育银鲫的96小时LC50<0.5ppm，为高毒。
实施例8
天维菌素对防治锚头鳋药效试验
药效试验在台州市黄岩区长潭水库附近暴发锚头鳋寄生虫病的鱼塘旁边的实验室中进行。试验用水来自发病鱼塘，实验容器为85cm×45cm×35cm的塑料水族箱，每个水族箱存放100L池水，水温(27.0±0.5)℃，pH 7.4～7.8，不间断充气。
供试药剂：
92％阿维菌素(abamectin)(浙江钱江生物化学股份有限公司)；
96％伊维菌素(Ivermectin)(浙江海正药业股份有限公司)；
95％天维菌素A(Tenvermectin A)(浙江海正药业股份有限公司)；
92％天维菌素B(Tenvermectin B)(浙江海正药业股份有限公司)。
在实验室内将上述原药分别配成1.8％阿维菌素乳油、1.8％伊维菌素乳油、1.8％天维菌素乳油A(天维菌素A单组分，其中杂质天维菌素B组分含量为0.02％)、1.8％天维菌素乳油B(天维菌素A:天维菌素B＝9:1(重量比，下同))、1.8％天维菌素乳油C(天维菌素B单组分，其中杂质天维菌素A组分含量为0.51％)的制剂备用。
1.8％天维菌素乳油A、B、C及1.8％阿维菌素乳油和1.8％伊维菌素乳油施用剂量分别为0.01mg/L、0.02mg/L和0.04mg/L，试验期间不换液。每个水族箱投放患病银鲫2条，投放前对每条供试鱼身上附着的锚头鳋计数。每次试验以清水为对照，每个药液浓度重复6次。试验开始后，前6h连续观察，之后不定期观察它们的行为、有无中毒症状及虫口减退情况。记录各试验组锚头鳋6h、12h、24h、48h、96h的残虫数，施药后银鲫体表寄生锚头鳋的虫口存活率见表8。用Henderson-Tilton公式计算校正防效，按照a＝0.05(0.01)标准，采用单因素法 LSD检验分析差异显著性。
Figure PCTCN2017079061-appb-000011
表8：施药后银鲫体表寄生锚头鳋的虫口存活率
Figure PCTCN2017079061-appb-000012
用0.02mg/L药剂施药24h后的相对防效见表格9。
表9：用0.02mg/L药剂施药24h后的相对防效
Figure PCTCN2017079061-appb-000013
Figure PCTCN2017079061-appb-000014
*其中，差异显著性栏中，字母相同表示没有显著差异。
从表9可以看出，天维菌素A与天维菌素B以不同重量比混合时(天维菌素A单组分，天维菌素A:天维菌素B＝9:1，天维菌素B单组分),对银鲫体表寄生锚头鳋有显著的防治效果，防治效果均在90％以上，优于同等用药量的阿维菌素和伊维菌素。
本发明的天维菌素的用途已经通过具体的实例进行了描述，本领域技术人员可借鉴本发明内容，适当改变原料、工艺条件等环节来实现相应的其它目的，其相关改变都没有脱离本发明的内容，所有类似的替换和改动对于本领域技术人员来说是显而易见的，都被视为包括在本发明的范围之内。

Claims (10)

  1. 如下式(I)的化合物中的一种或两者的混合物在制备用于防治人或动物寄生虫的药物中的用途：
    Figure PCTCN2017079061-appb-100001
    其中R选自CH3或C2H5，并且当R为CH3时为天维菌素A，当R为C2H5时为天维菌素B。
  2. 根据权利要求1所述的用途，其中所述动物选自猪、牛、狗、羊、兔、鸡、鸭或鹅。
  3. 根据权利要求1或2所述的用途，其中所述寄生虫选自线虫纲、昆虫纲或蛛形纲。
  4. 根据权利要求1-3任一项所述的用途，其中所述寄生虫选自圆线目，小杆目，蛔目，尖尾目，旋尾目，丝虫目，鞭尾目，双翅目，吸虱目，蚤目，蜱螨目或真螨目，优选圆线目，蛔目，丝虫目，鞭尾目，蜱螨目或真螨目。
  5. 根据权利要求1-4任一项所述的用途，其中所述寄生虫选自毛圆科，钩口科，结节科，网尾科，类圆科，蛔科，弓首科，禽蛔科，尖尾科，管状科，旋尾科，盖头虫科，毛细科，毛形科，鞭虫科，蚊科，蝇科，虱科，蚤科，硬蜱科或疥螨科，优选蛔科，禽蛔科，鞭虫科，硬蜱科或疥螨科。
  6. 根据权利要求1-5任一项所述的用途，其中所述寄生虫选自猪线虫、血虱、牛蜱虫、绵羊消化道线虫或绵羊疥螨。
  7. 根据权利要求1-6任一项所述的用途，其中所述用途是天维菌素A或天维菌素B在制备用于控制人或动物寄生虫的药物中的用途。
  8. 根据权利要求1-2所述的用途，其中所述动物选自鱼、甲壳类动物、软体动物或水生无脊椎动物，优选草鱼、异育银鲫、鲢鱼、麦穗鱼、食蚊鱼、鳙鱼、青虾、河蟹、圆田螺、松浦镜鲤及观赏鱼类等，更优选异育银鲫、草鱼、松浦镜鲤或观赏鱼类。
  9. 根据权利要求8所述的用途，其中所述寄生虫选自孢子虫、绦虫、线虫、艾美虫、肺吸虫、血吸虫、指环虫或锚头鲺。
  10. 根据权利要求8-9任一项所述的用途，其中所述用途是天维菌素A和天维菌素B的混合物在制备用于控制人或动物寄生虫的药物中的用途，优选的，所述混合物中天维菌素A与天维菌素B的重量比≥9:1，更优选≥19:1。
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