CN111265538B - 杠柳毒苷在制备驱杀鱼类体外寄生虫药物中的应用 - Google Patents
杠柳毒苷在制备驱杀鱼类体外寄生虫药物中的应用 Download PDFInfo
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Abstract
本发明属于鱼类寄生虫药物领域，公开了杠柳毒苷在制备驱杀鱼类体外寄生三代虫药物中的应用。杠柳毒苷来源于天然植物，无残留、无污染、无公害，在环境中易降解，并能在有效剂量范围内实现一次性全部杀灭寄生虫，达到防治三代虫病的效果。同时，杠柳毒苷对鱼的半致死浓度为杀灭三代虫半有效浓度的12.7倍，在杀虫有效剂量范围内对鱼安全，这个比值远远高于最常用的鱼类三代虫病防治药物‑‑福尔马林的比值（LC50/EC50=4.2），该化合物具有开发成新型环保防治鱼类体外寄生三代虫渔药的广阔应用前景。
Description
技术领域
本发明属于鱼类寄生虫药物技术领域，涉及杠柳毒苷的新用途，具体涉及杠柳毒苷在制备驱杀鱼类体外寄生虫(特别是三代虫)药物中的应用。
技术背景
三代虫是水产养殖中最常见的鱼类寄生虫之一，一般寄生于鱼类的体表、鳍条和鳃。大量三代虫的感染能够导致宿主鱼类鳍条糜烂、表皮增厚、呼吸困难等明显的症状，并且三代虫的吸附器官--后吸器能够破坏宿主鱼类皮肤的完整性，从而引起细菌、真菌和病毒等的继发性感染，给宿主鱼类造成极大的危害。为了有效的防治三代虫病，国内外的鱼病学家和基层技术人员做了大量的研究，筛选了一些对三代虫具有很好杀灭效果的药物，如福尔马林、鱼藤酮、甲苯咪唑、敌百虫等。然而，由于这些药物长期、频繁的使用，导致虫体抗药性的产生，严重影响药效。此外，由于虫体抗药性的产生，又不得不加大用药量，如此恶性循环，既使药物的有效性大打折扣，又加大了用药成本，更为严重的是造成了水体和环境的污染，甚至危害水产品安全。因此，随着我国对环境和食品安全的重视，迫切需要开发新的环保、高效的防治药物。我国中草药资源丰富，其成分易降解、残留低，已有研究表明部分中草药杀灭三代虫的效果较好，这为我们寻找绿色、高效、安全的杀三代虫药物开辟了新途径。
杠柳(Periplocasepium)又名香加皮、北五加皮等，主要分布在中国部分地区以及俄罗斯远东地区。根据《中国土农药志》记载，杠柳作为一种民间使用的杀虫植物由来已久，对农业害虫二十八星瓢虫、菜青虫及蚜虫等均具有较好的防控效果。以前的研究表明杠柳粗提物对农业害虫具有很强的杀虫效果(史清华,马养民,秦虎强.杠柳根皮化学成分及杀虫活性的初步研究.西北农业学报,2005,14(6):141-144；何玲,赵娟,师宝君等.杠柳杀虫组分f3-28对东方粘虫和小地老虎幼虫中肠消化酶活性的影响.昆虫学报,2010,53(11):1248-1255)。目前已从杠柳中分离得到多种化合物，包括强心苷类、C21甾类、萜类、黄酮类、甾醇类、香豆素类以及低聚糖类等，其中属于C21甾类的杠柳新苷类化合物是杠柳主要杀虫活性成分，比如杠柳新苷A、D、E、F、P、T及杠柳毒素NW等(李彦凯,吕博,胡兆农等.杀虫植物杠柳研究进展.农药学学报,2019:1-9)。但是这些提取物以及中药单体的杀虫种类都是农业害虫，没有涉及到其在鱼类寄生虫病害防治方面的应用。
杠柳毒苷是从杠柳中分离的一种具有甾核和不饱和五元内酯环结构的甲型强心苷，具有强心、抗炎、抗癌的作用，可用于心力衰竭、心脏性浮肿等症。其化学结构式为：
该化合物的分子式为C36H56O13，分子量为696.8，为无色片状结晶(丙酮)或白色针状结晶(水)。尽管杠柳提取物以及一些单体化合物对农业害虫具有很强的杀虫效果，但是并没有关于杠柳毒苷杀虫的报道。以前的研究表明甾类化合物的糖链对其杀虫活性具有较大的影响。已分离鉴定且具有杀虫活性C21甾类杠柳新苷类化合物的糖链位于苷元C20位，具有多个单糖；而杠柳毒苷的糖链位于苷元C3位，仅有两个单糖。这两类化合物在结构上较大的差异可能导致其生物活性具有明显的差异。因此，在现有技术中，仅有涉及杠柳提取物以及C21甾类杠柳新苷类化合物用于农业害虫的防治，没有进一步的关于杠柳毒苷用于水产鱼类寄生虫防治的报道。
发明内容
为了克服现有技术的缺点与不足，本发明的目的在于提供杠柳毒苷在制备驱杀鱼类体外寄生三代虫药物中的应用。
为了实现上述目的，本发明采用以下技术方案：
杠柳毒苷在制备驱杀鱼类体外寄生三代虫药物中的应用：杠柳毒苷对小林三代虫的驱杀效果存在剂量相关性，且当药物浓度达到2.5mg/L时，对小林三代虫的驱杀率达到100％，计算得知杠柳毒苷对小林三代虫48h的50％有效浓度(EC50)和90％有效浓度(EC90)分别是0.71和1.69mg/L。
进一步地，杠柳毒苷制备的驱杀鱼类体外寄生三代虫药物中可以含有一种或多种药学上可接受的载体或赋形剂，将药物制成药液或者粉剂。
进一步地，杠柳毒苷的有效浓度为2.5～3.5mg/L鱼类养殖用水。
本发明与现有技术相比，具有以下优点：
1)本发明对已知化合物杠柳毒苷发掘了新的用途，开拓了新的应用领域。
2)杠柳毒苷是一种无公害绿色新型渔药，对鱼类毒性低、不易产生耐药性，能一次性彻底杀灭三代虫，其效果显著。
3)杠柳毒苷对鱼的半致死浓度是杀灭三代虫半有效浓度的12.7倍，在杀虫有效剂量范围内对鱼安全。
4)使用方法简单。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1杠柳毒苷对小林三代虫的驱杀效果评价
1材料与方法
1.1试验动物
寄主模型为金鱼(Carassius auratus)，体重为4.85±0.92g，购自武汉市武昌区武珞路花鸟市场；寄生虫模型为小林三代虫(Gyrodactyluskobayashii)，为长江水产研究所水产动物药理与药残控制技术实验室活体保种。
1.2试验药物以及配制
试验所用杠柳毒苷纯度为98％(购自四川省维克奇生物科技有限公司，货号：wkq-00971，CAS号：13137-64-9)；称取杠柳毒苷粉末80mg，溶于80mL的二甲基亚砜(DMSO)配制成浓度为1000mg/L的储备液。
1.3试验试验方法
随机选取感染小林三代虫的金鱼(感染丰度为40～200虫/鱼)，分别置于20×12×10cm的缸中，每缸2尾金鱼，缸中事先加入含有不同浓度药物的0.5L曝气自来水，在20±1℃下浸泡48h。在实验过程中同时设置3个对照组：一个空白对照组，即曝气自来水中无任何药物加入；一个阴性对照组，即加入0.1％DMSO(实验用最高浓度药液中DMSO的含量)；一个阳性对照组，即加入不同浓度的甲醛溶液。在实验过程中，所有处理组和对照组都重复5次。实验过程中不喂食、不换水，并记录金鱼的死亡情况。药物处理前和实验结束后，均用50mg/L的MS-222将金鱼麻醉，统计其尾部鳍条上小林三代虫的数目，计算驱虫率。
在体条件下药物对三代虫驱虫效果使用以下公式进行计算：
当L>Lt时，E＝(L－Lt)/L×100％；
当L≤Lt时，E＝0
在这个公式中，E是药物的驱虫率，L是药物处理前金鱼尾鳍上小林三代虫的数目，Lt是药物处理后金鱼尾鳍上小林三代虫的数目。使用SPSS软件probit程序计算48h的50％有效浓度(EC50)和90％有效浓度(EC90)。
2杠柳毒苷对小林三代虫驱杀效果
在实验过程中，空白对照组和阴性对照组金鱼尾鳍上的小林三代虫数目都有不同程度增长，根据驱虫率计算公式得出，空白对照组和阴性对照组的驱虫率均为0。杠柳毒苷和福尔马林对小林三代虫的驱杀效果见表1。
表1杠柳毒苷和福尔马林对小林三代虫的驱杀效果
从表1可以看出，杠柳毒苷对小林三代虫的驱杀效果存在剂量相关性，且当药物浓度达到2.5mg/L时，对小林三代虫的驱杀率达到100％。计算得知杠柳毒苷对小林三代虫48h的50％有效浓度(EC50)和90％有效浓度(EC90)分别是0.71和1.69mg/L。
对照药物福尔马林对小林三代虫的驱杀效果存在剂量相关性，且当药物浓度达到30mg/L时，对小林三代虫的驱杀率达到100％。计算得知福尔马林对小林三代虫48h的50％有效浓度(EC50)和90％有效浓度(EC90)分别是11.39和22.72mg/L。实施例2杠柳毒苷对金鱼急性毒性试验
1材料与方法
1.1实验动物以及药品
试验用金鱼购自武汉市武昌区武珞路花鸟市场，要求体质健壮，规格均一，平均体重为4.48g，购回后在实验室中暂养7天左右。试验所用杠柳毒苷纯度为98％；称取杠柳毒苷粉末400mg，溶于400mL的二甲基亚砜(DMSO)配制成浓度为1000mg/L的储备液。
1.2试验方法
在试验开始前，为了避免金鱼的大量死亡，首先通过预实验确定导致金鱼100％死亡和未能引起金鱼死亡药物的最低浓度和最高浓度，然后在这些浓度区间设定药物的浓度进行毒性实验。
随机选取健康金鱼，放入盛有2L曝气自来水的26.5×16.5×12.5cm的缸中，每缸10尾金鱼，水温维持在20±1℃。暂养2天后，加入不同剂量的药物使之达到预设的药物浓度。此外，还设置了2个对照组，一个空白对照组，即缸中不添加任何药物；一个阳性对照组，即在缸中添加不同浓度的福尔马林溶液。每个实验组和对照组都设置3个平行。在试验期间随时观察记录试验鱼的死亡情况，如发现鱼中毒死亡，应即时捞出，以免影响水质。判断鱼死亡的方法是当鱼停止呼吸后(鳃盖运动停止)用玻璃棒或镊子轻击鱼的尾柄部，如果在3min之内鱼体不产生任何应激反应，即可判断死亡。随后统计在24h和48h内各药物浓度下试验金鱼的死亡情况。使用SPSS软件probit程序计算48h的50％致死浓度(LC50)和90％致死浓度(LC90)。
2杠柳毒苷对金鱼的急性毒性
表2杠柳毒苷和福尔马林对金鱼的急性毒性
从表2可以看出，福尔马林对金鱼的毒性存在剂量相关性，且当药物浓度达到70mg/L时，引起金鱼全部死亡。经计算得知，福尔马林对金鱼48h LC50和LC90分别是47.79和61.97mg/L。福尔马林对金鱼48h的LC50是其48h驱杀三代虫EC50的4.2倍。
杠柳毒苷对金鱼的毒性存在剂量相关性，且当药物浓度达到11mg/L时，引起金鱼全部死亡。经计算得知，杠柳毒苷对金鱼48h的LC50和LC90分别是9.03和10.02mg/L。结果表明：杠柳毒苷对金鱼48h的LC50是其48h驱杀三代虫EC50的12.7倍，该比值远大于福尔马林，可见杠柳毒苷在杀虫有效范围内对鱼安全。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (3)
1.杠柳毒苷在制备驱杀鱼类体外寄生小林三代虫药物中的应用，杠柳毒苷的化学结构式为：
2.根据权利要求1所述的杠柳毒苷在制备驱杀鱼类体外寄生小林三代虫药物中的应用，其特征在于，所述的药物含有一种或多种药学上可接受的载体或赋形剂。
3.根据权利要求1或2所述的应用，其特征在于，杠柳毒苷的有效浓度为2.5～3.5mg/L鱼类养殖用水。
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