伊维菌素长效透皮剂和普通注射剂在家兔体内的药代动力学比较研究

为比较研究制备的伊维菌素长效透皮制剂与普通伊维菌素注射剂药物代谢及药效时间,本研究制备伊维菌素含量分别为0.5%、1.0%和1.5%的长效透皮制剂,采用高效液相色谱法检测不同药量相同体积伊维菌素长效透皮制剂和普通伊维菌素注射剂(1.0%)在家兔体内的药代动力学,并通过PKSolver药代动力学处理软件对数据进行分析。结果显示,0.5%、1.0%、1.5%伊维菌素长效透皮剂和1.0%普通注射剂吸收半衰期分别为0.81、0.52、1.02和0.12 d;达峰时间为1.55、0.97、1.62和0.42 d;峰浓度为47.36、72.02、115.30和99.53 ng/mL;消除半衰期为3.61、5.92、5.59和1.79 d;平均滞留时间为5.27、7.37、5.13和2.16 d;药时曲线面积为1 488.70、3 081.98、3 161.20和480.00 ng·d/mL,伊维菌素长效透皮剂体内维持有效药物浓度的时间长达35 d,普通注射剂仅为9 d。结果表明,伊维菌素长效透皮剂效果稳定,可进行更深入的研究。     

伊维菌素微乳剂在绵羊体内的药代动力学研究

研究伊维菌素微乳剂在绵羊体内的药代动力学,对比高含量伊维菌素微乳剂与普通注射剂型的生物利用度差异。选取12只绵羊,分为2组,按照0.2 mg/kg体重分别皮下注射10 mg/mL伊维菌素注射液和30 mg/mL伊维菌素微乳剂。分别在给药前0.5 h,给药后2、4、6、8、10、12、16、20、24、36、48、96、144、192、240、336 h在颈静脉采集血液备用,用高效液相色谱荧光检测器对绵羊血浆中的伊维菌素进行检测,并利用内标法计算其含量。通过DAS2.1.1软件进行数据统计分析。结果显示,伊维菌素微乳剂组药时曲线下面积(AUC)为3 812.17 ng/mL·h,达峰浓度(C_(max))为97.71 ng/mL,达峰时间(T_(max))为12 h,消除半衰期(T_(1/2z))为43.46 h;伊维菌素注射液组AUC为2 501.25 ng/mL·h,C_(max)为48.15 ng/mL,T_(max)为24 h,T_(1/2z)为44.96 h。说明伊维菌素微乳剂吸收效果好,达峰时间短,达峰浓度高,生物利用度高。     

伊维菌素透皮溶液驱猪线虫效果试验

目前,驱除体内寄生虫的药物很多,给药途径多为注射或口服.伊维菌素是一种高效广谱驱虫药,为扩大给药途径,简化使用方法,浙江海正化工股份有限公司研制了0.5%伊维菌素透皮溶液.为探讨该制剂对猪消化道线虫的疗效,设计了本试验. 1 材料与方法 1.1 供试药物 0.5%伊维菌素透皮溶液,浙江海正化工股份有限公司生产,对照药物为15%盐酸左旋咪唑擦剂.     

伊维菌素纳米乳透皮制剂的研究

本试验研制伊维菌素纳米乳透皮制剂,并对其理化性能、稳定性、体外药物释放及透皮性能进行评价。采用三元相图筛选不同载药量的纳米乳,确定最佳载药量;采用响应面优化设计筛选纳米乳处方,考察了伊维菌素纳米乳的平均粒径、电位、形态、pH、黏度等性能;分别采用透析袋法和Franz扩散池法比较伊维菌素纳米乳透皮制剂与市售伊维菌素皮肤涂剂的体外释放行为和透皮性能。结果显示,载药量为2.00%时,纳米乳区域最大、最稳定;获得的优选处方为聚氧乙烯蓖麻油 :二乙二醇单乙基醚 :油酸乙酯 :伊维菌素 :水=26 :12 :7: 2: 53;所得伊维菌素纳米乳的平均粒径为18 nm;伊维菌素纳米乳在室温条件和4 ℃冰箱中保存1年仍稳定;其24 h皮肤累积渗透量和滞留量分别是市售伊维菌素皮肤涂剂的3.24和2.05倍。研究结果表明,研制的新型伊维菌素纳米乳透皮制剂具有制备工艺简便、稳定性好、透皮性能好等优点,具有很好的应用前景。     

伊维菌素浇泼剂对绵羊线虫的驱虫效力与安全性试验

应用0.5%伊维菌素浇泼剂按0.3,0.4,0.5mg/kg.b w剂量对绵羊沿背中线皮肤一次浇泼给药,并以伊维菌素注射剂0.2mg/kg.b w剂量做对照。结果:伊维菌素浇泼剂0.3mg/kg,0.4mg/kg.b w剂量对消化道线虫虫卵转阴率分别为85%和90%,减少率分别为89.1%和95.9%;对原圆科线虫幼虫转阴率分别为60%和75%,减少率分别为77.2%和86.7%;0.5mg/kg.b w剂量对消化道线虫虫卵转阴率和减少率均为100%,对原圆科线虫幼虫转阴率为85%,减少率为95.4%。解剖检查结果:伊维菌素浇泼剂三种剂量对绵羊消化道、呼吸道多属线虫均有效,总计驱虫率分别为90.8%,95.6%和99.7%,伊维菌素浇泼剂0.5mg/kg.b w剂量与伊维菌素注射剂0.2mg/kg.b w剂量驱虫效果基本一致;绵羊经皮给药可耐受1.0mg/kg.b w剂量。试验证明:伊维菌素浇泼剂经皮给药驱除绵羊线虫高效安全,临床推荐剂量以0.5mg/kg.b w为宜。     

伊维菌素4种剂型不同给药方法对牦牛皮蝇蛆病防治的比较研究

选用伊维菌素浇泼剂、注射剂、片剂、干混悬剂4种剂型,分别按0.5,0.2,0.3,0.3mg/kg体重剂量,对1.5岁牦牛在10月中旬给药,进行不同给药方法用于防治牦牛皮蝇蛆病的给药速度、劳动强度、使用的安全性、防治效果等方面的比较研究。结果:给药速度以浇泼剂最佳,其次为注射剂,再次为干混悬剂,片剂最慢;劳动强度以浇泼剂最佳,其次为注射剂与干混悬剂,再次为片剂;伊维菌素注射剂、浇泼剂和干混悬剂的防治效果佳,其驱净率和驱虫率均达100.00%,片剂较低,平均驱净率和驱虫率分别为95.41%和96.36%;同期检查阳性对照组牦牛皮蝇蛆平均感染率33.33%、平均感染强度7.5个虫体。试验表明,伊维菌素4种剂型防治牦牛皮蝇蛆病高效安全,其中浇泼剂优势明显。     

复方伊维菌素乳液在山羊体内的药代动力学研究

为了探讨复方伊维菌素乳液在动物体内的药物代谢,为兽医临床提供用药参考。试验选取7只山羊,每只山羊按0.1 mL/kg (伊维菌素0.2 mg/kg, 阿苯达唑10 mg/kg)剂量口服,给药后0.5、1、2、3、4、6、8、12、16、24、36、48、60 h颈静脉采血5 mL,分离血清,-20 ℃保存,用高效液相色谱仪检测样品血药浓度。试验结果表明,①伊维菌素在山羊体内的代谢情况为：0.5 h,0.112151 μg/mL; 第1次达峰时间为4 h, 0.302702 μg/mL;第2次达峰时间为16 h,0.258284 μg/mL;60 h,0.011118 μg/mL。②阿苯达唑在山羊体内的代谢情况为：0.5 h, 0.049285 μg/mL;第1次达峰时间为8 h,4.95283 μg/mL ;第2次达峰时间为16 h,5.694551 μg/mL;60 h,0.06434 μg/mL。复方伊维菌素中的伊维菌素和阿苯达唑在山羊体内代谢时间短,第60小时已达到很低的血药浓度。     

伊维菌素浇泼剂对牦牛胃肠道线虫的驱除效果

在甘肃省肃南县大河乡大岔村选择自然感染胃肠道线虫的1-2岁牦牛75头,随机分为5组,每组15头,Ⅰ、Ⅱ、Ⅲ组分别为伊维菌素浇泼剂试验组,分别按0.3、0.4、0.5 mg/kg体重剂量经背部皮肤浇泼给药;Ⅳ组为伊维菌素注射剂对照组,按0.2 mg/kg体重剂量皮下注射给药;Ⅴ组为空白对照组。另随机挑选牦牛10头供安全性观察,随机分为2组,每组5头,分别为伊维菌素浇泼剂0.7 mg/kg和1.0 mg/kg体重剂量试验组,经背部皮肤浇泼给药。结果表明：以0.5 mg/kg体重剂量伊维菌素浇泼剂对牦牛胃肠道线虫驱治效果最好,其虫卵转阴率、减少率和驱虫率分别达100%、100%和99.25%,对毛首线虫驱虫率为96.00%;0.3 mg/kg和0.4 mg/kg体重剂量伊维菌素浇泼剂的驱虫效果均低于0.5 mg/kg体重剂量组,且呈现驱虫效果随着药物剂量的增加而提高。同时,试验使用1.0 mg/kg体重剂量伊维菌素浇泼剂,所用试验牦牛给药后精神、呼吸、采食、排粪、运动等情况未见异常反应,表明本品毒性较低,临床使用安全高效。     

伊维菌素透皮溶液驱杀猪消化道线虫及疥螨的效果

猪消化道线虫病常引起消化道障碍和消化道、呼吸道疾病,使幼畜生长发育迟缓,成年猪育肥困难;而猪疥螨是规模化养殖场主要的体外寄生虫病之一,线虫和疥螨的寄生给猪场造成巨大的经济损失.伊维菌素是一种高效广谱驱虫药,使用很少剂量就能驱除家畜体内多种寄生虫和体外寄生虫,且药效期长.目前,伊维菌素的给药途径多为注射,为扩大给药途径,简化使用方法,特别是寻求畜主能简便给药的药物剂型,浙江海正药业股份有限公司研制了0.5%伊维菌素透皮溶液.为了探讨该制剂对猪消化道线虫病和疥螨病的疗效,进行如下试验.     

伊维菌素微球在山羊体内的药效学研究

探讨新型制剂伊维菌素微球在山羊体内的药效学。选取32只山羊〔平均体重(27.05±1.20)kg〕,随机分成4组(Ⅰ^Ⅳ),每组7Ⅳ),每组7⁹只。Ⅰ组0.3 mg/kg体重,皮下注射伊维菌素注射液;Ⅱ和Ⅲ组3 mg/kg体重,分别皮下注射伊维菌素PLA5微球和PLGA微球混悬液;Ⅳ组作为对照组,不给药,对山羊粪便虫卵数(EPG)进行检测。Ⅰ、Ⅱ组和Ⅲ组山羊在第14天虫卵减少率均为100%,虫卵全部转阴;在给药后91 d虫卵减少率分别为0、74.3%和80.0%、;在给药后123 d分别为0、61.8%和0。伊维菌素对山羊胃肠道线虫虫卵具有较好的驱除作用,PLGA微球和PLA5微球的药效维持长达120 d左右,表现出长效作用。     

伊维菌素注射剂与浇泼剂驱除藏犬肠道线虫的疗效

应用伊维菌素注射剂与浇泼剂,驱除藏犬肠道线虫,并用粪检法检查其疗效。结果表明：伊维菌素注射剂0.2mg/kg剂量对藏犬肠道线虫的虫卵转阴率与减少率均为100.0%;伊维菌素浇泼剂0.5mg/kg剂量转阴率及减少率为100%。     

伊维菌素2种剂型对牦牛皮蝇蛆病的规模防治示范效果观察

为观察伊维菌素浇泼剂、注射剂对牦牛皮蝇蛆病的防治示范效果,选择放牧饲养的牦牛,伊维菌素浇泼剂按0.5mg/kg体重剂量沿背中线浇泼给药,伊维菌素注射剂按0.2mg/kg体重剂量颈部皮下注射给药,同时留未防治的对照群,分别在3、5月份采用触摸法抽样进行防治效果检查。结果:伊维菌素浇泼剂防治示范组牦牛2次检查的皮蝇蛆感染率在1.61%~3.23%之间,平均感染率2.42%,查出瘤疱和皮肤虫孔总数7个,平均感染强度1.75个,感染范围0~2个。2次检查未防治的对照组牦牛皮蝇蛆感染率在33.33%~38.89%之间,平均感染率为36.11%,查出瘤疱和皮肤虫孔总数152个,平均感染强度4.22个,感染范围0~14个。结果表明:伊维菌素浇泼剂防治示范组牦牛皮蝇蛆病治愈率为98.39%,驱虫率99.08%~99.54%,平均驱虫率99.31%;伊维菌素注射剂防治示范组牦牛皮蝇蛆病治愈率在98.39%~100.0%之间,平均治愈率为99.20%,驱虫率98.62%~100.0%,平均驱虫率99.31%。2种剂型的推荐剂量均达到了高效安全,可在高寒牧区牦牛皮蝇蛆病防治中推广应用。     

Efficacy of Chinese Herbal Medicine Canine Acariasis Spirit on Demodex canis

In order to screen the Chinese herbal medicine for the treatment of Demodex canis, canine acariasis spirit was prepared by Foeniculum vulgare, Fructus cnidii and Bauhinia by water alcohol precipitation and distillation extraction methods. To observe the effect on Demodex canis, canine acariasis spirit was set to high, medium and low concentrations, the content of crude drug were 2.0, 1.0 and 0.5 g/mL, respectively. The experiment of killing Demodex canis was carried out by drop method. On this basis, 12 dogs inoculated with Demodex canis were treated. In order to verify the therapeutic effect, 45 clinically diagnosed dogs with Demodex canis were divided into three groups. The results showed that 3 doses of the traditional Chinese medicine canine acariasis spirit all had strong inhibition effect to kill mites, the high dose group could completely kill Demodex canis only 4 h after treatment, the action of 1% ivermectin control group was 8 h after treatment; 3 weeks later, a large number of new hair grew, rash and skin nodules disappeared, the skin lesion had healed in the affected area of high dose group, in 1% ivermectin treatment group, the dog skin improved, only a small amount of new hair grew, it couldn't cure standard; In the high and middle dose group, the average number of the ratio of skin scraping mites and the recurrence rate after drug withdrawal was 0 in one month later; The average number of mites proportion and recurrence rates of skin scrapings in 1% ivermectin treatment group were 10.63% and 9.17% in one month later; After 3 weeks of treatment, the total average eggs negative rate, cure rate and average cure days were 100.00%, 93.33% and 19.56 d in high dose traditional Chinese medicine canine acariasis spirit and 1% ivermectin combined treatment group, the results were better than the traditional Chinese medicine canine acariasis spirit and 1% ivermectin alone treatment group. The results showed that the effect of the high dose group self-made Chinese medicine canine acariasis spirit on killing Demodex canis in vitro, inoculation of Demodex canis and clinical therapeutic effect of natural infection cases were significantly better than 1% ivermectin control group, canine acariasis spirit as a traditional Chinese medicine preparation would have a good market development prospects.     

中药犬螨灵对犬蠕形螨的疗效试验

为筛选具有显著治疗犬蠕形螨的中药制剂,试验将中药小茴香、蛇床子、羊蹄根采用水煮醇沉及蒸馏等提取方法制备成中药制剂犬螨灵,并观察其对犬蠕形螨的疗效。将犬螨灵设为高、中、低3个浓度,其生药含量分别为2.0、1.0和0.5 g/mL,采用点滴法进行体外抑杀蠕形螨试验,在此基础上对12只接种蠕形螨的试验犬进行治疗试验,为验证治疗效果,对临床上已确诊的45只患有蠕形螨的病犬分3组进行临床治疗试验。结果显示,中药犬螨灵3种剂量均有较强的体外抑杀螨虫作用,高剂量组作用后4 h即可完全抑杀蠕形螨,1%伊维菌素对照组则为作用后8 h;高剂量组在治疗3周后,患处有大量新毛生长,红疹结节和皮屑消失,患处皮肤已痊愈,1%伊维菌素治疗组患犬皮肤好转,仅有少量新毛生长,不能达到痊愈标准;高、中剂量组皮肤刮取物螨虫数量平均比例及停药1个月后复发率均为0,1%伊维菌素治疗组皮肤刮取物螨虫数量平均比例及停药1月后的复发率分别为10.63%和9.17%。高剂量中药犬螨灵与1%伊维菌素两种药物联合治疗组,对临床上患病犬进行3周治疗,其虫卵平均转阴率、治愈率与平均治愈天数分别为100.00%、93.33%和19.56 d,其效果均优于中药犬螨灵与1%伊维菌素单独治疗组。结果表明,高剂量自制中药制剂犬螨灵对犬蠕形螨体外抑杀作用、接种蠕形螨试验犬与临床自然感染病例均有显著的治疗效果,优于1%伊维菌素对照组,犬螨灵作为中药杀螨虫制剂具有较好的市场开发前景。     

Failure of ivermectin and eprinomectin to control Amblyomma parvum in goats: characterization of acaricidal activity and drug pharmacokinetic disposition

The therapeutic efficacies of ivermectin (subcutaneous injection) and eprinomectin (topical treatment) given at two different dosage levels to goats naturally infested with Amblyomma parvum were assessed. Treatments included subcutaneous injection of ivermectin at 0.2 and 0.4mg/kg and extra-label pour-on administration of eprinomectin at 0.5 and 1mg/kgb.w. Ivermectin and eprinomectin failed to control Amblyomma parvum on goats. Treatment with ivermectin resulted in a low number of engorged female ticks in relation to untreated control goats and, at the highest dose rate (0.4mg/kg), the female engorgement weights were significantly lower and the pre-oviposition period significantly longer than those observed in ticks recovered from untreated control goats. The tick efficacy assessment was complemented in a separate group of tick-free goats with a pharmacokinetic characterization of eprinomectin (topically administered at 0.5, 1.0 and 1.5mg/kg) and ivermectin (subcutaneous treatment given at (0.2 and 0.4mg/kg) in goats. Heparinized blood samples were taken between 0 and 21 days post-treatment. Higher and more persistent drug plasma concentrations were recovered after the subcutaneous treatment with ivermectin compared to those obtained for eprinomectin topically administered. The understanding of the relationship among the pattern of drug absorption, the kinetic disposition and the resultant clinical efficacy is relevant to improve the poor performance observed for ivermectin and eprinomectin against A. parvum on goats.     

RP-HPLC检测复方注射剂中伊维菌素和吡喹酮的含量

为了用高效液相色谱法同时测定复方注射剂中伊维菌素和吡喹酮的含量。采用Hyper-C lone 5u C18柱（250 mm×4.60 mm,5μm）,以乙腈-甲醇-水（53∶35∶12）为流动相,流速为1.0mL/m in,检测波长254 nm,柱温30℃的液相检测方法。结果表明,在此色谱条件下,吡喹酮和伊维菌素的分离良好,吡喹酮和伊维菌素分别在30~500μg/mL和5~40μg/mL浓度范围内峰面积与浓度呈良好的线性关系（r2〉0.99）。按外标法以峰面积计算进行测定,吡喹酮和伊维菌素的平均回收率分别为98.93%和95.89%,RSD分别为0.33%和1.58%（n=9）。说明该方法简便、快速、准确,适用于复方吡喹酮注射液中吡喹酮和伊维菌素含量的测定。     

乙酰氨基阿维菌素注射用缓释剂质量标准与药学等效研究

依据《中华人民共和国兽药典》与《兽药研究技术指导原则汇编》等相关指导要求,对乙酰氨基阿维菌素（EPR）注射用缓释剂进行外观、黏度、pH、水分、密度、内毒素、含量及有关物质检测,建立EPR注射用缓释剂的质量标准并比较与参比制剂的药学等效性。含量与有关物质检测方法为使用ZORBAX Eclipse Plus C18柱（2.1 mm×50 mm,1.8 μm）;流动相：甲酸：水：乙腈（0.04 mL：40 mL：60 mL）;流速：0.4 mL/min;检测波长：245 nm;柱温：35 ℃;进样量：2 μL。在37 ℃,转速为50 r/min,0.5% SDS的PBS缓冲液条件下,比较自研与原研EPR注射用缓释剂的药学等效性。EPR注射用缓释剂外观澄清透明,平均相对黏度为46.45 mPa·s,平均pH为6.88,制剂中不含水分,密度为1.13 g/cm³,内毒素满足<0.1 EU/mL限度,含量>5%的标示值,有关物质的量<5%,检测结果均符合注射剂制剂要求;在同一条件下释放31 d后,自研与原研EPR注射用缓释剂累积释放量均超过80%,且自研与原研的相似因子（f2）值>50。自研EPR注射用缓释剂的检测结果均符合注射剂标准,自研与原研EPR注射用缓释剂具有药学等效。     

硫酸头孢喹肟在鸭体内的药动学及生物利用度研究

试验将20只2月龄健康番鸭,随机分为2组,每组10只,雌雄各半,分别进行静脉注射和口服硫酸头孢喹肟给药的药动学研究。静脉注射和口服的给药剂量分别为10和20 mg/kg。以反相HPLC测定血浆中硫酸头孢喹肟的浓度,血药浓度—时间数据用3P97药动学程序软件处理。鸭单剂量静脉注射给药后,血药浓度—时间数据符合无吸收二室开放模型,其主要动力学参数分别为:V（c）,（1.146±0.02） L/kg;t_1/2α,（0.290±0.02）h;t_1/2β,（1.691±0.15）h;AUC （6.635±0.18）（mg·h）/L;CL（s）,（1.508±0.04）L/（kg·h）。鸭口服硫酸头孢喹肟的血药浓度—时间数据符合一级吸收一室开放模型,主要动力学参数分别为:t_1/2（ka）,（0.45±0.05）h;t_1/2（ke）,（0.96±0.29）h;T_（peak）,（0.91±0.09）h;C_（max）,（3.14±0.64）mg/L;AUC,（8.29±1.26）（mg·h）/L;F,（62.55±0.10）%。硫酸头孢喹肟在体内的药动学特征表现为吸收迅速、分布广泛、消除迅速。但口服给药在鸭体内生物利用度低,可能由于硫酸头孢喹肟的脂溶性低,其在消化道吸收率低所致。但8 h内能保持有效血药浓度范围（（0.14±0.03）~（3.14±0.64）μg/mL）,可抑制鸭疫里默氏杆菌及其他细菌感染。     

Duration of Anthelmintic Effect of Three Formulations of Ivermectin (Oral,Injectable and Pour-on) Against Multiple Anthelmintic-Resistant <Emphasis Type="Italic">Haemonchus contortus</Emphasis> in Sheep

We report the results of investigations that were conducted in a sheep flock in Uttaranchal, India where repeated failure of anthelmintic medication was noted. The study revealed that Haemonchus contortus in sheep had developed resistance to benzimidazoles (fenbendazole, mebendazole and albendazole), imidazothiazole (levamisole) and salicylanide (rafoxanide), while it was fully susceptible to avermectins (ivermectin). Further, the suppression of nematode egg output in faeces of sheep naturally infected with multiple anthelmintic-resistant H. contortus following treatment with ivermectin tablet (0.4 mg/kg body weight (bw), orally), ivermectin injection (1% w/v, 0.2 mg/kg bw, subcutaneously) and ivermectin pour-on (0.5 w/v, 0.5 mg/kg bw) was also studied over a period of 10 weeks post treatment. It was noted that ivermectin tablet after initial clearance of infection (faecal egg count reduction 100%), could not prevent establishment of new patent natural infection for even a single day, while ivermectin pour-on and injection prevented the establishment of new infection for 7 and 14 days post treatment, respectively. Maximum protection period (duration for which mean faecal egg count of sheep reaches 500 eggs per gram of faeces or more) of 68 days was recorded in sheep treated with injectable ivermectin, followed by pour-on (60 days) and oral (53 days) preparations.