药物对不同品种犬的影响

伊(阿)维菌素是属于新型大环内酯类高效生物抗生素类杀虫、杀螨剂,其中B la为主要活性成分。伊(阿)维菌素通过剌激神经传递介质y-氨基丁酸的释放,干扰节肢动物正常的神经生理活动起到杀虫作用,而人和其他哺乳动物外周神经传递过程无此物质参与,因而对人及哺乳动物很安全。伊(阿)维菌素是大分子药物,一般不能通过血脑屏障进入脑细胞中,但柯利犬或幼犬因为血脑屏障发育不完善,药物得以进入脑细胞,从而造成中毒(这也是柯利犬容易对其他药物产生过敏中毒的原因)。虽然伊维菌素驱绦虫效果非常好,但副作用也比较大,仅限于成犬严格按照剂量使用,柯利牧羊犬禁用。     

Efficacy of avermectin B1 given orally against equine intestinal strongyles and Onchocera microfilaria

Three groups of horses and ponies (N = 13, 13 and 12) were treated with ivermectin paste (0.2 mg/kg p.o.), avermectin B1 solution (0.2 mg/kg p.o.), or fenbendazole suspension (10 mg/kg via nasogastric tube). The avermectin B1 was a 1% solution in a propylene glycolglycerol formal base. Faecal strongyle egg counts were performed before, and 14, 28, 42, 56 and 70 d, after treatment. Full-thickness skin biopsies from the neck, pectoral and umbilical regions were examined for Onchocera microfilaria before treatment, and again 14 and 70 d later. Ivermectin therapy produced a significant (P less than 0.01) decrease in mean strongyle egg counts 14, 28, 42 and 56 d after treatment. Avermectin B1 therapy resulted in significant (P less than 0.01) decreases in mean strongyle egg counts 14, 28 and 42 d after treatment. All horses given ivermectin or avermectin B1 had zero strongyle egg counts 14 and 28 d after treatment. Fenbendazole failed to significantly decrease strongyle egg counts. Both ivermectin and avermectin B1 resulted in zero microfilaria counts in all horses 14 d after treatment. On day 70 the percentage decrease in microfilaria counts were 100% and 99.6% respectively. Fenbendazole failed to significantly decrease microfilaria counts. The oral administration of this formulation of avermectin B1 appeared to be highly efficacious against intestinal strongyles and Onchocera microfilaria. The duration of anti-strongyle activity was, however, significantly (P less than 0.01) shorter than that of ivermectin paste.     

Central and peripheral neurotoxic effects of ivermectin in rats

Ivermectin is considered a very safe drug; however, there are reports of toxic effects in particularly sensitive populations or due to accidental overdose. The aim of this study was (1) to further characterize the central and peripheral toxic effects of ivermectin in animals and (2) to determine possible therapeutic strategies for use in cases of ivermectin poisoning. We tested the effects of experimental doses of ivermectin previously reported to cause various intensities of CNS depression. However, in our study, ivermectin at 2.5, 5.0 and 7.5 mg/kg i.v. did not produce visible CNS depression in rats and 10 mg/kg resulted in sleepiness and staggering 10 to 40 min after application, while a dose of 15 mg/kg caused CNS depression very similar to general anesthesia. Ivermectin dose-dependently potentiates thiopentone-induced sleeping time in rats. Flumazenil (0.2 mg/kg), the benzodiazepine antagonist, did not affect the action of thiopentone; however, it significantly reduced sleeping time in rats treated with a combination of ivermectin (10 mg/kg) and thiopentone (25 mg/kg; from 189.86 ± 45.28 min to 83.13 ± 32.22 min; mean ± SD). Ivermectin causes an increase in the tonus (EC(50)=50.18 μM) and contraction amplitude (EC(50)=59.32 μM) of isolated guinea pig ileum, very similar to GABA, but without the initial relaxation period. These effects are dose-dependent and sensitive to atropine. Our results confirm the central and peripheral GABAergic properties of ivermectin in mammals and also indicate involvement of the cholinergic system in its toxicity. In addition, the results suggest that flumazenil and atropine have potential clinical roles in the treatment of ivermectin toxicity.     

桑叶抗焦虑作用研究

目的：利用焦虑动物模型研究桑叶抗焦虑作用及其物质基础。方法：将小鼠随机分为空白对照组（蒸馏水0.375 mL）、地西泮对照组（0.0023 g/kg）、桑叶组（4.5 g/kg）、真空处理桑叶组（4.5 g/kg）,每组10只,雌雄各半,灌胃给药,1次/d,连续灌胃4 d后,依次采用自主活动仪、明暗箱、高架十字迷宫考察药物对小鼠的行为影响;高效液相色谱法（HPLC）检测行为学实验后小鼠脑神经递质含量。结果：与空白对照组比较,真空处理桑叶组可显著增加小鼠在明箱停留时间（P〈0.05）,并显著提高小鼠开臂滞留时间百分比（OT%）（P〈0.05）。小鼠脑内神经递质检测显示,真空处理桑叶组、桑叶组均可显著降低小鼠脑组织5-羟色胺（5-HT）浓度（P〈0.05）,去甲肾上腺素（NE）、多巴胺（DA）浓度也有降低,但无统计学差异。结论：桑叶具有抗焦虑作用,且其物质基础可能为γ-氨基丁酸（GABA）。     

The distribution and some pharmacokinetic parameters of ivermectin in pigs

Ivermectin was injected subcutaneously into five pigs at the usual dose rate of 300 µg/kg and found to distribute well to all tissues and body fluids which were sampled 24 h post-injection. Ivermectin was detected in the contents and mucus at all levels of the gastrointestinal tract. The drug was excreted in bile, with high concentrations of the drug in the intestines and faeces. High concentrations of ivermectin were measured in skin, ears and ear wax, suggesting that the drug should be effective in the treatment of ectoparasitic infestations, particularly ear mites. The high lipid solubility of the drug may explain the high concentrations found in ear wax and skin. Ivermectin was also detected in the body fluids and tissues of an untreated pig penned with the treated animals. Direct contact appeared to be necessary for transfer of ivermectin from the treated to the untreated pig but coprophagia or urine drinking is a possible explanation.The pharmacokinetics of ivermectin administered subcutaneously at a dose rate of 300 µg/kg to six pigs were studied. There was marked individual variation in the pharmacokinetics of ivermectin. In one pig the area under the plasma concentration-time curve was particularly high. This may reflect individual variation in uptake and excretion of the drug. The mean elimination half-life of the drug was 35.2 h, suggesting that the drug is cleared slowly from pigs with drug detectable in plasma for 6–10 days. This persistence should allow a short period of protection before re-infection with parasites.     

The pharmacokinetics and antiparasitic activity of ivermectin in Hutsul and Toric horses

The aim of this study was to compare the pharmacokinetics of ivermectin and its antiparasitic activity in two horse breeds. Eight Hutsul and 14 Toric horses were administered ivermectin orally at a dose of 0.2 mg/kg body weight. Blood samples were collected for 96 hr, and faecal samples were collected one day before and on days 14 and 21 after drug administration. Ivermectin concentrations in plasma samples were determined by high‐performance liquid chromatography. Ivermectin concentration was significantly higher in Toric than in Hutsul horses 90 min after ivermectin administration and was maintained at higher level for up to 96 hr. The area under the concentration versus the time curve from 0 to the last sampling point (AUC_0→t) and the maximum plasma concentration (C_max) were significantly higher in Toric than in Hutsul horses (1792.09 ± 246.22 μg × hr/L vs. 716.99 ± 255.81 μg × hr/L and 62.72 ± 17.97 ng/ml vs. 35.34 ± 13.61 ng/ml, respectively). No parasitic eggs were found in the faecal samples collected from both groups of horses on days 14 and 21 after drug administration. The obtained results indicate that although the pharmacokinetics of ivermectin may differ significantly between horse breeds, these differences do not affect the effectiveness of therapy.     

草鱼组织中阿维菌素和伊维菌素的多残留检测

建立了草鱼肌肉（包括皮）中阿维菌素和伊维菌素的多残留检测方法。样品用乙腈提取,正己烷脱脂净化,多拉菌素作内标,经1-甲基咪唑和三氟乙酸酐的乙腈溶液在室温下避光衍生化并在甲醇中水解后,进行HPLC-FLD检测分析。结果表明,阿维菌素和伊维菌素在5~100 ng/g范围内具有良好线性,检测限分别为1.0 ng/g和1.2 ng/g,定量限分别为3.4 ng/g和4.0 ng/g,日间提取回收率分别为96.42%~103.10%和94.23%~101.76%,日内和日间变异系数分别小于4.37%、6.82%和6.73%、8.84%。该方法高效、灵敏、简便,其灵敏度、回收率和重现性等符合有关兽药残留检测要求,可用于草鱼肌肉中阿维菌素和伊维菌素的多残留检测。     

Ivermectin effects on motor coordination and contractions of isolated rat diaphragm

Ivermectin, the antiparasitic drug from the macrocyclic lactones class raises attention due to its high efficiency against nematodes and arthropods and very specific toxic and side effects that it may produce in host. Dominant clinical symptoms of adverse effects and toxicity of ivermectin in animals are tremor, ataxia, CNS depression and coma which often results in mortality. In our study increasing intravenous doses of ivermectin, (6 or more times higher than therapeutic dose: 1.25, 2.5, 3.75, 5.0, 6.25 and 7.5 mg/kg), caused dose-dependent disturbance of motor coordination in treated rats. The median effective dose (ED50) that was able to impair the rota-rod performance in rats treated 3 min before testing was 2.52 mg/kg. This effect weakens over time, while in the rats treated 60 min before the rota-rod test, ED50 of ivermectin was 4.21 mg/kg. Whereas, all tested doses of ivermectin did not cause any other clinical symptoms of toxicity. Ivermectin has no effect on the contractions of isolated diaphragm caused by the EFS, which effectively blocked mecamylamine (100 μM) and pancuronium (1 and 2 μM). Effect on motor coordination is the first detectable clinical symptom of ivermectin toxicity and apparently is a result of its central effects.     

Anti-anxiety effect of ovary lipid extracted from Skipjack tuna (Katsuwonus pelamis) in rats

Using an elevated plus-maze test, we evaluated anxiety level in rats given ovary lipid extracted from Skipjack tuna (Katsuwonus pelamis; OLS). The percentage of open time was significantly higher in rats given OLS than in rats in the control group, but lower than in rats given diazepam (1.0 mg/kg body weight). Based on this fact and findings about other indicators, this study showed that OLS does not have as fast-acting and strong an anti-anxiety effect as diazepam but that continuous ingestion of OLS causes an anti-anxiety effect in animals.     

Ivermectin effects on motor coordination and contractions of isolated rat diaphragm

Ivermectin, the antiparasitic drug from the macrocyclic lactones class raises attention due to its high efficiency against nematodes and arthropods and very specific toxic and side effects that it may produce in host. Dominant clinical symptoms of adverse effects and toxicity of ivermectin in animals are tremor, ataxia, CNS depression and coma which often results in mortality. In our study increasing intravenous doses of ivermectin, (6 or more times higher than therapeutic dose: 1.25, 2.5, 3.75, 5.0, 6.25 and 7.5 mg/kg), caused dose-dependent disturbance of motor coordination in treated rats. The median effective dose (ED50) that was able to impair the rota-rod performance in rats treated 3 min before testing was 2.52 mg/kg. This effect weakens over time, while in the rats treated 60 min before the rota-rod test, ED50 of ivermectin was 4.21 mg/kg. Whereas, all tested doses of ivermectin did not cause any other clinical symptoms of toxicity. Ivermectin has no effect on the contractions of isolated diaphragm caused by the EFS, which effectively blocked mecamylamine (100 μM) and pancuronium (1 and 2 μM). Effect on motor coordination is the first detectable clinical symptom of ivermectin toxicity and apparently is a result of its central effects.     

不同驱虫药物对奶山羊消化道线虫驱虫效果研究

本研究旨在观察不同驱虫药物对奶山羊消化道线虫的驱虫效果,为今后寄生虫病的防治筛选更好的驱虫药物.选取奶山羊96只,分3组,每组32只,分别投喂伊维菌素注射液、芬苯达唑粉和伊维菌素芬苯达唑预混剂3种驱虫药物,采用饱和盐水漂浮法和麦克马斯特法检测驱虫前后线虫的感染情况.结果发现:伊维菌素注射液组虫卵转阴率为6.25％;芬苯...     

The Effect of Ivermectin on Convulsions in Rats Produced by Lidocaine and Strychnine

Ivermectin is one of the most commonly used drugs in pharmacotherapy of parasitic diseases in domestic and wild animals caused by parasitic nematodes and arthropods. However, ivermectin and other avermectins very often produce side-effects in hosts. The most dominant clinical symptom of ivermectin toxicity in domestic and wild animals is CNS depression. In nematodes, the target site of ivermectin’s action is glutamate-gated chloride-channel receptor and GABA receptor. The depressive effect of ivermectin in mammals might include more than one mechanism; therefore, the anticonvulsive effect of ivermectin against convulsions caused by lidocaine and strychnine was evaluated. Ivermectin antagonized lidocaine- and strychnine-induced convulsions in rats, although these have different mechanisms. In the present study, the anticonvulsive ED₅₀ of ivermectin for lidocaine-induced convulsions was 2.44 mg/kg (95% CL 1.67 to 3.57 mg/kg), whereas for convulsions induced by strychnine it was higher at 4.25 mg/kg (95% CL 2.32 to 3.78 mg/kg). At the same time, both anticonvulsive doses are significantly lower then the observed LD₅₀ of ivermectin (18.20 mg/kg). Furthermore, flumazenil (0.1 and 0.2 mg/kg), an antagonist of benzodiazepine receptors, antagonizes just one part of these anticonvulsive effects of ivermectin. Our results show the significant anticonvulsive properties of ivermectin and support the findings that ivermectin in the CNS of mammals produces multiple inhibitory effects, probably through participation in the function of GABA-sensitive and GABA-insensitive chloride channels.     

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.     

Cetirizine in horses: pharmacokinetics and effect of ivermectin pretreatment

The pharmacokinetics of the histamine H(1)-antagonist cetirizine and the effects of pretreatment with the antiparasitic macrocyclic lactone ivermectin on the pharmacokinetics of cetirizine were studied in horses. After oral administration of cetirizine at 0.2 mg/kg bw, the mean terminal half-life was 3.4 h (range 2.9-3.7 h) and the maximal plasma concentration 132 ng/mL (101-196 ng/mL). The time to reach maximal plasma concentration was 0.7 h (0.5-0.8 h). Ivermectin (0.2 mg/kg bw) given orally 1.5 h before cetirizine did not affect its pharmacokinetics. However, ivermectin pretreatment 12 h before cetirizine increased the area under the plasma concentration-time curve by 60%. The maximal plasma concentration, terminal half-life and mean residence time also increased significantly following the 12 h pretreatment. Ivermectin is an inhibitor of P-glycoprotein, which is a major drug efflux transporter in cellular membranes at various sites. The elevated plasma levels of cetirizine following the pretreatment with ivermectin may mainly be due to decreased renal secretion, related to inhibition of the P-glycoprotein in the proximal tubular cells of the kidney. The pharmacokinetic properties of cetirizine have characteristics which are suitable for an antihistamine, and this substance may be a useful drug in horses.     

Field performance of the equine parasiticide ivermectin in an oral paste

Ivermectin, a derivative of one of the avermectin compounds, was administered at 200 mcg per kg of body weight in an oral paste formulation to 80 mixed-breed ponies of both sexes and various ages. Twenty similar ponies received oral paste vehicle. Anthelmintic activity was determined by comparing fecal egg counts taken before and 14 days after ivermectin treatment to the counts of fecal samples from vehicle-treated controls. Commonly used equine vaccines were administered at the time of treatment. Sixteen of the 20 vehicle-treated ponies had positive counts prior to treatment and 17 were positive 14 days after treatment; 66 of the 80 ivermectin-treated ponies had positive counts prior to treatment; all 80 ponies had zero counts 14 days after treatment. The eggs were identified as strongylid in all the positive ponies while three ponies also hadOxyuris equi eggs prior to treatment.No adverse reactions were attributable to ivermectin oral paste treatment or concurrent vaccine administration.     

伊维菌素不同制剂在兽医临床的应用

对近年来伊维菌素的研究及其制剂的应用情况做了详细的综述,并分析了该类药物制剂在研究及应用中存在的问题。     

Comparative cost-effectiveness of ivermectin versus topical organophosphate in feedlot yearlings

A replicated-pen field trial was performed under commercial feedlot conditions in western Canada to determine the cost-effectiveness of administering ivermectin to yearling beef cattle upon entry to the feedlot after the grazing season, and to establish the level of trichostrongylid gastrointestinal parasite infection in this population, as estimated by fecal egg counts. Six thousand eight hundred and eighty-three, mixed breed, yearling steers were randomly allocated upon arrival at the feedlot to one of 2 experimental groups as follows: Ivermectin, which received topical ivermectin (0.5%) at the rate of 1.0 mL/10 kg body weight; or Fenthion, which received topical fenthion (20%) at the rate of 12 mL/295 kg body weight. There were 15 pens in each experimental group. Final weight, weight gain, average daily gain, and dry matter intake to gain ratio were significantly (P < 0.05) improved in the Ivermectin group as compared with the Fenthion group. There were no significant (P > or = 0.05) differences in initial weight, days on feed, or daily dry matter intake between the experimental groups. The geometric mean fecal egg counts at the time of allocation were 14.7 eggs/5 g and 16.6 eggs/5 g for the Ivermectin and Fenthion groups, respectively (P > or = 0.05). There were no significant (P > or = 0.05) differences in morbidity or mortality between the experimental groups. In the economic analysis, the significant improvements in feedlot performance in the Ivermectin group resulted in a net economic advantage of $4.20 CDN per animal.     

Anthelmintic efficacy on Parascaris equorum in foals on Swedish studs

Background

In the last few years stud farms have experienced increasing problems with Parascaris equorum infections in foals despite intensive deworming programs. This has led to the question as to whether the anthelmintic drugs used against this parasite are failing. This study aimed to investigate the efficacy of ivermectin, fenbendazole and pyrantel on the faecal output of ascarid eggs of foals.

Methods

A Faecal Egg Count Reduction Test (FECRT) was performed on nine large studs in Sweden. Anthelmintic drugs were given orally and faecal samples were examined for ascarid eggs on the day of deworming and 14 days later. Faecal Egg Count Reductions (FECRs) were calculated on arithmetic means of transformed individual FECRs and on arithmetic means of individual FECRs.

Results

Seventy-nine (48%) out of a total of 165 foals sampled were positive for P. equorum eggs before deworming and 66 of these met the criteria for being used in the efficacy assessment. It was shown that there was no, or very low activity of ivermectin on the output of ascarid eggs in the majority of the foals, whereas for fenbendazole and pyrantel it was >90%.

Conclusion

Ivermectin resistance was shown in 5 out of 6 farms. Therefore, ivermectin should not be the drug of choice in the control of P. equorum infections in foals. According to the results of this study, fenbendazole or pyrantel are still effective and should be used against this parasite.     

Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene

Objective-To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies. Animals-14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted. Procedures-Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration. Results-After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin. Conclusions and Clinical Relevance-The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1-1Δ mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process.     

Is anthelmintic resistance a concern for heartworm control? What can we learn from the human filariasis control programs?

Heartworm prophylaxis is currently largely dependent on the ability of avermectins and milbemycins to arrest the development of third and fourth stages of Dirofilaria immitis for prolonged periods, without producing adulticidal effects. Major control programs, dependent on the activity of ivermectin, are being implemented for human onchocerciasis and lymphatic filariasis. The avermectins and milbemycins act on glutamate-gated and gamma-aminobutyrate-gated chloride channel subunit proteins in nematodes. Ivermectin resistance has been widely described in trichostrongylid nematodes of ruminants. There is evidence that when ivermectin resistance occurs in nematodes, there may be selection on some, but not all of the genes that code for ligand-gated chloride channel subunit proteins as well as on some ABC-transporter genes, whose products may be involved in regulating macrocyclic lactone drug concentrations at receptors, and on some structural protein genes of amphidial neurones. Although ivermectin resistance has not been reported in filarial nematodes, there have recently been reports of suboptimal responses to ivermectin in Onchocerca volvulus. Evidence has been found of ivermectin selection on at least ABC-transporter genes and some neuronal structural protein genes in O. volvulus. To date, there is no evidence of avermectin/milbemycin resistance in D. immitis, also a filarial nematode. Chemotherapy against trichostrongylids of animals, human filariae, and D. immitis, relies on avermectins or milbemycins. However, control involves targeting different stages or processes in the nematode life cycles, different control strategies, different proportions of the nematode population in refugia, and different drug dosage rates. Consideration of the proportion of the D. immitis population normally in refugia, the life cycle stage targeted, and the anthelmintic dosages used suggest that it is unlikely that significant avermectin/milbemycin resistance will be selected in D. immitis with current treatment strategies.