The effect of feed quality on the kinetic disposition of orally administered triclabendazole in sheep

The effect of two qualities of feed on the kinetic disposition of triclabendazole (TCBZ) metabolites was investigated in sheep (n = 4) following oral administration of TCBZ at 10 mg/kg body weight. The same sheep were given sequentially two qualitatively different diets: a low-quality (LQ) diet based on wheat straw ad libitum, and a high-quality (HQ) diet based on barley+alfalfa. The triclabendazole sulphoxide (TCBZSO) and triclabendazole sulphone (TCBZSO₂) concentrations were determined in blood samples taken serially from the jugular vein between 5 min and 9 days after TCBZ administration. The parent drug TCBZ was not detected in any of the samples. The quality of feed affected the kinetics of both TCBZ metabolites. The rate of appearance (T_lag and T_max) in the jugular blood was slower and the formed amount (AUC) of TCBZSO was slightly higher when the sheep were on the LQ diet (T_lag = 7.74 h; T_max = 27.91 h; AUC = 1042 g.h/ml) than when they were offered the HQ diet (T_lag = 1.90 h; T_max = 16.01 h; AUC = 832.4 g.h/ml). The MRT of TCBZSO was about 40% longer with the LQ diet than with the HQ diet. Similarly, the rate of appearance of TCBZSO₂ in plasma of sheep was slower when they were on the LQ diet than when they were on the HQ diet, suggesting an impairment of the hepatic enzymatic activity involved in the oxidation of TCBZSO to TCBZSO₂.     

伊维菌素和三氯苯达唑在羊体内的药动学相互作用

【目的】研究联合应用伊维菌素和三氯苯达唑在蠕虫感染绵羊体内的药代动力学特征及相互影响,【方法】借助经典麦克麦斯特法定量检查羊群消化道蠕虫感染基础上选取每克粪便虫卵数大于1500个,且感染强度相近的泌乳期鄂尔多斯细毛羊15只,平均体重为（39.3±3.2）kg,年龄为4周岁。将15只受试羊禁食8 h后随机分成3组,按照预定试验设计给予不同药物：第1组皮下注射伊维菌素（0.2 mg•kg-1）,第2组灌服三氯苯达唑混悬液（12 mg•kg-1）,第3组皮下注射伊维菌素（0.2 mg•kg-1）的同时灌服三氯苯达唑混悬液（12 mg•kg-1）。分别于给药后第0.75、2、4、8、16、24、36、48、72、120、192和336 h,由颈静脉采集5 mL血样,离心分离血浆,冷冻保存待测。建立检测血浆伊维菌素（IVM）、三氯苯达唑（TCBZ）及其主要活性代谢产物三氯苯达唑亚砜（TCBZSO）浓度的高效液相色谱（HPLC）荧光检测法和紫外检测法,并对每个样品进行甲醇沉淀蛋白,经ODS C18固相萃取柱进行纯化处理后,分别测定各组血浆样品中的IVM、TCBZ及其主要代谢产物TCBZSO的浓度。色谱条件：反相C18柱,InertsilODS-SP(5 µm,4.6×150 mm,I.D.);流动相为V(甲醇+乙腈)﹕V(水)=95﹕5;激发波长364 nm,发射波长470 nm;流速为1.0 mL•min-1;柱温为室温;进样量为20 µL。最后将测定血药浓度数据用Phoenix WinNonlin药动学软件按非房室模型方法处理,计算出各试验组每只羊的相关药动学参数,并进行统计学分析。 【结果】血浆样品色谱图中IVM和内标物AVM色谱峰分离良好,保留时间分别为8.73 min和6.16 min,且不受血浆其他干扰峰的影响;TCBZ和TCBZSO以及内标物甲苯咪唑的保留时间分别为10.04、5.53和3.42 min,且在试验分析条件下具有良好的分离度,血浆内源性物质对目标峰没有干扰。对HPLC检测方法的绝对回收率、精密度和准确度等的考证结果均达到色谱测定要求。因此,本试验所建立的方法切实可行,能满足测定血浆样品各目标物的检测要求。联合应用IVM和TCBZ后,IVM的血浆峰浓度(Cmax)和药时曲线下面积（AUC）极显著下降,表观分布容积（Vd）、消除半衰期（T1/2ke）和体清除率（CLb）反而极显著增加;联合用药后TCBZSO的Vd、MRT和Tmax显著高于单独用药组,T1/2ke则极显著高于单独用药组。【结论】为蠕虫感染绵羊联合应用伊维菌素和三氯苯达唑后,在药代动力学方面相互产生了负面影响,未达到联合用药的真正目的。由此可见,在临床实践中联合用药时应考虑它们的药动学相互作用问题,应避免只根据体外药效学协同作用进行盲目配伍和联合用药,从而保证充分发挥各药物的原有药效和协同作用的目的。     

The efficacy and pharmacokinetics of long-term low-level intraruminal administration of tricalbendazole in buffalo with induced fasciolosis

A study was conducted on the pharmacokinetics and therapeutic efficacy of triclabendazole at three low dose rates of 0.5, 1.0 and 1.5 mg/kg body weight in buffaloes experimentally infected with Fasciola gigantica. The pharmacokinetics were compared with the effects of a single intraruminal dose at 24.0 mg/kg body weight in uninfected buffaloes. At all three dose rates, an equilibrium between the absorption of triclabendazole and the disposition of its metabolites was observed by days 3 and 4 and remained almost unchanged thereafter. Continuous daily dosing at 1.5 mg/kg body weight proved to be efficacious against liver fluke infection in buffaloes.Abbreviations TCBZ triclabendazole - p.i. post-infection - HPLC high-performance liquid chromatography - TCBZ-SO triclabendazole sulphoxide - TCBZ-SO2 triclabendazole sulphone - C _max peak concentration in plasma - T _max time to reach C _max - AUC area under the concentration-time curve - t _1/2 elimination half-life - epg eggs per gram     

Assessment of the pharmacological interactions between the nematodicidal fenbendazole and the flukicidal triclabendazole: In vitro studies with bovine liver microsomes and slices

Parasitic diseases have a significant impact on livestock production. Nematodicidal drugs, such as fenbendazole (FBZ) or its oxidized metabolite oxfendazole (OFZ), can be used along with the trematodicidal triclabendazole (TCBZ), to broaden the spectrum of anthelmintic activity. However, co‐exposure to these compounds could lead to drug–drug (D‐D) interactions and eventually alter the clinical profile of each active principle. The aim of this study was to assess the presence of such interactions by means of two in vitro models, namely bovine liver microsomal fractions and bovine precision‐cut liver slices (PCLSs). To this end, an in vitro assessment involving incubation of FBZ and TCBZ or a combination of FBZ and TCBZ was carried out. Results with microsomal fractions showed a 78.4% reduction (p = .002) in the rate of OFZ production upon co‐incubation, whereas the sulfoxide metabolite of TCBZ (TCBZSO) exhibited a decreasing tendency. With PCLS, OFZ accumulation in the incubation medium increased 1.8‐fold upon co‐incubation, whereas TCBZSO accumulation decreased by 28%. The accumulation of FBZ and OFZ in the liver tissue increased upon 2‐hr co‐incubation, from 2.1 ± 1.5 to 18.2 ± 6.1 (p = .0009) and from 0.4 ± 0.1 to 1.3 ± 0.3 nmol (p = .0005), respectively. These results confirm the presence of D‐D interactions between FBZ and TCBZ. Further studies are needed to determine the extent of involvement of drug‐metabolizing enzymes and membrane transporters in interactions between compounds largely used in livestock production systems.     

Efficacy against Fasciola hepatica and the pharmacokinetics of triclabendazole administered by oral and topical routes

Objective   To determine the efficacy of triclabendazole (TCBZ) against 28-day-old, early immature liver fluke in cattle and its pharmacokinetics following administration by the oral or topical (pour-on) route.
Procedures   Cattle (n = 18) were infected with 500 TCBZ-susceptible liver fluke metacercariae and randomly allocated to three groups. At 28 days after infection, the groups were: (1) untreated controls; (2) treated with oral TCBZ at 12 mg/kg in combination with oxfendazole and selenium (TOS); (3) treated with pour-on TCBZ at 30 mg/kg in combination with abamectin (TA). Blood samples were taken immediately prior to treatment and serially after treatment to assess the plasma profile of TCBZ metabolites. Ten weeks after treatment all animals were slaughtered and total liver fluke counts, fluke egg counts and liver pathology were assessed.
Results   Both the TOS and TA treatments resulted in significant reductions of 28-day-old liver fluke, as assessed by fluke counts and fluke egg counts at slaughter, and the reductions following TOS treatment were significantly greater than those following TA treatment. The blood profile of TCBZ metabolites in TOS-treated animals showed a significantly greater area under the plasma concentration time curve and a higher maximum observed concentration than those treated with TA. There was significantly less liver pathology in TOS-treated animals than in the TA-treated animals.
Conclusion   TCBZ administered orally at 12 mg/kg resulted in greater efficacy against 28-day-old, early immature liver fluke than was achieved by topical administration at 30 mg/kg. Plasma metabolites of TCBZ were higher and liver pathology was less in TOS-treated animals than in TA-treated animals.     

Livestock Management in Red-Billed Chough Feeding Habitat in Great Britain and the Isle of Man

In Great Britain, red-billed chough (Pyrrhocorax pyrrhocorax) breed in discrete populations along the west coast: on Islay and Colonsay, in the Inner Hebrides of Scotland; on the Isle of Man; in Wales; and in Cornwall. Chough are dependent on pastures grazed by sheep or cattle, and their survival therefore depends on sympathetic management of grassland. The Scottish population is in decline, and all other populations are growing or stable. Sixty-three farmers in these regions whose farms were known to support feeding chough were asked questions about their farm management using a structured, questionnaire-based personal interview. Islay farms were significantly larger and had more grazing area, with the lowest stocking densities. Welsh farms had the least cropping area and the smallest number of cattle. Cornwall had the smallest number of sheep per farm. Welsh farms were more likely to not house cattle during winter. Liver fluke in sheep and ticks and tick-borne disease were a higher concern on Islay than other regions, and abortion in sheep was of highest concern on the Isle of Man. Islay farmers applied between 4× and 13× as many synthetic pyrethroid (SP) treatments to cattle per year than farmers at other regions, and the application rate of triclabendazole (TCBZ) to sheep was higher on Islay than other regions. The rate of application of other products, including macrocyclic lactones, did not differ among regions. The study described here shows clear differences in the farm grazing management, in the priority given to animal health problems and in the frequency of application of veterinary parasiticides among four regions that provide feeding habitat for chough in the United Kingdom. These differences suggest that the viability of chough populations might be favored by higher-intensity grazing and low rates of application of veterinary parasiticides of either the TCBZ or SP, or both classes of parasiticides.     

羊组织中三氯苯唑及代谢物残留量检测方法研究

建立了一种可同时检测羊组织中三氯苯达唑及其代谢物三氯苯达唑酮残留的高效液相色谱检测方法。结果表明三氯苯达唑、三氯苯达唑酮浓度在20～600 ng/mL范围时与峰面积呈良好的线性关系,R2均大于0.999 9,方法的定量限为30μg/kg。三氯苯达唑、三氯苯达唑酮在30～300μg/kg的浓度添加水平上,其回收率在60%～100%,批内、批间的相对标准偏差均小于15%。     

国产三氯苯咪唑驱除山羊肝片形吸虫效果试验

以国产三氯苯咪唑对自然感染肝片形吸虫的山羊进行了驱虫试验，并以硝氯酚为药物对照。结果表明，三氯本咪唑5mg/kg体重的剂量对肝片形吸虫成虫和童虫的驱虫率分别为99.3%和92.9%，驱净率为75％；三氯苯咪唑10mg/kg体重的剂量对肝片形吸虫成虫和童虫的驱虫率均为100％，驱净率为100％；硝氯酚5mg/kg体重剂量对肝片形吸虫成虫驱虫率为100％，但对童虫的仅为74.3%，而驱净率仅为60％。在整个试验期间试验羊均无不良反应。     

三氯苯唑合成工艺研究

以2，3-二氯苯酚及1，2，4-三氯苯为原料，经硝化、氨化、相转移催化缩合、还原、环合和甲硫基化等6步反应合成三氯苯唑,总收率达34％。