Potentiation of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica following its co-administration with the metabolic inhibitor, ketoconazole
Potentiation of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica following its co-administration with the metabolic inhibitor, ketoconazole
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DOI：
10.1016/j.vetpar.2011.08.006
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发表时间：
2012-02-28
影响因子：
2.6
通讯作者：
Fairweather, I.
中科院分区：
文献类型：
--
作者：
Devine, C.;Brennan, G. P.;Fairweather, I.
在实验室大鼠模型中进行了一项体内研究，以监测三氯苯达唑（TCBZ）和酮康唑（KTZ）（细胞色素P450抑制剂）联合给药后4天内肝片形吸虫成虫的形态学变化。用耐三氯苯达唑的F.肝，口服给予剂量为10 mg/kg活重的三氯苯达唑和剂量为10 mg/kg活重的酮康唑。在处理后24、48、72和96 h（p.t）回收吸虫，并使用透射电子显微镜（TEM）评估吸虫超微结构的变化。结果显示，随着时间的推移，p.t.，吸虫超微结构变化的严重程度增加。随着时间的推移，基底内褶和相关粘多糖团的肿胀变得更加严重。高尔基复合体，如果存在的话，在感染后96小时的大小和数量都大大减少，并且从72小时时间段开始观察到亚皮层淹没。在p.t. 96小时观察到棘上的被膜覆盖物的一些脱落。结果表明，Oberon分离物在KTZ存在下对TCBZ作用比单独对TCBZ更敏感，加强了药物代谢改变参与耐药机制的想法。此外，他们支持TCBZ +抑制剂组合（旨在改变药物药代动力学和增强TCBZ的作用）可用于治疗F. TCBZ-R人群的概念。肝。(C)2011 Elsevier B. V.保留所有权利。
An in vivo study in the laboratory rat model has been carried out to monitor morphological changes in adult Fasciola hepatica over a 4-day period resulting from co-treatment with triclabendazole (TCBZ) and ketoconazole (KTZ), a cytochrome P450 inhibitor. Rats were infected with the triclabendazole-resistant Oberon isolate of F. hepatica, dosed orally with triclabendazole at a dosage of 10 mg/kg live weight and ketoconazole at a dosage of 10 mg/kg live weight. Flukes were recovered at 24, 48, 72 and 96 h post-treatment (p.t) and changes to fluke ultrastructure were assessed using transmission electron microscopy (TEM). Results showed an increase in the severity of changes to the fluke ultrastructure with time p.t. Swelling of the basal infolds and the associated mucopolysaccharide masses became more severe with time. Golgi complexes, if present, were greatly reduced in size and number by 96 h p.t., and sub-tegumental flooding was seen from the 72 h time-period onwards. Some sloughing of the tegumental covering over the spines was observed at 96 h p.t. The results demonstrated that the Oberon isolate is more sensitive to TCBZ action in the presence of KTZ than to TCBZ alone, reinforcing the idea that altered drug metabolism is involved in the resistance mechanism. Moreover, they support the concept that TCBZ + inhibitor combinations (aimed at altering drug pharmacokinetics and potentiating the action of TCBZ) could be used in the treatment of TCBZ-R populations of F. hepatica. (C) 2011 Elsevier B.V. All rights reserved.