Trichuris suis and Oesophagostomum dentatum Show Different Sensitivity and Accumulation of Fenbendazole, Albendazole and Levamisole In Vitro
Trichuris suis and Oesophagostomum dentatum Show Different Sensitivity and Accumulation of Fenbendazole, Albendazole and Levamisole In Vitro
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DOI：
10.1371/journal.pntd.0002752
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发表时间：
2014-04-01
影响因子：
3.8
通讯作者：
Thamsborg, Stig Milan
中科院分区：
文献类型：
--
作者：
Hansen, Tina V. A.;Nejsum, Peter;Thamsborg, Stig Milan
背景单剂量苯并咪唑类药物用于人类鞭虫感染的效果并不令人满意。同样地，苯并咪唑、芬苯达唑对猪鞭虫具有不同的功效，而齿口线虫对该药物高度敏感。对鞭虫病防治效果不佳的原因进行了分析。方法我们研究了芬苯达唑、阿苯达唑和左旋咪唑对T. suis和O. dentatum和体外蠕虫内苯并咪唑的母体药物化合物和代谢物的测量浓度。比较了不同种属间蠕虫内药物化合物的运动性和浓度，以及T. suis和O. dentatum对苯并咪唑的估计。比较了两种线虫的活虫和死蠕虫对药物的摄取。suis的活力下降幅度一般小于O.在苯并咪唑中孵育时，齿状回的细胞数减少，但在左旋咪唑中孵育时减少更多。B-max显著低于T。suis（106.6和612.7pmol/mg干虫组织）比O.当在芬苯达唑和阿苯达唑中孵育72小时时，分别为395.2、958.1 pmol/mg干虫组织。总药物浓度（pmol/mg干虫组织）在T. suis比O.在所有试验药物中孵育时，无论是杀死的还是活的有齿蠕虫（暴露于芬苯达唑的活蠕虫除外）。在T. suis（6-17.2%），O.结论：T. suis对BZ在体外似乎与较低的药物摄取有关。此外，芬苯达唑砜的相对较高的出现表明T. suis与O.人类鞭虫Trichuris trichiura与蛔虫蛔虫和钩虫Ancylostoma naturale和美洲钩虫一起是全世界最常见的肠道蠕虫。这些疾病加在一起使50多亿人面临感染风险。目前针对这些蠕虫的全球控制策略是定期施用驱虫药，主要是阿苯达唑和甲苯达唑，两者都属于药物类苯并咪唑。两种药物对T.鞭毛虫感染，但其原因尚不清楚。我们评估了两种苯并咪唑的体外作用;即，阿苯达唑、芬苯达唑和另一种驱虫剂左旋咪唑对鞭虫的作用（T. suis）和猪的结节蠕虫（齿口食道线虫（Oesophagostomum dentatum）。齿食道口线虫对苯并咪唑类药物的敏感性高于T.猪。我们测量并比较了两种线虫在活虫和死蠕虫中的药物摄取，我们的结果表明敏感性差异的原因是由于T. suis与O.有齿的此外，T.与O. dentatum，表明T. suis与O.有齿的
BackgroundThe single-dose benzimidazoles used against Trichuris trichiura infections in humans are not satisfactory. Likewise, the benzimidazole, fenbendazole, has varied efficacy against Trichuris suis whereas Oesophagostomum dentatum is highly sensitive to the drug. The reasons for low treatment efficacy of Trichuris spp. infections are not known.MethodologyWe studied the effect of fenbendazole, albendazole and levamisole on the motility of T. suis and O. dentatum and measured concentrations of the parent drug compounds and metabolites of the benzimidazoles within worms in vitro. The motility and concentrations of drug compounds within worms were compared between species and the maximum specific binding capacity (B-max) of T. suis and O. dentatum towards the benzimidazoles was estimated. Comparisons of drug uptake in living and killed worms were made for both species.Principal findingsThe motility of T. suis was generally less decreased than the motility of O. dentatum when incubated in benzimidazoles, but was more decreased when incubated in levamisole. The B-max were significantly lower for T. suis (106.6, and 612.7 pmol/mg dry worm tissue) than O. dentatum (395.2, 958.1 pmol/mg dry worm tissue) when incubated for 72 hours in fenbendazole and albendazole respectively. The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole). Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6-17.2%) as compared to O. dentatum (0.8-0.9%).Conclusion/SignificanceThe general lower sensitivity of T. suis towards BZs in vitro seems to be related to a lower drug uptake. Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum.Author SummaryThe human whipworm Trichuris trichiura is together with the roundworm Ascaris lumbricoides and the hookworms Ancylostoma duodenale and Necator Americanus the most common intestinal worms worldwide. Together they place more than 5 billion people at risk of infection. The current global control strategy against these worms is regular administration of anthelmintic drugs, mostly albendazole and mebendazole, both belonging to the drug-class benzimidazoles. Both drugs have a low effect against T. trichiura infections, but the reasons for this are not known. We evaluated the in vitro effect of two benzimidazoles; i.e., albendazole, fenbendazole, and another type of anthelmintic, levamisole, on the whipworm (T. suis) and the nodular worm (Oesophagostomum dentatum) of the pig. Oesophagostomum dentatum is highly sensitive towards benzimidazoles in comparison to T. suis. We measured and compared the drug uptake in both species in both living and killed worms.Our results suggest that the reason for the difference in sensitivity is due to a lower drug uptake into T. suis as compared to O. dentatum. Furthermore, T. suis was able to metabolise fenbendazole into an inactive metabolite to a much larger extent than O. dentatum, suggesting a higher detoxifying capacity of T. suis as compared to O. dentatum.