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首页> 外文期刊>PLOS Neglected Tropical Diseases >Exploring the Potential of Flubendazole in Filariasis Control: Evaluation of the Systemic Exposure for Different Pharmaceutical Preparations
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Exploring the Potential of Flubendazole in Filariasis Control: Evaluation of the Systemic Exposure for Different Pharmaceutical Preparations

机译：探索氟苯达唑在丝虫病控制中的潜力：不同药物制剂的全身暴露评估

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The goal of elimination of the human filariases would benefit greatly from the use of a macrofilaricidal agent. In vivo trials in humans and many experimental animal models suggest that flubendazole (FLBZ) is a highly efficacious macrofilaricide. However, since serious injection site reactions were reported in humans after parenteral FLBZ administration, the search for alternative pharmaceutical strategies to improve the systemic availability of FLBZ and its metabolites has acquired urgency in both human and veterinary medicine. The goal of the current work was to compare the systemic exposure of FLBZ formulated as either an aqueous hydroxypropyl-β-cyclodextrin (CD) or aqueous carboxymethyl cellulose (CMC) suspension or a Tween 80-based formulation (TWEEN) in rats and jirds (Meriones unguiculatus). Healthy animals of both species were allocated into four experimental groups of 44 animals each: FLBZ-CDoral and FLBZ-CDsc, treated with the FLBZ-CD formulation by the oral or subcutaneous routes, respectively; FLBZ-TWEENsc, dosed subcutaneously with the FLBZ-TWEEN formulation; and FLBZ-CMCoral, treated orally with the FLBZ suspension. The FLBZ dose was 5 mg/kg. FLBZ and its hydrolyzed (H-FLBZ) and reduced (R-FLBZ) metabolites were recovered in plasma samples collected from rats and jirds treated with the different FLBZ formulations. In both species, FLBZ parent drug was the main analyte recovered in the bloodstream. In rats, FLBZ systemic exposure (AUC0-LOQ) was significantly (P<0.05) higher after the FLBZ-CD treatments, both oral (4.8±0.9 μg.h/mL) and subcutaneous (7.3±0.6 μg.h/mL), compared to that observed after oral administration of FLBZ-CMC suspension (0.93±0.2 μg.h/mL). The same differences were observed in jirds. In both species, parenteral administration of FLBZ-TWEEN did not improve the systemic availability of FLBZ compared to FLBZ-CDoral treatment. In conclusion, formulation approaches that enhance the availability of flubendazole in the rat and jird may have therapeutic implications for a drug with poor or erratic bioavailability.
机译：消除人丝虫病的目标将受益于大杀丝剂的使用。在人体和许多实验动物模型中进行的体内试验表明，氟苯达唑（FLBZ）是一种高效的大丝杀虫剂。然而，由于在肠胃外注射FLBZ后有人报告了严重的注射部位反应，因此寻求替代药物策略以改善FLBZ及其代谢产物的全身利用率已在人和兽药中迫切需要。当前工作的目的是比较配制为羟丙基-β-环糊精（CD）或羧甲基纤维素（CMC）水性悬浮液或Tween 80型制剂（TWEEN）在大鼠和大鼠中的FLBZ的全身暴露（ Merguies unguiculatus）。将这两种动物的健康动物分为四个实验组，每组44个动物：FLBZ-CDoral和FLBZ-CDsc，分别通过口服或皮下途径用FLBZ-CD制剂处理; FLBZ-TWEENsc，皮下注射FLBZ-TWEEN制剂;和FLBZ-CMCoral，经FLBZ悬浮液口服处理。 FLBZ剂量为5mg / kg。 FLBZ及其水解的（H-FLBZ）和还原的（R-FLBZ）代谢物是从用不同FLBZ制剂处理过的大鼠和腹部收集的血浆样品中回收的。在这两个物种中，FLBZ母体药物是血液中回收的主要分析物。在大鼠中，口服（4.8±0.9μg.h/ mL）和皮下（7.3±0.6μg.h/ mL）的FLBZ-CD治疗后，FLBZ全身暴露（AUC0-LOQ）显着（P <0.05）更高与口服FLBZ-CMC悬浮液（0.93±0.2μg.h/ mL）后观察到的相比。在jirds中观察到相同的差异。在两个物种中，与FLBZ-CDoral治疗相比，肠胃外给药FLBZ-TWEEN均不能改善FLBZ的全身利用率。总而言之，提高大鼠和大鼠中氟苯达唑利用率的制剂方法可能对生物利用度差或不稳定的药物有治疗意义。

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