El-Feky Gina S, Mohamed Wael S, Nasr Hanaa E, El-Lakkany Naglaa M, Seif El-Din Sayed H, Botros Sanaa S
Department of Pharmaceutics, Faculty of Pharmacy, October University for Modern Sciences and Arts and Department of Pharmaceutical Technology, National Research Center, Cairo, Egypt
Department of Polymers and Pigments, National Research Center, Cairo, Egypt.
Antimicrob Agents Chemother. 2015;59(6):3501-8. doi: 10.1128/AAC.04875-14. Epub 2015 Apr 6.
Consideration of existing compounds always simplifies and shortens the long and difficult process of discovering new drugs specifically for diseases of developing countries, an approach that may add to the significant potential cost savings. This study focused on improving the biological characteristics of the already-existing antischistosomal praziquantel (PZQ) by incorporating it into montmorillonite (MMT) clay as a delivery carrier to overcome its known bioavailability drawbacks. The oral bioavailability of a PZQ-MMT clay nanoformulation and its in vivo efficacy against Schistosoma mansoni were investigated. The PZQ-MMT clay nanoformulation provided a preparation with a controlled release rate, a decrease in crystallinity, and an appreciable reduction in particle size. Uninfected and infected mice treated with PZQ-MMT clay showed 3.61- and 1.96-fold and 2.16- and 1.94-fold increases, respectively, in area under the concentration-time curve from 0 to 8 h (AUC0-8) and maximum concentration of drug in serum (Cmax), with a decrease in elimination rate constant (kel) by 2.84- and 1.35-fold and increases in the absorption rate constant (ka) and half-life (t1/2e) by 2.11- and 1.51-fold and 2.86- and 1.34-fold, respectively, versus the corresponding conventional PZQ-treated groups. This improved bioavailability has been expressed in higher efficacy of the drug, where the dose necessary to kill 50% of the worms was reduced by >3-fold (PZQ 50% effective dose [ED50] was 20.25 mg/kg of body weight for PZQ-MMT clay compared to 74.07 mg/kg for conventional PZQ), with significant reduction in total tissue egg load and increase in total immature, mature, and dead eggs in most of the drug-treated groups. This formulation showed better bioavailability, enhanced antischistosomal efficacy, and a safer profile despite the longer period of residence in the systemic circulation. Although the conventional drug's toxicity was not examined, animal mortality rates were not different between groups receiving the test PZQ-clay nanoformulation and conventional PZQ.
考虑现有化合物总是能简化和缩短专门研发针对发展中国家疾病的新药这一漫长而艰难的过程，这种方法可能会大幅节省潜在成本。本研究聚焦于通过将已有的抗血吸虫药吡喹酮（PZQ）掺入蒙脱石（MMT）粘土作为递送载体来改善其生物学特性，以克服其已知的生物利用度缺点。研究了PZQ - MMT粘土纳米制剂的口服生物利用度及其对曼氏血吸虫的体内疗效。PZQ - MMT粘土纳米制剂提供了一种具有控释速率、结晶度降低和粒径明显减小的制剂。用PZQ - MMT粘土处理的未感染和感染小鼠，与相应的传统PZQ治疗组相比，0至8小时浓度 - 时间曲线下面积（AUC0 - 8）和血清中药物最大浓度（Cmax）分别增加了3.61倍和1.96倍以及2.16倍和1.94倍，消除速率常数（kel）降低了2.84倍和1.35倍，吸收速率常数（ka）和半衰期（t1/2e）分别增加了2.11倍和1.51倍以及2.86倍和1.34倍。这种改善的生物利用度表现为药物疗效更高，杀死50%蠕虫所需剂量降低了3倍以上（PZQ - MMT粘土的PZQ 50%有效剂量[ED50]为20.25 mg/kg体重，而传统PZQ为74.07 mg/kg体重），在大多数药物治疗组中，总组织虫卵负荷显著降低，未成熟、成熟和死亡虫卵总数增加。尽管该制剂在体循环中的停留时间较长，但仍表现出更好的生物利用度、增强的抗血吸虫疗效和更安全的特性。虽然未检测传统药物的毒性，但接受测试的PZQ - 粘土纳米制剂组和传统PZQ组之间的动物死亡率没有差异。
