New, Combined, and Reduced Dosing Treatment Protocols Cure Trypanosoma cruzi Infection in Mice
New, Combined, and Reduced Dosing Treatment Protocols Cure Trypanosoma cruzi Infection in Mice
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DOI：
10.1093/infdis/jit420
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发表时间：
2014-01-01
影响因子：
6.4
通讯作者：
Tarleton, Rick L.
中科院分区：
文献类型：
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作者：
Bustamante, Juan M.;Craft, Julie M.;Tarleton, Rick L.
优先考虑制定毒性降低、疗效等同或提高的克氏锥虫感染治疗方案。我们测试了苄硝唑（BZ）、硝呋替莫司（NFX）和其他有前景的药物在间歇和联合治疗方案中治愈T。克氏感染由易感和耐药寄生虫株引发。BZ、NFX或oxaborale AN 4169的40天疗程治愈了100%的小鼠，而泊沙康唑（POS）和NTLA-1（硝基三唑）分别治愈了约90%和20%的小鼠。通过使用间歇性（每5天一次）方案或将5次每日剂量的POS与7次间歇性剂量的BZ组合来减少BZ或NFX的总剂量也提供了约100%的治愈。T.对BZ耐药的克氏菌株也被发现对其他药物（POS）耐药，延长治疗时间或联合用药并不能提高这些菌株的治愈率。因此，抗T. Cruzi化合物应该凭经验确定，靶向不同途径的化合物可以组合以产生具有降低的毒性的有效疗法。这项工作还表明，使用BZ和NFX的标准治疗方案可能会显着过量的患者，可能有助于不良事件。
The development of treatment protocols with reduced toxicity and equivalent or improved efficacy for Trypanosoma cruzi infection is a priority. We tested the effectiveness of benznidazole (BZ), nifurtimox (NFX), other prospective drugs in intermittent and combined treatment protocols to cure T. cruzi infection initiated with susceptible and drug-resistant parasite strains. A 40-day course of BZ, NFX, or the oxaborale AN4169 cured 100% of mice, whereas posaconazole (POS), and NTLA-1 (a nitro-triazole) cured approximately 90% and 20% of mice, respectively. Reducing the overall dosage of BZ or NFX by using an intermittent (once every 5 days) schedule or combining 5 daily doses of POS with 7 intermittent doses of BZ also provided approximately 100% cure. T. cruzi strains resistant to BZ were also found to be resistant to other drugs (POS), and extending the time of treatment or combining drugs did not increase cure rates with these isolates. Thus, dosing schedules for anti-T. cruzi compounds should be determined empirically, and compounds targeting different pathways may be combined to yield effective therapies with reduced toxicity. This work also suggests that standard treatment protocols using BZ and NFX may be significantly overdosing patients, perhaps contributing to the adverse events.