Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis.
Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis.
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DOI：
10.1021/acsinfecdis.1c00213
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发表时间：
2021-10-08
影响因子：
5.3
通讯作者：
Meibohm, Bernd
中科院分区：
文献类型：
--
作者：
Gonzalez-Juarrero, Mercedes;Lukka, Pradeep B.;Wagh, Santosh;Walz, Amanda;Arab, Jennifer;Pearce, Camron;Ali, Zohaib;Ryman, Josiah T.;Parmar, Keyur;Temrikar, Zaid;Munoz-Gutierrez, Juan;Robertson, Gregory T.;Liu, Jiuyu;Lenaerts, Anne J.;Daley, Charles;Lee, Richard E.;Braunstein, Miriam;Hickey, Anthony J.;Meibohm, Bernd
结核病（TB）治疗时间过长是耐多药结核病（MDR-TB）出现的主要原因。改进结核病治疗的一种方法是开发一种吸入性结核病治疗方法，当与口服结核病药物联合使用时，可以减轻并缩短治疗时间。壮观酰胺是壮观霉素的新型半合成类似物，对结核分枝杆菌 (Mtb)（包括 MDR 和 XDR Mtb 菌株）具有出色的活性。 Spectinamide-1599 被选为开发吸入疗法的有前途的候选药物。使用小鼠结核病模型和肺内气雾剂输送 spectinamide-1599，我们在感染 Mtb Erdman 菌株的 BALB/c 和 C3HeB/FeJ 小鼠中表征了该疗法的药代动力学和疗效。正如预期的那样，spectinamide1599 在血浆、肺和 ELF 中表现出剂量依赖性暴露，但与静脉或皮下给药相比，肺内给药的肺和血浆之间的暴露比高 12-40 倍。在慢性感染的 BALB/c 小鼠中，低剂量 (10 mg/kg) spectinamide-1599 每周三次，持续两个月，治疗一个月后的疗效与高剂量 (50-100 mg/kg) 相似。在 C3HeB/FeJ TB 模型中，肺内雾化给药 spectinamide-1599 (50 mg/kg) 或口服吡嗪酰胺 (150 mg/kg) 在单一疗法中疗效有限或无效，但当两种药物联合使用时，观察到协同效应，细菌减少量 >1.8 log10 CFU。在长达八周的治疗期间，肺内治疗的耐受性良好，没有任何明显的毒性。总体而言，这些结果有力地支持了肺内 spectinamide-1599 作为抗结核治疗组合伙伴的进一步开发。
The lengthy treatment time for tuberculosis (TB) is a primary cause for the emergence of multidrug resistant tuberculosis (MDR-TB). One approach to improve TB therapy is to develop an inhalational TB therapy that when administered in combination with oral TB drugs eases and shortens treatment. Spectinamides are new semisynthetic analogues of spectinomycin with excellent activity against Mycobacterium tuberculosis (Mtb), including MDR and XDR Mtb strains. Spectinamide-1599 was chosen as a promising candidate for development of inhalational therapy. Using the murine TB model and intrapulmonary aerosol delivery of spectinamide-1599, we characterized the pharmacokinetics and efficacy of this therapy in BALB/c and C3HeB/FeJ mice infected with the Mtb Erdman strain. As expected, spectinamide1599 exhibited dose-dependent exposure in plasma, lungs, and ELF, but exposure ratios between lung and plasma were 12–40 times higher for intrapulmonary compared to intravenous or subcutaneous administration. In chronically infected BALB/c mice, low doses (10 mg/kg) of spectinamide-1599 when administered thrice weekly for two months provide efficacy similar to that of higher doses (50–100 mg/kg) after one month of therapy. In the C3HeB/FeJ TB model, intrapulmonary aerosol delivery of spectinamide-1599 (50 mg/kg) or oral pyrazinamide (150 mg/kg) had limited or no efficacy in monotherapy, but when both drugs were given in combination, a synergistic effect with superior bacterial reduction of >1.8 log10 CFU was oberved. Throughout the up to eight-week treatment period, intrapulmonary therapy was well-tolerated without any overt toxicity. Overall, these results strongly support the further development of intrapulmonary spectinamide-1599 as a combination partner for anti-TB therapy.
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Bedaquiline和吡嗪酰胺治疗反应受肺病变异质性的影响，感染了C3HEB/FEJ小鼠。
影响因子：
5.3
作者：
Irwin SM;Prideaux B;Lyon ER;Zimmerman MD;Brooks EJ;Schrupp CA;Chen C;Reichlen MJ;Asay BC;Voskuil MI;Nuermberger EL;Andries K;Lyons MA;Dartois V;Lenaerts AJ
通讯作者：
Lenaerts AJ
DOI：
10.1186/cc8206
发表时间：
2009
期刊：
Critical care (London, England)
影响因子：
--
作者：
Luyt CE;Clavel M;Guntupalli K;Johannigman J;Kennedy JI;Wood C;Corkery K;Gribben D;Chastre J
通讯作者：
Chastre J
影响因子：
5.6
作者：
Maselli DJ;Keyt H;Restrepo MI
通讯作者：
Restrepo MI
影响因子：
4.1
作者：
Flume, P;Klepser, ME
通讯作者：
Klepser, ME
影响因子：
4.5
作者：
Madhura, Dora Babu;Trivedi, Ashit;Meibohm, Bernd
通讯作者：
Meibohm, Bernd