A novel formulation of tigecycline has enhanced stability and sustained antibacterial and antileukemic activity.
A novel formulation of tigecycline has enhanced stability and sustained antibacterial and antileukemic activity.
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DOI：
10.1371/journal.pone.0095281
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Schimmer AD
中科院分区：
文献类型：
--
作者：
Jitkova Y;Gronda M;Hurren R;Wang X;Goard CA;Jhas B;Schimmer AD
替加环素是一种广谱、一流的甘氨酰环素抗生素，目前用于治疗复杂的皮肤和腹腔内感染以及社区获得性肺炎。此外，我们已经证明，由于替加环素能够抑制线粒体翻译，因此其还具有抗急性髓性白血病（AML）的体外和体内活性。替加环素在复溶后相对不稳定，这种不稳定性可能会限制药物在治疗感染的非卧床输注中的使用，并可能妨碍开发治疗AML的最佳给药方案。本研究旨在确定一种制剂，该制剂可改善药物复溶后的稳定性，并保持其抗微生物和抗白血病活性。对一组化学添加剂进行了检测，以确定可增强替加环素溶液在室温下长达一周的稳定性的辅料。我们确定了一种新的制剂，该制剂含有氧还原剂抗坏血酸（3 mg/mL）和丙酮酸盐（60 mg/mL），溶于pH 7.0的盐水溶液中，其中替加环素（1 mg/mL）在避光条件下至少7天保持完整。该制剂还保留了药物的体外抗菌和抗白血病活性。此外，新制剂保留了替加环素的体内抗白血病活性。因此，我们鉴定并表征了替加环素的新制剂，其在重构后保持其稳定性和功效。
Tigecycline is a broad-spectrum, first-in-class glycylcycline antibiotic currently used to treat complicated skin and intra-abdominal infections, as well as community-acquired pneumonia. In addition, we have demonstrated that tigecycline also has in vitro and in vivo activity against acute myeloid leukemia (AML) due to its ability to inhibit mitochondrial translation. Tigecycline is relatively unstable after reconstitution, and this instability may limit the use of the drug in ambulatory infusions for the treatment of infection and may prevent the development of optimal dosing schedules for the treatment of AML. This study sought to identify a formulation that improved the stability of the drug after reconstitution and maintained its antimicrobial and antileukemic activity. A panel of chemical additives was tested to identify excipients that enhanced the stability of tigecycline in solution at room temperature for up to one week. We identified a novel formulation containing the oxygen-reducing agents ascorbic acid (3 mg/mL) and pyruvate (60 mg/mL), in saline solution, pH 7.0, in which tigecycline (1 mg/mL) remained intact when protected from light for at least 7 days. This formulation also preserved the drug's antibacterial and antileukemic activity in vitro. Moreover, the novel formulation retained tigecycline's antileukemic activity in vivo. Thus, we identified and characterized a novel formulation for tigecycline that preserves its stability and efficacy after reconstitution.
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影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
抑制线粒体翻译是人类急性髓样白血病的治疗策略。
影响因子：
50.3
作者：
Skrtić M;Sriskanthadevan S;Jhas B;Gebbia M;Wang X;Wang Z;Hurren R;Jitkova Y;Gronda M;Maclean N;Lai CK;Eberhard Y;Bartoszko J;Spagnuolo P;Rutledge AC;Datti A;Ketela T;Moffat J;Robinson BH;Cameron JH;Wrana J;Eaves CJ;Minden MD;Wang JC;Dick JE;Humphries K;Nislow C;Giaever G;Schimmer AD
通讯作者：
Schimmer AD
影响因子：
4.9
作者：
Petersen, PJ;Jacobus, NV;Testa, RT
通讯作者：
Testa, RT
影响因子：
15.9
作者：
Samudio, Ismael;Harmancey, Romain;Andreeff, Michael
通讯作者：
Andreeff, Michael
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca