SODIUM SULPHOMETHYL DERIVATIVES OF POLYMYXINS
SODIUM SULPHOMETHYL DERIVATIVES OF POLYMYXINS
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DOI：
10.1111/j.1476-5381.1964.tb01610.x
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发表时间：
1964-01-01
期刊：
影响因子：
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通讯作者：
WILKINSON, S
中科院分区：
文献类型：
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作者：
BARNETT, M;BUSHBY, SRM;WILKINSON, S
多粘菌素-B和多粘菌素-E(粘菌素)与甲醛和亚硫酸氢钠的处理方式不同，产生的磺甲基衍生物在急性毒性和体外和体内抗菌活性方面存在定量上的差异。这些衍生物的约60个样品的急性静脉注射LD50为母体抗生素的6倍至80多倍；体外和抗菌活性为母体抗生素的2%至12%，体内活性为母体抗生素的20%至50%，毒性最高的衍生物显示出最高的活性。用短时间和长时间孵育的方法，对不同年龄的溶液和肌肉注射后的人和狗的血液进行分析，结果表明，这些磺甲基衍生物的抗菌活性依赖于恢复到未取代形式，活性的差异是由于稳定性的差异。通过将这些磺甲基衍生物与稳定的乙酰基衍生物进行比较，支持了这些结论。体内活性较低，至少部分是由于取代形式在肾脏中的高排泄。电泳法表明，这些衍生物是复合的，其组分对应于单-五磺甲基多粘菌素。注射部位的疼痛是多粘菌素疗法最麻烦的副作用，而这些衍生品可以避免这种副作用。在注射了大约20倍于通常人体剂量的量的大鼠中，这些衍生品会导致一过性尿量减少和一过性蛋白尿。在给狗肌肉注射这些衍生物后，在脑脊液中检测不到抗生素，胆汁中的浓度与注射母体抗生素后没有显著差异。当脑室内注射到这些动物体内时，衍生物的毒性比母体化合物要小。这些研究表明，急性静脉毒性是一个有用的疗效指标，静脉注射LD50值约为100 mg/kg的衍生物是最令人满意的。由于活性依赖于对母体抗生素的还原，因此禁止将这些衍生物用于局部应用。
Variations in the treament of polymyxin-B and polymyxin-E (colistin) with formaldehyde and sodium-bisulfite produce sulfomethyl derivatives which differ quantitatively in acute toxicity and in antibacterial activities in-vitro and in-vivo. The acute intravenous LD50 values of some sixty samples of these derivatives range from six- to more than eighty-fold those of the parent antibiotics; the in-vitro and antibacterial activities range from 2 to 12% and the in-vivo activities from 20 to 50% of those of the parent antibiotics, with the most toxic derivatives showing the highest activities. When short and prolonged incubation methods are used, assays of the derivatives in solutions of different ages and of blood collected from man and dog after intramuscular injection, show that the antibacterial activities of these sulfomethyl derivatives depend on reversion to the unsubstituted form, and that the differences in the activities are due to variations in stability. These conclusions are supported by comparison of these sulfomethyl derivatives with stable acetyl derivatives. The lower in-vivo activity is due, at least partly, to the high renal excretion of the substituted form. Electrophoresis shows that the derivatives are composite, the components corresponding to mono- to pentasulfomethyl polymyxin. Pain at the injection site is the most troublesome side-effect of polymyxin therapy, and this is avoided with these derivatives. In rats injected with quantities some twenty-times the usual human dose, the derivatives cause transitory decrease in urinary output and transitory proteinuria. After intramuscular injection of these derivatives into dogs, no antibiotic is detectable in the cerebrospinal fluid and concentrations present in the bile are not significantly different from those after injection of the parent antibiotic. When injected intracisternally into these animals, derivatives are less toxic than the parent compounds. These studies show that acute intravenous toxicity is a useful index of therapeutic efficiency and that derivatives with intravenous LD50 values of about 100 mg/kg are the most satisfactory ones. Because activity depends on reversion to the parent antibiotic, the use of these derivatives for topical application is contraindicated.