Bergeron R J, Streiff R R, Creary E A, Daniels R D, King W, Luchetta G, Wiegand J, Moerker T, Peter H H
Department of Medicinal Chemistry, Medicine, University of Florida, Gainesville 32610-0485.
Blood. 1993 Apr 15;81(8):2166-73.
A comparative study of the iron-clearing properties of subcutaneously administered desferrioxamine B (DFO) with those of orally administered desferrithiocin sodium salt (1), desmethyl desferrithiocin (2), desazadesmethyl desferrithiocin sodium salt (3), desazadesmethyl desferrithiocin pivaloyloxymethyl ester (4), and desazadesmethyl-5,5-dimethyl desferrithiocin (5) in an iron-loaded Cebus monkey model and a non-iron overloaded bile duct-cannulated rat model is presented. All six drugs, which performed well in rodent studies, demonstrated increased efficiency in the Cebus monkey model. When administered to rodents at a daily dosage of 384 mumol/kg over a period of 10 days, drug 1 demonstrated severe renal toxicity. whereas drugs 3, 4, and 5 exhibited severe gastrointestinal (GI) toxicity. Under the same experimental protocol, drug 2 did not show significant toxic side effects. In addition, to further evaluate the iron-clearing properties of analogue 2, a dose-response study was performed in the primates that showed that iron excretion increased in a dose-dependent fashion.
本文介绍了在铁负荷的卷尾猴模型和非铁过载的胆管插管大鼠模型中，皮下注射去铁胺B（DFO）与口服去铁硫辛钠盐（1）、去甲基去铁硫辛（2）、去氮去甲基去铁硫辛钠盐（3）、去氮去甲基去铁硫辛新戊酰氧甲酯（4）和去氮去甲基-5,5-二甲基去铁硫辛（5）的铁清除特性的比较研究。在啮齿动物研究中表现良好的所有六种药物，在卷尾猴模型中均显示出更高的效率。当以384 μmol/kg的每日剂量给啮齿动物给药10天时，药物1表现出严重的肾毒性，而药物3、4和5表现出严重的胃肠道（GI）毒性。在相同的实验方案下，药物2未显示出明显的毒副作用。此外，为了进一步评估类似物2的铁清除特性，在灵长类动物中进行了剂量反应研究，结果表明铁排泄呈剂量依赖性增加。
