Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, CB 7362, 120 Mason Farm Rd, Chapel Hill, North Carolina, 27599-7362, USA.
AAPS J. 2013 Oct;15(4):1180-8. doi: 10.1208/s12248-013-9527-x. Epub 2013 Aug 30.
The threat of nuclear terrorism by the deliberate detonation of a nuclear weapon or radiological dispersion device ("dirty bomb") has made emergency response planning a priority. The only FDA-approved treatments for contamination with isotopes of the transuranic elements Am, Pu, and Cm are the Ca and Zn salts of diethylenetriaminepentaacetic acid (DTPA). These injectable products are not well suited for use in a mass contamination scenario as they require skilled professionals for their administration and are rapidly cleared from the circulation. To overcome the mismatch in the pharmacokinetics of the DTPA and the biokinetics of these transuranic elements, which are slowly released from contamination sites, the penta-ethyl ester of DTPA (C2E5) was prepared and formulated in a nonaqueous gel for transdermal administration. When gels comprised of 40% C2E5, 40-45% Miglyol® 840, and 15-20% ethyl cellulose were spiked with [(14)C]-C2E5 and applied to rat skin; over 60% of the applied dose was absorbed within a 24-h period. Radioactivity was observed in urinary and fecal excretions for over 3 days after removal of the gel. Using an (241)Am wound contamination model, transdermal C2E5 gels were able to enhance total body elimination and reduce the liver and skeletal burden of (241)Am in a dose-dependent manner. The efficacy achieved by a single 1,000 mg/kg dose to contaminated rats was statistically comparable to intravenous Ca-DTPA at 14 mg/kg. The effectiveness of this treatment, favorable sustained release profile of pro-chelators, and ease of administration support its use following radiological emergencies and for its inclusion in the Strategic National Stockpile.
核恐怖主义的威胁，包括故意引爆核武器或放射性分散装置（“脏弹”），使得应急响应规划成为当务之急。美国食品和药物管理局（FDA）批准的唯一用于治疗锕系元素镅（Am）、钚（Pu）和锔（Cm）同位素污染的治疗方法是乙二胺四乙酸二钠钙（Ca-DTPA）和锌盐（Zn-DTPA）。这些可注射产品并不适合在大规模污染情况下使用，因为它们需要专业人员进行管理，并且在体内循环中迅速清除。为了克服 DTPA 的药代动力学与从污染场所缓慢释放的这些锕系元素的生物动力学之间的不匹配，制备并配制了 DTPA 的五乙酯（C2E5），并将其制成非水凝胶用于经皮给药。当包含 40% C2E5、40-45% Miglyol® 840 和 15-20%乙基纤维素的凝胶中加入 [(14)C]-C2E5 并应用于大鼠皮肤时，超过 60%的应用剂量在 24 小时内被吸收。在去除凝胶后超过 3 天，放射性物质在尿液和粪便排泄中被观察到。使用（241）Am 伤口污染模型，经皮 C2E5 凝胶能够以剂量依赖性方式增强全身消除，并减少（241）Am 在肝脏和骨骼中的负担。对受污染大鼠进行单次 1000mg/kg 剂量的治疗效果在统计学上与 14mg/kg 的静脉注射 Ca-DTPA 相当。这种治疗方法的有效性、有利的前螯合剂持续释放谱以及给药的便利性支持在放射性紧急情况下使用，并支持将其纳入国家战略储备。
