DMSA, DMPS AND OTHER ORALLY ACTIVE DITHIOL CHELATORS

DSMA和DMPS是螯合剂，可有效地处理重金属， 人类的金属中毒 DMSA是一种孤儿药， 美国FDA于1991年1月批准用于治疗儿童铅中毒， 有望成为治疗这类疾病的首选药物。 DMPS已获得 德国FDA作为汞解毒剂。 高灵敏度和选择性 包括双甲烷衍生化、HPLC和荧光的分析测定 检测已经在这个实验室开发，并导致安全 分析测定，在人类中，这些螯合剂及其 代谢物。 关于任何药物的知识越多， 更安全的治疗用途。口服后， 在人类中，DMSA似乎通过血浆白蛋白转运到肾脏 在那里它似乎被生物转化为DMSA-半胱氨酸混合二硫化物。 这就提出了一个问题，螯合作用是否只发生在 肾-一个将被调查的问题。 似乎有一个少校 DMSA生物转化的物种差异。 小鼠、大鼠和 兔不将DMSA代谢为DMSA-半胱氨酸混合二硫化物。 的 DMSA的生物转化将继续在人类中阐明， 将开始。 DMPS金属螯合物的二价铅，汞，镉，和 Ni将被合成并确定其结构。 金属螯合物 将从尿液及其结构中分离DMPS和DMSA 测定 将测定DMSA和DMPS的氧化还原电位。 初步结果表明，DMPS挑战测试，以检测 “微接触”汞是有希望的。 这是一个跨学科 一名分子和细胞生物学家/药理学家、一名 化学家和医生将相互作用，以获得基本和应用 信息，通常在人类中，关于这些螯合剂。 的 长期目标是研究毒理学和药理学特性 这些口服有效的治疗剂， 将可用于人类治疗。

DSMA and DMPS are chelating agents that are effective for treating heavy metal intoxication in humans. DMSA, an orphan drug, was approved by the U.S. FDA in January 1991 for treating childhood lead poisoning and is expected to be the drug of choice for this. DMPS has been approved by the German FDA as a mercury antidote. Highly sensitive and selective analytical assays involving bimane derivatization, HPLC, and fluorescence detection have been developed in this lab and have resulted in the safe analytical determination, in humans, of these chelating agents and their metabolites. The more knowledge available about any drug, the better and safer therapeutic use can be made of it. After oral administration to humans, DMSA appears to be transported to the kidney by plasma albumin where it appears to be biotransformed to DMSA-cysteine mixed disulfides. This brings up the question as to whether chelation only takes place in the kidney - a question that will be investigated. There appears to be a major species difference in the biotransformation of DMSA. Mice, rats, and rabbits do not metabolize DMSA to the DMSA-cysteine mixed disulfide. The biotransformation of DMSA will continue to be elucidated in humans and that for DMPS will begin. The DMPS metal chelates of divalent Pb, Hg, Cd, and Ni will be synthesized and their structures determined. Metal chelates of DMPS and DMSA will be isolated from the urine and their structures determined. The redox potentials of DMSA and DMPS will be determined. Preliminary results indicate a DMPS challenge test to detect "mini-exposure" to mercury is promising. This is an interdisciplinary investigation in which a molecular and cellular biologist/pharmacologist, a chemist, and a physician will interact to gain basic and applied information, very often in humans, about these chelating agents. The long-term goal is to study the toxicological and pharmacological properties of these orally effective therapeutic agents so that safe chelating agents will be available for human therapy.