HYPOCALCEMIC AND PTH-INHIBITORY MECHANISMS OF WR2721

本研究项目的目的是系统地调查 低钙血症和甲状旁腺素分泌减少的基础， 我们在初步研究中发现， WR 2721，S-2-（3-氨基丙基氨基乙基）硫代磷酸。 该化合物 是一种有机硫代磷酸酯衍生物， 保护正常组织免受辐射和烷基化的毒性 药剂化疗 在该化合物的I期临床试验中， 患者出现低钙血症。 随后连续钙测量 在8名患者中， 9.48至7.44 mg/dl，同时血清PTH水平下降， 研究患者的平均浓度为4.75至1.6 pL-Eq/ml。 因此，我们计划 扩大这些初步意见，以确定机制， WR 2721降低血清钙水平以及降低 甲状旁腺激素释放。 我们将利用三个实验性的 技术，以实现这一目标。 首先，我们将做一个大型系列 完整犬和大鼠的清除率和代谢平衡研究， 证明了WR 2721低钙作用的体内特征。 这些研究将致力于确定以下方面的相对贡献： 改变甲状旁腺素释放和钙稳态的其他成分， 观察到低钙血症。 他们还将致力于检查临床 WR 2721作为PTH释放抑制剂和低钙血症抑制剂的用途 剂 第二个系列的实验将利用分散的牛 甲状旁腺细胞制备，以确定的影响和机制， WR 2721在高灵敏度模型系统中检测PTH的变化 release. 第三项实验技术将试图识别 整个动物以及单细胞钙动力学的变化， 可能是WR 2721改变血清钙水平的作用的基础。 vivo. 目前还没有有效的工具来监管 甲状旁腺激素分泌 因此，如果WR 2721实现其早期承诺， 作为一种有效降低血清钙的药物， 其他毒性作用以及能够抑制PTH释放， 作为治疗工具在各种条件下实现广泛的临床用途。

The aim of this research project will be to investigate in a systematic manner the basis for the hypocalcemia and reduction in PTH secretion which we have found in preliminary studies following the administration of WR2721, S-2-(3-aminopropylaminoethyl) phosphorothioic acid. This compound is an organic thiophosphate derivative which in animals selectively protects normal tissues against the toxicity of radiation and alkylating agent chemotheraphy. In Phase I clinical trials of this compound, one patient developed hypocalcemia. Subsequently serial calcium measurements in eight patients demonstrated both a consistent fall in serum calcium from 9.48 to 7.44 mg/dl and a concomitant fall in serum PTH levels in every patient studied from a average of 4.75 to 1.6 pL-Eq/ml. We therefore plan to extend these preliminary observations to identify the mechanism by which WR2721 reduces the serum calcium level as well as reduces the level of parathyroid hormone released. We will utilize three experimental techniques in order to achieve this aim. First we will do a large series of clearance and metabolic balance studies in intact dogs and rats to demonstrate the in vivo characteristics of WR2721 hypocalcemic action. These studies will be devoted to identifying the relative contributions of changing PTH release and other components of calcium homeostasis to the observed hypocalcemia. They also will be devoted to examining the clinical utility of WR2721 as an inhibitor of PTH release and as a hypocalcemi agent. The second series of experiments will utilize the dispersed bovine parathyroid cell preparation to identify the effects and mechanism of WR2721 in a highly sensitive model system to detect changes in PTH release. The third experimental technique will be to attempt to identify the changes in whole animal as well as single cell calcium kinetics which may underlie the effects of WR2721 to alter the serum calcium level in vivo. There are currently no effective tools for the regulation of parathyroid hormone secretion. Thus if WR2721 fulfills its early promise as being an agent effective in lowering serum calcium with virtually no other toxic effects as well as capable of inhibiting PTH release, it may achieve wide clinical use as a therapeutic tool in a variety of conditions.