Parathyroid Hormone in Prevention and Mitigation of Thrombocytopenia

描述（由申请方提供）：辐射事件后，暴露于0.7-10戈伊的个体将出现造血综合征，其中骨髓的辐射损伤将导致贫血、血小板减少症和中性粒细胞减少引起的感染并发症。这种综合征的有效治疗方案包括输血，但据估计，目前的血液制品供应，特别是血小板，需要增加1,300倍，以满足主要大都市地区的患者需求。另一种方法是开发一种增加患者自身血小板生成的策略。我们现在报告一个以前未认识到的作用，甲状旁腺激素（PTH）减轻血小板减少化疗骨髓消融术。我们在猕猴非人灵长类动物中的研究显示，PTH在开始每日治疗后7天显著增加血小板计数，效应量范围为1.3至2.0。基于这些数据，我们建议扩展我们的研究，以满足FDA对动物规则的要求，目标如下：1）确定人PTH（hPTH）减轻或预防辐射诱导的血小板减少症的能力，2）在一种动物物种中证明功效，预期成功的结果将为未来的非人灵长类动物研究提供适当的设计，3）使用动物研究结果测量，其基于用于检测人类疗效的相同指标，包括血小板减少持续时间、血小板最低值和恢复时间（> 20，000/L）。研究的血小板减少症持续时间将是导致30天30%致死率（LD 30/30）或30天95%致死率（LD 95/30）的辐射剂量后的前30天。4)将确定药代动力学和药效学，以选择人体有效剂量。PTH是由FDA批准的，商业上可用，理论上，可以立即放入战略国家储备。如果根据cGLP法规进行的本文拟定的研究证明辐射诱导的血小板减少症有显著改善，则将有大量证据证明PTH作为预防急性辐射暴露后主要发病率的治疗干预。在发生辐射事故后，治疗辐射病所需的血液制品，特别是血小板的数量预计会增加，超出现有的国家资源。我们已经观察到甲状旁腺激素可以增加人体自身的干细胞和血小板供应，并建议测试这种药物以确定这种效果的最佳剂量。这些研究的结果将提高我们对如何增加人体自身血细胞的认识，并可能应用于骨髓移植受者和血小板和干细胞计数不足的其他疾病。

DESCRIPTION (provided by applicant): Following a radiation incident, individuals exposed to 0.7-10 Gy will develop the hematopoietic syndrome, in which radiation injury to the bone marrow will lead to anemia, thrombocytopenia, and infectious complications due to neutropenia. Part of an effective treatment regimen for this syndrome includes blood transfusions, however it is estimated that the current supply of blood products, especially platelets, would need to increase 1,300 fold to address the patient needs of a major metropolitan area. An alternative approach would be the development of a strategy to increase the patient's own platelet production. We now report a previously unrecognized role for parathyroid hormone (PTH) on mitigating thrombocytopenia following chemotherapeutic myeloablation. Our studies in macaque nonhuman primates show PTH to significantly increase platelet counts 7 days after beginning daily therapy with an effect size ranging from 1.3 to 2.0. Based on these data, we propose to extend our studies to address the FDA requirements of the animal rule in the following objectives: 1) Determine the ability of human PTH (hPTH) to mitigate or prevent radiation-induced thrombocytopenia, 2) Demonstrate efficacy in one animal species with the anticipation that successful results would provide the appropriate design for future nonhuman primate studies, 3) Utilize animal study outcome measures which are based on the same indicators used to detect efficacy in humans including duration of thrombocytopenia, platelet nadir, and time to recovery (>20,000/¿l). The duration of thrombocytopenia studied will be the first 30 days following a radiation dose resulting in 30% lethality by 30 days (LD30/30) or 95% lethality by 30 days (LD95/30). 4) Pharmacokinetics and pharmacodynamics will be determined to allow selection of an effective dose in humans. PTH is approved by the FDA, commercially available, and theoretically, could be immediately placed into the Strategic National Stockpile. Should the studies proposed herein, performed according to cGLP regulations, demonstrate significant improvement in radiation-induced thrombocytopenia, there will be substantial evidence to pursue PTH as a therapeutic intervention in the prevention of major morbidity following acute radiation exposure. Following a radiation incident, the amount of blood products, particularly platelets, required for treatment of radiation sickness is projected to increase beyond the available national resources. We have observed parathyroid hormone to increase the body's own supply of stem cells and platelets and propose testing this drug to determine the best dose for such an effect. Results of these studies will improve our knowledge of how to increase the body's own blood cells and can potentially be applied to bone marrow transplant recipients and other diseases in which platelet and stem cell counts are inadequately low.