Parathyroid Hormone in Prevention and Mitigation of Thrombocytopenia

描述（由申请人提供）：在辐射事件发生后，暴露于0.7-10 Gy的个体将发展为造血综合征，其中骨髓的辐射损伤将导致贫血，血小板减少和中性粒细胞减少引起的感染性并发症。该综合征的有效治疗方案的一部分包括输血，但据估计，目前的血液制品供应，特别是血小板的供应需要增加1300倍，才能满足一个主要大都市地区患者的需求。另一种方法是开发一种策略来增加患者自身的血小板生成。我们现在报告了一个以前未被认识到的甲状旁腺激素（PTH）在减轻化疗骨髓消融后血小板减少症中的作用。我们对猕猴非人灵长类动物的研究表明，PTH在开始每日治疗7天后显著增加血小板计数，效应大小在1.3到2.0之间。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)确定人类PTH （hPTH）减轻或预防辐射引起的血小板减少的能力，2)在一种动物物种中证明有效性，期望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)利用动物研究结果测量基于用于检测人类有效性的相同指标，包括血小板减少持续时间，血小板最低水平和恢复时间（>20,000/¿l）。所研究的血小板减少的持续时间将是放射剂量导致30天内30%致死率（LD30/30）或30天内95%致死率（LD95/30）后的前30天。4)将确定药代动力学和药效学，以便选择人体有效剂量。甲状旁腺激素经FDA批准，可在市场上购买，理论上可以立即纳入国家战略储备。如果本文提出的研究，按照cGLP的规定进行，证明辐射引起的血小板减少症有显著改善，将有大量证据表明，将甲状旁腺激素作为一种治疗干预措施，预防急性辐射暴露后的主要发病率。在一次辐射事件之后，治疗放射病所需的血液制品，特别是血小板的数量预计将超过现有的国家资源。我们已经观察到甲状旁腺激素可以增加人体自身干细胞和血小板的供应，并建议测试这种药物以确定达到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，并有可能应用于骨髓移植受者和其他血小板和干细胞计数不够低的疾病。

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.