Parathyroid Hormone in Prevention and Mitigation of Thrombocytopenia

描述(申请人提供)：在发生辐射事故后，受到0.7-10Gy射线照射的个人会发展成造血综合征，骨髓受到辐射损伤会导致贫血、血小板减少和中性粒细胞减少引起的感染性并发症。这种综合征的有效治疗方案的一部分包括输血，然而，据估计，目前的血液产品供应，特别是血小板，将需要增加1300倍，以满足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己的血小板生成。我们现在报告甲状旁腺激素(PTH)在减轻化疗骨髓清除术后的血小板减少中的先前未知的作用。我们在猕猴非人类灵长类动物中的研究表明，甲状旁腺素在开始每日治疗7天后显著增加血小板计数，作用大小从1.3到2.0不等。基于这些数据，我们建议扩大我们的研究，以满足FDA对动物规则的以下目标的要求：1)确定人甲状旁腺激素(HPTH)缓解或预防放射性血小板减少症的能力；2)在一种动物物种上展示有效性，预计成功的结果将为未来的非人类灵长类动物研究提供适当的设计；3)利用动物研究结果指标，该指标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、血小板最低值和恢复时间(&gT；20,000/岁L)。研究的血小板减少的持续时间将是放射剂量后的第一个30天，30天前导致30%的致死率(LD30/30)或30天前95%的致死率(LD95/30)。4)将确定药代动力学和药效学，以便在人体上选择有效剂量。PTH获得了FDA的批准，可以商业化使用，理论上可以立即纳入国家战略储备。如果本文建议的研究根据cGLP法规进行，证明辐射引起的血小板减少症有显著改善，将有大量证据表明甲状旁腺素作为预防急性辐射暴露后主要发病率的治疗干预措施。在发生辐射事件后，治疗辐射病所需的血液产品，特别是血小板的数量预计将增加，超出国家现有资源的范围。我们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，并建议对这种药物进行测试，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了解，并有可能应用于骨髓移植接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.