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.
