Beclomethasone post exposure therapy for gastrointestinal acute radiation syndrom

描述（由申请方提供）：本提案涉及二丙酸倍氯米松（BDP）作为暴露后药物治疗的用途，其有可能减轻暴露于强电离辐射后与急性辐射综合征（ARS）相关的胃肠道（GI）损伤。ARS发生在毒性辐射暴露后，并涉及至少几个器官系统，主要导致骨髓（造血[HP]综合征）和GI（GI-ARS）毒性。在核灾难或恐怖分子引爆核弹的情况下，暴露于>2戈瑞（戈伊）的伤亡人员发生临床显著ARS的风险很高。暴露于超过10-12戈伊的高剂量辐射会引起急性胃肠道损伤，可导致5-10天内死亡。因此，骨髓和胃肠道的损伤程度是全身照射（TBI）后生存的主要决定因素。虽然骨髓移植和几种治疗药物可以挽救致命的造血损伤，但对于高剂量辐射后发生的胃肠道损伤没有治疗或预防措施。我们评价了二丙酸倍氯米松（BDP）（一种粘膜活性糖皮质激素）的口服制剂作为犬缓解急性GI综合征的治疗方法。证明该药物在GI-ARS中进一步研究的主要结果是在致死性TBI后2小时开始接受BDP治疗的犬中的生存获益。初步结果还表明BDP的功效从TBI后24小时开始。与此 在申请中，我们建议在比格犬中进一步评估口服药物，重点是TBI后至少24小时的干预。犬是重要的大型动物模型之一，将有助于确定BDP（或其他药物）的疗效，以便根据动物规则最终获得FDA许可。我们设想未来的研究将在小鼠模型中进行，以完善BDP在GI-ARS中的假定机制，威尔斯在非人灵长类动物中口服BDP的研究。 公共卫生相关性：该提案涉及使用二丙酸倍氯米松（BDP）作为暴露后药物治疗，其具有减轻暴露于强电离辐射后与急性辐射综合征（ARS）相关的胃肠道（GI）损伤的潜力。暴露于超过10-12戈伊的高剂量辐射会引起急性胃肠道损伤，可导致5-10天内死亡。在本项目中，我们建议评价比格犬经口给予BDP，重点是致死性全身照射（TBI）后至少24小时的干预。

DESCRIPTION (provided by applicant): This proposal concerns the use of beclomethasone dipropionate (BDP) as a post-exposure drug therapy having the potential to mitigate the gastrointestinal (GI) injury associated with acute radiation syndrome (ARS) following exposure to intense ionizing radiation. ARS occurs after toxic radiation exposure and involves at least several organ systems, primarily resulting in toxicity to the bone marrow (hematopoietic [HP] syndrome) and the GI (GI-ARS). In the event of a nuclear disaster or terrorist detonation of a nuclear bomb, casualties exposed to >2 Gray (Gy) are at high risk for development of clinically significant ARS. Exposure to high doses of radiation exceeding 10-12 Gy causes acute gastrointestinal injury which can result in death in 5-10 days. Thus, the extent of injury to the bone marrow and the GI tract are the principal determinants of survival after exposure to total- body irradiation (TBI). Although lethal hematopoietic injury can be rescued by bone marrow transplantation and several therapeutic drugs, there is no treatment or preventive measure for GI damage that occurs after high dose radiation. We evaluated an oral formulation of beclomethasone dipropionate (BDP), a mucosally active glucocorticoid, as a treatment of dogs to mitigate acute GI syndrome. The primary result that justifies further study of this drug in the GI-ARS is the survival benefit in dogs that have received BDP therapy starting 2 hours following lethal TBI. Preliminary results also suggest BDP efficacy starting at 24 hours after TBI. With this application, we are proposing further evaluation of the oral drug in beagle dogs with a focus on intervention at least 24 hours after TBI. The dog is one of the crucial large animal models that will aid in establishing efficacy of BDP (or other drugs) for eventual FDA licensure under the Animal Rule. We envision future studies that would occur in mouse models on refinement of the putative mechanisms of BDP in GI-ARS, as wells as studies of orally administered BDP in non-human primates. PUBLIC HEALTH RELEVANCE: This proposal concerns the use of beclomethasone dipropionate (BDP) as a post-exposure drug therapy having the potential to mitigate the gastrointestinal (GI) injury associated with acute radiation syndrome (ARS) following exposure to intense ionizing radiation. Exposure to high doses of radiation exceeding 10-12 Gy causes acute gastrointestinal injury which can result in death in 5-10 days. In this project, we are proposing evaluation of orally administered BDP in beagle dogs with a focus on intervention at least 24 hours after lethal total body irradiation (TBI).