Beclomethasone post exposure therapy for gastrointestinal acute radiation syndrom

描述(由申请人提供)：本提案涉及使用倍氯米松二丙酸酯(BDP)作为暴露后药物治疗，有可能减轻暴露于强烈电离辐射后与急性辐射综合征(ARS)相关的胃肠道(GI)损伤。急性呼吸窘迫综合征发生在有毒辐射暴露后，涉及至少几个器官系统，主要导致对骨髓(造血性[HP]综合征)和胃肠道(GI-ARS)的毒性。在发生核灾难或恐怖分子引爆核弹的情况下，暴露于~gt；2格雷(Gray)的伤亡人员患上具有临床意义的急性呼吸窘迫综合征的风险很高。暴露在超过10-12GY的大剂量辐射下会导致急性胃肠道损伤，可在5-10天内导致死亡。因此，骨髓和胃肠道的损伤程度是全身照射(TBI)后存活的主要决定因素。虽然骨髓移植和几种治疗药物可以挽救致命性的造血损伤，但对于大剂量辐射后发生的胃肠道损伤，尚无治疗或预防措施。我们评价了一种口服二丙酸倍氯米松(BDP)的制剂，它是一种粘膜活性糖皮质激素，用于治疗犬的急性胃肠道综合征。在GI-ARS中进一步研究这种药物的主要结果是，在致命性脑损伤后2小时开始接受BDP治疗的狗的生存受益。初步结果还表明，BDP的疗效始于脑损伤后24小时。有了这个 为了更好地应用，我们建议对Beagle犬的口服药物进行进一步的评估，重点是在创伤性脑损伤后至少24小时进行干预。狗是关键的大型动物模型之一，它将有助于建立BDP(或其他药物)的疗效，以根据动物规则最终获得FDA的许可。我们展望了未来将在小鼠模型上进行的关于GI-ARS中BDP推定机制的改进的研究，以及在非人类灵长类动物中口服BDP的研究。 公共卫生相关性：这项建议涉及使用倍氯米松二丙酸酯(BDP)作为暴露后药物治疗，有可能减轻暴露于强烈电离辐射后与急性辐射综合征(ARS)相关的胃肠道(GI)损伤。暴露在超过10-12GY的大剂量辐射下会导致急性胃肠道损伤，可在5-10天内导致死亡。在这个项目中，我们建议对Beagle犬口服BDP进行评估，重点是在致命性全身照射(TBI)后至少24小时进行干预。

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).