Beclomethasone post exposure therapy for gastrointestinal acute radiation syndrom

倍氯米松照射后治疗胃肠道急性放射综合征

基本信息

批准号：
8314917
负责人：
Kevin James Horgan
金额：
$ 30万
依托单位：
SOLIGENIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8314917
关键词：
Acute Animal Model Autologous Bone Marrow Transplantation Beclomethasone Beclomethasone Dipropionate Biological Availability Blinded Bone Marrow Bone Marrow Transplantation Bypass Canis familiaris Cessation of life Development Disasters Dose Drug Evaluation Drug Formulations Drug Kinetics Effectiveness Evaluation Event Exposure to Fred Hutchinson Cancer Research Center Future Gastrointestinal Injury Gastrointestinal tract structure Glucocorticoids Gray unit of radiation dose Hematopoietic Hour Inflammatory Injury Intervention Ionizing radiation Licensure Low Dose Radiation Measures Modeling Molecular Target Nuclear Oral Pharmaceutical Preparations Pharmacotherapy Phase III Clinical Trials Placebo Control Preventive Radiation Radiation Injuries Radiation Syndromes Rodent Model Supportive care Syndrome Therapeutic Therapeutic Intervention Time Toxic effect Transplantation Whole-Body Irradiation Work animal rule body system clinically significant cytokine gastrointestinal graft vs host disease high risk improved irradiation mouse model nonhuman primate radiation effect research study

项目摘要

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).

描述（由申请人提供）：该提案涉及使用二丙酸倍氯米松（BDP）作为暴露后药物疗法，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 发生在有毒辐射暴露后，至少涉及多个器官系统，主要导致骨髓（造血 [HP] 综合征）和胃肠道毒性 (GI-ARS)。如果发生核灾难或恐怖分子核弹爆炸，暴露于 >2 戈瑞 (Gy) 的伤亡人员面临发生具有临床意义的 ARS 的高风险。暴露于超过 10-12 Gy 的高剂量辐射会导致急性胃肠道损伤，并可能在 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）后生存的主要决定因素。虽然致命的造血损伤可以通过骨髓移植和几种治疗药物来挽救，但对于高剂量辐射后发生的胃肠道损伤尚无治疗或预防措施。我们评估了二丙酸倍氯米松 (BDP)（一种粘膜活性糖皮质激素）的口服制剂作为缓解狗急性胃肠道综合征的治疗方法。证明在 GI-ARS 中进一步研究该药物的主要结果是，在致命性 TBI 后 2 小时开始接受 BDP 治疗的狗的生存获益。初步结果还表明 BDP 在 TBI 后 24 小时开始发挥功效。有了这个在应用中，我们建议对比格犬口服药物进行进一步评估，重点是在 TBI 后至少 24 小时进行干预。狗是重要的大型动物模型之一，将有助于确定 BDP（或其他药物）的功效，以便最终根据动物规则获得 FDA 许可。我们设想未来将在小鼠模型中进行研究，以完善 BDP 在 GI-ARS 中的推定机制，以及在非人类灵长类动物中进行口服 BDP 的研究。公共健康相关性：该提案涉及使用二丙酸倍氯米松 (BDP) 作为暴露后药物治疗，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。暴露于超过 10-12 Gy 的高剂量辐射会导致急性胃肠道损伤，并可能在 5-10 天内导致死亡。在这个项目中，我们建议对比格犬口服 BDP 进行评估，重点是在致死性全身照射 (TBI) 后至少 24 小时进行干预。