Abstract

Background

High dose ionizing radiation exposure is associated with myelo-depression leading to pancytopenia and the expected clinical manifestations of acute radiation syndrome (ARS). Herein, we evaluated the efficacy of sargramostim (Leukine^®, yeast-derived rhu GM-CSF), with regimens delivered at 48, 72, 96, or 120 h after radiation exposure.

Methods

A randomized and blinded nonhuman primate (NHP) study was conducted to assess the effects of sargramostim treatment on ARS. NHPs were exposed to total body radiation (LD_83/60 or lethal dose 83% by Day 60) and were randomized to groups receiving daily subcutaneous dosing of sargramostim starting from either 48, 72, 96, or 120 h post-irradiation. Additionally, separate groups receiving sargramostim treatment at 48 h post-irradiation also received prophylactic treatment with azithromycin. Sargramostim treatment of each animal continued until the preliminary absolute neutrophil count (ANC) returned to ≥1000/μL post-nadir for three consecutive days or the preliminary ANC exceeded 10,000/μL, which amounted to be an average of 15.95 days for all treatment groups. Prophylactic administration of enrofloxacin was included in the supportive care given to all animals in all groups. All animals were monitored for 60 days post-irradiation for mortality, hematological parameters, and sepsis.

Results

Delayed sargramostim treatment at 48 h post-irradiation significantly reduced mortality (p = .0032) and improved hematological parameters including neutrophil but also lymphocyte and platelet counts. Additional delays in sargramostim administration at 72, 96, and 120 h post-irradiation were also similarly effective at enhancing the recovery of lymphocyte, neutrophil, and platelet counts compared to control. Sargramostim treatment also improved the survival of the animals when administered at up to 96 h post-irradiation. While sargramostim treatment at 48 h significantly reduced mortality associated with sepsis (p ≤ .01), the additional prophylactic treatment with azithromycin did not have clinically significant effects.

Conclusion

In a NHP ARS model, sargramostim administered starting at 48 h post-radiation was effective to improve survival, while beneficial hematological effects were observed with sargramostim initiated up to 120 h post exposure.

中文翻译：

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在非人灵长类全身辐射模型中暴露后 120 小时延迟施用沙格莫司亭的疗效

摘要

背景

高剂量电离辐射暴露与骨髓抑制有关，导致全血细胞减少症和急性放射综合征（ARS）的预期临床表现。^{在此，我们评估了沙格司亭（Leukine ®} ，酵母衍生的 rhu GM-CSF）的疗效，并在辐射暴露后 48、72、96 或 120 小时提供治疗方案。

方法

进行了一项随机盲法非人灵长类动物 (NHP) 研究，以评估沙格司亭治疗对 ARS 的影响。NHP 暴露于全身辐射（LD _83/60或第 60 天的致死剂量 83%），并随机分为从辐射后 48、72、96 或 120 小时开始每日皮下注射沙格司亭的组。此外，在照射后 48 小时接受沙格司亭治疗的不同组还接受了阿奇霉素的预防性治疗。每只动物持续进行沙格司亭治疗，直至初步绝对中性粒细胞计数（ANC）连续三天恢复到最低点后≥1000/μL，或初步ANC超过10,000/μL，所有治疗组平均15.95天。恩诺沙星的预防性给药包含在对所有组中所有动物的支持性护理中。照射后 60 天监测所有动物的死亡率、血液学参数和败血症。

结果

照射后 48 小时延迟沙格司亭治疗可显着降低死亡率 ( p  = .0032)，并改善血液学参数，包括中性粒细胞、淋巴细胞和血小板计数。与对照相比，在照射后 72、96 和 120 小时额外延迟沙格司亭给药对于增强淋巴细胞、中性粒细胞和血小板计数的恢复也同样有效。在照射后 96 小时内进行沙格莫司亭治疗还可以提高动物的存活率。虽然沙格司亭治疗 48 小时显着降低了脓毒症相关死亡率 ( p  ≤ .01)，但阿奇霉素的额外预防性治疗并未产生临床显着效果。

结论

在 NHP ARS 模型中，从辐射后 48 小时开始施用沙格莫司亭可有效提高生存率，而在辐射后 120 小时开始施用沙格莫司亭，观察到有益的血液学效应。