HE2100 (androst-5-ene-3β, 17β-diol), an Adrenal Hormone, Protects Rhesus Macaques from Lethal Total Body Irradiation (TBI)- Induced Severe Neutropenia and Thrombocytopenia.

HE2100 (androst-5-ene-3,17β-diol) is a naturally occurring adrenal steroid hormone being developed for the treatment of acute radiation syndrome (ARS). Previous studies of lethally irradiated rodents demonstrated a significant survival advantage for HE2100 treated groups (Whitnall et. al., Int. J. Immunopharm. 2000). In HE2100 treated rhesus macaques we have previously reported a tri-lineage recovery (neutrophils, platelets and red blood cells) of bone marrow following sublethal irradiation and a reduction in lethality following 6.00 Gy ⁶⁰Co TBI. Studies were conducted to further investigate the effects of this compound to prevent very severe radiation induced cytopenias and to enhance survival following TBI. Results refer to absolute neutrophil count <500 cells/μL and platelet count <20,000 platelets/μL. We report a meta-analysis of five studies involving 100 animals receiving TBI in the range of 6.00 – 6.34 Gy ⁶⁰Co. Animals were either untreated, or given vehicle, or 5–15 mg/kg of HE2100 IM for 5 consecutive days starting 2–3 hours after TBI. No clinical support such as transfusions or antibiotics was given in any of the studies. Animals were continuously monitored for core body temperature with an implanted telemetric thermometer. Blood counts were measured daily during expected cytopenic days. Studies were performed after Institutional Animal Care and Use Committee review and approval, observing strict euthanasia criteria. HE2100 afforded protection of the unsupported animals from lethal irradiation, decreasing the lethality overall, from 42% in the control group to 22% in the HE2100 treated group (mid-p=0.044). All deaths occurred between Study Days 14 and 26. The majority of animals (28/32, 87.5%) died by Study Day 20 reflective of ARS. Based on an analysis of days at risk, the cumulative incidence of days of severe neutropenia was reduced by 1.10 days (p=0.002), whereas the cumulative incidence of days of thrombocytopenia was reduced by 2.31 days (p=0.02). No cytopenias were recorded after Study Day 26 on surviving animals. Death in these animals correlated with severe thrombocytopenia and opportunistic infections from the gut and skin flora leading to hemorrhagic sepsis as the primary cause. HE2100-related increases in cellularity were noted in the bone marrow, spleen, and lymph nodes on Study Day 40. HE2100 appears to stimulate multi-lineage recovery, via early bone marrow hematopoietic stem cell progenitors following TBI injury in rhesus macaques.