Abstract
HE2100 (androst-5-ene-3β,17β-diol) is a naturally occuring adrenal steroid hormone that exhibits a relatively weak interaction with the androgen receptor, estrogen receptor-α and estrogen receptor-β but not the glucocorticoid receptor. We previously reported (
Blood [2003] 1002;20
) that subcutaneous HE2100 administration (daily for 10 days) eliminated severe neutropenia in rhesus macaques exposed to 400 cGy 60Co total body irradiation (TBI). The current study utilized the same model of myelosuppression in rhesus macaques and evaluated the activity of HE2100 when administered as a depot-type preparation on duration of Grade 4 neutropenia (<500/μL, G4 Neut), at least Grade 3 thrombocytopenia (<50,000/μL, G3 Thromb) and Grade 4 anemia (<6.5 g/dL, G4 Anemia). Blood was analysed daily during the cytopenic phase and approximately every three days at other times through Day 35 (irradiation Day 1) to minimize the effect of phlebotomy. HE2100 (15 mg/kg) was administered by daily intramuscular injection for 5 days (Regimen 5d-IM), by four once-weekly intramuscular injections (Regimen 1w-IM) or by four once-weekly subcutaneous injections (Regimen 1w-SQ). The first dose for all regimens was administered 2 to 4 hours after TBI. All groups comprised of 2 male and 1 female young adult rhesus macaques with the exception of the vehicle group (2 males and 2 females). Vehicle-treated animals experienced on average G4 Neut, G3 Thromb and G4 Anemia for 11.8, 3.5 and 4.0 days, respectively. Animals treated by 5d-IM experienced on average 2.7 days of G4 Neut, 0 days of G3 Thromb and 0 days of G4 Anemia. The values for Regimens 1w-IM and 1w-SQ were 6.0 and 4.5 days (G4 Neut), 0.3 and 0.3 days (G3 Thromb) 0 and 0 days (G4 Anemia), respectively. These results indicate that HE2100 depot-type preparations delivered by either 4 or 5 SQ or IM injections substantially reduced the duration of severe neutropenia following 400 cGy TBI. Major morbidity or mortality associated with acute Hematopoietic Syndrome is believed to result from sepsis associated with severe neutropenia. Hence it is possible that HE2100 would protect against acute Hematopoietic Syndrome-related major morbidy or mortality. The contribution of thrombocytopenia or severe anemia to Hematopoietic Syndrome-related major morbidity or mortality is unknown but it is possible that HE2100-mediated protection of these blood elements might be beneficial by, for example, reducing tissue hypoxia. In conclusion, HE2100 affords significant protection as a countermeasure to TBI in rhesus macaques. There is an umet medical need for a cost-effective countermeasure for acute Hematopoietic Syndrome that may result from exposure to a nuclear event. It is possible that the protection seen in rhesus macaques may extend to man.Author notes
Corresponding author
2005, The American Society of Hematology
2004
