Evaluation of Premarin in a Rat Model of Mild and Severe Hemorrhage

摘要

This report details a cumulative account of our research findings for the DARPA SBL program. Our rat model system enabled us to assess the effects of various soluble estrogens (cyclodextrin microencapsulate 17beta- estradiol E2), sulfate conjugated E2, Premarin and ethynylestrogen-3-sulfate EE-3-SO4, the formulation of choice. EE-3-SO4 has also been selected for IND application. For E2 we evaluated optimum doses and routes of entry, determining by pharmacokinetics that a 1 mg/kg dose delivered via intravenous or intraosseous routes was optimal. The high efficacy of E2-SO4 and EE-3-SO4, precluded combinatorial testing with other drugs as being difficult to evaluate and nonproductive. The mode of action for E2-SO4 with severe hemorrhage was evaluated with several techniques. MRI revealed that ATP production following E2 treatment was maintained at a level to sustain life, as was the prevention of lowered intracellular pH. SPECT-CT confirmed the enhancement of cardiac performance with E2 treatment, a finding corroborated by positive dP/dT measurements. Cardiovascular benefits from E2-SO4 and EE-3-SO4 treatment were also demonstrated in vitro with isolated vascular rings, confirming reduced vascular resistance.