Evaluation of Premarin in a Rat Model of Mild and Severe Hemorrhage
Abstract
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. The rings were also used to confirm that the relaxation was mediated by nitric oxide. Finally, it appears that steroid sulfatases are not involved in activating E2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 04, 2013
- Accession Number
- ADA607483
Entities
People
- Irshad H. Chaudry
- William J. Hubbard
Organizations
- University of Alabama