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WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock

Cristofaro, Patricia A. MD; Opal, Steven M. MD; Palardy, John E. BA; Parejo, Nicolas A. BA; Jhung, Jhung MD; Keith, James C. Jr DVM; Harris, Heather A. PhD

doi: 10.1097/01.CCM.0000227173.13497.56
Laboratory Investigations

Objective: To determine the effect of an estrogen receptor-β selective agent in experimental models of systemic infection and sepsis.

Design: WAY-202196, a nonsteroidal selective estrogen receptor-β agonist, was tested in the murine listeriosis model, the neutropenic rat Pseudomonas aeruginosa infection, and the mouse cecal ligation and puncture sepsis models.

Setting: University-affiliated biomedical research laboratory.

Subjects: BALB/c mice and Sprague-Dawley rats.

Interventions: WAY-202196 or control (vehicle) was administered orally in doses ranging from 1.5 to 50 mg/kg at various time points in the three experimental model systems.

Measurements and Main Results: Susceptibility of mice treated with a single oral dose of up to 50 mg/kg WAY-202196 did not differ from those treated with vehicle alone after systemic challenge by Listeria monocytogenes, suggesting a lack of generalized immunosuppression. In the neutropenic rat model, daily administration of WAY-202196 (50 mg/kg) significantly increased survival against an otherwise lethal challenge of P. aeruginosa 12.4.4 compared with the control group (83% vs. 25% survival; p < 0.05). Preservation of intestinal mucosal weight and prevention of histopathologic changes were also observed with the administration of WAY-202196. Similar results were obtained in a cecal ligation and puncture model, in which multiple oral doses of WAY-202196 (50 mg/kg) improved survival (83% vs. 0%; p < 0.05), preserved intestinal epithelial integrity, and significantly reduced systemic bacteremia and peritoneal interleukin-6 and tumor necrosis factor levels. The estrogen receptor-β agonist provided a comparable level of protection in both male and female animals.

Conclusion: These results indicate that oral administration of WAY-202196 preserved gastrointestinal barrier function and improved outcome in experimental models of systemic infection and inflammation. WAY-202196 and similar agents may prove useful clinically as a novel treatment strategy for the treatment or prevention of severe sepsis.

From the Infectious Disease Division, Memorial Hospital of Rhode Island, Brown Medical School, Providence, RI (PAC, SMO, JEP, NAP, JJ); Cardiovascular and Metabolic Diseases, Wyeth Research, Cambridge, MA (JCK); and Women’s Health Research Institute, Wyeth Research, Collegeville, PA (HAH).

Presented, in part, at the 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Meeting, Washington, DC, October 30 to November 2, 2004 (abstract B-792).

Dr. Opal received grants from Wyeth Labs and Chiron; Dr. Keith is a full-time employee of Wyeth Research, owns stock and has stock options in the company, and holds patents under Wyeth Research; Dr. Harris is a full-time employee of Wyeth Research and has a patent application filed; Dr. Cristofaro, Dr. Jhung, Mr. Parejo, and Mr. Palardy have not disclosed any potential conflicts of interest.

Supported, in part, by Wyeth Research.

© 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins