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NIH awards SUNY Upstate Medical University $719,000 for drug study

Study aimed at finding drug to prevent sepsis or sepsis-induced acute respiratory distress syndrome

SYRACUSE, N.Y.-Researchers at SUNY Upstate Medical University are embarking on the second phase of study funded by the National Institutes of Health to confirm the effectiveness of a modified tetracycline, COL-3, in preventing sepsis-induced acute respiratory distress syndrome (ARDS) and sepsis/sepsis shock in animal models. Sepsis and sepsis-induced ARDS are potentially fatal disorders in humans. The study also hopes to determine the appropriate time that the medication can be given to prevent the onset of the two disorders in the animal models. Successful results from the Phase II study may lead to testing of the drug in humans within the next few years.

Sepsis and sepsis-induced ARDS are two common yet potentially fatal disorders. Currently there are no FDA-approved drugs that have been shown to prevent sepsis or sepsis-induced ARDS or to decrease the morbidity and mortality effects of the disorders in humans.

"Sepsis is a severe blood infection that causes inflammation and often leads to septic shock and multiple organ failure," said one of the study's co-investigators, Charles Lutz, assistant professor of surgery. "It is a leading cause of death in intensive care units and the major precursor to the development of ARDS. ARDS develops following a pro-inflammatory event such as sepsis or a trauma to the body."

The $719,000 two-year grant was awarded through NIH's Small Business Technology Transfer (STTR) fund, created to bring medical products to market. SUNY Upstate is collaborating on the project with CollaGenex Pharmaceuticals Inc. in Newton Pa.; SUNY Stony Brook; and the University of Texas Medical Branch at Galveston. If the study is successful, SUNY Upstate will hold the patents on the medication for use in the prevention of sepsis/sepsis shock and sepsis-induced ARDS.

SUNY Upstate's participation in the study "Modified Tetracycline Effects on Sepsis-Induced Mortality," is conducted through the Department of Surgery. Study co-investigators, in addition to Lutz, are David Carney, M.D., clinical assistant professor of surgery; and Gary Nieman, research assistant professor of surgery. Robert Ploutz-Snyder, Ph.D., a biostatician with SUNY Upstate's Outcomes Research and Evaluation Center, serves as a study statistician.

According to Lutz, while COL-3's properties no longer kill bacteria, they have a potent anti-inflammatory effect."COL-3 is an effective anti-inflammatory agent that has a low toxicity profile and is relatively inexpensive," said Lutz. "These qualities make it an excellent candidate for prophylactic administration in patients at high risk for developing septic shock and/or ARDS, due to injuries such as severe trauma, pancreatitis, major burns, aspiration, pneumonia, multiple transfusions, cardiopulmonary bypass, smoke inhalation and septicemia. In fact it may prove to be the only effective means to date of decreasing the morbidity and mortality of septic shock and ARDS."

Results from the Phase I study conducted in 2003 at SUNY Upstate and also funded through a one-year, $100,000 NIH-STTR grant, provided evidence of the drug's promise in preventing sepsis and sepsis-induced ARDS in animal models. In this study the team developed a sophisticated model in pigs that was very close to sepsis-induced ARDS.

"We successfully developed a model of the disease that resulted in ARDS in all animals within 48 hours," said Nieman. "We found that COL-3 administration prior to injury in our control group completely prevented the development of ARDS. An unexpected and exciting effect of COL-3 administration was also the prevention of the development of septic shock."

In the Phase II study, the team will reduce the level of impurities in the drug and refine analytical methods. Researchers will also test the efficacy of COL-3 at preventing septic shock and sepsis-induced ARDS in pigs immediately following injury and again at 24 hours following injury to establish the treatment window for the Phase III clinical trial. A third goal of the study is to determine if COL-3 improves ten-day survival in a model of ovine primary ARDS caused by smoke inhalation or burn.

"Our objective is to demonstrate the COL-3 reduces mortality and ventilator-dependent days in a clinically applicable model of primary ARDS," Nieman said. "We hope to establish that COL-3 is effective in treating primary ARDS and in reducing not only morbidity but also mortality."