? Our objective is to develop a new treatment that will prevent or decrease the tissue damage caused by neutrophil infiltration after ischemia/reperfusion (I/R), which occurs as the result of stroke, coronary ischemia, trauma and other related conditions. Compounds called selectins play an important role in this neutrophil-mediated injury. Drugs currently available for treatment have not resulted in optimal protective effects during clinical application. Preliminary studies in our laboratories already indicated that a recently discovered synthetic drug, TBC-1269, which acts as a selectin blocker, provides protection against tissue damage in rats subjected to severe liver ischemia/reperfusion. Our results from the completed Phase I feasibility studies (see Final Report in section C) indicated that TBC-1269 was significantly protective when given at the time of reperfusion and at a dose of 40 mg/kg, for animals undergoing severe (90 min) liver ischemia. Functional and histological parameters remained near-normal in animals receiving TBC-1269. During this proposed Phase II grant, we will expand our study of TBC-1269 to more precisely determine 1) the correct time and dosing for maximum drug effectiveness; 2) to compare the therapeutic value of TBC-1269 to other selectin blockers and selectin knockouts; 3) to evaluate the benefits of adding other drugs, such as anti-integrin beta 2-/alpha 4- and anti-TNF-alpha, to the treatment plan; and, 4) to examine potential cell signalling mechanisms (MAPK cascade). Results of this innovative study could significantly improve the clinical outcome for patients at risk for suffering from ischemial/reperfusion injuries. Treatment with TCB-1269 will enhance the quality of life of millions of patients suffering from the large number of maladies associated with ischemia/reperfusion ischemic maladies. ? ?
