This proposal seeks support to study a new class of drugs, iron chelating agents, in advanced cardiac life support to prevent late deaths and brain damage following successful cardiopulmonary resuscitation. The relevant biochemical hypothesis states that free iron, liberated from bound intracellular stores during or after ischemia, combines with superoxide ions and hydrogen peroxide during reperfusion to catalyze initiation of free radical reactions that cause tissue damage. Chelation of intracellular iron by deferoxamine (a commercially available drug, that distributes to the intracellular space and has an high affinity for iron ions) may prevent such reactions. We have developed a rat model of total circulatory arrest and resuscitation in which cardiac arrest of 5 to 10 min duration is followed by external CPR. In preliminary studies intravenous deferoxamine was given after restoration of the heartbeat, and long term survival was the endpoint. Ten day survival was 64% in the deferoxamine treated group vs. 36% survival in the control group, a statistically significant difference (X/2 = 3.92,df = 1,p greater than 0.05). Thus, deferoxamine prevented late deaths. Subsequently, we have repeated the study of deferoxamine with similar, statistically significant results, and we have tested the drug in other model systems of ischemia and reperfusion and demonstrated a protective effect. The proposed research will focus on identification of the optimal dose and timing of deferoxamine treatment, the safety (therapeutic index) of the drug when given following circulatory arrest, and its site and mechanism of action as revealed by light and electron microscopy and by biochemical assays for markers of tissue lipid peroxidation.
Showing the most recent 10 out of 16 publications
