First human studies with a high-molecular-weight iron chelator

The release of free, reactive iron from cellular iron stores has been impli cated as an important contributor to tissue damage in a variety of clinical situations, including ischemia and reperfusion injury, hemorrhagic shock, and burn injury. Deferoxamine mesylate (DFO), the only iron chelator curren tly approved for clinical use, is used for the treatment of iron overload, including acute iron poisoning and treatment of chronic iron overload in tr ansfusion-dependent anemias such as P-thalassemia, However, it is not suita ble for acute care situations because of its toxicity, primarily hypotensio n when given at high intravenous doses, and its short plasma half-life. We have produced a high-molecular-weight iron chelator by chemically coupling DFO to hydroxyethyl starch. This novel chelator (HES-DFO) was administered to healthy mole subjects by intravenous infusion over a 4-hour period. The drug was well tolerated, and signs of DFO acute toxicity were not observed. Maximum plasma chelator levels of approximately 3 mmol/L were achieved wit h HES-DFO, which is more than an order of magnitude higher than has been re ported with injections of DFO. Drug residence time in plasma was markedly p rolonged, with an initial half-life of 22 to 33 hours. Urinary iron excreti on wets 7.1 +/- 2.2 mg in 48 hours in the highest dose group, as compared w ith 0.06 +/- 0.15 mg in control subjects who received normal saline infusio ns. Intravenous infusion of HES-DFO is well tolerated, produces substantial and prolonged plasma chelator levels, and markedly stimulates urinary iron excretion.