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

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Abstract

The release of free, reactive iron from cellular iron stores has been implicated 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 currently approved for clinical use, is used for the treatment of iron overload, including acute iron poisoning and treatment of chronic iron overload in transfusion-dependent anemias such as β-thal-assemia. However, it is not suitable for acute care situations because of its toxicity, primarily hypotension 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 male 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 with HES-DFO, which is more than an order of magnitude higher than has been reported with injections of DFO. Drug residence time in plasma was markedly prolonged, with an initial half-life of 22 to 33 hours. Urinary iron excretion was 7.1 ± 2.2 mg in 48 hours in the highest dose group, as compared with 0.06 ± 0.15 mg in control subjects who received normal saline infusions. Intravenous infusion of HES-DFO is well tolerated, produces substantial and prolonged plasma chelator levels, and markedly stimulates urinary iron excretion. (J Lab Clin Med 2000;135:57-65)

Section snippets

Test materials

HES-DFO was manufactured according to current Good Manufacturing Practices.42 The drug consists of hydroxyethyl starch to which deferoxamine is covalently conjugated according to published methods.38 The resulting compound is a high-molecular-weight iron chelator with a basic structure as shown in Fig 1.

. Molecular structure of HES-DFO.

It is polydisperse, with an average molecular weight of approximately 80,000. Eighty percent of the drug is between 14,000 and 200,000 in molecular weight. The

Clinical signs

All drug doses were well tolerated. There were no serious adverse reactions, and all subjects completed the trial.

No effects on blood pressure were observed at any dose of HES-DFO administered (see Fig 2 for results from the highest dose group).

. Blood pressures from the subjects receiving HES-DFO in group 4 (9 mL/kg dosing level). Shown are the mean systolic (closed squares ) and diastolic (open squares ) blood pressure measurements for this group of subjects. Bars show the standard deviations.

Discussion

The vascular retention of HES-DFO is strikingly different from that of DFO, the only iron chelator approved for clinical use. Lee et al39 reported an initial DFO half-life of approximately 17 minutes after a 24-hour intravenous infusion in patients with thalassemia, followed by a slower phase with a half-life of 3.05 hours. Summers et al40 reported a plasma half-life of 5 to 10 minutes in normal subjects. HES-DFO, on the other hand, decays to half its peak value in approximately 20 to 30 hours,

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    Reprint requests: Paul R. Dragsten, PhD, Biomedical Frontiers Inc, 1095 10th Ave SE, Minneapolis, MN 55414.

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