First human studies with a high-molecular-weight iron chelator☆,☆☆
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. 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).
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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Cited by (54)
Fluorene methoxycarbonyl-PEG-deferoxamine conjugates “hitchhike” with albumin in situ for iron overload therapy
2022, International Journal of PharmaceuticsCitation Excerpt :Among the previously reported drug conjugates, a few of them have successfully entered clinical trials. In the first Phase Ib clinical trial of high-molecular-weight iron chelator, the hydroxyethyl starch-DFO (HES-DFO) conjugates induced nearly twice as much excretion of iron as an equivalent dose of DFO in the evaluation of the pharmacokinetic data from the study (Dragsten et al., 2000). Subsequently, starch-DFO (S-DFO) also could increase the efficacy and reduce dose frequency in Phase Ib clinical trial (Harmatz et al., 2007).
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2016, Chelation Therapy in the Treatment of Metal IntoxicationSolid microparticles based on chitosan or methyl-β-cyclodextrin: A first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate
2015, Journal of Controlled ReleaseCitation Excerpt :In order to study the DFO pharmacokinetics, we have developed a liquid phase extraction method of this drug from plasma, suitable for LC–MS analysis. We have then performed an intravenous administration of the drug (200 μg) to rats and calculated its terminal half-life (15.4 ± 1.8 min) evidencing a value similar to that found in dogs [46] and confirming that after intravenous administration DFO is rapidly eliminated from the bloodstream [17,47]. Moreover, following the intravenous administration of the same dose, DFO was not detected in the CSF of rats at any considered time point.
A novel 5-fluorouracil prodrug using hydroxyethyl starch as a macromolecular carrier for sustained release
2012, Carbohydrate PolymersCitation Excerpt :HES has been conjugated with deferoxamine mesylate, and the conjugates exhibited no acute toxicity. In addition, the drug residence time in plasma was significantly prolonged with an initial half-life of 22–33 h (Dragsten et al., 2000). However, little work has been carried out on the conjugation of HES and 5-FU.
Synthesis and characterization of a triazine dendrimer that sequesters iron(III) using 12 desferrioxamine B groups
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Reprint requests: Paul R. Dragsten, PhD, Biomedical Frontiers Inc, 1095 10th Ave SE, Minneapolis, MN 55414.
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0022-2143/2000 $12.00 + 0 5/1/103202