Acute iron poisoning. Rescue with macromolecular chelators.

Mahoney, John R.; Hallaway, Philip E.; Hedlund, Bo E.; Eaton, John W.

doi:10.1172/jci114307

Cited by 60 publications

(34 citation statements)

References 16 publications

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“…For example, in individuals with iron overload, net negative iron balance could not be achieved unless the drug was given by constant chronic infusion (9). The (18).…”

Section: Resultsmentioning

confidence: 99%

Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers.

Hallaway

Eaton²,

Panter³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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153

154

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A class of high molecular weight iron chelators has been prepared by covalently attaching deferoxamine (DFO), by its amino group, to a variety of biocompatible polymers such as dextran and hydroxyethyl-starch. The ironbinding properties of DFO are virtually unchanged after the attachment procedure, but the toxicity and circulatory half-life are profoundly altered. Competitive iron-binding experiments indicate that the conjugates retain a high affinity for ferric iron. In addition, the derivatives inhibit iron-driven lipid peroxidation as effectively as the parent drug. However, the LD50 in mice (based on DFO equivalents) is -4000 mg/kg for dextran-DFO as compared to 250 mg/kg for free DFO. Consistent with the greatly decreased LD50, intravenous administration of the conjugates in dogs at a dose of 100 mg/kg (body weight) does not cause the severe hypotension associated with intravenous administration of DFO. The plasma half-lives of these adducts are increased >10-fold for dextran-DFO and hydroxyethylstarch-DFO compared to the free drug. Finally, and most importantly, the conjugates are effective in mediating in vivo iron mobilization and excretion. Because recent evidence implicates iron as an important component of tissue injury in many disease states, these high molecular weight iron chelators may have potential for improved therapy, allowing higher sustained plasma concentrations of the active drug.Deferoxamine B (DFO), a bacterial siderophore isolated from Streptomyces pilosus, is used in a variety of situations in research and clinical medicine where the effective removal of iron is desired (1). In addition to its high affinity (Kd 10-30 M) and specificity for ferric ions (2), DFO renders iron unreactive in free-radical-producing reactions (3, 4) that can damage biomolecules and tissues. For these reasons, DFO is used clinically in cases of acute iron intoxication (5-7) and more commonly to treat iron overload due to chronic transfusion therapy (8, 9). Unfortunately, this chelator has two properties that diminish its usefulness. (i) Its acute (5-7) and chronic (10) toxicity limit the dose that can be safely used. (ii) It has a very short plasma half-life (11) and, since it is not readily absorbed when given orally, it must be administered either by repeated intramuscular injection or by continuous subcutaneous infusion. We have synthesized a class of high molecular weight iron chelators by covalently attaching DFO to biocompatible polymers such as dextran and hydroxyethyl-starch. These DFO-polymer conjugates have not only longer plasma half-lives but also lower toxicity and the same iron chelating properties as the free drug.MATERIALS AND METHODS Chemicals. DFO was obtained as the mesylate salt, Desferal, from CIBA-Geigy; dextran was obtained as Rheomacrodex or Macrodex, as solutions in normal saline from Pharmacia LKB; hydroxyethyl-starch was obtained as HESPAN or modified pentafraction as solutions from DuPont Critical Care (Waukeegan, IL). Gallium was purchased from Johnson Matthey (Seabrook,...

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“…For example, in individuals with iron overload, net negative iron balance could not be achieved unless the drug was given by constant chronic infusion (9). The (18).…”

Section: Resultsmentioning

confidence: 99%

Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers.

Hallaway

Eaton²,

Panter³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

153

154

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“…In general, DFO is not injected intravenously for two reasons. First, it is a small molecule and is eliminated rapidly through the kidney, with a plasma half-life that is less than 10 min in humans (Mahoney et al, 1989;Dragsten et al, 2000). Second, the injec- 3.…”

Section: Downloaded Frommentioning

confidence: 99%

“…D, post-treatment with six 6-mg intranasal doses of 10% DFO (n ϭ 9) compared with intranasally administered water control (n ϭ 6). p values from Student's unpaired t test with #, p Ͻ 0.10 and ‫,ء‬ p Ͻ 0.05. tion of an intravenous bolus can cause acute hypotension that is rapid and can be lethal (Mahoney et al, 1989). Subcutaneous and intramuscular injections of DFO are often associated with local injection site reactions.…”

Section: Downloaded Frommentioning

confidence: 99%

Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Hanson

Roeytenberg²,

Martínez³

et al. 2009

J Pharmacol Exp Ther

197

119

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Deferoxamine (DFO) is a high-affinity iron chelator approved by the Food and Drug Administration for treating iron overload. Preclinical research suggests that systemically administered DFO prevents and treats ischemic stroke damage and intracerebral hemorrhage. However, translation into human trials has been limited, probably because of difficulties with DFO administration. A noninvasive method of intranasal administration has emerged recently as a rapid way to bypass the bloodbrain barrier and target therapeutic agents to the central nervous system. We report here that intranasal administration targets DFO to the brain and reduces systemic exposure, and that intranasal DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6-mg dose of DFO resulted in significantly higher DFO concentrations in the brain (0.9 -18.5 M) at 30 min after intranasal administration than after intravenous administration (0.1-0.5 M, p Ͻ 0.05).Relative to blood concentration, intranasal delivery increased targeting of DFO to the cortex approximately 200-fold compared with intravenous delivery. Intranasal administration of three 6-mg doses of DFO did not result in clinically significant changes in blood pressure or heart rate. Pretreatment with intranasal DFO (three 6-mg doses) 48 h before MCAO significantly decreased infarct volume by 55% versus control (p Ͻ 0.05). In addition, post-treatment with intranasal administration of DFO (six 6-mg doses) immediately after reperfusion significantly decreased infarct volume by 55% (p Ͻ 0.05). These experiments suggest that intranasally administered DFO may be a useful treatment for stroke, and a prophylactic for patients at high risk for stroke.

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“…DFO G was found to have fewer immunosuppressive properties and to exert less enhancement of virulence of Yersinia in vivo (5). Thus, DFO G might be a favorable alternative to DFO B in clinical DFO therapy.Moreover, studies have been conducted with DFO bound to hydroxyethyl starch (HES) and have indicated that HES-DFO improves safety without interference with the iron binding efficacy of DFO (22,29,32). In accordance with these results, HES-DFO was found to significantly attenuate systemic oxidant injury, resulting in less toxicity to the lung and kidney in early sepsis (30,34).…”

mentioning

confidence: 85%

Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

Schubert

Autenrieth

2000

Clin Diagn Lab Immunol

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The iron chelator desferrioxamine (DFO) B is widely used in the therapy of patients with iron overload. As a side effect, DFO may favor the occurrence of fulminant Yersinia infections. Previous work from our laboratory showed that this might be due to a dual role of DFO: growth promotion of the pathogen and immunosuppression of the host. In this study, we sought to determine whether conjugation of DFO to hydroxyethyl starch (HES-DFO) may prevent exacerbation of Yersinia infection in mice. We found HES-DFO to promote neither growth of Yersinia enterocolitica nor mitogen-induced T-cell proliferation and gamma interferon production by T cells in vitro. Nevertheless, in vivo HES-DFO promoted growth of Y. enterocolitica possibly due to cleavage of HES and release of DFO. The pretreatment of mice with DFO resulted in death of all mice 2 to 5 days after application of a normally sublethal inoculum of Y. enterocolitica, while none of the mice pretreated with HES-DFO died within the first 7 days postinfection. However, some of the HES-DFO-treated mice died 8 to 14 days postinfection. Thus, due to the delayed in vivo effect HES-DFO failed to trigger Yersinia-induced septic shock, which accounts for early mortality in DFO-associated septicemia. Moreover, our data suggest that DFO needs to be taken up by host cells in order to exert its immunosuppressive action. These results strongly suggest that HES-DFO might be a favorable drug with fewer side effects than DFO in terms of DFO-promoted fulminant infections.Yersinia enterocolitica is a gram-negative bacterium which is pathogenic for humans and rodents (23,25). Infection with this pathogen causes a wide range of clinical manifestations including enterocolitis and mesenteric lymphadenitis (28). In immunocompromised patients or patients with iron overload, Yersinia causes systemic infections with abscesses in spleen and liver (27,33,37).Previous work from this laboratory showed that desferrioxamine (DFO) may play a dual role in pathogenesis of Yersinia infection: growth and virulence promotion of Y. enterocolitica by iron provision to the pathogen and immunosuppression of the host. In fact, iron-loaded DFO (ferrioxamine [FO]) can be taken up and used as an iron source by Yersinia (16, 36). The genes encoding FO uptake have been characterized and are considered part of the virulence factors required for high-level pathogenicity of Yersinia (10, 11).On the other hand, DFO exerts effects on various components of the immune system of the host. DFO inhibits proliferation of T and B lymphocytes and cytokine production of macrophages and modulates interaction of polymorphonuclear leukocytes with yersiniae (3, 21). In keeping with these observations, we and others have demonstrated that DFO increases pathogenicity of Y. enterocolitica in mice, resulting in fatal septicemia and shock (5, 39, 40). Moreover, fatal septicemia with Yersinia and other microorganisms including the fungus Rhizopus sp. has been reported for patients undergoing DFO therapy (13,15,40).In an attempt to find drug...

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Acute iron poisoning. Rescue with macromolecular chelators.

Cited by 60 publications

References 16 publications

Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers.

Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers.

Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

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