A Trial to Investigate the Relationship between DFO Pharmacokinetics and Metabolism and DFO‐Related Toxicity

Porter, John B.; Faherty, A.; Stallibrass, L.; Brookman, L.; Hassan, Ijaz Javed; Howes, Colin

doi:10.1111/j.1749-6632.1998.tb10528.x

Cited by 28 publications

(28 citation statements)

References 5 publications

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“…Moreover, similar to our previous study, ULC-DFO was significantly more efficacious than DFO at iron mobilization at the dose given in our study. Although we could not determine the total iron excretion efficiency (ICE) of new chelators in comparison to DFO, the data obtained here (Figure 7) clearly show that long M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 16 circulating ULC-637 is more efficient in removing iron from the body. This finding has several very important consequences.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 51%

“…The exposure to low MW unconjugated DFO is associated with toxicity in several organs and experimental models [5,[14][15][16][17][18]29]. Furthermore, in vivo studies in mice and dogs demonstrate that DFO exposure can cause hypotension and fatalities at high concentration [5].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the MOA of DFO has been shown to result in non-compliance among large groups of patients, especially younger individuals [8,14]. Additional shortcomings of DFO include toxicity at higher doses which may result in hearing loss or blindness, and reactions at the infusion site [15][16][17]. Not surprisingly, one major aspiration of current research is a therapy with reduction in the arduous subcutaneous or intravenous administration of DFO.…”

Section: Introductionmentioning

confidence: 99%

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In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator

et al. 2016

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator

et al. 2016

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“…Iron-chelating therapy with deferoxamine was suspended at the pharmacological induction of pregnancy because of the possible ocular toxicity and teratogenicity of the drug, as reported in animal experiments [9]. In the absence of chelation, the accumulation and retention of iron in the placenta is remarkable.…”

Section: Discussionmentioning

confidence: 99%

Direct demonstration of iron in a term placenta in two cases of β‐thalassemia

Artico¹,

Ballati²,

Bosco³

et al. 2004

American J Hematol

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The aim of this study was to quantify iron in the placentas at the end of pregnancy in two patients suffering from b-thalassemia and compare the data to that recorded from the placentas of healthy women. Iron was quantified in placental specimens taken after the delivery. The specimens were subjected to chemical treatments in order to remove extracellular iron and leave the intracellular iron intact. After coloration, each specimen was subjected to quantitative analysis of images in order to identify and quantify iron. Our results demonstrated that in b-thalassemia there is an accumulation of iron in the outer basal cytoplasm of the epithelial cells of placental cotyledons. Am.

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“…20 min), the drug needs to be infused over prolonged periods of time and requires constant patient monitoring to avoid removing too much iron since it is a critical metal for downstream proteins involved in processes such as cellular respiration and metabolism. 12 In an attempt to address these problems, we are exploring an environment-responsive carrier system capable of taking advantage of the inflammatory environment characteristic of iron-overload conditions. It is important for the carrier to maintain the iron chelation capability of DFO while minimizing its well-known cytotoxicity issues in cells 13, 14 and to prolong drug residence time while incorporating suitable triggers for biodegradation of the carrier and elimination of iron- chelates from the body.…”

Section: Introductionmentioning

confidence: 99%

Enzymatically Biodegradable Polyrotaxane–Deferoxamine Conjugates for Iron Chelation

Liu

Lin

Purro

et al. 2016

ACS Appl. Mater. Interfaces

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Chelation therapy is frequently used to help reduce excess iron in the body, but current chelators such as Deferoxamine (DFO) are plagued by short blood circulation times, which necessitates infusions and can cause undesirable toxic side effects in patients. To address these issues, polyrotaxanes (PR) were synthesized by threading α-cyclodextrin (α-CD) onto poly(ethylene glycol) bis(amine) (PEG-BA, MW 3400 g/mol) capped with enzymatically cleavable bulky Z-L Phenylalanine (Z-L Phe) moieties. The resulting PR was conjugated to DFO and hydroxypropylated to generate the final polyrotaxane-DFO (hPR-DFO). The iron chelating capability of hPR-DFO was verified by UV-Vis absorption spectroscopy and the ability of materials to degrade into smaller CD-conjugated DFO fragments (hCD-DFO) in the presence of the protease was confirmed via Gel Permeation Chromatography (GPC). In vitro studies in iron-overloaded macrophages reveal that hPR-DFO can significantly reduce the cytotoxicity of the drug while maintaining its chelation efficacy, and that it is more rapidly endocytosed and trafficked to lysosomes of iron-overloaded cells in comparison to non-iron overloaded macrophages. In vivo studies indicate that iron-overloaded mice treated with hPR-DFO displayed lower serum ferritin levels (a measure of iron burden in the body) and could eliminate excess iron by both the renal and fecal routes. Moreover, there was no gross evidence of acute toxicological damage to the liver or spleen.

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A Trial to Investigate the Relationship between DFO Pharmacokinetics and Metabolism and DFO‐Related Toxicity

Cited by 28 publications

References 5 publications

In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator

In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator

Direct demonstration of iron in a term placenta in two cases of β‐thalassemia

Enzymatically Biodegradable Polyrotaxane–Deferoxamine Conjugates for Iron Chelation

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