Distribution and renal excretion of desferrioxamine and ferrioxamine in the dog and in the rat

Peters, G.; Keberle, H; Schmid, Kurt; Brunner, H R

doi:10.1016/0006-2952(66)90114-6

Cited by 75 publications

(24 citation statements)

References 9 publications

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“…The low efficacy of DFOM for in vivo Pu(IV) chelation may be attributed to its inadequate hexadentate denticity [Pu(IV) is 8-coordinate] and the weak acidity of its hydroxamic acid binding groups, which are not ionized at pH Ͻ8 (Sillen and Martell 1964;Peters et al 1966;Volf 1978;Smith and Raymond 1981).…”

Section: The Siderophoresmentioning

confidence: 98%

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Durbin¹

2008

Health Physics

106

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All of the actinides are radioactive. Taken into the body, they damage and induce cancer in bone and liver, and in the lungs if inhaled, and U(VI) is a chemical kidney poison. Containment of radionuclides is fundamental to radiation protection, but if it is breached accidentally or deliberately, decontamination of exposed persons is needed to reduce the consequences of radionuclide intake. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents. Ethylendiaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were introduced in the 1950's. DTPA is now clinically accepted, but its oral activity is low, it must be injected as a Ca(II) or Zn(II) chelate to avoid toxicity, and it is structurally unsuitable for chelating U(VI) or Np(V). Actinide penetration into the mammalian iron transport and storage systems suggested that actinide ions would form stable complexes with the Fe(III)-binding units found in potent selective natural iron chelators (siderophores). Testing of that biomimetic approach began in the late 1970's with the design, production, and assessment for in vivo Pu(IV) chelation of synthetic multidentate ligands based on the backbone structures and Fe(III)-binding groups of siderophores. New efficacious actinide chelators have emerged from that program, in particular, octadentate 3,4,3-LI(1,2-HOPO) and tetradentate 5-LIO(Me-3,2-HOPO) have potential for clinical acceptance. Both are much more effective than CaNa3-DTPA for decorporation of Pu(IV), Am(III), U(VI), and Np(IV,V), they are orally active, and toxicity is acceptably low at effective dosage.

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Section: The Siderophoresmentioning

confidence: 98%

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Durbin¹

2008

Health Physics

106

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“…However, the IM injections were painful and side effects included loss of appetite and weight. Intranasal (IN) administration is an alternative to IM injections that targets DFO, which has a short half-life in blood, directly to the central nervous system (CNS) Dhuria et al 2010;Peters et al 1966). Drugs administered IN travel extracellularly along the olfactory and trigeminal nerves to gain direct access to the CNS, bypassing the blood-brain barrier and minimizing systemic exposure (Dhuria et al 2010;Jogani et al 2008).…”

Section: Introductionmentioning

confidence: 97%

Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice

et al. 2012

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Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3β and HIF-1α, with more interleukin-1β and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3β and HIF-1α play a prominent role.

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“…For instance, 1 penetrates into hepatocytes and comes out as 2 (28,29). Compound 4, on the other hand, has little tendency to cross the cell membrane (30). Also, 2 has a half-life of several hours (31) while the half-life of 4 is 1 h (unpublished data).…”

mentioning

confidence: 99%

Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.

Kazmierski

Wolberg

Wilson

et al. 1996

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

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The hydroxamic acid siderophore ferrioxam- Nitric oxide (NO), a short-lived potent vasodilator, was first described as the endothelium-derived relaxation factor (EDRF) (1-3). The formation of NO from the guanidino nitrogen group of L-arginine is catalyzed by a group of enzymes termed constitutive (cNOs) and inducible (iNOs) NO synthases (3,4). The inducible form is not present constitutively in mammalian cells but is induced by proinflammatory stimuli such as bacterial lipopolysaccharide (LPS), Corynebacterium parvum, and the cytokines tumor necrosis factor-a, interleukin-1, or interferon-y, individually or in combination (5). Excess production of NO is reported to be associated with the development of hypotension associated with endotoxemia and sepsis (6-8).Inhibition of iNOs is a potential therapeutic approach to the treatment of septic shock (6-9). However, mechanisms to protect against the deleterious effects of NO overproduction constitute an alternative approach. For instance, free hemoglobin can scavenge NO and inhibit its biological effects (10). In LPS-treated mice, formation of a paramagnetic mononitrosyl iron complex with diethyldithiocarbamate (NO Fe DETC) was detected and characterized by electron paramagnetic resonance (11). The NO formed in this animal model was trapped with endogenous Fe2+ complexed with a considerable amount (500 mg/kg) of DETC that was administered to the animals during the course of the experiment (11). Mortality was not addressed in this study. On the other hand, administration of vitamin B12A to mice prevented and reversed endotoxinmediated hypotension and decreased mortality, possibly through binding of the vitamin with excess NO (12). Inhibition of several actions of NO, including protection of rats against endotoxin, was demonstrated with the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazolineoxyl-i-oxyl 3-oxide (13). We and others have characterized the in vivo models of induction of iNOs in mice and rats injected with C. parvum or C. parvum + LPS (14-18). We postulated that iron complexes could act as general NO scavengers and provide protection against septic shock. We screened a library of metal chelators and chelates and found that [Fe(III)

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Distribution and renal excretion of desferrioxamine and ferrioxamine in the dog and in the rat

Cited by 75 publications

References 9 publications

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice

Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.

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