Computer simulation of chelation therapy Plasma mobilizing index as a replacement for effective stability constant

May, Peter M.; Williams, David R.

doi:10.1016/0014-5793(77)80290-1

Cited by 102 publications

(17 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Binding of NTBI to various molecules have been reported using different methodologies. In computer simulation studies the major form of NTBI is found to be ferric bound to citrate where as nuclear magnetic resonance analysis point out ferric bound to citrate as well as acetate in hemochromatosis patients [46,48]. The interaction of iron is also shown with the major plasma protein albumin even when the Tf is not completely saturated [49].…”

Section: Sources and Status Of Ntbi In Circulationmentioning

confidence: 99%

Non Transferrin Bound Iron: Nature, Manifestations and Analytical Approaches for Estimation

Patel

Ramavataram

2012

Ind J Clin Biochem

View full text Add to dashboard Cite

show abstract

Section: Sources and Status Of Ntbi In Circulationmentioning

confidence: 99%

Non Transferrin Bound Iron: Nature, Manifestations and Analytical Approaches for Estimation

Patel

Ramavataram

2012

Ind J Clin Biochem

View full text Add to dashboard Cite

show abstract

“…The Trien would hold the copper labilized into plasma by D-Pen as a low mol. wt charged complex [5] thereby considerably facilitating its renal excretion. Such a therapeutic strategy is expected to lower the required D-Pen dosage and so minimise the side effects for which this drug is often responsible.…”

Section: Resultsmentioning

confidence: 99%

“…Computer models of the distribution of metal-ions amongst complexes in blood plasma have been published [3][4][5]. Essentially these are equilibrium calculations based upon stability constants and the respective metal and ligand concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…Also they have made it clear that chelation from serum albumin is not the 'modus operandi' through which D-penicillamine liberates copper(II) into low mol. wt form [5]. The apparent inability of this agent to procure albumin-bound copper cannot be Address correspondence to: Professor D. R. Williams correlated with the substantial cupruresis induced when this drug is administered to patients [6], This had led us to investigate the possible mechanisms of activity of chelating agents and in particular the influence of D-penicillamine upon ceruloplasmin in saline solution and in blood plasma.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The action of chelating agents in the removal of copper from ceruloplasmin An in vitro study

Jackson

1978

FEBS Letters

View full text Add to dashboard Cite

“…These findings are consistent with a shuttling mechanism for deferipronelike chelators and support the concept that zinc chelation by deferiprone is likely to be the principal mechanism of thymocyte apoptosis. A shuttling effect of low molecular weight chelators onto more stable higher weight chelators is well recognized for iron and other metals, 49,50 with there often being a marked synergism of metal removal when the use of a small kinetically labile ligand is combined with that of a larger hexadentate chelator. Typical examples are nitrilotriacetate/DFO with iron removal, 51 penicillanimine/DTPA with copper removal, 52 and salicylic acid/ethylenediaminetetraacetic acid with plutonium removal.…”

Section: Discussionmentioning

confidence: 99%

Cellular zinc content is a major determinant of iron chelator–induced apoptosis of thymocytes

Maclean

Cleveland

Porter

2001

Blood

View full text Add to dashboard Cite

Desferrioxamine (DFO) and the hydroxypiridinone (HPO) deferiprone (CP20) chelate iron as well as other metals. These chelators are used clinically to treat iron overload, but they induce apoptosis in thymocytes. Thymocyte apoptosis is potentiated by zinc deficiency, suggesting that these iron chelators may induce apoptosis by depleting stores of zinc. Exposure of murine thymocytes to either DFO or deferiprone resulted in significant reductions in the labile intracellular zinc pool. Moreover, increasing intracellular zinc levels, by chronic zinc dietary supplementation to mice or in vitro loading with zinc, abrogated deferiprone-induced murine thymocyte apoptosis. Bidentate hydroxypyridinones such as deferiprone interact with intracellular zinc pools in a manner distinct from that of DFO, which is a hexadentate iron chelator. Whereas deferiprone acts synergistically with the zinc chelator NNNN-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to induce apoptosis, DFO does not. This difference is most likely due to the ability of HPOs but not DFO to "shuttle" zinc onto acceptors such as metallothioneins. By nature of its structure, DFO is larger than deferiprone and is thus less able to access some intracellular zinc pools. Additionally, metal complexes of DFO are more stable than those of HPOs and thus are less likely to donate zinc to other acceptors. The ability of deferiprone to preferentially access zinc pools was also demonstrated by inhibition of a zinc-containing enzyme phospholipase C, particularly when combined with TPEN. These findings suggest that bidentate iron chelators access intracellular zinc pools not available to DFO and that zinc chelation is a mechanism of apoptotic induction by such chelators in thymocytes. IntroductionPatients with thalassemia and other refractory anemias require regular blood transfusions, and the most common cause of death is iron overload. Currently, desferrioxamine (DFO) is the first line treatment of transfusional iron overload, but it is orally inactive due to its high molecular weight and therefore must be given as subcutaneous infusions. Therefore, the design of an orally active, nontoxic, and selective iron chelator remains an important goal. The ideal iron chelator would prevent or modify iron-mediated pathological processes without undue toxicity.The bidentate 3-hydroxypyridin-4-ones (HPOs), of which deferiprone has been the most extensively used clinically, are a series of orally active iron chelators. Deferiprone is approximately one-third of the molecular weight of DFO and neutrally charged. Therefore, deferiprone is efficiently absorbed from the gut and enters intracellular metal pools more rapidly than DFO, where it can inhibit metalloenzymes such as ribonucleotide reductase. 1 In principle these properties could explain some of the toxic effects of this drug, which include neutropenia and bone marrow aplasia in laboratory animals 2,3 and agranulocytosis in some patients. 4,5 Although induction of bone marrow hypoplasia is dose-and time-dependent in laboratory...

show abstract

Computer simulation of chelation therapy Plasma mobilizing index as a replacement for effective stability constant

Cited by 102 publications

References 14 publications

Non Transferrin Bound Iron: Nature, Manifestations and Analytical Approaches for Estimation

Non Transferrin Bound Iron: Nature, Manifestations and Analytical Approaches for Estimation

The action of chelating agents in the removal of copper from ceruloplasmin An in vitro study

Cellular zinc content is a major determinant of iron chelator–induced apoptosis of thymocytes

Contact Info

Product

Resources

About