Iron continued chelation

Attempts have been made to reduce these side effects of hypertransfusion by continuous chelation therapy with desferrioxamine, but better products are needed. Animal experiments with 2,3-dihydroxybenzoic acid (2,3-DHB) are promising. Further studies of benzoic acid derivatives, hydroxamic acids and other compounds are in progress. The importance of reduction of iron absorption... 

The copper-chelating abihty of sahcylaldoxime has been used to remove copper from brine in a seawater desalination plant effluent. A carbon—sorbate bed produced by sorption of the oxime on carbon proved to be extremely effective in the continuous process (99). In another apphcation, the chelating abihty of sahcylaldoxime with iron and copper was used to stabilize bleaching powders containing inorganic peroxide salts (100). 

Coadministration of dexrazoxane Chelation of iron in the heart, correction of iron dysregulation or mitigation of free radical formation Approved for use in patients who continue DOX above 300 mg/m2 or require another anthracycline after a prior exposure to 300 mg of DOX/m2... 

Aconitase was first determined to be an Fe-S protein in 1972 by Kennedy, Rauner and Gawron (23). Chemical analyses of inactive enzyme gave values of 2 Fe and 3 S /protein of 66,000 daltons. The observed molar relaxivity of water protons by this preparation of aconitase was 473 M s l (25). This value was an order of magnitude lower than measured in the earlier preparation of Villafranca and Mildvan (21) and much closer to that of Fe-S proteins (26). One mole of Fe + per mole of protein was taken up by the enzyme upon activation in the presence of cysteine and ascorbate, or lost upon inactivation in the presence of the iron chelator ferrozine (27). Gawron s group also demonstrated a correlation between loss of one Fe and loss of enzyme activity, as well as the protection afforded by citrate against both losses. However, the presence of an Fe-S cluster in aconitase remained for the moment a curiosity, in particular because of the unusual Fe/S= stoichiometries. The essential Fe that is correlated with activity continued to be interpreted in terms of the "ferrous-wheel" model. 

Other photosensitisers in clinical or pre-clinical trials include zinc phthalocya-nine, aluminium sulphonated phthalocyanines, benzoporphyrins, benzochlorins and purpurin-lS-iV-alkylamides, all of which absorb strongly in the 675-700 nm region. An alternative approach to the photosensitisation in PDT involves the use of 5-aminolaevulinic acid (ALA). This compound itself is not a sensitiser but in human cells it is the key metabolic precursor in the biosynthesis of protoporphyrin IX, which can act as a photosensitiser. Normally the biosynthetic process would continue beyond protoporphyrin IX to the iron containing haem. However, by adding extra ALA and iron chelators, the ferrochelatase action is inhibited and the normal feedback mechanism by-passed resulting in a build up of protoporphyrin IX in the cell. The mechanism is illustrated in Figure 4.24. ... 

Desferrioxamine is expensive and must be taken by continuous injection. It is not absorbed through the intestine. Many potent iron chelators have been tested to find an effective one that can be taken orally, but only the drug deferiprone is currently used orally.In the long term, bone marrow transplants or gene therapy10 might cure the disease. 

The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2-3 days and presents as arrhythmias or conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and is asymptomatic in most cases. The chronic form results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 500-550 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. All anthracyclines can produce "radiation recall reaction," with erythema and desquamation of the skin observed at sites of prior radiation therapy. 

PLEX HT is a blend of chelating agents which has the ability to dissolve iron rust from cotton and cotton blend fabrics in strong caustic solutions such as are used in saturation of cotton fabric prior to continuous peroxide bleaching. It also has the ability to keep the chelated iron from redeposition as the pH drops during subsequent rinsing. 

New complexes containing azo- and hydrazinato-derivatized Schiff base ligands298 375 continue to be used for the analytical determination of vanadium.376 The vanadium complex was characterized for the Schiff base derived from the condensation reaction of benzoyl acetone and Girard s reagent P.377 Azophenolates of mononuclear and mixed valence dinuclear species have been reported.378 Naphthanol- or quinolinol-derivatized ligands prefer to chelate iron over vanadium.379... 

Although DFB therapy is effective in removing large quantities of iron rapidly, there are some drawbacks in its use. One of these is the short plasma residence time, about 30 minutes, idiich causes a significant reduction in the efficiency of DFB to remove iron. To counteract this rapid plasma clearance, the chelator is often administered by means of a portable pump that is worn by the patient and which continuously administers a controlled amount of the drug (7). On the other hand, the pump... 

Deferoxamine is a highly selective chelator of iron that theoretically binds ferric (Fe +) iron in a 1 1 molar ratio (100 mg deferoxamine to 8.5 mg ferric iron) that is more stable than the binding of iron to transferrin. Deferoxamine removes excess iron from the circulation and some iron from transferrin by chelating ferric complexes in equilibrium with transferrin. The resulting iron-deferoxamine complex, ferrioxamine, is then excreted in the urine. Its action on intracellular iron is unclear, but it may have a protective intracellular effect or may chelate extramitochondrial iron. The parenteral administration of deferoxamine produces an orange-red-colored urine within 3 to 6 hours because of the presence of ferrioxamine in the urine. For mild to moderate cases of iron poisoning, where its use is unclear, the presence of discolored urine indicates the persistent presence of chelatable iron and the need to continue deferoxamine. The reliance on discolored urine as a therapeutic end point has been challenged because it is not sensitive and is difficult to detect. ... 

In a continuation of the above study the first acid dissociation constant, Kau in the deprotonation of the 1 3 chelate of 2-(2-pyridyl)imidazoline with iron(III) was found to be 10-609 (AH° = 6.9 kcal mole-1). 

The trimethylsilylated silicic acids formed in this instance are soluble in conventional organic solvents, and their volatility is sufficiently high for them to be analysed by gas chromatography. Carzo and Hoebbel [411] carried out a comprehensive study of the chromatographic retention of various trimethylsilylated silicic acids on different stationary phases Apiezon L and silicone OV-1 and OV-17. The analysis of metals in the form of volatile complexes continues to attract attention, and have been described for analysing sodium [412], potassium [412], radium [413], caesium [413], barium [414], calcium [414], strontium [415], beryllium [416, 417], magnesium [418], zinc [419, 420], nickel [419], mercury [421], copper [422, 423], silver [424, 425], cadmium [421], indium [426, 427], g ium [428], scandium [217], cobalt [421], thallium [426], hafnium [429, 430], lead [431, 432], titanium [430], vanadium [433], chromium [434-436], manganese [426], iron [437], yttrium [438], platinum [439,440], palladium [439, 441, 442], zirconium [430], molybdenum [443], ruthenium [444], rhodium [445], rare earths [446—449], thorium [221, 450, 451] and uranium [221, 452]. The literature on GC analysis of metal chelates was reviewed by Sokolov [458]. 

For chronic iron intoxication e.g., thalassemia), an intramuscular dose of 0.5-1.0 g/day is recommended, although continuous subcutaneous administration (1-2 g/day) is almost as effective as intravenous administration. When blood is being transfused to patients with thalassemia, 2 g deferoxamine (per unit of blood) should be given by slow intravenous infusion (rate not to exceed 15 mg/kg/h) during the transfusion but not by the same intravenous fine. Deferoxamine is not recommended in primary hemochromatosis phlebotomy is the treatment of choice. Deferoxamine also has been used for the chelation of aluminum in dialysis patients. Deferoxamine is metabohzed principally by plasma enzymes, but the pathways have not been defined. The drug also is excreted readily in the urine. 

A comparative kinetic analysis of IRPl activation by NO and H2O2 in culture cells yielded the unexpected outcome that NO, unlike H2O2, elicits a slow activation of IRPl which, in kinetic terms rather resembles responses to iron starvation [136], Furthermore, iron starvation and NO result in a slow induction of both IRPl and IRP2, while H2O2 exclusively activates IRPl with rapid kinetics [126, 136]. IRPl induction by H2O2 is biphasic, in contrast to the effects of iron starvation and NO. While the iron chelator desferrioxamine and NO need to be continuously present for IRPl activation, the presence of H2O2 (at a minimal threshold eoncentration of 10 pm) is only required for 10-15 minutes, and then the activation of IRPl can be completed in the absence of the effector [136, 142]. 

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