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At least 19 recordsLinked to original sources
PubMed2000

Iron chelating agents for treating malaria.

BACKGROUND: Mortality from Plasmodium falciparum malaria remains high; death and sequelae occur in even in patients treated with antimalarial drugs. Researchers are exploring the effects of adding treatments to the main antimalarial regimens in an attempt to reduce mortality. Iron chelation is one potential chemotherapeutic adjuvant treatment. Before advocating adjunctive therapy, the effects of iron chelators in improving patient outcomes needs to be examined. OBJECTIVES: To assess the effects of iron-chelating agents combined with antimalarial drugs, or iron chelators alone, for treating Plasmodium falciparum malaria in adults and children, in relation to mortality, coma recovery time, parasite clearance, and adverse effects. SEARCH STRATEGY: Electronic searches of the Cochrane Library, MEDLINE, and EMBASE, using the standard Cochrane search strategy. Bibliographies of retrieved studies were scrutinized in order to identify further relevant trials. Organisations, experts and other individuals in malaria research were contacted for unpublished studies. SELECTION CRITERIA: All randomised controlled trials of adults or children with P.falciparum malaria. DATA COLLECTION AND ANALYSIS: Trials were identified and extracted by a single reviewer (HS) and checked by a second (MM). Inclusion criteria were applied, and data were extracted independently by both reviewers. Authors were contacted for missing and additional data. Meta-analysis used Relative Risk (RR) and 95% Confidence Intervals. MAIN RESULTS: No evidence of benefit or harm were shown in relation to mortality, but studies were small, and one trial was tending towards more deaths with the intervention when it was stopped. The risk of experiencing persistent seizures was significantly lower with desferrioxamine compared to placebo treatment (RR 0.80, 95% CI 0.67 to 0.95). Many adverse effects were more common in participants treated with desferrioxamine. REVIEWER'S CONCLUSIONS: Trends suggestive of both harm (death) and potential benefit (fewer seizures) are demonstrated in this review. It is not possible to comment on time to event outcomes that include coma recovery or parasitaemia as we are clarifying data with the trialists. Whether to conduct further trials will depend on a judgement about potential benefit.

Adult↗
PubMed1993

Malaria pigment and extracellular iron. Possible target for iron chelating agents.

Extracellular iron is necessary for many biochemical reactions involved in Plasmodium falciparum growth and multiplication. The incorporation of radioactive iron taken up by the parasite was found, electrophoretically and via gamma counting, to be mainly associated with the haemozoin only in the presence of the active metabolism of the parasite. The potent antimalarial activity of desferrioxamine, a ferric iron chelating agent, has shown that iron deprivation is inhibitory to the parasite. We propose that the mechanism of action of desferrioxamine in addition to the chelation of iron from the parasitic compartment, chelates iron from the haemozoin crystal resulting in free radical generation and parasite death. The ability of desferrioxamine and not the ferrous iron chelating agent, 2,2'-bipyridyl, to chelate the non-haem iron from the haemozoin structure indicates that the oxidative state of iron associated with the haemozoin structure is ferric in nature.

2,2'-Dipyridyl↗
PubMed1983

Inhibition of microsomal oxidation of alcohols and of hydroxyl-radical-scavenging agents by the iron-chelating agent desferrioxamine.

Rat liver microsomes (microsomal fractions) catalyse the oxidation of straight-chain aliphatic alcohols and of hydroxyl-radical-scavenging agents during NADPH-dependent electron transfer. The iron-chelating agent desferrioxamine, which blocks the generation of hydroxyl radicals in other systems, was found to inhibit the following microsomal reactions: production of formaldehyde from either dimethyl sulphoxide or 2-methylpropan-2-ol (t-butylalcohol); generation of ethylene from 4-oxothiomethylbutyric acid; release of 14CO2 from [I-14C]benzoate; production of acetaldehyde from ethanol or butanal (butyraldehyde) from butan-1-ol. Desferrioxamine also blocked the increase in the oxidation of all these substrates produced by the addition of iron-EDTA to the microsomes. Desferrioxamine had no effect on a typical mixed-function-oxidase activity, the N-demethylation of aminopyrine, nor on the peroxidatic activity of catalase/H2O2 with ethanol. H2O2 appears to be the precursor of the oxidizing radical responsible for the oxidation of the alcohols and the other hydroxyl-radical scavengers. Chelation of microsomal iron by desferrioxamine most likely decreases the generation of hydroxyl radicals, which results in an inhibition of the oxidation of the alcohols and the hydroxyl-radical scavengers. Whereas desferrioxamine inhibited the oxidation of 2-methylpropan-2-ol, dimethyl sulphoxide, 4-oxothiomethylbutyrate and benzoate by more than 90%, the oxidation of ethanol and butanol could not be decreased by more than 45-60%. Higher concentrations of desferrioxamine were required to block the metabolism of the primary alcohols than to inhibit the metabolism of the other substrates. The desferrioxamine-insensitive rate of oxidation of ethanol was not inhibited by competitive hydroxyl-radical scavengers. These results suggest that primary alcohols may be oxidized by two pathways in microsomes, one dependent on the interaction of the alcohols with hydroxyl radicals (desferrioxamine-sensitive), the other which appears to be independent of these radicals (desferrioxamine-insensitive).

Alcohols↗
PubMed1998

Pyridoxal isonicotinoyl hydrazone and its analogs: potential orally effective iron-chelating agents for the treatment of iron overload disease.

At present, the only iron (Fe) chelator in clinical use for the treatment of Fe overload disease is the tris-hydroxamate deferoxamine (DFO). However, DFO suffers from a number of disadvantages, including the need for subcutaneous infusion (12 to 24 hours a day, 5 or 6 times per week), its poor intestinal absorption, and high cost. Therefore, there is an urgent need for an efficient, economical, and orally effective Fe chelator. Pyridoxal isonicotinoyl hydrazone (PIH) is a tridentate Fe-chelating agent that shows high Fe chelation efficacy both in vitro in cell culture models and also in vivo in rats and mice. In addition, this chelator is relatively nontoxic, economical to synthesize, and orally effective, and it shows high selectivity and affinity for Fe. However, over the last 10 years the development of PIH and its analogs has largely been ignored because of justifiable interest in other ligands such as 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Unfortunately, recent clinical trials have shown that significant complications occur with L1 therapy, and it is controversial whether this chelator is effective at reducing hepatic Fe levels in patients. Because of the current lack of a clinically useful Fe chelator to replace DFO, PIH and its analogs appear to be potential candidate compounds that warrant further investigation. In this review we will discuss the studies that have been performed to characterize these chelators at the chemical and biologic levels as effective agents for treating Fe overload. The evidence from the literature suggests that these ligands deserve further careful investigation as potential orally effective Fe chelators.

Animals↗
PubMed1996

Inhibition of Trypanosoma cruzi epimastigotes in vitro by iron chelating agents.

The relative effectiveness of 20 iron chelating agents in suppressing the growth and multiplication of Trypanosoma cruzi epimastigotes has been examined in vitro. 1,2-Dimethyl-3-hydroxypyrid-4-one (L1) and several of its newly synthesised N-substituted analogs containing hydrophobic substituents were significantly more effective than deferoxamine, even though they possess only two donor sites for iron(III) while deferoxamine has six. Analogs with hydrophilic substituents were uniformly less active than L1 itself. Variations in effectiveness as the polarity of the compound is varied indicate that the ability to cross the cellular membrane is of critical importance in the determination of the in vitro trypanocidal activity of iron(III) chelating agents. A group of four tris(2-aminoethyl)amine based tris-imines were also screened, all of which had poor activity (0-28% inhibition). Among the other iron(III) chelating agents which showed a relatively high level of activity at 50 and 100 micrograms/ml were salicylhydroxamic acid (70 and 73% inhibition) and hydroxyurea (42 and 52% inhibition). N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and acetohydroxamic acid exhibited only slight activity at 50 and 100 micrograms/ml. The best of these iron(III) chelating agents were as effective against the epimastigote form at both 50 and 100 micrograms/ml (74-82% inhibition) as benznidazole (81% inhibition), the drug currently used in the clinic.

Animals↗
PubMed1990

Mechanisms of inhibition of mononuclear cell activation by the iron-chelating agent desferrioxamine.

Iron-withholding by the chelating agent desferrioxamine abrogates the proliferative response of human peripheral blood mononuclear cells (PBMC) to phytohaemagglutinin (PHA). The present study investigated whether desferrioxamine operates late in the activation process or, as recently suggested, at an early stage, by inhibiting the appearance of the interleukin-2 (IL-2) receptor. Human PBMC were stimulated with PHA (10 micrograms/ml) and [3H]thymidine ([3H]TdR) incorporation determined after 66 hr of culture. Greater than 90% inhibition was achieved by concentrations of desferrioxamine as low as 5 mumol/l present throughout culture, while IL-2 receptor expression (anti-Tac), analysed by FACS, was maintained at up to 75% of control levels. 300 mumol/l desferrioxamine present throughout culture abrogated [3H]TdR incorporation and additionally suppressed IL-2 receptor to 10-15% of control levels. In contrast, the same high dose of desferrioxamine when added for 2 hr to cells previously cultured for 66 hr produced 80% inhibition of [3H]TdR incorporation but failed to inhibit expression of the IL-2 receptor. Desferrioxamine rapidly achieved equilibrium across the cell membrane (within 60 min) and chelated 59Fe delivered to activated cells by the transferrin endocytic cycle. These results indicate that desferrioxamine can inhibit T-cell activation either early or late in the process by chelating iron and independently of an effect on the IL-2 receptor. In support of a dual effect of the drug is the finding that at 50 mumol/l, desferrioxamine-enhanced expression of the transferrin receptor occurred, an adaptive response made to intracellular iron depletion, while IL-2 receptor expression was inhibited.

Cell Division↗
PubMed1994

Iron-chelating agents in non-iron overload conditions.

PURPOSE: To review the current clinical experience with iron chelators in non-iron overload conditions. DATA SOURCES: The English-language literature was searched from 1983 through 1992 manually and using MEDLINE. STUDY SELECTION: Original articles, case reports, and abstracts addressing iron chelation. DATA EXTRACTION: Selected reports that described clinical applications of iron chelators in non-iron overload conditions were classified according to their stated mechanism of interference with disease activity. Articles stating the rationale for clinical use of iron chelators were also included. RESULTS: Iron chelators were used in non-iron overload conditions to produce antioxidant effects, antiproliferative effects, and antiprotozoal effects and for aluminum chelation. In addition, several reports described singular observations in various diseases. Deferoxamine is the only iron chelator available for clinical studies. The treatment-related (side) effects appear to be associated with patient iron levels. CONCLUSIONS: Randomized clinical trials are needed to confirm the promising effects of iron chelators in non-iron overload conditions. Oral iron chelators with fewer toxic effects are especially needed.

Aluminum↗
PubMed1983

Effect of a specific iron chelating agent on animal models of inflammation.

Iron is an important catalyst of oxidative radical reactions and promotes the formation of the hydroxyl radical from the superoxide anion radical and hydrogen peroxide. The stimulatory effect of the hydroxyl radical on lipid peroxidation prompted the speculation that free iron may directly promote inflammation and that iron chelating agents may have useful anti-inflammatory properties. This hypothesis is tested in animal models of inflammation with a specific iron chelating agent, desferrioxamine. At low doses (6 . 6 mg/kg) intraperitoneal desferrioxamine stimulated the induction of acute foot pad swelling in rats by monosodium urate but at higher doses (above 200 mg/kg) it suppressed this inflammatory reaction. A similar anti-inflammatory effect was observed in carrageenan-induced foot pad swelling. In guinea-pigs in which a Glynn-Dumonde synovitis was induced with bovine gammaglobulin, desferrioxamine (100 mg/kg) stimulated the acute inflammatory induction phase of this chronic allergic monoarthritis model. Repeated administration of desferrioxamine (100 mg/kg) from the seventh to the twelfth day after intra-articular challenge with bovine gammaglobulin markedly depressed the chronic inflammatory phase. In-vitro experiments suggest that desferrioxamine inhibits iron-catalysed lipid peroxidation when it is poorly saturated with iron, but loses this effect when it is iron saturated. Such an effect may explain our results with desferrioxamine in the animal studies and suggests that effective iron chelation and its removal may modify the inflammatory process in man.

Acute Disease↗
PubMedDate not supplied

[A comparative study of the antioxidant properties of polyhydroxamic acids, desferal and other iron chelating agents].

The effects of different iron chelators on both OH.-generation in Fenton reaction and lipid peroxidation products accumulation in brain homogenate were studied. Intensity of luminol-dependent chemiluminescence was the measure of OH.-radical generation. The rate of lipid peroxidation was estimated as malondialdehyde accumulation. It was shown, that inhibition of chemiluminescence by the tested substances increased in next series: ADP, polyhydroxamic acid (PHA), EDTA, desferal, o-phenanthroline, ascorbate. Inhibition of lipid peroxidation by these substances increased in other order: ADP, Ascorbate, EDTA, PHA, desferal, o-phenanthroline. The results obtained allow to conclude, that antioxidant activity of ascorbate is due to the trapping of OH. radicals; in contrast, inhibition of the free radical processes by other tested substances is due to binding of iron ions. Antioxidant effect of PHA is almost as strong as effects of desferal, o-phenanthroline and EDTA. The lowest antioxidant activity was found in the presence of ADP.

Antioxidants↗
PubMed1981

A rapid assay for evaluation of iron-chelating agents in rats.

The animal assay of potential new iron-chelating agents is at present dependent on cumbersome and imprecise iron balance studies in hypertransfused rodents. We report the development of a radioisotope assay in intact rats based on the transient labeling by ferritin 59Fe of the main source of chelatable iron within hepatocytes. The isotope was maximally available to chelators during the first 6 hr after its injection, nearly all the excretion being in the bile. The bile 59Fe/total iron ratio was independent of both the chelator and its dose. However, in iron-loaded rats, the ratio was reduced, and the isotope excretion was a less sensitive measure of intrahepatic chelation. In the proposed assay, test chelators were given to normal rats 2 hr after an intravenous injection of 59Fe-ferritin. Four hours later, the radioiron in the liver and in the gut gave a sensitive measure of the mobilization of hepatic iron to the bile. In addition, chemical iron determinations identified a small alternative source of urinary chelate with agents known to promote urine excretion in man. The assay gave a rapid and precise screen for chelators given by parenteral and oral routes.

Animals↗
PubMedDate not supplied

Esculetin antagonizes iron-chelating agents and increases the virulence of Listeria monocytogenes.

Iron is an essential compound for the growth and virulence of Listeria monocytogenes. In extracellular environments, iron often requires a siderophore to be acquired by microorganisms. Although it does not produce siderophores, L. monocytogenes can use some exogenous bacterial or fungal siderophores as well as a number of animal or plant o-diphenol compounds to overcome growth inhibition by the iron-chelating agents tropolone and 8-hydroxyquinoline. Esculin, a plant glycoside, can be hydrolysed by L. monocytogenes to the o-diphenol aglucon, esculetin. The latter neutralized in vitro growth inhibition induced by the iron-chelating agents. Furthermore, when injected into infected mice, esculetin enhanced mortality in a dose-dependent manner and increased bacterial counts in spleen induced by sublethal doses of L. monocytogenes. Esculetin apparently functioned as a siderophore for L. monocytogenes in murine tissues.

Animals↗
PubMed1980

Evaluation of iron-chelating agents in cultured heart muscle cells. Identification of a potential drug for chelation therapy.

Primary cultures of neonatal rat cardiac muscle cells incorporated radioiron from both [55Fe]transferrin and 59FeCl3 (added simultaneously). To evaluate the effect of iron chelators on such uptake, deferri chelators were added 6 hr after addition of the radioiron sources. The microbial chelator agrobactin was significantly more effective than the drug defoxamine in reduction of 55Fe uptake from [55Fe]transferrin; both chelators halted 59Fe3+ uptake. Agrobactin may have potential in chelation therpay for iron-overload disease. Certain other microbial chelators lowered radioiron uptake from either [55Fe]transferrin of 59FeCl3. These chelators should be useful inhibitors for studies of animal cell iron uptake and intracellular iron flow.

Animals↗
PubMed1986

Prevention of doxorubicin-induced killing of MCF-7 human breast cancer cells by oxygen radical scavengers and iron chelating agents.

This study investigated the effect of oxygen radical scavengers and iron chelating agents on the toxicity of doxorubicin for MCF-7 human breast cancer cells. Superoxide dismutase and catalase, but not the heat-inactivated enzymes, the hydroxyl radical scavenger N-acetylcysteine, and the organoselenium compound 2-phenyl-1-2-benzisoselenazol-3(2H)-one, which possesses glutathione peroxidase-like activity, significantly reduced or abolished tumor cell killing by doxorubicin. Similar protective activity was found only for those iron chelating agents capable of penetrating the tumor cell plasma membrane. These experiments suggest that an iron-dependent oxygen radical cascade contributes to the antineoplastic action of the anthracycline antibiotic doxorubicin.

Breast Neoplasms↗
PubMed1984

Development and evaluation of the improved iron chelating agents EHPG, HBED and their dimethyl esters.

The phenolic EDTA analogues ethylenediamine-N,N'-bis-(2- hydroxyphenylglycine ) ( EHPG ), N,N'-bis(2-hydroxybenzyl)-ethylenediamine diacetic acid ( HBED ), and their respective dimethyl esters ( dimethylEHPG and dimethylHBED ) were studied in hypertransfused rats. Radioiron bound to these compounds was cleared mainly by the liver and excreted in the bile. After a single 40 mg i.m. injection, the percentage of radioiron removed from 59Fe-ferritin-labelled hepatocytes and excreted in the bile was 4% in untreated controls, 24% for desferral , 42% for dimethylEHPG , 58% for EHPG , 63% for HBED , and 80% for dimethylHBED . DimethylHBED combines oral effectiveness with superior chelating ability, selective hepatocellular action, and low apparent toxicity. It may represent a significant advance in the development of new iron chelating drugs.

Administration, Oral↗
PubMed1982

Evaluation of iron-chelating agents in an in vivo system: potential usefulness of EHPG, a powerful iron-chelating drug.

Fifteen compounds with a high affinity to ferric iron have been screened for in vivo iron-chelating efficiency in a rat model. One of the most potent of these drugs was ethylenediamine-N,N'-bis(o-hydroxyphenylglycine) (EHPG). EHPG-induced iron excretion was up to 8 times higher than iron excretion induced by identical doses of desferrioxamine (DF). Studies employing selective radio-iron probes of reticuloendothelial and parenchymal iron stores showed that although EHPG is able to interact with both storage iron compartments, its effect on parenchymal iron is much more pronounced. Unlike DF which has two alternative routes of excretion, EHPG-induced iron excretion is restricted mainly to the gut. Although EHPG seems to be superior to DF in both its chelating efficiency and preferential interaction with hepatic parenchymal iron stores, information on its in vivo toxicity is at present insufficient and it cannot yet be recommended for clinical use.

Animals↗
PubMed2005

Iron and iron chelating agents modulate Mycobacterium tuberculosis growth and monocyte-macrophage viability and effector functions.

Excess of iron promotes Mycobacterium tuberculosis infection, its replication and progression to clinical disease and death from tuberculosis. Chelation of iron may reduce M. tuberculosis replication, restore host defence mechanisms and it could constitute an application in the prevention and treatment strategies where both iron overload and tuberculosis are prevalent. We investigated the effect of iron and iron chelating agents, like desferrioxamine and silybin, individually and in combination with iron on mycobacterial number, viability in culture and after recovery from monocyte-macrophages, together with monocyte-macrophages viability and oxidative defence. Mycobacterial number and viability in culture were assessed using real-time quantitative PCR of H37Rv IS6110 DNA, 16S rRNA and 85B mRNA, whereas the microplate AlamarBlue(TM) assay was used to detect viability in culture post-infection. Mitochondrial membrane potential and phosphatidyl serine exposure of monocyte-macrophages, detected using Mitotracker Red fluorescence and Annexin V binding, respectively, served as indicators of host cell viability. Superoxide generation served as marker of monocyte-macrophage effector functions. Extracellular H37Rv showed a significant increase in number and viability in presence of excess iron and, by large, a significant decrease in number and viability in presence of the iron chelating agents, silybin and desferrioxamine, compared to cultivation without supplementation. Intracellularly, excess iron increased H37Rv viability significantly but reduced monocyte-macrophages mitochondrial membrane potential and compromised superoxide production. Desferrioxamine had little influence on intracellular parameters, but consistently prevented effects of excess iron, while silybin significantly altered most intracellular parameters and mostly failed to prevent effects of excess iron. These findings suggest that chelation therapy should be considered in conditions of iron overload and that effective chelating agents like desferrioxamine, with limited intracellular access might need to be used in combination with lypophilic chelating agents.

Base Sequence↗