The industrial applications of chelating agents. Chelation and catalysis.
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Catalysis↗
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[Harmful effects of common drugs on the visual apparatus. The oligo-elements and chelating agents. B. Chelating agents].
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Chelating Agents↗
Developmental toxicity of metal chelating agents.
Chelation therapy is the basis for the treatment of metal poisoning. A number of chelating agents have been widely used since the 1950s. Since these agents can be potentially given to a metal-intoxicated pregnant woman, their intrinsic developmental toxicities are a matter of concern. While the embryo/fetal toxic effects of some chelators have been reported to occur at doses higher than those currently given in the medical treatment of metal poisoning, according to experimental data the potential use of other metal antidotes is controversial. In those cases, the benefits and risks of usage should be carefully weighed. The developmental toxicity of known chelators of clinical interest is presented here. Chelating agents were divided according to the following structurally related categories: polyaminocarboxylic acids, chelators with vicinal -SH groups, beta-mercapto-alpha-aminoacids, hydroxamic acids, ortho-hydroxycarboxylic acids, and miscellaneous agents. Since it has been demonstrated that the teratogenic potential of most chelators is, at least in part, due to induced trace element deficiencies, the advisability of mineral supplements during chelation treatment is also discussed.
Abnormalities, Drug-Induced↗
Intracellular plutonium: removal by liposome-encapsulated chelating agent.
Chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were successfully encapsulated within lipid spherules (that is, liposomes). Encapsutlated [(14)C]EDTA, given intravenously to mice, was retained longer in tissues that nonencapsulated [(14)C]EDTA. Encapsulated DTPA, given to mice 3 days after pluttonium injection, removed an additional fraction of plutonium in the liver, presumably intracellular, not available to nonencapslulated DTPA. It also further increased urinary excretion of plutonium. Introduction of chelating agents into cells by liposomal encapsulation is a promising new approach to the treatment of metal poisoning
Animals↗
Induction of hepatic metallothionein in mouse liver following administration of chelating agents.
Chelating agents commonly used in therapy of heavy metal intoxication alter the levels of essential metals in liver, kidneys, and serum. Induction of metallothionein synthesis in liver occurs following exposure to a variety of chemical and environmental insults and, in some cases, has been attributed to enhanced hepatic uptake of zinc. Therefore, the effect of acute exposure to seven common metal chelators on the concentration of metallothionein in liver was investigated. Adult male Swiss Webster mice were injected intraperitoneally with the chelators and hepatic metallothionein was quantified by the cadmium radioassay. Ethylenediaminetetraacetic acid (EDTA) produced a 5- to 6-fold increase in hepatic metallothionein 24 hr after injection of 0.75 to 3.0 g/kg. No significant increase in hepatic MT was observed until 12 hr following injection of EDTA (1.5 g/kg, ip). Maximal levels were reached between 12 and 48 hr following EDTA injection. Cadmium, a known inducer of hepatic metallothionein, produced a 15-fold increase in the concentration of MT in liver 24 hr following injection. By comparison, 2,3-dimercaptopropanol and diethyldithiocarbamate produced a 9-fold and 13-fold increase in hepatic metallothionein levels, respectively, 24 hr following injection. A 4- to 6-fold increase in metallothionein was observed 24 hr following injection of 2,3-dimercaptosuccinic acid, D,L-penicillamine, diethylenetriaminepentaacetic acid, and EDTA, while nitrilotriacetic acid elevated hepatic metallothionein levels by 2-fold. Alterations in the concentration of hepatic metallothionein by chelators may have implications for their efficacy in the treatment of cadmium intoxication.
Animals↗
[Studies on porphyrin related compounds and tumor tissue affinities. I. Synthesis of a carrier for tumor imaging agent, bifunctional chelating agent coupled porphyrin (ATN-2)].
A carrier for a new tumor imaging agent, a bifunctional chelating agent (BCA)-coupled porphyrin (ATN-2), has been synthesized from protoporphyrin dimethyl ester in 4 steps. At first, the hydrobromination of protoporphyrin dimethyl ester is carried out to obtain a monobromo derivative. The derivative is treated with ethylene glycol. The resulting porphyrin has an ether group at the either 7- or 12-position of the ring. Metallation with GaCl3 of the porphyrin having a ethylene glycol residue affords Ga-metalloporphyrin. Final condensation of the metalloporphyrin with diethylenetriaminepentaacetic acid (DT-PA) gave BCA-coupled porphyrin (ATN-2). The chelation of ATN-2 with 111InCl3 easily afforded [111In]ATN-2. This agent was used for imaging transplantable pancreatic carcinoma in Syrian golden hamster at 72 h after postinjection. The efficacy of the new agent was compared with that of [67Ga]citrate. The images with [111In]ATN-2 were found to be clearer than those with [67Ga]citrate. Therefore, ATN-2, a carrier for 111InCl3, seems to be more useful for tumor imaging agents.
Animals↗
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↗
In vitro studies of the calculus-inhibiting properties of tooth surface polishing agents and chelating agents.
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Animals↗
Environmental chemistry of aminopolycarboxylate chelating agents.
Aminopolycarboxylate chelating agents are under scrutiny due to their influence on metal availability and mobility and in particular due to their persistence in the environment. In this review chelate adsorption, metal-mobilization, metal-exchange, mineral dissolution, reactive transport, photodegradation, and chemical degradation are all shown to be substantially affected by the chelated metal ion. The different reactivities of the metal-complexes have to be considered when assessing the reactions of chelating agents in the environment because they occur in natural waters predominantly in the form of metal complexes. Knowing the speciation of chelating agents in natural waters is therefore crucial for predicting their environmental fate. Despite this importance, only a few speciation measurements have been reported for natural waters, and model calculations have been frequently used instead. These calculations are, however, complicated by slow metal-exchange reactions that result in a nonequilibrium speciation and by the presence of naturally occurring ligands that compete with the chelating agents for available metals. The basis for a refined risk assessment of aminocarboxylate chelates should be the actual speciation in the natural water directly determined by analytical methods. The discussion of the influence of chelates on metal availability and fate also has to include the potential presence of other aminopolycarboxylate chelating agents besides the well-known EDTA and NTA.
Biological Availability↗
Determination and metabolism of dithiol chelating agents: the zinc chelate of the dimethyl ester of meso-2,3-dimercaptosuccinic acid increase biliary excretion of cadmium and platinum.
meso-2,3-Dimercaptosuccinic acid is an orally active chelating agent useful for the treatment of lead intoxication. Since it is believed to be extracellular in its distribution, analogs have been synthesized in a search for one that will enter the cell and successfully complete for firmly bound intracellular toxic heavy metals such as cadmium and platinum. The biological properties of the zinc chelate of DiMeDMSA, ([Zn(DiMeDMSA)2]2- with tetramethylammonium or sodium as the counterion, have been investigated in the rat. In short-term (hourly) experiments, [Zn(DiMeDMSA)2]2- increased the biliary excretion of cadmium and platinum. In experiments of longer duration (days), severe renal toxicity was noted even in the absence of any exogenously administered cadmium chloride or cis-dichlorodiammineplatinum(II). The zinc content of the kidneys of rats receiving Na2[Zn(DiMeDMSA)2]2- was found to be about 10-fold greater than rats receiving saline or meso-dimethyldimercaptosuccinic acid. Although it appears that the source of the zinc is the injected [Zn(DiMeDMSA)2]2-, at this time it is unknown as to whether the toxicity is due to the Zn chelate molecule, per se, or Zn derived from the molecule after its degradative biotransformation.
Animals↗
Stability of injection solutions of vitamin B1 Part 1: Influence of chelating agents.
The chelating agents EDTA, DTPA and HEDTA increase the stability of thiamine hydrochloride solutions. The stabilizing efficiency of HEDTA and DTPA is highly superior to that of EDTA. There is an optimum concentration of EDTA at which its stabilizing effect is maximum; beyond this concentration, the stability of the vitamin decreases gradually by increasing EDTA concentration. EDTA at a comparatively high concentration (10 mmole/1) catalyzes thiamine degradation. The stabilizing action of DTPA increases gradually as a function of its concentration. On the other hand, HEDTA in a very low concentration (0.5 mmole/1) affords a definite inhibitory effect on the rate of thiamine cleavage. However, increasing HEDTA concentration from 0.5 up to 3.0 mmole/1 does not increase its stabilizing efficiency. At HEDTA concentrations higher than 3 mmole/1, the stability of the vitamin increases gradually as a function of the chelating agent concentration.
Chelating Agents↗
Treatment of experimental acute uranium poisoning by chelating agents.
Sixteen chelating agents were examined to determine their relative efficacy as antidotes in acute uranyl acetate intoxication in mice after subcutaneous administration. Chelators were administered intraperitoneally to male Swiss mice at a dose equal to one-fourth of their respective LD50 and the therapeutic effectiveness was calculated. Eight compounds resulted in a significant enhancement of the survival rate: Tiron, gallic acid, DTPA, p-aminosalicylic acid, sodium citrate, EDTA, 5-aminosalicylic acid and EGTA. Therapeutic indices (TI) were then determined for these chelating agents. Tiron (TI: 158), gallic acid (TI: 116) and DTPA (TI: 44.9) were the most effective antidotes. In subsequent experiments, uranyl acetate dihydrate was administered subcutaneously (10 mg/kg) in a 24 hr excretion and distribution study. The previous eight chelators were given intraperitoneally ten min. after the uranium administration. 5-Aminosalicylic acid and tiron were consistently the most effective in increasing the urinary and faecal excretion of uranium respectively. A decrease of the uranium concentration in kidneys and bone was also noted with tiron. Tiron appears to be the most effective agent of those tested in the prevention of acute uranium intoxication.
Animals↗
Protection of mice against the lethal effects of sodium metavanadate: a quantitative comparison of a number of chelating agents.
10 Chelating agents were administered to mice by intraperitoneal (i.p.) injection in order to compare their relative effectiveness in preventing death after a single i.p. injection of NaVO3. Ascorbic acid, Tiron (4,5-dihydroxy-1,3-benzene-disulfonic acid) and deferoxamine were the most effective antidotes for acute NaVO3-toxicity. The therapeutic index of ascorbic acid against 0.61 mmol/kg NaVO3 was found to be 95.2. This was 4.6 and 12.2 times greater than those of Tiron and Deferoxamine respectively. L-Cysteine greater than Na2CaEDTA greater than Na3CaDTPA reduced the acute mortality of mice following i.p. injection of NaVO3. Sodium salicylate, D,L-penicillamine, DMSA and DDC were not effective as antidotes for acute NaVO3-toxicity.
Animals↗
Mobilization of heavy metals by newer, therapeutically useful chelating agents.
Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, Dimaval) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulfide in which each of the sulfur atoms of DMSA is in disulfide linkage with an L-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.
Animals↗
Direct modulation of volume-regulated anion channels by Ca(2+) chelating agents.
Ca(2+) chelating agents are widely used in biological research for Ca(2+) buffering. Here we report that BAPTA, EDTA and HEDTA produce fast, reversible, voltage-dependent inhibition of swelling-activated Cl(-) current (I(Cl,swell)) in LNCaP prostate cancer epithelial cells that is unrelated to their Ca(2+) binding. BAPTA was the most effective (maximal blockade 67%, IC(50)=70 microM, at +100 mV) followed by EDTA and HEDTA. I(Cl,swell) blockade by EDTA was pH-dependent. BAPTA blocked I(Cl,swell) also in other cell types. We conclude that Ca(2+) chelating agents block I(Cl,swell) by acting directly on the underlying channel, and that the negative charge of the free chelator form is critical for the blockade.
Calcium↗
Effects of selected chelating agents on organ distribution and excretion of manganese after inhalation exposure to 54MnCl2. I. Injection of chelating agents.
The effect of 1,2-cyclohexylene-aminotetraacetic acid (CDTA), diethylenetriaminepentaacetis acid (DTPA) and 2,3-dimercaptol-1-propanesulphonic acid, sodium salt (DMPS) on Mn distribution and excretion in rats was examined after 1 hr exposure to 54MnCl2 (approximately 0.1 microgram Mn/m3). All complexing agents were injected i.p., 0.32 mM/kg/day, for 7 days, starting either immediately after exposure (day 0, group I), or 1 week after exposure (day 7, group II). The controls were injected i.p. with 4 ml/kg of 0.9% saline. Activity of 54Mn was determined in lung, liver, kidney, and brain, 24 hrs after the last treatment and in urine and feces collected for 24 hrs on days 1-7 and 8-14 respectively. CDTA and DTPA administered immediately after Mn exposure appeared to be most effective, resulting in a two-fold decrease of 54Mn in brain and kidney, and a statistically significant decrease in lung (DTPA) and liver (CDTA). In group II a two-fold decrease of 54Mn in kidney and liver was observed with CDTA. There was also a decrease after DTPA administration. DMPS was not effective in these experiments. On the first day after exposure, 54Mn levels in urine were more than 15 and 25 times higher for CDTA and DTPA, respectively than for saline, in the early treatment group. Excretion of Mn in feces was not affected. Our data show that the effectiveness of removing inhaled Mn depends both on the complexing agent and the time of its administration.
Animals↗
[Enhancement of 67Ga tumor-to-blood ratios by chelating agent (author's transl)].
Chelating agent, such as CaEDTA, CaDTPA, D-penicillamine, DMSA, desferoxamine, NTA, cysteine ethyl ester, BAL, alpha-MPG, phthalein complexone, were tested as a possible contrast enhancing agent for tumor imaging with 67Ga-citrate. The intravenous administration of a chelating agent to Ehrlich's tumor bearing mice, one hour after the injection of 67Ga-citrate, accelerated the blood clearance with only a very slight change of activity in the target, increasing the tumor-to-blood ratio, and consequently achieving a better visualization. Among the tested chelating agents, D-penicillamine showed the highest target-to-nontarget ratio at a shorter time: a good tumor-to-blood ratio, performed after 24 hr with non-treated animals, was achieved in only 1-3 hr with post-treated animals. Thus, D-penicillamine hold a considerable promise as a contrast enhancing agent for future clinical use.
Animals↗