Chelators as Antidotes of Metal Toxicity: Therapeutic and Experimental Aspects

Abstract

The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal poisoning are also different for each chelating drug. The chelating drugs with worldwide application are dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa(2)EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa(3)DTPA, ZnNa(3)DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic homologues and experimental chelating agents have been designed and tested in vivo for their metal binding effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal poisoning. Within this context it has been shown in experiments using young and adult animals that metal toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of new therapeutic chelation protocols for metal toxicity.

Posterior subcapsular opacity in two patients with thalassaemia major following deferiprone consumption

“…The presumed false negative histopathology may result from improper sampling or contamination and dilution of the affected subcapsular cortex with adjacent unaffected cortex. In addition, the competitive affinity of both, deferiprone and Prussian blue for iron chelation 11 may be responsible for the false negative result.…”

Cadmium Toxicity Revisited: Focus on Oxidative Stress Induction and Interactions with Zinc and Magnesium

“…The most common agents, which have been used against heavy metal poisoning since World War 2 are chelators, starting with British Anti-Lewisite (BAL). After the war, calcium disodium ethylenediaminetetraacetate (CaNa 2 EDTA), deferoxamine, and D-penicillamine were introduced in clinical practice (75). However, none of the available chelating drugs is effective against poisoning with Cd because it quickly enters the tissue and binds to metallothioneins (14,75).…”

“…However, none of the available chelating drugs is effective against poisoning with Cd because it quickly enters the tissue and binds to metallothioneins (14,75). Some chelating agents such as polyaminocarboxylic acids [e. g. CaNa 2 EDTA, calcium trisodium diethylenetriaminepentaacetate ( C a N a 3 D T PA ) , a n d z i n c t r i s o d i u m diethylenetriaminepentaacetate (ZnNa 3 DTPA)], carbodithioates, deferoxamine (DFO), N-acetylcysteine (NAC), and 2,3-dimercaptosuccinic acid and its esters have shown some effectiveness in experimental animals when applied very soon after Cd exposure (75).…”

The Role of Chelation in the Treatment of Other Metal Poisonings

“…Both deferiprone and deferasirox chelate copper and zinc and could potentially induce harm through deficiency of these trace essential nutrients. Other risks include agranulocytosis, renal failure, hepatic impairment (including hepatic fibrosis and frank failure), and gastrointestinal hemorrhage [49,50].…”

“…This is based on a fairly large body of literature. DTPA is nephrotoxic, teratogenic, embryotoxic, and associated with suppressed hematopoiesis [50]. DPTA is associated with significant bycatch of numerous other endogenous substances (calcium, zinc, magnesium, manganese, and metalloproteinase depletion).…”