Combined Early Treatment with Chelating Agents DMSA and CaDTPA in Acute Oral Cadmium Exposure

Abstract

The influence of chelating agents: meso-2,3-dimercaptosuccinic acid (DMSA); calcium trisodium diethylenetriaminepentaacetate (CaDTPA) and their combination on mobilisation of cadmium (Cd) was compared in female albino rats. After oral Cd administration chelators were applied either orally (DMSA) or intraperitoneally (CaDTPA) at various short time intervals after Cd. Three experiments were carried out with four treatment groups in each: 1) Cd (control); 2) Cd+DMSA; 3) Cd+CaDTPA; 4) Cd+DMSA+CaDTPA. Time intervals for chelator treatment after Cd administration were: immediate application in the first, half an hour in the second and one hour in the third experiment. At the end of each experiment cadmium was analysed in kidney and liver. Additionally in experiment 3 essential elements (Fe, Cu, Zn) were also determined in the same organs. In experiment 2 the effect of the treatment on urinary elimination of cadmium, copper and zinc were analysed. Results showed that the efficiency of Cd removal from the body (kidneys and liver) is lower when the time between Cd and chelating agents administration is longer. The two chelators differ in efficiency in mobilizing Cd, with DMSA being more efficient than CaDTPA. The combined therapy with the two chelators gave generally better results. It seems that DMSA which is given orally after oral Cd administration removes this element very efficiently from the gastrointestinal tract. CaDTPA, however, which is given parenterally removes absorbed Cd less efficiently, Organs are not significantly depleted in iron and copper after chelation treatment. Only zinc concentration was, however, significantly lower in the liver and higher in kidneys only after CaDTPA and combined DMSA+CaDTPA chelation.

In vitro assessment of chelating agents with regard to their abstraction efficiency of Cd2+ bound to plasma proteins

“…48 Importantly, the adverse effects that DTPA exerts on plasma Ca 2+ in vitro can be easily avoided in vivo if patients are administered with [Ca-DTPA] 3À rather than DTPA. 23,36,49 Overall, the conducted in vitro studies revealed that each of the investigated chelating agents greatly affected the plasma distribution of Cd 2+ and Zn 2+ at all investigated doses (Table 1). Owing to the aforementioned complex interplay between several molecular events regarding the interaction between a chelating agent and a metal ion binding site on any given plasma protein (see a-d above), the efficiency of the investigated chelating agents with regard to the abstraction of Cd 2+ from plasma proteins at 0.33 mM decreased in the order DTPA (100% abstraction, Fig.…”

“…The obtained results are relevant to better understand the findings from studies in which Cd 2+ treated animals were treated with various chelating agents. 23,36,50 In general, the administration of DMSA, DTPA and DMPS (at different doses and via different administration routes) decreased the toxicity of Cd 2+ , 21,36 decreased the Cd body burden 49,51 and increased urinary Cd excretion. 36 Our in vitro data clearly demonstrated that DTPA was most efficient in mobilizing plasma protein bound Cd 2+ to a small molecular weight complex followed by DMPS and DMSA (Table 1).…”

Comparative effects of meso-2,3-dimercaptosuccinic acid, monensin, and salinomycin on cadmium-induced brain dysfunction in cadmium-intoxicated mice

“…It might also induce apoptosis of cerebral cortical neurons by altering Ca homeostasis and the Ca-mediated signalling pathway (Xu et al , 2011 ; Yuan et al , 2013 ). In humans, alteration of endogenous levels of Cu and Fe in the brain causes diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis, autism spectrum disorders, Huntington’s disease, Parkinson’s disease, Wilson’s disease, and prion disease (Desai & Kaler, 2008 ; Salvador et al , 2011 ; Strausak et al , 2001 ; Valensin et al , 2016 ; Zucca et al , 2017 ). A high concentration of Zn in the brain may accelerate the formation of fibrillar β-amyloid aggregation, leading to neurodegeneration (Cuajungco & Faget, 2003 ; Jomova et al , 2010 ).…”

The Role of Chelation in the Treatment of Other Metal Poisonings

“…Efficacy of chelation for cadmium is markedly time dependent [74][75][76][77]. Provision as "late" as 2 hours or more had the potential for absent effect.…”

“…Succimer (DMSA) improved survival [80], modestly decreased cadmium retention [75,86], and provided dose-dependent survival benefit, although with increased renal burden [76]. Along with diethylenetriaminepentaacetate (DTPA), which yielded dose-dependent increased survival [76], decreased cadmium retention [75], and decreased residual cadmium [78], DMSA is probably the chelator that has shown the most benefit in animal models. D-Penicillamine was variously shown to increase renal cadmium burden [80], produce no survival benefit [76], and demonstrate lack of efficacy [87].…”