Arsenic chelation therapy

Karman, G.M., Flora, S.J.S. (2006). Combined administration of N-acetylcysteine (NAC) and monoisoamyl DMSA on tissue oxidative stress during arsenic chelation therapy. Biol. Trace Elem. Res. 110 43-60. 

The answer is A. This patient exhibits several signs of acute arsenic exposure, including the cholera-like gastrointestinal symptoms and probable dehydration. He may currently be in hypovolemic shock and beginning chelation therapy is the only recourse. Arsenic is a metabolic toxin because it inhibits enzymes that require lipoic acid as a coenzyme the PDH complex, the a-ketoglutarate dehydrogenase complex, and trans-ketolase of the pentose phosphate pathway. 

Treatment of acute arsenic poisoning includes removal from the exposure source, supportive measures for loss of fluids, and chelation therapy (Ibrahim et al., 2006). Chelators that can be used include dimercaprol or 2,3-dimercaptosuccinic acid. In cases of renal failure, hemodialysis should be considered. 

Arsenic Toxicosis. Urine arsenic is the best indicator of current or recent exposure. Atomic absorption spectrophotometry is preferred as the detection method. Hair or fingernail sampling may also be helpful. Use of blood is useful if analyzed soon after exposure or in cases of continuous chronic exposure. After acute exposure, chelation therapy is instituted utilizing either (1) Dimercaprol BAL (British Anti-Lewisite) and analogues ... 

Chronic Exposure (Arsenic). Primarily symptomatic treatment is chosen. Chelation therapy is practiced, but its usefulness in cases of chronic exposure is still questionable. 

The origins of chelation therapy can be traced back to the treatment of First World War soldiers who had suffered from gas attacks that used the arsenic-based toxin, Lewisite. A dithiol, British anti-Lewisite (BAL), was developed to remove the toxic metal. 

Similar to the mustard agents, exposure prevention is the first line of defense against lewisite. Rapid decontamination is especially relevant to lewisite exposure due to the rapid development of pain (1-2 min) associated with lewisite exposure. Unlike other vesicants, an effective antidote for lewisite toxicity exists in the form of British anti-lewisite (BAL 2,3-dimercaptopropanol) which binds with arsenicals, thereby countering the lewisite-induced damage. Such chelation therapy is associated with notable side effects (e.g. renal effects) and requires carefiil medical management. More effective analogs of BAL have been developed with less significant side effects. 

The co-administration of M. oleifera seed powder with arsenic protects animals from arsenic induced oxidative stress and reduce body arsenic burden (49). Exposure of rats to arsenie (2.5 mg/kg, intraperitoneally for 6 weeks) increases the levels of tissue reaetive oxygen species (ROS), metallothionein (MT) and thiobarbitnrie aeid reaetive substance (TEARS) and is accompanied by a decrease in the aetivities in the antioxidant enzymes such as superoxide dismutase (SOD), eatalase and glutathione peroxidase (GPx). Also, Arsenic exposed mice exhibits hver injury as reflected by reduced acid phosphatase (AGP), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) activities and altered heme synthesis pathway as shown by inhibited blood 8-aminolevulinic acid dehydratase (5-ALAD) activity. Co-administration of M. oleifera seed powder (250 and 500 mg/kg, orally) with arsenie significantly increases the activities of SOD, catalase, GPx with elevation in redueed GSH level in tissues (liver, kidney and brain). These ehanges are accompanied by approximately 57%, 64% and 17% decrease in blood ROS, liver metallothionein (MT) and lipid peroxidation respectively in animal eo-administered with M. oleifera and arsenic. There is a reduced uptake of arsenie in soft tissues (55% in blood, 65% in liver, 54% in kidneys and 34% in brain) following eo-administration of M. oleifera seed powder (particularly at the dose of 500 mg/kg). This points to the fact that administration of M. oleifera seed powder could be beneficial during chelation therapy with a thiol chelator (26). 

Chelation therapy often is begun with dimercaprol (3—4 mg/kg intramuscularly every 4—12 hours) until abdominal symptoms subside and charcoal (if given initially) is passed in the feces. Oral treatment with penicillamine then may be substituted for dimercaprol and continued for 4 days. Penicillamine is given in 4 divided doses to a maximum of 2 g/day. If symptoms recur after cessation of chelation therapy, a second course of penicillamine may be instituted. Succimer (2,3-dimercaptosuccinic acid), a derivative of dimercaprol, is efficacious in the treatment of arsenic poisoning but is FDA-approved only for lead chelation in children. 

Acute arsenic poisoning Acute arsenic poisoning results in severe gastrointestinal discomfort, vomiting, ricewater stools, and capillary damage with dehydration and shock. A sweet, garlicky odor may be detected in the breath and the stools. Treatment consists of supportive therapy to replace water and electrolytes, and chelation therapy with dimercaprol. 

Earlier we mentioned that chelation therapy is used in the treatment of lead poisoning. Other metals, such as arsenic and mercury, can also be removed using chelating agents. 

Pachauri, V, Mehta, A., Mishra, D., et al., 2013. Arsenic induced neuronal apoptosis in guinea pigs is Ca " dependent and abrogated by chelation therapy role of voltage gated calcium channels. Neurotoxicology 35, 137-145. 

The -SH groups of dimercaptopropanol react with heavy metal ions including arsenic, to form very stable five-membered chelate rings, displacing heavy metal ions that would otherwise bind to essential -SH groups of enzymes such as succinoxidase and pyruvic oxidase. In this way, most of the enzyme activity can be restored if therapy is commenced soon after exposure. 

There is limited evidence to recommend combined chelation and blood purification therapy for other heavy metal poisonings, such as copper, mercury, arsenic, and thalhum. There are case reports, however, outlining several such attempts. Treatment of cupric sulfate ingestion by dimercaprol and penicillamine chelation followed by hemoperfusion and hemodia-filtration has been reported [57]. An interesting case of inorganic mercury poisoning treated with DMPS chelation and continuous venous-venous hemodiafiltration (CVVHDF) was also reported [58]. It should be noted that treatment continued for 14 days with a hmited total removal of mercury (<13% of the ingested dose) in... 

In acute exposure prompt medical attention is critical. The victim should be immediately removed to fresh air and away from the source of exposure. Oxygen should be provided if there is a respiratory distress. Initial therapy should be directed at stopping the ongoing hemolysis by performing exchange transfusion. Currently there is no other treatment to decrease arsine hemolysis however, studies in vitro have shown that some dithiol chelators (meso-2,3-dimercaptosuccinic acid, DMSA 2,3-dimercapto-l-propanesulfonic acid, DMPS and 2,3-butanedithiol) are effective (see Further Reading). This should be followed by aims to restore renal function or compensate for lost renal function (hemodialysis). This process does not remove any formed arsenic from the exposed body. Administration of dimercaprol (British Anti-Lewisite, BAL) has no effect on arsine hemolysis, but it lowers blood arsenic levels resulting from arsine exposure. The use of chelators must be... 

After long-term exposure to arsenic, treatment with dimercaprol and penicillamine also may be used, but oral penicillamine alone usually is sufficient. The duration of therapy is determined by the clinical condition of the patient, and the decision is aided by periodic determinations of urinary arsenic concentrations. Adverse effects of the chelating agents may limit the usefulness of therapy. Dialysis may become necessary with severe arsenic-induced nephropathy successful removal of arsenic by dialysis has been reported. 

The mechanism of arsenic poisoning is illustrated by the following cartoon. Arsenic forms a coordination complex with thiol emits of a protein. Thiols (R-SH) are the sulfur analogs of alcohols, and much of the chemistry is similar. When DMSA is administered, the therapy relies on DMSA forming a better coordination (ate) complex with the metal. Formation of the new complex will clear the metal from the protein, and the DMSA complex should be soluble in water, thus allowing the body to excrete the complex in the urine. The Lewis base-Lewis acid properties of the metal (Lewis acid) and the chelating agent (DMSA, the Lewis base) are the basis of this therapy. 

---