Are we ready to replace dimercaprol (BAL) as an arsenic antidote?

Abstract

<jats:p> 1 Dimercaprol (BAL), 2,3-dimercaptopropanesulpho nate sodium (DMPS) and meso-2,3-dimercaptosucci nic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. </jats:p><jats:p> 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication - espe cially with lipophilic organoarsenicals - may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular avail ability. </jats:p><jats:p> 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (=Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. </jats:p><jats:p> 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL when ever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of- no-return is a limiting factor, BAL may still have a place as an arsenic antidote. </jats:p>

A case of secondary diabetes mellitus associated with chronic arsenic toxicity

“…[39] Additionally, animal models suggest that DMSA may be inferior to BAL in critically-intoxicated patients or those with chronic exposure (who will likely have a higher concentration of intracellular arsenic) due to the relatively high membrane permeability of BAL. [36,38] The present case provides an excellent example of the clinical progression of arsenicosis. Following her initial presenting symptoms of nausea and diarrhea (which are common initial symptoms of arsenic toxicity), her clinical course eventually included many of the known features of chronic exposure, including hyperkeratosis of the palms and soles, hyperpigmentation of the trunk and extremities, peripheral neuropathy, and hyperglycemia.…”

“…As previously discussed, the evidence suggests that BAL has a higher membrane permeability compared to DMSA, and may therefore have better efficacy in patients with chronic exposure. [36,38] Indeed, the patient's serum and urine arsenic levels dropped below the threshold for detection by the completion of her course of therapy. Additionally, the dose of BAL that was used (2.5 mg/kg) was within the recommended range of 2.5-3 mg/kg, above which dose-dependent adverse effects become more frequent.…”

“…[37] In animal models, DMSA was associated with improved survival and similar arsenic elimination rates as compared to BAL. [35,36,38] However, its efficacy for treatment of arsenic toxicity is limited to case reports and animal experiments; the only prospective trial using DMSA in humans, which was conducted in a small group of people in West Bengal exposed to arsenic-contaminated drinking water, showed no additional clinical improvement when compared to placebo. [39] Additionally, animal models suggest that DMSA may be inferior to BAL in critically-intoxicated patients or those with chronic exposure (who will likely have a higher concentration of intracellular arsenic) due to the relatively high membrane permeability of BAL.…”

Agentes quelantes sulfidrílicos: uma revisão

“…A presença de dois grupos -SH vicinais é reconhecida como a estrutura essencial para a eficácia do agente quelante (38). Em intoxicações agudas por mercúrio, por exemplo, uma das terapêuti-cas fundamentais é utilizar compostos que apresentem na sua estrutura grupos sulfidrílicos (-SH), incluindo o BAL, a D-penicilamina (36, 47, 32) e o ditiotreitol (DTT) (50).…”

The Renal Na+-Dependent Dicarboxylate Transporter, NaDC-3, Translocates Dimethyl- and Disulfhydryl-Compounds and Contributes to Renal Heavy Metal Detoxification

“…DMPS is formally derived from the relatively toxic dimercaprol (2,3-dimercatopropane; British anti-lewisite or BAL) by adding a hydrophilic sulfonate group and is now considered to replace BAL whenever the duration of therapy is not critical (30). In humans, urinary mercury excretion was enhanced by a factor of more than 15 from 106 g/24 h to 1754 g/24 h when DMPS was applied (31).…”