2, 3-Dimercaprol DMSA

One of the chemical derivatives of dimercaprol (BAL) is DMSA. DMSA is an orally active chelating agent, much less toxic than BAL, and its therapeutic index is about 30 times higher (Angle and Kuntzelman, 1989). The empirical formula of DMSA is C4H6O4S2 and its molecular weight is 182.21. It is a weak acid soluble in water. 

In severe lead poisoning sodium calciumedetate is commonly used to initiate lead excretion. It chelates lead from bone and the extracellular space and urinary lead excretion of diminishes over 5 days thereafter as the extracellular store is exhausted. Subsequently symptoms (colic and encephalopathy) may worsen and this has been attributed to redistribution of lead from bone to brain. Dimercaprol is more effective than sodium calciumedetate at chelating lead from the soft tissues such as brain, which is the rationale for combined therapy with sodium calciumedetate. More recently succimer (2,3-dimercaptosuccinic acid, DMSA), a water-soluble analogue of dimercaprol, has been increasingly used instead. Succimer has a high affinity for lead, is suitable for administration by mouth and is better tolerated (has a wider therapeutic index) than dimercaprol. It is licenced for such use in the USA but not the UK. 

Succimer is the meso isomer of 2,3-dimethylmercapto-succinic acid (DMSA). It is used as a lead chelator for oral administration (1). Nausea, vomiting, diarrhea, and anorexia are common. Rashes, sometimes necessitating withdrawal, have been reported in up to 10% of adults and 5% of children, and mild transient rises in serum transaminase activity in 6-10% (mostly adults) (2,3). Life-threatening hyperthermia occurred on two occasions in one subject, but no details were given. Iron can be safely and effectively given to patients taking succimer, which (unlike dimercaprol) does not appear to deplete iron stores or to form a toxic chelate that would preclude the parenteral administration of iron (3). 

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... 

DMPS and DMSA can be used to increase Hg excretion. Dimercaprol (BAL), used in the past for chelation, is contraindicated because it redistributes Hg to the brain. 

Two water-soluble analogs of dimercaprol have been studied as lewisite antidotes, namely meio-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto- 1-propane sulfonic acid (DMPS) (see review by Aposhian, 1993). Their structures are as follows ... 

DMPS and DMSA applied to the skin would probably be of value in lewisite-induced vesication. However, the disadvantages of dimercaprol largely relate to systemic treatment and the water-soluble analogues are unlikely to be better than dimercaprol ointment. 

Initial treatment of the acute phase of lead intoxication involves supportive measures. Prevention of further exposure is important. Seizures are treated with diazepam or phenytoin (see Chapter 19), fluid and electrolyte balances must be maintained, and cerebral edema is treated with mannitol and dexamethasone or controlled hyperventilation. The concentration of lead in blood should be determined or at least a blood sample obtained for analysis prior to initiation of chelation therapy. Chelation therapy is indicated in symptomatic patients or in patients with a blood lead concentration in excess of 50-60 pg/dL (about 2.5 pM). Four chelators are employed edetate calcium disodium (CaNa EDTA), dimercaprol, D-penicillamine, and succimer (2,3-dimercaptosuccinic acid [DMSA], chemet). CaNa EDTA and dimercaprol usually are used in combination for lead encephalopathy. 

B. Succimer Succimer (2.3-dimercaptosuccinic acid DMSA) is a water-soluble bidentate congener of dimercaprol with oral bioavailability. 

I. Pharmacology. Penicillamine is a derivative of penicillin that has no antimicrobial activity but effectively chelates some heavy metals such as lead, mercury, and copper. It has been used as adjunctive therapy after initial treatment with calcium EDTA (see p 440) or BAL (dimercaprol p 413), although its use has largely been replaced by the oral chelator sucdmer (DMSA, p 501) because of its poor safety profile. Penicillamine is well absorbed orally, and the penicillamine-metal complex is eliminated in the urine. No parenteral form is available. 

Section II Arsenic Arsine Lead Mercury Section III BAL (Dimercaprol) EDTA, Calcium (Calcium Disodium EDTA, Calcium Disodium Edetate, Calcium Disodium Versenate) Succimer (DMSA) Unithiol (DMPS)... 

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