Succimer(meso-2,3-dimercaptosuccinic acid [DMSA]) is a chelating agent that isused in the treatment of intoxication from several heavy metals. Awater-soluble analog of BAL (dimercaprol; see BAL [Dimercaprol]),succimer enhances the urinary excretion of lead and mercury. Its effecton elimination of the endogenous minerals calcium, iron, and magnesiumis insignificant. Minor increases in zinc and copper excretion mayoccur. In an animal model, oral succimer was not associated with asignificant increase in GI absorption of lead; the effect of oralsuccimer on GI absorption of mercury and arsenic is not known.

Afteroral administration, peak blood concentrations occur in approximately 3hours. Distribution is predominantly extracellular, and in the blood itis extensively bound (> 90%) to plasma proteins. Succimer iseliminated primarily in the urine, where 80–90% appears as mixeddisulfides, mainly 2:1 or 1:1 cysteine-succimer adducts. Studiessuggest that these adducts, rather than the parent drug, may beresponsible for metal chelating activity in vivo. The eliminationhalf-life of transformed succimer is approximately 2–4 hours. Renalclearance may be diminished in the setting of pediatric leadintoxication.

Drug Indications ::

Indications

Succimer is approved for treatment of leadintoxication, where it is associated with increased urinary excretionof the metal and concurrent reversal of metal-induced enzymeinhibition. Oral succimer is comparable to parenteral calcium EDTA [seeEDTA, Calcium (Calcium Disodium EDTA, Calcium Disodium Edetate, CalciumDisodium Versenate)] in decreasing blood lead concentrations. Althoughsuccimer treatment has been associated with subjective clinicalimprovement, controlled clinical trials demonstrating therapeuticefficacy have not been reported. A recent large, randomized,double-blind placebo-controlled trial of succimer in children withblood lead concentrations between 25 and 44 mcg/dL found no evidence ofbenefit on clinical outcome or long-term blood lead reduction.

Succimer is protective against the acute lethal and nephrotoxic effects of mercuric saltsin animal models and increases urinary mercury excretion in animals andhumans. It therefore may have clinical utility in the treatment ofhuman poisoning by inorganic mercury.

Succimer is protective against acute lethal effects of arsenic in animal models and may have potential utility in acute human arsenic poisoning.

Drug Contra-Indications ::

III. Contraindications. Historyof allergy to the drug. Because succimer and its transformationproducts undergo renal elimination, safety and efficacy in patientswith severe renal insufficiency are uncertain. There is no availableevidence that succimer increases hemodialysis clearance of toxic metalsin anuric patients.

Drug Adverse Effects ::

IV. Adverse effects

Gastrointestinaldisturbances including anorexia, nausea, vomiting, and diarrhea are themost common side effects and occur in less than 10% of patients. Theremay be a mercaptan-like odor to the urine; this has no clinicalsignificance.

Mild, reversible increases in liver transaminases have been observed in 6–10% of patients.

Rashes, some requiring discontinuation of treatment, have been reported in less than 5% of patients.

Isolated cases of mild to moderate neutropenia have been reported.

E. Minimalincreases (less than twofold) in urinary excretion of zinc and copperhave been observed and have minor or no clinical significance.

F. Use in pregnancy. FDAcategory C (indeterminate). Succimer has produced adverse fetal effectswhen administered to pregnant animals in amounts one to two orders ofmagnitude greater than recommended human doses. However, succimer hasalso diminished the adverse effects of several heavy metals in animalstudies. Its effect on human pregnancy has not been determined (seeTable III–1).

Drug Lab Interactions ::

Drug or laboratory interactions. No known interactions. Concurrent administration with other chelating agents has not been studied adequately.

Drug Dose Management ::

Dosage and method of administration (adults and children)

Lead poisoning. Availabilityin the United States is limited to an oral formulation (100-mgcapsules) officially approved by the FDA for use in children with bloodlead levels 45 mcg/dL. However, DMSA can also lower lead concentrations in adults. Note:Administration of DMSA should never be a substitute for removal fromlead exposure. In adults, the federal OSHA lead standard requiresremoval from occupational lead exposure of any worker with a singleblood lead concentration in excess of 60 mcg/dL or an average of threesuccessive values in excess of 50 mcg/dL; however, recent data suggestthat removal at lower blood lead levels may be warranted. Prophylactic chelation,defined as the routine use of chelation to prevent elevated blood leadconcentrations or lower blood lead levels below the standard inasymptomatic workers, is not permitted. Consult the local or state health department or OSHA (see Table IV–3) for more detailed information.

1. Give 10 mg/kg (or 350 mg/m2 in children) orally every 8 hours for 5 days and then give the same dose every 12 hours for 2 weeks.

2. Anadditional course of treatment may be considered. based onposttreatment blood lead levels and the persistence or recurrence ofsymptoms. Although blood lead levels may decline by more than 50%during treatment, patients with high body lead burdens may experiencerebound to within 20% of pretreatment levels as bone stores equilibratewith tissue levels. Check blood lead levels 1 and 7–21 days afterchelation to assess the extent of rebound and/or the possibility ofreexposure.

3. Experiencewith oral succimer for severe lead intoxications (ie, leadencephalopathy) is very limited. In such cases, consideration should begiven to parenteral therapy with calcium EDTA [see EDTA, Calcium(Calcium Disodium EDTA, Calcium Disodium Edetate, Calcium DisodiumVersenate)].

Mercury and arsenic poisoning

1. Intoxicationby inorganic mercury compounds and arsenic compounds may result insevere gastroenteritis and shock. In such circumstances, the capacityof the gut to absorb orally administered succimer may be impairedseverely, and use of an available parenteral agent such as unithiol(see Unithiol [DMPS]) or BAL (BAL [Dimercaprol]) may be preferable.

2. Give 10 mg/kg (or 350 mg/m2)orally every 8 hours for 5 days and then give the same dose every 12hours for 2 weeks. Extending the duration of treatment in the presenceof continuing symptoms or high levels of urinary metal excretion shouldbe considered but is of undetermined value.

Drug Chemical Formulations ::

Formulations

Oral. Succimer, meso-2,3-dimercaptosuccinic acid, DMSA (Chemet), 100-mg capsules in bottles of 100.

Parenteral. Aparenteral form of DMSA (sodium 2,3-dimercaptosuccinate), infused at adose of 1–2 g per day, has been in use in the People’s Republic ofChina but is not available in the United States.

The suggested minimum stocking level to treat a 70-kg adult for the first 24 hours is 21 capsules.

Disclaimer ::

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