THERAPEUTIC EFFICACY OF NEW DIMERCAPTOSUCCINIC ACID (DMSA) ANALOGS INACUTE ARSENIC TRIOXIDE POISONING IN MICE

The therapeutic efficacy of six newly synthesized analogues of dimerca ptosuccinic acid (DMSA) was investigated in acute arsenic trioxide poi soning in mice. Meso-2,3-di(acetylthio)succinic acid (DATSA) and meso- 2,3-di(benzoylthio)succinic acid (DBTSA) are analogues of DMSA with pr otected thiol groups (''prodrugs''), and DMDMS, DEDMS, DnPDMS, and DiP DMS are various di-esters of DMSA with methyl, ethyl, n-propyl, and is opropyl alcohols, respectively. Thirty minutes after s.c. injection of an LD80 of arsenic trioxide (65 mumol/kg) male NMRI mice were treated with a single equimolar dose (0.7 mmol/kg) of DMSA i. p. or one of th e analogues i. p. or via gastric tube (i. g.). Control animals receive d arsenic trioxide and saline 30 min later. The survival rate was reco rded for 30 days. All of the animals treated with DMSA i. p. survived and all controls died within 2 days. Administered i. g., DATSA and DBT SA increased the survival rate to 29% and 43%, and injected i.p. to 86 %. Treatment with DMDMS i. p. and i. g., and with DEDMS, DnPDMS, and D iPDMS i. g. did not reduce lethality. Given i.p., DnPDMS increased the survival rate to 72%, and DEDMS and DiPDMS to 86%, respectively. To i nvestigate the efficacy of the DMSA analogues in reducing the tissue c ontent of arsenic, male NMRI mice received an s. c. injection of an LD 5 Of arsenic trioxide containing a tracer dose of 73-As(III) (42.5 mum ol/kg body wt). Thirty minutes later, saline (controls) or a single eq uimolar dose (0.7 mmol/kg) of DMSA i. p., or one of the analogues i. p . or i.g. was administered. The arsenic content of various organs (blo od, liver, kidneys, heart, lungs, spleen, small intestine, large intes tine, brain, testes, skeletal muscle, and skin) at 30 min, 2 h, 4 h, 6 h, and 8 h after the arsenic injection was measured using a gamma cou nter. In all organs investigated, the efficacy of DATSA, DBTSA, DEDMS, and DnPDMS administered i. p and i. g., and of DiPDMS given i.p. in r educing the tissue content of arsenic was significantly higher compare d to saline (p < 0.05), but not superior to DMSA. Treatment with DMDMS i. p. or i. g., and DiPDMS i. g. showed much less or no reduction. Ge nerally, the elimination rate of arsenic following therapy i. p. was m ore effective compared to i. g. treatment. It is concluded that DATSA and DBTSA, i.p. and i. g., and DEDMS, DnPDMS, and DiPDMS, given i. p., are effective arsenic antidotes, but are not superior to DMSA. Differ ent substitution of the DMSA molecule resulted in altered therapeutic efficacy. The dependence of the antidotal efficacy on the route of adm inistration (i.p., i. g.) indicates differences in absorption or metab olism of the analogues. Shielding of the thiol groups did not exhibit any advantage, high lipophilicity of an arsenic antidote might be unfa vourable, and the limitation to the extracellular space might be the k ey to higher antidotal success in acute arsenic trioxide poisoning.