Antidotal efficacy of newly synthesized dimercaptosuccinic acid (DMSA) monoesters in experimental arsenic poisoning in mice.
The efficacy of four newly synthesized monoesters of meso-2,3-dimercaptosuccinic acid (DMSA), mono-i-amyl- (Mi-ADMS), mono-n-amyl- (Mn-ADMS), mono-i-butyl- (Mi-BDMS), and mono-n-butyl-meso-2,3-dimercaptosuccinate (Mn-BDMS) in increasing survival and arsenic elimination in experimental arsenic poisoning was investigated. Male mice (strain NMRI) received arsenite sc (survival study: 130 mumol/kg, 7 mice/group; elimination study: 85 mumol/kg (LD5) together with a tracer dose of 73As(III), 6 mice/group). After 30 min mice were treated with 0.7 mmol/kg of DMSA or a monoester ip or via gastric tube (ig). Control animals received saline ip. In the survival study mice were observed for 30 days. In the elimination study, the 73-arsenic content of several organs (blood, liver, heart, lung, kidneys, spleen, testes, brain, small intestine, large intestine, muscle, and skin) was measured 0.5, 2, 4, 6, and 8 hr after the arsenic injection using a gamma counter. Survival increased correspondingly well with the increase of arsenic elimination. DMSA, Mi-ADMS, Mn-ADMS, Mi-BDMS, and Mn-BDMS markedly decreased arsenic content in most organs as soon as 1.5 hr after treatment. Only in small and large intestine were higher arsenic amounts found, indicating a shift in arsenic elimination from the renal to the fecal route, and thereby suggesting a protective effect for the kidneys. Given ip, the monoesters turned out to be similarly as effective as the parent drug DMSA. Following ig treatment, the DMSA monoesters Mi-ADMS and Mn-ADMS seemed to be superior to DMSA with regard to survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Kreppel
H
H
Institut fuer Pharmakologie und Toxikologie, BSW, Sanitaetsakademie der Bundeswehr, Garching, Germany.
Reichl
F X
FX
Kleine
A
A
Szinicz
L
L
Singh
P K
PK
Jones
M M
MM
D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology*; D020261:Arsenic Poisoning; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000037:antagonists & inhibitors*; D001921:Brain / Q000187:drug effects; D004952:Esters / Q000494:pharmacology; D007420:Intestine, Large / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010087:Oxides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004113:Succimer / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*
D000931:Antidotes; D001152:Arsenicals; D004952:Esters; D010087:Oxides; D004113:Succimer; D000077237:Arsenic Trioxide