ABSTRACT
The ip LD50s of N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA) and British Anti-Lewisite (BAL) were 0.819 and 1.48 mmol/kg, respectively, in male albino mice. The ip ED50 of DMPA and BAL for prevention of the lethal effects of 0.15 mmol NaAsO2/kg was 0.022 and 0.169 mmol/kg, respectively. DMPA increased the LD50 of sodium arsenite by approximately 2.5-fold following two ip injections of 0.20 mmol DMPA/kg. The effectiveness of DMPA in reducing the toxicity of NaAsO2 was further demonstrated by its reversal of the sodium arsenite inhibition of pyruvate dehydrogenase multienzyme complex (PDH) activity in vitro. Similarly, in an in vivo experiment in which mice received 0.10 mmol NaAsO2/kg, and 30 min later were given 0.05 or 0.10 mmol/kg DMPA, there was a rapid recovery of PDH activity. The distribution of 74As in the tissues of male New Zealand rabbits was altered following im injection of 0.20 mmol/kg DMPA. Under these conditions, the tissue concentration of 74As was significantly decreased. For all tissues tested, the 74As content decreased by at least 50% as compared to that of untreated controls. DMPA was effective also in increasing both urinary and fecal excretion of arsenic. The stability of aqueous solutions of DMPA varies with the pH of the solution. DMPA is more stable in acid solution.
Subject(s)
Arsenic/toxicity , Dimercaprol/therapeutic use , Phthalic Acids/therapeutic use , Animals , Arsenic/metabolism , Dimercaprol/toxicity , Drug Interactions , Injections, Intraperitoneal , Injections, Subcutaneous , Lethal Dose 50 , Male , Mice , Phthalic Acids/toxicity , Pyruvate Dehydrogenase Complex/metabolism , Rabbits , Radioisotopes , Sulfhydryl CompoundsABSTRACT
meso-Dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propanesulfonic acid, Na salt (DMPS), and N-(2,3- dimercaptopropyl )- phthalamidic acid (DMPA) are water soluble analogs of 2,3-dimercapto-1-propanol (BAL). The relative effectiveness or therapeutic index of these dimercapto compounds in protecting mice from the lethal effects of an LD99 of sodium arsenite is DMSA greater than DMPS greater than DMPA greater than BAL in the magnitude of 42:14:4:1, respectively. DMPS, DMPA, or DMSA will mobilize tissue arsenic. BAL, however, increases the arsenic content of the brain of rabbits injected with sodium arsenite. These results raise the question as to the appropriateness of BAL as the treatment for systemic arsenic poisoning. Either DMSA or DMPS, when given sc or po, will protect rabbits against the lethal systemic effects of subcutaneously administered Lewisite . DMPS and DMSA have promise as prophylactics for the prevention of the vesicant action of Lewisite . The sodium arsenite inhibition of the pyruvate dehydrogenase (PDH) complex can be prevented and reversed in vitro or in vivo by DMPS, DMSA, DMPA, or BAL. Of them all, DMPS is most potent and BAL appears to be the least potent. The usefulness of all these dimercapto compounds would be enhanced by a careful study of their metabolism and biotransformation. These dimercapto compounds are in a great many respects orphan drugs. At this stage of their development, it is very difficult for the clinician to obtain funds to study them clinically even though they appear to be useful for treatment of poisoning by any one of the heavy metals.
Subject(s)
Antidotes , Arsenic Poisoning , Arsenicals , Arsenites , Dimercaprol/analogs & derivatives , Phthalic Acids/pharmacology , Sodium Compounds , Succimer/pharmacology , Sulfhydryl Compounds/pharmacology , Unithiol/pharmacology , Animals , Arsenates/poisoning , Arsenic/antagonists & inhibitors , Arsenic/metabolism , Arsenic/pharmacology , Brain/metabolism , Dimercaprol/pharmacology , Guinea Pigs , Male , Mice , Organ Size/drug effects , Pyruvate Dehydrogenase Complex/antagonists & inhibitors , RabbitsABSTRACT
The 74As content of the brain of rabbits was doubled following administration of BAL (2,3-dimercapto-1-propanol). DMPS (2,3-dimercapto-1-propanesulfonic acid, sodium salt), however, decreased the rabbit brain arsenic concentration. The use of BAL as the drug of choice for treatment of arsenic intoxication should be viewed with caution and re-examined.
Subject(s)
Arsenic/metabolism , Brain Chemistry/drug effects , Dimercaprol/pharmacology , Animals , Male , Rabbits , RadioisotopesABSTRACT
Dimercaptosuccinic acid (DMSA) has been receiving increasing interest as an antidote for poisoning by heavy metals. Of the various isomeric forms, meso-DMSA has been studied most extensively because its preparation and purification are relatively easy. Using a variety of in vitro and in vivo procedures, we have investigated and compared DL- and meso-DMSA as antidotes for sodium arsenite. The two forms of DMSA are equally effective in preventing or reversing, in vitro, the arsenite inhibition of the activity of mouse kidney pyruvate dehydrogenase (PDH) complex, DL-DMSA, however, is superior to meso-DMSA for the in vivo reversal of PDH activity as measured in vitro. The LD50 values of DL- and meso-DMSA in the mouse were 10.84 and 13.73 mmol/kg, ip, respectively. The ED50 values of the two DMSA forms were not significantly different in mice receiving a LD99 dose of sodium arsenite. DL- and meso-DMSA were equally effective in mobilizing tissue 74As of rabbits. The activity of DMSA as an arsenic antidote appeared to be independent of its isomeric structural configuration. There did not appear to be any great advantage in using DL-DMSA instead of meso-DMSA as an arsenic antidote.
