AMEBACIDAL AND PHARMACOLOGIC ACTIVITIES OF CARBARSONE OXIDE (P-CARBAMIDOPHENYLARSENOUS OXIDE) AND ITS DITHIOCARBOXYMETHYL AND DITHIOCARBOXYPHENYL DERIVATIVES

¹ Division of Pharmacology and Experimental Therapeutics and University of California Medical School, San Francisco

(1) Substitution of dithiocarboxymethyl or dithiocarboxyphenyl groups (in p-carbamidophenylarsenous acid) did not appreciably alter amebacidal activity, in vitro or in vivo.

(2) Toxicity and tolerance tests in mice, rats, rabbits and monkeys indicated that the dithiocarboxyphenyl derivative was the least toxic.

(3) Reaction of the gastric mucosa and peritoneum to the direct application of dithio derivatives was less severe than to the arsenoxide. The liver, lungs and kidneys were appreciably damaged after single toxic doses of the arsenoxide.

(4) Within the range of therapeutic activity, the short-term (11 day) chronic toxicity test in rats and the 30-day chronic tolerance test in monkeys resulted in minimal damage to tissues after the dithio derivatives.

(5) After carbarsone oxide (p-carbamidophenyl arsenous oxide), distribution studies revealed exceptionally high levels of arsenic in the bile, blood and urine, moderate amounts in the feces, and contents of the stomach and small intestine, and in the colon, kidneys and liver, and smaller amounts in the lungs, heart and spleen. Appreciable tissue levels persisted for at least 9 days in rats after chronic intragastric therapy.

(6) Dithio derivatives (C.C. 914 and 1037) also accumulated in large amounts in bile, feces, urine, liver, kidneys, cecum and colon, with moderate amounts in contents of the stomach, cecum, and small intestine, blood, lungs, heart and spleen, and small amounts in brain, pleural and peritoneal fluids and thymus. The levels attained in these tissues in rats and rabbits after short-term chronic toxicity tests, were appreciably higher than in monkeys, on the 30-day chronic tolerance test.

(7) As with other arsenoxides, the arsenic of carbarsone oxide and its dithio derivatives, was bound by tissues roughly in proportion to the toxicity of each drug. Higher concentrations in intestinal tissue and in bile have been reported following injection of phenyl arsenoxides than after proportional doses of arsonic acids (10). This observation was confirmed and is believed to be significant.

(8) The suggestion of Voegtlin (2) that protozoa contain and are dependent upon smaller absolute amounts of -SH groups than mammalian tissue cells agrees with the experimental evidence presented.