An approach to the evaluation of drugs for activity against Schistosoma mansoni in rhesus monkeys and several modifications regarding drug evaluations against this parasite in mice are presented.
Seven tris(p-aminophenyl)carbonium salts (TAC salts) and tris(p-aminophenyl)methanol (TAC hydroxide) killed mature and immature forms of a Puerto Rican strain of Schistosoma mansoni when given orally to mice.
TAC pamoate, TAC hydroxide, TAC chloride, and lucanthone HCl were studied extensively in infected mice and monkeys, and the last two substances were tested against sexually mature worms in vitro.
Lucanthone HCl (studied as a reference drug) had only feeble to moderate effect in mice or monkeys even though several rigorous oral regimens were tried. In mice, its action seemed to be restricted to mature worms. It was schistosomicidal in vitro only in high concentrations during a period of several days.
The three TAC substances resembled each other sufficiently in various studies to justify the following tentative characterization of their anthelmintic actions as a group. They are capable of killing a high proportion of mature and immature worms in mice and monkeys at well tolerated dose levels, are not highly effective intraperitoneally and are irritating by this route, are directly schistosomicidal in vitro at lower concentrations than lucanthone HCl, exhibit a flat-dose response relationship, are more effective in moderate doses for prolonged periods than in high doses for shorter periods, act slowly and probably by interfering with nutrition, and are not antagonized by p-aminobenzoic acid.
Therapeutic and prophylactic tests in mice and monkeys support the conclusion that certain TAC salts are worthy of trial in man for purpose of cure, protection against infection, and prevention of egg excretion. Preliminary observations in dogs indicated TAC pamoate to be distinctly less emetic than TAC chloride or TAC hydroxide.
Reference is made to work by others demonstrating oral action by TAC pamoate against the three most important schistosomes in man—S. mansoni, S. Haematobium, and S. japonicum.
Present address: Dept. Microbiology, The University of Texas, Medical Branch, Galveston.