STUDY OF TREATMENT OF CONGENITAL TOXOPLASMA-GONDII INFECTION IN RHESUS-MONKEYS WITH PYRIMETHAMINE AND SULFADIAZINE

The efficacy of the combination of pyrimethamine and sulfadiazine for the treatment of congenital Toxoplasma gondii infection in rhesus monk eys was studied. The dosage regimen for pyrimethamine and sulfadizine was established by pharmacokinetic studies in two monkeys. Those studi es showed that the distributions of both drugs followed a one compartm ent model. The serum elimination half lives were found to be 5.2 h for sulfadiazine and 44.4 h for pyrimethamine. Sulfadiazine reached a max imum concentration in serum of 58.7 mu g/ml, whereas a maximum concent ration in serum of 0.22 mu g/ml was found for pyrimethamine. Ten monke ys were infected intravenously with T. gondii at day 90 of pregnancy, which is comparable to the second trimester of organogenetic developme nt in humans. Treatment was administered to six monkeys, in whose fetu ses infection was diagnosed antenatally. From the moment that fetal in fection was proven, the monkeys were treated throughout pregnancy with 1 mg of pyrimethamine per kg of body weight per day and 50 mg of sulf adiazine per kg of body weight per day orally. The therapy was supplem ented with 3.5 mg of folinic acid once a week. No toxic side effects w ere found with this drug regimen. The parasite was no longer detectabl e in the next consecutive amniotic fluid sample, taken 10 to 13 days a fter treatment was started. Furthermore, T. gondii was also not found in the neonate at birth. The parasite was still present at birth in th ree of four untreated fetuses that served as controls. Both drugs cros sed the placenta very well. Concentrations in fetal serum varied from 0.05 to 0.11 mu g/ml for pyrimethamine and from 1.0 to 5.4 mu g/ml for sulfadiazine. In addition, pyrimethamine was found to accumulate in t he brain tissue, with concentrations being three to four times higher than the corresponding concentrations in serum. Thirty percent of the sulfadiazine was found to reach the brain tissue when compared with th e corresponding serum drug concentration. When administered early afte r the onset of infection, the combination of pyrimethamine and sulfadi azine was clearly effective in reducing the number of parasites in the fetus to undetectable levels.