Pyrimethamine levels in sera, cerebrospinal fluid(CSF), and ventricular fluid were measured by using reversed-phase high-pressure liquid chromatography. The specimens were from 37 infants receiving pyrimethamine for treatment of suspect or proven congenital toxoplasmosis. Pyrimethamine half-life in serum was 64 ± 12 h when determined by study of terminal-phase kinetics of samples obtained from nine babies. This half-life was significantly different (P = 0.008) from the pyrimethamine half-life (33 ± 12 h) determined by terminal-phase kinetics for two babies of the same age taking phenobarbital. Serum pyrimethamine levels at various intervals after dosages of pyrimethamine were also lower for infants receiving phenobarbital. Levels measured in sera from babies taking the same dose of pyrimethamine throughout their first year of life did not appear to vary significantly over time or at different ages (P > 0.05). Mean + standard deviation serum levels 4 h after a pyrimethamine dose were 1.297 ± 0.54 pg/ml for babies taking 1 mg of pyrimethamine per kg of body weight daily and 0.7 + 0.26 ,ug/ml for babies taking 1 mg/kg each Monday, Wednesday, and Friday. Levels in CSF were approximately 10 to 25% of concomitant levels in serum. Serum folate levels for infants who took 0.64 to 1.7 mg leukovorin per kg ranged from 33 to 663 ng/ml. To determine whether the levels of pyrimethamine in serum and CSF of treated infants were in a range that affected the most virulent, rapidly replicating, and standard laboratory strain of Toxoplasma gondii, effects of various concentrations of pyrimethamine and sulfadiazine on replication of T. gondii in vitro were assessed. The levels of the antimicrobial agents effective in vitro were in the range of levels of pyrimethamine achieved in sera and CSF. Although folinic acid could inhibit the therapeutic effect of pyrimethamine and sulfadiazine in vitro, inhibition was noted only at levels (.4,800 ng/ml) that were considerably higher than the folate levels found in the treated infants' sera.Pyrimethamine is a critical part of therapy for babies with congenital toxoplasmosis (15). It is also important in therapy of infants with human immunodeficiency virus infection who also have toxoplasmic encephalitis (16). Data concerning pharmacokinetics of this agent in infants and children are greatly needed, as there are no data available to guide rational selection of pyrimethamine dosage for such patients. MATERIALS AND METHODSPatients and sampling strategy. Sera were obtained from infants between the ages of 10 days and 1.5 years. The infants were receiving pyrimethamine for treatment of suspect or definite congenital toxoplasmosis. These sera were obtained in accordance with National Institutes of Health guidelines concerning human subjects, which includes informed consent from parents and guardians. In some instances, when cerebrospinal fluid (CSF) or cerebral ventricular fluid were available, these samples were also studied. In the feasibility phase of this study a recommendation was * Correspond...

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With the increasing number of patients undergoing experimental interferon therapy, there is a need for a method for monitoring how the patients respond to the drug. Interferon induces in cells exposed to it the accumulation of several enzymes, among them the (2'-5') oligo-A synthetase. A simple method previously developed was used to measure this enzyme in extracts of a small number of peripheral white blood cells. In 60 healthy volunteers, the enzyme level in the mononuclear cell fraction was found to be relatively high and constant. Daily intramuscular injections of 1--2 x 10(6) units leukocyte type interferon (IFN-alpha) increased the enzyme level 7--8 fold in mononuclear cells and in granulocytes. The enzyme stayed high until IFN injections were stopped. Patients with defective response to IFN were identified. We propose that this method be used for continuous monitoring of the patient's response whenever interferon therapy is undertaken.

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