V. Evaluation of Cross-Immunity against Type 1 Dengue Fever in Human Subjects Convalescent from Subclinical Natural Japanese Encephalitis Virus Infection and Vaccinated with 17D Strain Yellow Fever Vaccine
The metabolism of chlorguanide (CG) and chlorguanide triazine (CGT) has been investigated following intramuscular and intravenous administration of CG and CGT to monkeys and oral administration of CG to monkeys and man. In confirmation of earlier investigations in this Institute, it has been found that in both species CG is metabolized to CGT and to the free amine, p-chlorophenylbiguanide (PBG). These two derivatives and the parent drug were the only p-chloroaniline (PCA)-containing metabolites which could be detected in urine of either man or monkey.
In the monkey 60 to 80% of CG injected intravenously or intramuscularly was recovered in the urine as total PCA-containing metabolites; about one-third of this urinary PCA was CGT. In man the recovery of total PCA in urine after oral administration of CG ranged from 56 to 66%; of this about 60% was CG, 30% was CGT, and the remainder PBG.
Studies in monkeys indicated that serum levels of total metabolites (total PCA) after intramuscular or intravenous injection of CG quickly reached a peak and then fell rapidly for 1 to 2 hours. During the next 2 to 6 hours the concentrations of total PCA-containing materials in serum either did not change or showed a slight increase; this rather abrupt change in slope coincided temporally with the appearance of significant amounts of CGT and possibly PBG in the blood stream. The subsequent die-away curves for total PCA were quite flat when compared to the earlier portions of the curves. Similar results were obtained when CG was administered orally except that with slower absorption from the gastrointestinal tract the peculiar changes in slope coincidental with CGT elaboration appeared somewhat later, usually from 3 to 5 hours after drug administration. Also the proportion of CGT to total PCA in the blood stream was much larger in this case, suggesting that greater conversion of CG to CGT occurs when the drug is given orally and must first pass through the liver.
When CGT was administered to monkeys, the serum levels fell rapidly for 2 to 4 hours and then dropped more slowly. As a result, the serum levels of CGT during the period from 4 hours to 24 hours after drug administration were similar whether CG or an equal amount of CGT had been administered. In no instance did the levels of CGT derived from CG exceed those obtained when an equal amount of CGT had been given. These findings suggest that the superior activity of CG compared to CGT against primate malarias must be attributed in part to antimalarial activity inherent in the parent drug.