CHLOROQUINE AND DIHYDROQUININE. IN VITRO STUDIES OF THEIR ANTIMALARIAL EFFECT UPON PLASMODIUM KNOWLESI

¹ Department of Hematology, Walter Reed Army Institute of Research, Washington, D. C.

The influence of the antimalarial drugs chloroquine and dihydroquinine on the biosynthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and protein during the in vitro erythrocytic growth cycle of Plosmodium knowlesi was investigated. Chloroquine inhibited DNA and RNA synthesis more than it decreased protein synthesis. Dihydroquinine had a greater effect upon DNA than on either RNA or protein biosynthesis. These findings, together with observations of other investigators, suggested that inhibition of DNA replication is the primary mechanism of action of both anti-malarial drugs. Erythrocytes parasitized with P. knowlesi concentrated more chloroquine-3-H³ and dihydroquinine-H³ than normal blood cells. The specific antimalarial effect of both drugs is based on their selective accumulation in parasitized erythrocytes. The sensitivity of plasmodia to chloroquine decreased with progressing development of the plasmodium during one growth cycle. The mechanism of accumulation of chloroquine in parasitized erythrocytes, shown to fail in case of resistance to chloroquine, is unknown. However, it was shown that the amount of accumulated chloroquine-3-H³ was independent of the amount of plasmodial DNA, RNA, protein or malaria pigment.