DEVELOPMENT OF PYRONARIDINE-RESISTANE IN PLASMODIUM BERGHEI

Drug-sensitive P. berghei maintained by syringe passage for over 20 years was passed successively to clean mice under increasing selection pressure of pyronaridine base. Of the 5 mice administered single oral doses of 8 mg/kg (1.2 times its ED₅₀) in Passage 1, four mice were free from parasitemia 3～4 days after drug administration. From passage 2 onwards, an escalation of 2 mg/kg of pyronaridine per passage was performed. Five mice of Passage 2 were dosed with 10 mg/kg, but their parasitemia remained positive, This result suggested the commencement of drug resistance. By Passage 23, which was reached in about 5 1/2 months, a test dose of 2, 400 mg/kg (1.8 times its LD₅₀) was given to a group of mice to assess the drug sensitivity. Though some of the mice died of the dosage, none of the survivors was free of plasmodium parasite. It was evident that a pyronaridine-resistant line of P. berghei was fully developed as the parasites could tolerate a higher dose of pyronaridine than the hosts, bearing approximately a 300-fold resistance to pyronaridine when compared with the parent line.The virulence of pyronaridine-resistant line was much lower than that of its parent line. The sensitivity of pyronaridine-resistant line to 6 erythrocytic schizontocides chloroquine, piperaquinoline, amopyroquine, M-6407 (a 4-aminoquinoline), mepacrine, qinghaosu was also decreased significantly. By testing these drugs at doses over 3～10 times those effective to the parent line parasites, pyronaridine-resistant line failed to respond to the 6 drugs, indicating the presence of cross resistance of pyronaridine-resistant line to the 6 schizontocidal agents. However, when the pyronaridine pressure was lifted for 5 passages, the pyronaridine-resistant line was reverted to a pyronaridine sensitive line.