A strain of Plasmodium berghei was passed through mice which were maintained on a diet containing 0.008% chloroquine diphosphate and which had been treated intravenously with ethyl palmitate to destroy or diminish the phagocytic functions of the spleen. After 3½ months, the strain became highly resistant to maximum tolerated doses of chloroquine. The development of resistance seems to require certain critical conditions, and during many other attempts to produce a chloroquine-resistant strain, resistance seldom developed.
Resistance was unstable, and after passage through untreated mice for 4 months, chloroquine-resistance was lost. It could not easily be resuscitated.
The strain was cross-resistant to mepacrine but it was normally sensitive to pamaquin, sulphadiazine, pyrimethamine, metachloridine (SN 11437) and BW 377C54. (Proguanil and quinine were too toxic to the mice to be properly tested.) Resistance to chloroquine was independent of resistance to sulfanilamide and conversely.
A discussion is given of the dose-response curve as obtained in standard laboratory tests for antimalarial activity. The theoretical principles of these tests have never been satisfactorily formulated, but for practical purposes the best procedure is probably to plot the log of (percent parasitised cells in treated animals divided by percent parasitized cells in untreated controls) against the log dose. The test measures the response of the majority of (susceptible) parasites, and small resistant subpopulations (e.g. 1%) do not appreciably affect the response.