Abstract
After the initial selection and evaluation of BRL 6231 (I) described in Part III of this series, some investigations on the induction of resistance to this compound with Plasmodium berghei in mice were carried out.
A combination of initial small stepwise progression in dosage followed by large single doses of BRL 6231 upon established infections produced a resistant line of P. berghei from the N strain. This line required 12 times the dose level of BRL 6231 for 90% suppression compared to that required by the N strain. Resistance was stable in the absence of drug pressure after 20 serial passages.
Studies with the BRL 6231 resistant line of P. berghei against standard antimalarials in the four-day suppressive test showed there was no cross-resistance to chloroquine, mepacrine or sulphadimethoxine. The line was found to be hypersensitive to primaquine and showed cross-resistance to cycloguanil (fivefold) and pyrimethamine (fourfold).
When established infections of the cycloguanil-resistant B line of P. berghei were dosed with either BRL 6231 or pyrimethamine, recrudescence of infection and induction of resistance occurred more rapidly with pyrimethamine than BRL 6231.