Increased efforts in antimalarial drug discovery are urgently needed. The goal must be to develop safe and affordable new drugs to counter the spread of malaria parasites that are resistant to existing agents. Drug efficacy, pharmacology and toxicity are important parameters in the selection of compounds for development, yet little attempt has been made to review and standardize antimalarial drug-efficacy screens. Here, we suggest different in vitro and in vivo screens for antimalarial drug discovery and recommend a streamlined process for evaluating new compounds on the path from drug discovery to development.

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Antimalarial drug discovery: efficacy models for compound screening

Quinoline Antimalarials: Mechanisms of Action and Resistance and Prospects for New Agents

Data are provided on the activity of a variety of antimalarial drugs against drug-sensitive and drug-resistant lines of Plasmodium berghei in albino mice. Parallel data for the response of the drug-sensitive parasites to these compounds in vitro indicate whether the drugs have a chloroquine-like or quinine-like type of action, or neither. The value of this test system for drug evaluation is debated. It is concluded that the in vivo tests do provide a valuable indication of the potential use of a compound against drug-resistant malaria parasites of man. The tests may also provide a good indication of the future value of new compounds against strains of parasites that are already resistant to chloroquine. Where necessary, steps should be taken to protect promising new compounds.

The chemotherapy of rodent malaria, XXII. The value of drug-resistant strains of P. berghei in screening for blood schizontocidal activity.

Resistance of Plasmodium falcipanrm to chloroquine has been documented in most countries where there is transmission, over the last 2 decades (PETERS, 1987; PAYNE, 1989). Resistance to other antimalarials has followed in many countries. This article will focus on resistance occurring in chemotherapy rather than prophylaxis. Host factors, including pharmacokinetics and immunity, will not be reviewed.

The epidemiology of drug-resistant malaria.

Chloroquine: Mechanism of drug action and resistance in plasmodium falciparum

The chemotherapy of rodent malaria, XXVIII. The development of resistance to mefloquine (WR 142,490).

Mefloquine (WR 142,490) is a potent blood schizontocide active against drug-sensitive and drug-resistant lines of Plasmodium berghei. The ED50 and ED90 against the P. berghei N strain in albino mice are 1.5 and 3.8 mg/kg respectively. The highly chloroquine-resistant RC line is less sensitive and mefloquine is not fully effective at the maximum tolerated dose in the '4-day test'. Mefloquine has a similar mode of action to quinine both in vitro and (as demonstrated by the morphological changes it induces in P. berghei) in vivo, but is some 100 times more potent. Unlike quinine and WR 122,455 it appears not to interact with DNA. It has no causal prophylactic effect. Mixtures of mefloquine with pyrimethamine, sulphaphenazole or primaquine have an additive effect.

The chemotherapy of rodent malaria, XXVII. Studies on mefloquine (WR 142,490).

The chemotherapy of rodent malaria. XVII. Dynamics of drug resistance. 3. Influence of drug combinations on the development of resistance to chloroquine in P. berghei.

J. H. Portus

Papers

The chemotherapy of rodent malaria, XXVIII. The development of resistance to mefloquine (WR 142,490).

The chemotherapy of rodent malaria, XXVII. Studies on mefloquine (WR 142,490).

The chemotherapy of rodent malaria. XVII. Dynamics of drug resistance. 3. Influence of drug combinations on the development of resistance to chloroquine in P. berghei.

A virulent chloroquine-resistant strain of Plasmodium berghei berghei transmitted through Anopheles stephensi.