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

Organotin(IV)n+ complexes formed with biologically active ligands: equilibrium and structural studies, and some biological aspects

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.

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 experimental chemotherapy of leishmaniasis. VII. Drug responses of L. major and L. mexicana amazonensis, with an analysis of promising chemical leads to new antileishmanial agents.

A description is given of two methods for investigating the action of drugs against a viscerotropic Leishmania in mice. The parasite employed was isolated from a patient with kala-azar in Ethiopia. It is designated 'L. infantum LV9' and produces a visceral infection in NMRI mice. The biochemical typing characters of the parasite are described. In Method A, infected animals were treated from the 5th or 6th day after infection (D + 5 or D + 6) for five consecutive days. They were sacrificed 24 hours after the completion of drug treatment and an estimate was made of the amastigote load in the liver. A comparison of this with untreated controls gives an index of activity of a test drug, from 0 to 3. Method B is similar except that the ED50 and ED90 are determined by graphic analysis of data from graded drug doses. A comparison is made with sodium stibogluconate used as a positive drug control to yield a 'Pentostam Index'. The course of infection in BALB/c and NMRI mice is compared with that in random-bred Swiss mice in which 'L. infantum LV9' produces an inconsistent infection. An inoculum of 10(7) amastigotes produces a peak parasite intensity between D + 15 and D + 20. The ED50 and ED90 of sodium stibogluconate (Pentostam) (as Sbv) in Method B are 22 x 5 and 46 x 5 mg/kg sc daily x 5. (By Method A the single dose figures are 65 and 280 mg/kg.) For routine use a standard dose level of 120 mg/kg sc daily x 5 of Pentostam (Sbv) is used in Method B. The ED50 and ED90 of meglumine antimoniate (Glucantime) (as Sbv) in Method B are 11 x 6 and 66 x 7 mg/kg sc daily x 5. Data are given for other antimonials in Method A. Pentamidine and diminazene aceturate proved to have a slow action which was more readily demonstrated if the observation period was prolonged. Amphotericin B was moderately active but toxic to the host. The relevance of these models and a comparison of data found in the mouse and hamster are debated.

The experimental chemotherapy of leishmaniasis. IV. The development of a rodent model for visceral infection.

Two models have been established of leishmanial infections in random-bred TFW albino mice, one with Leishmania major LV39 and the other with L. mexicana amazonensis LV38. These parasites produce consistent lesions when injected subcutaneously a short distance anterior to the base of the tail. Consistent infections could not be produced in the mice with other lines of the L. mexicana group of skin-dwelling protozoa, nor with a line of L. braziliensis guyanensis (LV475). The development of procedures for the maintenance of these parasites, the routine infection of mice and drug testing are described. L. major inocula consist of 1--5 X 10(6) promastigotes derived from NNN culture. L. m. amazonensis inocula contain approximately 10(7) amastigotes obtained from lesions in hamsters. The effects of drugs on the rodent lesions are assessed by two methods. Method A provides a simple lesion score from 0 to 3 made when lesions in control animals begin to reach maximum development (about six weeks after infection). Method B summates earlier 'mean lesion scores' to provide a graphic analysis of doses giving 50 and 90% lesion suppression at the end of seven weeks after the start of treatment which is for five consecutive days (SD 50 and SD90). The activities of several compounds used for the treatment of human leishmanial infections (organic antimonials, diamidines, amphotericin B and primaquine) are compared in mice infected with L. major LV39, L. m. amazonensis LV78 and 'L. infantum LV9' (the latter as reported earlier). It is concluded that the rodent models provide a good parallel with the response to these compounds in man. The visceral organism is significantly more responsive to Pentostam and Glucantime than are L. major or L. m. amazonensis. Primaquine is active only against 'L. infantum LV9'. All three parasites in mice respond to Berenil, but not to pentamidine which is used in the treatment of kala-azar. Amphotericin B is effective against cutaneous and visceral infections, but precautions must be taken to ensure its absorption by experimental animals.

The experimental chemotherapy of leishmaniasis. VI. The development of rodent models for cutaneous infection with L. major and L. mexicana amazonensis.

B. L. Robinson

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 experimental chemotherapy of leishmaniasis. VII. Drug responses of L. major and L. mexicana amazonensis, with an analysis of promising chemical leads to new antileishmanial agents.

The experimental chemotherapy of leishmaniasis. IV. The development of a rodent model for visceral infection.

The experimental chemotherapy of leishmaniasis. VI. The development of rodent models for cutaneous infection with L. major and L. mexicana amazonensis.