A rapid, semiautomated microdilution method was developed for measuring the activity of potential antimalarial drugs against cultured intraerythrocytic asexual forms of the human malaria parasite Plasmodium falciparum. Microtitration plates were used to prepare serial dilutions of the compounds to be tested. Parasites, obtained from continuous stock cultures, were subcultured in these plates for 42 h. Inhibition of uptake of a radiolabeled nucleic acid precursor by the parasites served as the indicator of antimalarial activity. Results of repeated measurements of activity with chloroquine, quinine, and the investigational new drug mefloquine demonstrated that the method is sensitive and precise. Several additional antimalarial drugs and compounds of interest were tested in vitro, and the results were consistent with available in vivo data. The use of P. falciparum isolates with known susceptibility to antimalarial drugs also permitted evaluation of the cross-resistance potential of each compound tested. The applications and expectations of this new test system within a drug development program are discussed.

Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.

Report of a WHO Scientific Group (Part 3 of 3)

Mefloquine hydrochloride, a new 4-quinolinemethanol, was administered as a single oral dose to 47 volunteers infected with malaria. Treatment resulted in rapid clearence of fever and parasitemia. No recrudescence of parasites was observed after treatment of chloroquine-sensitive infections of Plasmodium falciparum. More significantly, in nonimmune persons with chloroquine-resistant infections, 1 gram of mefloquine cured 10 of 12 patients and 1.5 grams cured all 8 patients who received this dose of the drug. The marked activity of a single dose of mefloquine against chloroquine-resistant strains of Plasmodium falciparum suggests that this agent may be more useful than currently available drugs are for the treatment of drug-resistant malaria.

https://science.sciencemag.org/content/sci/190/4216/792.full.pdf

Mefloquine (WR 142,490) in the treatment of human malaria

Synopsis: Co-trimoxazole1 (trimethoprim-sulfamethoxazole) is a ‘broad spectrum’ antimicrobial which is active in vitro against a wide variety of micro-organisms. Clinical experience with this agent now spans a decade or more in many countries. While it is clearly established as the agent of first choice only in Pneumocystis carinii infections, it is effective in many other infectious diseases. Thus, it has been shown to be effective in acute and persistent or recurrent urinary tract infections (treatment and prophylaxis), ear, nose and throat infections (including β-lactamase producing H. influenzae), acute exacerbations of chronic bronchitis, enteric fever, gonorrhoea, prophylaxis in neutropenic patients, and in several other less well established areas of possible usefulness. Recent availability of a parenteral preparation has further expanded the potential clinical application of the drug.

Co-trimoxazole (trimethoprim-sulfamethoxazole): an updated review of its antibacterial activity and clinical efficacy.

Infections with Plasmodium falciparum and Plasmodium vivax in the owl monkey--model systems for basic biological and chemotherapeutic studies.

Two new investigational antimalarial drugs developed by the U.S. Army Malaria Research Program were tested in patients with multi-drug-resistant falciparum malaria from Vietnam. WR 33063, a phenanthrene methanol, cured 13 patients treated in the United States. All of these patients had suffered multiple recrudescences after treatment with standard antimalarial drugs. In addition, 23 of 25 patients with acute attacks of falciparum malaria treated in Vietnam were cured. The rate of clinical response was prompt. WR 30090, a quinoline methanol, similarly cured eight patients with multiple recrudescences in the United States and 23 of 26 patients in Vietnam. Adverse effects associated with the drugs were not seen. These drugs signify a major advance in the chemotherapy of drug-resistant falciparum malaria.

Treatment of falciparum malaria from Vietnam with a phenanthrene methanol (WR 33063) and a quinoline methanol (WR 30090).

Treatment of acute falciparum malaria from Vietnam with trimethoprim and sulfalene.

From 1965 to 1968 in Vietnam, there was a dramatic increase in the proportion of malaria infections caused by Plasmodium vivax. We studied 30 patients with acute vivax malaria in Vietnam and 12 at Walter Reed General Hospital to assess the responsiveness of their infections to suppressive amounts of chloroquine with primaquine (C-P). Each patient was treated with a single C-P tablet containing chloroquine (base) 300 mg and primaquine (base) 45 mg. Clinical and parasitological responses were prompt in all patients. No urine-chloroquine tests performed upon the patients on admission to the hospital in Vietnam showed detectable chloroquine excretion owing to previous drug administration. Failure to take the prescribed C-P chemoprophylaxis probably accounts for the high proportion of vivax malaria in Vietnam.

Bruce S. MacDonald

Papers

Treatment of falciparum malaria from Vietnam with a phenanthrene methanol (WR 33063) and a quinoline methanol (WR 30090).

Treatment of acute falciparum malaria from Vietnam with trimethoprim and sulfalene.

Plasmodium vivax from Vietnam. Response to chloroquine-primaquine.

Treatment ofFalciparum Malaria fromVietnam with a Phenanthrene Methanol (WR33063) anda Quinoline Methanol (WR30090)