Quinine, pyrimethamine, and sulphorthodimethoxine: Clinical response, plasma levels, and urinary excretion during the initial attack of naturally acquired falciparum malaria

Abstract

Plasma concentrations and urinary excretion rates of antimalarial drugs were studied during acute illness in 15 patients with naturally acquired falciparum malaria despite chloroquine-primaquine prophylaxis. The therapeutic regimen included single oral doses of sulphorthodimethoxine and pyrimethamine in combination with a 14 day course of quinine. The plasma half-life of a 1 Gm. dose of sulphorthodimethoxine was 200 hours with levels exceeding 8 mg. per 100 ml. for 4 days. Plasma-pyrimethamine concentrations remained relatively stable during the 14 day study. For both drugs a slow rate of urinary elimination accounts for sustained plasma levels following single doses. Doses of 650 mg. of quinine every 8 hours produced mean plasma levels in excess of 11 mg. per liter during the first 5 days. Thereafter the concentration gradually declined to levels observed in patients receiving quinine during relapse and experimental infections. Transient hepatic dysfunction during the acute phase of the illness may account for the initial elevation and subsequent decline during continued administration. In all patients the clinical illness was promptly controlled and no toxicity developed. There were no relapses. The advantages of single-dose oral therapy, the promising clinical results, and low incidence of toxicity suggest that sulphorthodimethoxine may be an important antimalarial drug and that further clinical and pharmacological investigation is warranted. This paper is Contribution No. 369 from the Army The emergence of chloroquine-resistant strains of Plasmodium falciparum and the high incidence of infection with these parasites has prompted intensive studies to develop effective drug therapy. Several combinations of antimalarial drugs have proven satisfactory for control of the clini-Research Program on Malaria,

Potentiating effect of pyrimethamine and sulfadoxine against dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi

“…Some sulfonamides were also shown to be alternative substrates of the enzyme dihydropteroate synthetase (37). We found that sulfadoxine, one of the sulfonamides widely used for the treatment of malaria, inhibited plasmodial dihydrofolate reductase, although the concentrations which affected the enzyme activity are some 10-fold higher than the therapeutic range (9). Similar to the inhibition by pyrimethamine (40), sulfadoxine was shown to competitively inhibit the enzyme from drugsensitive parasites and to inhibit noncompetitively the en- (12) at the point at which the combination of two drugs gives the most marked potentiation, i.e., ca.…”

Quinine disposition during malaria and during induced fever

“…5 Each patient received a single dose of 1 gm of sulfadoxine and 50 mg of pyrimethamine, and 540 mg of quinine base every 8 hr for 14 days. Plasma quinine concentrations were measured on days I through 7, 10, and 14.…”

Near-Infrared Dye-Aptamer Assay for Small Molecule Detection in Complex Specimens

“…We then determined the capability of the assay to detect quinine in urine. Previous reports have measured daily urinary quinine content of 150−450 mg for malaria patients, 24,25 implying concentrations in the range of several hundred micromolar based on an average daily urinary output of 1.5 L. Given the high sensitivity of our assay, we rationalized that a ∼40-fold dilution of urine would bring such quinine concentrations into the linear range. We, therefore, challenged aptamer-dye complexes with various concentrations of quinine spiked in 2.5% urine and obtained an identical LOD and linear range as in the buffer (Figure 4A−C).…”