Krishna, S., D.W. Waller, F. ter Kuile, D. Kwiatkowski, J. Crawley, C.F. Craddock, F. Nosten, D. Chapman, D. Brewster, and P.A. Holloway, Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1994. 88(1): p. 67-73. [PubMed Link]
Serial clinical and metabolic changes were monitored in 115 Gambian children (1.5-12 years old) with severe malaria. Fifty-three children (46%) had cerebral malaria (coma score < or = 2) and 21 (18%) died. Admission geometric mean venous blood lactate concentrations were almost twice as high in fatal cases as in survivors (7.1 mmol/L vs. 3.6 mmol/L; P < 0.001) and were correlated with levels of tumour necrosis factor (r = 0.42, n = 79; P < 0.0001) and interleukin 1-alpha (r = 0.6, n = 34; P < 0.0001). Admission blood venous glucose concentrations were lower in fatal cases than survivors (3.2 mmol/L, vs. 5.8 mmol/L; P < 0.0001). Treatment with quinine was associated with significantly more episodes of post-admission hypoglycaemia when compared with artemether or chloroquine. After treatment, lactate concentrations fell rapidly in survivors but fell only slightly, or rose, in fatal cases. Plasma cytokine levels fluctuated widely after admission. Sustained hyperlactataemia (raised lactate concentrations, 4 h after admission) proved to be the best overall prognostic indicator of outcome in this series. Lactic acidosis is an important cause of death in severe malaria.

Luxemburger, C., F. ter Kuile, F. Nosten, G. Dolan, J.H. Bradol, L. Phaipun, T. Chongsuphajaisiddhi, and N.J. White, Single day mefloquine-artesunate combination in the treatment of multi- drug resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1994. 88(2): p. 213-7. [PubMed Link]
The therapeutic efficacy and toxicity of a combination of low dose mefloquine (15 mg/kg) plus artesunate 10 mg/kg in one day (MA) was compared with the currently used regimen of high dose mefloquine (25 mg/kg) (MQ) in 552 patients with uncomplicated falciparum malaria in an area of multi-drug resistance on the Thai-Burmese border. MA gave faster clinical and parasitological responses and prevented early treatment failure; 15 patients in the MQ group (6%) were early failures (< 9 d) compared with none receiving MA (P = 0.0001). Overall failure rates by day 28 were 19% in the MA group and 24% in with MQ group (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.54-1.12). In the subgroup of patients who required re-treatment, MA proved significantly more effective than MQ; failure rates were 25% and 52% respectively (RR = 0.49, 95% CI = 0.29-0.83). Treatment failures were associated with mefloquine treatment in the previous month (RR = 1.72, 95% CI = 1.09-2.70) and diarrhoea (RR = 1.55, 95% CI = 1.05-2.28). Gastrointestinal side-effects and dizziness were more likely in the MQ group. There was no evident adverse effect associated with artesunate. A single day's treatment with artesunate augments the antimalarial efficacy of mefloquine.

Nosten, F., C. Luxemburger, F. ter Kuile, C. Woodrow, J.P. Eh, T. Chongsuphajaisiddhi, and N.J. White, Treatment of multidrug-resistant Plasmodium falciparum malaria with 3- day artesunate-mefloquine combination. Journal of Infectious Diseases, 1994. 170(4): p. 971-7. [PubMed Link]
Studies of 652 adults and children with acute uncomplicated falciparum malaria were done to determine the optimum treatment of multidrug- resistant Plasmodium falciparum malaria on the Thai-Burmese border. Single-dose artesunate (4 mg/kg) plus mefloquine (25 mg of base/kg) gave more rapid symptomatic and parasitologic responses than high-dose mefloquine alone but did not improve cure rates. Three days of artesunate (total dose, 10 mg/kg) plus mefloquine was 98% effective compared with a 28-day failure rate of 31% with high-dose mefloquine alone (relative risk [RR], 0.06; 95% confidence interval [CI], 0.02- 0.2; P < .0001). By day 63, the reinfection adjusted failure rates were 2% and 44%, respectively (P < .0001). Artesunate also prevented high- grade failures. Both drugs were well tolerated. No adverse effects were attributable to artesunate. Vomiting was reduced significantly by giving mefloquine on day 2 of treatment (RR, 0.40; 95% CI, 0.20-0.79; P = .009. Artesunate (10 mg/kg over 3 days) plus mefloquine (25 mg/kg) is currently the most effective treatment for falciparum malaria in this area of increasing mefloquine resistance.

Nosten, F., Artemisinin: large community studies. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1994. 88 Suppl 1: p. S45-6. [PubMed Link]
Prospective randomized trials with oral artemisinin derivatives have been conducted in over 1000 patients to determine the optimum treatment of multi-drug resistant falciparum malaria on the Thai-Burmese border. These drugs have proved valuable in 3 settings. (i) Primary treatment of uncomplicated malaria in combination with mefloquine, when they accelerate the rate of recovery, eliminate the risk of dangerous early failures, and if given for 3 d or more improve overall cure rates; (ii) treatment of recrudescent infections, which otherwise have a high failure rate; and (iii) oral treatment of patients with high parasitaemias (> or = 4%) but no clinical evidence of severity (a group who would usually receive parenteral quinine). The parenteral formulation of artemether is absorbed if given rectally, and this may offer a practical alternative method of treating severe malaria in rural areas.

Nosten, F., F. ter Kuile, L. Maelankiri, T. Chongsuphajaisiddhi, L. Nopdonrattakoon, S. Tangkitchot, E. Boudreau, D. Bunnag, and N.J. White, Mefloquine prophylaxis prevents malaria during pregnancy: a double- blind, placebo-controlled study. Journal of Infectious Diseases, 1994. 169(3): p. 595-603. [PubMed Link]
A double-blind, placebo-controlled study of mefloquine antimalarial prophylaxis in pregnancy (> 20 weeks of gestation) was conducted in 339 Karen women living in an area of multidrug-resistant malaria transmission on the Thai-Burmese border. Mefloquine gave > or = 86% (95% confidence interval [CI], 59%-94%) protection against Plasmodium falciparum and complete protection against Plasmodium vivax infections. Mefloquine prophylaxis was well tolerated; use of an initial loading dose (10 mg/kg) was associated with transient dizziness, but there were no other significant adverse effects on the mother, the pregnancy, or infant survival or development (followed for 2 years). Falciparum malaria was associated with maternal anemia and a mean reduction in birth weight in gravidae I, II, and III of 225 g (95% CI, 26-423). Maternal anemia at delivery (hematocrit < 30%) was associated with increased infant mortality: 26% versus 15% (relative risk, 1.9; 95% CI, 1.1-3.2). Mefloquine is safe and effective for antimalarial prophylaxis in the second half of pregnancy.

ter Kuile, F., P. Teja-Isavatharm, M.D. Edstein, D. Keeratithakul, G. Dolan, F. Nosten, L. Phaipun, H.K. Webster, and N.J. White, Comparison of capillary whole blood, venous whole blood, and plasma concentrations of mefloquine, halofantrine, and desbutyl-halofantrine measured by high-performance liquid chromatography. American Journal of Tropical Medicine and Hygiene, 1994. 51(6): p. 778-84. [PubMed Link]
Whole blood mefloquine, halofantrine, and desbutyl-halofantrine concentrations were measured by high-performance liquid chromatography in capillary blood, venous blood, and venous plasma samples from patients along the Thai/Burmese border with falciparum malaria who were treated with either mefloquine (25 mg/kg) or halofantrine (24 mg/kg or 72 mg/kg). The limits of detection for mefloquine, halofantrine, and desbutyl-halofantrine were 50, 15, and 10 ng/ml, respectively, with 200 microliters whole blood samples. There was a good linear correlation (r > 0.9) between capillary and venous blood and between whole blood and plasma for all three compounds. Mefloquine concentrations in venous and capillary blood were very similar (mean ratio 1.02, 95% confidence intervals [CI] 0.95-1.09, n = 60), but were 1.15 times higher (95% CI 1.03-1.29) in whole blood than in plasma (n = 22). The halofantrine and desbutyl-halofantrine concentrations were 1.27 (1.12-1.45, n = 23) and 1.34 (1.16-1.55, n = 24) times higher in venous compared to capillary blood, while halofantrine but not desbutyl-halofantrine concentrations were lower in whole blood than in plasma (mean ratios: halofantrine: 0.83 [0.72, 0.94], n = 39 and desbutyl-halofantrine: 1.05 [0.96-1.15], n = 41). Measurement of mefloquine, halofantrine, or desbutyl- halofantrine in capillary blood is an accurate and practical alternative to venous blood sampling, and is particularly useful for sampling with children, and under field conditions when technical facilities are limited.