Dolan, G., F. ter Kuile, V. Jacoutot, N.J. White, C. Luxemburger, L. Malankirii, T. Chongsuphajaisiddhi, and F. Nosten, Bed nets for the prevention of malaria and anaemia in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1993. 87(6): p. 620-6. [PubMed Link]
A prospective comparison of the antimalarial efficacy of bed nets was conducted with 341 pregnant women living in a mesoendemic malarious area of the Thai-Burmese border. Women in 3 adjacent study sites were allocated at random to receive either a single size permethrin- impregnated bed net (PIB), a non-impregnated bed net (NIB), or to a control group who used either their own family size non-impregnated bed net (FNIB) or no net. In one study site, but not the other 2, PIB significantly reduced parasite densities and, together with FNIB, reduced the incidence of malaria in pregnancy from 56% to 33% (relative risk = 1.67, confidence interval = 1.07-2.61, P = 0.03, allowing for parity). Anaemia proved a more sensitive marker of bed net antimalarial efficacy than parasite rates. The incidence of anaemia (haematocrit < 30%) at all study sites was significantly lower at delivery in the PIB (27%) and FNIB groups (21%) than in the NIB group (41%) or those using no net (56%). This suggests that a significant proportion of the malaria in pregnancy in this mesoendemic area was sub-patent. Both patent Plasmodium falciparum parasitaemia and anaemia were associated with a reduction in birth weight. Infant mortality was high (16%) and strongly associated with prematurity, low birth weight and maternal anaemia. PIB were well tolerated and had no apparent adverse effect on the pregnancy or infant development. Although the overall effect of bed nets on patent parasitaemia was marginal, they were associated with a significant reduction in maternal malaria-associated anaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Nosten, F., F. ter Kuile, K.L. Thwai, L. Maelankirri, and N.J. White, Spiramycin does not potentiate quinine treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1993. 87(3): p. 305-6. [PubMed Link]

Nosten, F., F. ter Kuile, C. Luxemburger, C. Woodrow, D.E. Kyle, T. Chongsuphajaisiddhi, and N.J. White, Cardiac effects of antimalarial treatment with halofantrine. Lancet, 1993. 341: p. 1054-6. [PubMed Link]
In a prospective electrocardiographic study of Karen patients with acute uncomplicated falciparum malaria, mefloquine (25 mg/kg) had no cardiac effects (n = 53), but halofantrine (72 mg/kg) induced consistent dose-related lengthening of the PR and QT intervals in all 61 patients treated. The likelihood of significant QTc prolongation (by more than 25% or a QTc of 0.55 s1/2 or more) was greater after halofantrine as retreatment following mefloquine failure than as primary treatment (7/10 vs 18/51; relative risk 2.0 [95% Cl 1.1-3.4], p = 0.04). More than 60% of the effect occurred with three doses of halofantrine (24 mg/kg). The arrhythmogenic potential of halofantrine should now be investigated.

ter Kuile, F., F. Nosten, C. Luxemburger, and N.J. White, Mefloquine prophylaxis. Lancet, 1993. 342: p. 551. [PubMed Link]

ter Kuile, F., G. Dolan, F. Nosten, M.D. Edstein, C. Luxemburger, L. Phaipun, T. Chongsuphajaisiddhi, H.K. Webster, and N.J. White, Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet, 1993. 341: p. 1044-9. [PubMed Link]
The continuing spread of multidrug resistance in Plasmodium falciparum malaria makes the search for alternative treatments ever more urgent. We have investigated the relative efficacy of halofantrine and mefloquine in two paired randomised trials on the Thai-Burmese border, a multidrug-resistant area. In the first trial, 198 patients with acute uncomplicated falciparum malaria were randomly assigned either the standard halofantrine regimen (24 mg/kg) or mefloquine (25 mg/kg). The cumulative failure rates by day 28 were 35% with halofantrine and 10% with mefloquine (p = 0.0002). In the second study of 437 patients, a higher dose of halofantrine (8 mg/kg every 8 h for 3 days = 72 mg/kg) was both more effective and better tolerated than mefloquine 25 mg/kg; the failure rates were 3% and 8% (p = 0.03), respectively, or 1% vs 6% after adjustment for possible reinfections (p = 0.009). The rate of failure was higher after retreatment than after primary treatment in all study groups. Halofantrine 72 mg/kg was especially effective in the retreatment of these recrudescent infections; the failure rate was 44% with mefloquine and 15% with high-dose halofantrine (relative risk 3.0 [95% CI 1.2-7.3], p = 0.008). Thus, high-dose halofantrine is better tolerated and more effective than mefloquine for the treatment of uncomplicated falciparum malaria in this area. However, evidence of possible cardiotoxicity will need to be investigated fully before a role can be established for halofantrine in the treatment of multidrug- resistant malaria.

Wangboonskul, J., N.J. White, F. Nosten, F. ter Kuile, R.R. Moody, and R.B. Taylor, Single dose pharmacokinetics of proguanil and its metabolites in pregnancy. European Journal of Clinical Pharmacology, 1993. 44(3): p. 247-51. [PubMed Link]
Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl- biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng.ml-1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng.h.ml-1.kg-1, respectively. Corresponding whole blood AUC values were 361 and 396 ng.h.ml-1.kg-1. The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng.ml- 1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml-1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies.(ABSTRACT TRUNCATED AT 250 WORDS)

White, N.J. and F. Nosten, Advances in chemotherapy and prophylaxis of malaria. Current Opinion in Infectious Diseases, 1993. 6: p. 323-330. [PubMed Link]