Bethell, D.B., P.T. Phuong, C.X. Phuong, F. Nosten, D. Waller, T.M. Davis, N.P. Day, J. Crawley, D. Brewster, S. Pukrittayakamee, and N.J. White, Electrocardiographic monitoring in severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1996. 90(3): p. 266-9.[PubMed Link]
Electrocardiographic monitoring over 24 h was performed with 53 patients with severe Plasmodium falciparum malaria (11 adults and 42 children) to assess the frequency of unrecognized cardiac arrhythmias. Nine patients (17%) died, 5 during the monitoring period and 4 afterwards. Pauses lasting 2-3 s were observed in 3 children, a single couplet in one, and a further child experienced frequent supraventricular ectopic beats which had not been detected clinically. In none of the patients who died could death be attributed to cardiac arrhythmia. Furthermore, no abnormality was detected which could have resulted from the often large doses of quinine, chloroquine or the artemisinin derivatives used for treatment. These results suggest that the heart is remarkably resilient even in the face of heavy parasite sequestration and other vital organ dysfunction, and that deaths from cardiac arrhythmias in severe malaria are rare. The need for routine cardiac monitoring of patients with severe and complicated P. falciparum malaria is questionable.

Luxemburger, C., R.N. Price, F. Nosten, F. Ter Kuile, T. Chongsuphajaisiddhi, and N.J. White, Mefloquine in infants and young children. Annals of Tropical Paediatrics, 1996. 16(4): p. 281-6.[PubMed Link]
In an area where multi-drug resistance in Plasmodium falciparum is a particular problem, more than 500 children under 5 years of age weighing > 5 kg were treated with mefloquine, either alone or combined with an artemisinin derivative, and followed up for a minimum of 28 days. The principal adverse effect was vomiting and this was associated with reduced efficacy of treatment (even when treatment was repeated). Later adverse effects occurred less frequently than in adults. There was no serious toxicity and, in particular, there were no neuropsychiatric side-effects. The high dose of mefloquine (25 mg/kg) required in this area is well tolerated by young children. It should be given in a divided dose of 15 mg/kg initially, followed by 10 mg/kg > or = 12 hours later.

Luxemburger, C., K.L. Thwai, N.J. White, H.K. Webster, D.E. Kyle, L. Maelankirri, T. Chongsuphajaisiddhi, and F. Nosten, The epidemiology of malaria in a Karen population on the western border of Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1996. 90(2): p. 105-11. [PubMed Link]
From November 1991 to November 1992 a prospective, descriptive study of malaria epidemiology was conducted in a Karen population on the western border of Thailand. Two study groups were selected at random and more than 80% of the subjects were followed for one year. In Group 1, comprising 249 schoolchildren (aged 4-15 years), daily surveillance for illness was combined with fortnightly malaria surveys. These children experienced 1.5 parasitaemic infections per child-year (95% confidence interval [CI] 1.3-1.7), of which 68% (193/285) were symptomatic (Plasmodium falciparum 84%, P. vivax 57%). The estimated pyrogenic densities were 1460/microL for P. falciparum and 181/microL for P. vivax. In Group 2, comprising subjects of all age from 428 households, malaria was diagnosed during two-monthly surveys, at weekly home visits, and otherwise by passive case detection. Malaria and splenomegaly prevalence rates were low in all age groups (spleen index 2-9%; P. falciparum prevalence rate 1-4%; P. vivax 1-6%). Group 2 subjects had 1.0 infections per person-year (95% CI 0.9-1.1), most of which were symptomatic (312/357; 87%). Malaria infections clustered in households. Overall, P. vivax caused 53% and P. falciparum 37% of the infections (10% were mixed), but whereas P. vivax was most common in young children, with a decline in incidence with increasing age, P. falciparum incidence rates rose with age to a peak incidence between 20 and 29 years, although the risk of developing a severe malaria decreased with increasing age. There was no death from malaria during the study. P. falciparum infections were more common in males, subjects with a history of malaria before the study, and in those who had travelled outside their village. These findings suggest a higher transmission rate for P. vivax than P. falciparum, although adults still suffered symptomatic malaria due to both species. The 2 malaria parasites found in this area contribute approximately 50% of infections each, but their clinical epidemiology is very different.

Nosten, F., C. Luxemburger, D.E. Kyle, W.R. Ballou, J. Wittes, E. Wah, T. Chongsuphajaisiddhi, D.M. Gordon, N.J. White, J.C. Sadoff, and D.G. Heppner, Randomised double-blind placebo-controlled trial of SPf66 malaria vaccine in children in northwestern Thailand. Lancet, 1996. 348: p. 701-7. [PubMed Link]
BACKGROUND: Previous efficacy trials of SPf66 malaria vaccine have produced conflicting results in different populations. We report a randomised double-blind trial of the SPf66 vaccine conducted in Karen children aged 2-15 living in a malarious region of northwestern Thailand. Recombinant hepatitis B vaccine was used as a comparator. METHODS: The study had a power of 90% to detect an efficacy of 30%, defined as a reduction in the incidence of first cases of symptomatic falciparum malaria after three doses of vaccine. 1221 children received three immunisations and were eligible for the primary efficacy analysis. Intense active and passive case detection continued over 15 months of follow-up. FINDINGS: The SPf66 vaccine was well tolerated, although 26 children had mild or moderately severe local or systemic allergic reactions, compared with none in the comparator group. The vaccine was immunogenic; after three doses, 73% of recipients had seroconverted. There were no deaths due to malaria during the study. During the 15-month period of evaluation there were 379 first cases of symptomatic falciparum malaria (195 in the SPf66 recipients, 184 in the comparator group); an SPf66 efficacy of -9% (95% CI -33 to 14, p = 0.41). No significant differences between the two study groups in parasite density or any other measure of malaria-related morbidity were detected. INTERPRETATION: These findings are consistent with a recent study showing lack of efficacy of SPf66 among Gambian infants and differ from earlier positive reports from South America and evidence of borderline efficacy from Tanzania. We conclude that SPf66 does not protect against clinical falciparum malaria and that further efficacy trials are not warranted.

Nosten, F. and M. van Vugt, Malaria:still no vaccine and very few drugs. Current Opinion in Infectious Diseases, 1996. 9: p. 429-434.[PubMed Link]

Price, R.N., F. Nosten, C. Luxemburger, F. ter Kuile, L. Paiphun, T. Chongsuphajaisiddhi, and N.J. White, Effects of artemisinin derivatives on malaria transmissibility. Lancet, 1996. 347: p. 1654-8. [PubMed Link]
BACKGROUND: On the western border of Thailand the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased, which suggests increased transmissibility of these resistant infections. We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives. METHODS: Between 1990 and 1995 we assessed gametocytaemia in a series of prospective studies of antimalarial drug treatment in 5193 adults and children with acute uncomplicated falciparum malaria in an area of malarious hill forest on the western border of Thailand. Weekly parasite counts from thick and thin blood films were done during the 4-week (1990-93) or 9-week (1993-95) follow- up period. Gametocyte positivity rates and person gametocyte week (PGW) rates were calculated to measure gametocyte carriage and transmission potential. FINDINGS: In primary P falciparum infections the gametocyte carriage rate was significantly higher after treatment with mefloquine than after treatment with the artemisinin derivatives (PGW 34.1 [95% CI 25.2-42.9] vs 3.9 [1.9-5.9] per 1000 person weeks; relative risk 8.0 [4.1-15.6]; p<0.0001). Recrudescent infections were associated with increased gametocyte carrier rates (relative risk 2.2 [1.6-3.0]; p<0.0001), but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98] compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with quinine retreatment (p<0.001). The introduction of the artemisinin derivatives in routine treatment at this study site in mid 1994 was associated with a reduction in the subsequent incidence of falciparum malaria of 47 (25- 69)% INTERPRETATION: Although environmental changes affect vector numbers, and hence malaria incidence, artemisinin derivatives were found to reduce the transmission potential of falciparum malaria. Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance.

Teja-Isavadharm, P., F. Nosten, D.E. Kyle, C. Luxemburger, F. Ter Kuile, J.O. Peggins, T.G. Brewer, and N.J. White, Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay. British Journal of Clinical Pharmacology, 1996. 42(5): p. 599-604.[PubMed Link]
1. The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg-1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.- ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA). 2. Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l-1 and for DHA of 1009 (639 to 1379) nmol l-1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half- life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.-ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3. Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC (0.6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4. These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.

Warrell, D.A., N.J. White, F. Nosten, and N. Day, Tropical medicine in and out of the tropics. Lancet, 1996. 347: p. 1111-2. [PubMed Link]