Fried, M., F. Nosten, A. Brockman, B.J. Brabin, and P.E. Duffy, Maternal antibodies block malaria. Nature, 1998. 395(6705): p. 851-2. [PubMed Link]

Lindsay, S.W., J.A. Ewald, Y. Samung, C. Apiwathnasorn, and F. Nosten, Thanaka (Limonia acidissima) and deet (di-methyl benzamide) mixture as a mosquito repellent for use by Karen women. Medical and Veterinary Entomology, 1998. 12(3): p. 295-301. [PubMed Link]
The prevention and treatment of drug-resistant malaria is becoming increasingly difficult. On the Thai-Myanmar border multi-drug resistant strains of falciparum malaria are increasing and, because the malaria vector Anopheles bite outdoors during early evening, insecticide house- spraying or impregnated bednets provide only limited protection. Therefore, the protective efficacy of repellent formulations containing di-methyl benzamide (deet) and permethrin against local vectors was estimated, when applied to the skin, and their acceptability amongst pregnant Karen women who are at relatively high risk from malaria was assessed. Human landing catches of mosquitoes showed that almost complete protection was achieved using different formulations of 20% deet and 0.5% permethrin for up to 6 h. All-night collections from human subjects indicated that this repellent combination reduced exposure to malaria parasites by at least 65 and 85% for those transmitted by Anopheles minimus and An. maculatus, respectively, the two principal vectors in this area. Pregnant women in the camps preferred repellents which were mixed with 'thanaka', a root paste made from pulp of the wood apple tree, Limonia acidissima, used locally as a cosmetic. Apart from a temporary warming sensation where repellent thanaka was applied to the skin, the repellents were well tolerated. An intervention trial is currently in progress to determine whether deet mixed with thanaka can protect pregnant women against malaria in this part of the world. Bioassays using a laboratory strain of Aedes aegypti demonstrated that thanaka is itself slightly repellent at high dosages and the mixture with deet provides protection for over 10 h. This treatment would therefore also provide some personal protection against dengue, which is increasing locally, transmitted by Ae. aegypti and Ae. albopictus biting during the daytime.

Looareesuwan, S., P. Olliaro, N.J. White, T. Chongsuphajaisiddhi, A. Sabcharoen, K. Thimasarn, F. Nosten, P. Singhasivanon, S. Supavej, S. Khusmith, S. Wylings, T. Kanyok, D. Walsh, P.A. Leggat, and E.B. Doberstyn, Consensus recommendation on the treatment of malaria in Southeast Asia. Southeast Asian Journal of Tropical Medicine and Public Health, 1998. 29(2): p. 355-60.[PubMed Link]

Luxemburger, C., A. Brockman, K. Silamut, F. Nosten, M. van Vugt, F. Gimenez, T. Chongsuphajaisiddhi, and N.J. White, Two patients with falciparum malaria and poor in vivo responses to artesunate. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998. 92(6): p. 668-9.[PubMed Link]

Luxemburger, C., M. van Vugt, T. Slight, R.N. Price, T. Chongsuphajaisiddhi, P. Chanthavanich, N.J. White, and F. Nosten, Early vomiting of mefloquine in children with malaria is not modified by the timing of antipyretic treatment. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998. 92(5): p. 562-3. [PubMed Link]

Luxemburger, C., J. Rigal, and F. Nosten, Health care in refugee camps. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998. 92(2): p. 129-30. [PubMed Link]

Luxemburger, C., F. Nosten, D.E. Kyle, L. Kiricharoen, T. Chongsuphajaisiddhi, and N.J. White, Clinical features cannot predict a diagnosis of malaria or differentiate the infecting species in children living in an area of low transmission. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998. 92(1): p. 45-9. [PubMed Link]
The differentiation of malaria from other causes of fever in the absence of microscopy is notoriously difficult. Clinical predictors of malaria have been studied in an area of low and unstable transmission on the western border of Thailand. In 1527 children aged 2-15 years who were followed prospectively for 7 months, 82% (1254) had at least one febrile episode. Malaria caused 24% (301) of the first febrile episodes (Plasmodium falciparum 128, P. vivax 151, P. malariae 1, mixed infections with P. falciparum and P. vivax 21). Each malaria case was matched with the next child of similar age presenting to the dispensary with another cause of fever. Clinical symptoms or signs associated with a final diagnosis of malaria were: confirmed fever (> or = 38 degrees C) (odds ratio [OR] 1.6, 95% confidence interval [95% CI] 1.4-1.9), headache (OR 1.5, 95% CI 1.3-1.9), muscle and/or joint pain (OR 2.0, 95% CI 1.6-2.8), nausea (OR 1.7, 95% CI 1.4-2.3), clinical anaemia (OR 1.4, 95% CI 1.3-3.3), palpable spleen (OR 1.3, 95% CI 1.1-1.7), palpable liver (OR 1.4, 95% CI 1.1-2.1), absence of cough (OR 1.6, 95% CI 1.4-2.0), and absence of diarrhoea (OR 1.5, 95% CI 1.2-2.4). None of these signs alone or in combination proved a good predictor of malaria. The best diagnostic algorithms (history of fever and headache without cough, and history of fever with an oral temperature > or = 38 degrees C [sensitivity 51% for both, specificity 72 and 71%, respectively]) would result in prescription of antimalarial drugs in 28-29% of the non- malaria febrile episodes, and only 49% of the true malaria cases. Thus half of the potentially life-threatening P. falciparum infections would not be treated. Although multivariate analysis identified vomiting, confirmed fever, splenomegaly and hepatomegaly as independent risk factors for a diagnosis of falciparum malaria, use of these signs to differentiate falciparum from vivax malaria, and thus to determine antimalarial treatment, was insufficiently sensitive or specific. Malaria diagnosis should be confirmed by microscopical examination of a blood slide or the use of specific dipstick tests in areas of low transmission where highly drug-resistant P. falciparum coexists with P. vivax.

McGready, R., T. Cho, J.J. Cho, J.A. Simpson, C. Luxemburger, L. Dubowitz, S. Looareesuwan, N.J. White, and F. Nosten, Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998. 92(4): p. 430-3. [PubMed Link]
An artemisinin derivative (artesunate or artemether) was used for the treatment of multidrug-resistant Plasmodium falciparum malaria in 83 Karen pregnant women in Thailand; 55 women were treated for recrudescent infection following quinine or mefloquine, 12 for uncomplicated hyperparasitaemic episodes, and 16 had not declared their pregnancy when treated. The women were followed weekly until delivery. Artesunate and artemether were well tolerated and there was no drug- related adverse effect. Recrudescence within 42 d occurred in 16% of the treated episodes. Overall 73 pregnancies (88%) resulted in live births, 3 (4%) in abortions and 2 (3%) in still births, and 5 women were lost to follow-up before delivery. There was no congenital abnormality in any of the newborn children, and the 46 children followed for more than one year all developed normally.

McGready, R., T. Cho, L. Hkirijaroen, J. Simpson, T. Chongsuphajaisiddhi, N.J. White, and F. Nosten, Quinine and mefloquine in the treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy. Annals of Tropical Medicine and Parasitology, 1998. 92(6): p. 643-53. [PubMed Link]
Between 1991 and 1996, 372 pregnant women with uncomplicated, multidrug- resistant Plasmodium falciparum malaria, living on the western border of Thailand, were treated with either mefloquine (N = 194), quinine (N = 93) or both drugs (N = 85). Antimalarial treatment was generally well tolerated; the most common side-effects were dizziness (42%) and tinnitus (35%) following quinine, and anorexia (23%) and dizziness (36%) following mefloquine. In the patients treated for primary infections with melfloquine, 6% failed to clear their parasitaemia by day 7 and 28% failed by day 42. The corresponding figures for quinine were 4% and 23%, respectively. The failure rates in the 117 women treated for recrudescent infections were higher, the increase being significant for quinine (38%; P = 0.03) but not for mefloquine (37%). The percentage of pregnant women who had patent gametocytaemia on presentation ranged from 4%-19%. Over 50% of the patients were anaemic (haematocrit < 30%) on presentation and 52% of those not anaemic on enrolment developed anaemia during follow-up. Mefloquine and quinine, the only antimalarials generally available for the treatment of highly drug-resistant P. falciparum in pregnancy, give unsatisfactory treatment responses when used as single agents. New, safe and effective regimens are needed for the treatment of pregnant women with multidrug- resistant falciparum malaria.

McGready, R., J.A. Simpson, N.J. White, F. Nosten, and S.W. Lindsay, Smoking cheroots reduces birthweight. Lancet, 1998. 352(9139): p. 1521-2. [PubMed Link]

Nosten, F., M. van Vugt, and N.J. White, Intrarectal artemisinin derivatives. Medecine Tropicale, 1998. 58(3): p. 63-4. [PubMed Link]
The artemisinin derivatives are the most potent antimalarials. They are rapidly absorbed orally, parenterally and intra-rectally. The latter mode of administration is particularly interesting in rural tropics. Preliminary studies have shown that artemisinin and its derivatives artesunate and artemether are effective when given intrarectally. More studies are needed to establish the optimum regimen.

Nosten, F., T.T. Hien, and N.J. White, Use of artemisinin derivatives for the control of malaria. Medecine Tropicale, 1998. 58(3): p. 45-9. [PubMed Link]
Since 1994, the combination of mefloquine and artesunate is the standard treatment for uncomplicated Plasmodium falciparum malaria in the population of displaced persons on the Western border of Thailand. As a result, the fall of mefloquine efficacy was stopped and the incidence of falciparum malaria reduced. This is attributed to the effects of the artemisinin derivatives on transmissibility. Similar trends were observed in Vietnam where artemisinin is widely used. Combination therapies that include an artemisinin derivative could have a major role in the control of malaria and the spread of drug resistance.

Nosten, F., M. van Vugt, and R. McGready. Community based studies on the treatment of multi-drug resistant falciparum malaria. in ICOPA ix. 1998. Chiba-Japan.[PubMed Link]

Paul, R.E., I. Hackford, A. Brockman, C. Muller-Graf, R. Price, C. Luxemburger, N.J. White, F. Nosten, and K.P. Day, Transmission intensity and Plasmodium falciparum diversity on the northwestern border of Thailand. American Journal of Tropical Medicine and Hygiene, 1998. 58(2): p. 195-203. [PubMed Link]
Genetic analysis of the number of Plasmodium falciparum genotypes per infected person in regions of holoendemic and hyperendemic malaria suggest that in areas of lower transmission intensity, significantly fewer parasite genotypes per infected person should be found. A predominance of single clone infections in the human population could generate the controversial clonal population structure proposed for P. falciparum by Tibayrenc and others. Characterization of P. falciparum from individuals on the Thai-Burmese border, an area of hypoendemic transmission, revealed a higher number of genotypes per infected person than that predicted. Possible reasons for this observation are discussed, with particular attention paid to human migration and multidrug resistance.

Price, R., M. van Vugt, F. Nosten, C. Luxemburger, A. Brockman, L. Phaipun, T. Chongsuphajaisiddhi, and N. White, Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria. American Journal of Tropical Medicine and Hygiene, 1998. 59(6): p. 883-8. [PubMed Link]
The therapeutic efficacy and toxicity of artesunate (2mg/kg/day for five days, then 1 mg/kg/day for two days: total=12 mg/kg) was compared with that of artemether (4 mg/kg followed by 2 mg/kg/day for two days, then 1 mg/kg/day for four days: total=12 mg/kg) for the treatment of recrudescent multidrug-resistant falciparum malaria in an open randomized trial in 443 patients living on the western border of Thailand. Parasite and fever clearance times were similar in both groups; within 48 hr 94% (95% confidence interval [CI]=91-96%]) of the treated patients were aparasitemic and 93% (95% CI=89-96%) were afebrile. Symptom resolution and resolution of hepatomegaly were slightly slower in the artesunate group; adjusted hazards ratio=1.5 (95% CI=1-2.0, P < 0.01) and 2.2 (95% CI=1.4-8, P=0.04), respectively. There was no significant difference in times to resolution or development of anemia or splenomegaly between treatment groups. By day 28, 3% (95% CI=0.3-5%) of the patients treated with artesunate and 6% of those treated with artemether (95% CI = 2-9%) had recurrent infections (P=0.3). Both regimens were very well tolerated, with no significant adverse effects attributable to either derivative. Overall, these data suggest that the two oral artemisinin derivatives are safe, highly effective, and result in equivalent therapeutic responses in the treatment of drug-resistant falciparum malaria.

Price, R.N., F. Nosten, and N.J. White, Prolongation of the QTc interval in African children treated for falciparum malaria. American Journal of Tropical Medicine and Hygiene, 1998. 59(4): p. 503. [PubMed Link]

Price, R., C. Luxemburger, M. van Vugt, F. Nosten, A. Kham, J. Simpson, S. Looareesuwan, T. Chongsuphajaisiddhi, and N.J. White, Artesunate and mefloquine in the treatment of uncomplicated multidrug- resistant hyperparasitaemic falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998. 92(2): p. 207-11. [PubMed Link]
Oral artesunate is the most effective treatment for uncomplicated hyperparasitaemia in falciparum malaria. To assess the contribution of mefloquine to therapeutic efficacy in an area endemic for mefloquine- resistant Plasmodium falciparum, an open randomized comparison of a 5 d course of oral artesunate (total dose 12 mg/kg) with and without a single dose of mefloquine (25 base mg/kg) was conducted in 100 adults and children with uncomplicated hyperparasitaemia (> 4% parasitized red blood cells). Both regimens were well tolerated and gave equally rapid clinical responses (84% of patients were aparasitaemic and 96% were afebrile within 48 h), but the recrudescence rate assessed at day 42 was 6% in those receiving artesunate with mefloquine compared to 36% in those receiving artesunate alone (adjusted hazard ratio 7, 95% confidence interval [95% CI] 2-32; P < 0.01). In addition, the efficacy of a 7 d course of artesunate, with and without the addition of mefloquine, was monitored in 178 patients who were not part of the randomized comparison. The failure rate was again lower in those receiving artesunate and mefloquine--7% (95% CI 2-13) compared with 26% (95% CI 8-44) in patients treated with artesunate alone. An oral regimen of 5 d or more of artesunate, together with mefloquine (25 mg/kg) given on day 2, is an effective treatment for uncomplicated hyperparasitaemic falciparum malaria in this area of high level multidrug resistance.

van Vugt, M., F. Ezzet, L. Phaipun, F. Nosten, and N.J. White, The relationship between capillary and venous concentrations of the antimalarial drug lumefantrine (benflumetol). Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998. 92(5): p. 564-5. [PubMed Link]

van Vugt, M., A. Brockman, B. Gemperli, C. Luxemburger, I. Gathmann, C. Royce, T. Slight, S. Looareesuwan, N.J. White, and F. Nosten, Randomized comparison of artemether-benflumetol and artesunate- mefloquine in treatment of multidrug-resistant falciparum malaria. Antimicrobial Agents and Chemotherapy, 1998. 42(1): p. 135-9. [PubMed Link]
An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether- benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.