L Phaipun

Shoklo Malaria Research Unit

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François Nosten

Shoklo Malaria Research Unit

Nicholas J. White

University of Oxford

Feiko O. ter Kuile

Kenya Medical Research Institute

C. Luxemburger

John Radcliffe Hospital

T Chongsuphajaisiddhi

Mahidol Oxford Tropical Medicine Research Unit

Ric N. Price

Menzies School of Health Research

Michèle van Vugt

Amsterdam University Medical Centers

Michael D. Edstein

Brisbane School of Theology

H. Kyle Webster

University of Oxford

Rose McGready

Mahidol Oxford Tropical Medicine Research Unit

Cooperative Institutions

Mahidol Oxford Tropical Medicine Research Unit

Mahidol University

Shoklo Malaria Research Unit

University of Oxford

University of Amsterdam

John Radcliffe Hospital

Armed Forces Research Institute of Medical Science

Menzies School of Health Research

Charles Darwin University

Angkor Hospital for Children

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Treatment of Uncomplicated Multidrug‐Resistant Falciparum Malaria with Artesunate‐Atovaquone‐Proguanil

Clinical Infectious Diseases (2002)

Michèle van Vugt Elisabetta Leonardi L Phaipun Thra Slight Khin Thway

In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.

Artesunate

Atovaquone

Proguanil

10.1086/344901

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Citations (78)

Mefloquine-resistant falciparum malaria on the Thai-Burmese border

The Lancet (1991)

François Nosten Feiko O. ter Kuile T Chongsuphajaisiddhi Nicholas J. White Feiko O. ter Kuile

Sulfadoxine

10.1016/0140-6736(91)92798-7

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Citations (242)

Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria.

American Journal of Tropical Medicine and Hygiene (1998)

Ric N. Price Michèle van Vugt François Nosten C. Luxemburger A Brockman

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.

Artesunate

Artemether

10.4269/ajtmh.1998.59.883

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Citations (78)

Mefloquine treatment ofacutefalciparum malaria: aprospective studyofnon-serious adverse effects in3673patients

Feiko O. ter Kuile François Nosten C. Luxemburger Dennis E. Kyle P Teja-Isavatharm

is being used increasinglyfor the treatment and prevention of falciparummalaria in many parts of the world, particularlysouth-east Asia (1). As with the structurally relatedcinchona alkaloids (quinine, quinidine), minor side-effects following mefloquine treatment are morecommon than with the other available antimalarialssuch as chloroquine (2, 3), halofantrine (4), sulfa-doxine-pyrimethamine (FansidarTM) (5, 6), and the

Halofantrine

Quinine

Quinidine

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Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients.

PubMed (1995)

Feiko O. ter Kuile François Nosten C. Luxemburger Dennis E. Kyle P Teja-Isavatharm

Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The tolerance of various treatment regimens containing either mefloquine 15 mg/kg (M15) or 25 mg/kg (M25) was evaluated in 3673 patients aged between 6 months and 88 years. Early vomiting (within 1 hour) is an important determinant of treatment outcome in these areas, despite re-administration of the dose. Overall, 7 % of the patients vomited within an hour. Significant risk factors were age < or = 6 years (relative risk (RR), 3.9) or > or 50 years (RR, 2.7), the higher mefloquine dose (M25) (RRm 2.7), vomiting < 24 hours before enrolment (RR, 2.5), axillary temperature > 38.0 degrees C (RR, 1.6), and parasitaemia > 10,000/microliter (RR, 1.3). In children < or = 2 years, 30% vomited with M25, and 13% did not tolerate a repeat dose. Vomiting was reduced 40% by splitting the higher dose (RR, 0.6; 95% CI, 0.4-0.8), and 50% by giving mefloquine on the second day in combination with artesunate (RR, 0.5; CI, 0.3-0.9). Anorexia, nausea, vomiting, dizziness, and sleeping disorders were 1.1-1.4 times more frequent with M25 than M15 in the three days following treatment, but were similar in the single or split-dose M25 groups, despite twofold higher mefloquine concentrations obtained with the latter. There was no evidence that diarrhoea, headache, and abdominal pain were associated with mefloquine use. High-dose mefloquine is well tolerated but should be given as a split dose.

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Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.

American Journal of Tropical Medicine and Hygiene (1999)

Ric N. Price Michèle van Vugt L Phaipun C. Luxemburger J. A. Simpson

In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral artemisinin derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an artemisinin derivative were associated with more side effects than those with an artemisinin derivative alone; acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P < 0.001). Oral artesunate and artemether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs.

Artesunate

10.4269/ajtmh.1999.60.547

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Citations (274)

Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria

Transactions of the Royal Society of Tropical Medicine and Hygiene (1997)

Ric N. Price François Nosten C. Luxemburger Michèle van Vugt L Phaipun

On the western border of Thailand, in an area endemic for multi-drug resistant Plasmodium falciparum malaria, therapeutic responses were assessed in 1967 patients with uncomplicated falciparum malaria treated with 3 d of artesunate (total dose 12 mg/kg) plus mefloquine (total dose 25 mg/kg).The regimen was well tolerated and resulted in a rapid clinical response; within 48 h, 96% of patients were aparasitaemic and 94% were afebrile. After correcting for reinfections, the cure rate by day 42 was 89% (95% confidence interval [95% CI] 87–91%).Three independent factors were found to predict recrudescence: age < 14 years (adjusted hazards ratio [AHR] = 1·6, 95% CI 1·1–2·3), initial parasitaemia greater than > 40000/μL (AHR = 1·6, 95% CI 1·2–2·2), and pure P. falciparum infections (AHR = 1·8, 95% CI 1·3–2·7). These 3 factors combined accounted for 62% of all treatment failures. Patients who received mefloquine on admission with a high admission parasitaemia (> 40 000/μL) had a three-fold (95% CI 1μ3–7) risk of subsequent recrudescence compared with those who received their mefloquine on the second or third day (P = 0·01). There has been no decline in the efficacy of the 3 d artesunate plus mefloquine regimen since it was introduced in 1992. This regimen is safe, well tolerated, and highly effective in the treatment of multi-drug resistant falciparum malaria.

Artesunate

Regimen

10.1016/s0035-9203(97)90032-8

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Citations (162)

Risk factors for gametocyte carriage in uncomplicated falciparum malaria.

American Journal of Tropical Medicine and Hygiene (1999)

Ric N. Price François Nosten J. A. Simpson C Luxemburger L Phaipun

The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment. In a multiple logistic regression model five factors were found to be independent risk factors at presentation for the development or persistence of gametocytemia during follow up; patent gametocytemia on admission (adjusted odds ratio [AOR] = 7.8, 95% confidence interval [CI] = 3.7-16, P < 0.001), anemia (hematocrit <30%) (AOR = 3.9, 95% CI = 2.3-6.5, P < 0.001), no coincident P. vivax malaria (AOR = 3.5, 95% CI = 1.04-11.5, P < 0.04), presentation with a recrudescent infection (AOR = 2.3, 95% CI = 1.3-4.1, P < 0.004), and a history of illness longer than two days (AOR = 3.3, 95% CI = 1.7-6.6, P < 0.001). Patients whose infections responded slowly to treatment or recrudesced subsequently were also more likely to carry gametocytes than those who responded rapidly or were cured (relative risks = 1.9, 95% CI = 1.3-2.7 and 2.8, 95% CI = 2.0-4.0, respectively; P < 0.001). These data provide further evidence of important epidemiologic interactions between P. falciparum and P. vivax, and drug resistance and transmission potential.

Primaquine

10.4269/ajtmh.1999.60.1019

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Citations (231)

Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria.

American Journal of Tropical Medicine and Hygiene (1999)

Michèle van Vugt Polrat Wilairatana B Gemperli Insa Gathmann L Phaipun

The new oral fixed combination artemether-lumefantrine (CGP 56697) has proved to be an effective and well-tolerated treatment of multi-drug resistant Plasmodium falciparum malaria, although cure rates using the four-dose regimen have been lower than with the currently recommended alternative of artesunate-mefloquine. Two six-dose schedules (total adult dose = 480 mg of artemether and 2,880 mg of lumefantrine) were therefore compared with the previously used four-dose regimen (320 mg of artemether and 1,920 mg of lumefantrine) in a double-blind trial involving 359 patients with uncomplicated multidrug-resistant falciparum malaria. There were no differences between the three treatment groups in parasite and fever clearance times, and reported adverse effects. The two six-dose regimens gave adjusted 28-day cure rates of 96.9% and 99.12%, respectively, compared with 83.3% for the four-dose regimen (P < 0.001). These six-dose regimens of artemether-lumefantrine provide a highly effective and very well-tolerated treatment for multidrug-resistant falciparum malaria.

Artemether/lumefantrine

Artemether

Lumefantrine

10.4269/ajtmh.1999.60.936

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Citations (194)

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)

Feiko O. ter Kuile P Teja-Isavatharm Michael D. Edstein Duangsuda Keeratithakul G. Dolan

"Comparison of Capillary Whole Blood, Venous Whole Blood, and Plasma Concentrations of Mefloquine, Halofantrine, and Desbutyl-Halofantrine Measured by High-Performance Liquid Chromatography" published on Dec 1994 by The American Society of Tropical Medicine and Hygiene.

Halofantrine

Venous blood

Blood plasma

10.4269/ajtmh.1994.51.778

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Citations (18)