A double-blind clinical trial of a combination of mefloquine, sulfadoxine and pyrimethamine in symptomatic falciparum malaria

Fansimef is a combination of 250 mg of mefloquine, 500 mg of sulfadoxine, and 25 mg of pyrimethamine per tablet. A total of 150 adult male Zambian patients who had symptomatic Plasmodium falciparum parasitaemia were treated in a double-blind randomized fashion with either one, two or three tablets of Fansimef. All patients in the three treatment groups showed an S-type response. The rates of clearance of parasitaemia and fever were similar in all treatment groups. Tolerance was good at all dose levels. The main side-effects were abdominal discomfort, weakness and lassitude, dizziness, and pruritus, but these were mild, transient and required no specific treatment. Vomiting occurred only in 4% of patients given the highest dose of three tablets. The results of various haematological and biochemical investigations and urinalysis were not adversely altered by the administration of Fansimef.     

Falciparum malaria treated with a fixed combination of mefloquine, sulfadoxine and pyrimethamine: a field study in adults in Burma

In a field study conducted in Burma, 54 semi-immune adults suffering from falciparum malaria (mean parasite count, 15 328/mm³ before treatment) were given a single dose of a fixed combination of 750 mg mefloquine base, 1500 mg sulfadoxine, and 75 mg pyrimethamine (3 tablets of Fansimef). All these patients were cleared of asexual parasites by day 7, giving a cure rate of 100%; the mean clearance time was 2.6 days. Reappearance of parasitaemia occurred in 10 patients on or before day 7 and persisted for one day in 8 of them and for two days in 2 patients. It eventually disappeared without further treatment. No recrudescence occurred during the follow-up time of four weeks despite the fact that there was active transmission of Plasmodium falciparum in the area throughout the whole of the study period. The drug was generally well tolerated, though mild to moderate giddiness was reported by 49 patients (90.7%) and severe giddiness by 3 patients (5.5%). Nausea occurred in 25 patients (46.3%) and vomiting in 17 (31.5%).     

Double-blind trial to find dose range using a fixed combination of mefloquine, sulfadoxine and pyrimethamine in falciparum malaria: a field study on adults in Burma

In a field study conducted in Burma, 60 semi-immune adults were randomly assigned to 2 treatment groups. The first (mean parasite count, 12717/mm3) received a single dose of a fixed combination of 500 mg mefloquine base, 1000 mg sulfadoxine and 50 mg pyrimethamine (2 tablets of 'Fansimef') plus 1 tablet placebo. The second group (mean parasite count, 11 863/mm3) were given 3 tablets of the same medication. The study was double-blind. Parasite count was checked daily for the first week and weekly for a further 3 weeks. Average times for parasite clearance were 1.47 d in patients receiving 2 tablets, and 1.87 d in those given 3 tablets. Asexual parasites reappeared on day 28 in one patient in each group, although they had been free of parasites during the previous 4 weeks; this could be due to reinfection. The drugs were generally well tolerated, though mild and transient giddiness was seen in 80% of patients in the first group and 96% in the second. Nausea was reported by 33% and 43% of patients respectively. No vomiting occurred in the first group but 8 patients vomited in the second (P less than 0.01). In conclusion it seems possible to treat falciparum malaria in semi-immune adults, weighing less than 60 kg, with a single dose of 500 mg mefloquine base, 1000 mg sulfadoxine and 50 mg pyrimethamine (2 tablets), instead of the higher dose (3 tablets) currently recommended. This reduces treatment cost and improves tolerance of the drugs.     

Tolerability of long-term malaria prophylaxis with the combination mefloquine + sulfadoxine + pyrimethamine (Fansimef): results of a double blind field trial versus chloroquine in Nigeria

A randomized double blind study in long term malaria chemoprophylaxis was performed to compare the tolerability of Fansimef (1 tablet containing 250 mg mefloquine + 500 mg sulfadoxine + 25 mg pyrimethamine per week) with chloroquine (300 mg per week). 211 Austrian industrial workers and their families in Warri, Nigeria, participated in this study; 101 received Fansimef and 110 chloroquine for 3-18 months (mean 41 weeks). Prophylaxis was discontinued because of adverse effects in 7 volunteers in the Fansimef group (mainly insomnia, palpitations, dizziness, nausea and headache) and in 2 volunteers of the chloroquine group (headache and loss of hair in one volunteer, nausea, dizziness and vomiting in the other). Most of the adverse effects could be due to the mefloquine component. A few minor complaints of burning eyes, nausea and gastric pain were reported in both groups. Laboratory checks performed at 3-monthly intervals showed a slight, transient and clinically irrelevant (but statistically significant) increase of serum glutamic-oxalacetic transaminase and gamma-glutamyl transpeptidase at month 3 in the Fansimef group. An attack of acute Plasmodium falciparum malaria occurred in one volunteer 6 weeks after discontinuation of prophylaxis with Fansimef. Antibodies against blood stage parasites could be demonstrated by the indirect immunofluorescence test at different stages of the study, indicating that these two antimalarials are not causal prophylactic agents.     

A phase II/III double-blind, dose-finding clinical trial of a combination of mefloquine, sulfadoxine, and pyrimethamine (Fansimef) in falciparum malaria

Fansimef is a combination of 250 mg mefloquine (base), 500 mg sulfadoxine, and 25 mg pyrimethamine per tablet. One hundred and fifty adult male Brazilian patients at Belém (Pará), who had peripheral blood smears positive for Plasmodium falciparum, with or without clinical symptoms of falciparum malaria, were treated in a double-blind randomized fashion with either one, two or three tablets of Fansimef. Of those receiving one tablet (48 patients), 81% were cured and 19% exhibited RI recrudescences. All the patients receiving two or three tablets of Fansimef (49 patients in each group) were cured. The rates of initial clearance of parasitaemia and fever were similar in all treatment groups. Tolerance was good at all dose levels. The main side-effects included nausea, vomiting, dizziness, diarrhoea and abdominal pain, but these were mild and transient and required no specific treatment. The incidence of vomiting and nausea was highest in patients given the three-tablet dose. The results of various haematological, biochemical and urine analyses were not adversely altered by the administration of Fansimef.     

Mefloquine, sulfadoxine, and pyrimethamine in the treatment of symptomatic falciparum malaria: a double-blind trial for determining the most effective dose

A total of 89 adult male Thai patients who had acute, uncomplicated falciparum malaria were treated in a double-blind randomized trial with a single oral dose of two or three tablets, each consisting of 250 mg mefloquine, 500 mg sulfadoxine, and 25 mg pyrimethamine (MSP). The two-tablet regimen produced a cure rate (S response) of 93%, the three-tablet regimen a cure rate of 98%. The mean duration of parasitaemia for the two- and three-tablet groups was 50 and 29 hours, respectively, while the mean duration of fever was 43 and 40 hours, respectively. Differences between the groups were not statistically significant. Tolerance was good at both dose levels. The main side-effects were abdominal discomfort, nausea, vomiting, dizziness, and diarrhoea, but these were mild, transient, and required no specific treatment. The results of haematological and biochemical investigations and of urinalysis revealed no drug-related changes following administration of MSP. The electrocardiograms of some patients revealed sinus bradycardia or sinus arrythmia, but these conditions were transient, symptomless, and clinically not significant.     

Amodiaquine combined with sulfadoxine/pyrimethamine versus artemisinin-based combinations for the treatment of uncomplicated falciparum malaria in Africa: a meta-analysis

Drug resistance in Plasmodium falciparum is a major obstacle to malaria control. Artemisinin-based combination therapy (ACT) is being advocated to improve treatment efficacy and to delay development of resistance. Here we summarise the available data on the efficacy of amodiaquine plus sulfadoxine/pyrimethamine (AQ+SP) versus ACTs in the treatment of uncomplicated malaria in sub-Saharan Africa. We searched for randomised trials in which patients with uncomplicated malaria treated with AQ+SP were compared with those treated with either amodiaquine plus artesunate (AQ+AS), artesunate plus sulfadoxine/pyrimethamine (AS+SP) or artemether/lumefantrine (AL). Medline, EMBASE, Cochrane Central Register of Controlled Trials and reference lists up to July 2005 were searched. Two reviewers independently extracted the data. The primary outcome measure was treatment failure by Day 28. Outcome measures were combined using a random effects model. Seven randomised trials of 4472 children were included. Trial quality was generally high. Treatment failure of AQ+SP was significantly reduced compared with AS+SP (relative risk (RR)=0.56, 95% CI 0.42-0.75), but increased compared with AL (RR=2.80, 95% CI 2.32-3.39). The overall failure rate of AQ+SP was similar compared with AQ+AS (RR=1.12, 95% CI 0.81-1.54), but there was significant heterogeneity of results across the studies. All the treatment regimens were safe and well tolerated. AQ+SP should be considered in some settings before the full implementation of an ACT.     

Studies on the resistance of malaria to chloroquine and to a combination of chloroquine and pyrimethamine in Peninsular Malaysia

In vivo chloroquine resistance surveys, which allowed for detection of late recrudescing RI resistance, were conducted in three regions of Peninsular Malaysia, which were previously not recognized as having appreciable drug resistance. Among the 485 Plasmodium falciparum infections tested resistance rates ranged locally from 20 % to 67 % in those with parasitaemias over 1,000 per mm³, and 5 % to 59 % in all parasitaemias. The region found to have the most serious resistance was western Pahang. In one study a combination of chloroquine and pyrimethamine proved no more efficacious than chloroquine alone. Most of the resistance encountered was the late recrudescing RI type. There was no apparent correlation between drug resistance and Anopheles balabacensis as this species was not found despite intensive collections in two of the three main regions. There was no evidence of resistance among the 222 P. vivax and 35 P. malariae infections also tested.     

Efficacy of chloroquine and sulfadoxine/pyrimethamine for the treatment of uncomplicated falciparum malaria in Koumantou, Mali

We report the results of an in vivo antimalarial efficacy study with chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) conducted between 2003 and 2004 in Koumantou, southern Mali. A total of 244 children were included in the study; 210 children were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrudescence from re-infection. Global failure proportions at Day 14, without taking into account re-infections, were 44.2% (95% CI 34.9-53.5%) in the CQ group and 2.0% (95% CI 0.0-4.8%) in the SP group. PCR-adjusted failure proportions at Day 28 were even higher in the CQ group (90.5% (95/105), 95% CI 84.8-96.2%) and relatively low in the SP group (7.0% (7/100), 95% CI 1.9-12.1%). These results show that CQ is no longer efficacious in Koumantou. The use of SP in monotherapy is likely to compromise its efficacy. We recommend the use of artemisinin-based combination therapy as first-line treatment for uncomplicated Plasmodium falciparum malaria in Koumantou.     

In vitro susceptibility of Plasmodium falciparum malaria to pyrimethamine, sulfadoxine, trimethoprim and sulfamethoxazole, singly and in combination

Two isolates of Plasmodium falciparum (F 32 and K 1) were tested against sulfadoxine (SDX), sulfamethoxazole (SMZ), pyrimethamine (PYR) and trimethoprim (TMP), using a 48 h microtest, with RPMI-1640 low in PABA and folic acid. The IC50 for F 32 was: PYR 6.1 X 10(-9) M (mol/litre), TMP 1.3 X 10(-7) M, Fansidar (SDX/PYR 80:1) less than 10(-8) to 1.3 X 10(-10) M and cotrimoxazole (SMZ/TMP 20:1) 2.6 X 10(-7) to 1.3 X 10(-8) M. The IC50 for K 1 was: PYR greater than 10(-6) M, TMP 8.2 X 10(-7) M, Fansidar 4.1 X 10(-7) to 1.1 X 10(-9) M and cotrimoxazole 1.8 X 10(-6) to 9.0 X 10(-8) M. The difference in IC50 between F 32 and K 1 against TMP and cotrimoxazole is much less than the difference between the IC50 values against PYR and Fansidar, indicating that cross-resistance between PYR and TMP exists, but is not complete. A method for calculating the IC50 by linear regression analysis is described.     

A double-blind trial of a fixed combination of mefloquine plus sulfadoxine-pyrimethamine compared with sulfadoxine-pyrimethamine alone in symptomatic falciparum malaria

A total of 100 male Zambian patients with symptomatic falciparum malaria were treated with either two tablets of mefloquine plus sulfadoxine—pyrimethamine (Fansimef) or three tablets of sulfadoxine—pyrimethamine (Fansidar) as a single dose. The patients were kept under observation from day 0 (day of treatment) to day 28 and all were cured. An S-type of response was seen in all patients; one patient in the Fansimef group inexplicably remained positive for Plasmodium falciparum trophozoites until day 6. There were no cases of recrudescence.     

Susceptibility of Plasmodium falciparum in vitro to chloroquine, mefloquine, quinine and sulfadoxine/pyrimethamine in Somalia: relationships between the responses to the different drugs.

The susceptibilities of Plasmodium falciparum to chloroquine, mefloquine, quinine and sulfadoxine/pyrimethamine were investigated in Mogadishu in 1988, after chloroquine resistance had spread widely in Somalia. Possible correlations of the responses to these drugs were also investigated. Standard World Health Organization in vitro micro-tests were performed. Of 76 isolates tested for chloroquine susceptibility, 58 (76%) were resistant to the drug with mean EC50 and EC99 values of 1.06 x 10(-6) mol/litre and 10.44 x 10(-6) mol/litre of blood, respectively, indicating a high prevalence and degree of resistance. In contrast, all isolates tested were inhibited by mefloquine 3.2 x 10(-6) mol/litre of blood, quinine at 2.56 x (-6) mol/litre of blood-medium mixture, and sulfadoxine/pyrimethamine at 6.0/0.075 x 10(-6) mol/litre of blood-medium mixture, indicating full sensitivity to these 3 drugs. However, a significant positive correlation was found between responses to quinine and chloroquine and between those to quinine and mefloquine; the responses to chloroquine and mefloquine were not correlated. The results may suggest that sites responsible for the correlation are shared between quinine and chloroquine but not essentially between chloroquine and mefloquine. Thus the evolution of chloroquine resistance together with increased use of quinine treatment of P. falciparum may increase the risks of development of quinine resistance, whereas the development of mefloquine resistance would not be triggered by chloroquine resistance.     

Falciparum malaria in eastern Thailand: a randomized trial of the efficacy of a single dose of mefloquine.

Reported are the results of a randomized trial of a single dose of mefloquine (15 mg/kg or 25 mg/kg body weight) for the treatment of uncomplicated multidrug-resistant falciparum malaria. Of the 110 adult patients enrolled in the study 57 were randomly assigned to the 15 mg/kg group and 53 to the 25 mg/kg group. The baseline characteristics of the patients did not differ significantly in the two groups, except that those in the 15 mg/kg group had lower haemoglobin levels. Adverse effects following treatment were commoner in the 25 mg/kg group, but not significantly so. Seven patients (6%) did not complete the 42-day follow-up. The parasitological failure rates in the 15 and 25 mg/kg groups were, respectively, 50% (28/56) and 43% (25/53) on day 28, and 62% (33/53) and 56% (28/50) on day 42. Treatment failures were not correlated with the serum mefloquine concentrations on day 2, and 13 out of 19 patients with serum mefloquine concentrations > 2000 micrograms/l on day 2 showed an R response during the follow-up. The mean ratio between the concentrations of the (SR)-(-) and (RS)-(+) enantiomers of mefloquine on day 2 was 3.37, indicating that there are differences in their pharmacokinetics. Re-treatment of patients who showed an R response with seven days of quinine (30 mg.kg-1.day-1)+tetracycline (25 mg.kg-1.day-1) was successful in 93% of the cases.     

Tolerance of mefloquine alone and in combination with sulfadoxine-pyrimethamine in the prophylaxis of malaria

A randomized double blind study was performed to evaluate the tolerance and the acceptance of mefloquine alone (Lariam) compared to a combined drug regimen consisting of mefloquine, sulfadoxine and pyrimethamine (MSP; Fansimef) in the prophylaxis of malaria. 175 Europeans travelling to different malaria endemic areas received either mefloquine alone (250 mg/week) or its combination with sulfadoxine (500 mg/week) plus pyrimethamine (25 mg/week). One person taking mefloquine and two taking MSP discontinued the drug intake because of moderate clinical side effects. Mild and moderate adverse clinical reactions predominantly concerning the gastro-intestinal tract and the autonomous nervous system were reported with a significantly higher occurrence in the MSP group. With both prophylactic regimens, reversibly elevated liver enzyme activities (glutamate oxalate transaminase and glutamate pyruvate transaminase [GPT]) were observed after prophylaxis. The increase of GPT serum activity correlated significantly with relatively high GPT levels before prophylaxis in both groups. This finding suggests a limited use of both regimens in cases of liver dysfunction. One case of mefloquine-resistant Plasmodium falciparum malaria was observed from West Africa; this patient was cured by a standard regimen of chloroquine.     

Therapeutic efficacy of chloroquine and sulfadoxine/pyrimethamine against Plasmodium falciparum infection in Somalia

OBJECTIVE: To assess the efficacy of chloroquine and sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum infections in Somalia. METHODS: Patients with clinical malaria in Merca, an area of high transmission of the disease, were treated with the standard regimens of chloroquine (25 mg/kg) or sulfadoxine/pyrimethamine (25 mg sulfadoxine and 1.25 mg pyrimethamine per kg). Similar patients in Gabiley, an area of low transmission, received the standard regimen of chloroquine. The clinical and parasitological responses were monitored for 14 days. FINDINGS: Chloroquine treatment resulted in clinical failure in 33% (n = 60) and 51% (n = 49) of the patients in Merca and Gabiley respectively. There were corresponding parasitological failures of 77% RII/RIII and 35% RII/RIII. Patients who experienced clinical failure had significantly higher initial parasitaemia than those in whom there was an adequate clinical response, both in Merca (t = 2.2; P t = 2.8; P n = 50) of the patients achieved an adequate clinical response despite a parasitological failure rate of 76% RII/RIII. CONCLUSION: Chloroquine should no longer be considered adequate for treating clinical falciparum malaria in vulnerable groups in the areas studied. Doubts about the therapeutic life of sulfadoxine/pyrimethamine in relation to malaria are raised by the high levels of resistance in the Merca area and underline the need to identify suitable alternatives.     

Evaluation of lambdacyhalothrin-impregnated bednets in a malaria endemic area of India. Part 1. Implementation and acceptability of the trial

In malaria endemic forested villages in Orissa State, India, a 3-year comparison of nylon nets treated with lambdacyhalothrin at 25 mg/m2, untreated nets, and no nets was carried out. Treated nets retained high insecticidal efficacy for more than 7 months. Nets washed after 3 months of use gave 98% kill in a bioassay with a 3-min exposure. Based on these bioassays during the first year, nets were later reimpregnated at 6-monthly intervals with participation of the users. Compliance with the use of nets was good. Eighty-eight percent of nets were usable even after 3 years. The main benefits perceived by treated net users were reductions in malaria, mosquito bites, head louse infestations, and other nuisance insects. The trial was well accepted by the community. Issues related to social marketing and promotion of nets are discussed.