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Plasmodium falciparum malaria in Thailand is resistant to available antimalarial drugs, which necessitates the search for alternative drugs. In a clinical trial mefloquine 1250 mg in divided doses was compared with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 adult men, aged 15-50 years and weighing 45-65 kg, with acute uncomplicated falciparum malaria, no history of liver or kidney diseases, and not history of tasking antimalarials for this episode of illness were recruited at the Bangkok Hospitak for Tropical Diseases. 12 were treated with mefloquine and 34 with oral artemether. Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Parasites did not clear from the blood of 2 patients in the mefloquine group, although there was a decrease in parasitemia. The other 10 patients in the mefloquine group has a good initial response with mean parasite clearance times and fever clearance times of 64 and 27 hours respectively. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs. 64 hours), and a significantly better cure rate (97 vs. 64%) with fewer episodes of dizziness and vomiting. Oral artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported with 600 mg intramuscular artemether given over 5 days. Mefloquine 1250 mg has a cure rate of 80-84% but it produces side effects such as vomiting. The treatment with artemether should last at least 5 days with a dose above 600 mg for a cure rate approaching 100%. This treatment is still likely to be more acceptable to patients than the combination regimen of quinine plus tetracycline for 7 days. These findings suggest that neither artemether nor mefloquine is effective against the intrahepatic stage of Plasmodium vivax. Primaquine is the choice of drug for radical cure.
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PMID:Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria. 135 18

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.
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PMID:Tolerability of long-term malaria prophylaxis with the combination mefloquine + sulfadoxine + pyrimethamine (Fansimef): results of a double blind field trial versus chloroquine in Nigeria. 290 58

A double-blind, placebo-controlled study of mefloquine antimalarial prophylaxis in pregnancy (> 20 weeks of gestation) was conducted in 339 Karen women living in an area of multidrug-resistant malaria transmission on the Thai-Burmese border. Mefloquine gave > or = 86% (95% confidence interval [CI], 59%-94%) protection against Plasmodium falciparum and complete protection against Plasmodium vivax infections. Mefloquine prophylaxis was well tolerated; use of an initial loading dose (10 mg/kg) was associated with transient dizziness, but there were no other significant adverse effects on the mother, the pregnancy, or infant survival or development (followed for 2 years). Falciparum malaria was associated with maternal anemia and a mean reduction in birth weight in gravidae I, II, and III of 225 g (95% CI, 26-423). Maternal anemia at delivery (hematocrit < 30%) was associated with increased infant mortality: 26% versus 15% (relative risk, 1.9; 95% CI, 1.1-3.2). Mefloquine is safe and effective for antimalarial prophylaxis in the second half of pregnancy.
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PMID:Mefloquine prophylaxis prevents malaria during pregnancy: a double-blind, placebo-controlled study. 779 76

In 1991 and 1992, a prospective randomized trial was conducted on the northern Thai-Cambodian border. That trial compared the efficacy and tolerance of two mefloquine regimens for the treatment of uncomplicated Plasmodium falciparum malaria in an area with multi-drug-resistant P. falciparum. The resolution of fever and other symptoms was faster with high-dose mefloquine (25 mg/kg of body weight [M25 group; n = 68]) than with the conventional 15-mg/kg dose (M15 group; n = 71). There were no early treatment failures (days 7 to 9) in the M25 group, but there were 5 (7%) treatment failures in the M15 group (P = 0.03). The incidences of treatment failures by day 28 were 40% with the M15 group and 11% with the M25 group (P = 0.0004). By day 42, these values had risen to 50 and 27%, respectively (P = 0.01). The risk of treatment failure was highest in children (relative risk, 2.1; 95% confidence interval, 1.3 to 3.4) and patients with posttreatment diarrhea (relative risk, 2.0; 95% confidence interval, 1.3 to 3.1). Over half of the recrudescences in the M25 group occurred between days 28 and 42, whereas 17% of the recrudescences in the M15 group occurred between days 28 and 42 (P = 0.02). Thus, the sensitivity of assessment was significantly increased with longer follow-up. Treatment failure was associated with a delayed parasite clearance and an inadequate hematological recovery. Upper gastrointestinal side effects and dizziness were significantly more common in the M25 group, but overall, the high dose was relatively well tolerated, in particular by children. An increase in the dose to 25 mg/kg can prolong the therapeutic use of mefloquine in areas with multi-drug-resistant P.falciparum malaria where high-grade resistance to mefloquine is still rare.
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PMID:Comparison of two mefloquine regimens for treatment of Plasmodium falciparum malaria on the northeastern Thai-Cambodian border. 823 16

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.
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PMID:Quinine and mefloquine in the treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy. 992 43

The objective of this study was to determine the safety and efficacy of atovaquone and proguanil hydrochloride combination therapy for the prophylaxis of Plasmodium falciparum malaria in at-risk nonimmune subjects in South Africa. This open-label trial was conducted at research sites in South Africa during the main malaria transmission season, February through July. The study volunteers were temporarily living in, or traveling to, a malaria-endemic area. They received I tablet of 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for up to 10 weeks. Subjects were monitored using sequential clinical and laboratory assessments. Thick blood smears were stained and evaluated by a central laboratory. An immunochromatographic test for P. falciparum was also used for on-site patient management. Prophylactic success was summarized using a 95% confidence interval for the proportion of subjects who did not develop parasitemia or who withdrew due to a treatment-related adverse event. A total of 175 subjects (15% women) were enrolled in the trial. The mean duration of drug exposure was 8.9 weeks. The combination of atovaquone and proguanil hydrochloride was well tolerated. The most frequently reported adverse events considered possibly related to study treatment were headache (7%), abdominal pain (2%), increased cough (2%), and skin disorder (2%). No serious adverse events were reported, and no treatment-emergent effects were noted for any laboratory variables. One subject who was noncompliant with therapy developed parasitemia, and 3 subjects withdrew due to a treatment-related adverse event (2 subjects with headache and 1 with nausea and dizziness). The prophylaxis success rate was 97%. In this study, atovaquone and proguanil hydrochloride combination therapy had an excellent safety and efficacy profile for prophylaxis of P. falciparum malaria in nonimmune subjects.
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PMID:Safety and efficacy of atovaquone and proguanil hydrochloride for the prophylaxis of Plasmodium falciparum malaria in South Africa. 1036 39

Artemether-lumefantrine (A-L), a new fixed-dose oral antimalarial drug, combines the fast onset of action of artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria. The extensive clinical trial database of A-L has allowed a comprehensive evaluation of its tolerability and safety in a total of 1869 patients (including 243 children aged 5-12 years and 368 children aged < 5 years). The most commonly reported and possibly related adverse effects following A-L therapy involved the gastro-intestinal (abdominal pain, anorexia, nausea, vomiting, diarrhoea) and central nervous (headache, dizziness) systems. Pruritus and rash were reported by < 2% of patients. More than 90% of the reported adverse events, many of which overlapped considerably with the clinical symptomatology or evolution of acute malaria, were rated mild to moderate in intensity. Compared to A-L, significantly higher incidences of vomiting and pruritus were observed with chloroquine, dizziness, nausea and vomiting with mefloquine, somnolence with pyrimethamine + sulfadoxine, and vomiting and dizziness with quinine. There were no serious or persistent neurological side-effects related to A-L administration. A-L did not lead to any clinically relevant alterations of the laboratory parameters. Serial electrocardiographic data were available for 713 patients. The frequency of QT interval prolongations was similar to or lower than that observed with chloroquine, mefloquine, or artesunate + mefloquine; these changes were considerably less frequent than with quinine or halofantrine. All patients with QT prolongation remained asymptomatic and no adverse clinical cardiac events were reported. Artemether-lumefantrine can thus be expected to show, both in children and in adults, a favourable safety profile for the treatment of acute, uncomplicated, P. falciparum malaria; it could as well be a reserve treatment option for travellers to endemic countries.
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PMID:An integrated assessment of the clinical safety of artemether-lumefantrine: a new oral fixed-dose combination antimalarial drug. 1112 48

The efficacy-safety and pharmacokinetics of the six-dose regimen of artemether-lumefantrine (Coartem/Riamet; Novartis Pharma AG, Basel, Switzerland) were assessed in a randomized trial in 219 patients (> or = 12 years old) with acute, uncomplicated Plasmodium falciparum malaria in Thailand. One hundred and sixty-four patients received artemether-lumefantrine and 55 received the standard treatment combination of mefloquine-artesunate. Both drugs induced rapid clearance of parasites and malaria symptoms. The 28-day cure rates were 95.5% (90% confidence interval [CI] = 91.7, 97.9%) for artemether-lumefantrine and 100% (90% CI = 94.5, 100%) for mefloquine-artesunate. This high-dose regimen of artemether-lumefantrine was very well tolerated, with very good compliance. The most frequent adverse events were headache, dizziness, nausea, abdominal pain, dyspepsia, vomiting, and skin rash. Overall, only 2% of patients in both groups showed QTc prolongations but without any cardiac complication, and no differences were seen between patients with and without measurable baseline plasma levels of quinine or mefloquine. Plasma levels of artemether, dihydroartemisinin, and lumefantrine were consistent with historical data for the same dose regimen, and were higher, particularly for lumefantrine, than those previously observed with the four-dose regimen, explaining the greater efficacy of the six-dose regimen in a drug-resistant setting. These results confirm the excellent safety and efficacy of the six-dose regimen of artemether-lumefantrine in the treatment of multidrug-resistant P. falciparum malaria.
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PMID:A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. 1146 11

In late 2003, the efficacies of mefloquine monotherapy and of an artesunate-mefloquine combination, for the oral treatment of uncomplicated, Plasmodium falciparum malaria, were investigated and compared in New Halfa, in eastern Sudan. Of the patients who completed the 28 days of follow-up, 40 were treated only with single-dose mefloquine (at a dose of 25 mg/kg), and 38 with artesunate (at 4 mg/kg. day) for 3 days followed by single-dose mefloquine (at 15 mg/kg), given on the third day. Compared with those given the combination, the patients given mefloquine alone were more likely to suffer nausea, vomiting and dizziness (25.0% v. 2.6%; P=0.005) and to be found gametocytaemic (12.5% v. 0%; P=0.02) after treatment, and more likely to be found febrile (i.e. with a temperature >37.5 degrees C) on day 2 (25.0% v. 2.6%; P=0.005), although no patients were found febrile on day 3. Six of the patients--three (7.5%) of those given mefloquine only and three (7.9%) of those given the combination (P>0.05)--appeared to be treatment failures. Parasite genotyping indicated, however, that, although five of these six patients had true recrudescences, one (who had been treated with the combination) had been re-infected during the follow-up. The true frequencies of cure were therefore 92.5% after mefloquine alone and 94.7% after the combination (P>0.05). Thus, although the treatments appeared equally effective in clearing parasitaemias, the combination was better at clearing gametocytaemias and was less likely to cause adverse side-effects. It remains unclear why mefloquine given alone was almost 10-fold more likely to trigger adverse effects than treatment with a combination that contained the same drug. This may be a reflection of the different mefloquine doses and, for the patients given the combination, of the use of artesunate before the mefloquine treatment.
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PMID:Efficacies of mefloquine alone and of artesunate followed by mefloquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan. 1581 29

The combination of artesunate and mefloquine is currently one of the most effective treatments for multidrug-resistant Plasmodium falciparum malaria. Simultaneous, rather than sequential treatment with the two drugs, would allow better patient compliance. We therefore evaluated three-day treatment with artesunate combined with either 2 or 3 days of mefloquine co-administered once a day with artesunate. The study was an open, randomized trial for acute, uncomplicated falciparum malaria and was conducted at the Bangkok Hospital for Tropical Diseases. One hundred and twenty adult patients were randomized to two treatment groups. Group 1 patients received 4 mg/kg/day of artesunate for 3 days and 3 daily doses of 8.0 mg/kg/day mefloquine given with artesunate. Group 2 patients received the same dose of artesunate and the same total dose of mefloquine (25 mg/kg). However, the mefloquine was given as 15 mg/kg on the first day and 10 mg/kg/ on the second day, again with artesunate. The baseline demographic and clinical characteristics of the patients in the two groups were similar. The cure rates for the 3-day and 2-day mefloquine regimens were 100% and 99%, respectively. There were no significant differences in either median fever clearance times (group 1=32 hours; group 2=33 hours) or mean parasite clearance times (group 1=42.3 hours; group 2=43.3 hours). Both regimens were well tolerated and there were no significant differences in the incidence of adverse effects. Nausea or vomiting occurred in 3.8% of patients in both groups and transient dizziness occurred in 4% of group 1 and 9% of group 2 patients. These results suggest that a 3-day regimen of mefloquine administered with artesunate is effective and well tolerated. This practical regimen could improve patient compliance.
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PMID:An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria. 1612 22


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