Artesunate and Mefloquine Combination for Falciparum Malaria Treatment

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 threeday 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. artemisinin derivative, such as artesunate, with mefloquine (Looareesuwan et al, 1994, 1996; Nosten et al, 1994). Artesunate is very well tolerated, but in order to be effective as monotherapy, treatment for at least 5 days is required (Looareesuwan et al, 1992b, 1997). When used alone, recrudescence rates in the order of 10% to 20% have been reported, which may be attributable to the short half life of the compound (Li et al, 1994; Baradell and Fitton, 1995). Mefloquine was introduced in the 1980s and remains effective in most endemic areas for both the treatment and prophylaxis of malaria. The drug is generally well tolerated but may occasionally be associated with neuropsychiatric adverse effects (White, 1994; Palma et al, 1993). A series of controlled studies showed high efficacy rates and good tolerability for the combination (Price et al, 1999; SOUTHEAST ASIAN J TROP MED PUBLIC HEALTH 592 Vol 36 No. 3 May 2005 Luxemburger et al, 1994; Bunnag et al, 1996, 1997; Price et al, 1995, 1998; Thimasarn et al, 1997; van Vugt et al, 1998), and consequently, it has become a standard regimen for the treatment of uncomplicated malaria in Southeast Asia. However, treatment recommendations differ, in regards to both duration, from 1 day (Luxemburger et al, 1994) to 5 or more days (Looareesuwan et al, 1992b; Price et al, 1998), and in regards to dose. Mefloquine is generally begun at the end of the course of artesunate or used on the first and second days of artesunate treatment. However, the dose and duration of mefloquine administration remain controversial and combination therapy may present logistical problems and lead to decreased patient compliance. A fixed dose combination has the advantage of simplicity and allows the drugs to be combined in one formulation. The aim of the present study was to investigate the efficacy and safety of simultaneously administered artesunate 4 mg/kg/day (total dose 12 mg/kg) given once daily for a total of 3 days with mefloquine (total dose 25 mg/kg) divided into three doses (8 mg/kg/day) given once daily. This regimen was compared to a conventional artesunate-mefloquine sequential combination regimen (artesunate 4 mg/kg/day given once daily for a total of 3 days together with mefloquine 15 mg/kg/day co-administration on the first day and 10 mg/kg/day on the second day). MATERIALS AND METHODS This study was conducted in Thailand at the Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University. Study approval was given by the Ethics Committee of the Faculty of Tropical Medicine. Patients 15 years of age or older weighing at least 39 kg and presenting with microscopically confirmed Plasmodium falciparum malaria were eligible for the trial if they or a responsible family member gave informed consent. Subjects with signs and symptoms of severe or complicated malaria (World Health Organization, 2000) were excluded, as were individuals unable to tolerate oral medications, pregnant or lactating females, individuals allergic to study drugs or patients who had taken any antimalarial drug within 2 weeks of admission. All patients were admitted to the hospital for 28 days or agreed to stay in a nonmalaria endemic area for 28 days to exclude reinfection. All patients were followed up weekly. Each patient was sequentially assigned to one of two regimens: Group 1, patients were given artesunate 4 mg/kg/day for three days, (Gullin Pharmaceutical Corp, China, 50 mg/tablet) with mefloquine 8 mg/kg/day (250 mg/tablet) once a day for three days. Group 2, patients were given artesunate 4 mg/kg/day for three days with mefloquine 15 mg/kg/ on the first day and 10 mg/kg on the second day. Artesunate was given with mefloquine and patients who vomited within one hour after drug administration were redosed with both drugs. On enrollment, a medical history was obtained, a full baseline physical examination was conducted, and blood was taken for routine hematology and biochemistry. Clinical signs and symptoms were recorded daily during the first week and then weekly until patients were discharged. Oral temperature, pulse, and respiratory rates were measured every 4 hours and the blood pressure was recorded once daily. Routine laboratory examinations were performed on days 0, 7, 14, 21, and 28. Malaria parasite counts were made prior to treatment and every 12 hours until negative, then once daily for 28 days. Blood films were considered negative if no parasites were seen in 200 oil immersion fields. Parasite counts per μl using Field’s stained smears were determined by counting the number of asexual parasites per 200 white blood cells in thick blood films or per 1,000 red blood cells in thin blood films. Clinical efficacy was assessed by determining the 28-day cure rate and by measuring parasite and fever clearance times (World Health Organization, 1973). The 28-day cure rate was defined as the proportion of patients who had no asexual parasitemia within seven days of initiation of treatment and who had no subsequent recrudescence within 28 days. Cure rates were evaluated on an intent-to-treat basis. The parasite clearance time (PCT) was the number of hours from the start of treatment until the first blood film became and remained negative for the next 24 hours. The fever clearance time (FCT) was the number of hours from the beginning of treatment until the patient’s temperature decreased to 37.5oC or lower, and remained below this temperature for at least the next 48 hours. ARTESUNATE AND MEFLOQUINE COMBINATION FOR FALCIPARUM MALARIA TREATMENT Vol 36 No. 3 May 2005 593 Standard descriptive and statistical analyses were conducted using version 6.04 of the EpiInfo software (Centers of Disease Control, Atlanta, GA). Comparisons were made using the chi-square and Student’s t-test, and the MannWhitney U test, where appropriate.