Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged 1-5 years. Single day mefloquine-artesunate combination in the treatment of multi-drug resistant falciparum malaria. A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children. Comparison of oral artesunate and quinine plus tetracycline in acute uncomplicated falciparum malaria. Single dose artemisinin-mefloquine versus mefloquine alone for uncomplicated falciparum malaria. Pharmacokinetics of mefloquine alone or in combination with artesunate. Single dose artemisinin-mefloquine treatment for acute uncomplicated falciparum malaria. [An efficacy and tolerance study of oral artesunate alone and in combination with mefloquine in the treatment of uncomplicated falciparum malaria in an endemic area of Pará, Brazil]. A randomized comparative study of artemisinine (qinghaosu) suppositories and oral quinine in acute falciparum malaria. Double blind randomised clinical trial of oral artesunate at once or twice daily dose in falciparum malaria. Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand. A preliminary report. Monotherapy with sodium artesunate for uncomplicated falciparum malaria in Thailand: a comparison of 5- and 7-day regimens. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Randomized trial of mefloquine alone and artesunate followed by mefloquine for the treatment of acute uncomplicated falciparum malaria. Randomised comparative study of mefloquine, qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria. Comparative effectiveness of artemisinin suppositories and oral quinine in children with acute falciparum malaria. Artemether-mefloquine combination in multidrug resistant falciparum malaria. Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria. Artemether or artesunate followed by mefloquine as a possible treatment for multidrug resistant falciparum malaria. In vivo efficacy of chloroquine, halofantrine, pyrimethamine-sulfadoxine and qinghaosu (artesunate) in the treatment of malaria in Calabar, Nigeria. A comparative clinical trial of two different regimens of artemether plus mefloquine in multidrug resistant falciparum malaria. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. A comparative study of artesunate and artemether in combination with mefloquine on multidrug resistant falciparum malaria in eastern Thailand. Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria. A comparative clinical trial of artemether and the sequential regimen of artemether-mefloquine in multidrug resistant falciparum malaria. Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria. Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients.
A randomized, open trial involving 260 Tanzanian children, aged 1-5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven-day parasitological cure rates were 94% (95% CI 88-97.5) for CGP 56697 and 35.4% (95% CI 25.9-45.8) for chloroquine. Using the same definition, the 14-day parasitological cure rates were 86.4% (95% CI 78.5-92.2) for CGP 56697 and 10.3% (95% CI 5.1-18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first-line drug in an area of high malaria transmission and very high levels of chloroquine resistance. The therapeutic efficacy and toxicity of a combination of low dose mefloquine (15 mg/kg) plus artesunate 10 mg/kg in one day (MA) was compared with the currently used regimen of high dose mefloquine (25 mg/kg) (MQ) in 552 patients with uncomplicated falciparum malaria in an area of multi-drug resistance on the Thai-Burmese border. MA gave faster clinical and parasitological responses and prevented early treatment failure; 15 patients in the MQ group (6%) were early failures (< 9 d) compared with none receiving MA (P = 0.0001). Overall failure rates by day 28 were 19% in the MA group and 24% in with MQ group (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.54-1.12). In the subgroup of patients who required re-treatment, MA proved significantly more effective than MQ; failure rates were 25% and 52% respectively (RR = 0.49, 95% CI = 0.29-0.83). Treatment failures were associated with mefloquine treatment in the previous month (RR = 1.72, 95% CI = 1.09-2.70) and diarrhoea (RR = 1.55, 95% CI = 1.05-2.28). Gastrointestinal side-effects and dizziness were more likely in the MQ group. There was no evident adverse effect associated with artesunate. A single day's treatment with artesunate augments the antimalarial efficacy of mefloquine. We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697. In Thailand Plasmodium falciparum malaria is highly resistant to available antimalarials. Investigations on the efficacy of existing antimalarials and of alternative drugs are urgently needed. Artesunate has been shown to be effective against falciparum malaria, but is associated with a high recrudescence rate. We have carried out a comparative clinical trial of the standard regimen of quinine + tetracycline versus oral artesunate at a 700-mg total dose given over 5 days to patients with acute uncomplicated falciparum malaria. The 64 male patients who took part in the study were randomized to receive either quinine-tetracycline (33 patients) or oral artesunate (31 patients). All the patients were admitted to the Bangkok Hospital for Tropical Diseases for 28 days. Oral artesunate had faster parasite and fever clearance times than the combination quinine-tetracycline, but the cure rate was not significantly different for the two regimens. However, the occurrence of adverse effects, such as tinnitus, was significantly higher in the quinine-tetracycline group. Surprisingly nausea and dizziness were rather common with artesunate. The possibility of neurological adverse effects for artesunate should also be borne in mind. Oral artesunate (700 mg given over 5 days) is effective and better tolerated than the combination quinine-tetracycline. The cure rate we obtained is higher than that reported in previous studies with 600 mg of oral artesunate given over 5 days. Oral artesunate can be considered as an alternative drug for multiple-drug-resistant falciparum malaria; however, adverse effects, particularly neurotoxicity, should be closely monitored before its widespread use can be recommended.(ABSTRACT TRUNCATED AT 250 WORDS) The efficacy of the combination of a single oral dose of 500 mg artemisinin with a single 500 mg oral dose of mefloquine (AM) in the treatment of uncomplicated falciparum malaria was compared to mefloquine therapy alone (M) in a double-'blind' randomized study in an endemic area in the south of Viet Nam where single low dose treatment was employed and where mefloquine had been recently introduced. 231 patients, 117 AM and 114 M, were studied. Failure of therapy occurred in 1 AM patient and in 3 M patients. The radical cure rate was 84% for the AM regimen and 65% for the M regimen (P = 0.002). Recrudescence (including an unknown percentage of reinfections) occurred in 15% of AM patients and in 30% of M patients (P = 0.01). The mean parasite clearance time was 40 h (SD = 16) for AM and 60 h (SD = 27) for the M regimen (P = 0.0001). No effect of artemisinin was noted on gametocytes present on admission, but new gametocytes developed less frequently in the AM group. The addition of a single dose of 500 mg artemisinin to 500 mg mefloquine increased the efficacy and reduced the rate of recrudescence, but this regimen was not adequate and, for short course regimens, more doses of artemisinin as well as higher, doses of mefloquine should be studied. A randomized comparative trial of the pharmacokinetics and pharmacodynamics of oral doses of mefloquine and of mefloquine in combination with artesunate was carried out on 20 Thai male patients with acute, uncomplicated falciparum malaria. The patients were randomized to receive either mefloquine alone (8 patients; 1250 mg of mefloquine--initial dose, 750 mg; followed 6 hours later by 500 mg), or in combination with oral artesunate (12 patients--initial dose, 200 mg of artesunate; followed by 750 mg and 500 mg of mefloquine 6 hours and 12 hours later, respectively). The patients who received mefloquine alone all showed initially good responses to the treatment, with mean +/- SD values for the fever clearance time (FCT) and parasite clearance time (PCT) of 44.7 +/- 43.1 hours and 82.3 +/- 52.3 hours, respectively. Two patients had recrudescences on day 20 and day 31 (RI response). The cure rate was 75%, and one patient had Plasmodium vivax in his peripheral blood on day 52. The patients who received the combination treatment were clinically markedly improved, with a relatively shorter FCT (31.2 +/- 12.4 hours) and significantly shorter PCT (47.5 +/- 19.6 hours). Four had recrudescences on days 12, 18, 26 and 33; the cure rate was 66%. Artesunate caused three significant changes in mefloquine pharmacokinetics: a decrease in the maximum concentration (Cmax: 1623 ng.ml-1 versus 2212 ng.ml-1); an increase in the clearance rate (Cl/f:2.9 ml.min-1.kg-1 versus 1.1 ml.min-1.kg-1); and an expansion of the volume of distribution (Vdz/f: 31.8 l.kg-1 versus 25.0 l.kg-1). For the treatment of patients with acute falciparum malaria, the combination of artemisinin as a single dose with a single dose of mefloquine was studied in 4 separate prospective trials, comprising 405 adults and 139 children with uncomplicated falciparum malaria in 2 in-patient and 2 rural out-patient studies in Viet Nam. Adults received oral artemisinin and children artemisinin suppositories. Randomized comparative treatment schedules were: artemisinin alone for 5 d, mefloquine-sulfadoxine-pyrimethamine (MSP), or quinine plus sulfadoxine-pyrimethamine (SP). Parasite clearance times (PCT) were rapid for artemisinin treated inpatients (90%: 14.8-20.4 h) but also for patients receiving MSP (PCT 90%: 18.0 h) and quinine (PCT 90%: 22.5 h). The recrudescence rate (RI) during a 28 d follow-up period among the patients given artemisinin plus mefloquine was 15% in the adult in-patients and zero in the adult and children out-patients. RI in the artemisinin 5 d treatment group was 33.3%; among those given artemisinin plus SP it was 47.3% in in-patients and in out-patients 46.1%. In the MSP treated out-patients RI was 1.5% in adults and zero in children. Artemisinin as a single dose (oral in adults and as a suppository in children) in combination with mefloquine was effective in rapidly lowering parasitaemia and in preventing recrudescence in hospital in-patients and in out-patients attending a rural health clinic. MSP alone as a single dose also rapidly reduced parasitaemia (but not as quickly as the artemisinin-mefloquine combination in out-patient children) and prevented recrudescence. With the objective to evaluate the efficacy and tolerance of artesunate in the treatment of noncomplicated falciparum malaria in endemic area of the State of Pará, 153 patients were randomized and studied in three groups, distributed by therapeutical scheme (I received mefloquine 1000 mg, II used artesunate 600 mg followed by mefloquine 500 mg). Evaluation was made by daily clinical and parasitological examination, in the first 7 days, and weekly until the 35th day of the follow-up. Biochemical and hematological analysts previously done and on the 7th day, targeting cure control and identification of possible effects related to drugs administration. As to sex, parasitemia and fever, studied groups were homogeneous. Time for parasitemia disappearance was shorter in the groups II and III respectively, whose therapeutical schemes had artesunate. Fever disappearance was quicker in the group treated with the combination of drugs. Clinical and biochemical alterations associated with drugs administration did not show significant differences among the studied groups. Early disappearance of fever and parasitemia, and absence of important side effects suggest that artesunate, isolated or administrated in combination with mefloquine, constitutes an able therapeutical procedure to constitutes and able therapeutical procedure to contribute for disease control in that region. In adult patients with acute falciparum malaria in Ho Chi Minh City, Vietnam, a more rapid reduction in parasite count (50% clearance in 11.3 h) and complete clearance (41.8 h) was obtained in 32 adult patients randomly assigned to received artemisinine suppositories than was obtained with 30 patients receiving oral quinine (20.8 h and 68.1 h). There were higher degrees of resistance (RII, 3 cases; RI early, 1 case) with quinine than with artemisinine but in a subgroup of patients quinine reduced parasitaemia as rapidly as artemisinine (50% clearance 13.6 h and 10.1 h respectively). Recrudescence (RI, delayed), occurred in 16 patients receiving artemisinine compared with 6 receiving quinine. Artemisinine suppositories, because of ease of administration, efficacy, and lack of side effects or risk of overdose, have advantages for the early treatment of falciparum malaria by possibly reducing the morbidity and mortality associated with a high or sustained parasitaemia. A double blind randomised comparative trial of the efficacy of daily dose (200 mg as an initial dose followed by 100 mg daily for another 4 days) and twice daily dose (100 mg 12 hourly for 2 doses on the first day, followed by 50 mg 12 hourly for another 8 doses) regimens of oral artesunate at 600 mg was studied in 59 Thai patients with uncomplicated falciparum malaria. Fifty patients had a complete 28-day follow-up period. Both regimens produced similar efficacy with no difference in adverse effects. The patients with the daily artesunate regimen had mean fever and parasite clearance times of 20 and 40 hours, respectively. The cure rate was 72%. Eight patients had recrudescence during days 15 to 28 while 8 showed P. vivax in their peripheral blood between days 12 and 21. The patients with the twice daily regimen had mean fever and parasite clearance time of 28 and 40 hours, respectively. The cure rate was 76%. Six patients had recrudescence during days 15 and 27 while 7 showed P. vivax during days 12 and 23. We suggest that the duration of the treatment may be a more important factor determining the efficacy of artesunate rather than the frequency of the doses. Further studies based on pharmacokinetics are therefore needed to improve the cure rate to 100% to prevent the spread of P. falciparum, particularly in areas where there are high numbers of multi-drug resistant strains. A 5-day course of oral artesunate at total doses of 1200, 600, 650 mg and intramuscular artemether 480 mg proved effective (90-100% cured) in the treatment of multidrug resistant falciparum malaria in Thailand. Shorter courses yielded high recrudescence rates. The fever clearance and parasite clearance times were short. The side effects were mild and transient including occasional abnormal electrocardiograms and pain at the injection site. Slight reduction of neutrophil leucocytes and reticulocytes was observed. Further studies of artesunate and artemether should be carried out to find the optimum dosage regimen and to clarify the hematological effects. We compared the safety and efficacy of two treatment regimens using sodium artesunate in 91 randomized patients with uncomplicated falciparum malaria acquired in Thailand. One group of 45 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 4 days for a total of 1200 mg (group I: 5-day treatment). A second group of 46 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 6 days for a total of 1600 mg (group II: 7-day treatment). Both regimens were well tolerated. All patients were followed for a total of 28 days. By the third day of treatment, most patients were blood smear negative for parasites. Eighty-two patients completed the 28-day follow-up period and were used for describing the cure rate. All patients treated with the 5-day regimen were cured. In the 7-day treatment group, 98% (39 of 40) of the patients were cured; one patient developed late recrudescence (RI). There were no significant differences in fever clearance or parasite clearance between the two groups. However, 13 patients (five in group I and eight in group II) developed Plasmodium vivax infection during the follow-up period. We conclude that 5- or 7-day regimens of sodium artesunate with a total dose of 1200-1600 mg are effective and safe in treating falciparum malaria acquired in Thailand. The increasing frequency of therapeutic failures in falciparum malaria in Thailand shows an urgent need for effective drugs or drug combinations. Artesunate, a qinghaosu derivative, is effective in clearing parasitaemia rapidly, but the recrudescence rate can be as high as 50%. We have compared artesunate followed by mefloquine with each drug alone in acute, uncomplicated falciparum malaria. 127 patients were randomly assigned treatment with artesunate (600 mg over 5 days), mefloquine (750 mg then 500 mg 6 h later), or artesunate followed by mefloquine. All patients were admitted to hospital for 28 days to exclude reinfection. Cure was defined as no recrudescence during the 28 days' follow-up. The cure rates for mefloquine and artesunate alone were 81% (30/37 patients) and 88% (35/40); the combination was effective in all of 39 patients. Fever and parasite clearance times were significantly shorter in the groups that received artesunate than in the mefloquine-only group. The frequency of nausea and vomiting was slightly, but not significantly, higher among patients who received both drugs than in the other groups. The combination of artesunate followed by mefloquine is highly effective and well tolerated in patients with acute, uncomplicated falciparum malaria in Thailand. Mefloquine is the main antimalarial used for treatment of falciparum malaria patients at the malaria clinics in Thailand. However, the cure rate with mefloquine alone has declined seriously in recent years. The efficacy and tolerability of a sequential treatment of artesunate followed by mefloquine was therefore compared with those of mefloquine alone, in a randomized therapeutic trial involving 125 patients with acute uncomplicated falciparum malaria. Sixty-three patients received mefloquine alone (750 mg given immediately, followed by 500 mg 6 h later) and 62 each received 800 mg artesunate over 2 days (200 mg every 12 h) followed 6 h later by a single, 750-mg dose of mefloquine. All patients were admitted to the hospital in Bangkok for 28 days to exclude re-infection. Most patients (107) completed the study; 18 left the hospital prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 74% (42/57) for mefloquine alone and 92% (46/50) for artesunate followed by mefloquine. The mean parasite clearance time was significantly shorter (P < 0.001) in the group treated with the sequential combination than in the group treated with mefloquine alone, but the mean fever clearance times were not significantly different (P = 0.26). Most patients responded well to the treatment regimens and none suffered from serious toxic adverse reactions. Only four patients who were treated with mefloquine alone had parasitaemia persisting to day 7 (RII), thus requiring alternative follow-up treatment.(ABSTRACT TRUNCATED AT 250 WORDS) A prospective trial in 80 patients randomly allocated to four antimalarial treatment regimens--mefloquine plus pyrimethamine-sulfadoxine ('Fansidar'); mefloquine plus qinghaosu; mefloquine, fansidar, and qinghaosu; and qinghaosu alone--was carried out on Hainan Island, China, in patients with chloroquine-resistant falciparum malaria. A radical cure with slight side-effects was obtained with mefloquine plus fansidar; the addition of qinghaosu greatly increased the rate of parasite clearance with no additional side-effects. Qinghaosu alone had a rapid rate of parasite clearance, no side-effects, but a high recrudescence rate. These antimalarial drugs seem to act at different stages of the asexual parasite cycle and their most efficient use may depend on when in the course of the disease they are given. Because of the continuing appearance of drug-resistant strains of Plasmodium falciparum combination drug therapy is now indicated, but which drugs and how best they should be used remains to be decided. nan Plasmodium falciparum in Thailand is highly resistant to chloroquine and sulfadoxine/pyrimethamine and there is increasing resistance to the alternative antimalarials, quinine and mefloquine. In eastern Thailand, the cure rates of mefloquine at 750 and 1250 mg were 30% and 55%, respectively. The use of drug combinations may be necessary in areas where drug-resistant parasites exist. 159 male Thai patients in Chantaburi, eastern Thailand, were allocated at random to receive either oral artemether at a single dose of 300 mg on the first day followed by mefloquine 750 mg at 24 h and 500 mg at 30 h (group A), or oral artemether at a single dose of 300 mg on the first day, mefloquine 750 mg at 24 h and placebo at 30 h (group B). The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Most patients in both groups had a rapid initial response to treatment, parasitaemia being cleared within 24 h and fever cleared within 48 h in both groups. The cure rates were 97% and 90%, respectively, for groups A and B. No serious adverse effect was seen in either group; mild and transient nausea, vomiting and loss of appetite were noted. The adverse effects did not differ between the 2 groups. The results suggested that a single oral dose of artemether (300 mg) can markedly improve the cure rate of mefloquine at a dose of 750 or 1250 mg in multiple drug-resistant falciparum malaria. One hundred fifty-one patients with acute uncomplicated falciparum malaria were enrolled in a randomized, open-label study of oral artemether given alone for five or seven days or a sequential treatment of oral artemether followed by mefloquine. Forty patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 500 mg over a five-day period: Group I. Fifty-eight patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 750 mg over a seven-day period: Group II. Fifty-three patients received oral artemether, 200 mg every 8 hr for a total dose of 600 mg, followed 8 hr later with mefloquine (1,250 mg divided into two doses given 6 hr apart: Group III. All patients were admitted to the hospital for 28 days to exclude reinfection and 131 patients remained through the 28-day follow-up. Only two, nine, and nine patients in Groups I, II, and III, respectively, left the hospital prior to study completion for reasons unrelated to their treatment. Cure rates for the three groups were 74% (28 of 38) for Group I, 98% (48 of 49) for Group II, and 98% (43 of 44) for Group III. Mean fever and parasite clearance times were not significantly different (32.8, 27.5, and 31.4 hr for fever clearance times and 40.2, 40.6, and 36.7 hr for parasite clearance times of Groups I, II, and III, respectively) nor were any adverse effects seen. In vitro drug susceptibility testing of admission and recrudescent parasite isolates was conducted for 10 patients. These data showed no decreased response to artemether or dihydroartemisinin in recrudescent isolates when compared with admission isolates. The results of this study suggest that sequential treatment for two days with oral artemether (600 mg) followed by mefloquine (1,250 mg) is effective and well-tolerated in patients with acute uncomplicated falciparum malaria and may be an alternative treatment for multidrug-resistant falciparum malaria, particularly useful for treating patients in rural areas where the period of admission to the hospital should be as short as possible. A seven-day regimen of artemether alone (750 mg) is also very effective, yet requires prolonged administration of drug after malaria symptoms disappear. Plasmodium falciparum in south-east Asia is highly resistant to chloroquine and sulfadoxine-pyrimethamine. Mefloquine used to be the chemosuppressant drug of choice in areas with chloroquine resistance. However, sensitivity to this drug has recently decreased in Thailand, Cambodia and Myanmar, and there is no suitable single alternative drug. We therefore investigated possible alternative combination therapies for multidrug resistant falciparum malaria. 120 male Thai patients at Makarm Malaria Clinic, Chantaburi, in eastern Thailand were allocated at random to receive either oral artemether (group A) or artesunate (group B) at a single dose of 300 mg on day 1, both followed by mefloquine, 750 and 500 mg at 24 and 30 h, respectively. Follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups had a rapid initial response to treatment; in most cases parasitaemia was cleared within 24 h, and fever was cleared within 24 h in 62% and 76.7% of the patients in groups A and B, respectively. 58 patients in group A and 57 in group B completed follow-up and cure rates were 98% and 97%, respectively. Reinfection could not be excluded for the 3 patients with recrudescences; all were cured with a repeated course of treatment. No serious adverse effect was observed in either group, only mild and transient nausea, vomiting and loss of appetite, with no significant difference between the 2 groups. These results suggest that a single oral dose of 300 mg of either artemether or artesunate followed by 1250 mg of mefloquine in 2 divided doses is effective against multiple drug resistant falciparum malaria. Either regimen can be considered as a suitable 'stand-by' in endemic areas of multiple drug resistant falciparum malaria. We used the WHO in vivo seven day test, extended to 14 day follow up to evaluate the efficacy of the alternative antimalarial drugs in Nigeria (1992), where chloroquine resistant P. falciparum (CRPD) has been confirmed. One thousand and four patients were screened. Those fulfilling recruitment criteria were randomly treated with chloroquine (CQ), n = 50, halofantrine (H), n = 53, pyrimethamine-sulfadoxine (P-S), n = 52 and qinghaosu (Q), n = 53. Parasitological treatment failures were found with all drugs i.e. CQ-53.6pc, H-9.5pc, P-S-28.5pc and Q-2.0pc. H and Q were significantly more efficacious than CQ and P-S, p < 0.003 and p < 0.006, respectively. similarly symptom clearance after 48 hours by H and Q, was 76.3pc and 94pc respectively, better than CQ. P-S was not significantly better than CQ, 64.4pc and 63.3pc, respectively, p > 0.05. The symptom clearance rate of CQ has markedly reduced from 97.7pc to 67.7pc, and in increased proportion of RIII, from 5.9pc to 14.3pc, are signs of increase in chloroquine resistant Plasmodium falciparum. Drug resistant P. falciparum in Nigeria constitutes a serious problem to malaria chemotherapy. Plasmodium falciparum in Thailand is highly resistant to available antimalarial drugs. Artemether, a derivative of artemisinin, is a promising compound currently used to cope with this situation but the course of treatment has to be at least 5 d. An effective short treatment course of this drug is possible when used in combination with mefloquine. We now report a trial of different regimens of the combination artemether/mefloquine. Fifty-seven male Thai patients, admitted to the Bangkok Hospital for Tropical Diseases, were allocated at random to receive oral artemether 300 mg as an initial dose, followed by either the standard dose of mefloquine (750 mg) at 24 h or a higher dose of mefloquine (750 mg at 24 h, then 500 mg at 30 h). Patients were followed up in hospital for 42 d. Two patients, both in the high dose mefloquine group, were excluded as they failed to attend for follow-up. All patients had a rapid initial response to treatment with median parasite clearance times of 37 and 40 h, median fever clearance times of 33.5 and 30.5 h, and cure rates of 75 and 96% (P = 0.0248), for the standard and high doses of mefloquine respectively. No serious adverse effect was found; mild and transient dizziness, nausea, vomiting and diarrhoea were noted in half of the patients in each group. The results suggest that a 30 h short course of artemether plus mefloquine at high dose should be used in areas with documented mefloquine resistance. Studies of 652 adults and children with acute uncomplicated falciparum malaria were done to determine the optimum treatment of multidrug-resistant Plasmodium falciparum malaria on the Thai-Burmese border. Single-dose artesunate (4 mg/kg) plus mefloquine (25 mg of base/kg) gave more rapid symptomatic and parasitologic responses than high-dose mefloquine alone but did not improve cure rates. Three days of artesunate (total dose, 10 mg/kg) plus mefloquine was 98% effective compared with a 28-day failure rate of 31% with high-dose mefloquine alone (relative risk [RR], 0.06; 95% confidence interval [CI], 0.02-0.2; P < .0001). By day 63, the reinfection adjusted failure rates were 2% and 44%, respectively (P < .0001). Artesunate also prevented high-grade failures. Both drugs were well tolerated. No adverse effects were attributable to artesunate. Vomiting was reduced significantly by giving mefloquine on day 2 of treatment (RR, 0.40; 95% CI, 0.20-0.79; P = .009. Artesunate (10 mg/kg over 3 days) plus mefloquine (25 mg/kg) is currently the most effective treatment for falciparum malaria in this area of increasing mefloquine resistance. Plasmodium falciparum in Thailand is highly resistant to chloroquine, sulfadoxine-pyrimethamine and there is increasing resistance to quinine and mefloquine. The use of qinghaosu derivatives alone or in combination with mefloquine has been shown successfully effective against multidrug resistant P. falciparum in many clinical trials. However their applications with ambulatory treatment should be assessed. 394 uncomplicated falciparum malaria cases studied at Trat and Chanthaburi malaria clinics, eastern Thailand, were allocated at random to receive either one of the seven following regimens: A) artesunate 600 mg over 2 days and mefloquine 1,250 mg in divided doses. B) artemether 640 mg over 2 days and mefloquine 1,250 mg in divided doses. C) artesunate alone 700 mg over 5 days period. D) artemether alone 800 mg over 5 days period. E) quinine plus tetracycline for 7 days. F) mefloquine 1,250 mg in divided doses and G) artesunate 600 mg over 2 days period and mefloquine 750 mg. The follow-up was on Days 1, 2, 7, 14, 21 and 28. Patients tolerated all regimens very well and there was no serious side effects. The adverse effects did not differ among the seven regimens. The cure rates were 98.7, 97.1, 97.9, 96.7, 92.3, 100 and 95.2%, respectively. There was no significant difference of cure rates among various regimens. A total of 16 P. vivax and 1 P. malariae reinfections were reported among the study groups during the second half of the follow-up period, 14 of which were from the groups administered short action drugs (artesunate, artemether or quinine). The results suggested that either artesunate 600 mg or artemether 640 mg in combination with mefloquine 1,250 mg over a period of two days should be considered as alternative regimens for treating uncomplicated multi-drug resistant falciparum malaria. Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or artemether (34). Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), 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 by previous studies with 600 mg intramuscular artemether given over 5 days. Oral artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria. A randomized, comparative clinical trial for assessment of the efficacy of two antimalarial regimens, artemether alone and the sequential regimen artemethermefloquine, was carried out in 109 Thai male patients with acute uncomplicated, multidrug resistant falciparum malaria who were admitted to the Bangkok Hospital for Tropical Diseases. Fifty-three patients received oral artemether at a total dose of 700 mg (300 mg initially, followed by 100 mg daily for 4 days), and 56 patients received the sequential regimen of artemether-mefloquine (300 mg oral artemether initially, followed by 750 mg oral mefloquine after 24 h). Patients in both groups had a rapid initial response to treatment, with a median parasite clearance time of 40 h compared with 43.5 h for the sequential regimen. Median fever clearance times were 42.5 h and 32.5 h for artemether and the sequential regimen respectively. Parasitaemia reoccurred in patients of both groups during the follow up period, six in the artemether and three in the sequential regimen (cure rates were 88 and 94%). No serious adverse effects were observed in either group of patients. To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of multidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai-Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer (P < 0.001). After adjusting for reinfections the failure rates were 13.9% for the artesunate combination, 12.3% for the artemether combination and 49.2% for mefloquine alone (P < 0.0001; relative risk 3.8 [95% confidence interval 2.6-5.4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective. 1. The aim of this study was to assess the pharmacokinetics, clinical efficacy and safety of artemisinin alone and in combination with mefloquine. 2. Thirty-eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days) or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co-administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route. Patients were hospitalized at the Kibaha Designated District Hospital, Kibaha, Tanzania, for 6 days and a follow up for 3 weeks was performed. 3. Treatment with the artemisinin/mefloquine combination resulted in a shorter parasite clearance time (PCT) of 24 (22, 27; 95% confidence interval) h vs 31 (27, 36) h and fever subsidence time (FST) of 14 (12, 16) h vs 20 (18, 23) h compared with artemisinin monotherapy. The 95% CI for the difference of the PCT and FST were 1.7, 12 and 3, 10, respectively. Parasites were detected in 7 out of 17 patients (41%) receiving artemisinin monotherapy at the 3rd and 4th week follow up visits. No parasites were detected after the combination therapy. 4. The maximum plasma concentrations (Cmax) were similar after artemisinin monotherapy (615.4 +/- 387.0 ng ml-1) and in combination with mefloquine (851.8 +/- 523.6 ng ml-1). Elimination half-lives (t1/2) were also identical at 2.2 +/- 0.6 h and 2.5 +/- 0.7 h, respectively. However, the AUC values were higher (P < 0.05) after combination therapy (3252 +/- 1873 ng ml-1 h) than after monotherapy (2234 +/- 1502 ng ml-1 h). The oral clearance values were lower (P < 0.05) after combination therapy (195.4 +/- 86.9 l h-1) than after monotherapy (314.3 +/- 189.4 l h-1). PCT and FST normalized to initial parasitaemia correlated with AUC(0, t) (rs = 0.56, P = 0.02, rs = 0.58, P = 0.01, respectively) and with Cmax (rs = 0.62, P = 0.01, rs = 0.68, P = 0.005, respectively) in the artemisinin monotherapy only. 5. One patient on the combination therapy developed a psychiatric condition and two patients on the monotherapy developed skin itch. The study compared the clinical efficacy and safety of oral artemisinin and oral artesunate as well as artemisinin pharmacokinetics during and after resolution of falciparum malaria. Forty adults with symptomatic falciparum malaria were allocated at random to treatment with either oral artemisinin (500 mg single dose on day 1 followed by 250 mg twice daily for 4 d and then another 500 mg single dose on day 6) or with oral artesunate (100 mg single dose on day 1 followed by 50 mg twice daily for 5 d). Patients were admitted to hospital at the Kibaha Designated District Hospital, Kibaha, Tanzania for the duration of treatment. The patients were seen once weekly for 3 more weeks. The time to parasite clearance (PCT) after oral artesunate (26.4 +/- 3.6 h) was shorter (P = 0.002) than after artemisinin (31 +/- 3.6 h). The fever subsidence time (FST) after oral artesunate (18.9 +/- 4.0 h) was also shorter (P = 0.04) than after artemisinin (21.8 +/- 4.6 h). Parasites were detected in 4 (20%) and 7 (35%) patients after completing treatment with artesunate and artemisinin respectively. In these patients the parasitaemia reappeared at the 3rd or 4th week of follow-up. Standard haematology, blood biochemistry and urinalysis, performed before drug intake and again on days 6 and 14, were normal. No clinical abnormality was observed during the study period. Artemisinin plasma concentrations, determined by high performance liquid chromatography with post-column derivatization and detection by ultraviolet light, were followed up to 8 h after drug administration on days 1 and 6. Artemisinin absorption was rapid, the maximum plasma concentrations (Cmax) being attained at about 3 h. Artemisinin areas under the plasma concentration-time curve (AUC) and the Cmax values were about 6 times higher after the first dose on day 1 than on day 6. This decrease in artemisinin plasma concentration is suggestive of an increase in metabolic capacity due to pronounced autoinduction.
The evidence suggests that artemisinin drugs are effective and safe for treating uncomplicated malaria. There is no evidence from randomised trials that one artemisinin derivative is better than the others. In areas where there is mefloquine resistance, combination therapy with an artemisinin derivative appears to improve sustained parasite clearance compared with either drug alone.

This review summarizes trials up to 1999. For the reasons in the 'What's new' section, this review will no longer be updated.