Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. Comparison of rectal artemisinin with intravenous quinine in the treatment of severe malaria in Ethiopia. Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. A randomized comparative study of artemisinine (qinghaosu) suppositories and oral quinine in acute falciparum malaria. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. A trial of artemether or quinine in children with cerebral malaria. Severe and complicated malaria treated with artemisinin, artesunate or artemether in Viet Nam. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Comparison of artesunate and quinine in the treatment of Sudanese children with severe Plasmodium falciparum malaria. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Rectal versus intravenous quinine for the treatment of childhood cerebral malaria in Kampala, Uganda: a randomized, double-blind clinical trial. Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. Single dose artemisinin-mefloquine treatment for acute uncomplicated falciparum malaria. Resistance of Plasmodium falciparum to antimalarial drugs in Equatorial Guinea. Preliminary report: a comparative clinical trial of artemether and quinine in severe falciparum malaria.
Severe malaria remains a major cause of mortality and morbidity for children living in many tropical regions. With the emergence of strains of Plasmodium falciparum resistant to both chloroquine and quinine, alternative antimalarial agents are required. The artemisinin group of compounds are rapidly effective in severe disease when given by intramuscular or intravenous injection. However, these routes of administration are not always available in rural areas. In an open, randomized comparison 109 Vietnamese children, aged between 3 months and 14 years, with severe P.falciparum malaria, were allocated at random to receive artemisinin suppositories followed by mefloquine (n = 37), intramuscular artesunate followed by mefloquine (n = 37), or intravenous quinine followed by pyrimethamine/sulfadoxine (n = 35). There were 9 deaths: 2 artemisinin, 4 artesunate and 5 quinine-treated children. There was no difference in fever clearance time, coma recovery, or length of hospital stay among the 3 groups. However, parasite clearance times were significantly faster in artemisinin and artesunate-treated patients than in those who received quinine (P < 0.0001). Both artemisinin and artesunate were very well tolerated, but children receiving these drugs had lower peripheral reticulocyte counts by day 5 of treatment than those in the quinine group (P = 0.011). No other adverse effect or toxicity was found. There was no treatment failure in these 2 groups, but 4 patients in the quinine group failed to clear their parasites within 7 d of starting treatment and required alternative antimalarial therapy. Artemisinin suppositories are easy to administer, cheap, and very effective for treating children with severe malaria. In rural areas where medical facilities are lacking these drugs will allow antimalarial therapy to be instituted earlier in the course of the disease and may therefore save lives. To compare the clinical efficacy and safety of artemisinin suppository with quinine injection.
                Comparative open randomised study.
                A government regional referral hospital in Ethiopia.
                Sixty five adult patients of both sexes: 32 for artemisinin and 33 for quinine with complicated severe falciparum malaria.
                Therapeutic responses and adverse reactions.
                The clinical and laboratory data in both groups of patients on admission were comparable. The parasite clearance time (PCT), fever subsidence time (FST) and coma resolution time (CRT) were shorter in the artemisinin treated group. There was no significant different in the parasitological cure rates in both arms of treatment. No correlation was observed between the initial parasite density and PCT or FST in both groups of treatment. Mortality rates were similar both in the artemisinin and quinine groups. The common adverse effects observed in most patients receiving quinine, in an increasing order of occurrence were; vomiting, dizziness, hypoglycaemia and tinnitus, which were all relatively rare with artemisinin. Some patients treated with artemisinin showed tenesmus which was not observed in any patient treated with quinine.
                The rectal artemisinin is more efficacious and safer than the intravenous quinine. Thus, artemisinin may be considered a potential drug which can replace quinine in the treatment of severe malaria in Ethiopia provided it is made available at affordable prices. Seventy-nine comatose cerebral malaria patients given standard supportive treatment were randomized to receive specific antimalarial chemotherapy of intravenous quinine, intravenous artesunate, or artemisinin suppositories. Artesunate and artemisinin reduced peripheral asexual parasitaemia significantly more rapidly than quinine (90% clearance time 16 h, 18.9 h and 34.5 h respectively), but did not significantly reduce the duration of coma or mortality. The rapid lowering of peripheral parasitaemia may not ameliorate complications already present. These results demonstrate that artemisinin suppositories are as effective as artesunate and quinine given intravenously, and have economic and practical advantages for the treatment of severe malaria in areas remote from major medical centres. However, large numbers of patients will need to be studied if differences in mortality between the 3 treatment groups are to be demonstrated. 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. Artemisinin (qinghaosu) and its derivatives are rapidly effective antimalarial drugs derived from a Chinese plant. Preliminary studies suggest that these drugs may be more effective than quinine in the treatment of severe malaria. We studied artemether in Vietnam, where Plasmodium falciparum has reduced sensitivity to quinine.
                We conducted a randomized, double-blind trial in 560 adults with severe falciparum malaria. Two hundred seventy-six received intramuscular quinine dihydrochloride (20 mg per kilogram of body weight followed by 10 mg per kilogram every eight hours), and 284 received intramuscular artemether (4 mg per kilogram followed by 2 mg per kilogram every eight hours). Both drugs were given for a minimum of 72 hours.
                There were 36 deaths in the artemether group (13 percent) and 47 in the quinine group (17 percent; P = 0.16; relative risk of death in the patients given artemether, 0.74; 95 percent confidence interval, 0.5 to 1.11). The parasites were cleared more quickly from the blood in the artemether group (mean, 72 vs. 90 hours; P < 0.001); however, in this group fever resolved more slowly (127 vs. 90 hours, P < 0.001), the time to recovery from coma was longer (66 vs. 48 hours, P = 0.003), and the hospitalization was longer (288 vs. 240 hours, P = 0.005). Quinine treatment was associated with a higher risk of hypoglycemia (relative risk, 2.7; 95 percent confidence interval, 1.7 to 4.4; P < 0.001), but there were no other serious side effects in either group.
                Artemether is a satisfactory alternative to quinine for the treatment of severe malaria in adults. In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain.
                We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat.
                We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009).
                Artesunate should become the treatment of choice for severe falciparum malaria in adults. Cerebral malaria has a mortality rate of 10 to 30 percent despite treatment with parenteral quinine, a situation that may worsen with the spread of quinine resistance. Artemether is a new antimalarial agent that clears parasites from the circulation more rapidly than quinine, but its effect on mortality is unclear.
                We conducted a randomized, unblinded comparison of intramuscular artemether and intramuscular quinine in 576 Gambian children with cerebral malaria. The primary end points of the study were mortality and residual neurologic sequelae.
                Fifty-nine of the 288 children treated with artemether died in the hospital (20.5 percent), as compared with 62 of the 288 treated with quinine (21.5 percent). Among the 418 children analyzed at approximately five months for neurologic disease, residual neurologic sequelae were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11 of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment for potential confounders, the odds ratio for death was 0.84 (95 percent confidence interval, 0.53 to 1.32) in the artemether group, and for residual neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There were fewer local reactions at the injection site with artemether than with quinine (0.7 percent vs. 5.9 percent, P = 0.001).
                Artemether is as effective as quinine in the treatment of cerebral malaria in children. One hundred and seventy five Vietnamese adults with severe and complicated malaria admitted to a rural district hospital were entered into an open randomized comparative study to compare 4 treatment regimens based on artemisinin and its derivatives. The median time of defervescence was 48 h (95% confident interval [CI] 38-58 h) in those given intramuscular (i.m.) artemether, 42 h (95% CI 36-48 h) in those given artemisinin suppositories, 36 h (95% CI 30-42 h) in those receiving artesunate (i.m.) and 30 h (95% CI 18-42 h) in those receiving intravenous artesunate (P = 0.13). The respective median parasite clearance times were 30 h (95% CI 26-34 h), 30 h (95% CI 24-36 h), 24 h (95% CI 15-33 h), and 24 h (95% CI 15-33 h) (P = 0.30); the median times for recovery of consciousness were 47 h (95% CI 31-63 h), 24 h (95% CI 18-30 h), 30 h (95% CI 18-42 h), and 24 h (95% CI 4-44 h) (P = 0.18); and the mortality rates were 11.1%, 17.6%, 10.2% and 16.6%, respectively (P = 0.64). There was no significant difference in efficacy between the 4 treatments. Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently. Sixty-six children presenting to Singa hospital, Sudan with different manifestations of severe Plasmodium falciparum malaria were randomly divided into two well-matched groups (33 in each arm) to receive either intravenous artesunate 2·4 mg/kg at 0, 12, and 24 hours, then daily, or intravenous quinine 20mg/kg initially then 10mg/kg three times a day. There was no significant difference in the fever, parasite clearance, and coma resolution times. Three patients died, one in the artesunate and two in the quinine groups. One patient developed hypoglycaemia following quinine infusion. Thus, artesunate can be used for the treatment of severe falciparum malaria.
                Copyright © 2010 Royal Society of Tropical Medicine and Hygiene. A randomized, open-label comparison of artesunate and quinine was conducted in 113 adults with clinically severe falciparum malaria in western Thailand. Mortality was 12% with artesunate and 22% with quinine treatment (relative risk, 0.53; 95% confidence interval, 0.23-1.26; P=.22). Multiple logistic regression analysis found admission plasma lactate level, Glasgow Coma Scale score, and total serum bilirubin level to be independent risk factors for death. Coma recovery and times to normalize plasma lactate levels were similar, but the parasite clearance time was much shorter among artesunate-treated patients (P=.019). Fewer patients became hypoglycemic during artesunate therapy (10%) than during quinine therapy (28%) (P=.03). Artesunate is at least as effective as quinine in the treatment of adults with severe malaria. Larger trials are required to determine whether mortality is reduced among patients treated with artesunate. Although artemesinin derivatives are promising for the treatment of severe Plasmodium falciparum malaria, intravenous quinine remains the most affordable treatment. However, administration of intravenous quinine is often not feasible in rural areas in Africa because of the lack of simple equipment or trained staff. We compared the efficacy and safety of intrarectal quinine with those of intravenous quinine in the treatment of childhood cerebral malaria.
                In a randomized, double-blind clinical trial at Mulago Hospital (Kampala, Uganda), Uganda's national referral hospital, we studied 110 children aged 6 months to 5 years who had cerebral malaria. Patients were randomized to receive either intrarectal or intravenous quinine. Main outcome measures included parasite clearance time, fever clearance time, coma recovery time, time to sit unsupported, time to begin oral intake, time until oral quinine was tolerated, and death.
                Overall, there was no difference in the clinical and parasitological outcomes between the 2 groups (data are mean+/-standard deviation, intrarectal quinine group vs. intravenous quinine group): coma recovery time, 19.4+/-18.1 h versus 17.0+/-12.1 h; fever clearance time, 26.7+/-16.1 h versus 29.9+/-18.1 h; and parasite clearance time, 43.2+/-14.2 h versus 41.9+/-15.2 h. Mortality was similar in both groups; 4 of 56 patients in the intrarectal quinine group died, and 5 of 54 patients in the intravenous quinine group died (odds ratio, 1.3; 95% confidence interval, 0.3-5.2). Intrarectal quinine was well tolerated, and no major immediate adverse events occurred.
                Intrarectal quinine is efficacious and could be used as an alternative in the treatment of childhood cerebral malaria, especially in situations in which intravenous therapy is not feasible. Dihydroartemisinin-piperaquine (DP) is a new and relatively inexpensive artemisinin-containing fixed-combination antimalarial treatment. An adult treatment course contained 6.4 mg/kg dihydroartemisinin (DHA), which is >40% lower than the level in most artemisinin-containing combinations. This raised the possibility that the efficacy of the current coformulation may not be optimal in the treatment of multidrug-resistant falciparum malaria.
                In 2 large randomized, controlled studies in Thailand, the recommended dose of DP was compared with a regimen with additional artemisinin derivative (12 mg/kg; DP+) and with mefloquine plus artesunate (MAS3).
                A total of 731 patients were included: 201 in a hospital-based study and 530 in a community study. Day-28 cure rates in the hospital-based study were 100% (95% confidence interval [CI], 93.9%-100%) in the MAS3 and DP+ groups and 98.3% (95% CI, 91%-99.7%) in the DP group, with a single recrudescence on day 21. In the community study, polymerase chain reaction genotyping-adjusted cure rates on day 63 were 96.1% (95% CI, 92.6%-99.7%) in the DP group, 98.3% (95% CI, 96.1%-100%) in the DP+ group, and 94.9% (95% CI, 91.2%-98.6%) in the MAS3 group (P=.2). Adverse events were few, with an excess of mild abdominal pain in the DP group.
                The current dosage of DP (6.4 mg/kg DHA and 51.2 mg/kg piperaquine phosphate) given over the course of 48 h is highly effective, safe, and well tolerated for the treatment of multidrug-resistant falciparum malaria, and its efficacy is not improved by the addition of more DHA. 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. One hundred and sixty-six children from Equatorial Guinea, all under 10 years of age and with acute uncomplicated falciparum malaria, were randomly allocated to four groups and treated with one of the following regimens: chloroquine or amodiaquine (25 mg base/kg body weight over 3 days), quinine (8 mg/kg every 8 h for 3 or 5 days), and sulphadoxine-pyrimethamine (25-1.25 mg/kg, in one dose). The parasite clearance rates up to day 14 were 28% with chloroquine, 74% with amodiaquine, and 95% with quinine or sulphadoxine-pyrimethamine. The times required to clear asexual blood forms of Plasmodium falciparum in sensitive cases were 64, 70, 73 and 65 h, respectively. Although quinine and sulphadoxine-pyrimethamine are equally effective, quinine is recommended for treatment of multidrug-resistant malaria in paediatric patients, essentially because of the risk of serious reactions to sulpha drugs. Health providers are, however, encouraged to keep supplies of sulphadoxine-pyrimethamine as an option and to refer patients quickly, if required. Twenty-six patients with severe falciparum malaria were randomized to be treated with quinine or artemether. Twelve patients received quinine at the standard dose and fourteen patients received artemether intramuscularly at a total dose of 640 mg over 7 days. The patients were kept in the hospital for at least 7 days. Peripheral smear was performed 6-hourly until there was no parasitemia, then daily until discharged. Adverse effects were monitored through physical examination, laboratory findings and questionnaires. Laboratory examination was performed on admission, day 2, day 4 weekly until discharged. The patients in both groups were comparable in age, body weight, admission parasitemia, hemoglobin and white blood cell count. The survival rates were 93% and 58% in artemether and quinine groups, respectively (p = 0.052 at 95% confidence, using Fisher's exact test). The parasite and fever clearance times, and the time taken to gain consciousness in cerebral malaria patients were not significantly different between the two groups. Adverse effects in the quinine group consisted of dizziness and vertigo which were found in 4 patients. No adverse effects were noticed in the artemether group. This preliminary report suggests that artemether is a good alternative drug for severe falciparum malaria and seems to be better than quinine regarding survival rate and side effects. Confirmation of these findings in a larger study size is needed.
The evidence suggests that artemisinin drugs are no worse than quinine in preventing death in severe or complicated malaria. No artemisinin derivative appears to be better than the others. 

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