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Review |

Rectal Administration of Artemisinin Derivatives for the Treatment of Malaria FREE

Harin A. Karunajeewa, FRACP; Laurens Manning, MB,BS; Ivo Mueller, PhD; Kenneth F. Ilett, PhD; Timothy M. E. Davis, FRACP
[+] Author Affiliations

Author Affiliations: Medicine Unit, School of Medicine and Pharmacology, University of Western Australia, Fremantle, Australia (Drs Karunajeewa, Manning, and Davis); Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia (Dr Ilett); and Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea (Dr Mueller).

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JAMA. 2007;297(21):2381-2390. doi:10.1001/jama.297.21.2381.
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Published online

Context Rectal administration of artemisinin derivatives is a potentially lifesaving emergency treatment of severe malaria. Many different preparations are marketed in tropical countries, but their pharmacokinetic disposition and clinical efficacy may vary.

Objective To review the pharmacokinetics, efficacy, and safety of rectally administered artesunate, artemisinin, dihydroartemisinin, and artemether.

Data Sources We searched the MEDLINE, EMBASE, Cochrane Database of Clinical Reviews, Global Health, Web of Science, and CINAHL computerized databases up to December 2006, along with reviewing unpublished data from conference proceedings, pharmaceutical companies, and regulatory applications. Studies in languages other than English were translated.

Study Selection Studies were included involving rectal administration of an artemisinin derivative to healthy volunteers or patients with measurement of plasma drug concentrations or rates of initial parasite clearance. Both single-arm and comparative trials were included.

Data Extraction Forty-five studies were identified, of which 39 eligible studies were included in the review. Primary efficacy outcome measures included parasite density as a percentage of baseline at 12 and 24 hours following the first dose. Pharmacokinetic variables included maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration–time curve. Weighted means were calculated from available data.

Data Synthesis Thirty-two studies provided valid clinical efficacy data: 19 of artesunate, 10 of artemisinin, 2 of dihydroartemisinin, and 1 of artemether. All demonstrated prompt parasite clearance, with evidence of a dose-dependent effect for artesunate. Mortality rates in severe malaria (weighted means, 0%-13%) were consistent with those expected. Eight studies compared rectal artemisinin with conventional parenteral treatment (quinine, artemether, or artesunate) for severe malaria. Despite similar clinical outcomes, rectal artemisinin derivatives initiated parasite clearance more rapidly than parenteral treatment (percentage of baseline at 12 hours, ≤27% vs ≥56%, respectively). Eighteen pharmacokinetic studies were identified, including 13 of artesunate. There was marked interindividual variability in most pharmacokinetic variables, but artesunate achieved an earlier Tmax and higher Cmax and area under the plasma concentration–time curve than other artemisinin derivatives.

Conclusions Available rectal preparations of artemisinin derivatives differ in their pharmacokinetic disposition. Most available evidence pertains to artesunate and artemisinin. Despite marked interindividual variability in bioavailability, rectal preparations appear to have acceptable therapeutic efficacy, including in severe illness.

Rectal antimalarial treatment can be a valuable public health strategy in the rural tropics, where most malaria-associated morbidity and mortality occur.1 Use of a suppository is generally feasible when oral therapy is precluded by vomiting, prostration, or impaired consciousness, and it does not require the training and facilities needed for intravenous or intramuscular injection. Although restlessness and malaria-associated diarrhea may complicate administration, rectal dosing by non–medically trained personnel could enable early treatment of severely ill patients in remote communities before transfer for further treatment in a central facility. Because the artemisinin derivatives have a wide therapeutic margin, are active against multidrug-resistant Plasmodium falciparum, and have adequate rectal absorption,2 they hold great promise in this respect. In a recent review of its tropical diseases research program, the World Health Organization (WHO) identified one such rectally administered derivative, artesunate, as having the potential to reduce mortality from complications such as cerebral malaria, especially in children, if given before the patient is able to receive definitive therapy.3

The artemisinin derivatives clear parasites more rapidly than any other class of antimalarial.4 Their potential clinical benefit was highlighted in a recent large-scale Asian study that compared intravenous artesunate with intravenous quinine in severe malaria and found a lower mortality rate in artesunate-treated adults.5 Further studies are in progress to determine whether this finding applies to African children, the group that contributes most to global malaria mortality.6 Nevertheless, it is unclear whether rectally administered artemisinin derivatives have comparable efficacy with parenteral artesunate. Drug disposition after rectal administration will differ from that following intravenous or intramuscular injection, a situation further complicated by the variety of formulations of artemisinin derivatives that are currently available for rectal use (Table 1). Pharmacokinetic properties may vary significantly among products, and recommended dosing schedules have largely been determined empirically.

Table Graphic Jump LocationTable 1. Pharmaceutical Preparations of Artemisinin Derivatives for Rectal Administration

Artemisinin and 3 artemisinin derivatives, artesunate, dihydroartemisinin, and artemether, are currently marketed in various parts of the world. All can be administered either orally or rectally, and all except dihydroartemisinin can be given intramuscularly; artesunate is the only one that can be administered intravenously8 Of the 4 artemisinin derivatives, dihydroartemisinin (which is the active metabolite of artesunate and artemether) has the greatest in vitro activity against P falciparum, but all are more potent than other established antimalarial drugs.8

Drugs used for pretransfer treatment of malaria in a remote setting need to clear circulating parasite forms rapidly, thus preventing the microvascular sequestration that can lead to life-threatening vital organ dysfunction.9 Measures of initial parasite clearance are, therefore, an important surrogate marker of therapeutic response. The most useful measure is parasite density expressed as a percentage of the baseline measurement at 12 and 24 hours. Alternative measures include the time to 50% and 90% reductions in parasitemia. Other pharmacodynamic markers of treatment response include total parasite clearance time, fever clearance time, and clinical and parasitological cure rates. Unfortunately, the calculation of fever clearance time is poorly standardized, making between-study comparisons difficult. Clinical and parasitological cure are conventionally evaluated over 28 days, but shorter (14-day) and longer (56-day) follow-up periods have been used. The main pharmacologic variables influencing cure rates are those determining parasite exposure to therapeutic drug concentrations, namely duration of therapy and the half-lives of the drugs used. Since the artemisinin derivatives, which have relatively short half-lives, are recommended to be used as part of combination therapy with a longer-half-life partner compound, cure rates are of secondary interest in the evaluation of effect of rectal artemisinin drugs given as sole initial therapy.

The aim of the present review was to evaluate published data on the pharmacokinetics and efficacy of rectally administered artemisinin derivatives for initial treatment of uncomplicated or severe malaria. Artesunate, the derivative with the most clinical data and the widest application in this context, is highlighted, but rectal formulations of other artemisinin drugs available in endemic areas are also included.

We searched the MEDLINE, EMBASE, Cochrane Database of Clinical Reviews, Global Health, Web of Science, and CINAHL computerized databases up to December 2006 with a strategy that used both key words and Medical Subject Heading term searches comprising (artesunate or artesunic acid, or dihydroartemisinin or dihydroqinghaosu or artemisinin or qinghaosu or artemether) and (rectal or suppository or suppositories). We contacted pharmaceutical companies for unpublished data, reviewed conference proceedings, and used reference lists from retrieved articles to identify other relevant studies. Articles published in languages other than English were translated into English. Studies could be included in the review if (1) they were human clinical studies including healthy volunteers or patients of any age, regardless of Plasmodium species or clinical status, in which participant number, age, and clinical status were specified; (2) they involved rectal administration of an artemisinin derivative; and (3) they measured either plasma drug concentrations or parasite clearance assessed from serial blood smears taken at least every 6 hours. The search strategy was conducted simultaneously and independently by 2 investigators (H.A.K. and L.M.), then cross-checked. Both single-arm and comparative trials were included. For comparative clinical trials, methodological quality was assessed independently by 2 reviewers (H.A.K. and T.M.E.D.) using the Maastricht-Amsterdam score list.10 The 11 items relating to internal validity were used, and studies fulfilling at least 6 of these criteria were considered of high quality.

Primary efficacy variables of interest included parasite density as a percentage of baseline at 12 and 24 hours and/or time to 50% reduction in parasitemia. If not reported, parasite density as a percentage of baseline at 12 and 24 hours was derived from raw data by dividing 12-hour and 24-hour parasite densities by the baseline densities, if available, or by interpolation of graphical representations. A parasite density at 12 hours of less than 60% has been used as a cut point in comparing early parasite clearance between different antimalarial regimens.11 Total parasite clearance time, mortality, and reported adverse events were also included. Because raw data were not always available, measures of central tendency and variance used in the original articles were reproduced as stated rather than converted to a standardized method. Where calculations were performed on raw data, mean (± standard deviation) and (for non–normally distributed data) median (range) were used.

The pharmacokinetic variables of interest were maximal plasma concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration–time curve (AUC). All drug concentrations were converted to nanomoles using molecular weights of 284.4, 282.4, and 298.4 Da for dihydroartemisinin, artemisinin, and artemether, respectively. When studies did not provide doses in milligrams per kilogram, these were approximated by dividing the total administered dose by either the reported mean participant body weight or, for adults, an assumed weight of 65 kg for white or African participants and 50 kg for Southeast Asian participants.

To summarize the efficacy and pharmacokinetic data for each drug, data from each study were used to generate a weighted mean for each variable according to the formula

1 × n1 + μ2 × n2 + μ3 × n3 . . . + μt × nt)/(n1 + n2 + n3 . . . + nt),

where μ is the individual study mean, n is the number of participants in the study, and t is the total number of studies included. When mean values were unavailable or could not be calculated from published data, median values were substituted for μ. Mortality data were obtained from studies of moderately severe or severe malaria.

Description of Included Studies

Twenty-five studies of artesunate suppositories were identified. Of these, 2 were excluded because of absence of pharmacokinetic or efficacy end points,12,13 leaving 23 studies. Of these, 18 evaluated Plasmotrim Rectocaps (Mepha Pharmaceuticals, Aesch-Basel, Switzerland) administered as combinations of 50- and 200-mg suppositories.11,1432 Five were unpublished (Joseph Andoh, MD, et al, unpublished data, February 10–March 19, 1998),7 4 of which were sourced from a submission made by WHO to the US Food and Drug Administration in 2002,7 which included 2 studies detailing bioequivalence and clinical data relating to another formulation of artesunate suppositories available as 100- and 400-mg doses (WHO Tropical Disease Research and Scanpharm A/S, Birkerød, Denmark).

Fourteen studies of rectally administered artemisinin were identified.3346 Three were excluded, 1 because it involved patients infected with Plasmodium vivax33 and the others, 1 of which was unpublished,34 because they provided inadequate participant details.34,35 Of 4 studies of dihydroartemisinin4750 and 2 of artemether,51,52 all were included except for 1 dihydroartemisinin study with inadequate participant details.50

Clinical Efficacy

Artesunate. A total of 356 artesunate-treated patients were enrolled in studies of severe malaria and 287 in studies of moderately severe infection (Table 2). For studies of severe disease, the definitions of severity varied and were sometimes poorly specified, complicating between-study comparisons. Because there was significant heterogeneity in dosing regimens for rectal artesunate, these data were dichotomized into initial doses of less than 5 mg/kg and more than 5 mg/kg. Several studies used a low-dose regimen with 1.8 to 4.4 mg/kg administered repeatedly over the first 12 hours.14,16,18,21,27,28,32 These showed generally slower parasite clearance during the first 12 hours and a weighted mean total parasite clearance time that was twice as long as that seen with the higher-dose regimen.7,19,20,22,24,25,29,30,33(and unpublished data by J. Andoh, MD, et al) There were 6 deaths in artesunate-treated patients enrolled in studies of severe malaria (1.7%) and 2 in studies of moderately severe infection (0.7%).

Table Graphic Jump LocationTable 2. Clinical Efficacy of Rectally Administered Artemisinin Derivatives

Artemisinin. The artemisinin studies involved 350 patients and, with the exception of 1 African study of severely ill adults,37 were performed in Vietnam or China in patients with infections ranging from uncomplicated to severe (Table 2).36,37,3945 Few calculated (or provided data necessary to calculate) parasite density as a percentage of baseline at 12 and 24 hours. However, in the 6 studies that reported time to 50% reduction in parasitemia, the mean or median values ranged from 7 hours to 11.3 hours, comparable with that for rectal artesunate. The weighted mean mortality in artemisinin-treated patients was relatively high at 12.9% but included a study of children with cerebral malaria that reported mortality of 5%.44

Dihydroartemisinin. There have been only 2 studies of dihydroartemisinin suppositories, involving a total of 180 patients (Table 2).48,49 One of these49 showed much slower initial parasite clearance than that seen in studies of other preparations, with the mean parasite density rising to 30% above baseline at 12 hours before falling to 70% at 24 hours. The dose used in this study was relatively low (3 mg/kg) and was variable, with some patients receiving as little as 2.3 mg/kg. A similar dose was used in the second study of dihydroartemisinin,48 but no direct comparison could be made because markers of early parasite clearance were not determined. There were no deaths from severe malaria in either of these studies.

Artemether. Only 1 trial of artemether suppositories is available51 and is summarized in Table 2.

Comparative Studies

A number of studies have directly compared rectal artemisinin drugs with conventional therapies, including 2 studies using artesunate,11,24 4 using artemisinin,37,41,44,45 and 1 each involving dihydroartemisinin48 and artemether.51 In each of these 8 studies, the similarity of the groups at baseline, adherence to therapy, withdrawal/dropouts, and timing of outcome assessments appeared acceptable, and the short-term measures of efficacy (primarily parasite clearance) implied an intention-to-treat analysis, meaning a score of 5 of 5 for these aspects. For all except the study by Hien et al41 (in which the artemisinin suppositories became unavailable during the trial), the randomization appeared adequate, suggesting that 7 studies were of high quality (score ≥6).11,24,37,44,45,48,51 Nevertheless, the study by Aceng et al51 was the only one of these that used patient blinding (with a rectal placebo), and the reporting of allocation concealment and of blinding of care providers and outcome assessors was variable, while cointerventions were often either not stated or not comparable between groups.

Barnes et al11 compared rectally administered artesunate with parenteral quinine in children and adults with moderately severe malaria in Malawi and South Africa. By 12 hours, 92% of children and 96% of adults treated with rectal artesunate had achieved reductions in parasitemia to less than 60% of baseline compared with 14% and 38% of quinine-treated children and adults, respectively, a difference that was maintained at 24 hours. Children treated with rectal artesunate also had more rapid clearance of fever than quinine-treated children, but there were no statistically significant differences seen with other markers of clinical response, including time to return of ability to drink or take tablets orally. A study by Karunajeewa et al24 compared rectal artesunate with intramuscular artemether, a commonly used alternative to parenteral quinine for severe malaria, in 79 children with severe malaria in Papua New Guinea. This showed statistically significant differences in parasite density as a percentage of baseline at 12 hours and times to 50% and 90% reduction in parasitemia in favor of rectal artesunate. The authors concluded from plasma drug concentration data that these differences were likely due to relatively low and erratic absorption of intramuscular artemether. There were no between-treatment differences in clinical outcomes, including measures of fever clearance and return to oral intake status.

Four studies have compared artemisinin suppositories with either intravenous quinine or parenteral artesunate.37,41,44,45 The 3 using quinine as a comparator all showed significantly faster parasite clearance (times to 50% and 90% reduction in parasitemia and total parasite clearance time) in the artemisinin group.37,41,44 However, other clinical markers, including fever clearance, coma duration, and mortality, were similar. Regardless of whether intravenous or intramuscular artesunate was used as the comparator, no significant differences were seen with rectal artemisinin for parasitological or other outcomes.

A study by Esamai et al48 that compared dihydroartemisinin suppositories with intravenous quinine demonstrated a more rapid total parasite clearance time with the artemisinin derivative, but markers of early parasite clearance were not calculated and there was no statistically significant difference in fever clearance. Aceng et al51 compared rectally administered artemether with intravenous quinine in 103 Ugandan children with cerebral malaria. There were no significant differences between treatment groups for clinical (fever clearance time, time to regaining consciousness, and time to oral intake status) and parasitological outcomes.

Pharmacokinetics

Nineteen pharmacokinetic studies, 6 in healthy volunteers and 13 in adults or children with uncomplicated, moderately severe, or severe malaria, were identified and are summarized in Table 3. There was marked interindividual variability in most pharmacokinetic measures, but conventional doses of artesunate achieved an earlier Tmax and higher Cmax than other artemisinin derivatives. The 14 pharmacokinetic studies of rectal artesunate included healthy adult volunteers,15,17 adults with uncomplicated malaria,16 and children with uncomplicated,21,22,31 moderately severe,25 or severe30 malaria (Table 3). No study was able to demonstrate a relationship between any pharmacokinetic variable and clinical outcome. Few studies were of sufficient size to enable examination of the effect of covariates on pharmacokinetics.

Table Graphic Jump LocationTable 3. Pharmacokinetic Studies of Rectally Administered Artemisinin Derivatives

The results of 3 pharmacokinetic studies of rectal artemisinin performed in mostly male white or Vietnamese participants are summarized in Table 3.36,38,39 Participants were either healthy volunteers or had uncomplicated malaria. No study involved children or adults with moderate or severe disease. The study of dihydroartemisinin suppositories was performed in adults with uncomplicated malaria.47 The study of rectal artemether52 used a parenteral formulation (Kunming Pharmaceuticals, Kunming, China) dissolved in arachis oil and rectally self-injected by healthy white volunteers. There is a suppository formulation of artemether,51 but its pharmacokinetic properties are unknown.

Safety and Tolerability of Rectal Artemisinin Derivatives

More than 1600 patients, including more than 600 children, have received a rectal artemisinin drug in published or unpublished trials (Table 2 and Table 3). Adverse events have not been reported in a standardized manner. Minor adverse events have included dizziness, transient fever occurring approximately 24 hours after parasite clearance, and gastrointestinal symptoms (nausea, vomiting, abdominal pain, constipation, or diarrhea).23,24,28,34,37,43 It is unclear whether these symptoms relate to the artemisinin drugs, a coadministered partner drug, or malaria itself.

No symptoms suggestive of neurotoxicity have been described in any study evaluating a rectally administered artemisinin derivative, including those using artesunate at doses of up to 20 mg/kg25,30 and artemisinin at doses of up to 40 mg/kg.44 Although tenesmus has been described in up to 26% of those administered artemisinin suppositories,34,37,43 no study has described rectal bleeding or anal irritation that would indicate a local inflammatory reaction.

Artemisinin derivatives formulated for rectal administration have the potential to be widely used in tropical countries. Their intended role is primarily as pretransfer antimalarial therapy for sick children in remote communities, but their application may extend to other contexts, even in developed countries. There is, therefore, a need for increased awareness of the pharmacologic properties and efficacy of rectally administered artemisinin compounds. It is likely that artesunate suppositories will remain the most widely prescribed drug in this respect,3 but availability, cost, and sociopolitical factors may result in an increase in use of alternative derivatives.

Similar to experience with oral and parenteral artemisinin formulations, the introduction of rectal derivatives into clinical use has not followed classic pathways of rational drug development. Rectal absorption of these compounds must be prompt and reliable if they are to have a rapid parasiticidal effect, but supportive pharmacokinetic and pharmacodynamic data have lagged behind the widespread availability of a variety of formulations that are administered using empirically derived dosing regimens. Reasons for this include the practical challenges of performing pharmacokinetic studies in representative patient samples in the rural tropics and the lack of stringent control of drug licensing in many developing countries. Because pharmaceutical factors can influence pharmacokinetic disposition, preparations of the same derivative from different manufacturers may not be bioequivalent.

The data reviewed showed mean or median Tmax values of 1 to 4 hours for artesunate compared with values of 4 to 7 hours for artemisinin and dihydroartemisinin and 3 hours for artemether. Similarly, artesunate administered at more than 10-mg/kg doses resulted in mean or median Cmax and AUC values 3 to 10 times those achieved with artemisinin (7-12 mg/kg), dihydroartemisinin (3 mg/kg), or artemether (5 mg/kg). These values suggest a therapeutic advantage for artesunate, but more data are needed for dihydroartemisinin and artemether. Although it is unclear whether earlier and higher plasma concentrations confer therapeutic advantage, it is notable that initial parasite clearance was slower for low-dose artesunate regimens (weighted mean parasite density as a percentage of baseline at 12 hours, 62.3% for low-dose regimens vs 16.1% for high-dose regimens; Table 2), with the slowest clearance in a study of low-dose rectal dihydroartemisinin.49

The most striking aspect of the pharmacokinetic studies reviewed was the degree of interindividual variability in pharmacokinetic measures. The bioavailability of artesunate has been reported to be as low as 6%,25 and coefficients of variation for Cmax and AUC are also wide for the other rectally administered artemisinin derivatives. This implies that a small proportion of patients are at risk of subtherapeutic drug concentrations. Because even very low plasma concentrations are likely to exceed the parasite minimal inhibitory concentration,8 the clinical significance of this variability may be minor. In addition, even with close monitoring, the possibility exists that suppositories are expelled, a potentially serious situation that argues for multiple dosing in the first 24 hours.22

The artemisinin derivatives appear to be safe and well tolerated,55,56 and the present review suggests that there are no additional concerns associated with rectal administration. Although tenesmus and a burning sensation were reported in some studies of rectal artemisinin,44 there has been no evidence suggesting proctitis of the type that occurs with rectal quinine.57 The brain-stem lesions observed in laboratory animals receiving prolonged supratherapeutic doses of lipid-soluble artemisinin derivatives58 have never been convincingly demonstrated in humans, and it is reassuring that there were no descriptions of neurotoxic symptoms in the approximately 1600 participants, more than one third of whom were children, treated with rectal artemisinin compounds in the studies reviewed herein. This includes doses of up to 20 mg/kg of artesunate and 40 mg/kg of artemisinin.25,30,44 It is of interest that higher doses of artesunate may be associated with reduced bioavailability,25 which could help protect against possible toxic effects.

A number of comparative trials provide some evidence that rectal preparations may initiate parasite clearance more rapidly than conventional treatment, including parenteral quinine and artemether.11,24,37,41,44,45,48,51 Recent experience with intravenous artesunate suggests that prompt parasite clearance is associated with reduced mortality in severe malaria in adults.4 None of the comparative trials of rectal artemisinin derivatives were powered to assess mortality as an end point, although it is noteworthy that other clinical markers (including fever clearance and coma duration) were similar to those with the comparator drugs. Because of the large sample sizes required for a noninferiority study, it is unlikely there will ever be a trial comparing a rectal artemisinin with conventional treatment for severe malaria using mortality as an end point. Therefore, markers of early parasite clearance and pharmacokinetic measures (including their variability) will be the most useful end points in future trials.

The present study had limitations. First, our weighted mean estimates of efficacy and pharmacokinetic variables were often from small numbers of studies with incomplete data. This made formal assessment of statistical heterogeneity difficult. Our derived results must be interpreted with caution as a result, but the summary data from individual studies cited in the tables support our overall conclusions. Second, the definition of severe (including cerebral) malaria included a variable number of components and different severity cut points. Although the pharmacokinetic properties of the artemisinin drugs do not appear to be influenced by disease severity,59 a greater number of studies and more uniform definition of severity would have facilitated an analysis of parasite clearance measures by clinical status.

Available data support artesunate at doses of more than 10 mg/kg and artemisinin at 12 mg/kg as having good clinical efficacy regardless of factors such as age, sex, and race/ethnicity. Artesunate appears to be the better option given its more rapid absorption and higher plasma concentrations at these doses. However, the present review highlights the need for more pharmacologic and efficacy data for all rectal artemisinin drugs, including studies involving (1) head-to-head comparisons of the initial clinical efficacy of different formulations and dose regimens (especially involving dihydroartemisinin and artemether); (2) pharmacokinetic analysis including bioavailability and its predictors and effect on parasite clearance; and (3) well-characterized severely ill patients with intravenous artesunate as a comparator. Given the concerns regarding lower limits of bioavailability and pending further research particularly in the context of severe malaria, prescribing should be consistent with current WHO guidelines that restrict use to pretransfer treatment when oral therapy is not possible and where injectable antimalarial drugs are unavailable, followed by prompt definitive treatment (intravenous artesunate/quinine or a full course of an approved oral artemisinin-based combination therapy) as dictated by the clinical state of the patient.

Corresponding Author: Timothy M. E. Davis, FRACP, School of Medicine and Pharmacology, Fremantle Hospital, PO Box 480, Fremantle 6959, Western Australia, Australia (tdavis@cyllene.uwa.edu.au).

Author Contributions: Drs Karunajeewa and Davis had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Karunajeewa, Davis.

Acquisition of data: Karunajeewa, Manning, Davis.

Analysis and interpretation of data: Karunajeewa, Manning, Mueller, Ilett, Davis.

Drafting of the manuscript: Karunajeewa, Ilett, Davis.

Critical revision of the manuscript for important intellectual content: Manning, Mueller, Davis.

Statistical analysis: Karunajeewa, Manning, Mueller.

Obtained funding: Ilett, Davis.

Administrative, technical, or material support: Davis.

Study supervision: Davis.

Financial Disclosures: Drs Karunajeewa, Ilett, and Davis report having received funding for investigator-initiated research from Mepha Pharmaceuticals, Aesch-Basel, Switzerland, manufacturers of artesunate suppositories. Drs Karunajeewa and Davis also report having received honoraria for writing technical reports for Mepha Pharmaceuticals. No other authors reported financial disclosures.

Funding/Support: This study was supported by National Health and Medical Research Council (NHMRC) of Australia grant 353663 to Drs Karunajeewa, Ilett, and Davis.

Role of the Sponsor: The NHMRC had no role in the design of the study, in data collection or analysis, in interpretation of the data, or in the preparation, review, or approval of the manuscript.

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PubMed   |  Link to Article
Gomez Landires EA. Efficacy of artesunate suppository followed by oral mefloquine in the treatment of severe falciparum malaria in endemic areas where resistance to chloroquine exists in Ecuador.  Jpn J Trop Med Hyg. 1996;24:(suppl 1)  17-24
Halpaap B, Ndjave M, Paris M, Benakis A, Kremsner PG. Plasma levels of artesunate and dihydroartemisinin in children with Plasmodium falciparum malaria in Gabon after administration of 50-milligram artesunate suppositories.  Am J Trop Med Hyg. 1998;58:365-368
PubMed
Karunajeewa HA, Ilett KF, Dufall K.  et al.  Disposition of artesunate and dihydroartemisinin after administration of artesunate suppositories in children from Papua New Guinea with uncomplicated malaria.  Antimicrob Agents Chemother. 2004;48:2966-2972
PubMed   |  Link to Article
Karunajeewa HA, Kemiki A, Alpers MP.  et al.  Safety and therapeutic efficacy of artesunate suppositories for treatment of malaria in children in Papua New Guinea.  Pediatr Infect Dis J. 2003;22:251-256
PubMed
Karunajeewa HA, Reeder J, Lorry K.  et al.  Artesunate suppositories versus intramuscular artemether for treatment of severe malaria in children in Papua New Guinea.  Antimicrob Agents Chemother. 2006;50:968-974
PubMed   |  Link to Article
Krishna S, Planche T, Agbenyega T.  et al.  Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria.  Antimicrob Agents Chemother. 2001;45:509-516
PubMed   |  Link to Article
Looareesuwan S, Wilairatana P, Andrial M. Artesunate suppository for the treatment of severe falciparum malaria in Thailand.  Jpn J Trop Med Hyg. 1996;24:13-15
Looareesuwan S, Wilairatana P, Molunto W, Chalermrut K, Olliaro P, Andrial M. A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand.  Am J Trop Med Hyg. 1997;57:348-353
PubMed
Looareesuwan S, Wilairatana P, Vanijanonta S, Viravan C, Andrial M. Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria.  Ann Trop Med Parasitol. 1995;89:469-475
PubMed
Navaratnam V, Mansor SM, Mordi MN, Akbar A, Abdullah MN. Comparative pharmacokinetic study of oral and rectal formulations of artesunic acid in healthy volunteers.  Eur J Clin Pharmacol. 1998;54:411-414
PubMed   |  Link to Article
Pengsaa K, Sirivichayakul C, Na-Bangchang K.  et al.  Life-saving rectal artesunate for complicated malaria in children.  Southeast Asian J Trop Med Public Health. 2005;36:597-601
PubMed
Sabchareon A, Attanath P, Chanthavanich P.  et al.  Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria.  Am J Trop Med Hyg. 1998;58:11-16
PubMed
Thwe Y, Than M, Phay S, Oo AZ, Soe AY. Artesunate suppository-mefloquine tablets (Plasmotrim, Rectocaps, mefloquine, Lactab) in the treatment of severe falciparum malaria.  Jpn J Trop Med Hyg. 1996;24:25-32
Li YQ. Effect of qinghaosu by rectal administration in the treatment of vivax malaria [in Chinese].  Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 1984;2:279
PubMed
Li GQ, Xingbo G. Clinical studies on artemisinin suppositories, artesunate and artemether. Paper presented at: IV World Conference on Clinical Pharmacology and Therapeutics; July 29-30, 1989; Mannheim-Heidelberg, Germany
Guo XB, Fu LC. Comparative study of artemisinin suppositories and piperaquine phosphate in the treatment of falciparum malaria.  Zhong Xi Yi Jie He Za Zhi. 1989;9:475-477, 453
PubMed
Ashton M, Nguyen DS, Nguyen VH.  et al.  Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria.  Clin Pharmacol Ther. 1998;63:482-493
PubMed   |  Link to Article
Birku Y, Makonnen E, Bjorkman A. Comparison of rectal artemisinin with intravenous quinine in the treatment of severe malaria in Ethiopia.  East Afr Med J. 1999;76:154-159
PubMed
Koopmans R, Ha LD, Duc DD.  et al.  The pharmacokinetics of artemisinin after administration of two different suppositories to healthy Vietnamese subjects.  Am J Trop Med Hyg. 1999;60:244-247
PubMed
Koopmans R, Duc DD, Kager PA.  et al.  The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria.  Trans R Soc Trop Med Hyg. 1998;92:434-436
PubMed   |  Link to Article
Arnold K, Tran TH, Nguyen TC, Nguyen HP, Pham P. A randomized comparative study of artemisinine (qinghaosu) suppositories and oral quinine in acute falciparum malaria.  Trans R Soc Trop Med Hyg. 1990;84:499-502
PubMed   |  Link to Article
Hien TT, Arnold K, Vinh H.  et al.  Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria.  Trans R Soc Trop Med Hyg. 1992;86:582-583
PubMed   |  Link to Article
Hien TT, Tam DT, Cuc NT, Arnold K. Comparative effectiveness of artemisinin suppositories and oral quinine in children with acute falciparum malaria.  Trans R Soc Trop Med Hyg. 1991;85:210-211
PubMed   |  Link to Article
Li GQ, Guo XB, Jian HX.  et al.  Observation on the efficacy of qinghaosu suppository in 100 cases of falciparum malaria.  J Tradit Chin Med. 1985;5:159-161
PubMed
Cao XT, Bethell DB, Pham TP.  et al.  Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria.  Trans R Soc Trop Med Hyg. 1997;91:335-342
PubMed   |  Link to Article
Ha V, Nguyen NH, Tran TB.  et al.  Severe and complicated malaria treated with artemisinin, artesunate or artemether in Viet Nam.  Trans R Soc Trop Med Hyg. 1997;91:465-467
PubMed   |  Link to Article
Tran TH, Arnold K, Nguyen TH.  et al.  Single dose artemisinin-mefloquine treatment for acute uncomplicated falciparum malaria.  Trans R Soc Trop Med Hyg. 1994;88:688-691
PubMed   |  Link to Article
Ilett KF, Batty KT, Powell SM.  et al.  The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria.  Br J Clin Pharmacol. 2002;53:23-30
PubMed   |  Link to Article
Esamai F, Ayuo P, Owino-Ongor W.  et al.  Rectal dihydroartemisinin versus intravenous quinine in the treatment of severe malaria: a randomised clinical trial.  East Afr Med J. 2000;77:273-278
PubMed
Wilairatna P, Krudsood S, Silachamroon U.  et al.  Clinical trial of sequential treatments of moderately severe and severe malaria with dihydroartemisinin suppository followed by mefloquine in Thailand.  Am J Trop Med Hyg. 2000;63:290-294
PubMed
Zhao KC, Song ZY. Pharmacokinetics of dihydroqinghaosu in human volunteers and comparison with qinghaosu.  Yao Xue Xue Bao. 1993;28:342-346
PubMed
Aceng JR, Byarugaba JS, Tumwine JK. Rectal artemether versus intravenous quinine for the treatment of cerebral malaria in children in Uganda: randomised clinical trial.  BMJ. 2005;330:334
PubMed   |  Link to Article
Teja-Isavadharm P, Nosten F, Kyle DE.  et al.  Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay.  Br J Clin Pharmacol. 1996;42:599-604
PubMed
Hien TT. An overview of the clinical use of artemisinin and its derivatives in the treatment of falciparum malaria in Viet Nam.  Trans R Soc Trop Med Hyg. 1994;88:(suppl 1)  S7-S8
PubMed   |  Link to Article
Simpson JA, Agbenyega T, Barnes KI.  et al.  Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.  PLoS Med. 2006;3:e444
PubMed   |  Link to Article
McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria.  Cochrane Database Syst Rev. 2000;(2):CD000527
PubMed
Price R, van Vugt M, Phaipun L.  et al.  Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.  Am J Trop Med Hyg. 1999;60:547-555
PubMed
Barennes H, Balima-Koussoube T, Nagot N, Charpentier JC, Pussard E. Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial.  BMJ. 2006;332:1055-1059
PubMed   |  Link to Article
Brewer TG, Grate SJ, Peggins JO.  et al.  Fatal neurotoxicity of artemether and artemether.  Am J Trop Med Hyg. 1994;51:251-259
PubMed
Davis TM, Phuong HL, Ilett KF.  et al.  Pharmacokinetics and pharmacodynamics of intravenous artesunate in severe falciparum malaria.  Antimicrob Agents Chemother. 2001;45:181-186
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Pharmaceutical Preparations of Artemisinin Derivatives for Rectal Administration
Table Graphic Jump LocationTable 2. Clinical Efficacy of Rectally Administered Artemisinin Derivatives
Table Graphic Jump LocationTable 3. Pharmacokinetic Studies of Rectally Administered Artemisinin Derivatives

References

Breman J. The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden.  Am J Trop Med Hyg. 2001;64(1–2):(suppl)  1-11
PubMed
Hien TT, White NJ. Qinghaosu.  Lancet. 1993;341:603-608
PubMed   |  Link to Article
 Fifteenth Programme Report of the UNDP/World Bank/WHO Special Programme for Research & Training in Tropical Diseases: Progress (1999-2000). Publication TDR/GEN/01.5. http://www.who.int/tdr/publications/publications/pdf/pr15/pr15.pdf. Accessed April 25, 2007
McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria.  Cochrane Database Syst Rev. 2000;(2):CD000256
PubMed
Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.  Lancet. 2005;366:717-725
PubMed   |  Link to Article
Anstey NM, Price RN, White NJ. Improving the availability of artesunate for treatment of severe malaria.  Med J Aust. 2006;184:3-4
PubMed
World Health Organization.  FDA Briefing Document for the Anti-infective Drug Products Advisory Committee: Artesunate Rectal Capsules. Geneva, Switzerland: World Health Organization; July 10, 2002
Ilett K, Batty K. Artemisinin and its derivatives. In: Yu VL, Edwards G, McKinnon PS, et al, eds. Antimicrobial Therapy and Vaccines, Vol II: Antimicrobial Agents. Pittsburgh, Pa: ESun Technologies LLC; 2005:981-1002
White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo.  Antimicrob Agents Chemother. 1997;41:1413-1422
PubMed
van Tulder M, Furlan A, Bombardier C, Bouter L. Updated method guidelines for systematic reviews in the Cochrane Collaboration back review group.  Spine. 2003;28:1290-1299
PubMed
Barnes KI, Mwenechanya J, Tembo M.  et al.  Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study.  Lancet. 2004;363:1598-1605
PubMed   |  Link to Article
Kaona FA, Tuba M. A qualitative study to identify community structures for management of severe malaria: a basis for introducing rectal artesunate in the under five years children in Nakonde District of Zambia.  BMC Public Health. 2005;5:28
PubMed   |  Link to Article
Makundi EA, Malebo HM, Mhame P, Kitua AY, Warsame M. Role of traditional healers in the management of severe malaria among children below five years of age: the case of Kilosa and Handeni Districts, Tanzania.  Malar J. 2006;5:58
PubMed   |  Link to Article
Awad MI, Alkadru AM, Behrens RH, Baraka OZ, Eltayeb IB. Descriptive study on the efficacy and safety of artesunate suppository in combination with other antimalarials in the treatment of severe malaria in Sudan.  Am J Trop Med Hyg. 2003;68:153-158
PubMed
Awad MI, Eltayeb IB, Baraka OZ, Behrens RH, Alkadru AM. Pharmacokinetics of artesunate following oral and rectal administration in healthy Sudanese volunteers.  Trop Doct. 2004;34:132-135
PubMed
Benakis A, Binh TQ, Keundjian A, Scheiwe MW. Pharmacokinetics/pharmacodynamics findings after repeated administration of artesunate thermostable suppositories (Rectocaps) in Vietnamese patients with uncomplicated malaria.  Eur J Drug Metab Pharmacokinet. 2006;31:41-45
PubMed   |  Link to Article
Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST. Pharmacokinetic study of a new pharmaceutical form of artesunate (Plasmotrim-200 Rectocaps) administered in healthy volunteers by the rectal route.  Jpn J Trop Med Hyg. 1996;24:(suppl 1)  39-45
Bhatt KM, Bhatt SM, Omonge E, Oteko L, Andrial M. Efficacy and tolerability of a sequential artesunate suppository-mefloquine treatment of severe falciparum malaria.  Jpn J Trop Med Hyg. 1996;24:(suppl 1)  59-63
Gomez EA, Jurado MH, Cambon N. Randomised efficacy and safety study of two 3-day artesunate rectal capsule/mefloquine regimens versus artesunate alone for uncomplicated malaria in Ecuadorian children.  Acta Trop. 2003;89:47-53
PubMed   |  Link to Article
Gomez Landires EA. Efficacy of artesunate suppository followed by oral mefloquine in the treatment of severe falciparum malaria in endemic areas where resistance to chloroquine exists in Ecuador.  Jpn J Trop Med Hyg. 1996;24:(suppl 1)  17-24
Halpaap B, Ndjave M, Paris M, Benakis A, Kremsner PG. Plasma levels of artesunate and dihydroartemisinin in children with Plasmodium falciparum malaria in Gabon after administration of 50-milligram artesunate suppositories.  Am J Trop Med Hyg. 1998;58:365-368
PubMed
Karunajeewa HA, Ilett KF, Dufall K.  et al.  Disposition of artesunate and dihydroartemisinin after administration of artesunate suppositories in children from Papua New Guinea with uncomplicated malaria.  Antimicrob Agents Chemother. 2004;48:2966-2972
PubMed   |  Link to Article
Karunajeewa HA, Kemiki A, Alpers MP.  et al.  Safety and therapeutic efficacy of artesunate suppositories for treatment of malaria in children in Papua New Guinea.  Pediatr Infect Dis J. 2003;22:251-256
PubMed
Karunajeewa HA, Reeder J, Lorry K.  et al.  Artesunate suppositories versus intramuscular artemether for treatment of severe malaria in children in Papua New Guinea.  Antimicrob Agents Chemother. 2006;50:968-974
PubMed   |  Link to Article
Krishna S, Planche T, Agbenyega T.  et al.  Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria.  Antimicrob Agents Chemother. 2001;45:509-516
PubMed   |  Link to Article
Looareesuwan S, Wilairatana P, Andrial M. Artesunate suppository for the treatment of severe falciparum malaria in Thailand.  Jpn J Trop Med Hyg. 1996;24:13-15
Looareesuwan S, Wilairatana P, Molunto W, Chalermrut K, Olliaro P, Andrial M. A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand.  Am J Trop Med Hyg. 1997;57:348-353
PubMed
Looareesuwan S, Wilairatana P, Vanijanonta S, Viravan C, Andrial M. Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria.  Ann Trop Med Parasitol. 1995;89:469-475
PubMed
Navaratnam V, Mansor SM, Mordi MN, Akbar A, Abdullah MN. Comparative pharmacokinetic study of oral and rectal formulations of artesunic acid in healthy volunteers.  Eur J Clin Pharmacol. 1998;54:411-414
PubMed   |  Link to Article
Pengsaa K, Sirivichayakul C, Na-Bangchang K.  et al.  Life-saving rectal artesunate for complicated malaria in children.  Southeast Asian J Trop Med Public Health. 2005;36:597-601
PubMed
Sabchareon A, Attanath P, Chanthavanich P.  et al.  Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria.  Am J Trop Med Hyg. 1998;58:11-16
PubMed
Thwe Y, Than M, Phay S, Oo AZ, Soe AY. Artesunate suppository-mefloquine tablets (Plasmotrim, Rectocaps, mefloquine, Lactab) in the treatment of severe falciparum malaria.  Jpn J Trop Med Hyg. 1996;24:25-32
Li YQ. Effect of qinghaosu by rectal administration in the treatment of vivax malaria [in Chinese].  Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 1984;2:279
PubMed
Li GQ, Xingbo G. Clinical studies on artemisinin suppositories, artesunate and artemether. Paper presented at: IV World Conference on Clinical Pharmacology and Therapeutics; July 29-30, 1989; Mannheim-Heidelberg, Germany
Guo XB, Fu LC. Comparative study of artemisinin suppositories and piperaquine phosphate in the treatment of falciparum malaria.  Zhong Xi Yi Jie He Za Zhi. 1989;9:475-477, 453
PubMed
Ashton M, Nguyen DS, Nguyen VH.  et al.  Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria.  Clin Pharmacol Ther. 1998;63:482-493
PubMed   |  Link to Article
Birku Y, Makonnen E, Bjorkman A. Comparison of rectal artemisinin with intravenous quinine in the treatment of severe malaria in Ethiopia.  East Afr Med J. 1999;76:154-159
PubMed
Koopmans R, Ha LD, Duc DD.  et al.  The pharmacokinetics of artemisinin after administration of two different suppositories to healthy Vietnamese subjects.  Am J Trop Med Hyg. 1999;60:244-247
PubMed
Koopmans R, Duc DD, Kager PA.  et al.  The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria.  Trans R Soc Trop Med Hyg. 1998;92:434-436
PubMed   |  Link to Article
Arnold K, Tran TH, Nguyen TC, Nguyen HP, Pham P. A randomized comparative study of artemisinine (qinghaosu) suppositories and oral quinine in acute falciparum malaria.  Trans R Soc Trop Med Hyg. 1990;84:499-502
PubMed   |  Link to Article
Hien TT, Arnold K, Vinh H.  et al.  Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria.  Trans R Soc Trop Med Hyg. 1992;86:582-583
PubMed   |  Link to Article
Hien TT, Tam DT, Cuc NT, Arnold K. Comparative effectiveness of artemisinin suppositories and oral quinine in children with acute falciparum malaria.  Trans R Soc Trop Med Hyg. 1991;85:210-211
PubMed   |  Link to Article
Li GQ, Guo XB, Jian HX.  et al.  Observation on the efficacy of qinghaosu suppository in 100 cases of falciparum malaria.  J Tradit Chin Med. 1985;5:159-161
PubMed
Cao XT, Bethell DB, Pham TP.  et al.  Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria.  Trans R Soc Trop Med Hyg. 1997;91:335-342
PubMed   |  Link to Article
Ha V, Nguyen NH, Tran TB.  et al.  Severe and complicated malaria treated with artemisinin, artesunate or artemether in Viet Nam.  Trans R Soc Trop Med Hyg. 1997;91:465-467
PubMed   |  Link to Article
Tran TH, Arnold K, Nguyen TH.  et al.  Single dose artemisinin-mefloquine treatment for acute uncomplicated falciparum malaria.  Trans R Soc Trop Med Hyg. 1994;88:688-691
PubMed   |  Link to Article
Ilett KF, Batty KT, Powell SM.  et al.  The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria.  Br J Clin Pharmacol. 2002;53:23-30
PubMed   |  Link to Article
Esamai F, Ayuo P, Owino-Ongor W.  et al.  Rectal dihydroartemisinin versus intravenous quinine in the treatment of severe malaria: a randomised clinical trial.  East Afr Med J. 2000;77:273-278
PubMed
Wilairatna P, Krudsood S, Silachamroon U.  et al.  Clinical trial of sequential treatments of moderately severe and severe malaria with dihydroartemisinin suppository followed by mefloquine in Thailand.  Am J Trop Med Hyg. 2000;63:290-294
PubMed
Zhao KC, Song ZY. Pharmacokinetics of dihydroqinghaosu in human volunteers and comparison with qinghaosu.  Yao Xue Xue Bao. 1993;28:342-346
PubMed
Aceng JR, Byarugaba JS, Tumwine JK. Rectal artemether versus intravenous quinine for the treatment of cerebral malaria in children in Uganda: randomised clinical trial.  BMJ. 2005;330:334
PubMed   |  Link to Article
Teja-Isavadharm P, Nosten F, Kyle DE.  et al.  Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay.  Br J Clin Pharmacol. 1996;42:599-604
PubMed
Hien TT. An overview of the clinical use of artemisinin and its derivatives in the treatment of falciparum malaria in Viet Nam.  Trans R Soc Trop Med Hyg. 1994;88:(suppl 1)  S7-S8
PubMed   |  Link to Article
Simpson JA, Agbenyega T, Barnes KI.  et al.  Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.  PLoS Med. 2006;3:e444
PubMed   |  Link to Article
McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria.  Cochrane Database Syst Rev. 2000;(2):CD000527
PubMed
Price R, van Vugt M, Phaipun L.  et al.  Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.  Am J Trop Med Hyg. 1999;60:547-555
PubMed
Barennes H, Balima-Koussoube T, Nagot N, Charpentier JC, Pussard E. Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial.  BMJ. 2006;332:1055-1059
PubMed   |  Link to Article
Brewer TG, Grate SJ, Peggins JO.  et al.  Fatal neurotoxicity of artemether and artemether.  Am J Trop Med Hyg. 1994;51:251-259
PubMed
Davis TM, Phuong HL, Ilett KF.  et al.  Pharmacokinetics and pharmacodynamics of intravenous artesunate in severe falciparum malaria.  Antimicrob Agents Chemother. 2001;45:181-186
PubMed   |  Link to Article
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