Warhurst, DC; Adagu, IS; Beck, HP; Duraisingh, MT; Kirby, GC; von Seidlein, L; Wright, CW; (2001) Mode of action of artemether lumefantrine (COARTEM): The sole, fixed, oral ADCC and its role in combatting multidrug resistance. The Southeast Asian journal of tropical medicine and public health, 32 (suppl.). pp. 4-8. ISSN 0125-1562 https://researchonline.lshtm.ac.uk/id/eprint/1904 Downloaded from: http://researchonline.lshtm.ac.uk/1904/ DOI:

Summary Objective To ascertain whether mefloquine (MQ) produces electrocardiogram (ECG) changes that could be a risk for Torsades de Pointe (TdP), a potentially malignant, ventricular tachyarrhythmia. Methods We measured the Fridericia corrected QT (QTcF) intervals on 12 lead ECGs on days (D) 0, 3, 7 in Plasmodium falciparum infected adults, treated with oral artesunate (AS) and MQ as a new fixed dose ( n = 25) combination or loose tablets ( n = 25) over 3 days. Target total doses were 12 mg/kg of AS and 24–25 mg/kg of MQ. MQ concentrations ([MQ]) were measured by HPLC. Results All ECG intervals were similar between drug arms and were combined for analysis. Mean QTcF values were 389 (D0), 407 (D3) and 399 (D7) ms (Ps < 0.003 vs. D0); corresponding heart rates and [MQ]s were 83, 67 and 73 beats/minute (Ps≤0.0003 vs. D0) and 0, 3095 and 1721 ng/ml. One male patient (loose arm) had a D3 QTcF 504 ms (D0 406 ms, D7 433 ms). In the modelling of QTcF and JTcF from D0 to D7, significant effects were observed individually for [MQ], temperature and heart rate (HR). The MQ AUC 0‐∞ was not a significant factor. Using a manual descending, model building approach to select variables, the HR was the only significant variable ( P = 0.001) over time in the model that best explained the changes in the QTcF and JTcF intervals. Conclusions In this small group of patients, slowing heart rates due to malaria resolution best explained the observed increases in the QTcF intervals.

ABSTRACT A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P ≤ 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P ≤ 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement.

Although cerebral malaria is a major life-threatening complication of Plasmodium falciparum infection, its pathophysiology is not well understood. Prolonged activation of the T helper type 1 (Th1) response characterized by the production of pro-inflammatory cytokines such as IFN-gamma and TNF-alpha has been suggested to be responsible for immunopathological process leading to cerebral malaria unless they are downregulated by the anti-inflamatory cytokines produced by the Th2 response. The T cell immunoglobulin and mucin domain (TIM) family of proteins are cell surface proteins involved in regulating Th1 and Th2 immune responses. In this study, the possible association between the polymorphisms of TIM1, TIM3, and TIMD4 genes and the severity of malaria was examined in 478 adult Thai patients infected with P. falciparum malaria. The TIM1 promoter haplotype comprising three derived alleles, -1637A (rs7702919), -1549C (rs41297577) and -1454A (rs41297579), which were in complete linkage disequilibrium, was significantly associated with protection against cerebral malaria (OR = 0.41; 95% CI = 0.24-0.71; P= 0.0009). Allele-specific transcription quantification analysis revealed that the level of mRNA transcribed from TIM1 was higher for the protective promoter haplotype than for the other promoter haplotype (P= 0.004). Engagement with TIM1 in combination with T cell receptor stimulation induces anti-inflammatory Th2 cytokine production, which can protect the development of cerebral malaria caused by overproduction of pro-inflammatory Th1 cytokines. The present results suggest that the higher TIM1 expression associated with the protective TIM1 promoter haplotype confers protection against cerebral malaria.

Pulmonary complication in severe Plasmodium falciparum malaria is manifested as a prolonged impairment of gas transfer or the more severe acute respiratory distress syndrome (ARDS). In either clinical presentation, vascular permeability is a major component of the pathologic process. In this report, we examined the effect of clinical P falciparum isolates on barrier function of primary dermal and lung microvascular endothelium in vitro. We showed that parasite sonicates but not intact infected erythrocytes disrupted endothelial barrier function in a Src-family kinase-dependent manner. The abnormalities were manifested both as discontinuous immunofluorescence staining of the junctional proteins ZO-1, claudin 5, and VE-cadherin and the formation of interendothelial gaps in monolayers. These changes were associated with a loss in total protein content of claudin 5 and redistribution of ZO-1 from the cytoskeleton to the membrane and the cytosolic and nuclear fractions. There was minimal evidence of a proinflammatory response or direct cellular cytotoxicity or cell death. The active component in sonicates appeared to be a merozoite-associated protein. Increased permeability was also induced by P falciparum glycophosphatidylinositols (GPIs) and food vacuoles. These results demonstrate that parasite components can alter endothelial barrier function and thus contribute to the pathogenesis of severe falciparum malaria.

We examined a possible association of three single nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF) promoter -1031T>C (rs1799964), -863C>A (rs1800630), and -857C>T (rs1799724) with severe malaria in 466 adult patients having Plasmodium falciparum malaria in northwest Thailand. Four TNF promoter alleles comprising these three SNPs were detected in the studied population. The frequency of the TNF U04 allele designated -1031C, -863C, and -857C was found to be significantly greater in patients with cerebral malaria than in patients with mild malaria (12.6%, cerebral malaria vs 5.6%, mild malaria; odds ratio =2.5; P=0.002). The association of U04 with susceptibility to cerebral malaria was not caused by linkage disequilibrium with any specific HLA-B and -DRB1 alleles.

The aim of this study was to assess the immunoglobulin (Ig)-subclass distribution of antimalarial antibody responses in 110 and 169 Thai patients with complicated and uncomplicated Plasmodium falciparum malaria, respectively. Antimalarial plasma IgG subclasses and IgE antibody levels against a crude malaria blood stages, and antigen preparation were determined using enzyme-linked immunosorbent assay (ELISA). On admission, the levels of anti-P. falciparum IgG1, IgG2 and IgG3 were significantly lower in patients with complicated malaria than uncomplicated malaria (IgG1, P < 0.0001; IgG2, P < 0.0001; IgG3, P < 0.0001). The levels of antimalarial IgE were slightly lower, but not statistically significant (P = 0.389) in the complicated malaria. After adjusting all antibody levels and age, anti-P. falciparum IgG3 levels remained significantly associated with complicated malaria. None of the other antibody concentrations showed statistically significant associations with complicated malaria. The anti-P. falciparum IgG3 levels were related to the IgG1 as well as IgG2 levels. A correlation between anti-P. falciparum IgG2 and IgE was observed in the complicated malaria group, and this may indicate their roles in the severity of disease. Our data suggest that anti-P. falciparum IgG3 is associated with a reduced risk of complicated malaria and that antimalarial Ig-subclasses are differently regulated in patients with complicated and uncomplicated malaria.

To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy.

mechanisms, including activating chemotaxis, increasing vascular permeability, propagating the inflammatory cytokine cascade, and stimulating macrophage action and smooth muscle cell migration (12, 13). For example, COX-2 and its prostaglandin E2 production have been shown to induce production of the proinflammatory cytokine interleukin-6 (13), an important cytokine that stimulates CRP production in the liver. Thus, COX-2 may promote acute inflammatory processes after AMI. Statins may decrease CRP concentrations and have effects on inflammation, plaque stabilization, and improvement of endothelial function in acute coronary syndrome. Our findings confirm that atorvastatin can decrease CRP concentrations in early-stage AMI. However, atorvastatin can inhibit COX-2 expression, which is closely correlated with CRP. This finding suggests that atorvastatin might have antiinflammatory effects at least partly through the COX-2 pathway. Hernandez-Presa et al. (14) also found that atorvastatin decreased COX-2 expression in a rabbit model of atherosclerosis and in cultured vascular smooth muscle cells. The mechanism underlying this effect of atorvastatin is probably related to inhibition of nuclear factor-B activity secondary to a decrease in isoprenylation of proteins involved in intracellular signal transduction necessary for their correct function, because COX-2 is controlled by this transcription factor, and it has been confirmed that statins can directly decrease nuclear factor-B activity (15).

Malaria remains a major cause of morbidity and mortality in tropical countries and subtropical regions in the world. Southeast Asia has the most resistant malaria parasites in the world, which has limited treatment options in this region. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The combination of dihydroartemisinin (DHA) and piperaquine (PQP) in the form of Artekin® has been developed as an alternative to established combinations, such as artesunate-mefloquine, primarily to reduce treatment costs and toxicity. We conducted a study comparing a standard treatment for acute uncomplicated falciparum malaria (artesunate 4 mg/kg/day together with mefloquine 8 mg/kg/day oral route once a day for 3 days) (Group A) and a combination of dihydroartemisinin 40 mg and piperaquine 320 mg in the form of Artekin® given once a day for 3 days (Group B) to determine safety, efficacy, and tolerability. One hundred and eighty patients were randomly enrolled at the ratio of 1:2 into groups A:B. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time or parasite clearance time between both groups. The 28day cure rates were high, at 100% and 99%, in groups A and B, respectively. We conclude that Artekin® was as effective and well-tolerated as artesunate-mefloquine, and can be used alternatively as the current treatment for multidrug-resistant P. falciparum malaria. SOUTHEAST ASIAN J TROP MED PUBLIC HEALTH 1086 Vol 36 No. 5 September 2005 (Nosten and Brasseur, 2002). Southeast Asia has the most resistant malaria parasites in the world, which has limited treatment options in this region (WHO, 2001). In Thailand, the treatment of acute uncomplicated falciparum malaria is becoming more difficult because of increasing resistance to all of the antimalarial drugs, except the artemisinin derivatives (Wilairatana et al, 2002). To combat the further spread of resistance, it is generally accepted that combinations of antimalarial drugs that include an artemisinin derivative should be used, and, if possible, that preparations should be formulated in a single tablet (Hien et al, 2004). The artemisinin derivatives (artesunate and the recently developed dihydroartemisinin, which is short-acting but powerful drug) have been studied extensively in the treatment of falciparum malaria in Thailand, and are well-tolerated. Their main drawback is that conventional courses (35 days) are associated with high rates of recrudescence, typically >25%. In addition, there is the risk that parasite resistance will develop when antimalarial drugs are used alone (Warhurst, 1999). Because artemisinin derivatives are now the first-line treatment for multidrug-resistant falciparum malaria in many tropical countries, the appearance of artemisinin-resistant Plasmodium falciparum would have serious implications. Thus development of suitable combinations of an artemisinin compound with a second drug is therefore a priority (WHO, 2001). At present, artesunate has been registered by the Thai FDA for use in the treatment of falciparum malaria. Mefloquine is another antimalarial drug, which is better tolerated than quinine and can be administered during a day, but resistance to mefloquine has developed when used alone. Furthermore, in Thailand where multidrug resistance is encountered, a high dose (25 mg/kg) of mefloquine is recommended for use as a combination with other short-acting antimalarial drugs (Nosten et al, 1991). Recently, clinical trials have shown that artesunate combined with mefloquine is effective and wel l-tolerated (Looareesuwan et al, 1992, 1994, 1996; Price et al, 1997); therefore, this regimen has been chosen for treating multidrug resistant falciparum malaria in Thailand. However, some patients cannot to lerate the adverse effects of mefloquine. Piperaquine phosphate (1,3-bis[1-(7chloro-4’-quinolyl)-4’-piperazinyl]) phosphate) replaced chloroquine as the recommended treatment for Plasmodium falciparum malaria in China in 1978 and was used extensively for mass prophylaxis and treatment. Reported adverse events are generally similar to those observed with chloroquine, although pruritus is uncommon. (Tropical Medicine Institute, 2003). Piperaquine was proved to be effective and well-tolerated, and no cross-resistance with chloroquine was observed (Chen et al, 1982). More recently, piperaquine has been used as part of shortcourse artemisinin-based combination oral therapies designed to have high cure rates and few side effects, and to reduce malaria transmission (Denis et al, 2002; Davis et al, 2005). Artekin® (compound dihydroartemisinin), a combinat ion of dihydroartemisin in 40mg, piperaquine 320mg per tablet (Batch No. 20011204 Mfg. 120401 Exp. 120403), supplied free of charge by Holleykin Pharmaceutical Co Ltd, Guangzhou, China is claimed to be highly effective. In addition, this combination is welltolerated and convenient to use (3 days’ treatment). This compound has been on clinical trial and proved safe and well-tolerated in China, Vietnam, Lao PDR, Cambodia, and elsewhere (Karunajeewa et al, 2003; Hien et al, 2004). We propose here a clinical trial of Artekin® vs artesunate and mefloquine (a standard regimen for treatment of multidrug-resistant falciparum malaria in Thailand) at the Bangkok Hospital for Tropical Diseases, to determine efficacy, safety, and tolerability. MATERIALS AND METHODS Study site and recruitment procedures All patients were included who fulfilled the inclus ion cr i ter ia (acute uncompl icated falciparum malaria, either male or female; if female, pregnancy test negative before enrolment into the study, positive asexual forms of P. falciparum in blood smear, weight > 40 kg and age > 14 years, ability to take oral medication, agreement to stay in hospital for at least 28 ARTEKIN® VS ARTESUNATE-MEFLOQUINE IN FALCIPARUM MALARIA Vol 36 No. 5 September 2005 1087 days). Informed consent for the study was obtained from the patients or their guardians before enrolment into the study. The patients were admitted to the Bangkok Hospital for Tropical Diseases for 28 days to exclude reinfection and to assess the safety and efficacy of Artekin® and artesunate plus mefloquine. We excluded severe malaria according to WHO criteria (WHO, 2000), severe vomiting not allowing oral medication, pregnancy or lactating female, significant concomitant systemic diseases (for example systemic bacterial infections, liver and/or kidney insufficiencies, chronic disease or severe malnutrition), diseases requiring therapy other than malaria, ingestion of other antimalarials in the past 14 days or presence of urine sulfonamides or 4-aminoquinolones. Clinical evaluation, including neurological examination focused on brain stem, cerebellar function, muscle strength in all limbs, extraocular and facial muscle strength, deep tendon reflexes, and finger-to-nose tests; parasite counts were performed 12-hourly until negative, then daily for 28 days. Malaria parasite counts per microliter were obtained by calculation against white blood cell counts for a thick film. Geometric mean parasites were used as the standard method. Blood films were considered negative if no parasites were seen in 200 oil-immersion microscopic fields. Fever clearance time was taken as the period from the start of treatment until the oral temperature decreased to 37.5oC and remained below this temperature for the next 48 hours. Side-effects were defined as signs and symptoms that occurred or became more severe after treatment started. Cure rate at day 28 (cured patients/evaluable patients x 100%) was defined as the absence of parasite recrudescence during 28 days of follow-up. For any RI, RII, or RIII failure (WHO, 1973), standard antimalarial drugs of the hospital would be given. Adverse events would also be treated by standard procedures at the Bangkok Hospital for Tropical Diseases. This study was approved by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Study drug administration An open randomized clinical trial of Artekin® vs Artesunate-Mefloquine was conducted at the Bangkok Hospital for Tropical Diseases, Mahidol University. Upon admission to the ward, patients were randomly treated at a ratio of 1:2 in groups A:B, as follows: Group A: AM: Artesunate (4 mg/kg/day) was given by oral route once a day for 3 days together with mefloquine 8mg/kg/day for 3days. Group B: Artekin: Artekin® (2 mg/kg/day of dihydroartemisinin and 15 mg/kg/day piperaquine) was given by oral route once a day for 3 days (Artekin® 1 tab contains DHA 40 mg + piperaquine 320 mg). All patients were treated symptomatically as indicated (eg intravenous fluid and antipyretics.) according to the standard practice in the hospital. In cases of RI, RII, or RIII responses (WHO, 1973), other antimalarial drugs (eg quinine plus tetracycline for falciparum malaria, and chloroquine followed by primaquine for vivax malaria) were used as indicated. Patients who vomited within one hour after drug administration were re-dosed. Monitoring for safety Patients were given physical examinations and adverse reactions during the study were recorded with the date and time at which they occurred and disappeared. Adverse effects were assessed on the basis of non-suggestive questioning by the study investigators; these included gastrointestinal, central nervous system, cardiovascular and dermatological effects, as well as other changes possibly attributable to the study drugs. Routine blood investigations (hematology and biochemistry) and urinalysis were performed prior to (Day 0) and weekly for 4 weeks of the study period. Statistical analysis Statistical analysis was performed using the Analyze It Add-Ins for Excel for Windows. All the p-values reported were from 2-tailed testing, and the statistically significant level was set at 0.05. Data distri

ABSTRACT The adhesion of Plasmodium falciparum -infected erythrocytes (IRBCs) to human dermal microvascular endothelial cells (HDMECs) under flow conditions is regulated by a Src family kinase- and alkaline phosphatase (AP)-dependent mechanism. In this study, we showed that the target of the phosphatase activity is the ectodomain of CD36 at threonine-92 (Thr 92 ). Mouse fibroblasts (NIH 3T3 cells) transfected with wild-type CD36 or a mutant protein in which Thr 92 was substituted by Ala supported the rolling and adhesion of IRBCs. However, while the Src family kinase inhibitors PP1 and PP2 and the specific AP inhibitor levamisole significantly reduced IRBC adhesion to wild-type CD36 transfectants as with HDMECs, the inhibitors had no effect on IRBC adhesion to the mutant cells. Using a phosphospecific antibody directed at a 12-amino-acid peptide spanning Thr 92 , we demonstrated directly that CD36 was constitutively phosphorylated and could be dephosphorylated by exogenous AP. Endothelial CD36 was likewise constitutively phosphorylated. The phosphospecific antibody inhibited IRBC adhesion to HDMECs that could be reversed by preincubating the antibody with the phosphorylated but not the nonphosphorylated peptide. Pretreatment of HDMECs with AP abrogated the effect of PP1 on IRBC adhesion. Collectively, these results are consistent with a critical role for CD36 dephosphorylation through Src family kinase activation in regulating IRBC adhesion to vascular endothelium.

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

Preclinical studies have shown that curdlan sulphate (CRDS), a sulphated 1-->3-beta-D glucan, inhibits Plasmodium falciparum in vitro and down-modulates the immune response. A direct, non-specific effect on cytoadherence and rosetting may be predicted, as has been described with other sulphated polysaccharides, e.g. heparin. The anticoagulant effect of CRDS is 10-fold lower than heparin. Curdlan sulphate has, therefore, emerged as a candidate for adjunct medication in the treatment of severe/cerebral malaria. Two clinical studies were conducted using CRDS as adjunct medication to conventional therapy (artesunate) in patients with severe and severe/cerebral malaria. Both studies were double-blind and placebo-controlled to evaluate the efficacy and safety of the combination. Curdlan sulphate appeared to reduce the severity of the disease process, e.g. fever clearance time was shortened. Due to the small number of patients, there was no difference in mortality. The two treatment arms in both studies showed similar results for all laboratory parameters. The only adverse event recorded during CRDS treatment was an increase in activated partial thromboplastin time. This can be monitored easily. It seems that the patients who may benefit most are severe/cerebral cases with no organ damage on admission.

Our previous study showed that in vitro susceptibility of Plasmodium vivax to chloroquine has significantly decreased in Thailand within the past two decades. Thus, the evaluation of alternative antimalarials for treatment of vivax malaria is needed. The aim of this study was to examine parasitological and clinical efficacy of an artemisinin derivative (artesunate) for the treatment of vivax malaria in patients who were admitted to the Bangkok Hospital for Tropical Diseases. We randomly allocated patients aged 12-56 years to receive 3.3mg/kg (adult dose 200 mg) on the first day, and for the next four days each patient was given 1.65 mg/kg orally (adult dose 100 mg), total dose = 600 mg. After the five-day course of artesunate, primaquine was given: a single oral dose of 15mg for 14 days. A total number of 42 patients received treatment. All participants were followed up for 28 days. In all the cases, both parasitemia and fever were resolved rapidly; the mean fever clearance time and parasite clearance time, 14.6 and 36.7 hours, respectively, showed that therapeutic response to artesunate was better than that of chloroquine. The 14-day cure rate was 100%, but reappearance of parasitemia was seen in two patients on days 21 and 25 following treatment, respectively. These two cases of failure rate should be considered as true relapse rather than recrudescence, since the relapse interval in Southeast Asian vivax malaria according to recent findings seems to be 3 weeks after start of treatment, if primaquine is not given or an inadequate amount is given. In conclusion, artesunate might be useful in treatment of vivax malaria, causing a good blood schizontocidal effect. However, to prevent emerging resistance it should never be used alone.

To study the influence of season on Plasmodium vivax gametocyte carriage, the relationship between monthly rainfall and the proportion of P. vivax patients with detectable gametocytaemia was analysed. Most of the data used came from 6807 aggregated observations collected, in a refugee camp on the Thai-Burmese border, between January 2000 and December 2002. There was a positive correlation between rainfall and the incidence of P. vivax infection (Spearman's rho=+0.42; P =0.01) but the prevalence of gametocyte carriage among those with P. vivax infection was negatively correlated with rainfall (Spearman's rho=-0.58; P <0.001). The latter, negative correlation remained significant after controlling for the proportion of visitors relative to camp residents (P =0.003). Migrations, changes in transmission patterns, seasonal haematological changes, and ultraviolet immunosuppression are discussed as potential explanations for these observations.

The pharmacokinetics of oral dihydroartemisinin (DHA) following the dose of 2 and 4 mg/ kg body weight dihydroartemisinin (Twisinin, T-2 Program, Thailand) and 4 mg/kg body weight oral artesunate (AS; Guilin Pharmaceutical Works, Guangxi, China) were investigated in 20 healthy Thai volunteers (10 males, 10 females). All formulations were generally well tolerated. Oral DHA was rapidly absorbed from gastrointestinal tract with marked inter-individual variation. The pharmacokinetics of DHA following the two dose levels were similar and linearity in its kinetics was observed. Based on the model-independent pharmacokinetic analysis, median (95% CI) values for Cmax of 181 (120-306) and 360 (181-658) ng/ml were achieved at 1.5 hours following 2 and 4 mg/kg body weight dose, respectively. The corresponding values for AUC0-infinity, t1/2z, CL/f and Vz/f were 377 (199-1,128) vs 907 (324-2,289) ng.h/ml, 0.96 (0.70-1.81) vs 1.2 (0.75-1.44) hours, 7.7 (4.3-12.3) vs 6.6 (3.1-10.1) l/kg, and 90.5 (28.6-178.2) vs 6.6 (3.1-10.1) ml/min/kg, respectively (2 vs 4 mg/kg dose). Oral AS was rapidly biotransformed to DHA, which was detectable in plasma as early as 15 minutes of AS dosing. Following 4 mg/kg dose, median (95% CI) value for Cmax of 519 (236-284) ng/ml was achieved at 0.7 (0.25-1.5) hours. AUC0-infinity, and t1/2z were 657 (362-2,079) ng.h/ml, 0.74 (0.34-1.42) hours, respectively. Cmax of DHA following oral AS were significantly higher, but total systemic exposure was greater following oral DHA at the same dose level (4 mg/kg body weight). There was no significant sex difference in pharmacokinetics of DHA.