An open randomized clinical trial of Artekin vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria.

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 28-day 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.

The pharmacokinetics of oral dihydroartemisinin and artesunate in healthy Thai volunteers.

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.

Comparative clinical trial of two-fixed combinations dihydroartemisinin-napthoquine-trimethoprim (DNP) and artemether-lumefantrine (Coartem/Riamet) in the treatment of acute uncomplicated falciparum malaria in Thailand.

An open randomized comparison of two-fixed dose artemisinin derivative-containing combination regimens was conducted in adults with acute uncomplicated multidrug resistant falciparum malaria in Thailand. DNP, a combination of dihydroartemisinin with napthoquine and trimethoprim developed recently in China, has been evaluated in China, Vietnam, Cambodia and Thailand. This study was performed to compare the safety, tolerability and efficacy of DNP and artemether-lumefantrine/Coartem. One hundred and thirty eligible uncomplicated falciparum malaria patients were enrolled into the study. Patients were randomly assigned in a 2:1 ratio into group A, which received DNP one tablet twice a day for one day; and group B, which received Coartem/Riamet four tablets twice a day for 3 days. The cure rates at 28-day were 99% and 97% in group A and group B, respectively. No serious adverse events occurred. We concluded that both DNP and Coartem/ Riamet were safe, well tolerated and highly efficacious in the treatment of acute uncomplicated falciparum malaria in Thailand.

Application of yeast enolase as antigen for immunodiagnosis of malaria.

In 1998, we reported that Plasmodium falciparum (Pf) enolase was useful as the capture antigen for the immunodiagnosis of malaria. In the present study, we modified a fluorescence-ELISA for the diagnosis of malaria by applying yeast enolase or rabbit muscle enolase as antigen. Sera from 67 falciparum malaria patients and 15 vivax malaria patients were tested by the method. Positivity rates of the former was 82.1% against yeast enolase antigen and 90.5% against rabbit muscle enolase antigen, and those of latter was 93.3% against both enolase antigens. Mean antibody level (RFU values) of sera from falciparum and vivax malaria patients were significantly higher than those from healthy individuals. There was a significant correlation between anti-yeast and anti-rabbit muscle enolase antibody level (RFU values) in the group of falciparum subjects (r = 0.401, p<0.001). A significant correlation between RFU values against yeast enolase antigen and indirect fluorescent antibody titers against crude Pf antigen in the same subjects was recognized (r = 0.518, p<0.001). Longitudinal changes of RFU values against yeast enolase for the following 4 weeks after admission were also examined for sera from falciparum malaria patients. Patients with more severe malaria showed increasing RFU values as the clinical courses progressed. However, in the mild cases, each RFU value stayed unchanged during the course. We concluded that yeast and rabbit muscle enolase could be appropriately used as antigen for the immunodiagnosis of malaria.

Serological evaluation of malaria patients in Thailand: antibody response against electrophoresed antigenic polypeptides of Plasmodium falciparum.

It was reported that a 47kDa antigenic polypeptide of Plasmodium falciparum had been strongly presented by the sera from 1) imported Japanese malaria patients with severe symptoms and 2) symptomatic and parasitemic inhabitants in endemic areas in the Sudan, Malaysia and the Philippines. In the present study, we observed the reactivity of the sera from falciparum malaria patients who had been hospitalized in the Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, and compared the antibody response against the 47kDa antigenic polypeptide according to the severity of the patients. It was observed that antibodies to this molecule were more commonly shared in sera from severer patients, although the IFAT titers against the whole P. falciparum parasite antigen were lower in the group, which suggested that this antibody against the 47kDa molecule was playing a specific role at a severe stage of the infection. Determination of the immunological features of the antigenic molecules of parasites by this type of sero-epidemiological study will provide a new assay system for evaluation of immune status of individuals in different severity and suggest a way of vaccine development.