Transient lesion in the splenium of the corpus callosum in acute uncomplicated falciparum malaria.

Patients with acute uncomplicated Plasmodium falciparum malaria have no evident neurologic disorder, vital organ dysfunction, or other severe manifestations of infection. Nonetheless, parasitized erythrocytes cytoadhere to the endothelium throughout their microvasculature, especially within the brain. We aimed to determine if 3 Tesla magnetic resonance imaging studies could detect evidence of cerebral abnormalities in these patients. Within 24 hours of admission, initial magnetic resonance imaging examinations found a lesion with restricted water diffusion in the mid-portion of the splenium of the corpus callosum of 4 (40%) of 10 male patients. The four patients who had a splenial lesion initially had evidence of more severe hemolysis and thrombocytopenia than the six patients who had no apparent abnormality. Repeat studies four weeks later found no residua of the lesions and resolution of the hematologic differences. These observations provide evidence for acute cerebral injury in the absence of severe or cerebral malaria.

Factors associated with acute renal failure in severe falciparum [corrected] malaria patients.

Acute renal failure (ARF) is a common cause of morbidity and mortality in severe malaria infection. We evaluated factors associated with acute renal failure in severe malaria by comparing patients with severe malaria with and without ARF admitted to the Hospital for Tropical Diseases, Bangkok, Thailand. Nine hundred fifteen severe malaria patients were included in the study, of whom 195 had ARF and 720 did not have ARF. We found jaundice, anemia, hypoalbuminemia, hyponatremia, hyperkalemia, acidosis, leukocytosis, elevated transaminases (SGOT and SGPT) and cerebral malaria, were significantly associated with ARF among patients with severe malaria (p < 0.05). Patients who have ARF and any of these clinical or laboratory manifestations of severe malaria should be monitored and managed properly, since early detection and treatment may reduce morbidity and mortality.

Arterolane, a new synthetic trioxolane for treatment of uncomplicated Plasmodium falciparum malaria: a phase II, multicenter, randomized, dose-finding clinical trial.

BACKGROUND: Drug-resistant Plasmodium falciparum malaria necessitates development of novel drugs for treatment.The present study assessed the efficacy and safety of 3 dose levels of arterolane (RBx 11160), a synthetic trioxolane, for treatment of acute uncomplicated falciparum malaria. METHODS: In this randomized, double-blind, multicenter, parallel-group, dose-finding, phase II trial, 230 patients from 4 centers in Thailand, India, and Tanzania (mainland and Zanzibar) received either 50 mg (n=78), 100mg (n=76), or 200 mg (n=76) of arterolane once daily for 7 days. Patients (aged 13-65 years) with asexual parasite density of 1000-100,000 parasites/microL were included and were followed up for 28 days. The median time to 90% parasite clearance (PC90) was evaluated. RESULTS: The median PC90 was longer in the group receiving the 50-mg dose (19.4 h), compared with the groups receiving the 100-mg dose (12.8 h) and 200-mg dose (12.6 h) (P < .01). The polymerase chain reaction-corrected adequate clinical and parasitological responses on day 28 were 63%, 71%, and 72% for the groups receiving the 50-mg, 100-mg, and 200-mg doses, respectively, by intention-to-treat analysis (odds ratio, 1.55; 95%confidence interval, 0.78-3.06, for comparison of the 200-mg and 50-mg dose groups). Treatment was generally well tolerated. No patient died or experienced any serious adverse event. Mild complaints were reported in <10%of the patients and were similar in the 3 groups. Biochemistry and hematological analyses did not show any signof drug toxicity in any patient. CONCLUSION: Arterolane at daily doses of 100 and 200 mg is a rapidly acting, effective, and safe synthetic antimalarial drug, which may potentially represent an alternative to artemisinin derivatives in antimalarial combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00362050.

Intravenous ibuprofen (IV-ibuprofen) controls fever effectively in adults with acute uncomplicated Plasmodium falciparum malaria but prolongs parasitemia.

Because some febrile patients are unable to swallow or retain oral antipyretic drugs, we carried out a double-blind, placebo-controlled trial in which intravenous ibuprofen (IV-ibuprofen) was given to adults hospitalized with fever associated with acute uncomplicated falciparum malaria treated with oral artesunate plus mefloquine. Thirty patients received IV-ibuprofen 400 mg and 30 received placebo every 6 hours for 72 hours. Reduction in the area above 37.0 degrees C versus time curve was significantly greater for IV-ibuprofen than for placebo during the first 72 hours after first administration. No patients developed severe malaria; parasite clearance was delayed in the patients whose fevers were controlled by IV-ibuprofen (median 37.3 hours versus 23.7 hours in the placebo group [P = 0.0024]). This difference did not appear to be clinically important Adverse events, none considered severe, occurred equally in both groups. IV-ibuprofen was effective and well tolerated in reducing fever in febrile inpatients with malaria.

Cerebral malaria: a new way forward with magnetic resonance imaging (MRI).

Magnetic resonance studies offer a new way through the impasse that now seems to block further progress in disentangling the pathogenesis and improving the treatment of cerebral malaria, a catastrophic neurologic complication of infection with Plasmodium falciparum. The underlying mechanisms responsible for coma in cerebral malaria are still unknown and the relative contributions of the microvascular sequestration of infected erythrocytes, the inflammatory response to P. falciparum, disordered hemostasis, and other factors remain controversial. For more than a century, neuropathologic studies have provided the basis for concepts of causation of cerebral malaria. Magnetic resonance techniques now offer non-invasive means of determining essential anatomic, metabolic, biochemical, and functional features of the brain in patients with cerebral malaria during life that could transform our understanding of the pathogenesis of cerebral malaria and lead to the development of new neuroprotective treatments.

Blood stage Plasmodium falciparum antigens induce immunoglobulin class switching in human enriched B cell culture.

This study aimed to demonstrate class switch recombination (CSR) in heavy chain expressing immunoglobulin G (IgG) and IgE in human B cells after exposure to Plasmodium falciparum schizont lysate. Human B cells (CD20+CD27-) were cultured with crude P. falciparum antigen (cPfAg) and anti-CD40. On Day 4 post-exposure, total RNA from B cells was prepared and the occurrence of CSR from IgM to IgG and/or IgE was investigated by reverse transcription-polymerase chain reaction. Molecular markers to detect active CSR included enzyme activation-induced cytidine deaminase mRNA, gamma and epsilon-germline transcripts (gamma, epsilon-GLT), circle transcript (CT) and mature transcript (gamma and epsilon-mRNA) expression. On Day 7 and Day 14 after exposure, levels of Igs in the culture supernatant were determined by enzyme-linked immunosorbent assay. Our findings showed that we could demonstrate cPfAg-stimulated B cells undergoing CSR by use of the expressed CSR markers and the increase in specific IgG and IgE indicating the potential of this approach in the study of CSR in P. falciparum-stimulated B cells.

Use of peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for Plasmodium falciparum malaria: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Despite the use of potent antimalarial drugs, the fatality rate associated with severe malaria remains high. Adjunctive therapies that target the immunopathological responses to infection may decrease mortality associated with severe malaria. We hypothesized that peroxisome proliferator-activated receptor gamma agonists (eg, rosiglitazone) would modulate the host's innate immune response to malaria and improve outcome. METHODS: In a randomized, double-blind, placebo-controlled, phase I/II trial of treatment for malaria acquired in Thailand, we investigated the safety, tolerability, and efficacy of rosiglitazone use for parasite clearance and for reducing malaria-induced inflammation. Sequential patients with uncomplicated Plasmodium falciparum malaria were randomly assigned to 1 of 2 groups: 70 patients received rosiglitazone 4 mg twice daily for 4 days, and 70 patients received a placebo twice daily for 4 days. Both groups also received standard antimalarial therapy (ie, a fixed combination of 1000 mg of atovaquone per day for 3 days and 400 mg of proguanil per day for 3 days). Primary efficacy outcomes were 50% and 90% parasite clearance times (PCTs). Secondary outcomes were fever clearance time, levels of inflammatory mediators, blood glucose measurements, aminotransferase levels, admission to intensive care, and subjective tolerability of study drug. RESULTS: For the 70 patients who received rosiglitazone, parasite clearance from peripheral blood was significantly enhanced, compared with the 70 patients who received a placebo (mean 50% PCT, 19.0 h vs. 24.6 h [p = .029]; mean 90% PCT, 30.9 h vs. 40.4 h [p = .004]). Also, the patients who received rosiglitazone had reduced inflammatory responses to infection, compared with the patients who received a placebo (ie, interleukin-6 levels at 24 h [p < .005] and at 48 h [p = .013] and monocyte chemoattractant protein-1 level at 48 h [p = .05]). There were no significant differences between the 2 groups with regard to safety and tolerability of treatment, and there were no admissions the intensive care unit or deaths. CONCLUSIONS: The use of rosiglitazone is a well-tolerated adjunct to standard therapy for nonsevere P. falciparum malaria. Treatment with rosiglitazone increased parasite clearance and decreased inflammatory biomarkers associated with adverse malaria outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00149383 .

Misclassification of drug failure in Plasmodium falciparum clinical trials in southeast Asia.

Most trials of antimalarials occur in areas in which reinfections are possible. For Plasmodium falciparum, reinfections are distinguished from recrudescences by polymerase chain reaction analysis of 3 polymorphic genes. However, the validity of this approach has never been rigorously tested. We tested for misclassification in 6 patients from clinical trials in Thailand and Cambodia who were classified as being reinfected by the standard polymerase chain reaction protocol. Using heteroduplex tracking assays and direct DNA sequencing, we found that 5 (83%) of 6 patients were misclassified. Misclassification in this manner overestimates the efficacy of antimalarials and delays the recognition of decreasing therapeutic efficacy, thus delaying potential changes in policy.

Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children.

BACKGROUND: Limited tools exist to identify which individuals infected with Plasmodium falciparum are at risk of developing serious complications such as cerebral malaria (CM). The objective of this study was to assess serum biomarkers that differentiate between CM and non-CM, with the long-term goal of developing a clinically informative prognostic test for severe malaria. METHODOLOGY/PRINCIPAL FINDINGS: Based on the hypothesis that endothelial activation and blood-brain-barrier dysfunction contribute to CM pathogenesis, we examined the endothelial regulators, angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), in serum samples from P. falciparum-infected patients with uncomplicated malaria (UM) or CM, from two diverse populations--Thai adults and Ugandan children. Angiopoietin levels were compared to tumour necrosis factor (TNF). In both populations, ANG-1 levels were significantly decreased and ANG-2 levels were significantly increased in CM versus UM and healthy controls (p<0.001). TNF was significantly elevated in CM in the Thai adult population (p<0.001), but did not discriminate well between CM and UM in African children. Receiver operating characteristic curve analysis showed that ANG-1 and the ratio of ANG-2:ANG-1 accurately discriminated CM patients from UM in both populations. Applied as a diagnostic test, ANG-1 had a sensitivity and specificity of 100% for distinguishing CM from UM in Thai adults and 70% and 75%, respectively, for Ugandan children. Across both populations the likelihood ratio of CM given a positive test (ANG-1<15 ng/mL) was 4.1 (2.7-6.5) and the likelihood ratio of CM given a negative test was 0.29 (0.20-0.42). Moreover, low ANG-1 levels at presentation predicted subsequent mortality in children with CM (p = 0.027). CONCLUSIONS/SIGNIFICANCE: ANG-1 and the ANG-2/1 ratio are promising clinically informative biomarkers for CM. Additional studies should address their utility as prognostic biomarkers and potential therapeutic targets in severe malaria.

Role of known molecular markers of resistance in the antimalarial potency of piperaquine and dihydroartemisinin in vitro.

Using a range of laboratory-adapted and genetically modified Plasmodium falciparum parasite isolates, we investigated the interaction between dihydroartemisinin and piperaquine (PIP), the individual components of an artemisinin combination therapy currently under development, in addition to the role of known drug resistance genes in parasite susceptibility in vitro. All but one parasite line investigated displayed an interaction of dihydroartemisinin and PIP that was antagonistic, although the degree of antagonism was isolate dependent. In terms of resistance markers, the pfcrt haplotypes CVIET and SVMNT were positively associated with reduced sensitivity to PIP, with parasites carrying the South American CQR (SVMNT) allele being generally less sensitive than CVIET parasites. Parasites carrying the CQS (CVMNK) allele displayed a further increase in PIP sensitivity compared with CVIET and SVMNT parasites. Our data indicate that PIP sensitivity was not affected by pfmdr1 sequence status, despite positive correlations between the structurally related compound amodiaquine and pfmdr1 mutations in other studies. In contrast, neither the pfcrt nor pfmdr1 sequence status had any significant impact on susceptibility to dihydroartemisinin.

Defective erythropoietin production and reticulocyte response in acute Plasmodium falciparum malaria-associated anemia.

To elucidate the relationship between falciparum malaria-associated anemia and serum erythropoietin (Epo) levels and reticulocyte response during acute malaria infection, 87 adults aged 18-65 years presenting with acute, uncomplicated malaria were examined on enrollment and for 28 days of follow-up. The 87 patients were divided into 2 groups: those with anemia (n = 45) and those without (n = 42). Serum samples were taken on admission (Day 0), then on Days 7, 21, and 28, to measure the reticulocyte count, absolute reticulocyte count, reticulocyte hemoglobin content, and erythropoietin level (Epo). The absolute reticulocyte counts for the anemic patients were significantly higher than for those without anemia on Days 0, 7, 21, and 28. The serum Epo levels for the anemic patients were significantly higher than the non-anemic group only on Day 0 (44.39 +/- 4.06 vs 25.91 +/- 4.86 mlU/ml, p < 0.001). Inadequate Epo production was found in 31.03% (27/87) of patients on Day 0, 37.93% (33/87) on Day 7, 43.67% (38/87) on Day 21, and 39.08% (34/87) on Day 28. These results indicate defective Epo production and reticulocyte response in adult patients suffering from acute P. falciparum malaria, which differs from pediatric patients. Our findings may provide the basis for further study into the choice of therapeutic strategies to treat acute P. falciparum malaria-associated anemia with recombinant human Epo to correct refractory anemia due to malaria.

Heritability of P. falciparum and P. vivax malaria in a Karen population in Thailand.

The majority of studies concerning malaria host genetics have focused on individual genes that confer protection against rather than susceptibility to malaria. Establishing the relative impact of genetic versus non-genetic factors on malaria infection and disease is essential to focus effort on key determinant factors. This relative contribution has rarely been evaluated for Plasmodium falciparum and almost never for Plasmodium vivax. We conducted a longitudinal cohort study in a Karen population of 3,484 individuals in a region of mesoendemic malaria, Thailand from 1998 to 2005. The number of P. falciparum and P. vivax clinical cases and the parasite density per person were determined. Statistical analyses were performed to account for the influence of environmental factors and the genetic heritability of the phenotypes was calculated using the pedigree-based variance components model. The genetic contribution to the number of clinical episodes resulting from P. falciparum and P. vivax were 10% and 19% respectively. There was also moderate genetic contribution to the maximum and overall parasite trophozoite density phenotypes for both P. falciparum (16%&16%) and P. vivax (15%&13%). These values, for P. falciparum, were similar to those previously observed in a region of much higher transmission intensity in Senegal, West Africa. Although environmental factors play an important role in acquiring an infection, genetics plays a determinant role in the outcome of an infection with either malaria parasite species prior to the development of immunity.

Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria.

BACKGROUND: This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria. METHODS: A total of 70 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrolment criteria were recruited in the pharmacokinetic study. Patients were treated with two different dosage regimens of fosmidomycin in combination with clindamycin as follows:Group I: fosmidomycin (900 mg) and clindamycin (300 mg) every 6 hours for 3 days (n = 25); and Group II: fosmidomycin (1,800 mg) and clindamycin (600 mg) every 12 hours for 3 days (n = 54). RESULTS: Both regimens were well tolerated with no serious adverse events. The 28-day cure rates for Group I and Group II were 91.3 and 89.7%, respectively. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about 24 hr after the first dose. The pharmacokinetics of both fosmidomycin and clindamycin analysed by model-independent and model-dependent approaches were generally in broad agreement. There were marked differences in the pharmacokinetic profiles of fosmidomycin and clindamycin when given as two different combination regimens. In general, most of the dose-dependent pharmacokinetic parameters (model-independent C(max): 3.74 vs 2.41 microg/ml; C(max-ss): 2.80 vs 2.08 microg/ml; C(max-min-ss): 2.03 vs 0.71 microg/ml; AUC: 23.31 vs 10.63 microg.hr/ml (median values) were significantly higher in patients who received the high dose regimen (Group II). However, C(min-ss) was lower in this group (0.80 vs 1.37 microg/ml), resulting in significantly higher fluctuations in the plasma concentrations of both fosmidomycin and clindamycin following multiple dosing (110.0 vs 41.9%). Other pharmacokinetic parameters, notably total clearance (CL/F), apparent volume of distribution (V/F, V(z)/F) and elimination half-life (t(1/2z), t(1/2e)) were also significantly different between the two dosage regimens. In addition, the dose-dependent pharmacokinetics of both fosmidomycin and clindamycin tended to be lower in patients with recrudescence responses in both groups. CONCLUSION: The findings may suggest that dosing frequency and duration have a significant impact on outcome. The combination of fosmidomycin (900 mg) and clindamycin (300-600 mg) administered every six hours for a minimum of five days would constitute the lowest dose regimen with the shortest duration of treatment and which could result in a cure rate greater than 95%.

Differences in genetic population structures of Plasmodium falciparum isolates from patients along Thai-Myanmar border with severe or uncomplicated malaria.

BACKGROUND: There have been many reports on the population genetic structures of Plasmodium falciparum from different endemic regions, but few studies have examined the characteristics of isolates from patients with different clinical outcomes. The population genetic structures of P. falciparum isolates from patients with either severe or uncomplicated malaria were examined. METHODS: Twelve microsatellite DNA loci from P. falciparum were used to assess the population genetic structures of 50 isolates (i.e., 25 isolates from patients with severe malaria and 25 from patients with uncomplicated malaria) collected in the Thai-Myanmar border area between 2002 and 2005. RESULTS: Genetic diversity and effective population sizes were greater in the uncomplicated malaria group than in the severe malaria group. Evidence of genetic bottlenecks was not observed in either group. Strong linkage disequilibrium was observed in the uncomplicated malaria group. The groups demonstrated significant genetic differentiation (P < 0.05), and allele frequencies for 3 of the 12 microsatellite loci differed significantly between the two groups. CONCLUSION: These findings suggest that the genetic structure of P. falciparum populations in patients with severe malaria differs from that in patients with uncomplicated malaria. The microsatellite loci used in this study were presumably unrelated to antigenic features of the parasites, but, these findings suggest that some loci may influence the clinical outcome of malaria.

Lack of association of the HbE variant with protection from cerebral malaria in Thailand.

Hemoglobin E (HbE; beta26Glu --> Lys) is the most common variant of the beta-globin gene in Southeast Asia; it has been suggested that it confers resistance against Plasmodium falciparum malaria. In this study 306 adult patients with P. falciparum malaria (198 mild and 108 cerebral malaria patients) living in northwest Thailand were investigated to examine whether the HbE variant is associated with protection from cerebral malaria. Our results revealed that the sample allele frequency of HbE was not significantly different between mild (7.3%) and cerebral malaria (7.4%) patients. Thus, the HbA/HbE polymorphism would not be a major genetic factor influencing the onset of cerebral malaria in Thailand.

Dynamic changes in white blood cell counts in uncomplicated Plasmodium falciparum and P. vivax malaria.

Total and differential white blood cell (WBC) counts are basic and essential indicators in any type of illness resulting from infection. In malaria, WBC counts are generally characterized as low to normal during treatment. WBC-counts data, before and during treatment with artemisinin derivatives, was gathered for patients with either Plasmodium falciparum or Plasmodium vivax infection (at 28-day follow-up), to investigate dynamic changes in WBC count. We analyzed and compared the WBC counts of 1,310 inpatients presenting with uncomplicated P. falciparum and P. vivax malaria at the Hospital for Tropical Diseases, in Bangkok, Thailand. Before-treatment, a statistically significant negative correlation was found between initial WBC count and highest temperature on admission. Before and during treatment, WBC counts were significantly lower in P. falciparum than P. vivax infection on days 0 and 7, but the numerical difference was small. We also found clinically significantly low WBC counts during the acute stages of both types of malaria, which subsequently normalized by day 28 follow-up. This finding has important clinical implications for the conventional method of estimating parasitemia using an assumed WBC count of 8,000 cells/microL. The most significant finding in our analysis is that WBC counts in acute P. falciparum and P. vivax malaria are significantly lower than previously assumed for estimating malaria-parasite density. However, these abnormalities returned to normal within several weeks after artemisinin-derivative-based treatment.

Hyponatraemia and hypokalaemia in adults with uncomplicated malaria in Thailand.

In a retrospective study of 1415 patients aged 15 and over, we determined the incidence of clinically important hyponatraemia and hypokalaemia in adults with uncomplicated malaria. On admission, serum concentrations of sodium (135-145 mmol/L) and potassium (3.5-5.0 mmol/L) were found outside these reference ranges in 81% of patients. Severe hypokalaemia (K+ <3.0 mmol/L) and severe hyponatraemia (Na+ <125 mmol/L occurred in 4.4% and 0.6% of the patients, respectively. For hypokalaemia (43%) and hyponatraemia (37%), hypovolaemia, blood urea to creatinine ratio and high serum glucose (>100 mg/dL) were all independent factors (P < 0.001). Other independent predictors for hypokalaemia were Plasmodium vivax infection, female gender; and for hyponatraemia, P. falciparum infection, male gender, concentrations of G-6-PD and serum bicarbonate.

Longitudinal study of Plasmodium falciparum and Plasmodium vivax in a Karen population in Thailand.

BACKGROUND: Clinical case treatment of malaria infections where Plasmodium falciparum and Plasmodium vivax are sympatric has achieved effective reductions in P. falciparum prevalence and incidence rates, but has been less successful for P. vivax. The high transmissibility of P. vivax and its capacity to relapse have been suggested to make it a harder parasite species to control. METHODS: A clinical malaria case treatment programme was carried out over a decade in a Karen community composed of seven hamlets on the Thai-Myanmar border. RESULTS: From 1994 to 2004, prevalence rates of both P. falciparum and P. vivax decreased by 70-90% in six of the seven study hamlets, but were unchanged in one hamlet. Overall, incidence rates decreased by 72% and 76% for P. falciparum and P. vivax respectively over the period 1999-2004. The age-incidence and prevalence curves suggested that P. vivax was more transmissible than P. falciparum despite a greater overall burden of infection with P. falciparum. Male gender was associated with increased risk of clinical presentation with either parasite species. Children (< 15 years old) had an increased risk of presenting with P. vivax but not P. falciparum. CONCLUSION: There was a considerable reduction in incidence rates of both P. vivax and P. falciparum over a decade following implementation of a case treatment programme. The concern that intervention methods would inadvertently favour one species over another, or even lead to an increase in one parasite species, does not appear to be fulfilled in this case.

Suppression of Plasmodium falciparum by serum collected from a case of Plasmodium vivax infection.

BACKGROUND: It has frequently been reported that Plasmodium vivax suppressed Plasmodium falciparum and ameliorated disease severity in patients infected with these two species simultaneously. The authors investigate the hypothesis that immunological responses stimulated by P. vivax may play a role in suppressing co-infecting P. falciparum. METHODS: Sera, taken sequentially from one of the authors (YN) during experimental infection with P. vivax, were added to in vitro cultures of P. falciparum. Cross-reactive antibodies against P. falciparum antigens, and cytokines were measured in the sera. RESULTS: Significant growth inhibitory effects upon P. falciparum cultures (maximally 68% inhibition as compared to pre-illness average) were observed in the sera collected during an acute episode. Such inhibitory effects showed a strong positive temporal correlation with cross-reactive antibodies, especially IgM against P. falciparum schizont extract and, to a lesser degree, IgM against Merozoite Surface Protein (MSP)-119. Interleukin (IL)-12 showed the highest temporal correlation with P. vivax parasitaemia and with body temperatures in the volunteer. CONCLUSION: These results suggest the involvement by cross-reactive antibodies, especially IgM, in the interplay between plasmodial species. IL-12 may be one of direct mediators of fever induction by rupturing P. vivax schizonts, at least in some subjects. Future studies, preferably of epidemiological design, to reveal the association between cross-reactive IgM and cross-plasmodial interaction, are warranted.

Efficacy of Artequick versus artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand.

To determine the efficacy, safety and tolerability of an alternative short-course, artemisinin-based combination therapy for acute uncomplicated Plasmodium falciparum malaria, we compared Artequick--a fixed-dosed combination of artemisinin (80 mg), piperaquine (400 mg), and primaquine (4 mg), per tablet--with a standard regimen of artesunate-mefloquine. A total of 130 patients were randomly assigned to treatment with an orally administered, once-daily, 3-day regimen of either Artequick (Group A: 3.2 mg/Kg/day of artemisinin, 16 mg/Kg/day of piperaquine, and 0.16 mg/Kg/day of primaquine) or artesunate-mefloquine (Group B: artesunate, 4 mg/Kg/day, with mefloquine, 8 mg/Kg/day). Patients receiving each regimen had a rapid clinical and parasitological response. All treatments were well tolerated, and no serious adverse effects occurred. No significant differences were found in fever- and parasite-clearance times between the two study groups. The 28-day cure rates were similarly high, at 98.5% and 100%, in groups A and B, respectively. We conclude that Artequick was as effective and well tolerated as artesunate-mefloquine and could be used as an alternative treatment for multidrug-resistant Plasmodium falciparum malaria in Southeast Asia.