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Introduction: While hyperparasitemia is considered an important indicator for the development of severe malaria, there is currently no consensus on the quantitative definition of hyperparasitemia. This study was conducted to establish a cutoff point for peripheral parasitemia among patients with Plasmodium falciparum malaria, to define severe malaria. Methods: The clinical presentations of 200 uncomplicated P. falciparum malaria, and 189 severe P. falciparum malaria, patients, admitted to the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, were analyzed. Results: A peripheral parasitemia of 0.5% was found to be the optimal cutoff point for defining severe malaria, demonstrating highest sensitivity (85.1%), specificity (62.0%), and accuracy (73.2%). Conclusion: Symptoms of severe falciparum malaria depend on many factors. For the definition of hyperparasitemia in areas of low or seasonal transmission, peripheral parasitemia of 0.5% might be considered a cutoff point for discrimination between severity levels. This value might be useful for the clinical management of malaria, particularly in hypo-endemic areas, unstable transmission areas, and other areas with similar transmission patterns. [ABSTRACT FROM AUTHOR]

To ascertain whether mefloquine (MQ) produces electrocardiogram (ECG) changes that could be a risk for Torsades de Pointe (TdP), a potentially malignant, ventricular tachyarrhythmia. 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. 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 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. In this small group of patients, slowing heart rates due to malaria resolution best explained the observed increases in the QTcF intervals. [ABSTRACT FROM AUTHOR]

Background: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax.Methods: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia.Results: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention.Conclusions: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .). [ABSTRACT FROM AUTHOR]

In patients with falciparum malaria, plasma concentrations of cell-derived microparticles correlate with disease severity. Using flow cytometry, we quantified red blood cell-derived microparticles (RMPs) in patients with malaria and identified the source and the factors associated with production. RMP concentrations were increased in patients with Plasmodium falciparum (n = 29; median, 457 RMPs/μL [range, 13-4,342 RMPs/μL]), Plasmodium vivax (n = 5; median, 409 RMPs/μL [range, 281-503/μL]), and Plasmodium malariae (n = 2; median, 163 RMPs/μL [range, 127-200 RMPs/μL]) compared with those in healthy subjects (n = 11; median, 8 RMPs/μL [range, 3-166 RMPs/μL]; P = .01). RMP concentrations were highest in patients with severe falciparum malaria (P = .01). Parasitized red cells produced >10 times more RMPs than did unparasitized cells, but the overall majority of RMPs still derived from uninfected red blood cells (URBCs). In cultures, RMP production increased as the parasites matured. Hemin and parasite products induced RMP production in URBCs, which was inhibited by N-acetylcysteine, suggesting heme-mediated oxidative stress as a pathway for the generation of RMPs. [ABSTRACT FROM AUTHOR]

Chloroquine has been the standard treatment for Plasmodium vivax malaria for more than 40 years in most regions of the world. Recently, however, chloroquine-resistant P. vivax has been reported from Oceania, several parts of Asia, and South America. In order to assess the situation in Thailand, 886 patients with vivax malaria who were admitted to the Bangkok Hospital for Tropical Diseases from 1992 to 1997 were followed prospectively. Most of the patients had been infected on the western border of Thailand and were experiencing their first malarial infection when admitted. All received oral chloroquine (approximately 25 mg base/kg body weight, administered over 3 days) and then were randomized to receive primaquine (15 mg daily for 14 days) or no further treatment. All the patients were initially responsive to chloroquine, clearing their parasitaemias within 7 days, and there were no significant differences in the clinical or parasitological responses between those treated with primaquine and those given no further treatment. Plasmodium vivax parasitaemias re-appeared within 28 days of chloroquine treatment in just four patients. In each of these four cases, re-treatment with the same regimen of chloroquine resulted in eradication of the parasitaemia, with no further appearance of parasitaemia during the next, 28-day, follow-up period. These data indicate that virtually all acute (i.e. blood-stage) P. vivax infections acquired in Thailand can still be successfully treated with chloroquine. [ABSTRACT FROM AUTHOR]

Examines whether the severity of malarial fever affected the excretion of fertile Ascaris eggs in patients co-infected with A. lumbricoides and Plasmodium vivax in Thailand. Eosinophil counts; Maximum axillary temperature of the patients; Hemoglobin concentration.

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-γ and TNF-α 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In concurrent infections in vivo, the blood stages of Plasmodium vivax suppress those of Plasmodium falciparum. To see if the paroxysm (i.e. the periodic febrile episode) of P. vivax infection contributes to this suppression, sera from a P. vivax-infected volunteer were added to cultures of whole blood taken from cases of P. falciparum malaria. The crude 'rate' of schizont generation from the ring forms, measured as the percentage of all asexual parasites that were schizonts after incubation for 24 h, was similar whether the cultures contained serum samples collected during paroxysms or those collected, from the same volunteer, at other times (19.1% v. 18.9%; P=0.842). After a random-effect linear regression was used to adjust for disparities between the P. falciparum isolates, however, the degree of schizont maturation, measured as the mean number of nuclei per schizont, was significantly lower for the cultures with 'paroxysm serum' than for those with 'non-paroxysm serum' (4.8 v. 5.3; P=0.002). The proportion of schizonts considered mature was also significantly lower when 'paroxysm serum' was used (3.7% v. 6.3%: P=0.03). This appears to be the first in-vitro study in which sera collected during a paroxysm of P. vivax have been shown to inhibit the maturation of P. falciparum schizonts. The role of this mechanism in intra- and inter-specific competition is discussed. [ABSTRACT FROM AUTHOR]

Aims The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. Methods In part I of the study three different artemotil dose regimens were explored in three groups of 6–9 patients for dose finding: 3.2 mg kg-1 on day 0 and 1.6 mg kg-1 on days 1–4 (treatment A), 1.6 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1–4 (treatment B), 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1–4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20–22 patients with standard i.m. artemether treatment: 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1–4 (treatment R). Results Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P =0.0408) and for difference C vs R it was 2, 19 h (P =0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil... [ABSTRACT FROM AUTHOR]

The kinetic profiles of soluble chondroitin-sulphate A (CSA), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin were investigated in 17 patients hospitalized with Plasmodium falciparum malaria. The aim was to see if these circulating adhesion molecules could be considered as markers for the severity of P. falciparum malaria. The levels of all the adhesion molecules were found to be higher in the sera from all the malaria cases, both severe and uncomplicated, than in those from uninfected controls. The elevation in plasma CSA, reported for the first time, was statistically very significant (P=0.00001). However, when severe cases were compared with the uncomplicated, there were no significant differences in the level of any of the receptors except ICAM-1, which was highest in those with the severe disease (P=0.01). The absence of any significant correlation between the plasma concentration of CSA and malaria severity indicates that this adhesion molecule could not be used to predict the severity of malaria, although its role in sequestration of the parasites in pregnant women is well established. [ABSTRACT FROM AUTHOR]