Effect of artesunate and mefloquine in combination on the Fridericia corrected QT intervals in Plasmodium falciparum infected adults from Thailand.

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.

New fixed-dose artesunate-mefloquine formulation against multidrug-resistant Plasmodium falciparum in adults: a comparative phase IIb safety and pharmacokinetic study with standard-dose nonfixed artesunate plus mefloquine.

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 < or = 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P < or = 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.

Erythrocyte sequestration and anemia in severe falciparum malaria. Analysis of acute changes in venous hematocrit using a simple mathematical model.

Microvascular erythrocyte sequestration, the characteristic pathological feature of falciparum malaria, was evaluated using a mathematical model in 46 patients with severe infections. From admission radioisotopic circulating red cell volumes and simultaneous venous hematocrits, the model-derived sequestrum hematocrit (mean [95% confidence limits]: 0.70 [0.43-0.97], n = 29) was twice that of peripheral blood (0.33 [0.30-0.36]). Serial reticulocyte and radiolabeled erythrocyte counts indicated that small numbers of cells enter the circulation during initial therapy. The mean fall in hematocrit over 84 h in 26 nontransfused patients conformed to a three-term equation. A first-order decline (t1/2 2.0 h [0.6-3.4]) suggested an average 7.5% plasma volume expansion through rehydration. A zero-order 6.3% (3.1-9.5) fall (t1/2 25.7 h [21.2-30.2]) occurred contemporaneously with a fall in mean parasitemia from 4.5% (3.6-5.4); from these data the model-derived average sequestered erythrocyte volume (4.8% of the admission hematocrit) was similar to the peripheral parasite burden. A second, first-order fall (t1/2 1,047 h [278-1,816]) indicated loss of uninfected erythrocytes with mean lifespan 62 d. Predicted total plasma volume expansion during initial therapy (21.2%) was similar to radioisotopic estimates in 11 patients (17.3% [2.0-33.1]). Application of the model to individual patient data showed wide variations in relative proportions of circulating and sequestered parasitized cells. The model provides evidence of the nature and fate of all parasitized erythrocytes in malaria.

The use of the multi-organ-dysfunction score to discriminate different levels of severity in severe and complicated Plasmodium falciparum malaria.

Clinical presentation of Plasmodium falciparum malaria reflects a continuum from asymptomatic to multi-organ manifestation and death. Severe malaria is defined by the World Health Organization as a qualitative variable. We used the multi-organ dysfunction score (MODS) as a quantitative approach for severity in 29 patients with severe and complicated P. falciparum malaria to test its usefulness in discriminating different severity levels. The MODS on admission was highly correlated with the duration of symptoms after admission (r = 0.73, P < 0.001) and the serum level of tumor necrosis factor alpha (r = 0.41, P = 0.03). In addition, the simplified MODS, based mainly on clinical findings, was also correlated with liver and renal dysfunction during hospitalization (alanine transaminase, r = 0.42, P = 0.02; blood urea nitrogen, r = 0.45, P = 0.015). A score >or= 16 was associated with significantly longer disease duration (P = 0.018). Thus, this score might provide a predictive value for morbidity in P. falciparum malaria.

Curdlan sulphate in human severe/cerebral Plasmodium falciparum malaria.

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.

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.

An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria.

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.

Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum.

The emergence and spread of multidrug-resistant Plasmodium falciparum compromises the treatment of malaria, especially during pregnancy, where the choice of antimalarials is already limited. Artesunate (n=528) or artemether (n=11) was used to treat 539 episodes of acute P. falciparum malaria in 461 pregnant women, including 44 first-trimester episodes. Most patients (310 [57.5%]) received re-treatments after earlier treatment with quinine or mefloquine. By use of survival analysis, the cumulative artemisinin failure rate for primary infections was 6.6% (95% confidence interval, 1.0-12.3), compared with the re-treatment failure rate of 21.7% (95% confidence interval, 15.4-28.0; P=.004). The artemisinins were well tolerated with no evidence of adverse effects. Birth outcomes did not differ significantly to community rates for abortion, stillbirth, congenital abnormality, and mean gestation at delivery. These results are reassuring, but further information about the safety of these valuable antimalarials in pregnancy is needed.

Case-control studies on host factors in severe malaria.

Although molecular biology has illustrated the phenotypic heterogeneity of Plasmodium falciparum, there are still no specific markers of virulence. As parasite virulence is an important determinant of severe malaria, the choice of comparison groups in the study of host factors influencing severity is a delicate issue. Ignoring parasite factors in the selection of controls potentially leads to biased comparisons between a majority of cases with virulent parasites and a majority of controls with non-virulent parasites. This article discusses how to avoid this virulence bias in the absence of specific markers of virulence.

Population pharmacokinetics of mefloquine in patients with acute falciparum malaria.

OBJECTIVE: To construct a population pharmacokinetic model for mefloquine in the treatment of falciparum malaria. BACKGROUND: Mefloquine is the treatment of choice for multidrug-resistant falciparum malaria. The factors that influence the pharmacokinetic properties of mefloquine in acute malaria are not well characterized. METHODS: The pharmacokinetic properties of mefloquine were evaluated in 257 patients with acute falciparum malaria by use of nonlinear mixed-effects modeling. Two different oral dose regimens were used: (1) a split dose of 15 mg base/kg initially followed by 10 mg/kg 24 hours later (n = 159) and (2) a single dose of 25 mg/kg (n = 98). Mefloquine was combined with artesunate in 105 (41%) patients (74 received a split dose and 31 received a single dose). RESULTS: Splitting the mefloquine dose increased the area under the concentration-time curve [AUC(0-infinity)] by 50% (95% confidence interval [CI], 36% to 65%) for monotherapy and by 20% (95% CI, 3% to 40%) for combined therapy. The apparent volume of distribution (V/F) was significantly lower in patients receiving split doses of mefloquine monotherapy (mean, 8.14 L/kg; 95% CI, 7.49 to 8.86 L/kg) compared with a single dose (mean, 20.37 L/kg; 95% CI, 16.26 to 25.51 L/kg). Patients who received mefloquine monotherapy and cleared parasitemia in less than 48 hours had a significantly higher AUC(0-infinity) independent of any confounders, compared with patients with slower parasite clearance (geometric mean [95% CI], 50,373 ng/mL x day [46,121 to 55,017 ng/mL x day] versus 45,583 ng/mL x day [42,306 to 49,125 ng/mL x day]). CONCLUSIONS: The pharmacokinetic properties of mefloquine in malaria were relatively unaffected by demographic variables (other than body weight) or disease severity. If it is assumed that apparent clearance and volume of distribution are unaffected by dose regimen, then splitting the 25 mg/kg mefloquine dose improves oral bioavailability and the therapeutic response in the treatment of acute falciparum malaria.

Quinine pharmacokinetics and toxicity in cerebral and uncomplicated Falciparum malaria.

Acute pharmacokinetics of intravenously infused quinine were studied in 25 patients with cerebral malaria and 13 with uncomplicated falciparum malaria. In patients with cerebral malaria receiving the standard dose of 10 mg/kg every eight hours, plasma quinine concentrations consistently exceeded 10 mg/liter, reaching a peak 60 +/- 25 hours (mean +/- 1 S.D.) after treatment was begun and then declining. Quinine total clearances (Cl) and total apparent volumes of distribution (Vd) were significantly lower than in uncomplicated malaria (Cl, 0.92 +/- 0.42 compared with 1.35 +/- 0.6 ml/min/kg, p = 0.03; Vd, 1.18 +/- 0.37 compared with 1.67 +/- 0.34 liter/kg, p = 0.0013). There was no significant difference between the two groups in elimination half-times (t/2) or renal clearances (Cu) (t/2, 18.2 +/- 9.7 compared with 16 +/- 7.0 hours; Cu, 0.21 +/- 0.16 compared with 0.21 +/- 0.08 ml/min/kg). In nine patients studied following recovery, Cl (3.09 +/- 1.18 ml/min), Vd (2.74 +/- 0.47 liter/kg), and Cu (0.53 +/- 0.22 ml/min/kg) were significantly greater (p less than or equal to 0.0004), and t/2 was significantly shorter (11.1 +/- 4.1 hours, p = 0.006) than during the acute illness. Cu accounted for approximately 20 percent of Cl in all groups. Renal failure did not alter the disposition kinetics in cerebral malaria. There was no clinical or electrocardiographic evidence of cardiotoxicity and no permanent neurotoxicity. Quinine toxicity in cerebral malaria has probably been overemphasized. The benefits of high plasma concentrations in the acute phase of this life-threatening disease appear to outweigh the risks, particularly in view of the increasing resistance of Plasmodium falciparum to quinine in Southeast Asia.

Plasma macrophage colony-stimulating factor and P-selectin levels in malaria-associated thrombocytopenia.

Thrombocytopenia is a common finding in malaria. In clinical trials, recombinant macrophage colony-stimulating factor (M-CSF) causes a reversible, dose-dependent thrombocytopenia, and high M-CSF has been reported in autoimmune thrombocytopenias. P-selectin, which is secreted into the plasma following platelet/endothelial activation or damage, is elevated in certain consumptive thrombocytopenic disorders. The relationships between thrombocytopenia, M-CSF and P-selectin were analysed in 63 patients with severe (n = 13) or uncomplicated (n = 26) P. falciparum (PF) or P. vivax (PV) malaria (n = 24). On admission, 69% of PF patients and 75% of PV patients were thrombocytopenic (platelets < 150 x 10(9)/l). M-CSF was elevated in PF (3021 +/- 1844 pg/ml) and PV (2602 +/- 1668 pg/ml) patients, compared to controls (589 +/- 200 pg/ml). The platelet count was inversely correlated with M-CSF in PF (r = -0.681), and in PV malaria (r = -0.548). Elevated P-selectin was found in severe PF malaria, but not in PV malaria. Severe PF malaria was associated with marked thrombocytopenia, very high M-CSF, elevated P-selectin and compelling evidence of disseminated intravascular coagulopathy (DIC). Platelet counts, M-CSF and P-selectin returned to control values in 7-14 days. These data suggest that elevated M-CSF in malaria, by enhancing macrophage activity, may result in increased macrophage-mediated platelet destruction. Further, platelet/endothelial activation or damage, as measured by P-selectin, or DIC could intensify thrombocytopenia in severe PF malaria, but does not appear to contribute to thrombocytopenia in uncomplicated PF or PV malaria.

Human cerebral malaria in Thailand: a clinico-pathological correlation.

Based on the cerebral malaria coma scale, 39 falciparum malaria autopsy cases from the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand were divided into two groups of patients that had either cerebral malaria or non-cerebral malaria. We then studied significant pathological differences, such as parasitized erythrocyte (PRBC) sequestration, ring hemorrhages and cerebral edema, between these two groups in order to investigate the correlation between the clinical coma scale and pathological findings. Patients with a coma grade of 2 and higher were designated as having cerebral malaria, and had erythrocyte PRBC sequestration in cerebral microvessels. Ninety four percent (94%) of cerebral microvessels showed PRBC sequestration when quantitatively analyzed. On the other hand, only 13% of cerebral microvessels showed sequestration in non-cerebral malaria patients with a coma grade of 1 and lower, although some degree of PRBC sequestration was found in 50% of these patients. Our study, therefore, clearly demonstrated that the degree of the PRBC sequestration in cerebral microvessels appeared to correlate closely with the clinical coma scale.

A comparison of three different dihydroartemisinin formulations for the treatment of acute uncomplicated falciparum malaria in Thailand.

We compared the safety and efficacy of three formulations of dihydroartemisinin for the treatment of acute uncomplicated falciparum malaria in patients who received a total dose of 600 mg dihydroartemisinin over 5 days. The first group was treated by dihydroartemisinin produced and formulated in the People's Republic of China, the second group was treated by dihydroartemisinin produced in Vietnam but formulated by the Government Pharmaceutical Organization of Thailand and the third group was treated by dihydroartemisinin produced and formulated by the Government Pharmaceutical Organization of Thailand. All patients were admitted to hospital to evaluate safety and efficacy for a total of 28 days. By the third day of treatment, most patients were blood-smear negative for parasites and none had serious adverse effects. Minor symptoms such as nausea, dizziness and headache were similar in the three groups and disappeared after 3 days of treatment. One-hundred and thirty-three patients completed the 28-day follow-up period. The cure rates of groups I, II and III were 80%, 85% and 92%, respectively (P > 0.02). There were no significant differences in fever clearance or parasite clearance among the three groups. We conclude that the three formulations of dihydroartemisinin produced and formulated in different countries were safe and effective in treating uncomplicated falciparum malaria acquired in Thailand.

Serum laminin in malaria.

AIM: To determine serum laminin concentrations in patients with uncomplicated Plasmodium falciparum malaria. METHODS: An enzyme linked immunosorbent assay (ELISA) was used to determine serum laminin concentrations in 54 patients with acute uncomplicated P falciparum malaria during and after treatment, and in 17 control subjects in Bangkok, Thailand. RESULTS: Raised concentrations of soluble laminin were observed in patients (mean (SD) concentration 628 (225) ng/ml), compared with normal controls (490 (116) ng/ml), during the acute phase of the disease. During treatment, serum laminin concentrations decreased and returned to normal within three days. Serum laminin concentrations were correlated with parasite counts before treatment, and with the serum concentration of soluble intercellular adhesion molecule-1 (ICAM-1), soluble E-selectin, and soluble tumour necrosis factor receptor at 55 kilodaltons. CONCLUSIONS: These findings are compatible with an increased production or release of laminin in P falciparum malaria, which could indicate a role for the subendothelial basement membrane in the pathogenesis of the disease.

Glucose turnover in severe falciparum malaria.

To investigate glucose metabolism in acute falciparum malaria, [3-3H]glucose turnover was measured in 18 normoglycemic adult Thais (eight males, 10 females; median age, 28 years) with severe infections. Eleven patients were studied before quinine treatment, 15 while receiving quinine, and 10 during convalescence. In paired studies conducted before and after initial intravenous quinine, plasma glucose level decreased from a median (95% confidence limits) of 5.5 (3.0 to 6.6) to 4.6 (2.5 to 6.1) mmol/L (P < or = .027, n = 8), and plasma insulin level increased 9.3 (-3.2 to 30.0) mU/L (P = .02). Glucose turnover decreased during the 4-hour quinine infusion from 3.04 (2.12 to 4.23) to 1.89 (1.20 to 2.54) mg/kg.min-1 (P < .004), as did the metabolic clearance rate for glucose (2.87 [1.88 to 7.83] to 2.50 [1.43 to 4.55) mL/kg.min-1; P = .008). Glucose turnover and clearance measured both after initial quinine treatment and in convalescence were similar (P = .234 and .344, respectively; n = 7). In the series as a whole, there was an inverse association between pretreatment turnover and the simultaneous plasma glucose level (rs = -.76, P < .01; n = 11), a stronger inverse relationship between glucose clearance and plasma glucose level (rs = -.88, P < .001), and a positive association between pretreatment turnover and oral temperature (rs = .65, P < .025; n = 10). These data suggest that, as in other severe illnesses, glucose turnover is high in untreated patients, but that glycolysis by mature parasite forms may accelerate glucose disposal.(ABSTRACT TRUNCATED AT 250 WORDS)

Red cell quinine concentrations in falciparum malaria.

Red cell concentrations of quinine were measured in cerebral malaria and in uncomplicated falciparum malaria both in the acute stage and 1 month after recovery. Red cell quinine elimination half times were significantly shorter than the corresponding plasma half times in cerebral malaria and convalescent uncomplicated cases (P less than 0.001), but not in acute uncomplicated cases (P = 0.12). The ratio of red cell:plasma concentration fell progressively from the 2nd day (0.49) to the 6th day (0.26) of treatment. On admission this ratio was positively correlated with the blood parasite count (P = 0.02). Red cell quinine concentration may be relevant to the assessment of drug resistance, and to the design of treatment regimens.

Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group.

The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was > 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.

Binding of quinine to plasma proteins in falciparum malaria.

Plasma protein binding of quinine was measured in 12 patients with cerebral malaria on the first and seventh day of treatment, and in 7 patients with uncomplicated falciparum malaria on admission and also one month later. Binding was significantly higher and therefore the proportion of free drug was lower in cerebral malaria patients (free: total quinine concentration; 7.2 +/- 3.5%, mean +/- SD, on admission; 7.4 +/- 5.3% on day 7) compared with uncomplicated malaria patients on admission (10.2 +/- 5.8%) or following recovery (11.0 +/- 5.5%, n = 6) P = 0.011. Binding was significantly correlated with the red cell/total concentration ratio r = 0.56, P less than 0.0001. The ratio of cerebrospinal fluid to free (unbound) plasma quinine was 0.55 +/- 0.33 which suggests that quinine does not freely cross the blood brain barrier. These findings are relevant to the interpretation of total plasma or serum concentration, and may explain the rarity of serious quinine toxicity in severe falciparum malaria.

IgE deposition in brain microvessels and on parasitized erythrocytes from cerebral malaria patients.

Postmortem brain tissues of 21 cerebral malaria cases were obtained in Myanmar and Vietnam. The tissues were examined by light microscopy and by an immunohistochemical method. Brain microvessels (capillaries and venules) were examined for the presence of immunoglobulins IgE and IgG, Plasmodium falciparum antigen, and parasitized erythrocytes (PRBC). Deposition of IgE, IgG, and P. falciparum antigen was observed in the microvessels from all specimens examined. Sequestered PRBC in the microvessels were positive for IgG in all 21 cases and for IgE in six cases. In the latter cases, the percentage of microvessels with sequestered PRBC was > 50%, with the frequency of IgE-positive cells ranging from 42% to 52%. In contrast, in five cases that were only weakly positive for IgE, the percentage of microvessels with sequestered PRBC was remarkably low (< 1%). These data indicate that the degree of deposition of IgE in microvessels and on PRBC from cerebral malaria patients correlated with that of PRBC sequestration. As IgE-containing immune complexes are known to induce local overproduction of tumor necrosis factor-alpha (TNF-alpha), a major pathogenic factor in cerebral malaria, IgE may contribute to the pathogenesis of this severe disease.