Abstract. In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral artemisinin derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an artemisinin derivative were associated with more side effects than those with an artemisinin derivative alone; acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P Ͻ 0.001). Oral artesunate and artemether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs.
Dengue shock syndrome is a severe complication of dengue hemorrhagic fever (DHF), characterized by a massive increase in vascular permeability. Plasma cytokine concentrations were prospectively studied in 443 Vietnamese children with DHF, of whom 6 died. Shock was present in 188 children on admission to hospital, and in 71 children it developed later. Contrary to expectations, certain inflammatory markers (interleukin-6 and soluble intercellular adhesion molecule-1) were lower in the group with shock, and this may reflect the general loss of protein from the circulation due to capillary leakage. Only soluble tumor necrosis factor receptor (TNFR) levels showed a consistent positive relationship with disease severity. In patients with suspected DHF without shock, admission levels of sTNFR-75 in excess of 55 pg/mL predicted the subsequent development of shock, with a relative risk of 5.5 (95% confidence interval, 2.3-13.2). Large-scale release of soluble TNFR may be an early and specific marker of the endothelial changes that cause dengue shock syndrome.
Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.
The efficacy and safety of the 6-dose regimen of artemether-lumefantrine were assessed in an open randomized trial in children and adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand between November 1997 and March 1998. 200 patients were enrolled in 2 centres: 150 received artemether-lumefantrine (i.e., a median total dose of 9.6 mg/kg [interquartile range 8.7-10.7] and 57.9 mg/kg of lumefantrine [52.4-64.0]) and 50 the standard combination of artesunate (12 mg/kg over 3 d) and mefloquine (25 mg/kg). All patients had rapid initial clinical and parasitological responses. The 28 d cure rates were high: 97.7% (95% confidence interval [95% CI] 93.5-99.5%) for artemether-lumefantrine and 100% (95% CI 92.5-100%) for artesunate-mefloquine. The 6-dose regimen of artemether-lumefantrine was better tolerated than, and as effective as, artesunate-mefloquine, the current standard treatment in this area of multidrug-resistant P. falciparum malaria.
Western North America has an average elevation that is ∼2 km higher than cratonic North America. This difference coincides with a westward decrease in average lithospheric thickness from ∼240 to <100 km. Tomographic models show that slow shear wave velocity anomalies lie beneath this region, coinciding with the pattern of basaltic magmatism. To investigate relationships between magmatism, shear wave velocity, and temperature, we analyzed a suite of >260 basaltic samples. Forward and inverse modeling of carefully selected major, trace, and rare earth elements were used to determine melt fraction as a function of depth. Basaltic melt appears to have been generated by adiabatic decompression of dry peridotite with asthenospheric potential temperatures of 1340 ± 20 °C. Potential temperatures as high as 1365 °C were obtained for the Snake River Plain. For the youngest (i.e., <5 Ma) basalts with a subplate geochemical signature, there is a positive correlation between shear wave velocities and trace element ratios such as La/Yb. The significance of this correlation is explored by converting shear wave velocity into temperature using a global empirical parameterization. Calculated temperatures agree with those determined by inverse modeling of rare earth elements. We propose that regional epeirogenic uplift of western North America is principally maintained by widespread asthenospheric temperature anomalies lying beneath a lithospheric plate, which is considerably thinner than it was in Late Cretaceous times. Our proposal accounts for the distribution and composition of basaltic magmatism and is consistent with regional heat flow anomalies.
1 The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg‐1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.‐ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA). 2 Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l‐1 and for DHA of 1009 (639 to 1379) nmol l‐1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half‐life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.‐ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3 Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC(0,6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4 These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.
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.
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