Oseltamivir and inhaled zanamivir as influenza prophylaxis in Thai health workers: a randomized, double-blind, placebo-controlled safety trial over 16 weeks.

OBJECTIVES: Long-term chemoprophylaxis using neuraminidase inhibitors may be needed during influenza epidemics but safety data are limited to several weeks. We sought to assess the tolerability of oseltamivir and zanamivir as primary prophylaxis over 16 weeks. METHODS: We conducted a parallel group, double blind, 2 (active drug) :1 (placebo) randomized trial of oral oseltamivir/placebo or inhaled zanamivir/placebo over 16 weeks in healthy, Thai hospital professionals at two Bangkok hospitals. The primary endpoint was study withdrawal due to drug-related (possibly, probably, definitely) serious or adverse events (AEs) graded ≥ 2. RESULTS: Recruited subjects numbered 129 oseltamivir/65 placebo and 131 zanamivir/65 placebo. A total of 102 grade ≥ 2 AEs were reported or detected in 69 subjects: 23/129 (17.8%) versus 15/65 (23.1%) (P=0.26), and 23/131 (17.6%) versus 8/65 (12.3%) (P=0.28). Intercurrent infections/fevers [26/102 (25.5%)], abnormal biochemistry [25/102 (24.5%)] and gastrointestinal symptoms [18/102 (17.6%)] were the most frequently reported AEs. There were no drug-related study withdrawals. Eight serious AEs were all due to intercurrent illnesses. Laboratory, lung function and ECG parameters were similar between drugs and placebos. CONCLUSIONS: Oseltamivir and zanamivir were well tolerated in healthy hospital professionals. Both drugs can be recommended for primary influenza prophylaxis for up to 16 weeks.

Optimizing the culture of Plasmodium falciparum in hollow fiber bioreactors.

The hollow fiber bioreactor (HFBR) is a cell culturing system allowing continuous perfusion of medium. It was designed to grow microorganisms in a dynamically altering medium mimicking change in the in vivo intravascular and extravascular compartments. The cell compartment (extra capillary space) and medium compartment (intra capillary space) are connected through pores of semipermeable fiber membranes. These membranes allow exchange of gas and nutrients. We have adapted this system for the ex vivo culture of Plasmodiumfalciparum at high parasite densities. A Thai P. falciparum isolate (TM036) cultured in RPMI, supplemented with 0.5% Albumax II, could be maintained continuously in the system by daily changes of a small volumes of medium. Under optimized conditions the HFBR cultures attained 8% parasitemia in 40% hematocrit, thereby providing a total parasite biomass of 6.0 x 10(9) parasitized erythrocytes. The main problem encountered was clogging of micropores in the hollow fiber system by cellular debris over time. Although 'reverse flushing' partly prevented this, a larger pore size might be needed to overcome this problem. The system opens new possibilities for the study of in vitro drug sensitivity under conditions mimicking in vivo pharmacokinetics, and the selection of anti-malarial drug resistance and associated parasite biological and genomic changes.

Pharmacokinetics of high-dose oseltamivir in healthy volunteers.

The effects of loading doses and probenecid coadministration on oseltamivir pharmacokinetics at four increasing dose levels in groups of eight healthy adult Thai volunteers (125 individual series) were evaluated. Doses of up to 675 mg were well-tolerated. The pharmacokinetics were dose linear. Oseltamivir phosphate (OS) was rapidly and completely absorbed and converted (median conversion level, 93%) to the active carboxylate metabolite. Median elimination half-lives (and 95% confidence intervals [CI]) were 1.0 h (0.9 to 1.1 h) for OS and 5.1 h (4.7 to 5.7 h) for oseltamivir carboxylate (OC). One subject repeatedly showed markedly reduced OS-to-OC conversion, indicating constitutionally impaired carboxylesterase activity. The coadministration of probenecid resulted in a mean contraction in the apparent volume of distribution of OC of 40% (95% CI, 37 to 44%) and a reduction in the renal elimination of OC of 61% (95% CI, 58 to 62%), thereby increasing the median area under the concentration-time curve (AUC) for OC by 154% (range, 71 to 278%). The AUC increase for OC in saliva was approximately three times less than the AUC increase for OC in plasma. A loading dose 1.25 times the maintenance dose should be given for severe influenza pneumonia. Probenecid coadministration may allow considerable dose saving for oseltamivir, but more information on OC penetration into respiratory secretions is needed to devise appropriate dose regimens.

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.

Migration histories of multidrug-resistant tuberculosis patients from the Thailand-Myanmar border, 2012-2014.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing public health threat in South-East Asia. TB is typically a disease of poverty and can be spread by infectious humans who migrate from one region to another. DESIGN: We interviewed 20 MDR-TB patients on the Thailand-Myanmar border with regard to their migration histories. Migration origins and destinations were mapped. RESULTS: All but one participant had a history of migration, and maps of migration ranges revealed wide geographic dispersal. Most described living and work conditions that could contribute to the spread of drug-resistant TB, including numerous contacts and crowded living quarters. CONCLUSION: Our results show that at least some migrant workers in the region carry MDR-TB, and indicate that this subgroup of the population is important with regard to the transmission of MDR-TB throughout the region. Migrants in this region come into contact with high numbers of people and may be able to spread the disease across wide geographic ranges. Access to diagnosis and treatment and socio-economic development are at least as important as any TB control measures, meaning that innovative and bold approaches that extend across international borders are needed to address these problems.

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)

Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment.

Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P > .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P < .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria.

Glycerol metabolism in severe falciparum malaria.

Gluconeogenesis and liver blood flow (LBF) in severe falciparum malaria were assessed from the clearance and metabolic response to intravenously administered glycerol (0.3 g/kg) and Indocyanine Green ([ICG] 0.4 mg/kg), respectively. Fasting baseline blood glycerol concentrations (mean +/- SD) were significantly higher in acute malaria (133 +/- 65 mumol/L, n = 14), than in convalescence (65 +/- 31 mumol/L, n = 9, P = .01), but basal triacylglycerol concentrations were similar. Estimated glycerol turnover was also more than twice as high in acute malaria compared with convalescence (1.36 +/- 0.87 v 0.54 +/- 0.15 mumol.min-1.kg-1, P = .015). The increment in plasma glucose (AUC0-55 min) following glycerol infusion was greater during acute malaria compared with convalescence (median [range], +31.6 [-0.9 to +107.6] v +14.5 [-103 to +27.1] mmol.min-L-1, P < .05), but the insulin increments were similar (P = .9), indicating reduced tissue insulin sensitivity. The increment in venous lactate (AUC0-55 min) was higher in severely ill patients (17.2 [-7.8 to +53.4] mmol.min.L-1, n = 10) compared with patients with moderately severe malaria (-3.1 [-8.7 to 3.2] mmol.min-L-1, n = 4, P = .01). LBF estimated from ICG clearance was lower during acute illness than in convalescence (mean +/- SD, 15.5 +/- 2.3 v 18.6 +/- 2.9 mL.min-1.kg-1, P = .007) and correlated inversely with the basal venous lactate concentration (rs = .53, P < .05). LBFs less than 15 mL.min-1.kg-1 were associated with hyperlactatemia, and all four fatal cases had LBFs of less than 12 mL.min-1.kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct nephrotoxicity of Russell's viper venom demonstrated in the isolated perfused rat kidney.

Envenoming by Russell's Viper (Vipera russelli) is an important cause of acute renal failure. The mechanism of renal damage is unresolved. It is difficult to obtain evidence of a direct nephrotoxic action because of the coincidental disturbance to the systemic circulation. We studied the action of Russell's Viper venom on the function of the isolated perfused rat kidney. Direct nephrotoxic action was indicated by a dose dependent decrease in inulin clearance and an increase in fractional excretion of sodium seen at venom concentrations down to 50 ng/ml, a concentration likely to be achieved in the human circulation after envenoming. The isolated perfused kidney was also used to assess the efficiency of antivenom and for a comparison with snake venoms from the Thai cobra (Naja kauothia) and the Nigerian Saw-Scaled Viper (Echis ocellatus).

Assessment of the neurotoxicity of parenteral artemisinin derivatives in mice.

In all experimental mammals tested (rats, dogs, primates), intramuscular injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stem centers predominantly involved in auditory processing and vestibular reflexes. Artesunate, the most widely used of these compounds, is a water soluble hemisuccinate derivative given parenterally either by intravenous or intramuscular injection. The neurotoxic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-day regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detected with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. These were reversible in all but one (artemether) mouse. At 100 mg/kg/day, eight of 36 artemether recipients, two of 36 artesunate recipients, and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnormalities of balance and equilibrium, whereas only four artesunate recipients (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence interval) for death or disability was 5.3 (2.6-11.2) for artemether recipients. Intramuscular artemether is significantly more neurotoxic than intramuscular artesunate in this murine model.

Contribution of humoral immunity to the therapeutic response in falciparum malaria.

The contribution of humoral immunity to the therapeutic response in acute falciparum malaria was assessed in a case-control study. Forty adult Thai patients with acute falciparum malaria who had subsequent recrudescent infections and 40 patients matched for age, therapeutic regimen, and disease severity who were cured by Day 28 were studied. All cured patients had positive immunoglobulin (Ig) G to ring-infected erythrocyte surface antigen (RESA) in their admission plasma, compared with only 60% of patients who failed to respond to treatment (P < 0.001). The proportion of IgM-positive cases at admission was also higher in the successfully treated group than in the group with failure (70% versus 30%) (P < 0.001). The geometric mean (95% confidence interval) reciprocal IgG titer at admission was significantly higher in cured patients (187.0 [83.5-418.3]) compared with those who experienced treatment failure (11.6 [5.1-26.5]) (P < 0.001). The patients with uncomplicated malaria who were both IgG and IgM positive at admission had significantly shorter fever clearance times and lower admission parasitemia levels compared with those who were negative (P = 0.01 and P = 0.02, respectively). The median (range) in vitro parasite multiplication rate was significantly lower in cultures containing positive anti-RESA antibody plasma compared with those containing normal plasma (0.7 [0.1-3.5] versus 2.6 [0.1-12.1]; P < 0.001). These results suggest that antimalarial antibodies may play an important supportive role in the therapeutic response to antimalarial drugs during acute falciparum malaria.

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.

Characteristics of Plasmodium vivax-infected erythrocyte rosettes.

To investigate the rosette formation properties of Plasmodium vivax, blood was sampled from 26 adult Thai patients admitted with acute P. vivax malaria and a predominance of trophozoite and schizont stages in their peripheral blood smears. In each case, P. vivax-infected cells formed spontaneous rosettes with two or more uninfected red blood cells. Rosette formation of P. vivax was dependent on the divalent cations (Ca2+/Mg2+) and was highly sensitive to trypsin and heparin, but, unlike P. falciparum, rosettes of P. vivax did not reform after removal of heparin. Plasma taken from patients with either acute uncomplicated P. falciparum or P. vivax malaria reversed rosette formation of all P. vivax isolates whereas plasma from uninfected controls had no effect. There was a small but significant increase in rosette-reversing activity in plasma taken during the convalescent period (P < 0.001). The increment in reversal activity was significantly greater in plasma taken following recovery from P. vivax malaria compared with P. falciparum malaria. This suggests that P. vivax rosette reversal activity is antibody mediated and has both species-specific and cross-species components.

Rosette formation by Plasmodium vivax.

In contrast to Plasmodium falciparum, infections with P. vivax are seldom fatal. Red blood cells containing mature forms of P. falciparum sequester in the microvasculature of vital organs, and adhere to vascular endothelium (cytoadherence) and to uninfected red cells (rosetting). Rosetting of P. falciparum has been associated with the lethal syndrome of cerebral malaria. We have studied the rosetting properties of red blood cells infected with P. vivax obtained from adults with acute malaria in Thailand. Of 35 parasite isolates studied, 25 (71%) showed rosetting with a mean proportion of 41% of infected red cells (SD 34%, range 14-100%). Rosetting of P. vivax was related to maturation of the parasite; only cells containing parasites with visible malaria pigment rosetted. Rosetting and parasitaemia were not correlated. However, unlike P. falciparum, cells infected with P. vivax did not adhere to human umbilical vein endothelial cells, to C32 melanoma cells, to platelets, or to purified adhesion receptor molecule CD36. These findings suggest that thrombocytopenia in vivax malaria is not related to platelet-red cell attachment, and that rosetting alone is insufficient to cause the syndrome of cerebral malaria.

Persistence of Plasmodium falciparum HRP-2 in successfully treated acute falciparum malaria.

The potential for Plasmodium falciparum histidine-rich protein-2 (PfHRP-2) dipstick tests to predict antimalarial treatment failure was investigated in a prospective study in Thailand of 38 patients admitted with severe malaria and 54 hospitalized with uncomplicated P. falciparum infections. Of these, 40 had subsequent recrudescence of their infections. Overall, 89% of patients with severe malaria and 61% of patients with uncomplicated malaria had positive PfHRP-2 dipstick tests for > 2 weeks following the start of treatment. Persistence was correlated positively with admission parasite counts, PfHRP-2 intensity scores and disease severity. PfHRP-2 tests which remained positive for > 2 weeks and PfHRP-2 reactive intensity scores on admission, at day 7 and day 14 did not predict treatment failure independent of admission parasitaemia. Freezing and thawing the blood samples did not significantly affect PfHRP-2 results tested by the dipstick technique. The PfHRP-2 dipstick test provides a useful indicator of recent severe malaria, but does not predict the therapeutic response.

Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand.

Between 1981 and 1992, 196 Thai adults with severe falciparum malaria were treated with a quinine loading dose regimen. Nineteen patients died (10%) and 6 developed late hypoglycaemia. There was no serious cardiovascular or nervous system toxicity. Although there was no evidence of high grade resistance, and no change in the mortality rate, in recent years an increasing proportion of patients had a delayed clinical and parasitological response to treatment. Since 1988, 78% (29/37) of patients with cerebral malaria were unconscious for > 72 h compared with 41% (11/27) between 1981 and 1987 (P = 0.002). In the past 2 years parasite clearance times have exceeded 96 h in 33% (26/78) of patients compared with 14% (15/102) previously (P = 0.006). Quinine remains an effective treatment for severe multi-drug resistant falciparum malaria in this area, but there is now evidence of a decline in the immediate therapeutic response, and its efficacy will need close monitoring as resistance increases further.

Polymorphonuclear leucocyte elastase in Plasmodium falciparum malaria.

Sixty-one patients with falciparum malaria were studied prospectively to determine the plasma concentrations of the lysosomal proteinase, polymorphonuclear leucocyte elastase (PMN-elastase) and their relationship to disease severity. The patients were divided into 3 groups; severe (parasitaemia > 5%) or vital organ dysfunction (n = 23), moderate (parasitaemia 1%-5% without complications) (n = 15), and mild (parasitaemia < 1%) (n = 23). The mean plasma PMN-elastase level in 10 healthy Thai volunteers was 49.5 (SD = 21.6) ng/ml (range 33-65 ng/ml). Plasma PMN-elastase concentrations on admission were elevated (> 2 x SD above normal) in all patients with severe malaria and were above 100 ng/ml in 86.6% and 65% of the moderately severe and mild patients respectively. PMN-elastase levels during the first 3 hospital days were significantly higher in severe malaria compared with the other 2 groups (P = < 0.001-0.013). The levels decreased as the patients became afebrile and aparasitaemic. Admission plasma concentrations of PMN-elastase correlated directly with bilirubin (rs = 0.50, P < 0.001), serum glutamic oxalacetic transaminase (rs = 0.54, P0.001), parasite count (rs = 0.62, P < 0.001), blood urea nitrogen (rs = 0.54, P < 0.001) and inversely with antithrombin III activity (rs = 0.54, P < 0.001) and the platelet count (rs = 0.58, P < 0.001). Polymorphonuclear leucocyte activation may contribute to the pathogenesis of severe malaria.

Synergy of antithrombin III concentrate and antivenom in preventing coagulopathy in a rat model of Malayan pit viper envenoming.

The effects of unrefined equine antivenom and antithrombin III (AT-III) concentrate on the coagulopathy induced by systemic envenomation by Malayan pit viper (Calloselasma rhodostoma; MPV) venom were investigated in a rat model. 37 rats received an intramuscular injection of MPV venom and serial blood samples were taken from the femoral vein for simple whole blood clotting tests and measurement of AT-III activity. 30 min after venom injection, treatment (antivenom, AT-III or both) was given intravenously. 6 rats were untreated and all developed uncoagulable blood and AT-III depletion 90-210 (median 180) min after venom injection. A combination of high dose AT-III concentrate (0.5 units/g) and antivenom (20 micrograms/g) prevented abnormal clotting (P less than 0.001), whereas AT-III alone, antivenom alone, or a combination of low dose AT-III (0.25 units/g) and antivenom did not (P less than 0.05). These results suggest that the coagulation abnormality in MPV envenomation is secondary to activation of the coagulation cascade at several levels, and that treatment with antivenom alone may not be sufficient to reverse or prevent this phenomenon.

Fever in uncomplicated Plasmodium falciparum malaria: randomized double-'blind' comparison of ibuprofen and paracetamol treatment.

Fever almost invariably accompanies uncomplicated falciparum malaria. In a randomized, double-'blind' study, we compared a single dose of ibuprofen (10 mg/kg, n = 8) with paracetamol (15 mg/kg, n = 8) for the treatment of fever > 38.5 degrees C due to uncomplicated falciparum malaria. Ibuprofen was significantly more effective than paracetamol in lowering temperatures throughout the first 4.5 h after dosing (P = 0.016) and should be considered as an antipyretic agent in the management of uncomplicated falciparum infections, providing there is no contraindication to its use.

The effect of plasma free fatty acids and long-chain triglycerides on glucose metabolism in uncomplicated falciparum malaria.

To investigate the therapeutic potential of increased plasma free fatty acid (FFA) and triglyceride concentrations in hypoglycaemic patients receiving quinine, 32 untreated Thai adults with uncomplicated falciparum malaria were allocated at random to one of 4 regimens: 2 mg/kg/min dextrose infused over 60 min either alone (group A) or with a prior injection of 5000 units of heparin and simultaneous Intralipid infusion (group C), or 4 min/kg/min dextrose alone (group B) or with heparin and Intralipid (group D). Quinine (10 mg/kg) was also infused over 60 min in all cases. In patients of groups A and C, mean changes in plasma glucose concentrations from the beginning to the end of the infusion were 0.1 (SD 0.8) and 1.0 (SD 0.7) mmol/L respectively (P = 0.015). In groups B and D, plasma glucose increased by 1.8 (SD 1.2) and 2.2 (SD 0.4) mmol/L respectively (P < 0.5). Plasma FFA levels fell by approximately 50% during the infusion in groups A and B but increased by a similar percentage in groups C and D. Despite significant mean increases in plasma insulin during the infusion (from 12.2 milliunits (mu)/L in group A to 38.8 mu/L in group D), no rebound hypoglycaemia was observed in any patient during the ensuing 7 h. These data suggest that the glycaemic response to dextrose given at high rates, which match average glucose utilization in a severely ill patient with malaria, is not augmented by increased plasma FFA and long-chain triglycerides. However, this strategy increases the glycaemic efficacy of lower dextrose infusion rates and the combination could, therefore, reduce the volumes of hypertonic dextrose required to prevent hypoglycaemia in severely ill patients in whom optimal fluid balance is crucial.