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Biomedical subjects

N J White

Publications and source records attributed to N J White.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of artemether and chloroquine for severe malaria in Gambian children.

Artemether is an oil-soluble methyl ether of artemesinin (qinghaosu). It has been studied extensively in China, where it has been shown to be rapidly effective in severe falciparum malaria. Nearly all the patients studied previously were adults. We have investigated the efficacy of artemether in children with moderate or severe falciparum malaria. In the preliminary study of moderately severe malaria, 30 Gambian children were randomised in pairs to receive either intramuscular artemether (4 mg/kg loading dose followed by 2 mg/kg daily) or intramuscular chloroquine ('Nivaquine') 3.5 mg base/kg every 6 h. Both drugs were well tolerated and rapidly effective. The times to parasite clearance were significantly shorter in the artemether recipients (mean 36.7 [SD 11.3] vs 48.4 [16.8] h, p less than 0.05). 43 children with severe malaria were then randomised to receive intramuscular treatment with the same regimens of artemether (n = 21) or chloroquine (n = 22) as used in the preliminary study. 8 children (19%) died. There were no significant differences between the two groups in the clinical, haematological, biochemical, or parasitological measures of therapeutic response in survivors and there was no evidence of local or systemic toxicity. Despite similar parasite counts on admission, clearance times overall were longer in severe malaria than in moderate malaria. Artemether is a well tolerated and rapidly effective parenteral treatment for severe malaria in children, and would be especially valuable in areas with chloroquine-resistant P falciparum.

Animals↗
PubMed1992

Absorption of intramuscular phenobarbitone in children with severe falciparum malaria.

The absorption of intramuscular phenobarbitone 7 mg.kg-1 was studied in 11 Karen children aged between 1.7 and 11 y with severe falciparum malaria. Eight of the children were comatose. Clinical findings were compared with those in 9 further children with severe malaria of similar age range (four of whom were unconscious), who received an identical placebo. One child, who had received placebo, had repeated convulsions and died 1 h after admission to hospital. The remainder made an uncomplicated recovery. There were no convulsions subsequent to treatment, although the study was too small to assess anticonvulsant efficacy. There was no observable toxicity, but phenobarbitone recipients had a significant tendency to deepen in their level of coma or to become sleepy within the 4 h after drug administration. Phenobarbitone was rapidly absorbed, reaching a mean (range) peak concentration of 34.2 [29.3-42.6] mumol.l-1 in a median (range) of 4 (2.5-12) h. These values are comparable to those previously reported in healthy children and in children with febrile convulsions. Intramuscular phenobarbitone is well absorbed in children with severe malaria; the optimum prophylactic anticonvulsant dose remains to be determined.

Absorption↗
PubMed1992

Hepatic blood flow and metabolism in severe falciparum malaria: clearance of intravenously administered galactose.

1. Hypoglycaemia and lactic acidosis are important manifestations of severe falciparum malaria. To investigate hepatic gluconeogenesis in acute falciparum malaria, liver blood flow and galactose clearance were estimated in seven adult patients with moderately severe infection and seven patients with severe infection (three of whom died later). Nine patients were restudied in convalescence. 2. Liver blood flow, determined from the plasma clearance of Indocyanine Green, was lower in acute illness than in convalescence [16.1 (7.0) versus 23.9 (7.2) ml min-1 kg-1, mean (SD)], but this difference was not statistically significant (P = 0.15). There was a significant inverse correlation between admission venous plasma lactate concentrations and the liver blood flow estimated from the clearance of Indocyanine Green (rs = 0.71, P = 0.004). 3. The plasma clearance of galactose after intravenous injection was similar in the acute [15.4 (4.90) ml min-1 kg-1] and convalescent study [12.8 (2.1) ml min-1 kg-1]. The ratio of galactose clearance to Indocyanine Green clearance was significantly higher in acute disease [1.41 (0.51)] than in convalescence [0.70 (0.34)], largely because of the elevated ratios in severely ill patients [1.48 (0.50)]. 4. The rise in blood glucose concentration after galactose administration was significantly higher during acute illness [1.48 (0.72) mmol/l] than in convalescence [0.67 (0.41) mmol/l, P = 0.022], but the insulin response was similar, indicating reduced tissue insulin sensitivity. There was no significant change in the plasma concentrations of other metabolites (lactate, pyruvate, alanine and triacylglycerol) in either study. 5. These results suggest that the segment of the glycolytic pathway between galactose and glucose is unimpaired in patients with severe falciparum malaria.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1992

Acute renal failure in patients with severe falciparum malaria.

Since 1988 in this referral center for severe cases of malaria for South Vietnam, a specialist team has managed malaria-associated renal failure (MARF) with peritoneal dialysis, and the mortality rate of MARF has fallen from 75% (78 of 104) to 26% (27 of 104) (P < .0002). Sixty-four patients with MARF (of whom 12 died) were compared to 66 patients with severe malaria whose serum creatinine levels remained < 250 mumol/L (six died). MARF had the clinical and biochemical features of acute tubular necrosis and was significantly associated with liver dysfunction (P < .05). A fatal outcome was associated significantly with anuria, a short history of illness, multisystem involvement, and high parasitemia. Most patients died from complications related to renal failure. Recovery of renal function was unrelated to parasitemia or hemoglobinuria; the median (range) time until urine output exceeded 20 mL/(kg.d) was 4 (0-19) days, and the time (mean +/- SD) for serum creatinine level to return to normal was 17 +/- 6 days. MARF can be managed effectively by prompt and careful peritoneal dialysis, but more effective dialysis or diafiltration might reduce the mortality rate further.

Acute Kidney Injury↗
PubMed1992

Pseudomonas pseudomallei liver abscesses: a clinical, laboratory, and ultrasonographic study.

Ultrasonography revealed evidence of liver abscess in 126 patients who were admitted to one hospital in northeastern Thailand over a 3-year period. There were 50 cases for which a pyogenic bacterial etiology was confirmed; 34 cases (group 1) were caused by Pseudomonas pseudomallei (nine patients died) and 16 cases (group 2) were caused by other bacteria (two patients died). Melioidosis was associated with anemia and underlying diabetes or renal disease; right-upper-quadrant pain and jaundice were more common in group 2 (P less than .05). Blood cultures were positive for bacteria in 68% of group 1 and 50% of group 2. Chest radiographs revealed abnormalities in 17 of 30 group 1 patients and 6 of 12 group 2 patients. The radiographic appearances of a blood-borne pneumonia suggested melioidosis. The serum indirect hemagglutination assay for antibodies to P. pseudomallei was of limited value in differentiating the two types of abscesses. Multiple hypoechoic areas on ultrasonography were significantly associated with melioidosis (P less than .01); associated splenic abscess occurred in 19 group 1 patients but only one group 2 patient (2-107, 95% confidence interval; odds ratio, 19). In an area where P. pseudomallei is endemic, these characteristic ultrasonographic findings should prompt immediate treatment for melioidosis.

Adolescent↗
PubMed1992

Measures of capillary permeability in acute falciparum malaria: relation to severity of infection and treatment.

Capillary permeability was investigated in 32 Thai patients aged 14-49 years who had acute falciparum malaria with use of three distinct techniques: quantitation of the urinary albumin/creatinine ratio (ACR), estimation of the transcapillary escape rate of radiolabeled albumin (TER), and retinal photography/fluorescein angiography. Fourteen patients had uncomplicated infections and 18 were severe cases. The severely ill patients had significantly higher ACRs (median, 4.8 mg/mmol; 95% confidence limits, 2.4-19.9 mg/mmol) and TERs (median, 8.3%/h; 95% confidence limits, 6.2-13.2%/h) than the uncomplicated cases (ACR: median, 2.1 mg/mmol; 95% confidence limits, 6.2-13.2%/h) than the uncomplicated cases (ACR: median, 2.1 mg/mmol; 95% confidence limits, 1.0-8.8 mg/mmol; TER: median, 5.9%/h; 95% confidence limits, 3.8-10.6%/h; P = .014 and .042). Both variables were significantly associated with biochemical indices of disease severity including total serum bilirubin levels (rs greater than or equal to 0.398, P less than .025 in each case), but there were no significant differences between ACRs and TERs among comatose and noncomatose patients with severe infections (P greater than or equal to .08). Retinopathy (hemorrhages, cotton-wool spots, capillary nonperfusion, and/or extravasation of fluorescein) was found in eight severely ill patients and in two uncomplicated cases. Fluorescein leakage was evident in six patients. Although fluorescein leakage had the strongest parametric correlation with the presence of coma relative to both ACR and TER in the full patient series (r = 0.58, P less than .01), multiple linear regression analysis indicated that concentrations of plasma lactate (t = 2.998, P = .006) and serum creatinine (t = 2.200, P = .036) were the factors responsible for this association. These data do not support a role for tissue edema in the pathogenesis of cerebral malaria but reveal an association between markers of disease severity and a generalized increase in systemic capillary permeability.

Adolescent↗
PubMed1992

Tumor necrosis factor in septicemic melioidosis.

Plasma concentrations of the cytokine tumor necrosis factor (TNF) were measured serially in 91 patients suspected of having septicemic melioidosis. This was confirmed in 55. TNF was detectable in admission plasma (TNF0) in 3 of 15 survivors of septicemic melioidosis and 21 of 26 fatal cases (P less than .001). The median (range) TNF0 concentration in melioidosis patients who died was 96 (1-4774) pg/ml, and the median time to death was 25 (5-672) h. TNF0 was inversely correlated with the lowest mean arterial pressure in the succeeding 12 h (Spearman's rank correlation coefficient = .67, 2P less than .001). Three patterns of TNF plasma concentrations were evident: relatively constant values between 100 and 500 pg/ml (n = 7), high admission concentrations (greater than 1000 pg/ml) associated with early death (n = 4), and an apparent pulse release after treatment, with peak values greater than 1000 pg/ml, which then declined with a mean (SD) apparent half-time of 131 (50) min (n = 8). Further studies are necessary to determine whether TNF contributes to lethality in melioidosis.

Adolescent↗
PubMed1992

High-dose mefloquine in the treatment of multidrug-resistant falciparum malaria.

The therapeutic efficacy and toxicity of a high-dose (25 mg/kg) mefloquine regimen (M25) and the currently recommended regimen of 15 mg/kg (M15) were compared in 199 patients with acute falciparum malaria in an area with deteriorating multidrug resistance on the Thai-Burmese border. The clinical and parasitologic responses were significantly more rapid with M25. The incidence of treatment failures by day 7-9 was 7% for M15 and 1% for M25 (P = .03) and had increased to 40% and 9%, respectively, by day 28 (P < .0001). Overall failure rates were highest in children (P = .02). Parasite clearance times were a good predictor of the therapeutic response; all patients with parasitemia persisting > 5 days after treatment experienced subsequent recrudescence. Side effects were dose-related and included dizziness, anorexia, nausea, vomiting, and fatigue. Although vomiting < 1 h after treatment was more likely in young children, children overall tolerated mefloquine better than adults, and men better than women. The optimum treatment dose of mefloquine in this area is 25 mg/kg.

Acute Disease↗
PubMed1992

Prolonged elevation of interleukin-8 and interleukin-6 concentrations in plasma and of leukocyte interleukin-8 mRNA levels during septicemic and localized Pseudomonas pseudomallei infection.

Patients suffering from serious bacterial infection present to the hospital after early inflammatory events, such as release of tumor necrosis factor (TNF), have been initiated. The role of other cytokines, such as interleukin-8 (IL-8), a neutrophil chemoattractant and activator, in the pathophysiology of human sepsis is not well characterized, and there are only limited data on IL-6. We studied serial concentrations of TNF, IL-6 (involved in the acute-phase response), and IL-8 in plasma and leukocyte levels of mRNA for these cytokines in patients with localized and septicemic Pseudomonas pseudomallei infection on admission to the hospital and during a prolonged recovery phase (up to 30 days). Of 18 patients, 8 had detectable plasma IL-8 and all had raised plasma IL-6 concentrations. In patients who died median initial concentration of IL-8 (167 pg/ml; range, 97 to 362 pg/ml) and IL-6 (4,800 pg/ml; range, 60 to 9,245 pg/ml) in plasma were higher than those in survivors (P less than 0.008 and P = 0.007, respectively). Septic patients who survived and patients with localized disease had similar cytokine levels. Plasma IL-8 and IL-6 concentrations were elevated throughout the inpatient period of recovery. Circulating leukocytes contained mRNA for IL-8 but not for IL-6 and TNF, and they may secrete IL-8. An elevated plasma IL-6 concentration (greater than 1,000 pg/ml) had 75% mortality) was the best predictor of mortality in P. pseudomallei sepsis. Fifty percent of patients with detectable plasma IL-8 concentrations died. In contrast, plasma TNF bioactivity did not relate to outcome; 75% of patients who did never had detectable plasma TNF activity.

Adult↗
PubMed1992

Thrombocytopenia in malaria.

The relationship between platelet counts and platelet bound (direct) or platelet directed (indirect) serum antibody concentrations was studied in 17 patients with Plasmodium falciparum malaria and 12 patients with P. vivax malaria. Platelet counts rose with recovery from infection from 196 +/- 84 x 10(9)/l (mean +/- SD) and 195 +/- 34 x 10(9)/l to 319 +/- 99 and 283 +/- 62 x 10(9)/l respectively (p less than 0.002), but there was no relationship between either absolute platelet count or changes in counts and either indirect or direct platelet antibody levels. These findings suggest that a non-immunologically mediated mechanism is involved in the pathogenesis of thrombocytopenia in malaria.

Adolescent↗
PubMed1991

Mefloquine-resistant falciparum malaria on the Thai-Burmese border.

Mefloquine is the treatment of choice for uncomplicated multiresistant falciparum malaria, and in combination with sulphadoxine and pyrimethamine (MSP) at a single dose of 15/30/1.5 mg/kg, respectively, has been used in Thailand for the past 6 years. In 1985-86, MSP cured over 98% of 5192 patients with falciparum malaria on the Thai-Burmese border. 4 years later we studied the efficacy of MSP in 395 patients at the same location. The cure rate at 28 days was 70.8% (95% Cl 67-77.2%). The proportion of early treatment failures (in whom parasitaemia did not clear) had risen from 0.27 to 3.7% (p less than 0.0001). Failure rates were 50% in children under 6 years old, 29% in the 6-15 age group, and 19% in adults (p less than 0.001). Patients with early treatment failure were retreated with 25 mg/kg mefloquine, but 27% had a further recrudescence of infection within 28 days. The mean (95% Cl) serum mefloquine concentration at the time of first recrudescence was 638 (546-730) ng/ml, a value previously associated with successful treatment. Mefloquine concentrations were no lower in those with recrudescent infections than in age-matched successfully treated patients, suggesting that pharmacokinetic factors were not responsible for the high treatment-failure rate. Plasmodium falciparum has developed resistance to mefloquine rapidly, despite the addition of sulphadoxine and pyrimethamine and strict control of drug administration. The MSP combination should now be abandoned.

Adolescent↗