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Biomedical subjects

F Nosten

Publications and source records attributed to F Nosten.

At least 91 records · Page 5Linked to original sources
PubMed1993

Cardiac effects of antimalarial treatment with halofantrine.

In a prospective electrocardiographic study of Karen patients with acute uncomplicated falciparum malaria, mefloquine (25 mg/kg) had no cardiac effects (n = 53), but halofantrine (72 mg/kg) induced consistent dose-related lengthening of the PR and QT intervals in all 61 patients treated. The likelihood of significant QTc prolongation (by more than 25% or a QTc of 0.55 s1/2 or more) was greater after halofantrine as retreatment following mefloquine failure than as primary treatment (7/10 vs 18/51; relative risk 2.0 [95% Cl 1.1-3.4], p = 0.04). More than 60% of the effect occurred with three doses of halofantrine (24 mg/kg). The arrhythmogenic potential of halofantrine should now be investigated.

Adolescent↗
PubMed1993

Single dose pharmacokinetics of proguanil and its metabolites in pregnancy.

Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng.ml-1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng.h.ml-1.kg-1, respectively. Corresponding whole blood AUC values were 361 and 396 ng.h.ml-1.kg-1. The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng.ml-1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml-1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Biguanides↗
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

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↗
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↗
PubMed1991

Mefloquine pharmacokinetics and resistance in children with acute falciparum malaria.

The pharmacokinetic properties of mefloquine hydrochloride (15 mg base kg -1) were studied in 12 Karen children (five girls, seven boys) aged between 5 and 10 years presenting with uncomplicated falciparum malaria. The drug was well tolerated. Mean (s.d.) peak blood drug concentrations of 2031 (831) ng ml-1 were reached in a median of 8 (range 6-24) h. Mean (s.d.) estimates for oral clearance and mean residence time were 0.52 (0.27) ml min -1 kg -1 and 15.3 (4.7) days, respectively. These values are similar to those reported previously in adults. In one child parasitaemia failed to clear despite whole blood mefloquine concentrations which peaked at 1744 ng ml -1; parasitaemia rose and fever recurred when blood drug concentrations had fallen to 442 ng ml -1. The prevalence of highly mefloquine resistant parasites such as this can be expected to increase under drug pressure in this area.

Animals↗
PubMed1990

Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study.

1. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten received 250 mg mefloquine base weekly and ten received identical tablets of 125 mg base/week. 2. Both dose regimens were well tolerated. Malaria was prevented effectively, there were no serious adverse effects, all pregnancies proceeded normally, and there were no abnormalities in the babies followed up to 2 years. 3. The median time from dose administration to peak whole blood mefloquine concentration was 6 (range 3-24) h. Mean (+/- s.d.) peak and trough concentrations in the seventh week were 722 +/- 279 and 488 +/- 155 ng ml-1 with the 250 mg/week dose, and 390 +/- 81 and 185 +/- 53 ng ml-1 with the 125 mg/week dose regimens respectively. These blood concentration values are lower than those reported previously in non-pregnant adults. 4. One and two compartmental models were fitted to the whole blood concentration-time data. Mean (+/- s.d.) clearance (CL/F) was 0.78 +/- 0.27 ml min-1 kg-1, and the apparent terminal elimination half-life (t1/2) was 11.6 +/- 7.9 days. 5. Further studies to determine the oral bioavailability of mefloquine are needed, but these results suggest that clearance may be increased in late pregnancy. These preliminary results of good efficacy without significant toxicity are encouraging, and a more extensive evaluation of mefloquine antimalarial prophylaxis in pregnancy is now warranted.

Birth Weight↗
PubMed1987

Malaria on the Thai-Burmese border: treatment of 5192 patients with mefloquine-sulfadoxine-pyrimethamine.

Multidrug-resistant falciparum malaria is a major health problem along the Thai-Burmese border. From July 1985 until December 1986 a total of 5192 patients with falciparum malaria (1734 males, 3458 females) from this area were given supervised treatment with the combination mefloquine-sulfadoxine-pyrimethamine (MSP). The radical cure rate, assessed 21 days after drug administration, was 98.4% for the first 1975 patients, and 98.8% when assessed at 28 days for the remaining 3217 patients. In 3.8% of cases, parasites were still detected in peripheral blood smears on day 7 after treatment but this had fallen to 0.27% by day 9. Adverse reactions among the first 1975 patients were: vertigo (7.5% of patients), vomiting (5.8%), epigastric pain (0.6%), and transient confusional state (one case). MSP is an effective and well-tolerated drug for the treatment of drug-resistant falciparum malaria; however, delayed parasite clearance may give a false impression of RII resistance.

Adult↗
PubMedDate not supplied

Malaria during pregnancy in an area of unstable endemicity.

A prospective study of malaria during pregnancy was conducted between September 1986 and December 1989 in an area of unstable (mesoendemic) malaria transmission on the Thai-Burmese border. Antenatal clinics were set up in camps for displaced persons of the Karen ethnic minority and 1358 pregnant women were enrolled at a mean estimated gestational age of 23 weeks (standard deviation 5.7 weeks) and were followed weekly until delivery. Malaria developed in 505 women (37.2%); 80.2% of infections were Plasmodium falciparum, 17.1% were P. vivax, and 2.7% were mixed. Primigravidae were infected more commonly than multigravidae: 153/322 (47.5%) compared with 318/953 (33.3%) (P less than 0.001). The incidence of malaria declined from the 20th week of gestation (12%) towards term (4.4%). Most infections were detected before symptoms developed, and there were no deaths associated with malaria. Despite this, malaria was associated with an overall 123 g reduction in birthweight (95% confidence interval [CI] 34-212 g). This reduction was largely accounted for by lower birthweights of babies born to infected primigravidae (mean reduction 151 g, 95% CI 21-282 g) and women in their 2nd and 3rd pregnancies (mean reduction 185 g, 95% CI 84-286 g). The incidence of anaemia requiring treatment was higher in women who developed malaria, 149/420 (35.4%) compared with 191/670 (28.5%), and was proportional to the number of parasitaemic episodes. Thus, despite regular antenatal clinic attendance with prompt detection and treatment of malaria (the currently employed antimalarial strategy in areas with multidrug-resistant P. falciparum), malaria still had a significant adverse effect on pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Intracranial pressure in childhood cerebral malaria.

Lumbar punctures were performed in 40 Gambian children with acute cerebral malaria aged between 18 months and 10 years. The mean opening pressure was elevated in 32 (80%) of the children, but was not significantly different in the 14 fatal cases compared with survivors: 110 (standard deviation 71) versus 131 (58) mm of cerebrospinal fluid respectively. Cerebral perfusion pressures were also similar in the 2 groups: 64 (20) mm Hg versus 64 (11) mm Hg respectively. There was no clear clinical evidence of raised intracranial pressure, and no evidence of deterioration immediately following lumbar puncture. Nevertheless brain swelling, and consequent brain-stem compression, may contribute to a fatal outcome in cerebral malaria--particularly in those children who die from sudden respiratory arrest. A prospective evaluation of osmotic agents in childhood cerebral malaria seems to be justified.

Child↗
PubMedDate not supplied

Bed nets for the prevention of malaria and anaemia in pregnancy.

A prospective comparison of the antimalarial efficacy of bed nets was conducted with 341 pregnant women living in a mesoendemic malarious area of the Thai-Burmese border. Women in 3 adjacent study sites were allocated at random to receive either a single size permethrin-impregnated bed net (PIB), a non-impregnated bed net (NIB), or to a control group who used either their own family size non-impregnated bed net (FNIB) or no net. In one study site, but not the other 2, PIB significantly reduced parasite densities and, together with FNIB, reduced the incidence of malaria in pregnancy from 56% to 33% (relative risk = 1.67, confidence interval = 1.07-2.61, P = 0.03, allowing for parity). Anaemia proved a more sensitive marker of bed net antimalarial efficacy than parasite rates. The incidence of anaemia (haematocrit < 30%) at all study sites was significantly lower at delivery in the PIB (27%) and FNIB groups (21%) than in the NIB group (41%) or those using no net (56%). This suggests that a significant proportion of the malaria in pregnancy in this mesoendemic area was sub-patent. Both patent Plasmodium falciparum parasitaemia and anaemia were associated with a reduction in birth weight. Infant mortality was high (16%) and strongly associated with prematurity, low birth weight and maternal anaemia. PIB were well tolerated and had no apparent adverse effect on the pregnancy or infant development. Although the overall effect of bed nets on patent parasitaemia was marginal, they were associated with a significant reduction in maternal malaria-associated anaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Single day mefloquine-artesunate combination in the treatment of multi-drug resistant falciparum malaria.

The therapeutic efficacy and toxicity of a combination of low dose mefloquine (15 mg/kg) plus artesunate 10 mg/kg in one day (MA) was compared with the currently used regimen of high dose mefloquine (25 mg/kg) (MQ) in 552 patients with uncomplicated falciparum malaria in an area of multi-drug resistance on the Thai-Burmese border. MA gave faster clinical and parasitological responses and prevented early treatment failure; 15 patients in the MQ group (6%) were early failures (< 9 d) compared with none receiving MA (P = 0.0001). Overall failure rates by day 28 were 19% in the MA group and 24% in with MQ group (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.54-1.12). In the subgroup of patients who required re-treatment, MA proved significantly more effective than MQ; failure rates were 25% and 52% respectively (RR = 0.49, 95% CI = 0.29-0.83). Treatment failures were associated with mefloquine treatment in the previous month (RR = 1.72, 95% CI = 1.09-2.70) and diarrhoea (RR = 1.55, 95% CI = 1.05-2.28). Gastrointestinal side-effects and dizziness were more likely in the MQ group. There was no evident adverse effect associated with artesunate. A single day's treatment with artesunate augments the antimalarial efficacy of mefloquine.

Adolescent↗
PubMedDate not supplied

Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance.

Serial clinical and metabolic changes were monitored in 115 Gambian children (1.5-12 years old) with severe malaria. Fifty-three children (46%) had cerebral malaria (coma score < or = 2) and 21 (18%) died. Admission geometric mean venous blood lactate concentrations were almost twice as high in fatal cases as in survivors (7.1 mmol/L vs. 3.6 mmol/L; P < 0.001) and were correlated with levels of tumour necrosis factor (r = 0.42, n = 79; P < 0.0001) and interleukin 1-alpha (r = 0.6, n = 34; P < 0.0001). Admission blood venous glucose concentrations were lower in fatal cases than survivors (3.2 mmol/L, vs. 5.8 mmol/L; P < 0.0001). Treatment with quinine was associated with significantly more episodes of post-admission hypoglycaemia when compared with artemether or chloroquine. After treatment, lactate concentrations fell rapidly in survivors but fell only slightly, or rose, in fatal cases. Plasma cytokine levels fluctuated widely after admission. Sustained hyperlactataemia (raised lactate concentrations, 4 h after admission) proved to be the best overall prognostic indicator of outcome in this series. Lactic acidosis is an important cause of death in severe malaria.

Acidosis, Lactic↗
PubMedDate not supplied

Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria.

To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of multidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai-Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer (P < 0.001). After adjusting for reinfections the failure rates were 13.9% for the artesunate combination, 12.3% for the artemether combination and 49.2% for mefloquine alone (P < 0.0001; relative risk 3.8 [95% confidence interval 2.6-5.4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective.

Administration, Oral↗
PubMedDate not supplied

Predictors of mefloquine treatment failure: a prospective study of 1590 patients with uncomplicated falciparum malaria.

The factors which identify patients at risk of treatment failure were characterized in 1590 children and adults with uncomplicated falciparum malaria treated with 15 or 25 mg/kg of mefloquine on the borders of Thailand. Six independent predictors of failure were identified using multiple logistic regression. Age < or = 2 years (odds ratio [OR] 4.54), 3-15 years (OR 4.4), vomiting < 30 min after a single dose of 25 mg/kg (despite re-administration of the dose) (OR 2.5) and diarrhoea after treatment (OR 3.6) were the strongest predictors of failure by day 7. Parasitaemias > 10 000/mm3 (OR 1.4), and fever with a history of recent vomiting (OR 1.6) were risk factors for recrudescence of the infection between days 10 and 28. Patients treated with mefloquine in the previous 2 months were also at increased risk of failure (OR 2.38), particularly if they were anaemic (haematocrit < 30%) (OR 5.96), which suggested that they had recrudescent infections at presentation. Combined, these 6 factors identified half of all treatment failures. Vomiting and diarrhoea accounted for 24% of the early failures in children. Patients at increased risk of treatment failure should be monitored closely and given early alternative treatment if fever and parasites persist for > or = 3 d.

Adolescent↗