Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria

Currently recommended prophylactic regimens for Plasmodium falciparum malaria are associated with a high incidence of adverse events and/or suboptimal efficacy. In a double-blind, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of atovaquone/proguanil hydrochloride (250 mg/100 mg per tablet) to eliminate preexisting infection. Immediately thereafter, subjects were randomized to one of the three prophylactic regimens to receive one atovaquone/proguanil tablet daily (n = 68), two atovaquone/proguanil tablets daily (n = 65), or placebo (n = 65) for 10 weeks. The study endpoint for any subject was the development of parasitemia, evident on blood smear, during prophylaxis. Of the evaluable subjects, all in the low-dose (54 of 54) and high-dose (54 of 54) atovaquone/proguanil groups remained malaria-free during the 10-week prophylaxis period, in contrast to only 48% (26 of 54) in the placebo group (P < .001). Both atovaquone/proguanil prophylactic regimens were as well tolerated as placebo. Thus, atovaquone/proguanil appears to be highly efficacious and safe as prophylaxis for P. falciparum malaria.     

In vitro drug sensitivity and clinical aspects of Plasmodium falciparum malaria in African children

OBJECTIVE: To compare body mass index (BMI), lipid, lipoprotein and apolipoprotein concentrations according to the Hind III and Pvu II restriction polymorphisms of the LPL gene in obese subjects. DESIGN: Cross sectional study of anthropometric and lipid variables in relation to genetic factors. SETTING: Nutrition Outpatient Clinic of Bichat Hospital in Paris, France. SUBJECTS: 236 unrelated patients (162 women and 74 men) were selected on the basis of 120% of ideal body weight. MAIN OUTCOME MEASURES: Anthropometry (body mass index, waist to hip ratio), blood lipids and lipoproteins, determination of LPL Hind III and Pvu II genotypes. RESULTS: Digestion with Hind III generated two alleles, H1 (absence of cutting site) and H2 (presence of cutting site), with frequencies of 0.30 and 0.70 respectively. Digestion with Pvu II generated two alleles P1 and P2 with frequencies of 0.49 and 0.51 respectively. The Hind III polymorphism was significantly associated with body mass index (BMI) (P < 0.05). The H2H2 genotype was associated with hypertriglyceridemia: 68% of the hypertriglyceridemic subjects have the H2H2 genotype vs 43% of the normotriglyceridemic group (P < 0.05). Plasma triglyceride levels varied significantly among the Hind III genotypes, H2H2 genotype having the highest total and VLDL-triglyceride levels; the Hind III polymorphism also showed a significant association with HDL2-cholesterol. These associations were only seen in women and were not explained by the variations in BMI and age. No significant associations were found between lipid traits and Pvu II genotype. CONCLUSION: These results suggest that genetic variation in the LPL gene in obese subjects is associated with hypertriglyceridemia and possibly with a predisposition to obesity.     

Drug-resistant Plasmodium falciparum malaria in the eastern Transvaal

In March 1993, a study was undertaken in the Komatipoort/Malelane area to monitor the in vitro sensitivity of Plasmodium falciparum to antimalarial drugs currently in use in South Africa. Of the 12 isolates collected, 7 were successfully tested for sensitivity to chloroquine and quinine, 6 for mefloquine susceptibility, and 5 for sensitivity to Fansidar. Four of the isolates were resistant to chloroquine at RIII level, 1 at RII level, and 2 were sensitive. All isolates were found to be sensitive to both quinine and mefloquine. Results suggested possible resistance to Fansidar. These findings have implications for tourists travelling to this area.     

Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.     

Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum. In vitro simulation of in vivo pharmacokinetics

The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine-sensitive (F32) strain of Plasmodium falciparum. A method of repetitive dosing and extending the culture observation period to 28-30 days was used to mimic the in vivo pharmacokinetic situation. Plasmodium falciparum was exposed to artemisinin from 10(-8) to 10(-5) M, mefloquine from 3 x 10(-9) to 10(-5) M and their combinations. The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours. The drug-dosing duration was 3 days. Neither artemisinin nor mefloquine alone provided radical clearance of P. falciparum, even when maximum concentrations (10(-5) M) were applied. The antiparasitic activity of artemisinin and mefloquine were significantly higher when dosed alone. Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefloquine respectively were significantly lower when used in combination. At concentrations normally reached in vivo, this effect was clearly synergistic (P = 0.016) Our in vitro model of intermittent dosing of artemisinin and mefloquine combinations for 3 days provides significant evidence of positive interaction between the two compounds. Lower combination concentrations around the MIC-values for the individual compounds showed synergistic effect, and high concentrations showed additive effect. This indicates that such drug combinations may provide radical clearance at concentrations lower than those required for single-drug treatment.     

Risk factors of chloroquine resistance in Plasmodium falciparum malaria

Sources of asbestos in drinking water may be natural deposits or the use of asbestos cement for water distribution. 50 water samples were selected in Austria to detect fibre contamination from either geology or asbestos cement by comparison with control areas and by comparison of raw and treated water. Standardized EPA/BGA methodology with transmission electron microscopy, energy dispersive X-ray analysis and selected area electron diffraction was used to quantify concentrations of different sized amphibole and chrysotile fibres. In 10 areas with asbestos deposits and in 14 areas with use of asbestos cement pipes asbestos concentrations in drinking water were low and not significantly different from 6 control areas (median 32,000 total asbestos fibres per litre). The relative highest concentration was found in an area with natural deposits at the source of the water supply (190,000 per litre). In areas without natural deposits the increase of asbestos concentrations from origin to consumer of water was not significant and unrelated to water aggressiveness, age and length of asbestos cement pipes. This could be mainly due to the fact that in areas with aggressive water asbestos cement pipes have been coated in Austria. A sample from a cistern, however, showed considerable asbestos contamination and raises concern about the use of surface water for room air humidification.     

Quinine pharmacokinetics in young children with severe malaria

In this study, we determined selenium concentrations in serum samples of healthy women (146 pregnant and 74 nonpregnant) living in the Mediterranean area of the coast of Granada (southeast Spain). The subjects were distributed in two groups: group A (pregnant women), divided into three categories according to the trimester of pregnancy, and group B (nonpregnant women). No significant differences were observed in the selenium levels either among pregnant women according to the trimester of pregnancy or in the group of nonpregnant women. No other significant differences were determined as regards the age of pregnant women (P > 0.05). Serum selenium levels are slightly lower during pregnancy. Considering that serum selenium levels affect the body selenium status, the concentrations determined establish the non-existence of selenium problems in the daily dietary intake with respect to maternal and fetal necessities during pregnancy.     

Mannose-binding lectin plasma levels and gene polymorphisms in Plasmodium falciparum malaria

The contribution of mannose-binding lectin (MBL) to protection from malaria was assessed by comparing plasma concentrations of MBL and the frequency of MBL gene polymorphisms in groups of Gabonese children participating in a prospective study of severe and mild malaria due to infection with Plasmodium falciparum. At admission, a higher proportion of patients with severe malaria had a low level of MBL compared with subjects with mild malaria (0.35 vs. 0.19, P = .02). Two mutations in codons 54 and 57 of the MBL gene were detected. They were present at higher frequency in those with severe malaria (0.45 vs. 0.31, P = .04). These results suggest that deficient innate immune responses, in the form of low MBL levels, may be a risk factor for severe malaria in some young children who lack well-developed, clinically protective acquired immune responses.     

Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria

The activity of atovaquone in patients with oligosymptomatic Plasmodium falciparum malaria was assessed in an open, non-comparative clinical study. The patients showed a good clinical response, but there was a high rate of recrudescence. The activity of atovaquone in combination with another antimalarial agent should be investigated.     

Efficacy of oral pyronaridine for the treatment of acute uncomplicated falciparum malaria in African children

Pyronaridine is a new antimalarial agent developed in China. In this randomized, unblinded study, the safety, tolerance, and clinical efficacy of pyronaridine (n = 44) were evaluated and compared with those of chloroquine (n = 44), the standard first-line antimalarial drug in most of Africa, in 88 Cameroonian children with acute uncomplicated falciparum malaria. The target sample size was determined to detect a 35% difference in in vivo resistance between the two treatment groups, with 95% power. Clinical and parasitological responses were monitored for 14 days on an outpatient basis. Seven children (3 treated with pyronaridine and 4 treated with chloroquine) were lost to follow-up and were excluded from the analysis. All 41 patients treated with pyronaridine were cured. Treatment failure was observed in 16 (40%) of the 40 children treated with chloroquine. In vitro assays indicated that 23 of 40 clinical isolates obtained from patients treated with pyronaridine were resistant in vitro to chloroquine. Side effects associated with pyronaridine intake were minor and transient. Pyronaridine is safe and well tolerated by symptomatic Cameroonian children, and it is highly efficacious in Africa, where chloroquine resistance is well established.     

Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum

Chromosome 2 of Plasmodium falciparum was sequenced; this sequence contains 947,103 base pairs and encodes 210 predicted genes. In comparison with the Saccharomyces cerevisiae genome, chromosome 2 has a lower gene density, introns are more frequent, and proteins are markedly enriched in nonglobular domains. A family of surface proteins, rifins, that may play a role in antigenic variation was identified. The complete sequencing of chromosome 2 has shown that sequencing of the A+T-rich P. falciparum genome is technically feasible.     

Hypopituitarism as a late complication of Plasmodium falciparum malaria: a possible relationship?

Plasmodium falciparum infection causes serious symptoms in the acute phase of the illness. Long-term sequelae are less common. In the following case report we describe a patient who developed hypopituitarism after a severe cerebral malaria infection, which was only recognized 17 years thereafter.     

Subacute Plasmodium falciparum malaria in 43 patients returning from areas with chloroquine in Africa

PURPOSE: To identify clinical and biological features of subacute falciparum malaria, risk factors, and to evaluate the efficacy of curative treatment. PATIENTS AND METHODS: Diagnostic criteria were the association of apyrexia, anemia, little or no parasitemia and a high titer of anti-Plasmodium antibodies. Forty-three cases were observed in subjects returning from chloroquine-resistant areas in Africa. They were matched with controls for age, country of residence and duration of stay. Controls were missionaries who attended our unit for a routine medical check-up during the study period. RESULTS: The clinical presentation and biological features were similar to "malarial cachexia", a condition mainly described in non-immune children in endemic areas. Splenomegaly was present in 58% of the patients. Biological features included little or no parasitemia, an overall decrease in the blood cell count, an increased erythrocyte sedimentation rate and a high titer of anti-Plasmodium antibodies. This syndrome was not correlated with the frequency of chloroquine resistance, the area of stay (urban or rural) or to the kind of chemoprophylaxis. CONCLUSIONS: This study describes subacute resistant falciparum malaria in patients who had prolonged stay in chloroquine-resistant areas of Africa associating splenomegaly, cytopenia and a low or absent parasitemia. Subacute chloroquine-resistant malaria could be due to host factors which remained to be determined by prospective immunological studies. Curative treatment with mefloquine is effective.     

Quinine and mefloquine in the treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy

Between 1991 and 1996, 372 pregnant women with uncomplicated, multidrug-resistant Plasmodium falciparum malaria, living on the western border of Thailand, were treated with either mefloquine (N = 194), quinine (N = 93) or both drugs (N = 85). Antimalarial treatment was generally well tolerated; the most common side-effects were dizziness (42%) and tinnitus (35%) following quinine, and anorexia (23%) and dizziness (36%) following mefloquine. In the patients treated for primary infections with melfloquine, 6% failed to clear their parasitaemia by day 7 and 28% failed by day 42. The corresponding figures for quinine were 4% and 23%, respectively. The failure rates in the 117 women treated for recrudescent infections were higher, the increase being significant for quinine (38%; P = 0.03) but not for mefloquine (37%). The percentage of pregnant women who had patent gametocytaemia on presentation ranged from 4%-19%. Over 50% of the patients were anaemic (haematocrit < 30%) on presentation and 52% of those not anaemic on enrolment developed anaemia during follow-up. Mefloquine and quinine, the only antimalarials generally available for the treatment of highly drug-resistant P. falciparum in pregnancy, give unsatisfactory treatment responses when used as single agents. New, safe and effective regimens are needed for the treatment of pregnant women with multidrug-resistant falciparum malaria.     

The pharmacokinetics of quinine in patients with hepatitis

The pharmacokinetics of quinine were studied in six patients with hepatitis B infection (during acute and convalescent periods) and six healthy subjects. A single 10 mg kg-1 dose of quinine was given intravenously over 2 h. Pharmacokinetic parameters of quinine during the acute phase of the infection were not different from those during the recovery phase. However, when compared with those obtained from healthy subjects, significant changes were found. The terminal elimination half-life was prolonged (17 and 15 vs 10 h) and clearance was lower (2.9 and 2.3 vs 3.5 ml min-1 kg-1). Unbound quinine concentration in plasma at 2 h was approximately 10% of the total concentration in all subjects in the three study groups. A prolonged QTc interval (< 25%) was observed in all groups. The present data suggest that current dosage regimens of quinine used in the treatment of falciparum malaria may not be suitable for malaria patients with acute hepatitis or those who have had hepatitis within the past 3 months.     

Pharmacokinetics of mefloquine combined with artesunate in children with acute falciparum malaria

To study the biologic role of migration inhibitory factor (MIF), a pleiotropic cytokine, we generated a mouse strain lacking MIF by gene targeting in embryonic stem cells. Analysis of the role of MIF during sepsis showed that MIF-/- mice were resistant to the lethal effects of high dose bacterial lipopolysaccharide (LPS), or Staphylococcus aureus enterotoxin B (SEB) with D-galactosamine and had lower plasma levels of tumor necrosis factor alpha (TNF-alpha) than did wild-type mice, but normal levels of interleukin (IL)-6 and IL-10. When stimulated with LPS and interferon gamma, macrophages from MIF-/- mice showed diminished production of TNF-alpha, normal IL-6 and IL-12, and increased production of nitric oxide. MIF-/- animals cleared gram-negative bacteria Pseudomonas aeruginosa instilled into the trachea better than did wild-type mice and had diminished neutrophil accumulation in their bronchoalveolar fluid compared to the wild-type mice. Thioglycollate elicited peritoneal exudates in uninfected MIF-/- mice, but showed normal neutrophil accumulation. Finally, the findings of enhanced resistance to P. aeruginosa and resistance to endotoxin-induced lethal shock suggest that the counteraction or neutralization of MIF may serve as an adjunct therapy in sepsis.