The effect of three-monthly albendazole treatment on malarial parasitemia and allergy: a household-based cluster-randomized, double-blind, placebo-controlled trial.

BACKGROUND: Helminth infections are proposed to have immunomodulatory activities affecting health outcomes either detrimentally or beneficially. We evaluated the effects of albendazole treatment, every three months for 21 months, on STH, malarial parasitemia and allergy. METHODS AND FINDINGS: A household-based cluster-randomized, double-blind, placebo-controlled trial was conducted in an area in Indonesia endemic for STH. Using computer-aided block randomization, 481 households (2022 subjects) and 473 households (1982 subjects) were assigned to receive placebo and albendazole, respectively, every three months. The treatment code was concealed from trial investigators and participants. Malarial parasitemia and malaria-like symptoms were assessed in participants older than four years of age while skin prick test (SPT) to allergens as well as reported symptoms of allergy in children aged 5-15 years. The general impact of treatment on STH prevalence and body mass index (BMI) was evaluated. Primary outcomes were prevalence of malarial parasitemia and SPT to any allergen. Analysis was by intention to treat. At 9 and 21 months post-treatment 80.8% and 80.1% of the study subjects were retained, respectively. The intensive treatment regiment resulted in a reduction in the prevalence of STH by 48% in albendazole and 9% in placebo group. Albendazole treatment led to a transient increase in malarial parasitemia at 6 months post treatment (OR 4.16(1.35-12.80)) and no statistically significant increase in SPT reactivity (OR 1.18(0.74-1.86) at 9 months or 1.37 (0.93-2.01) 21 months). No effect of anthelminthic treatment was found on BMI, reported malaria-like- and allergy symptoms. No adverse effects were reported. CONCLUSIONS: The study indicates that intensive community treatment of 3 monthly albendazole administration for 21 months over two years leads to a reduction in STH. This degree of reduction appears safe without any increased risk of malaria or allergies. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN83830814.

Therapeutic effects of various solvent fractions of Alstonia boonei (apocynaceae) stem bark on Plasmodium berghei-induced malaria.

Malaria, the most important parasitic disease afflicting man is the leading cause of mortality and morbidity in the world. Chemotherapy remains the mainstay for the treatment and prevention of the disease in the absence of an effective vaccine. The incidence of resistance of malaria parasites to chemotherapy is increasing and complicated. This study was therefore undertaken in order to evaluate the therapeutic effects of fractions of the stem bark of A. boonei on P. berghei-induced malaria using chloroquine as control. Different doses (200 mg/kg and 400 mg/kg body weight) of methanolic extract (ME), n-hexane (HF), chloroform (CF), ethylacetate(EF) and aqueous (AF) fractions of the stem bark of A. boonei were administered orally to albino mice. Five milligrammes chloroquine base per kilogramme body weight (5 mg/kg bw) was used as positive control while the negative control mice received only the vehicle (5% v/v tween 80). The results obtained showed that the 400 mg/kg bw dose was more effective with respect to the parasite clearance than the 200 mg/kg bw dose. The 400 mg/kg bw dose of ME gave 68.1% percent parasite clearance. The CF gave the highest clearance of 98.4% at 400 mg/kg bw after 7 days treatment while chloroquine at 5 mg/kg bw gave 100% parasite clearance. The order of increasing potency of the fractions (parasite clearance) was (EF 50.0% < AF 60.3% < HF 63.1%, < CF 98.4%) indicating that the active principle in the stem bark was highest in the CF. Percentage parasitemia following exposure to these fractions also decreased in all groups in the same order and was only significant (p < 0.05) in CF (0.11%) compared to the untreated control group. The ME of A. boonei also caused increase in PCV by 15.5%. Purification enhanced PCV value as the HF and CF fractions gave 19.0% and 24.5% increases, respectively. However, 31.5% increase in PCV was obtained in the albino mice treated with chloroquine. The EF and AF gave increase of 10.0% and 11.0% increase relative to the negative control treated mice. The high bioactivity of CF and HF indicate that the putative compound(s) in A. boonei are lipophillic and further purification could enhance greater activity. Further work is required to isolate the bioactive compound for a promising antimalarial drug from the chloroform fraction.

Effect of nutritional status on response to treatment with artemisinin-based combination therapy in young Ugandan children with malaria.

The relationship between malnutrition and malaria in young children is under debate, and no studies evaluating the association between malnutrition and response to artemisinin-based combination therapies (ACTs) have been published. We evaluated the association between malnutrition and response to antimalarial therapy in Ugandan children treated with ACTs for repeated episodes of malaria. Children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years. All HIV-exposed and HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis (TS). The primary exposure variables included height-for-age and weight-for-age z scores. Outcomes included parasite clearance at days 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. Two hundred ninety-two children were randomized to DP or AL, resulting in 2,013 malaria treatments. Fewer than 1% of patients had a positive blood smear by day 3 (DP, 0.2%; AL, 0.6% [P = 0.18]). There was no significant association between height-for-age or weight-for-age z scores and a positive blood smear 2 days following treatment. For children treated with DP but not on TS, decreasing height-for-age z scores of <-1 were associated with a higher risk of recurrent parasitemia than a height-for-age z score of >0 (hazard ratio [HR] for height-for-age z score of <-1 and ≥-2 = 2.89 [P = 0.039]; HR for height-for-age z score of <-2 = 3.18 [P = 0.022]). DP and AL are effective antimalarial therapies in chronically malnourished children in a high-transmission setting. However, children with mild to moderate chronic malnutrition not taking TS are at higher risk for recurrent parasitemia and may be considered a target for chemoprevention.

The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses.

Lentinan, a (1-3)-beta glucan from Lentinus edodes, is an effective immunostimulatory drug. We tested the effects of lentinan during blood-stage infection by Plasmodium yoelii 17XL (P.y17XL). Pre-treatment of mice with lentinan significantly decreased the parasitemia and increased their survival after infection. Enhanced IL-12, IFN-gamma and NO production induced by lentinan in spleen cells of infected mice revealed that the Th1 immune response was stimulated against malaria infection. In vitro and in vivo, lentinan can result in enhanced expression of MHC II, CD80/CD86, and Toll-like receptors (TLR2/TLR4), and increased production of IL-12 in spleen dendritic cells (DCs) co-cultured with parasitized red blood cells (pRBCs). Moreover, both the number of CD4(+)CD25(+) regulatory T cells (Tregs) and the levels of IL-10 secreted by Tregs were reduced by pre-treatment with lentinan in the spleen of malaria-infected mice. Meanwhile, apoptosis of CD4(+) T cell in spleens of mice pretreated with lentinan was significantly reduced. In summary, lentinan can induce protective Th1 immune responses to control the proliferation of malaria parasites during the blood-stage of P.y17XL infection by stimulating maturation of DCs to inhibit negative regulation of the Th1 immune response by Tregs. Taken together, our findings suggest that lentinan has prophylactic potential for the treatment of malaria.

Chemosensitizing action of cepharanthine against drug-resistant human malaria, Plasmodium falciparum.

We have established a system of in vitro and in vivo assays to prioritize plant extracts that can serve as a source of drug candidates for the treatment of malaria, an infectious disease that affects nearly 40% of the world's population. In the present study, we have investigated the biological potential of one such plant-derived drug lead, cepharanthine. In vitro growth inhibition studies indicated this compound possessed good antiplasmodial activity without mediating a cytotoxic response. Based on this selectivity, evaluations were performed with an in vivo mouse model. Moderate activity was observed, inhibiting parasite growth by 46% at a dose of 100 mg/kg body weight (BW). We further assessed the ability of cepharanthine to serve as a drug in combination with a standard antimalarial regimen. Like chloroquine, cepharanthine inhibited the trophozoite stage of parasite growth. Isobolographic analyses revealed synergism with chloroquine, but only with the drug-resistant malaria clone, and single-dose drug-interaction studies demonstrated that cepharanthine lowered the half-maximal inhibitory concentration of chloroquine from 148.5 to 37.8 nM. In summary, since activity in the mouse model was only moderate, cepharanthine may be of greater value as a modulator of resistance, capable of prolonging the clinical utility of chloroquine.

Comparative efficacy of chloroquine plus chlorpheniramine and pyrimethamine/sulfadoxine in acute uncomplicated falciparum malaria in Nigerian children.

The efficacy of pyrimethamine/sulfadoxine (PS) and chloroquine plus chlorpheniramine, a histamine H1 receptor blocker which reverses chloroquine insensitivity in Plasmodium falciparum in vitro, was evaluated in 100 consecutive children with acute symptomatic uncomplicated falciparum malaria. Parasitaemia on day 3 following initiation of treatment, fever and symptom clearance times were significantly lower in the chloroquine/chlorpheniramine (CQ/CP) combination group than in the PS group. The cure rate was also significantly higher in the combination group. The combination cured all children who had failed PS treatment. Gametocytaemia and the gametocyte carrier rate following therapy were significantly lower in the combination group than in those receiving PS. Both treatments were well tolerated but adverse drug reactions were commoner in the children given PS. CQ/CP is effective in PS treatment failure in Nigerian children and may be useful for this condition in African children in general.

Dietary iron supplementation does not aggravate experimental malaria in young rats.

The hypotheses that iron-deficient hosts are less susceptible to severe malaria and that iron supplementation aggravates infection have been supported by some clinical and experimental evidence. In the present study, the course of Plasmodium berghei infection was monitored in an experimental model of dietary iron deficiency and iron supplementation. Weanling Wistar rats were fed purified diets with different iron concentrations: 20 mg/kg (Group D, n = 24), 50 mg/kg (Group N, n = 24) and 100 mg/kg (Group S, n = 12). After 15 d, rats from Group D were anemic (mean hemoglobin 81 g/l). The next day, 12 rats from Group D (thereafter Group DS) and 12 rats from Group N (thereafter Group NS) were transferred to the same iron-supplemented diet as in Group S, whereas the remaining animals (Groups D, N and S) were maintained on the original diets for further 14 d. At that time, 9 rats from each group were inoculated intraperitoneally with 10(6) erythrocytic parasites (P. berghei ANKA strain), whereas 3 rats from each group remained as noninfected controls. All animals were killed 14 d after inoculation, when significantly lower levels of hemoglobin, serum iron and percent transferrin saturation were found in infected animals from Group D compared with all other groups. However, the time course of parasitemias was similar in all groups. These data indicate that the development of P. berghei was neither suppressed by iron deficiency nor enhanced by iron supplementation in this model. Furthermore, iron repletion during infection did produce a noticeable improvement of hematological variables in previously iron-deficient animals.