Antiplasmodial activity of sesquiterpene lactone from Carpesium rosulatum in mice.

In the previous work, methanol extracts of Carpesium rosulatum (Compositae) were found to have high antiplasmodial activity against Plasmodium falciparum in vitro, this activity being largely attributable to a ineupatorolides A (I-A). In the present study, encouragingly, I-A was also found to have potential antimalarial activity in vivo when tested against Plasmodium berghei in mice. I-A (2, 5, 10 mg kg(-1) day(-1)) exhibited a significant blood schizontocidal activity in 4-day early infection, repository evaluation, and in established infection with a significant mean survival time comparable to that of the standard drug, chloroquine (5 mg kg(-1) day(-1)). The I-A possesses a promising antiplasmodial activity, which can be exploited in malaria therapy.

Co-administration of Na-EDTA and diminazene aceturate (DA) to mice infected with DA-resistant Trypanosoma brucei.

This study investigated the effects of co-administration of Na-EDTA and diminazene aceturate (DA) on the level of parasitaemia (LOP), parasite clearance, packed cell volume (PCV) and post-infection survival time (PIST) in mice infected with DA-resistant Trypanosoma brucei. Five groups of 10 mice were treated as follows: infected and treated with Na-EDTA+DA; infected and treated with DA alone; infected and treated with Na-EDTA alone; infected-untreated; and uninfected-untreated. The co-administration of Na-EDTA and DA led to reduced LOP and improvements in PCV (P<0.05), as compared with treatment with DA alone. Mice treated with Na-EDTA+DA had a marginally (P>0.05) higher PIST than did mice treated with DA alone. Comparison of the group given Na-EDTA alone with the infected-untreated group showed that the former group had a significantly lower (P<0.01) LOP, improved PCV (P<0.05) and higher (P<0.01) PIST. It was concluded that the co-administration of Na-EDTA and DA led to a slight potentiation of DA in the treatment of mice infected with DA-resistant T. brucei, and that the administration of Na-EDTA alone significantly enhanced the resistance of the infected mice.

Effects of cannabinoid treatment on Chagas disease pathogenesis: balancing inhibition of parasite invasion and immunosuppression.

Trypanosoma cruzi invades heart cells via a calcium-dependent, G protein-mediated mechanism, leading to severe cardiac inflammation considered by some to be autoimmune in nature. Cannabinoids inhibit calcium flux and G protein signalling; as potent immunosuppressive agents, they are effective in the treatment of autoimmune disease but contraindicated for the treatment of infections. We compared the action of the synthetic cannabinoid R(+)WIN55,212 and its inactive isomer S(-)WIN55,212 on cardiac myoblast invasion: R(+)WIN55,212 inhibited invasion by over 85%. We then tested for efficacy in modulating pathogenesis in mice by assaying parasite burden in heart and blood, cellular and humoral immunity to parasite and self antigens, and mortality. R(+)WIN55,212 significantly reduced cardiac inflammation but led to considerably increased parasitaemia. Cardiac parasitosis and mortality were not significantly different in treatment and control groups. We conclude that cannabinoids can block cardiac cell puncture repair mechanisms, thereby inhibiting trypanosome invasion as predicted by the mode of drug action, but, also inhibit immune cell effector functions, offsetting the benefit of inhibition parasite cell invasion. Refined use of cannabinoids may prove therapeutic in the future, but our results raise concern about the effect of cannabis use on those chronically infected by T. cruzi and on heart cell homeostasis generally.

Trypanosoma cruzi: host selenium deficiency leads to higher mortality but similar parasitemia in mice.

Selenium is an essential trace element and its deficiency was implicated in heart diseases. We recently showed low Se levels in chronic chagasic patients with cardiomyopathy. Herein, mice were depleted in Se by feeding the mothers with chow containing only 0.005 mg Se/kg and maintaining this diet for offspring, that were further infected with Trypanosoma cruzi. Survival rate was significantly lower in Se deficient than in control mice. Parasitemia was similar in all groups. Necrotic heart lesions were found after infection (high CK-MB levels). No outbreaks of parasite growth were detected in chronic survivors submitted or not to a second Se depletion. The present results confirm our hypothesis that a nutritional deficiency in Se is associated to a higher mortality during T. cruzi infection. The potential beneficial effect of Se supplementation is a perspective. Hypothesis to explain the higher susceptibility of Se-depleted mice to T. cruzi infection are discussed.

Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomised double blind placebo controlled trial.

OBJECTIVE: To study the effects of zinc supplementation on malaria and other causes of morbidity in young children living in an area holoendemic for malaria in west Africa. DESIGN: Randomised, double blind, placebo controlled efficacy trial. SETTING: 18 villages in rural northwestern Burkina Faso. PARTICIPANTS: 709 children were enrolled; 685 completed the trial. INTERVENTION: Supplementation with zinc (12.5 mg zinc sulphate) or placebo daily for six days a week for six months. MAIN OUTCOME MEASURES: The primary outcome was the incidence of symptomatic falciparum malaria. Secondary outcomes were the severity of malaria episodes, prevalence of malaria parasite, mean parasite densities, mean packed cell volume, prevalence of other morbidity, and all cause mortality. RESULTS: The mean number of malaria episodes per child (defined as a temperature >/=37.5 degrees C with >/=5000 parasites/microliter) was 1.7, 99.7% due to infection with Plasmodium falciparum. No difference was found between the zinc and placebo groups in the incidence of falciparum malaria (relative risk 0.98, 95% confidence interval 0.86 to 1.11), mean temperature, and mean parasite densities during malaria episodes, nor in malaria parasite rates, mean parasite densities, and mean packed cell volume during cross sectional surveys. Zinc supplementation was significantly associated with a reduced prevalence of diarrhoea (0.87, 0.79 to 0.95). All cause mortality was non-significantly lower in children given zinc compared with those given placebo (5 v 12, P=0.1). CONCLUSIONS: Zinc supplementation has no effect on morbidity from falciparum malaria in children in rural west Africa, but it does reduce morbidity associated with diarrhoea.

Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria.

To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose.

Beneficial effect of selenium supplementation during murine infection with Trypanosoma cruzi.

Selenium (Se) has been shown to function as an antioxidant that may enhance immunity during microbial infection. To investigate the effect of elevated levels of Se on the course of experimental Chagas' disease, 5 groups of C3HeB/FeJ mice were infected with 10(3) bloodform trypomastigotes of a Brazil strain of Trypanosoma cruzi while receiving supplements of 0 ppm, 2 ppm, 4 ppm, 8 ppm, or 16 ppm Se as sodium selenate in drinking water. After 64 days of infection, survival ranged from 0 to 60%, with groups receiving 4 ppm and 8 ppm Se exhibiting 60% survival and the group without Se exhibiting 0% survival. In addition, parasitemia levels of mice supplemented with Se were significantly lower (P<0.01) than in nonsupplemented mice. The results of the present study suggest that Se supplementation does have a beneficial effect during murine infection with T. cruzi, resulting in decreased parasitemias and increased longevity.

Vitamin A supplementation and childhood malaria in northern Ghana.

Two companion, randomized, placebo-controlled trials of prophylactic vitamin A supplementation provided the opportunity to assess the impact of supplementation on malaria parasitemia, morbidity, and mortality in young children in northern Ghana. In the mortality study, 21,906 children were visited every 4 mo over 2 y, and in the morbidity study 1455 children were visited weekly for 1 y. There was no difference between children supplemented with vitamin A and those given placebo in malaria mortality rates (rate ratio = 1.03; 95% CI 0.74, 1.43) or fever incidence based on reported symptoms. Malaria parasitemia rates, parasite densities in children with a positive blood smear, and rates of probable malaria illness also did not differ between treatment groups. There was no correlation between serum retinol at the beginning of the trial and subsequent malaria parasitemia in children who received placebo (r = 0.01). It is concluded that vitamin A supplementation had no impact on malaria in this population.