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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chloroquine and ammonium chloride, by virtue of their basic properties, have been shown to raise endocytic and lysosomal pH and thereby interfere with normal iron metabolism in a variety of cell types, including mononuclear phagocytes. Cellular iron metabolism is of critical importance to Legionella pneumophila, an intracellular bacterial pathogen whose capacity to multiply in human mononuclear phagocytes is dependent upon the availability of intracellular iron. In view of this, we have studied the effects of chloroquine and ammonium chloride on L. pneumophila intracellular multiplication in human monocytes. Chloroquine, at a concentration of 20 microM, and ammonium chloride, at a concentration of 20 mM, inhibited L. pneumophila intracellular multiplication by 1.4 +/- 0.2 (SEM) logs and 1.5 +/- 0.2 logs, respectively. Chloroquine- and ammonium chloride-induced inhibition of L. pneumophila intracellular multiplication was completely reversed by iron nitrilotriacetate, an iron compound which is soluble in the neutral to alkaline pH range, but not by iron transferrin, which depends upon acidic intracellular conditions to release iron. Chloroquine had no major direct effect on L. pneumophila multiplication in artificial media except at extremely high concentrations (15,000-fold that which inhibited L. pneumophila multiplication in mononuclear phagocytes), and inhibition at such concentrations was not reversed by iron nitrilotriacetate. This study demonstrates that chloroquine and ammonium chloride inhibit the intracellular multiplication of L. pneumophila by limiting the availability of iron to the bacterium. It is possible that such a mechanism of action underlies chloroquine's antimicrobial effect against other intracellular pathogens, such as the agents of malaria and tuberculosis.
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PMID:Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. 205 29

Oxidative stress has been incriminated as a deleterious factor in the development of malaria parasites. Various chemical reductones which can undergo cyclic oxidation and reduction, such as ascorbate have been shown to cause oxidative stress to red blood cells. This, naturally-occurring and redox-active compound, can induce the formation of active oxygen derived species, such as superoxide radicals (.O2-), hydrogen peroxide (H2O2) and hydroxyl radical (OH.). The formation of the hydroxyl radical, the ultimate deleterious species, is mediated by the redox-active and available transition metals iron and copper in the Haber-Weiss reaction. During the development of the parasite, hemoglobin is progressively digested and a concurrent release of high levels of iron-containing breakdown products takes place within the red blood cell. Indications for the progressive increase in redox-active iron during the growth of P. falciparum have been recently found in our lab: a) adventitious ascorbate proved highly detrimental to the parasite when added to the mature forms. In contrast, if the parasitized erythrocytes were in the early phase following invasion, and only low levels of iron-containing structures had been liberated, then the observed effect was a small promotion of parasite development. b) erythrocytes containing mature parasites were more potent than erythrocytes containing ring forms as a source for redox-active iron in the ascorbate-driven metal-mediated degradation of DNA. The addition of extracts from parasitized erythrocytes and ascorbate to DNA caused a dose and time dependent DNA degradation. Non-infected erythrocytes had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of oxidant stress by iron available in advanced forms of Plasmodium falciparum. 206 Aug 37

An iron supplementation trial had been performed in a southern village of Togo during the rainy season when occurs malaria transmission. 241 infants from 6 to 36 months old were matched in two randomized groups. The first one (G1) received oral iron supplementation every day during three months. The second group (G2) received placebo. Tablet administration was double blind made. A third group (G3) had been created from two others with anaemic infants and received daily iron supplementation. Three biological and clinical surveys were done, i) before the trial (T0), ii) after supplementation (T3) and iii) six months later (T9). Several parameters were studied including malaria parasite density and titration of malaria antibodies. For each group the prevalence of Plasmodium falciparum was identical in the three surveys. Means of parasite density decreased during and after rainy season but variations were not significant. High parasitaemia frequency (i.e. greater than 10,000 parasitized red cells per mm3, considered as pyrogenic threshold) were identical in all groups and decreased after rainy season. Antibodies titers did not show any variation in the three groups. It seems that iron supplementation did not modify in 6 to 36 months infants the susceptibility to malaria nor the organism response.
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PMID:[Effects od iron supplementation on malaria infection]. 206 3

Recently introduced chloroquine resistant malaria has altered the clinical picture and complicated the overall management of malaria. 113 adults with proved malaria admitted at Harare Central Hospital, Zimbabwe, were evaluated to determine the incidence, nature, relationship to morbidity and mortality and response to treatment of the complications due to malaria. 47.7 pc (52 of 109) patients had relatively chloroquine resistant malaria. 87.4 pc (99 of 113) had complications whose percentage frequency of occurrence were: Anaemia 51.2 pc, diarrhoea and/or vomiting 42.2 pc, cerebral malaria +/- fits 39.2 pc, renal insufficiency +/- hyperkalaemia 26.4 pc, hypoglycaemia 15.6 pc, jaundice 15.2 pc, neuro-psychiatric 15.0 pc, shock 10.6 pc, concurrent sepsis 8.9 pc, pulmonary oedema 3.5 pc and hyperpyrexia 1.7 pc. Multiple complications in the same patient were common. The combination of cerebral malaria and renal insufficiency had the worst mortality (p less than 0.001). All patients dialysed, however, survived. Non-iron deficiency anaemia, 91.7 pc (51 of 55) and diarrhoea and/or vomiting, were common, worsened morbidity but not mortality (p = 0.555). A seriously-ill patient with malaria should be suspected of having complications and chloroquine resistance and should be referred promptly to a centre with facilities for dialysis. Anti-malaria drugs should be mixed in a dextrose solution and iron supplements should not be given routinely.
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PMID:Complications of seasonal adult malaria at a central hospital. 209 79

Of 138 patients with malaria, 90 were found to be having Plasmodium falciparum in their peripheral blood smears. Megaloblastosis alone or in combination with the other patterns of erythropoiesis was observed in 82.1 percent cases of chronic P. falciparum malaria as compared to 36.3 and 26.5 per cent cases of acute P. falciparum and P. vivax malaria respectively. Iron deficiency was observed in 15.5 percent cases of chronic P. falciparum, 18.2 per cent cases of acute P. falciparum and 13.3 per cent patients of P. vivax infection. Of patients with chronic falciparum malaria, 33.3 percent revealed features of both megaloblastosis and defective iron utilization and transient hypoplasia of marrow was observed in 8.9 per cent of these cases.
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PMID:Patterns of erythropoiesis and anaemia in malaria. 209 29

Nitric oxide (NO) produced by cytokine-treated macrophages and hepatocytes plays a vital role in protective host responses to infectious pathogens. NO inhibits iron-sulfur-dependent enzymes involved in cellular respiration, energy production, and reproduction. Synthesis of L-arginine-derived nitrite (NO2-), the oxidative end product of NO, directly correlates with intracellular killing of Leishmania major, an obligate intracellular protozoan parasite of macrophages: the level of NO2- production is a quantitative index for macrophage activation. The competitive inhibitor of NO synthesis, monomethylarginine (NGMMLA), inhibits both parasite killing and NO2- production. For Leishmania, the parasite itself participates in the regulation of this toxic effector mechanism. This participation is mediated by parasite induction of tumor necrosis factor alpha (TNF alpha), an autocrine factor of macrophages: NO synthesis by interferon-gamma (IFN-gamma)-treated cells can be blocked by monoclonal antibodies to TNF alpha. NO production by IFN gamma-treated hepatocytes is of special interest in malaria infections: sporozoite-infected hepatocytes kill the intracellular malaria parasite after treatment with IFN gamma; this killing is inhibited by NGMMLA.
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PMID:Cellular mechanisms of nonspecific immunity to intracellular infection: cytokine-induced synthesis of toxic nitrogen oxides from L-arginine by macrophages and hepatocytes. 212 24

Deferoxamine is a compound with iron chelating properties. Body depletion of this mineral, according to some authors, might influence the metabolism of plasmodia that thrive in the erythrocytes. In order to verify this possibility, we administered daily doses of 300 or 1.000 mg/kg of the compound, for five days and again 15 days, to mice infected with Plasmodium berghei. The parameters used to check the activity of deferoxamine were mortality of the animals and the count of blood parasites. The results showed a progressive increase of mortality and of the parasitemia in all animals, without differences in relation to the controls. So, at least on hand of the present study, the mentioned substance cannot be considered useful for the treatment of malaria.
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PMID:[The possible therapeutic effect of deferoxamine in experimental infections of mice by Plasmodium berghei]. 213 36

Chloroquine is a weak base which has been shown to inhibit lysosomal acidification. Chloroquine inhibits iron uptake in reticulocytes at a concentration of 0.5 mM. It is also effective in the control of malaria and other parasitic diseases. We now report that chloroquine inhibits NADH diferric transferrin reductase as well as the proton release stimulated by diferric transferrin from liver and HeLa cells. Ammonium chloride which also inhibits endosome acidification does not significantly inhibit the NADH diferric transferrin reduction. NADH diferric transferrin reductase of isolated rat liver plasma membrane is inhibited by chloroquine at concentrations similar to those required for inhibition of diferric transferrin reduction by whole cells. Ferricyanide reduction by whole cells is also inhibited by chloroquine. These observations provide an alternative mechanism for chloroquine control of acidification of endosomes and suggests a new approach to control of protozoal parasites through inhibition of a transmembrane oxidoreductase which controls transmembrane proton movement.
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PMID:Transplasma membrane electron and proton transport is inhibited by chloroquine. 217 87

The mechanism(s) underlying the apparent resistance to malaria in certain inherited red cell disorders and iron deficiency anaemia remain poorly understood. The possibility that microcytic erythrocytes might inhibit parasite development, by physical restriction or reduced supply of nutrients, has been considered for many years, and never formally investigated. We sought to determine whether in vitro growth studies of P. falciparum could provide evidence to suggest that small red cell size contributes to malaria resistance in those red cell disorders in which microcytosis is a characteristic feature. Invasion and development of P. falciparum in iron deficient red cells (mean values for mean cell volume [MCV] 66 fl, mean cell haemoglobin [MCH] 19 pg) and in the red cells of two gene deletion forms of alpha-thalassaemia (mean MCV 71 fl, MCH 22 pg) were normal, assessed both morphologically, and by 3H-hypoxanthine incorporation. Although parasite appearances were normal in all cell types, morphological abnormalities were noted in iron deficient and thalassaemic cells parasitized by mature stages of P. falciparum, notably cellular ballooning and extreme hypochromia of the red cell cytoplasm. Using electron microscopy, the red cell cytoplasm in parasitized thalassaemic cells showed reduced electron density and abnormal reticulation. Normal invasion rates were observed following schizogony in microcytic cells of both types. Our findings indicate that whilst minor morphological abnormalities may be detected in parasitized iron deficiency and thalassaemic erythrocytes, development of P. falciparum in these conditions is not limited by small erythrocyte size.
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PMID:Unrestricted growth of Plasmodium falciparum in microcytic erythrocytes in iron deficiency and thalassaemia. 218 91

Iron deficiency and vitamin A deficiency are both reported to predispose to infection morbidity and to mortality. In both situations, however, the data are insufficient to draw firm conclusions, primarily owing to flaws in the design of the studies. To be sure, these are difficult studies to carry out, and the investigators whose reports have been reviewed should be praised rather than adversely criticized for their efforts. In the case of iron deficiency, there is a further complication in interpretation, that is the suggestion that iron deficiency states may be protective and that conditions of iron overload may predispose to infection. These concepts appear to pertain most convincingly to malaria and Yersinia infections, and to situations in which iron dextran is given parenterally to young children in the first few months of life. There are still two few data to suggest that oral iron is harmful and there is no reason at present that it should not be employed for the correction of iron deficiency anemia.
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PMID:Micronutrients and susceptibility to infection. 219 69


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