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

To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double-blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria.
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PMID:Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia. 163 34

Malaria constitutes one of the major health threats in the tropical and sub-tropical areas of the world. Yet, few advances were made in recent years in revealing the mode of action of the common and most economically affordable antimalarial drugs, the schizontocidal 4-aminoquinolines. Data presented indubitably repudiate the previous notions that these drugs act by either halting the feeding of the parasite on its host erythrocyte cytosol or repressing nucleic acid synthesis due to intercalation into the parasite's DNA. A novel target for drugs is outlined, i.e. they are shown to inhibit in vitro the release of iron from acidified host cell cytosol, consisting mostly of hemoglobin, a process that could provide this trace element to the parasite. Resistance to quinoline-containing drugs is the principal reason for the present resurgence of malaria. Drug-resistant parasites accumulate less of these weak base-like drugs in the acidic digestive vacuoles. A kinetic model is presented, indicating that diminishing drug accumulation is due to decreased vacuolar proton pump activity and is not a result of a putative multidrug resistance (MDR) efflux pump. Findings to date on the molecular biology of parasite mdr genes are reviewed. These indicate no correlation between gene expression or mutations and phenotypic drug resistance. Reversal of parasite drug resistance by relevant compounds in MDR cancer cells seems to involve mechanism(s) different from the inhibition of the MDR pump in cancer cells.
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PMID:Quinoline-containing antimalarials--mode of action, drug resistance and its reversal. An update with unresolved puzzles. 173 99

Anthropometric measurements were made and serum iron and ferritin levels determined in a group of Gambian children at the beginning of the rainy season and these findings were related to the malaria experience of the children during the following malaria transmission season. Susceptibility to malaria was not correlated with prior weight-for-age, height-for-age, weight-for-height or serum albumin, or with serum iron, serum iron binding capacity nor serum ferritin. Thus, our findings do not provide any support for the view that poor nutritional status, as assessed by anthropometric measurements, or iron deficiency protect against malaria infection. Children who developed a clinical attack of malaria accompanied by a high level of parasitaemia tended to have a higher mean weight-for-age at the beginning of the rainy season than did children who had a clinical attack accompanied by a low level of parasitaemia, but the difference between groups was not statistically significant. However, they had a significantly higher mean serum ferritin level (P less than 0.01).
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PMID:The relationship between anthropometric measurements and measurements of iron status and susceptibility to malaria in Gambian children. 178 Sep 80

A cross-sectional study on malaria was undertaken in May 1989 in the settlements of Kalta and Barsuan iron ore mines situated in a hilly area of Sundargarh district. Fever surveys revealed slide positivity rates of 33.9% and 34.8% in Kalta and Barsuan, respectively. Malaria infection rates as recorded through mass blood surveys in the resident population were 23.5 and 13.8%, respectively. Children up to 9 years age suffered most from malaria and in the age group of 2-9 years 37.3%, children had enlarged spleens with an average enlarged spleen (AES) index of 1.7. P. falciparum was the most prevalent species followed by P. vivax and P. malariae. Malaria vectors viz., An. fluviatilis and An. culicifacies were present in high densities. The present paper also brings out the economic loss due to malaria to the mining industry.
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PMID:Prevalence of malaria and economic loss in two major iron ore mines in Sundargarh district, Orissa. 181 Jul 46

Free radicals, intermediates in the tissue damage caused by radiation, are formed, inter alia, in interactions catalyzed by iron, which synergizes with radiation and some cytostatics (anthracyclins) in causing cell damage. Conversely, iron chelators can counteract cell damage. Similarly, antioxidants can slow atherogenesis, caused in part by oxidative stress and free radicals. Cell damage is also prevented by physiological defense systems like superoxide dismutase, against endogenous free radicals formed by granulocytes, monocytes, etc. Iron can thus induce free radicals which cause DNA double strand breaks and oncogene activation. This is suggested by four epidemiological studies suggesting a higher cancer risk in patients with larger iron stores than in those with small iron stores. In addition to its effect on carcinogenesis, iron can also maintain the growth of malignant cells as well as growth of pathogens. Breast cancer cells, for instance, display 5-15 times more transferrin receptors than normal breast tissue. Iron-carrying transferrin is in fact a growth factor. Hyposideremia in patients with cancer or infection is not a paraphenomenon but a functioning defense mechanism ('nutritional immunity'). If this immunity is broken by iron administration, relapses of diseases like tuberculosis, brucellosis, and malaria have been described. While iron-deficiency anemia should of course be diagnosed, treated and if possible prevented, there are good reasons to avoid over-utilization of medicamental iron.
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PMID:Iron, free radicals and cancer. 182 Apr 88

Dihydroorotate dehydrogenase (DHODase) has been purified 400-fold from the rodent malaria parasite Plasmodium berghei to apparent homogeneity by Triton X-100 solubilization followed by anion-exchange, Cibacron Blue F3GA-agarose affinity, and gel filtration chromatography. The purified enzyme has a molecular mass of 52 +/- 2 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and of 55 +/- 6 kDa by gel filtration chromatography, and it has a pI of 8.2. It is active in monomeric form, contains 2.022 mol of iron and 1.602 acid-labile sulfurs per mole of enzyme, and does not contain a flavin cofactor. The purified DHODase exhibits optimal activity at pH 8.0 in the presence of the ubiquinone coenzyme CoQ6, CoQ7, CoQ9, or CoQ10. The Km values for L-DHO and CoQ6 are 7.9 +/- 2.5 microM and 21.6 +/- 5.5 microM, respectively. The kcat values for both substrates are 11.44 min-1 and 11.70 min-1, respectively. The reaction product orotate and an orotate analogue, 5-fluoroorotate, are competitive inhibitors of the enzyme-catalyzed reaction with Ki values of 30.5 microM and 34.9 microM, respectively. The requirement of the long-chain ubiquinones for activity supports the hypothesis of the linkage of pyrimidine biosynthesis to the electron transport system and oxygen utilization in malaria by DHODase via ubiquinones [Gutteridge, W. E., Dave, D., & Richards, W. H. G. (1979) Biochim. Biophys. Acta 582, 390-401].
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PMID:Purification and characterization of dihydroorotate dehydrogenase from the rodent malaria parasite Plasmodium berghei. 184 78

We describe here a family of biomimetic iron carriers that display high binding efficiency for ferric ions and favorable permeation properties across erythrocytic membranes. These carriers inhibit in vitro growth of Plasmodium falciparum by scavenging intracellular iron. The chemical features were realized by reproducing the iron-binding cavities of natural iron carriers (siderophores) and by systematic substitutions of their hydrophilic envelopes for more hydrophobic ones. In contrast to natural carriers, which participate in receptor-mediated iron uptake in cells and act as growth promoters, our synthetic carriers were designed to penetrate cellular membranes by diffusion, scavenge intracellular iron, and thereby act as growth inhibitors. Based on these properties we designate the compounds reversed siderophores and refer to the specific analogs of the natural ferrichrome as synthetic ferrichromes. The antimalarial activity of the synthetic ferrichromes correlated with their lipophilicity, and this antimalarial activity was averted when the chelators were applied as iron (III) complexes. The sites of synthetic ferrichrome action reside in the intraerythrocytic parasite and not in serum or on normal erythrocyte components. The agents were effective against all stages of parasite growth and against a variety of multidrug-resistant strains of P. falciparum. The most potent agent of this synthetic ferrichrome series, SF1-ileu, was not toxic to mammalian cells in culture and was 15-fold more potent and 20-fold faster acting than desferrioxamine. Taken in toto, these agents constitute a series of promising candidates for future use in malaria chemotherapy.
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PMID:Reversed siderophores act as antimalarial agents. 186 83

Plasma membrane electron transport was studied in a protozoan cell, Tetrahymena pyriformis, by assaying transmembrane ferricyanide reduction and the reduction of iron compounds. The rates of ferricyanide reduction varied between 0.5 and 2.5 mumol/g dry wt. per min, with a pH optimum at 7.0-7.5. Other active non-permeable electron acceptors, with redox potentials from +360 to -125 mV, were cytochrome c, hexaammine ruthenium chloride, ferric-EDTA, ammonium ferric citrate, and indigo di-, tri- and tetrasulfonates. It was found that Tetrahymena cells can reduce external electron acceptors with redox potentials at pH 7.0 down to -125 mV. Ferricyanide stimulates ciliary action. Transmembrane ferricyanide reduction by Tetrahymena was not inhibited by such mitochondrial inhibitors as antimycin A, 2-n-heptyl-4-hydroxyquinoline N-oxide, or potassium cyanide, but it responded to inhibitors of glycolysis. Transmembrane ferricyanide reduction by Tetrahymena appears to involve a plasma membrane electron transport chain similar to those of other animal cells. As in other cells, the transmembrane electron transport is associated with proton release which may be involved in internal pH control. The transmembrane redox system differs from that of mammalian cells in a 20-fold greater sensitivity to chloroquine and quinacrine. The Tetrahymena ferricyanide reduction is also inhibited by chlorpromazine and suramin. Sensitivity to these drugs indicates that the transplasma membrane electron transport and associated proton pumping may be a target for drugs used against malaria, Trypanosomes and other protozoa.
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PMID:Chloroquine-sensitive transplasmalemma electron transport in Tetrahymena pyriformis: a hypothesis for control of parasite protozoa through transmembrane redox. 190 70

The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes, and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3-hydroxypyridin-4-ones, a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast, there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94, and 96 had a strong antimalarial effect, similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action, our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.
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PMID:The effect of N-alkyl modification on the antimalarial activity of 3-hydroxypyridin-4-one oral iron chelators. 199 Nov 72

Ferriprotoporphyrin IX (FPIX) forms a coordination complex with chloroquine, an anti-malarial drug. The FPIX-chloroquine complex strongly promotes the peroxidative cleavage of phospholipid membrane. Iron in the complex is essential for the complex to induce lipid peroxidation. In this paper a more detailed mechanism of the complex promoted lipid peroxidation was investigated. Apotransferrin exhibited no apparent inhibition of the complex evoked lipid peroxidation, indicating no mobilization of iron from the complex. No significant inhibitory effect by superoxide dismutase, catalase and sodium benzoate on the complex induced lipid peroxidative reaction, suggesting little involvement of superoxide anion, hydrogen peroxide and hydroxyl radical in the reaction. Quinine and mefroquine, blood shizontocidal drugs as well as chloroquine, formed a complex with FPIX and each complex more rapidly induced lipid peroxidation than FPIX alone. Primaquine, which is not as effective as quinine or mefroquine on an intraerythrocytic malaria parasite, neither coordinated to FPIX nor promoted lipid peroxidation. The complex formation between FPIX and chloroquine, quinine or mefroquine could play a key role in their anti-malarial actions.
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PMID:The chemical basis for the ferriprotoporphyrin IX-chloroquine complex induced lipid peroxidation. 204 70


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