Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A recombinant iron-containing superoxide dismutase (recFeSOD) of Entamoeba histolytica was produced in a prokaryotic expression system. Purified recFeSOD was found to be enzymatically active as determined by (i) inhibition of ferri-cytochrome c reduction, (ii) dismutation of superoxide anions generated by human neutrophils and (iii) inhibition of nitroblue tetrazolium reduction. The enzymatic properties of recFeSOD were similar to those of the native protein in trophozoite extracts. In an ELISA using recFeSOD as antigen, 96% of sera from patients having invasive amebiasis were reactive whereas none of the healthy controls or of patients suffering from malaria, bacterial or viral infections were reactive. Only sera of Toxoplasma-, Leishmania- or Trypanosoma-infected individuals exhibited partial cross-reactivity to recFeSOD.
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PMID:Recombinant expression, purification and biochemical characterization of a superoxide dismutase from Entamoeba histolytica. 134 Mar 12

Desferrioxamine B (DFO, Desferal), an iron chelator, was earlier shown to be active against Plasmodium falciparum in vitro and in vivo. The present open pilot study served to assess its clinical tolerability and efficacy in human malaria under hospital conditions. Continuous intravenous DFO was administered to 28 Thai males at a dose of 100 mg/kg over 24 h for 3 consecutive days. No other antimalarial therapy was administered unless recrudescence had occurred. The first 14 patients had symptomatic Plasmodium vivax (P.v.) malaria, while the other 14 patients were suffering from uncomplicated Plasmodium falciparum malaria (P.f.). Both groups were treated in Bangkok, where malaria transmission does not take place, and followed up, on the ward, for 3 weeks (P.v. group) or 4 weeks (P.f. group) after the start of therapy. In both groups DFO reduced the parasitaemia to zero within 106 and 57 h respectively. The fever clearance time was 55 and 60 h, respectively. The overall tolerability of DFO was good but 4 P.v. and 5 P.f. patients had transient visual blurring. Recrudescences were observed on average 15, respectively 10 days after the start of therapy. Only 2 P.v. patients and none of the P.f. patients remained free of recrudescences during the observation period. There was no apparent gametocytocidal effect of DFO on P.f.
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PMID:Plasmodicidal effect of desferrioxamine B in human vivax or falciparum malaria from Thailand. 135 61

Human monocyte-derived macrophages ingest diamide-treated red blood cells (RBC), anti-D immunoglobulin (Ig)G-opsonized RBC, or Plasmodium falciparum ring-stage parasitized RBC (RPRBC), degrade ingested hemoglobin rapidly, and can repeat the phagocytic cycle. Monocytes fed with trophozoite-parasitized RBC (TPRBC), which contain malarial pigment, or fed with isolated pigment are virtually unable to degrade the ingested material and to repeat the phagocytic cycle. Monocytes fed with pigment display a long-lasting oxidative burst that does not occur when they phagocytose diamide-treated RBC or RPRBC. The phorbol myristate acetate-elicited oxidative burst is irreversibly suppressed in monocytes fed with TPRBC or pigment, but not in monocytes fed with diamide-treated or IgG-opsonized RBC. This pattern of inhibition of phagocytosis and oxidative burst suggests that malarial pigment is responsible for the toxic effects. Pigment iron released in the monocyte phagolysosome may be the responsible element. 3% of total pigment iron is labile and easily detached under conditions simulating the internal environment of the phagolysosome, i.e., pH 5.5 and 10 microM H2O2. Iron liberated from pigment could account for the lipid peroxidation and increased production of malondialdehyde observed in monocytes fed with pigment or in RBC ghosts and liposomes incubated at pH 6.5 in presence of pigment and low amounts of H2O2. Removal of the labile iron fraction from pigment by repeated treatments with 0.1 mM H2O2 at pH 5.5 reduces pigment toxicity. It is suggested that iron released from ingested pigment is responsible for the intoxication of monocytes. In acute and chronic falciparum infections, circulating and tissue-resident phagocytes are seen filled with TPRBC and pigment particles over long periods of time. Moreover, human monocytes previously fed with TPRBC are unable to neutralize pathogenic bacteria, fungi, and tumor cells, and macrophage responses decline during the course of human and animal malaria. The present results may offer a mechanistic explanation for depression of cellular immunity in malaria.
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PMID:Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. 140 49

Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15-50% despite antimalarial therapy. In order to determine whether combining iron chelation with quinine therapy speeds recovery of consciousness, the authors conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be under age 6, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they cannot be aroused. Deferoxamine (100 mg/kg of body weight/day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pryimethamine. The time to recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 time that among the 41 who received the placebo (95% confidence interval [CI], 0.7-2.3; the median time to recovery was 20.2 hours in the deferoxamine group, and 43.1 hours in the placebo group (p=0.38). Among 50 patients in deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95% CI, 1.1-4-7), decreasing the median recovery time from 68.2 to 24.1 hours (p=0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95% CI, 1.2-3.6). Among all 83 patients, mortality was 17% in the deferoxamine group and 22% in the placebo group (p=0.52). It is concluded that iron chelation therapy may speed the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.
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PMID:Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. 845 79

Non-heme iron is essential for the asexual growth of the human malaria parasite Plasmodium falciparum in mature erythrocytes. Utilization of iron bound to serum transferrin by the parasitized cells has been postulated, but direct evidence for its specific delivery has not been reported. Here we demonstrate that normal levels of transferrin in human serum are not required for intraerythrocytic P. falciparum growth: culture medium immunodepleted 500-1000 fold in human transferrin was capable of supporting parasitemias and rates of invasion comparable to those observed in non-depleted medium. 55Fe bound to transferrin was not taken up by infected cells. A transferrin-independent non-heme iron uptake activity was, however, detected in both infected and uninfected erythrocytes when iron was presented to the cells as 55Fe-NTA or 55Fe-citrate. Although the uptake activity was not parasite specific, the radiolabel was found in association with parasites mechanically released from the infected erythrocytes, indicating that it is delivered to the intracellular organism. Evidence is presented that the transferrin-independent iron uptake activity is time-, temperature- and concentration-dependent, but apparently not energy-dependent.
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PMID:A transferrin-independent iron uptake activity in Plasmodium falciparum-infected and uninfected erythrocytes. 143 78

The emergence of drug resistant malaria has prompted an intensified search for new antimalarials or combinations of such drugs. Iron chelating agents may represent a new approach to antimalarial treatment and could possibly be used in combination with classical antimalarials. Plasmodium falciparum (FCR-3) strain used at a 1% haematocrit, was subjected to various combinations of the classic antimalarials (chloroquine, pyrimethamine and quinine) and iron chelating agents (desferrioxamine and 2,2'-bipyridyl) in vitro. Tritiated hypoxanthine incorporation was used to determine the growth of the malarial parasites. The iron chelating agents and classic antimalarials when tested alone were found to inhibit the growth of the late stages of the parasite. The combination of the classic antimalarials and iron chelating agents resulted in additive effects on the in-vitro growth of P. falciparum.
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PMID:The combined effect of iron chelators and classical antimalarials on the in-vitro growth of Plasmodium falciparum. 145 91

Malaria parasites have been shown to be more susceptible to oxidative stress than their host erythrocytes. In the present work, a chloroquine resistant malaria parasite, Plasmodium falciparum (FCR-3) was found to be susceptible in vitro to a pyridoxal based iron chelator--(1-[N-ethoxycarbonylmethylpyridoxlidenium]-2-[2'-pyridyl ] hydrazine bromide--(code named L2-9). 2h exposure to 20 microM L2-9 was sufficient to irreversibly inhibit parasite growth. Desferrioxamine blocked the drug effect, indicating the requirement for iron. Oxygen however, was not essential. Spectrophotometric analysis showed that under anoxic conditions, L2-9-Fe(II) chelate undergoes an intramolecular redox reaction which presumably involves a one electron transfer and is expected to result in the formation of free radical. Spin trapping coupled to electron spin resonance (ESR) studies of L2-9-iron chelate showed that L2-9-Fe(II) produced free radicals both in the presence and absence of cells, while L2-9-Fe(III) produced free radicals only in the presence of actively metabolising cells.
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PMID:Growth inhibition of Plasmodium falciparum involving carbon centered iron-chelate radical (L., X-)-Fe(III) based on pyridoxal-betaine. A novel type of antimalarials active against chloroquine-resistant parasites. 166 64

Dihydroorotate dehydrogenase purified from mitochondria of Plasmodium berghei, a rodent malaria parasite, mediates production of superoxide radical during oxidation of dihydroorotate to orotate. Reduction of dichlorophenolindophenol or cytochrome c or nitroblue tetrazolium was significantly inhibited by superoxide dismutase or theonyltrifluoroacetone, a specific iron chelator of the enzyme. These results, together with the recent evidence of manganese-superoxide dismutase activity in malarial mitochondria [Ranz, A., and Meshnick, S.R. (1989) Exp. Parasitol. 69, 125-128], suggest that the production of superoxide radical may occur in vivo.
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PMID:Malarial dihydroorotate dehydrogenase mediates superoxide radical production. 166 40

Iron and folate status were evaluated in a group of 106 Gambian children with malaria and variable degrees of anaemia. In children with malaria, normal or increased levels of red cell folate were found in 75 patients at presentation and in 15 patients 1-2 weeks after treatment with anti-malarials alone, despite the presence of giant metamyelocytes and megaloblasts in the bone marrow in some cases. Twenty-eight per cent of patients were found to have deficient bone marrow iron stores but malaria could not be directly implicated as the cause of this deficiency. Iron deficiency could also not be implicated as the sole cause of dyserythropoiesis in patients with malarial anaemia. Excess storage iron and the presence of ring sideroblasts were found in the bone marrow in some cases. It is concluded that the morphological changes including dyserythropoiesis, occasional megaloblasts, giant metamyelocytes and ring sideroblasts seen in the bone marrows of these children are manifestations of disturbed marrow function in malaria and are not related to haematinic deficiency. Because of the high rate of iron deficiency found in these patients it is recommended that Gambian children with severe anaemia should receive iron therapy after adequate treatment of malaria.
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PMID:Iron and folate status in Gambian children with malaria. 170 43

A free radical is any species capable of independent existence that contains one or more unpaired electrons. Free radical reactions have been implicated in the pathology of more than 50 human diseases. Radicals and other reactive oxygen species are formed constantly in the human body, both by deliberate synthesis (e.g. by activated phagocytes) and by chemical side-reactions. They are removed by enzymic and nonenzymic antioxidant defence systems. Oxidative stress, occurring when antioxidant defences are inadequate, can damage lipids, proteins, carbohydrates and DNA. A few clinical conditions are caused by oxidative stress, but more often the stress results from the disease. Sometimes it then makes a significant contribution to the disease pathology, and sometimes it does not. Several antioxidants are available for therapeutic use. They include molecules naturally present in the body [superoxide dismutase (SOD), alpha-tocopherol, glutathione and its precursors, ascorbic acid, adenosine, lactoferrin and carotenoids] as well as synthetic antioxidants [such as thiols, ebselen (PZ51), xanthine oxidase inhibitors, inhibitors of phagocyte function, iron ion chelators and probucol]. The therapeutic efficacy of SOD, alpha-tocopherol and ascorbic acid in the treatment of human disease is generally unimpressive to date although dietary deficiencies of the last two molecules should certainly be avoided. Xanthine oxidase inhibitors may be of limited relevance as antioxidants for human use. Exciting preliminary results with probucol (antiatherosclerosis), ebselen (anti-inflammatory), and iron ion chelators (in thalassaemia, leukaemia, malaria, stroke, traumatic brain injury and haemorrhagic shock) need to be confirmed by controlled clinical trials. Clinical testing of N-acetylcysteine in HIV-1-positive subjects may also be merited. A few drugs already in clinical use may have some antioxidant properties, but this ability is not widespread and drug-derived radicals may occasionally cause significant damage.
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PMID:Drug antioxidant effects. A basis for drug selection? 172 62


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