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)

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

The effectiveness of antimalarials depends on its pharmacodynamics ie inhibitory effect on the parasites and unwanted effects on the host. It also depends on the pharmacokinetics of the drugs. The ideal antimalarials are drugs that show curative activity in the absence of toxicity to the host. Recommendation for antimalarial dosage regimens should be based on pharmacokinetic and pharmacodynamic studies in appropriate populations ie ethnic groups, adults children, and in pregnancy. Chloroquine remains the drug of choice for treating malaria caused by Plasmodium species other than P. falciparum. Even in the presence of chloroquine resistance the drug may still be quite useful, especially in areas with high communal immunity. In general sulfadoxine/pyrimethamine (S/P) should be used as an alternative antimalarial when chloroquine fails. The decision to change to S/P from chloroquine depends on many factors. Quinine still remains the drug of choice for severe chloroquine-resistant falciparum malaria. Resistance to mefloquine has appeared the exact mechanism being unknown. In general, before the use of any combination of antimalarial drugs the superiority (efficacy and side-effects) over each of the individual drugs should be clearly demonstrated. The combination of mefloquine with sulfadoxine/pyrimethamine was made on the grounds that the combination would delay the resistance to mefloquine. Desferrioxamine will hardly be an agent to be used on its own for treating malaria due to the high recrudescent rate. However, a recent report indicated that its association with antimalarial drugs in the management of severe and complicated falciparum malaria shortens fever and parasite clearance time and resolves complications faster than the standard antimalarial drug alone. Clinical trials with halofantrine has been done in several countries in the region from 1988 to the present with diverse results. Further studies on a larger scale should be carried out to ascertain whether these are due to variation in drug absorption or drug resistance. An improved formulation of halofantrine must be developed to ensure adequate absorption and bioavailability. The artermisinin group of antimalarials is known to be highly effective and independent, in its mode of action, from standard malaria drugs but associated with high recrudescent rate. Phase II studies are needed for determining/optimizing therapeutic dose regimens and to ensure safer and more effective use of these compounds.
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PMID:Overview: clinical pharmacology of antimalarials. 136 73

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

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

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

The susceptibility of the chloroquine-resistant malaria parasite Plasmodium falciparum (FCR-3) to a pyridoxal-based iron chelator was tested. 10 microM of the chelator 1[N-ethoxycarbonylmethyl-pyridoxy-lidenium]-2-[2'-pyri dyl] hydrazine bromide (code name L2-9) effectively inhibited growth in vitro of the parasites. Presaturation of the chelator with either ferric or ferrous iron partially blocked the inhibitory effect. Two hours' exposure of parasites to 20 microM L2-9 was sufficient to inhibit their growth irreversibly. Desferrioxamine blocked the inhibitory effect of L2-9. It is suggested that the chelator may be acting by generating free radicals in complexing intracellular iron.
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PMID:Inhibition of Plasmodium falciparum growth by a synthetic iron chelator. 220 2

Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.
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PMID:Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro. 220 10

The activity of desferrioxamine (Desferal) and desferrithiocin (a newly developed oral iron chelator) was evaluated against the liver stage of Plasmodium yoelii and P. falciparum in the rodent and the human hepatocyte in vitro culture system. The two iron chelators were found to inhibit the liver schizogony of both the rodent and the human Plasmodium species at concentrations achievable in vivo. P. falciparum proved to be more sensitive (ic 95% below 20 micromol/l than P. yoelii (ic 95% 50-100 micromol/l). As assessed by electron microscopy, drug administration was associated with focal clarification of the cytoplasm thought to be reversible. As desferrioxamine and desferrithiocin are known to be equally active on the blood stage of rodent and human plasmodia, iron chelators are deserving of further investigation as potential alternative candidates to existing drugs for radical cure of malaria.
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PMID:Iron chelators: in vitro inhibitory effect on the liver stage of rodent and human malaria. 305 18

It has been suggested that P. falciparum takes up iron from serum and that desferrioxamine, an iron chelating agent, inhibits parasite growth. We have now shown, however, that when all the iron is transferrin bound, P. falciparum, in culture, takes up less than 7 pmol Fe/10(9) parasites/24 h and that incorporation is increased only in the presence of a high molecular weight iron complex not naturally found in serum. Furthermore, removal of iron serum did not reduce parasite growth, and addition of excess iron was inhibitory. Desferrioxamine inhibited growth, but this inhibition was reduced under conditions in which the transfer of iron from transferrin to desferrioxamine was accelerated. We conclude that P. falciparum does not directly utilize serum iron and that desferrioxamine does not inhibit the parasite by interfering with the supply of iron from the incubation medium. The results are relevant to clinical data which suggest that added nutritional iron enhances the host susceptibility to malaria.
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PMID:A reappraisal of the effects of iron and desferrioxamine on the growth of Plasmodium falciparum 'in vitro': the unimportance of serum iron. 352 14

Plasmodium vinckei kills NMRI mice within 6 days after infection. Treatment of infected animals with desferrioxamine B for 5 days was found to suppress the parasitemia in a dose-dependent manner. The desferrioxamine B-iron complex (DFO/Fe3+) was ineffective, which suggests that the iron-chelating capacity of free desferrioxamine B is the antimalarial principle. All mice survived when they were given 0.3 mg desferrioxamine B/g every 12 hr for 14 days after infection. In addition, they were resistant to reinfection for at least 8 weeks. Eight months after desferrioxamine B treatment, all mice had lost their induced immunity and were as susceptible to malaria as controls. These results illustrate the dependence of the malarial parasite on ionic iron and suggests new methods for the therapy of parasitic diseases.
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PMID:Plasmodium vinckei: suppression of mouse infections with desferrioxamine B. 402 47


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