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)

We report here the nucleotide sequence of hsp90 (heat shock protein 90) of Plasmodium falciparum. Computer analysis of the deduced protein sequence revealed an unusually large region of charged amino acids when compared to hsp90 from other species. This region shows striking homology to the calcium binding domain of calreticulin, the major calcium binding protein of endoplasmic reticulum. Phylogenetic tree analysis indicates that P. falciparum hsp90 is more closely related to hsp90 from plants than to hsp90 from vertebrates or other parasites. The malaria hsp90 is an ATP binding protein encoded by a single gene constitutively expressed in both asexual (trophozoite) and sexual (gametocyte) stage parasites. The hsp90 protein is homologous to a previously identified 90-kDa antigen strongly recognised by both sera from vaccinated monkeys and monoclonal antibody XIV/7.
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PMID:Molecular characterization of the heat shock protein 90 gene of the human malaria parasite Plasmodium falciparum. 783 76

To test the efficacy of chlorproguanil prophylaxis, 156 malaria-free schoolchildren in the coastal region of Kenya were allocated at random to receive either 7.5 mg chlorproguanil daily, 50 mg chlorproguanil weekly, 100 mg proguanil daily, or 100 mg calcium lactate weekly (placebo). The children were followed up daily for 169 d, by which time Plasmodium falciparum parasitaemia had occurred in 92% of the placebo group, 31% of the daily proguanil group, 38% of the daily chlorproguanil group and 55% of the weekly chlorproguanil group. There was significant reduction (P < 0.001) in the risk of parasitaemia in all the groups receiving chemoprophylaxis. Daily chlorproguanil and daily proguanil were equally effective, and significantly more effective than weekly high dose chlorproguanil. No significant toxicity was reported or observed. Thus daily chlorproguanil 20 mg/60 kg is a cheap and effective alternative to proguanil for chemoprophylaxis.
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PMID:Daily chlorproguanil is an effective alternative to daily proguanil in the prevention of Plasmodium falciparum malaria in Kenya. 797 77

Various types of calcium channel blockers verapamil, gallopamil, devapamil, diltiazem, and nifedipine and a calmodulin inhibitor R24571 were evaluated for reversal of chloroquine(CQ) resistance of Plasmodium falciparum in an in vitro system. The results demonstrated that some of the above Ca2+ antagonists such as verapamil, gallopamil, devapamil and diltiazem were found to exert remarkable reversal activity of CQ resistance of the falciparum parasite in vitro, while the others like nifedipine and R24571 had no reversal properties of CQ resistance of the parasite. In addition, reversal activities of the CQ resistance by enantiomers of some calcium channel blockers(R-(+)-verapamil, R-(+)-gallopamil and R-(+)-devapamil), which do not bind to the calcium channel, were also observed in this study. The data strongly indicate that the mechanism of reversal of CQ resistance of falciparum malaria in vitro is independent of the calcium channel.
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PMID:Reversal of chloroquine resistance in falciparum malaria by some calcium channel inhibitors and optical isomers is independent of calcium channel blockade. 806 42

The merozoite surface protein-1 of the human malaria parasite Plasmodium falciparum undergoes an extracellular proteolytic cleavage (secondary processing) intrinsic to successful erythrocyte invasion. In the T9/96 clone of P. falciparum the protease responsible has been characterised as a membrane-associated, calcium-dependent activity, sensitive to irreversible inhibitors of serine proteases. Here we extend these studies and show that secondary processing activity in intact merozoites of P. falciparum strains expressing the alternative dimorphic type of merozoite surface protein-1 has identical characteristics, and that the cleavage site is close to or identical to that in the protein from T9/96. The protease responsible is shown to be parasite-derived, and able to catalyse processing of native substrate only when present in the same membrane. Cleavage of the substrate follows apparent first order kinetics for at least 2 half-lives. It is concluded that secondary processing of both dimorphic forms of the P. falciparum merozoite surface protein-1 is a conserved event, mediated by a mechanistically conserved protease located on the merozoite surface. These observations provide clues to the identity of the protease and show that, irrespective of the dimorphic type, secondary processing results in the same, highly conserved region of the merozoite surface protein-1 remaining on the surface of the invading merozoite.
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PMID:A conserved parasite serine protease processes the Plasmodium falciparum merozoite surface protein-1. 811 10

To investigate metabolic disturbances in an animal model of human malaria, four rhesus monkeys (Macaca mulatta) were infected with Plasmodium coatneyi, a parasite which induces cytoadherence of infected erythrocytes. When moribund or the parasitaemia had plateaued, the monkeys were sacrificed (3 animals) or treated with chloroquine (1 animal). Blood and cerebrospinal fluid (CSF) were sampled at intervals between inoculation and sacrifice or treatment. Arterial and CSF glucose and lactate rose during infection, indicating evolving insulin resistance. The arteriovenous difference in glucose concentration also increased, consistent with increased glucose consumption by parasitised tissues. Arterial plasma lactate rose but a positive arteriovenous concentration difference suggested tissue lactate uptake. The animal with the highest plasma lactate at sacrifice remained hyperglycaemic but also had the highest CSF lactate, the greatest cerebral sequestration and neurological depression, and biochemical and histological evidence of severe hepatic pathology. Serum cholesterol and corrected serum calcium fell consistently during infection; serum phosphate was also reduced in animals without renal impairment. These preliminary results indicate that lactic acidosis is a late complication of severe malaria and, by implication from this and other studies, hypoglycaemia occurs even later; other metabolic changes during P. coatneyi infection in rhesus monkeys also parallel those of severe falciparum malaria in humans. The model could be used in further studies of malaria-associated metabolic dysfunction and its management.
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PMID:Metabolic disturbances in Plasmodium coatneyi-infected rhesus monkeys. 802 92

The kinetics of phosphoinositol 4,5 bisphosphate hydrolysis products in activated Plasmodium falciparum gametocytes suggests a role for inositol trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG) in the signal transduction pathway of malaria gametocytes. To investigate further this role, compounds that have an effect on the metabolism and biologic functions of these second messengers were tested in an in vitro system. Gentamycin, 2,3 diphosphoglycerate (2,3 DPG) and magnesium ion (Mg2+), inhibitors of Ins(1,4,5)P3 5' phosphatase, all stimulated gametocytes to exflagellate in suspended animation buffer, pH 7.4, at room temperature. In addition, methylxanthines, caffeine and theobromine, calcium ionophore (A-23187), and external calcium also stimulated exflagellation. In contrast, neomycin, an aminoglycoside that inhibits phospholipase C activity, and heparin, an antagonist of Ins(1,4,5)P3 binding to its receptor, inhibited microgamete formation. Quinine and chloroquine which can inhibit both phospholipase A and C activity also inhibited gametocyte exflagellation. The consistent manner in which these various compounds affect gametocyte activation further implicates phosphoinositol turnover in the signal transduction pathway of falciparum gametocytes.
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PMID:Use of pharmacological agents to implicate a role for phosphoinositide hydrolysis products in malaria gamete formation. 824 Apr 17

The induction mechanism of gamete formation (gametogenesis) in a rodent malaria parasite, Plasmodium berghei, was investigated using Ca2+ antagonists, protein kinase inhibitors and amiloride, an inhibitor of monovalent cation/H+ exchange. Treatment with 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8, a Ca2+ release inhibitor) and W-7/W-66 (calmodulin inhibitors) blocked formation of male gametes by inhibiting DNA synthesis from 1.5C to 8C level. In contrast, inhibitors of cAMP/cGMP-dependent protein kinases such as H-8, H-87, H-89 and staurosporine also ceased the development of gametocytes, but DNA synthesis in male gametocytes occurred as in the controls. Electron microscopy revealed that male gametocytes treated with TMB-8 and W-7 failed to enlarge nuclei and to form axonemes in the cytoplasm. In female gametocytes, treatment with both Ca2+ antagonists resulted in a dramatic morphological change in the endoplasmic reticulum (ER), which is thought to be a Ca2+ store. The ER network condensed near nuclei and was laminated by the abnormal attachment of ribosomes between two ER membranes. On the other hand, male gametocytes treated with protein kinase inhibitors or amiloride had enlarged nuclei and axonemes, but failed to develop further. The ER network in female gametocytes treated with these inhibitors was similar to that in the controls.
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PMID:The roles of Ca2+/calmodulin- and cGMP-dependent pathways in gametogenesis of a rodent malaria parasite, Plasmodium berghei. 838 16

Previous studies have shown depressed serum corrected calcium and phosphate concentrations in acute falciparum malaria. To characterize malaria-associated disturbances in mineral homoeostasis further, serum ionized calcium and intracellular phosphate were measured in 18 patients (10 with falciparum malaria, 8 with vivax malaria) and 10 healthy controls. Six patients (4 falciparum, 2 vivax) had admission serum ionized calcium concentrations below the absolute control range (< 1.15 mmol/litre) and a further six (3 falciparum, 3 vivax) developed ionized hypocalcaemia during treatment. The patients with falciparum malaria had the lowest values at presentation (median [95% confidence intervals in brackets]: 1.17 [1.12-1.23] vs. 1.20 [1.18-1.24] mmol/litre in controls, P = 0.035) in the presence of depressed simultaneous serum parathormone concentrations (1.2 [0.6-1.9] vs. 1.6 [1.1-2.6] pmol/litre; P = 0.05). Admission serum phosphate concentrations were lower in the malaria patients (P = 0.007 vs. controls), especially in those with falciparum malaria (0.85 [0.7-1.1] vs. 1.2 [1.1-1.3] mmol/litre in controls; P = 0.002); patients with falciparum malaria also had significantly lower intracellular phosphate than controls (0.74 [0.58-0.90] vs. 0.88 [0.66-1.04] mmol/litre red cells; P = 0.047). There was a weak association between serum corrected and ionized calcium in the malaria patients (rs = 0.31, n = 18, P > 0.1), but serum and intracellular phosphate correlated significantly (rs = 0.71, n = 17, P < 0.001) with a regression line slope of 0.49 and intercept of 0.27 mmol/litre of red cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum ionized calcium, serum and intracellular phosphate, and serum parathormone concentrations in acute malaria. 846 94

A study was conducted in vitro to assess the ability of calcium antagonists to reverse trypanocidal resistance in Trypanosoma evansi. Susceptibility patterns of sensitive and resistant parasites were evaluated against calcium antagonists of several chemical classes (verapamil, cyproheptidine, desipramine and chlopromazine), alone and in combination with suramin, diminazene aceturate or melarsen oxide cyteamine. The putative resistance modulators were intrinsically antitrypanosomal, but were unable to reverse resistance to any of the trypanocides tested. It was thus concluded that resistance to these trypanocides in T. evansi may differ from drug resistance mechanisms occurring in cancer cells, malaria or in South American trypanosomosis, where calcium antagonists have successfully reversed resistance.
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PMID:Trypanocidal resistance in Trypanosoma evansi in vitro: effects of verapamil, cyproheptidine, desipramine and chlorpromazine alone and in combination with trypanocides. 863 92

Modulating agents that circumvent the Plasmodium falciparum resistance to antimalarials are components without any intrinsic antimalarial activity but able, in association with a standard antimalarial drug, to restore the sensitivity of Plasmodium falciparum to this drug. Two hypotheses are forwarded about their possible mechanisms of action : the mechanisms involving the inhibition of the drug efflux and the mechanisms involving the inhibition of antimalarial drug metabolic degradation. None of these mechanisms is able to alone explain the effect of all modulating agents. The future use prospects of these compounds are limited by their in vivo toxicity. That relevant to the calcium channels blockers seems to be circumvented by the use of dextro-enantiomers. A toxicity relevant to a possible accumulation of the antimalarial in healthy, non target cells must be also suspected. Moreover the use of these agents evidences a socio-economic problem : a complete new development of the association (antimalaria plus modulatin drugs) is needed and that, in developing countries. Nevertheless, the agents modulating the Plasmodium falciparum resistance are a new approach for the treatment of resistant malaria which might give a recrudescence of activity to the old antimalarials as chloroquine.
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PMID:[Role of modulators in Plasmodium falciparum resistance to antimalarials]. 864 62


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