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)

Human cerebral malaria is caused by a protozoan parasitic with no cure till date. The isolation of brain capillaries i.e. microvessels has permitted the in vitro study related to cerebral function. Microvessels were isolated from normal and P. yoelii infected mice brain cortex and subjected to biochemical characterization by the following enzyme markers viz alkaline phosphatase, gamma-glutamyI transpeptidase and monoamine oxidase and electron microscopically. Limited studies have been carried out in relation to drug metabolizing enzymes in cerebral microvessels of rodents. The present studies have been carried out in relation to status of drug metabolizing enzymes during P. yoelii infection in cerebral microvessels of mice. The data obtained depicted a clear cut impairment of cytochrome P450 (a terminal monooxygenase) and related indices viz b5, benzopyrene hydroxylase, aminopyrene-n-demethylase, aniline hydroxylase except NADH cytochrome e reductase which increased during P. yoelii infection in mice as compared to normal. Further the oral drug administration (arteether) treatment brought back the altered MFO system normal a week alter cessation of drug treatment.
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PMID:Studies on drug metabolizing enzymes during arteether treatment of Plasmodium yoelii nigeriensis infected mice cerebral microvessels. 1663

With 2-methoxy-6-chloroacridone as a lead compound, we synthesized and tested acridone derivatives to develop a better understanding of the anti-malarial structure-activity relationships. Over 30 acridone derivatives were synthesized. The most potent compounds contained extended alkyl chains terminated by trifluoromethyl groups and located at the 3-position of the tricyclic system. Acridones optimized in the length of the side chain and the nature of the terminal fluorinated moiety exhibited in vitro anti-malarial IC(50) values in the low nanomolar and picomolar range and were without cytotoxic effects on the proliferation and differentiation of human bone marrow progenitors or mitogen-activated murine lymphocytes at concentrations up to 100,000-fold higher. Based on a structural similarity to known anti-malarial agents it is proposed that the haloalkoxyacridones exert their anti-malarial effects through inhibition of the Plasmodium cytochrome bc(1) complex. Haloalkoxyacridones represent an extraordinarily potent novel class of chemical compounds with the potential for development as therapeutic agents to treat or prevent malaria in humans.
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PMID:Evaluation and lead optimization of anti-malarial acridones. 1682 46

The diverse habitats and diets encountered during the life cycle of an Anopheles mosquito have necessitated the development of extensive families of detoxification enzymes. Expansion of the three detoxification enzyme families (cytochrome P450s, carboxylesterases and glutathione transfereases), has occurred in mosquitoes compared with Drosophila, however, very little is known regarding the developmental expression of theses genes. Using a custom made microarray we determined the expression profile of the detoxification genes in adults, larvae and pupae of the malaria vector A. gambiae. The expression of approximately one quarter of these genes was developmentally regulated. The expression profile of each of these genes and the information this data provides on putative functions of the mosquito detoxification enzymes is discussed.
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PMID:Differential expression of the detoxification genes in the different life stages of the malaria vector Anopheles gambiae. 1690 39

We analyzed mitochondrial genomes of two avian malaria protozoa, Plasmodium gallinaceum and Plasmodium juxtanucleare. Both mitochondrial genomes were estimated to be 6,002 and 6,014 bp in length, respectively, and to have the identical gene organization and contents to that of other Plasmodium species previously analyzed; three functional genes for cytochrome c oxidase subunit I, III, and cytochrome (cyt b), with following sets of discontinuous and scrambled 15 ribosomal subunit RNA (rRNA) genes. Similarities of the three protein-coding genes showed closer relationship within avian malaria protozoa rather than mammalian Plasmodium species. In addition, we showed the tandem repeated structure of each mitochondrial genome of both P. gallinaceum and P. juxtanucleare as well as previously found in mammalian Plasmodium species. This study revealed the complete sequences and structure of the mitochondrial genomes of avian malaria protozoa for the first time.
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PMID:Complete nucleotide sequences of the mitochondrial genomes of two avian malaria protozoa, Plasmodium gallinaceum and Plasmodium juxtanucleare. 1704 98

Malaria has been reported to modulate the activity of cytochrome-P450 enzymes (CYP). Since CYPs are involved both in the activation and detoxication of xenobiotics, we investigated whether malaria would modify the effects of chemical carcinogens in the bone-marrow micronucleus assay. Female C57BL6 mice were infected with Plasmodium berghei (ANKA) and treated (ip route) with cyclophosphamide (CPA, 25 mg/kg body weight), 7,12-dimethylbenz[a]anthracene (DMBA, 50mg/kg body weight) or ethyl methanesulfonate (EMS, 150 mg/kg body weight), on post-infection days 9-12 when parasitemia was > or =9% of RBC. Controls were age-paired non-infected mice. Bone marrows were sampled at 24 and 48 h (CPA), 24 h (EMS) or 48 h (DMBA) after treatment. The background incidence of polychromatic erythrocytes with micronuclei (MN-PCE) in malaria-infected mice was approximately twofold the background incidence in non-infected controls. Effects of indirect clastogens (CPA and DMBA) in the micronucleus assay were attenuated while the effect of EMS, a direct clastogen, was enhanced by infection. In a separate experiment, malaria was shown to decrease activities of ethoxy-(EROD, a marker for CYP1A) and benzyloxy-(BROD, CYP2B) resorufin-O-dealkylases in liver microsomes. The foregoing findings are consistent with the hypothesis that malaria-caused attenuation of genotoxicity arose from a down modulation of CYP isoforms that convert CPA (CYP2B) and DMBA (CYP1A) into their active metabolites.
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PMID:Malaria infection modulates effects of genotoxic chemicals in the mouse bone-marrow micronucleus test. 1785 Nov 16

Anopheles sundaicus s.l., a major malaria vector taxon, occurs primarily along coastal areas and on islands in Southeast Asia. Our previous studies using cytochrome oxidase I, cytochrome-b, and internal transcribed spacer 2 markers discriminated three allopatric species: An. sundaicus s.s. in northern Borneo, An. epiroticus in Southeast Asia, and An. sundaicus E on Sumatra and Java, Indonesia. Morphological comparisons of three developmental stages did not reveal unique diagnostic characters that could reliably distinguish the three species. Therefore, we developed a multiplex polymerase chain reaction (PCR) assay based on two mitochondrial DNA markers to unambiguously identify them. This PCR was tested on 374 specimens from 24 different geographical populations, expanding our knowledge of the distribution of these species.
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PMID:Polymerase chain reaction identification of three members of the Anopheles sundaicus (Diptera: Culicidae) complex, malaria vectors in Southeast Asia. 1791 1

Malaria and tuberculosis (TB) are two major global diseases mostly affecting the developing countries. Their treatment is often complex because of the drugs used, multidrug resistance, drug interactions and logistic problems such as drug availability and access. Patients are treated for TB for a minimum of 6 months and may concomitantly develop and be treated for malaria, especially during the rainy season. Rifampicin, a standard component of combination regimens for treating TB, is a potent inducer of hepatic cytochrome and other metabolic enzymes and is able to influence the pharmacokinetics of many drugs. Rifabutin, another rifamycin used less frequently than rifampicin, can also interact with drugs metabolized through the hepatic cytochromes. The mechanisms of any interaction of rifamycins with drugs used in malaria are not well defined. To complicate matters, acute malaria also plays a role in the pharmacokinetics and pharmacodynamics of drugs (i.e. quinine). The aim of this paper is to review known and potential drug-drug interactions between rifampicin, rifabutin and antimalarial drugs.
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PMID:Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs. 1871 60

Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene. A two-compartment model was fitted to 169 plasma DEAQ concentrations from 103 Ghanaian children aged 1 to 14 years with uncomplicated malaria treated either with AQ alone (n = 15) or with AS plus AQ (n = 88). The population clearance of DEAQ appeared to increase nonlinearly with body weight, and the central volume of distribution of DEAQ was higher (P < 0.001) in the AS-plus-AQ group than in the AQ-only group. The maximum plasma DEAQ concentration was higher (P < 0.001), and the population distribution half-life was shorter (P < 0.01), in the AQ-only group than in the AS-plus-AQ group. The total areas under the plasma DEAQ concentration-time curves (P = 0.68) and elimination half-lives (P = 0.39) were similar for the two groups. There was a high frequency (0.179) of the non-wild-type allele of CYP2C8, but no differences between CYP2C8 genotypes with regard to AQ efficacy or safety were evident. The sample size, however, was limited, so monitoring of AQ toxicity in the study area is still indicated. The nonlinear clearance of DEAQ and the wide variability in kinetic parameters have safety implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination.
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PMID:Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria. 1877 60

Pyrethroid resistance in Anopheles funestus is a potential obstacle to malaria control in Africa. Tools are needed to detect resistance in field populations. We have been using a positional cloning approach to identify the major genes conferring pyrethroid resistance in this vector. A quantitative trait locus (QTL) named rp1 explains 87% of the genetic variance in pyrethroid susceptibility in two families from reciprocal crosses between susceptible and resistant strains. Two additional QTLs of minor effect, rp2 and rp3, were also detected. We sequenced a 120-kb BAC clone spanning the rp1 QTL and identified 14 protein-coding genes and one putative pseudogene. Ten of the 14 genes encoded cytochrome P450s, and expression analysis indicated that four of these P450s were differentially expressed between susceptible and resistant strains. Furthermore, two of these genes, CYP6P9 and CYP6P4, which are 25 and 51 times overexpressed in resistant females, are tandemly duplicated in the BAC clone as well as in laboratory and field samples, suggesting that P450 gene duplication could contribute to pyrethroid resistance in An. funestus. Single nucleotide polymorphisms (SNPs) were identified within CYP6P9 and CYP6P4, and genotyping of the progeny of the genetic crosses revealed a maximum penetrance value f(2) = 1, confirming that these SNPs are valid resistance markers in the laboratory strains. This serves as proof of principle that a DNA-based diagnostic test could be designed to trace metabolic resistance in field populations. This will be a major advance for insecticide resistance management in malaria vectors, which requires the early detection of resistance alleles.
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PMID:Two duplicated P450 genes are associated with pyrethroid resistance in Anopheles funestus, a major malaria vector. 1919 25

It has been reported that malaria reduces cytochrome-P450 (CYP) content and monooxygenase activities in the mammalian host liver. The mechanism by which malaria modulates CYP activities, however, remains unclear. In this study we found that activities of ethoxy- and benzyloxy-resorufin-O-dealkylases, p-nitrophenol-hydroxylase and erythromycin-N-demethylase (mediated by CYP1A, 2B, 2E1 and 3A, respectively) were depressed, while uridine-glucuronosyl-transferase (a phase 2 enzyme) was unaltered in liver microsomes of Plasmodium berghei-infected (parasitemia >20%) male Swiss Webster mice. Prolongation of midazolam sleeping time and a slower clearance of chlorzoxazone were also noted in infected mice. Reductions of hepatic levels of CYP1A2, 2E1 and 3A11 mRNAs indicated that malaria downregulated these CYP-mediated activities at a pre-translational level.
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PMID:Malaria downmodulates mRNA expression and catalytic activities of CYP1A2, 2E1 and 3A11 in mouse liver. 1950 Oct 84


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