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

Mutations in the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes of Plasmodium falciparum have been correlated with and used to detect antifolate treatment failure, such as sulfadoxine-pyrimethamine (SP), in regions endemic for malaria. To determine the association between molecular markers of SP resistance and in vivo drug resistance, a quick and simple technique that detects single nucleotide polymorphisms in the DHFR and DHPS genes, using PCR-ELISA and sequence-specific oligonucleotide probes, was applied to 53 isolates obtained from an in vivo study in Sistan and Baluchistan Province, in southeastern Iran. Overall, 11.3% of these isolates were obtained from patients with SP treatment failure. Four DHFR polymorphisms (codons 51, 59, 108, and 164) and five DHPS polymorphisms (codons 436, 437, 540, 581, and 613) were investigated. Mutations DHFR Asn-108, DHFR Arg-59, and DHPS 436-Ala/Phe were very common (100, 81.1, and 85%, respectively). Plasmodium falciparum was isolated from 96% of patients with at least two DHFR/DHPS mutations. All resistant isolates had at least three mutations. The high prevalence of mutation associated with antifolate resistance may point toward low drug efficacy in the future.
 ...
PMID:Genotypes and in vivo resistance of Plasmodium falciparum isolates in an endemic region of Iran. 1702 59

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 5-Methyltetrahydrofolate, 9-aminocamptothecin; AdPEDF.11, AE-37, albumin interferon alfa, alicaforsen sodium, alvocidib hydrochloride, AMG-706, arginine butyrate, avanafil, axitinib, azimilide hydrochloride; BAY-579352, belagenpumatucel-L, beta-lapachone, BHT-3009, BIBW-2992, bremelanotide, BX-471; Casopitant mesylate, cediranib, certolizumab pegol, CH-1504, ChimeriVax-West Nile, clofazimine, CpG-7909, curcumin, Cypher; Dapoxetine hydrochloride, darusentan, diflomotecan, D-methionine, dnaJP1, D-serine, DTPw-HB Hib-MenAC, DTPw-HepB-Hib; E-7010, ecogramostim, edodekin alfa, EGFRvlll peptide vaccine, elcometrine, elcometrine/ethinylestradiol, elsilimomab, enrasentan, ertumaxomab, etalocib sodium, exisulind; Fenretinide, fesoterodine, fingolimod hydrochloride, fontolizumab; Gefitinib, gemtuzumab ozogamicin, ghrelin (human), GV-1001; HTU-PA, human papillomavirus vaccine; Indacaterol, indiplon, interleukin-21, intranasal insulin, irinotecan hydrochloride/floxuridine, ISIS-301012, ispinesib mesylate, ixabepilone; K562/GM-CSF; Lapatinib, L-BLP-25, linezolid, liposome encapsulated paclitaxel, LY-2124275; MC-1, MC-1/lisinopril, MDX-066, melanoma vaccine, MMR-V, multivalent (ACYW) meningitis vaccine; Nilotinib, nobori, nociceptin; Oblimersen sodium, orbofiban acetate, ospemifene; Paliperidone, panitumumab, PEG-filgrastim, PEGylated interferon alfacon-1, perflubutane, pertuzumab, phenserine tartrate, phVEGF-A165, pleconaril, prasugrel, prednisolone sodium metasulfobenzoate; R-411, recombinant malaria vaccine, rhGM-CSF, roflumilast, romidepsin, ruboxistaurin mesilate hydrate; Sirolimus-eluting stent, SR-4554, St. John's Wort extract; Talabostat, Taxus, TGN-255, tifacogin, tiotropium bromide, tolevamer sodium, trabectedin, tretinoin LF; Vatalanib succinate; Yellow fever vaccine, YM-155.
 ...
PMID:Gateways to clinical trials. 1723 18

An effective malaria vaccine which protects against all stages of Plasmodium infection may need to elicit robust CD8(+) and CD4(+) T cell and antibody responses. To achieve this, we have investigated strategies designed to improve the immunogenicity of DNA vaccines encoding the Plasmodium yoelii pre-erythrocytic stage antigens PyCSP and PyHEP17, by targeting the encoded proteins to the MHC Classes I and II processing and presentation pathways. For enhancement of CD8(+) T cell responses, we targeted the antigens for degradation by the ubiquitin (Ub)/proteosome pathway following the N-terminal rule. We constructed plasmids containing PyCSP or PyHEP17 genes fused to the Ub gene: plasmids where the N-terminal antigen residues were mutated from the stabilizing amino acid methionine to destabilizing arginine, plasmids where the C-terminal residues of Ub were mutated from glycine to alanine, and plasmids in which the potential hydrophobic leader sequences of the antigens were deleted. For enhancement of CD4(+) T cell and antibody responses, we targeted the antigens for degradation by the endosomal/lysosomal pathway by linking the antigen to the lysosome-associated membrane protein (LAMP). We found that immunization with DNA vaccine encoding PyHEP17 fused to Ub and bearing arginine induced higher IFN-gamma, cytotoxic and proliferative T cell responses than unmodified vaccines. However, no effect was seen for PyCSP using the same targeting strategies. Regarding Class II antigen targeting, fusion to LAMP did not enhance antibody responses to either PyHEP17 or PyCSP, and resulted in a marginal increase in lymphoproliferative CD4(+) T cell responses. Our data highlight the antigen dependence of immune enhancement strategies that target antigen to the MHC Class I and II pathways for vaccine development.
 ...
PMID:Targeting antigen to MHC Class I and Class II antigen presentation pathways for malaria DNA vaccines. 1760 49

Chloroquine (CQ) remains the household drug for the treatment of malaria especially among pregnant women. However, there are reports that CQ inhibits the contractile process in non-pregnant rat's uterus. The aim of this study is to compare responses to CQ between non-pregnant and pregnant mice and identify some mechanisms involved. Experiments were carried out in non-pregnant and pregnant mice pretreated 24 hours before with 1.5 mg/kg-body weight stilboesterol given orally. Strips of uterine smooth muscle, approximately 5 mm in diameter, were mounted in a 20 ml organ bath containing De Jalon solution bubbled with a 95% O2-5% CO2 gas mixture. Responses of the strips to graded concentration of acetylcholine (ACh) (10(-9) to 10(-5) mol/L), oxytocin (OXY) (10(-5) to 10(-2) IU/ml) and CQ (10(-6) to 4 x 10(-4) mol/L) were investigated. The strips were then incubated in 4 x 10(-4) mol/L CQ for 15 mins and the cumulative dose responses for OXY were repeated. To investigate mechanism of action, the strips were incubated for 15 mins in N(w)-nitro L-arginine methyl ester (L-NAME) and the cumulative responses to CQ repeated. Each investigation was carried out in fresh tissue mounted on Grass Model FT03 force transducer coupled unto a 4-channel Grass Model 7D Polygraph. CQ (low to moderate level), ACh and OXY led to increases in contractile responses in the uteri. There were greater contractile responses in non-pregnant than pregnant mice to CQ and ACh. At high doses, CQ had an inhibitory effect on the uterine contraction. Incubating in CQ led to abolition of contractile responses to OXY and ACh. In the presence of L-NAME, inhibitory effect of CQ at high doses was attenuated in pregnant mice only. The results suggest that CQ at high doses inhibits contractile responses in non-pregnant and pregnant mice. Enhanced nitric oxide bioactivity attenuated this inhibitory effect.
 ...
PMID:Effect of chloroquine on strips of non-pregnant and pregnant mice uteri in-vitro. 1768 66

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia-peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33-1.47) than in MSM (1.82; 95% CI = 1.7-2.02) and controls (1.93; 95% CI = 1.8-2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6-34; P = 0.006) and exhaled NO by 55% (95% CI = 32-73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.
 ...
PMID:Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. 1795 70

Malaria is a major threat to world health. The identification of parasite targets for drug development is a priority and parasitic protein kinases suggest themselves as suitable targets as many display profound structural and functional divergences from their host counterparts. In this paper, we describe the structure of the orphan protein kinase, Plasmodium falciparum protein kinase 7 (PFPK7). Several Plasmodium protein kinases contain extensive insertions, and the structure of PFPK7 reveals how these may be accommodated as excursions from the canonical eukaryotic protein kinase fold. The constitutively active conformation of PFPK7 is stabilized by a structural motif in which the role of the conserved phosphorylated residue that assists in structuring the activation loop of many protein kinases is played by an arginine residue. We identify two series of PFPK7 ATP-competitive inhibitors and suggest further developments for the design of selective and potent PFPK7 lead compounds as potential antimalarials.
 ...
PMID:Structures of P. falciparum protein kinase 7 identify an activation motif and leads for inhibitor design. 1827 14

Chloroquine (CQ) is used to treat malaria and a variety of inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. However, CQ is known to cause cytotoxicity of which mechanism is still uncertain. This study investigated the molecular mechanism responsible for the cell death in CQ-treated A172 human glioblastoma cells. CQ-induced apoptotic cell death of the cells in a time- and concentration-dependent manner. CQ also increased the production of nitric oxide in the cells. However, the pretreatment with aminoguanidine (AG) and N-Omega-nitro-l-arginine methyl ester (NAME), nitric oxide synthase inhibitors, did not block the CQ-induced cell death. In contrast to NO level increase, the level of intracellular reactive oxygen species (ROS) and their extracellular release were transiently and mildly increased by CQ. In addition, CQ depleted cellular GSH content, which was accompanied with time-dependent increase in GSH peroxidase without any significant change in GSH reductase activity. Glutathione (GSH) S-transferase activity was only transiently increased at 15 min treatment with CQ. Furthermore, the CQ-induced cell death was significantly suppressed when intracellular GSH decrease was prevented by the pretreatment with N-acetylcysteine (NAC) or glutathione ethylester (GSH-EE). At the same time, the pretreatment of the cells with NAC and GSH-EE significantly blocked the CQ-induced NO increase, representing that CQ-induced NO increase was resulted from the depletion of GSH. CQ also induced time-dependent increase in Bax level and caspase-3 activity with no change in Bcl-2 level. Overall, these results suggest that CQ-induced NO increase and cell death are dependent on GSH depletion, the cellular redox changes.
 ...
PMID:Chloroquine-induced nitric oxide increase and cell death is dependent on cellular GSH depletion in A172 human glioblastoma cells. 1835 72

UAP56 (U2AF65 associated protein) is a member of the DEAD-box helicase family. Helicases are essential enzymes generally involved in the metabolism of nucleic acids. The gene encoding a member of DEAD-box family was cloned and characterized from the human malaria parasite Plasmodium falciparum. PfU52 is homologous to UAP56 and contains the RNA-dependent ATPase, RNA helicase and RNA binding activities. Using the parasite extract we report that PfU52 is involved in splicing reaction. Site-directed mutagenesis studies indicate that the conserved residues glycine 181, isoleucine 182 and arginine 206 are involved in RNA binding and this activity is required for the enzymatic activities of PfU52. PfU52 is expressed in all the intraerythrocytic developmental stages of the parasite. In the present study we have reported the detailed characterization of PfU52 from P. falciparum and these results advance the knowledge regarding the function of UAP56 in general.
 ...
PMID:Isolation and characterization of Plasmodium falciparum UAP56 homolog: evidence for the coupling of RNA binding and splicing activity by site-directed mutations. 1872 39

Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g,L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the K(m) of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.
 ...
PMID:Pharmacokinetics of L-arginine in adults with moderately severe malaria. 1883 85

Merozoite surface protein-1(19) (MSP-1(19)) specific antibodies which include processing inhibitory, blocking and neutral antibodies have been identified in individuals exposed to Plasmodium falciparum. Here we intend to look at the effect of single and multiple amino acid substitutions of MSP-1(19) on the recognition by polyclonal antibodies from children living in Igbo-Ora, Nigeria. This would provide us with information on the possibility of eliciting mainly processing inhibitory antibodies with a recombinant MSP-1(19) vaccine. Blood was collected from children in the rainy season and binding of anti-MSP-1(19) antibodies to modified mutants of MSP-1(19) was analysed by ELISA. The MSP-1(19) mutant proteins with single substitutions at positions 22 (Leu-->Arg), 43 (Glu-->Leu) and 53 (Asn-->Arg) and the MSP-1(19) mutant protein with multiple substitutions at positions 27+31+34+43 (Glu-->Tyr, Leu-->Arg, Tyr-->Ser, Glu-->Leu); which had inhibitory epitopes; had the highest recognition. Children recognised both sets of mutants with different age groups having different recognition levels. The percentage of malaria positive individuals (32-80%) with antibodies that bound to the mutants MSP-1(19) containing epitopes that recognise only processing inhibitory and not blocking antibodies, were significantly different from those with antibodies that did not bind to these mutants (21-28%). The amino acid substitutions that abolished the binding of blocking antibodies without affecting the binding of inhibitory antibodies are of particular interest in the design of MSP-1(19) based malaria vaccines. Although these MSP-1(19) mutants have not been found in natural population, their recognition by polyclonal antibodies from humans naturally infected with malaria is very promising for the future use of MSP-1(19) mutants in the design of a malaria vaccine.
 ...
PMID:Antibody specificities of children living in a malaria endemic area to inhibitory and blocking epitopes on MSP-1 19 of Plasmodium falciparum. 1908 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>