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Sent on Friday, 2010 Dec 31Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Eur J Immunol. 2010 Nov 29. [Epub ahead of print]Serum and organ-associated anti-hemoglobin humoral autoreactivity: Association with anti-Sm responses and inflammation.Bhatnagar H, Kala S, Sharma L, Jain S, Kim KS, Pal R.National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex, New Delhi, India. AbstractThe release of hemoglobin (Hb) occurs in some infectious and autoimmune diseases characterized by inflammation. As levels of haptoglobin (Hp) fall, free Hb can cause pathology. Humoral autoreactivity to human Hb was demonstrated in the sera of systemic lupus erythematosus (SLE), leishmania and malaria patients. Serum anti-murine Hb antibody levels in lupus-prone mice also exhibited an age-dependent increase, with progressive organ sequestration; significant isotypic correlation was observed with anti-dsDNA antibodies. A suggestive link between anti-Hb and anti-Sm responses was observed: Human lupus sera expressing anti-Sm antibody reactivity preferentially contained heightened levels of anti-Hb autoantibodies, and immunization of lupus-prone mice with Sm led to enhanced anti-murine Hb reactivity. Human and murine anti-Hb monoclonal antibodies were generated, some of which were preferentially reactive toward disease-associated methemoglobin. Epitope-mapping studies revealed evidence of intra-molecular cross-reactivity. One such autoantibody synergized with Hb to enhance the secretion of pro-inflammatory cytokines while eliciting the increased production of monocyte migratory signals from endothelial cells. Preferential usage of specific variable region gene segments was not observed, although somatic mutations were documented. These studies reveal that, while the etiology, specificity and sequences of anti-Hb autoreactive antibodies can vary, they occur quite frequently and can have inflammatory consequences. |
| PMID: 21192050 [PubMed - as supplied by publisher] | |
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| 2. | Drug Test Anal. 2010 Dec 29. [Epub ahead of print]Characterization, thermal stability studies, and analytical method development of Paromomycin for formulation development.Khan W, Kumar N.Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Sector 67, S.A.S. Nagar-160062, India. AbstractParomomycin (PM) is an aminoglycoside antibiotic, first isolated in the 1950s, and approved in 2006 for treatment of visceral leishmaniasis. Although isolated six decades back, sufficient information essential for development of pharmaceutical formulation is not available for PM.The purpose of this paper was to determine thermal stability and development of new analytical method for formulation development of PM. PM was characterized by thermoanalytical (DSC, TGA, and HSM) and by spectroscopic (FTIR) techniques and these techniques were used to establish thermal stability of PM after heating PM at 100, 110, 120, and 130 °C for 24 h. Biological activity of these heated samples was also determined by microbiological assay. Subsequently, a simple, rapid and sensitive RP-HPLC method for quantitative determination of PM was developed using pre-column derivatization with 9-fluorenylmethyl chloroformate. The developed method was applied to estimate PM quantitatively in two parenteral dosage forms.PM was successfully characterized by various stated techniques. These techniques indicated stability of PM for heating up to 120 °C for 24 h, but when heated at 130 °C, PM is liable to degradation. This degradation is also observed in microbiological assay where PM lost ∼30% of its biological activity when heated at 130 °C for 24 h. New analytical method was developed for PM in the concentration range of 25-200 ng/ml with intra-day and inter-day variability of < 2%RSD. Characterization techniques were established and stability of PM was determined successfully. Developed analytical method was found sensitive, accurate, and precise for quantification of PM. Copyright © 2010 John Wiley & Sons, Ltd. |
| PMID: 21191974 [PubMed - as supplied by publisher] | |
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| 3. | ChemMedChem. 2010 Dec 29. [Epub ahead of print]Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1.Spinks D, Ong HB, Mpamhanga CP, Shanks EJ, Robinson DA, Collie IT, Read KD, Frearson JA, Wyatt PG, Brenk R, Fairlamb AH, Gilbert IH.Drug Discovery Unit, Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, Scotland, DD1 5EH (UK), Fax: (+44) 1382-386-373. AbstractGenetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$=7 nM), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low K(m) to K(i) ratio (K(m)=25 nM and K(i)=2.3 nM, respectively). |
| PMID: 21191958 [PubMed - as supplied by publisher] | |
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| 4. | AAPS PharmSciTech. 2010 Dec 30. [Epub ahead of print]Physicochemical Characterization of NPC 1161C, A Novel Antimalarial 8-Aminoquinoline, in Solution and Solid State.Dutta AK, Stodghill SP, Wyandt CM.Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, Oxford, Mississippi, 38677, USA, asishdutta@hotmail.com. AbstractNPC 1161C is a novel antimalarial drug of interest because of its superior curative and prophylactic activity, and favorable toxicity profile against in vivo and in vitro models of malaria, pneumocystis carinii pneumonia, and leishmaniasis. The preformulation studies performed included determination of pK(a)s, aqueous and pH solubility, cosolvent solubility, log P, pH stability, thermal analysis, and preliminary hygroscopicity studies. The mean pK(a1), pK(a2), and pK(a3) were determined to be 10.12, 4.07, and 1.88, respectively. The aqueous solubility was found to be 2.4 × 10(-4) M having a saturated solution pH of 4.3-5.0 and a low intrinsic solubility of 1.6 × 10(-6) M. A mathematical model of the pH-solubility profile was derived from pH 2.2 to 8.0. An exponential decrease in solubility was observed with increasing pH. The excess solid phase in equilibrium with the solution in aqueous buffers was determined to be the free-base form of the drug. A significant increase in solubility was observed with all the cosolvents studied, in both unbuffered and buffered systems. Mean log P of the salt and the free base were estimated to be 2.18 and 3.70, respectively. The compound had poor stability at pH 7.0 at 37°C, with a t (90) of 3.58 days. Thermal analysis of the drug using DSC and TGA revealed that the drug is present as a semi-crystalline powder, which transformed into the amorphous state after melting. The drug was also found to sublime at higher temperatures. Determination of physicochemical properties of NPC 1161C provided useful information for the development of a dosage form and preclinical evaluation. |
| PMID: 21191676 [PubMed - as supplied by publisher] | |
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| 5. | BMJ. 2010 Dec 29;341:c6760. doi: 10.1136/bmj.c6760.Longlastin g insecticidal nets for prevention of Leishmania donovani infection in India and Nepal: paired cluster randomised trial.Picado A, Singh SP, Rijal S, Sundar S, Ostyn B, Chappuis F, Uranw S, Gidwani K, Khanal B, Rai M, Paudel IS, Das ML, Kumar R, Srivastava P, Dujardin JC, Vanlerberghe V, Andersen EW, Davies CR, Boelaert M.London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. AbstractOBJECTIVE: To test the effectiveness of large scale distribution of longlasting nets treated with insecticide in reducing the incidence of visceral leishmaniasis in India and Nepal. DESIGN: Paired cluster randomised controlled trial designed to detect a 50% reduction in incidence of Leishmania donovani infection. SETTING: Villages in Muzaffarpur district in India and Saptari, Sunsari, and Morang districts in Nepal. PARTICIPANTS: 13 intervention and 13 control clusters. 12 691 people were included in the analysis of the main outcome (infection), and 19 810 were enrolled for the secondary (disease) end point. INTERVENTION: Longlasting insecticidal nets (treated with deltamethrin) were distributed in the intervention clusters in December 2006. MAIN OUTCOME MEASURES: Infection was determined by direct agglutination test at 12 and 24 months after the intervention in those who had negative results (titre <1:1600) at baseline. The effect estimate was computed as the geometric mean of the risk ratios for seroconversion for each cluster pair (net/no net), with its 95% confidence interval. Formal tests of effect of no intervention were obtained with a paired t test. RESULTS: There was no significant difference in the risk of seroconversion over 24 months in intervention (5.4%; 347/6372) compared with control (5.5%; 345/6319 people) clusters (risk ratio 0.90, 95% confidence interval 0.49 to 1.65) nor in the risk of clinical visceral leishmaniasis (0.99, 0.46 to 1.40). Adjustment for covariates did not alter these conclusions. CONCLUSIONS: There is no evidence that large scale distribution of longlasting insecticidal nets provides additional protection against visceral leishmaniasis compared with existing control practice in the Indian subcontinent. The observed effect was small and not significant, though the confidence intervals did not exclude a 50% change in either direction. Trial registration Clinical Trials NCT 2005-015374. |
| PMID: 21190965 [PubMed - in process] | |
| 6. | BMJ. 2010 Dec 29;341:c6751. doi: 10.1136/bmj.c6751.Prevention of Leishmania donovani infection.Desjeux P.Institute for OneWorld Health, San Francisco, CA 94111, USA. |
| PMID: 21190964 [PubMed - in process] | |
| 7. | J Biol Chem. 2010 Dec 3;285(49):37964-75. Epub 2010 Sep 13.Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug.Pallavi R, Roy N, Nageshan RK, Talukdar P, Pavithra SR, Reddy R, Venketesh S, Kumar R, Gupta AK, Singh RK, Yadav SC, Tatu U.Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka 560012, India. AbstractUsing a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases. |
| PMID: 20837488 [PubMed - indexed for MEDLINE] | |
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| 8. | Glycobiology. 2010 Aug;20(8):1034-45. Epub 2010 Apr 22.A new class of mechanism-based inhibitors for Trypanosoma c ruzi trans-sialidase and their influence on parasite virulence.Carvalho ST, Sola-Penna M, Oliveira IA, Pita S, Gonçalves AS, Neves BC, Sousa FR, Freire-de-Lima L, Kurogochi M, Hinou H, Nishimura S, Mendonça-Previato L, Previato JO, Todeschini AR.Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Bloco G, Rio de Janeiro, RJ, Brasil. AbstractOne of the most interesting aspects of Trypanosoma cruzi is its adaptation to obtain sialic acid from its host, fulfilling this need exclusively through the reaction catalyzed by enzymatically active trans-sialidase (aTS), thought to play an important role in the pathogenesis of Chagas' disease. Herein, we report that 2-difluoromethyl-4-nitrophenyl-3,5-dideoxy-d-glycero-alpha-d-galacto-2-nonulopyranosid acid (NeuNAcFNP) inactivates aTS time- and dose-dependently, and this inhibition was not relieved removing the inhibitor. Also, NeuNAcFNP causes a decrease in infection of mammalian cells. Characterization of labeled aTS by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry revealed that inactivation of the enzyme occurs through formation of a covalent bond between Arg245 and Asp247 and the inhibitor aglycone. Participation of Asp247 in the catalytic mechanism was proved by constructing a TSD247A mutant, which presents only residual activity. Molecular dynamic simulations indicate that the D247A mutation results in a more open catalytic cleft. In summary, NeuNAcFNP is the first reported mechanism-based inhibitor of aTS, representing a new template for drug design and opening new possibilities for chemotherapy of Chagas' disease, as well as for the elucidation of aTS function in T. cruzi pathogenesis and biology. |
| PMID: 20466651 [PubMed - indexed for MEDLINE] | |
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| 9. | Glycobiology. 2010 Aug;20(8):982-90. Epub 2010 Apr 7.Continuous nonradioactive me thod for screening trypanosomal trans-sialidase activity and its inhibitors.Sartor PA, Agusti R, Leguizamón MS, Campetella O, de Lederkremer RM.Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina. AbstractTrypanosoma cruzi, the agent of American trypanosomiasis is unable to synthesize sialic acid (SA). Instead of using the corresponding nucleotide sugar as donor of the monosaccharide, the transfer occurs from alpha-2,3-linked SA in the host sialoglycoconjugates to terminal beta-galactopyranosyl units of the parasite mucins. For that purpose, T. cruzi expresses a glycosylphosphatidylinositol-anchored trans-sialidase (TcTS) that is shed into the milieu, being detected in the blood during the acute phase of the infection. The essential role of TcTS in infection and the absence of a similar activity in mammals make this enzyme an attractive target for the development of alternative chemotherapies. However, there is no effective inhibitor toward this enzyme. In vitro, 3'-sialyllactose (SL) as donor and radioactive lactose as acceptor substrate are widely used to measure TcTS activity. The radioactive sialylated product is then isolated by anion exchange chromatography and measured. Here we describe a new nonradioactive assay using SL or fetuin as donor and benzyl beta-d-Fuc-(1-->6)-alpha-d-GlcNAc (1) as acceptor. Disaccharide 1 was easily synthesized by regioselective glycosylation of benzyl alpha-d-GlcNAc with tetra-O-benzoyl-d-fucose followed by debenzoylation. Compound 1 lacks the hydroxyl group at C-6 of the acceptor galactose and therefore is not a substrate for galactose oxidase. Our method relies on the specific quantification of terminal galactose produced by trans-sialylation from the donor to the 6-deoxy-galactose (D-Fuc) unit of 1 by a spectrophotometric galactose oxidase assay. This method may also discriminate sialidase and trans-sialylation activities by running the assay in the absence of acceptor 1. |
| PMID: 20375068 [PubMed - indexed for MEDLINE] | |
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