Thursday, March 12, 2009

What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results
Items 1 -10 of 25

1: Methods Mol Biol. 2009;534:1-12.

Saturation transfer difference NMR spectroscopy as a technique to investigate protein-carbohydrate interactions in solution.

Haselhorst T, Lamerz AC, Itzstein M.

Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, 4222, Australia, t.haselhorst@griffith.edu.au.

Saturation transfer difference (STD) Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful method for studying protein-ligand interactions in solution. The STD NMR method is capable of identifying the binding epitope of a ligand when bound to its receptor protein. Ligand protons that are in close contact with the receptor protein receive a higher degree of saturation, and as a result stronger STD NMR signals can be observed. Protons that are either less or not involved in the binding process reveal no STD NMR signals. Therefore, the STD NMR method is an excellent tool to investigate how a binding ligand interacts with its receptor molecule. The STD NMR experiment is easy to implement and only small amounts of native protein are required. This chapter comprises a detailed experimental protocol to acquire STD NMR spectra and determine the binding epitope of a ligand bound to its target protein. As representative examples the ligands uridyl-triphosphate (UTP) and uridyl-glucose-diphosphate (UDP-glucose) when bound to the Leishmania major UDP-glucose-pyrophosphorylase (UGP) as target protein are examined.

PMID: 19277538 [PubMed - in process]

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2: Curr Opin Infect Dis. 2009 Apr;22(2):126-30.

Molecular epidemiology of leishmaniasis in Asia (focus on cutaneous infections).

Katakura K.

Laboratory of Parasitology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. kenkata@vetmed.hokudai.ac.jp

PURPOSE OF REVIEW: Leishmaniasis has a wider geographical distribution than before. This review focuses on molecular epidemiological studies of new foci of cutaneous leishmaniasis in South and Southeast Asia. RECENT FINDINGS: In Pakistan, the main causative agent in southern dry areas was determined as Leishmania major followed by Leishmania tropica. There was no correlation between the skin lesion types and the causative species. In the western Indian Himalayas, L. tropica and Leishmania donovani have been reported as the causative pathogens. In Nepal, molecular methods revealed the first case of L. major cutaneous leishmaniasis. Microsatellite analysis of Sri Lankan strains isolated from cutaneous leishmaniasis patients identified L. donovani strains that were closely related to a group of visceral L. donovani isolates from India, Bangladesh, and Nepal. In Taiwan, a third case of indigenous cutaneous leishmaniasis was reported, and the parasite was L. tropica. SUMMARY: The distribution of cutaneous leishmaniasis has expanded definitively in South and Southeast Asia. Because the possible sandfly vector species are distributed widely over the disease endemic areas, further epidemiological studies are required. Microsatellite analysis of the parasites will be a powerful tool for population genetic and epidemiological studies of Leishmania species in Asia.

PMID: 19276879 [PubMed - in process]

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3: Curr Opin Pulm Med. 2009 Mar 6. [Epub ahead of print]

Parasitic lung infections.

Vijayan VK.

Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India.

PURPOSE OF REVIEW: Global climate change and population explosion leading to changes in natural ecosystem and travel across the continents have resulted in an increase in the transmission of parasites to human beings. This review focuses on recent advancements in parasitic lung infections. RECENT FINDINGS: Invasive parasitic diseases including lung infections are increasingly being reported in patients with immunodeficiency syndromes. A recombinant kinesin-related antigen of Leishmania donovani has been validated with ELISA using urine samples for the diagnosis of visceral leishmaniasis. Pyruvate kinase deficiency has been shown to provide protection against Plasmodium falciparum infection. Intravenous artesunate is an alternative drug for the treatment of severe malaria. The best way to protect from malaria is the use of long-lasting insecticide-treated bednets. Biennial treatment with praziquantel has been found to be cost-effective treatment for control of infection with Schistosoma haematobium. Pulmonary paragonimiasis can be diagnosed by fine needle aspiration biopsy of pulmonary nodules. Strongyloides stercoralis hyperinfection can mimic accelerated idiopathic pulmonary fibrosis. Migratory nodular shadows with halos are important chest computed tomographic findings in human toxocariasis. SUMMARY: Patients with immunodeficiency syndromes (HIV infection, organ transplantation and immunosuppressive drugs, including corticosteroids) should be evaluated for early detection of parasitic lung infections.

PMID: 19276810 [PubMed - as supplied by publisher]

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4: Curr Drug Targets. 2009 Mar;10(3):246-60.

Electron microscopy in antiparasitic chemotherapy: a (close) view to a kill.

Vannier-Santos MA, De Castro SL.

Laboratório de Biomorfologia Parasitária, Unidade de Microscopia Eletrônica, Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil. vannier@bahia.fiocruz.br

Electron microscopy may be useful in chemotherapy studies at distinct levels, such as the identification of subcellular targets in the parasites and the elucidation of the ultimate drug mechanism of action, inferred by the alterations induced by antiparasitic compounds. In this review we present data obtained by electron microscopy approaches of different parasitic protozoa, such as Trypanosoma cruzi, Leishmania spp., Giardia lamblia and trichomonads, under the action of drugs, demonstrating that the cell architecture organization is only determined in detail at the ultrastructural level. The transmission electron microscopy may shed light (i.e. electrons) not only on the affected compartment, but also on the manner it is altered, which may indicate presumable target metabolic pathways as well as the actual toxic or lethal effects of a drug. Cytochemical and analytical techniques can provide valuable information on the composition of the altered cell compartment, permitting the bona fide identification of the drug target and a detailed understanding of the mechanism underneath its effect. Scanning electron microscopy permits the recognition of the drug-induced alterations on parasite surface and topography. Such observations may reveal cytokinetic dysfunctions or membrane lesions not detected by other approaches. In this context, electron microscopy techniques comprise valuable tools in chemotherapy studies.

PMID: 19275561 [PubMed - in process]

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5: Curr Drug Targets. 2009 Mar;10(3):240-5.

Genomic databases and the search of protein targets for protozoan parasites.

Timmers LF, Pauli I, Barcellos GB, Rocha KB, Caceres RA, de Azevedo WF Jr, Soares MB.

Faculdade de Biociências, Laboratório de Bioquímica Estrutural, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.

The development of databases devoted to biological information opened the possibility to integrate, query and analyze biological data obtained from several sources that otherwise would be scattered through the web. Several issues arise in the handling of biological information, mainly due to the diversity of biological subject matter and the complexity of biological approaches towards phenomena of the living world. The integration of genomic data, three-dimensional structures of proteins, biological activity, and drugs availability allows a system approach to the study of the biology. Here we review the current status of these research efforts to develop genomic databases for protozoan parasites, such as the apicomplexan parasites, Trypanosoma cruzi and Leishmania spp. These databases may help in the discovery and development of new drugs against parasite-mediated diseases.

PMID: 19275560 [PubMed - in process]

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6: Curr Drug Targets. 2009 Mar;10(3):193-201.

Selection of targets for drug development against protozoan parasites.

de Azevedo WF Jr, Soares MB.

Faculdade de Biociências, Laboratório de Bioquímica Estrutural, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil. walter@azevedolab.net

Sequencing of parasite genomes opened the possibility to identify potential protein targets for drug development. Several protein targets have been found in the genome of Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei and Leishmania major. Bioinformatics analysis is an important tool for the identification of protein targets for drug development against parasitic diseases. In this review we comment about three protein targets, identified in parasite genomes, and discuss the main features that may guide future efforts for virtual screening initiatives.

PMID: 19275556 [PubMed - in process]

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7: Curr Drug Targets. 2009 Mar;10(3):178-92.

Current treatment and drug discovery against Leishmania spp. and Plasmodium spp.: a review.

Cruz AK, de Toledo JS, Falade M, Terrão MC, Kamchonwongpaisan S, Kyle DE, Uthaipibull C.

Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. akcruz@fmrp.usp.br

Malaria and leishmaniasis are the most prevalent tropical diseases caused by protozoan parasites. Half of world's population is at risk of malaria and more than 2 million of new cases of leishmaniasis occur annually. There are no vaccines available for these diseases and current treatments suffer from several limitations. Therefore, novel drugs for malaria and leishmaniasis are much-needed. This article reviews the agents currently in use for treatment of these diseases, their known mechanisms of action and weaknesses. We present an overview of the main strategies for drug discovery and the relevance of these parasites genomics/proteomics data for a rational search of molecular targets and matching leads. In this direction, we emphasize the importance of the highly integrated partnerships and networks between scientists in academic institutions and industry involving several countries that promise to increase the chances of success and enhance cost-effectiveness in drug discovery against these parasitic diseases. In addition, we approach the available assays for testing lead compounds in large scale and their limitations for they represent one of the bottlenecks in the pipeline for novel drug discovery. We conclude the article presenting a recent coordinated initiative (TDR Transfection Network) established to overcome some of these limitations by the generation of Plasmodium and Leishmania transgenic parasites better suited for HTS platforms.

PMID: 19275555 [PubMed - in process]

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8: Drugs. 2009;69(3):361-92. doi: 10.2165/00003495-200969030-00010.

Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections.

Moen MD, Lyseng-Williamson KA, Scott LJ.

Wolters Kluwer Health mid R: Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA.

Liposomal amphotericin B (AmBisome(R)) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B. It is active against clinically relevant yeasts and moulds, including Candida spp., Aspergillus spp. and filamentous moulds such as Zygomycetes, and is approved for the treatment of invasive fungal infections in many countries worldwide. It was developed to improve the tolerability profile of amphotericin B deoxycholate, which was for many decades considered the gold standard of antifungal treatment, despite being associated with infusion-related events and nephrotoxicity. In well controlled trials, liposomal amphotericin B had similar efficacy to amphotericin B deoxycholate and amphotericin B lipid complex as empirical therapy in adult and paediatric patients with febrile neutropenia. In addition, caspofungin was noninferior to liposomal amphotericin B as empirical therapy in adult patients with febrile neutropenia. For the treatment of confirmed invasive fungal infections, liposomal amphotericin B was more effective than amphotericin B deoxycholate treatment in patients with disseminated histoplasmosis and AIDS, and was noninferior to amphotericin B deoxycholate in patients with acute cryptococcal meningitis and AIDS. In adults, micafungin was shown to be noninferior to liposomal amphotericin B for the treatment of candidaemia and invasive candidiasis. Data from animal studies suggested that higher dosages of liposomal amphotericin B might improve efficacy; however, in the AmBiLoad trial in patients with invasive mould infection, there was no statistical difference in efficacy between the standard dosage of liposomal amphotericin B 3 mg/kg/day and a higher 10 mg/kg/day dosage, although the standard dosage was better tolerated. Despite being associated with fewer infusion-related adverse events and less nephrotoxicity than amphotericin B deoxycholate and amphotericin B lipid complex, liposomal amphotericin B use is still limited to some extent by these adverse events. Both echinocandins were better tolerated than liposomal amphotericin B. The cost of liposomal amphotericin B therapy may also restrict its use, but further pharmacoeconomic studies are required to fully define its cost effectiveness compared with other antifungal agents. Based on comparative data from well controlled trials, extensive clinical experience and its broad spectrum of activity, liposomal amphotericin B remains a first-line option for empirical therapy in patients with febrile neutropenia and in those with disseminated histoplasmosis, and is an option for the treatment of AIDS-associated cryptococcal meningitis, and for invasive Candida spp. or Aspergillus spp. infections. Amphotericin B, a macrocyclic, polyene antifungal agent, is thought to act by binding to ergosterol, the principal sterol in fungal cell membranes and Leishmania cells. This results in a change in membrane permeability, causing metabolic disturbance, leakage of small molecules and, as a consequence, cell death. In vitro and in vivo studies have shown that liposomal amphotericin B remains closely associated with the liposomes in the circulation, thereby reducing the potential for nephrotoxicity and infusion-related toxicity associated with conventional amphotericin B. Amphotericin B shows very good in vitro activity against a broad spectrum of clinically relevant fungal isolates, including most strains of Candida spp. and Aspergillus spp., and other filamentous fungi such as Zygomycetes. Liposomal amphotericin B has proven effective in various animal models of fungal infections, including those for candidiasis, aspergillosis, fusariosis and zygomycosis. Liposomal amphotericin B also shows immunomodulatory effects, although the mechanisms involved are not fully understood, and differ from those of amphotericin B deoxycholate and amphotericin B colloidal dispersion. In adult patients with febrile neutropenia, intravenous liposomal amphotericin B has nonlinear pharmacokinetics, with higher than dose-proportional increases in exposure being consistent with reticuloendothelial saturation and redistribution of amphotericin B in the plasma compartment. Liposomal amphotericin B is rapidly and extensively distributed after single and multiple doses, with steady-state concentrations of amphotericin B attained within 4 days and no clinically relevant accumulation of the drug following multiple doses of 1-7.5 mg/kg/day. In autopsy tissue, the highest concentrations of the drug were found in the liver and spleen, followed by the kidney, lung, myocardium and brain tissue. Elimination of liposomal amphotericin B, like that of amphotericin B deoxycholate, is poorly understood; its route of metabolism is not known and its excretion has not been studied. The terminal elimination half-life is about 7 hours. No dosage adjustment is required based on age or renal impairment. In several randomized, double-blind trials (n = 73-1095) in adult and/or paediatric patients, liposomal amphotericin B was effective as empirical therapy or as treatment for confirmed invasive fungal infections, including invasive candidiasis, candidaemia, invasive mould infection (mainly aspergillosis), histoplasmosis and cryptococcal meningitis. All agents were administered as an intravenous infusion; the typical dosage for liposomal amphotericin B was 3 mg/kg/day. Treatment was generally given for 1-2 weeks. Participants in trials evaluating empirical therapy had neutropenia and a persistent fever despite antibacterial treatment and had received chemotherapy or undergone haematopoietic stem cell transplantation. As empirical therapy in adult and paediatric patients, liposomal amphotericin B appeared to be as effective as amphotericin B deoxycholate (approximately 50% of patients in each group achieved treatment success) or amphotericin B lipid complex (approximately 40% of liposomal amphotericin B recipients experienced treatment success). Of note, in the first trial, results of the statistical test to determine equivalence between treatments were not reported. In the second trial, efficacy was assessed as an 'other' endpoint. In another trial, caspofungin was shown to be noninferior to liposomal amphotericin B, with approximately one-third of patients in each group experiencing treatment success. Liposomal amphotericin B was significantly more effective than amphotericin B deoxycholate for the treatment of moderate to severe disseminated histoplasmosis in patients with AIDS, with 88% and 64% of patients, respectively, having a successful response. Liposomal amphotericin B was noninferior to amphotericin B deoxycholate for the treatment of cryptococcal meningitis in terms of mycological success. Micafungin therapy was shown to be noninferior to liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidiasis. In a substudy in paediatric patients, which was not powered to determine noninferiority, liposomal amphotericin B was as effective as micafungin for the treatment of candidaemia or invasive candidiasis. In this patient population, within each trial, 90% of adult patients and approximately three-quarters of paediatric patients in both treatment groups experienced a successful response. In patients with invasive mould infection (mainly aspergillosis), there was no difference in efficacy between a higher dosage of liposomal amphotericin B (10 mg/kg/day) and the standard dosage (3 mg/kg/day), with 46% and 50% of patients experiencing a favourable overall response. In well designed clinical trials, liposomal amphotericin B was generally at least as well tolerated as other lipid-associated formulations of amphotericin B and better tolerated than amphotericin B deoxycholate in adult and paediatric patients. Compared with other amphotericin B formulations, liposomal amphotericin B treatment was associated with a lower incidence of infusion-related adverse events and nephrotoxicity. A higher than recommended dosage of liposomal amphotericin B (10 mg/kg/day) was associated with an increased incidence of nephrotoxicity compared with the standard dosage (3 mg/kg/day), although the incidence of infusion-related reactions did not differ between treatment groups. In general, liposomal amphotericin B treatment was not as well tolerated as echinocandin therapy in well designed clinical trials. As empirical therapy or for the treatment of confirmed invasive fungal infections in adult patients, liposomal amphotericin B recipients experienced more infusion-related events and nephrotoxicity than caspofungin or micafungin recipients. There was no difference in the incidence of these adverse events between the liposomal amphotericin B and micafungin groups in a study in paediatric patients.

PMID: 19275278 [PubMed - in process]

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9: Phytother Res. 2009 Mar 10. [Epub ahead of print]LinkOut

Selective antileishmania activity of 13,28-epoxy-oleanane and related triterpene saponins from the plant families Myrsinaceae, Primulaceae, Aceraceae and Icacinaceae.

Vermeersch M, Foubert K, Luz RI, Puyvelde LV, Pieters L, Cos P, Maes L.

Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Antwerp University, Groenenborgerlaan 171, 2020 Antwerp, Belgium.

Maesa saponins with the 13,28-epoxy-oleanane triterpene core skeleton were described recently to possess strong and selective in vitro and in vivo antileishmania activity. In the absence of direct chemical derivatization possibilities, a structure-based literature search was carried out to explore a structure-activity relationship. Crude alcohol extracts from several plant species of Myrsinaceae, Primulaceae, Aceraceae and Icacinaceae were evaluated for in vitro activity against Leishmania infantum intracellular amastigotes and cytotoxicity on MRC-5(SV2) cells, while the saponin content was evaluated qualitatively by TLC. A clear correlation was found between the presence of close analogue 13,28-epoxy-oleanane triterpene saponins and potent and selective antileishmania activity. This was most striking in Maesa species, except for M. macrosepala. Interesting activities were also found in extracts that did not exactly match the TLC characteristics of the Maesa saponin references, as was the case for Ardisia angusta, A. amherstiana, A. caudata, A. gigantifolia, A. roseiflora, Myrsine affinis, Acer brevipes and A. laurinum var. petelotii. This study indicates that the 13,28-epoxy-oleanane triterpene moiety is essential for selective antileishmania potential and that several other plant species could still be explored for antileishmania drug discovery. Copyright (c) 2009 John Wiley & Sons, Ltd.

PMID: 19274770 [PubMed - as supplied by publisher]

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10: Mem Inst Oswaldo Cruz. 2009 Feb;104(1):62-6.LinkOut

Lesion aspirate culture for the diagnosis and isolation of Leishmania spp. from patients with cutaneous leishmaniasis.

Luz ZM, da Silva AR, Silva Fde O, Caligiorne RB, Oliveira E, Rabello A.

Laboratório de Pesquisas Clínicas, Centro de Referência em Leishmanioses, Instituto René Rachou, Fiocruz, Belo Horizonte, MG, Brasil, 30190-002. profeta@cpqrr.fiocruz.br

The detection of Leishmania spp. in skin lesion aspirates, using a puncture technique, was evaluated in 76 patients with cutaneous leishmaniasis (CL) who were referred to a Leishmaniasis Reference Centre in Brazil. CL was defined based on skin lesions suggestive of the disease and on a positive result of the Montenegro skin test or Giemsa-stained imprints of biopsy fragments. The aspirates were cultured using a vacuum tube device containing culture medium and evaluated for the presence of Leishmania spp. The biphasic medium culture was examined once a week for three weeks. Promastigotes were observed in 53/76 (69.7%) cultures. Stained smears from 60 of the 76 patients were evaluated using PCR-RFLP to detect the conserved minicircle region of Leishmania spp. and to classify the parasite. Of these patients, 45 (75%) showed positive results in aspirate culture and 15 presented negative results. The PCR was positive in 80% (53/60) samples. The PCR-RFLP profile was determined in 49 samples, of which 45 (92%) showed a pattern compatible with Leishmania (Viannia) braziliensis. The aspirate culture is a sensitive and feasible method for diagnosing CL and may be routinely adopted by health services for L. (V.) braziliensis isolation and identification.

PMID: 19274378 [PubMed - in process]

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