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Sent on Saturday, 2011 Sep 03Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Sci Pharm. 2011 Sep;79(3):389-428. Epub 2011 May 10.Neglected Disease - African Sleeping Sickness: Recent Synthetic and Modeling Advances.Paliwal SK, Verma AN, Paliwal S.SourceBanasthali University, Distt-Tonk, 304022, Rajasthan, India. AbstractHuman African Trypanosomiasis (HAT) also called sleeping sickness is caused by subspecies of the parasitic hemoflagellate Trypanosoma brucei that mostly occurs in sub-Saharan Africa. The current chemotherapy of the human trypanosomiases relies on only six drugs, five of which have been developed more than 30 years ago, have undesirable toxic side effects and most of them show drug-resistance. Though development of new anti-trypanosomal drugs seems to be a priority area research in this area has lagged far behind. The given review mainly focus upon the recent synthetic and computer based approaches made by various research groups for the development of newer anti-trypanosomal analogues which may have improved efficacy and oral bioavailability than the present ones. The given paper also attempts to investigate the relationship between the various physiochemical parameters and anti-trypanosomal activity that may be helpful in development of potent anti-trypanosomal agents against sleeping sickness. |
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| 2. | PLoS Negl Trop Dis. 2011 Aug;5(8):e1297. Epub 2011 Aug 23.The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing.Diaz-Gonzalez R, Kuhlmann FM, Galan-Rodriguez C, Madeira da Silva L, Saldivia M, Karver CE, Rodriguez A, Beverley SM, Navarro M, Pollastri MP.SourceInstituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain. AbstractBACKGROUND:Target repurposing utilizes knowledge of "druggable" targets obtained in one organism and exploits this information to pursue new potential drug targets in other organisms. Here we describe such studies to evaluate whether inhibitors targeting the kinase domain of the mammalian Target of Rapamycin (mTOR) and human phosphoinositide-3-kinases (PI3Ks) show promise against the kinetoplastid parasites Trypanosoma brucei, T. cruzi, Leishmania major, and L. donovani. The genomes of trypanosomatids encode at least 12 proteins belonging to the PI3K protein superfamily, some of which are unique to parasites. Moreover, the shared PI3Ks differ greatly in sequence from those of the human host, thereby providing opportunities for selective inhibition. METHODOLOGY/PRINCIPAL FINDINGS:We focused on 8 inhibitors targeting mTOR and/or PI3Ks selected from various stages of pre-clinical and clinical development, and tested them against in vitro parasite cultures and in vivo models of infection. Several inhibitors showed micromolar or better efficacy against these organisms in culture. One compound, NVP-BEZ235, displayed sub-nanomolar potency, efficacy against cultured parasites, and an ability to clear parasitemia in an animal model of T. brucei rhodesiense infection. CONCLUSIONS/SIGNIFICANCE:These studies strongly suggest that mammalian PI3/TOR kinase inhibitors are a productive starting point for anti-trypanosomal drug discovery. Our data suggest that NVP-BEZ235, an advanced clinical candidate against solid tumors, merits further investigation as an agent for treating African sleeping sickness. |
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| 3. | PLoS Negl Trop Dis. 2011 Aug;5(8):e1288. Epub 2011 Aug 23.Infection Parameters in the Sand Fly Vector That Predict Transmission of Leishmania major.Sta mper LW, Patrick RL, Fay MP, Lawyer PG, Elnaiem DE, Secundino N, Debrabant A, Sacks DL, Peters NC.SourceLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America. AbstractTo identify parameters of Leishmania infection within a population of infected sand flies that reliably predict subsequent transmission to the mammalian host, we sampled groups of infected flies and compared infection intensity and degree of metacyclogenesis with the frequency of transmission. The percentage of parasites within the midgut that were metacyclic promastigotes had the highest correlation with the frequency of transmission. Meta-analysis of multiple transmission experiments allowed us to establish a percent-metacyclic "cutoff" value that predicted transmission competence. Sand fly infections initiated with variable doses of parasites resulted in correspondingly altered percentages of metacyclic promastigotes, resulting in altered transmission frequency and disease severity. Lastly, alteration of sand fly oviposition status and environmental conditions at the time of transmission also influenced transmission frequency. These observations have implications for transmission of Leishmania by the sand fly vector in both the laboratory and in nature, including how the number of organisms acquired by the sand fly from an infection reservoir may influence the clinical outcome of infection following transmission by bite. |
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| 4. | PLoS Negl Trop Dis. 2011 Aug;5(8):e1281. Epub 2011 Aug 23.Genetic Diversity and Population Structure of the Secondary Symbiont of Tsetse Flies, Sodalis glossinidius, in Sleeping Sickness Foci in Cameroon.Farikou O, Thevenon S, Njiokou F, Allal F, Cuny G, Geiger A.SourceUMR 177, IRD-CIRAD, CIRAD TA A-17/G, Campus International de Baillarguet, Montpellier, France. AbstractBACKGROUND:Previous studies have shown substantial differences in Sodalis glossinidius and trypanosome infection rates between Glossina palpalis palpalis populations from two Cameroonian foci of human African trypanosomiasis (HAT), Bipindi and Campo. We hypothesized that the geographical isolation of the two foci may have induced independent evolution in the two areas, resulting in the diversification of symbiont genotypes. METHODOLOGY/PRINCIPAL FINDINGS:To test this hypothesis, we investigated the symbiont genetic structure using the allelic size variation at four specific microsatellite loci. Classical analysis of molecular variance (AMOVA) and differentiation statistics revealed that most of the genetic diversity was observed among individuals within populations and frequent haplotypes were shared between populations. The structure of genetic diversity varied at different geographical scales, with almost no differentiation within the Campo HAT focus and a low but significant differentiation between the Campo and Bipindi HAT foci. CONCLUSIONS/SIGNIFICANCE:The data provided new information on the genetic diversity of the secondary symbiont population revealing mild structuring. Possible interactions between S. glossinidius subpopulations and Glossina species that could favor tsetse fly infections by a given trypanosome species should be further investigated. |
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| 5. | Indian J Hematol Blood Transfus. 2010 Sep;26(3):78-82. Epub 2010 Sep 30.Hematologic changes in visceral leishmaniasis/kala azar.Varma N, Naseem S.AbstractVisceral Leishmaniasis (VL) or Kala Azar is a chronic infectious disease caused by parasites of the Leishmania donovani complex that can cause various hematologic manifestations. It is characterized by fever, enlargement of liver and spleen, weight loss, pancytopenia and hypergammaglobinemia. It is endemic in the Indian subcontinent, mainly seen in the states of Bihar and West Bengal. Patients with VL can present to the haematologist for various haematological problems prior to receiving the diagnosis of VL. Anaemia is the most common haematological manifestation of VL. VL may also be associated with leucopenia, thrombocytopenia, pancytopenia, hemophagocytosis and disseminated intravascular coagulation. Hematological improvement is noted within a week and complete hematological response occurs in 4-6 weeks of treatment. Relapses are rare and increased risk of being diagnosed with hematolymphoid malignancies on long term follow up is not noted. |
| 6. | Curr Opin Rheumatol. 2011 Aug 31. [Epub ahead of print]State of the art: what we know about infectious agents and myositis.Gan L, Miller FW.SourceNational Institutes of Health Clinical Research Center, Bethesda, Maryland, USA. AbstractPURPOSE OF REVIEW:Increasing evidence suggests that the idiopathic inflammatory myopathies (IIMs) result from certain environmental exposures in genetically susceptible individuals. Investigations have demonstrated that a variety of infections not only cause infectious myopathies but also could be possible triggers for IIM. This review summarizes published studies on the possible roles of infections in inflammatory muscle disease. RECENT FINDINGS:Many infectious agents have been linked to the development of IIMs via case reports, epidemiologic investigations, and animal models. Additional agents possibly involved in triggering the development of IIMs have been recently described, including Torque teno virus (TTV) and Borrelia burgdorferi. Novel animal models of myositis have been recently developed using Leishmania infantum or Chikungunya virus (CHIKV). New technologies to assess infectious agents include high-throughput methods for pathogen identification and novel approaches to identify gene expression of pathogens in tissues. SUMMARY:Understanding the causes of IIMs remains limited in part due to the rarity and heterogeneity of these disorders. Although no definitive studies have yet linked infectious agents with IIMs, additional evidence is accumulating and novel technologies may allow improved understanding of the roles of infections in IIMs and for possible future therapeutic and preventive measures. |
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| 7. | Curr Opin Infect Dis. 2011 Oct;24(5):418-22.Recent advances in post-kala-azar dermal leishmaniasis.Mondal D, Khan MG.SourceInternational Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh. AbstractPURPOSE OF REVIEW:Post-kala-azar dermal leishmaniasis (PKDL) is a challenge for clinicians and researchers, because its burden is poorly investigated and pathogenesis is disputable. However, recent studies contributed to understanding of the pathogenesis of PKDL especially its association with host immunological factors, and also how to improve its diagnosis and treatment. This review focuses on recent advances in diagnosis, new insights into pathogenesis and case management. RECENT FINDINGS:Information regarding the burden of PKDL, especially in Bangladesh, is now available. Association between skin parasite burden and different clinical forms of PKDL has been explored. The diagnostic importance of detection of Leishmania donovani DNA in the peripheral blood buffy coat and in skin specimens by PCR has been studied. Variable effects of different antileishmanial drugs on immune response have been observed. Finally, high efficacy of miltefosine for treatment of PKDL has been demonstrated. SUMMARY:The incidence of PKDL is reducing in India after introduction of miltefosine and amphotericin B for treatment of visceral leishmaniasis. It remains higher in Bangladesh and in Sudan. Parasite burden is higher in nodular and papular forms of PKDL compared to the macular form of the disease. The demonstration of Leishmania DNA in peripheral blood buffy coat and in skin specimens can help to diagnose 40-75% clinically suspected PKDL individuals. An initial cure rate of 95% has been achieved with miltefosine for treatment of PKDL. However, the efficacy of combination therapy should be explored to reduce the treatment duration and hence to improve treatment compliance. |
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| 8. | Phytochemistry. 2011 Aug 30. [Epub ahead of print]Leishmanicidal effects of piperine, its derivatives, and analogues on Leishmania amazonensis.Ferreira C, Soares DC, Barreto-Junior CB, Nascimento MT, Freire-de-Lima L, Delorenzi JC, Lima ME, Atella GC, Folly E, Carvalho TM, Saraiva EM, Pinto-da-Silva LH.SourceInstituto de Veterinária, Universidade Federal Rural do Rio de Janeiro (UFRRJ), Seropédica, RJ, Brazil; Instituto de Microbiologia Prof. Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. AbstractLeishmaniasis is a tropical disease caused by protozoan parasites of the genus Leishmania which affects 12million people worldwide. The discovery of drugs for the treatment of leishmaniasis is a pressing concern in global health programs. The aim of this study aim was to evaluate the leishmanicidal effect of piperine and its derivatives/analogues on Leishmania amazonensis. Our results showed that piperine and phenylamide are active against promastigotes and amastigotes in infected macrophages. Both drugs induced mitochondrial swelling, loose kinetoplast DNA, and led to loss of mitochondrial membrane potential. The promastigote cell cycle was also affected with an increase in the G1 phase cells and a decrease in the S-phase cells, respectively, after piperine and phenylamide treatment. Lipid analysis of promastigotes showed that piperine reduced triglyceride, diacylglycerol, and monoacylglycerol contents, whereas phenylamide only reduced diacylglycerol levels. Both drugs were deemed non toxic to macrophages at 50μM as assessed by XTT (sodium 2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt), Trypan blue exclusion, and phagocytosis assays, whereas low toxicity was noted at concentrations higher than 150μM. None of the drugs induced nitric oxide (NO) production. By contrast, piperine reduced NO production in activated macrophages. The isobologram analysis showed that piperine and phenylamide acted synergistically on the parasites suggesting that they affect different target mechanisms. These results indicate that piperine and its phenylamide analogue are candidates for development of drugs for cutaneous leishmaniasis treatment. Copyright © 2011 Elsevier Ltd. All rights reserved. |
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| 9. | Actas Dermosifiliogr. 2011 Aug 30. [Epub ahead of print]Unsuspected Visceral Leishmaniasis Infiltrating a Squamous Cell Carcinoma. [Article in English, Spanish] Armengot-Carbó M, Carmena-Ramón R, Rodrigo-Nicolás B, Ferrando-Marco J.SourceServicio de Dermatología, Hospital Arnau de Vilanova, Valencia, España. AbstractAmastigotes of the genus Leishmania have been observed in biopsies of apparently unrelated lesions in patients with AIDS and visceral leishmaniasis. We describe the case of a 40-year-old man with human immunodeficiency virus infection and severe immunodepression in whom the presence of the parasite was detected as an incidental finding on histological study of a perianal squamous cell carcinoma. This finding led to the diagnosis and subsequent treatment of previously unsuspected visceral leishmaniasis. In a review of the literature we have found no previous examples of this association. Copyright © 2011 Elsevier España, S.L. y AEDV. All rights reserved. |
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