Spelling suggestions: "subject:"trypanosoma ""
131 |
Fluorescence-based reporter substrate for monitoring RNA editing in Trypanosomatid pathogensMoshiri, Houta. January 2008 (has links)
No description available.
|
132 |
Regioisomers of the Dinitroaniline Scaffold: Exploring Tubulin Assembly Inhibition through Novel Antikinetoplastid AgentsLatibeaudiere, Kirk D. 10 September 2008 (has links)
No description available.
|
133 |
Protoberberine-type Alkaloids as Lead Compounds for the Treatment of African Sleeping Sickness, Leishmaniasis, and MalariaBahar, Mark 19 June 2012 (has links)
No description available.
|
134 |
Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis and CancerAbacha, Yabalu Z., Forkuo, A.D., Gbedema, S.Y., Mittal, N., Ottilie, S., Rocamora, F., Winzeler, E.A., van Schalkwyk, D.A., Kelly, J.M., Taylor, M.C., Reader, J., Birkholtz, L-M., Lisgarten, D.R., Cockcroft, J.K., Lisgarten, J.N., Palmer, R.A., Talbert, R.C., Shnyder, Steven, Wright, Colin W. 26 April 2022 (has links)
Yes / The prospect of eradicating malaria continues to be challenging in the face of increasing
parasite resistance to antimalarial drugs so that novel antimalarials active against asexual,
sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials
need to be affordable and available to those most in need and, bearing in mind climate
change, should ideally be sustainable. The West African climbing shrub Cryptolepis
sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid,
cryptolepine (1), has been shown to have antimalarial properties, and the synthetic
analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial
agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C.
sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with
respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and
7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with
N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds
were active against Plasmodia in vitro, but 6 showed the most selective profile with
respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI
= 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites
IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently
inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the
most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type
ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant
ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at
doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C.
sanguinolenta may be utilized as a sustainable source of novel compounds that may lead
to the development of novel agents for the treatment of malaria, African trypanosomiasis,
and cancer.
|
135 |
Determinantes progn?sticos de pacientes portadores de insufici?ncia card?aca cr?nica secund?ria ? cardiomiopatia da doen?a de Chagas na lista de espera para transplante card?aco.Dib, Jorge Adas 06 June 2008 (has links)
Made available in DSpace on 2016-01-26T12:51:19Z (GMT). No. of bitstreams: 1
jorgeadasdib_tese.pdf: 343099 bytes, checksum: ab3f9830cf7060129a9dcec26d66b83c (MD5)
Previous issue date: 2008-06-06 / No previous study has addressed the question of prognostic determinants for patients with Chagas? cardiomyopathy at the terminal stage listed for heart transplantation. Casuistic and Method: All patients listed for heart transplantation at our institution from August, 2000 to March, 2005 were considered for the study. Patients removed from the waiting list for clinical status improvement were excluded from the investigation. Patients were followed until death, cardiac transplantation or the end of the study period. Cardiac transplant recipients were censored at the time of transplantation. No patient was lost to follow up. A Cox regression hazards model was used to establish independent predictors of all-cause mortality. Variables previously demonstrated to predict mortality in either Chagas or non-Chagas? disease heart failure were entered the univariate analysis. Separate analyses were performed for Chagas and non-Chagas? disease patients. Results: Median follow up was 32 (15,121) days in Chagas disease and 79 (14,151) days in non-Chagas? disease patients. In Chagas disease patients, the hemodynamic instability (p=0.01; hazard ratio=0,077, 95% confidence interval, 0.01 to 0.58) as well as the transpulmonary gradient (p=0.02; hazard ratio=1.15, 95% confidence interval, 1.02 to 1.30) were retained as independent predictors of all-cause mortality. Serum sodium levels (p=0.002; hazard ratio=0.81; 95% confidence interval, 0.71 to 0.93) was independent predictor of all-cause mortality for non-Chagas? disease patients. Conclusion: The hemodynamic instability and transpulmonary gradient were independent predictors of all-cause mortality for Chagas? disease patients listed for heart transplantation. A larger, prospective cohort study is needed to validate our findings. / At? agora nenhum estudo preocupou-se em estabelecer determinantes progn?sticos para pacientes com insufici?ncia card?aca cr?nica terminal secund?ria ? cardiomiopatia da doen?a de Chagas na fila de espera para transplante card?aco. Casu?stica e M?todo: Todos os pacientes alocados em fila de espera de transplante card?aco em nossa institui??o, de agosto de 2000 a mar?o de 2005, foram inicialmente considerados para o estudo. Os pacientes que foram removidos da lista de espera em virtude de melhora no estado cl?nico foram retirados do estudo. Os pacientes foram acompanhados at? a morte, transplante card?aco ou a data final estipulada para o estudo. Os pacientes receptores de transplante de cora??o foram retirados do estudo na data em que o ato operat?rio ocorreu. N?o se perdeu contato com os pacientes durante o acompanhamento cl?nico enquanto na fila de espera de transplante card?aco. O modelo de an?lise de riscos proporcionais de Cox foi utilizado para se estabelecer vari?veis de predi??o independentes de mortalidade geral. As vari?veis que eram capazes de predizer mortalidade geral em pacientes com insufici?ncia card?aca cr?nica secund?ria ? cardiomiopatia da doen?a de Chagas ou a outras cardiomiopatias foram utilizadas no modelo univariado. An?lises univariadas foram feitas nos pacientes chag?sicos e n?o chag?sicos separadamente. Resultados: A mediana do tempo de acompanhamento cl?nico foi 32 (15, 121) dias nos pacientes chag?sicos e 79 (14, 151) dias nos pacientes n?o chag?sicos. Nos pacientes chag?sicos, a instabilidade hemodin?mica (p=0,01; raz?o de risco=0,077, intervalo de confian?a de 95% entre 0,01 e 0,58) e o gradiente transpulmonar (p=0,02; raz?o de risco =1,15, intervalo de confian?a de 95% entre 1,02 e 1,30) foram as vari?veis de predi??o independentes de mortalidade geral. Os n?veis s?ricos de s?dio (p=0,002; raz?o de risco =0,81; intervalo de confian?a de 95% entre 0,71 e 0,93) foi a vari?vel de predi??o independente para os pacientes n?o chag?sicos na fila de espera para transplante card?aco. Conclus?es: A instabilidade hemodin?mica e o gradiente transpulmonar foram preditores independentes de mortalidade geral em pacientes com insufici?ncia card?aca cr?nica secund?ria ? cardiomiopatia da doen?a de Chagas na lista de espera para transplante card?aco. Um estudo prospectivo de coorte longitudinal ? necess?rio para validar os resultados obtidos nesta investiga??o.
|
136 |
Caractérisation de l' interaction entre les trypanosomes africains et les cellules endothéliales : activation, inflammation et rôle des trans-sialidases / Characterization of the interaction of African trypanosomes with endothelial cells : activation, Inflammation and role of trans-sialidasesAmmar, Zeinab 26 November 2013 (has links)
La trypanosomose est la maladie parasitaire la plus dévastatrice en Afrique, et affecte à la fois les hommes et le bétail. Vu l’inefficacité des stratégies de contrôle actuelles, une stratégie alternative dite “anti-maladie” a été proposée dans le cadre de la trypanosomose animale. Elle vise à neutraliser les effets de la maladie plutôt qu’à éliminer le parasite. Une telle stratégie nécessite une meilleure compréhension du développement de la pathologie ainsi qu’une caractérisation détaillée des facteurs de virulence impliqués. Dans ce contexte, nous nous sommes intéressés à l’étude de l’interaction hôte/pathogène entre les trypanosomes Africains et l’endothélium de l’hôte mammifère. En comparant quatre espèces différentes de trypanosomes Africains, nous avons montré que leurs capacités d’activation des cellules endothéliales étaient distinctes. Nous avons clairement démontré que T. congolense, T. vivax et T. b. gambiense activent les cellules endothéliales via la voie de NF-ƘB, alors que T. b. brucei est incapable d’activer cette voie. Cette activation a induit une résponse pro-inflammatoire in vitro et in vivo, ce qui souligne l’importance de ce mécanisme dans le développement de la maladie. Pour la première fois, nous avons identifié une activité sialidase chez le parasite de l’homme T. brucei gambiense, et nous avons démontré que les trans-sialidases trypanosomales sont les médiateurs de cette activation endothéliale et de la réponse inflammatoire consécutive, et ceci à la fois chez les trypanosomes africains d’homme et d’animaux. De plus, nous avons montré que l’activation endothéliale implique l’activité lectin-like des trans-sialidases et non pas l’activité catalytique, ainsi que des récepteurs sialylés sur la surface endothéliale. En conclusion, ce travail a apporté des avancées considérables dans la compréhension de la relation hôte/pathogène et a permis de désigner les sialidases comme un facteur de virulence central dans le dialogue intermoléculaire durant les trypanosomoses, en faisant une cible de choix pour le vaccin « anti-maladie ». / Trypanosomiasis remains by far the most devastating parasitic disease in Africa affecting both humans and livestock. The current control strategies being not efficient, an alternative “anti-disease” strategy aiming to neutralize the pathological effects of the parasite rather than to eliminate it, was proposed. Therefore, it is essential to understand the development of pathogenesis and characterize the involved pathogenic factors. In this context, we wanted to elucidate the host-pathogen interaction between the African trypanosomes and the mammalian host endothelium. By comparing four different trypanosomes species, we showed that they displayed distinct capacities for activation of endothelial cells. We clearly demonstrated that T. congolense, T. vivax and T. b. gambiense activate the endothelial cells via the NF-ƘB pathway, but not T. b. brucei. This activation caused a pro-inflammatory response in vitro and in vivo, showing the importance of this mechanism in the development of pathogenesis. For the first time, we identified sialidase activity in the human parasite T. brucei gambiense, and demonstrated that the trypanosomal trans-sialidases are the mediators of this endothelial activation and its consequent inflammatory response, for both human and animal trypanosomes. Additionnally, we showed that endothelial cell activation is mediated by the lectin-like domain of the trans-sialidase rather than the catalytic site, and involves sialylated receptors of the endothelial cell surface. In conclusion, our study brings considerable insights into the host-pathogen relationship and designates sialidases as a central virulence factor in the molecular crosstalk during trypanosomiasis, which makes it a perfect target for the anti-disease strategy.
|
137 |
Ethyl Pyruvate and HIV-1 Protease Inhibitors in Drug Discovery of Human African TrypanosomiasisMengistu, Netsanet 28 September 2015 (has links) (PDF)
Referat:
Background: Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease of humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100% mortality. However, the available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to the probable similarities in cell metabolism among tumor and trypanosoma cells, some of the current registered drugs against HAT were derived from cancer chemotherapeutic research. Here too, for the first time, we have demonstrated that the simple ester, ethyl pyruvate, comprises such properties. On the other hand initial studies have confirmed the efficacy of protease inhibitors in treatment of Trypanosoma cruzi, Plasmodium falciparum and Leishmania major. However, studies on efficacy and specific proteases inhibition using HIV-1 protease inhibitors on T. brucei cells remain untouched.
Methodology/Principal findings: The current study covers efficacy and corresponding target evaluation of ethyl pyruvate and HIV-1 protease inhibitors (ritonavir and saquinavir) on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, zymography, phase contrast microscopic video imaging and ex vivo drug toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki=3.0±0.29 mM). The potential of this compound as an anti-trypanosomal drug is also strengthened by its fast acting property, killing cells within three hours post exposure. This was demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, this drug produced minimal side effects in human erythrocytes and is known to easily cross the blood-brain-barrier (BBB) which makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug resistance tests indicate irreversible killing of cells and a low chance of drug resistance development under applied experimental conditions. In addition to ethyl pyruvate our experimental study on HIV-1 protease inhibitors showed that both ritonavir (RTV) (IC50=12.23 µM) and saquinavir (SQV) (IC50=11.49 µM) effectively inhibited T. brucei cells proliferation. The major proteases identified in these cells were the cysteine- (~29kDa Mr) and metallo- (~66kDa Mr) proteases. Their proteolytic activity was, however, not hampered by either of these two protease inhibitors.
Conclusion/Significance: Our results present ethyl pyruvate as a safe and fast acting drug. Hence, because of its predefined property to easily cross the BBB, it can probably be a new candidate agent to treat the heamolymphatic as well as neurological stages of sleeping sickness. Similarly, HIV-1 protease inhibitors, SQV and RTV, exhibited their antitrypanosomal potential but require further anlysis to identify their specific targets.
|
138 |
Biogeographical patterns of African trypanosomoses for improved planning and implementation of field interventionsCecchi, Giuliano 29 November 2011 (has links)
Spatially-explicit information is essential for planning and implementing interventions against vector-borne diseases. This is also true for African trypanosomoses, a group of diseases of both humans and animals caused by protozoa of the Genus Trypanosoma, and transmitted by tsetse flies (Genus Glossina).<p>In this thesis the knowledge gaps and the requirements for an evidence-based decision making in the field of tsetse and trypanosomoses are identified, with a focus on georeferenced data and Geographic Information Systems (GIS). Datasets, tools and analyses are presented that aim to fill some of the identified knowledge gaps.<p>For the human form of the disease, also known as sleeping sickness, case detection and treatment are the mainstay of control, so that accurate knowledge of the geographic distribution of infections is paramount. In this study, an Atlas was developed that provides village-level information on the reported occurrence of sleeping sickness. The geodatabase underpinning the Atlas also includes the results of active screening activities, even when no cases were detected. The Atlas enables epidemiological maps to be generated at a range of scales, from local to global, thus providing evidence for strategic and technical decision making.<p>In the field of animal trypanosomosis control, also known as nagana, much emphasis has recently been placed on the vector. Accurate delineation of tsetse habitat appears as an essential component of ongoing and upcoming interventions against tsetse. The present study focused on land cover datasets and tsetse habitat. The suitability for tsetse of standardized land cover classes was explored at continental, regional and national level, using a combination of inductive and deductive approaches. The land cover classes most suitable for tsetse were identified and described, and tailored datasets were derived.<p>The suite of datasets, methodologies and tools presented in this thesis provides evidence for informed planning and implementation of interventions against African trypanosomoses at a range of spatial scales. / Doctorat en Sciences agronomiques et ingénierie biologique / info:eu-repo/semantics/nonPublished
|
139 |
Ethyl Pyruvate and HIV-1 Protease Inhibitors in Drug Discovery of Human African TrypanosomiasisMengistu, Netsanet 21 September 2015 (has links)
Referat:
Background: Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease of humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100% mortality. However, the available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to the probable similarities in cell metabolism among tumor and trypanosoma cells, some of the current registered drugs against HAT were derived from cancer chemotherapeutic research. Here too, for the first time, we have demonstrated that the simple ester, ethyl pyruvate, comprises such properties. On the other hand initial studies have confirmed the efficacy of protease inhibitors in treatment of Trypanosoma cruzi, Plasmodium falciparum and Leishmania major. However, studies on efficacy and specific proteases inhibition using HIV-1 protease inhibitors on T. brucei cells remain untouched.
Methodology/Principal findings: The current study covers efficacy and corresponding target evaluation of ethyl pyruvate and HIV-1 protease inhibitors (ritonavir and saquinavir) on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, zymography, phase contrast microscopic video imaging and ex vivo drug toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki=3.0±0.29 mM). The potential of this compound as an anti-trypanosomal drug is also strengthened by its fast acting property, killing cells within three hours post exposure. This was demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, this drug produced minimal side effects in human erythrocytes and is known to easily cross the blood-brain-barrier (BBB) which makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug resistance tests indicate irreversible killing of cells and a low chance of drug resistance development under applied experimental conditions. In addition to ethyl pyruvate our experimental study on HIV-1 protease inhibitors showed that both ritonavir (RTV) (IC50=12.23 µM) and saquinavir (SQV) (IC50=11.49 µM) effectively inhibited T. brucei cells proliferation. The major proteases identified in these cells were the cysteine- (~29kDa Mr) and metallo- (~66kDa Mr) proteases. Their proteolytic activity was, however, not hampered by either of these two protease inhibitors.
Conclusion/Significance: Our results present ethyl pyruvate as a safe and fast acting drug. Hence, because of its predefined property to easily cross the BBB, it can probably be a new candidate agent to treat the heamolymphatic as well as neurological stages of sleeping sickness. Similarly, HIV-1 protease inhibitors, SQV and RTV, exhibited their antitrypanosomal potential but require further anlysis to identify their specific targets.:Bibliographic description ii
Acronyms iii
1. Introduction 1
1.1. Disease background 1
1.2. Epidemiological distribution and disease transmission dynamics 1
1.3. Biology and life cycle of the trypanosomatidea 3
1.4. Public health significance 4
1.5. Clinical stages and disease progression 5
1.6. Current challenges of disease control 6
1.7. Current drugs and their clinical applications 9
1.8. Targets for drug discovery 12
1.8.1. Energy metabolism 12
1.8.2. Proteolysis 17
1.9. Ethyl pyruvate 18
1.10. HIV-1 Protease Inhibitors 21
2. Aim of the study 22
3. Materials and Methods 24
4. Results 31
5. Discussion 45
6. Conclusion 53
7. Supporting information 54
8. Summary 56
9. References 62
Erklärung über die eigenständige Abfassung der Arbeit 77
Curriculum vitae 78
Publications and Presentations 81
Acknowledgement 83
|
140 |
Modelling the control of tsetse and African trypanosomiasis through application of insecticides on cattle in Southeastern UgandaKajunguri, Damian 03 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: In Uganda, cattle are an important reservoir of Trypanosoma brucei rhodesiense, a parasite
that causes human African trypanosomiasis or sleeping sickness. We developed mathematical
models to examine the transmission of T. b. rhodesiense by tsetse vector species,
Glossina fuscipes fuscipes in a host population that consists of humans, domestic and wild
mammals, and reptiles. The models were developed and analysed based on the situation in
Tororo district in Southeastern Uganda, where sleeping sickness is endemic and which has a
cattle and human population of 40, 000 and 500, 000, respectively. Assuming populations of
cattle and humans only, the impact of mass chemoprophylaxis and vector control through
insecticide-treated cattle (ITC) is evaluated. Keeping 12% or 82% of the cattle population
on insecticides that have an insecticidal killing effect of 100% at all times or trypanocides
that have 100% efficacy, respectively, can lead to the control of T. b. rhodesiense in both
humans and cattle. Optimal control of T. b. rhodesiense is shown to be achieved through
ITC alone or a combination of chemoprophylaxis and ITC, the former being the cheapest
control strategy. Allowing for the waning effect of insecticides and including wildhosts,
T. b. rhodesiense control can be achieved by keeping 21% or 27% of the cattle population
on insecticides through whole-body or restricted application, respectively. Restricting
the treatment of insecticides to adult cattle only would require 24% or 33% of the adult
cattle population to be kept on insecticides through whole-body or restricted application,
respectively, to control T. b. rhodesiense. A cost-effectiveness and benefit-cost analysis of
using ITC to control T. b. rhodesiense show that restricted application of insecticides is
a cheaper and more beneficial strategy compared to whole-body treatment. The results of
the study show that the restricted application of insecticides on cattle provides a cheap,
safe and farmer-based strategy for controlling tsetse and trypanosomiasis. / AFRIKAANSE OPSOMMING: In Uganda is beeste ’n belangrike reservoir van Trypanosoma brucei rhodesiense, ’n parasiet
wat tripanosomiase of slaapsiekte in mense veroorsaak. Ons het wiskundige modelle ontwikkel
wat die oordrag van T. b. Rhodesiense deur tesetse vektor spesies, Glossina fuscipes
fuscipes in ’n draer populasie wat bestaan uit mense, mak en wilde diere en reptiele, ondersoek.
Die modelle was ontwikkel en geanaliseer gebaseer op die oordrag situasie in die
Tororo distrik in Suidoostelike Uganda, ’n gebied waar slaapsiekte endemies is en wat ’n
populasie van 40, 000 beeste en 500, 000 mense het. Die impak van massa chemoprofilakse
en vektor beheer deur insekdoder-behandelde beeste is gevalueer onder die aanname van
bees en mens populasies alleenlik. Beheer oor T. b. Rhodesiense in beide mense en beeste
kan verkry word deur of 12% van die bees populasie te behandel met ’n insekdoder wat
100% effektief is ten alle tye of 82% van die bees populasie te behandel met tripanosiedes
wat 100% effektief is. Daar is aangetoon dat optimale beheer van T. b. Rhodesiense
bereik kan word deur die gebruik van insekdoders alleenlik of ’n kombinasie van insekdoders
en chemoprofilakse, hoewel eersgenoemde die goedkoopste strategie is. Wanneer die
kwynende effek van insekdoders asook wilde diere as draers in ag geneem word, kan T.
b. Rhodesiense beheer verkry word deur 21% van beeste se hele liggaam met insekdoders
te behandel of 27% gedeeltelik te behandel. As slegs volwasse beeste met insekdoders
behandel word, moet 24% se hele liggaam of 33% gedeeltelik behandel word vir beheer
van T. b. Rhodesiense. ’n Koste-effektiwiteit en voordeel-koste analise van insekdoders as
beheermaatstaf vir T. b. Rhodesiense toon aan dat gedeeltelike behandeling van die bees
se liggaam die goedkoper en meer voordelige strategie is in vergelyking met behandeling
van die hele liggaam. Die resultate van die studie wys dat gedeeltelike behandeling van
beeste met insekdoders ’n goedkoop, veilige en landbouer-gebaseerde strategie is om tsetse
en tripanosomiase te beheer.
|
Page generated in 0.0377 seconds