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bisphosphonates inhibit the growth of trypanosoma brucei, trypanosoma cruzi, leishmania donovani, toxoplasma gondii, and plasmodium falciparum: a potential route to chemotherapy.we have investigated the effects in vitro of a series of bisphosphonates on the proliferation of trypanosoma cruzi, trypanosoma brucei rhodesiense, leishmania donovani, toxoplasma gondii, and plasmodium falciparum. the results show that nitrogen-containing bisphosphonates of the type used in bone resorption therapy have significant activity against parasites, with the aromatic species having in some cases nanomolar or low-micromolar ic(50) activity values against parasite replication (e.g. o-ris ...200111300872
the story of cgp 40 215: studies on its efficacy and pharmacokinetics in african green monkey infected with trypanosoma brucei rhodesiense.cgp 40 215 is an inhibitor of s-adenosylmethionine decarboxylase, a key enzyme in trypanosomal polyamine biosynthesis. it is highly active against trypanosoma brucei rhodesiense and t. b. gambiense in vitro and in the corresponding rodent models, and therefore was a promising candidate for further development as a new drug against human african trypanosomiasis. we conducted initial pharmacokinetic and efficacy studies in african green monkeys: based on two dose-finding studies, an infection-trea ...200111348531
molecular characterization of field isolates of human pathogenic trypanosomes.the accurate identification of each of the three subspecies of trypanosoma brucei remains a challenging problem in the epidemiology of sleeping sickness. advances in molecular characterization have revealed a much greater degree of heterogeneity within the species than previously supposed. only group 1 t. b. gambiense stands out as a separate entity, defined by several molecular markers. t. b. rhodesiense is generally too similar to sympatric t. b. brucei strains to be distinguished from them by ...200111348534
identification and characterization of trypanocides by functional expression of an adenosine transporter from trypanosoma brucei in yeast.the causative agents of sleeping sickness, trypanosoma brucei rhodesiense and t. brucei gambiense, do not synthesize purines de novo but salvage purine bases and nucleosides from their hosts. we used yeast as an expression system for functional characterization of the trypanosomal adenosine transporter tbat1. a selection of purine analogs and flavonoids were tested for their ability to interfere with adenosine transport, with the aims of identifying (a) trypanocidal tbat1 substrates, and (b) inh ...200111357935
analysis of macrophage activation in african trypanosomiasis.african trypanosomes cause a fatal disease of man and animals that is characterized by extensive functional, histological, and pathological changes in the lymphoid tissues of infected hosts, including an increase in the numbers and activation state of macrophages. macrophage activation during infection is the result of exposure of these cells to parasite components and host-derived ifn-gamma, produced in response to parasite antigens. the balance of these different activation signals may determi ...200111358974
the lysosomal targeting and intracellular metabolism of trypanosome lytic factor by trypanosoma brucei brucei.trypanosome lytic factor (tlf) provides innate protection for humans against infection by the animal pathogen trypanosoma brucei brucei but not against the agent of human african sleeping sickness, trypanosoma brucei rhodesiense. tlf exists in two forms, tlf-1 and tlf-2. prior studies suggested that tlf-1 causes lysosomal disruption and subsequent cell death in t. b. brucei. here we confirm the lysosomal targeting of tlf-1 by immunolocalization with the trypanosome lysosomal membrane protein p67 ...200111420109
evidence for multiple origins of human infectivity in trypanosoma brucei revealed by minisatellite variant repeat mapping.in recent years a wide variety of biochemical and molecular typing systems has been employed in the study of parasite diversity aimed at investigating the level of genetic diversity and delineating the relationship between different species and subspecies. however, such methods have failed to differentiate between two of the classically defined subspecies of the protozoan parasite trypanosoma brucei: the human infective, t. b. rhodesiense, which causes african sleeping sickness, and the non-huma ...200111428466
novel inhibitors of trypanosoma cruzi dihydrofolate reductase.there is an urgent need for the development of new drugs to treat chagas' disease, which is caused by the protozoan parasite trypanosoma cruzi. the enzyme dihydrofolate reductase (dhfr) has been a very successful drug target in a number of diseases and we decided to investigate it as a potential drug target for chagas' disease. a homology model of the enzyme was used to search the cambridge structural database using the program dock 3.5. compounds were then tested against the enzyme and the whol ...200111451529
minor cytotoxic and antibacterial compounds from the rhizomes of amomum aculeatum.a new cytotoxic 1,7-dioxa-dispiro[5.1.5.2]pentadeca-9,12-dien-11-one derivative, aculeatin d, and a new alkenone, 5-hydroxy-hexacos-1-en-3-one, have been isolated as minor compounds from the rhizomes of amomum aculeatum. their structures have been determined mainly by nmr spectroscopy and mass spectrometry. aculeatin d showed high cytotoxicity against the kb and the l-6 cell line with ic(50) of 0.38 microg/ml and 1 microg/ml, respectively. additionally, it revealed remarkable activity against tw ...200111454360
the epidemiology and control of human african trypanosomiasis.human african trypanosomiasis is caused by trypanosoma brucei gambiense in west and central africa, and by trypanosoma brucei rhodesiense in east and southern africa. in recent years there has been a dramatic resurgence of gambian trypanosomiasis in central africa, especially in the democratic republic of congo, angola and sudan. the disease is quiescent in most of west africa, as is rhodesian trypanosomiasis the other side of the continent. the epidemiology of gambian trypanosomiasis is reviewe ...200111461032
trypanocidal activity of dicationic compounds related to pentamidine.eight dicationic compounds related to pentamidine were studied for trypanocidal activity in seven trypanosome isolates. in vitro studies revealed that diamidines are more potent than diimidazolines. for example, 2 (a diamidine) and 4 (a diimidazoline) inhibited the growth of ketri 243 with ic50 values of 2.3 and 900 nm, respectively. introduction of polar groups into the linker decreased the effectiveness of the compounds against drug-resistant trypanosomes. in compounds with a 2-butene linker b ...200111525843
veterinary link to drug resistance in human african trypanosomiasis? 200111530144
the origins of a new trypanosoma brucei rhodesiense sleeping sickness outbreak in eastern uganda.sleeping sickness, caused by two trypanosome subspecies, trypanosoma brucei gambiense and trypanosoma brucei rhodesiense, is a parasitic disease transmitted by the tsetse fly in sub-saharan africa. we report on a recent outbreak of t b rhodesiense sleeping sickness outside the established south-east ugandan focus, in soroti district where the disease had previously been absent. soroti district has been the subject of large-scale livestock restocking activities and, because domestic cattle are im ...200111530149
cultural and physiological observations on trypanosoma rhodesiense and trypanosoma gambiense. 1949.1. a diphasic medium of simple preparation is described for the indefinite cultivation of t. rhodesiense and t. gambiense. 2. the chief advantage of the medium is that it contains rabbit blood and thus obviates the necessity of using human blood. 3. the flagellates develop only to the proventricular stage; hence the cultures are noninfective. 4. the proventricular forms of both t. rhodesiense and t. gambiense consume sugar with the concomitant formation of acid. they are aerobic fermenters. 5. v ...200111534630
the classic paper of tobie, von brand, and mehlman (1950) revisited. 200111534631
chemotherapeutic approaches to protozoa: kinetoplastida--current level of knowledge and outlook.the possibilities for treating haemoflagellate infections (african trypanosomiasis) are very limited (table 1; mehlhorn and schrevel 1995; croft 1997; hunter 1997; wang 1997; trouiller and olliaro 1998). all the available drugs have severe side-effects in humans and animals. vaccination is not really an option, in view of the wide antigen variability. at present, there are several drug combinations in clinical trials: suramin/eflornithine, suramin/metronidazole, suramin/pentamidine, melarsoprol/ ...200111570565
nitric oxide and cytokine synthesis in human african trypanosomiasis.plasma and cerebrospinal fluid (csf) concentrations of nitrate and the cytokines interferon (ifn)-gamma, tumor necrosis factor (tnf)-alpha, interleukin (il)-10, and il-4 were measured in 91 african trypanosomiasis patients before and after treatment. nitrate levels overall were not significantly elevated over those for control persons, but a marginal increase in plasma nitrate was detected in patients reporting illness of <40 days' duration. plasma ifn-gamma and total tnf-alpha concentrations in ...200111574928
activity of human trypanosome lytic factor in mice.the inability of the cattle pathogen trypanosoma brucei brucei to infect humans is due to an innate factor in human serum termed trypanosome lytic factor (tlf). human haptoglobin-related protein is the proposed toxin in tlf and can exist either as a component of a minor subclass of high-density lipoprotein (tlf-1) or as a lipid free, high molecular weight protein complex (tlf-2). the trypanolytic activity of both tlf-1 and tlf-2 has been studied in vitro but their relative contributions to prote ...200111606222
the phenomenon of treatment failures in human african trypanosomiasis.treatment of human african trypanosomiasis (hat or sleeping sickness) relies on a few drugs which are old, toxic and expensive. the most important drug for the treatment of second stage infection is melarsoprol. during the last 50 years treatment failures with melarsoprol were not a major problem in trypanosoma brucei gambiense patients. commonly a relapse rate of 5-8% was reported, but in recent years it has increased dramatically in some important foci of t. b. gambiense sleeping sickness. tre ...200111703845
active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of trypanosoma brucei rhodesiense.cysteine protease activity of african trypanosome parasites is a target for new chemotherapy using synthetic protease inhibitors. to support this effort and further characterize the enzyme, we expressed and purified rhodesain, the target protease of trypanosoma brucei rhodesiense (mvat4 strain), in reagent quantities from pichia pastoris. rhodesain was secreted as an active, mature protease. site-directed mutagenesis of a cryptic glycosylation motif not previously identified allowed production o ...200111704274
increased trypanolytic activity in sera of sleeping sickness patients after chemotherapy.we tested sera from patients previously treated for human african trypanosomiasis, from patients infected with trypanosomes, and from individuals never diagnosed with african trypanosomiasis living in the trypanosoma brucei gambiense sleeping sickness focus of mbini in equatorial guinea for their trypanolytic activity against bloodstream forms of t. b. rhodesiense expressing a metacyclic and bloodstream variant surface glycoprotein (vsg). nearly 80% of the sera from treated patients showed high ...200111737844
in vitro antiprotozoal activity of extract and compounds from the stem bark of combretum molle.the antiprotozoal activity of the ethiopian medicinal plant combretum molle (r. br. ex g. don.) engl & diels (combretaceae) was evaluated by in vitro testing against plasmodium falciparum, trypanosoma brucei rhodesiense, trypanosoma cruzi and leishmania donovani. the acetone fraction of the stem bark of this plant prepared by soxhlet extraction was inactive against the intracellular amastigotes of l. donovani and t. cruzi in murine peritoneal macrophages but showed significant activity against e ...200111746844
identification of human-infective trypanosomes in animal reservoir of sleeping sickness in uganda by means of serum-resistance-associated (sra) gene.the expansion of sleeping sickness caused by trypanosoma brucei rhodesiense beyond its traditional focus in southeast uganda has been linked with large-scale livestock restocking. to assess the risk presented to the human population by domestic livestock, human-infective t b rhodesiense must be distinguished from non-human-infective t brucei brucei, since both parasites can be present in cattle. we investigated the use of a simple genetic marker to characterise parasites collected from cattle in ...200111755607
[the epidemiology of human african trypanosomiasis: a complex multifactorial history].sleeping sickness has long been known from descriptions by arab merchants and slave traders. however it was not until 1901 that forbes discovered the offending agent and 1903 that bruce described the role of the tsetse fly. the basic epidemiological transmission cycle was described less than 10 years later. although the main outline of the original model can still be considered as sound, subsequent research has greatly expanded our knowledge. molecular biology has identified different parasites ...200111803821
[diagnosis of human african trypanosomiasis in 2001].human african trypanosomiasis is characterized by a non-specific clinical presentation with no consistent, pathognomonic manifestations. however definite diagnosis is necessary to avoid unnecessary therapeutic risks with toxic drugs. further complicating this situation is the frequent need to achieve field diagnosis in remote locations with limited facilities. serological tests such as catt (card agglutination trypanosomiasis test) are useful for initial population screening to identify suspects ...200111803824
stage determination and follow-up in sleeping sickness.in order to select a correct treatment after primary diagnosis of trypanosomiasis infection, accurate assessment of the disease stage, haemo-lymphatic or meningo-encephalitic, is essential. this is achieved by lumbar puncture and subsequent examination of the cerebrospinal fluid. these examinations have to be repeated during 2 years after treatment, and only after the cerebrospinal fluid has normalized one can decide on complete cure. the currently used cerebrospinal fluid parameters, i.e. white ...200111803826
[technical reasons for the re-emergence of sleeping sickness].in the 1920s the epidemic outbreak of human african trypanosomiasis was so deadly that government authorities decided to take large-scale action. it was by giving jamot absolute administrative and financial autonomy to apply his ideas that the disease was successfully controlled. after jamot determined efforts against the disease continued so that, by the dawn of decolonization, many considered the problem of sleeping sickness as resolved. control programs progressively slowed and virtually ceas ...200111803836
[distribution and spread of human african trypanosomiasis: value of genetic identification of the trypanosomes].numerous factors extrinsic to trypanosome populations have been implicated in the distribution and spread of human african trypanosomiasis (hat), but quantification of these factors has proven difficult. an easier method of monitoring hat consists of tracking parasites by genetic identification of trypanosomes in hosts and vectors. this method requires distinction between trypanosoma brucei rhodesiense and trypanosoma brucei gambiense followed by determination of the genotype of each subspecies ...200111803837
anisomorphic cell division by african trypanosomes.in the bloodstream of a mammalian host, african trypanosomes are pleomorphic; the shorter, non-proliferative, stumpy forms arise from longer, proliferative, slender forms with differentiation occurring via a range of morphological intermediates. in order to investigate how the onset of morphological change is co-ordinated with exit from the cell cycle we first characterized slender form cell division. outgrowth of the new flagellum was found to occur at a linear rate, so by using outgrowth of th ...200111822664
vernoguinosterol and vernoguinoside, trypanocidal stigmastane derivatives from vernonia guineensis (asteraceae).two bitter stigmastane derivatives, vernoguinosterol (1) and vernoguinoside (2), have been isolated from the stem bark of vernonia guineensis and their structures eludicated using spectroscopic methods. the new compounds exhibit trypanocidal activity.200211830150
molecular characterization of three gut genes from glossina morsitans morsitans: cathepsin b, zinc-metalloprotease and zinc-carboxypeptidase.insect gut enzymes are involved in digestion of dietary proteins. additionally, these enzymes have been implicated in the process of pathogen establishment in several insects including the tsetse fly (diptera:glossinidae), which is the vector for african trypanosomes. both the male and female tsetse can transmit trypanosomes and are strict blood feeders during all stages of their development. here, we describe the molecular characterization of three gut genes: cathepsin b (gmcatb), zinc-metallop ...200211841503
[trypanosomiasis--a real risk for tourists visiting national parks in tanzania].african sleeping sickness is no longer a rare disease among tourists visiting national parks in tanzania. the disease is caused by a parasite, trypanosoma brucei, which is transmitted by the tsetse fly. two species infect humans: trypanosoma brucci gambiense and trypanosoma brucei rhodesiense; the last form is re-emerging in parts of africa. untreated this disease carries a mortality of nearly 100%. this article describes a case of african sleeping sickness in a tourist visiting tanzania, which ...200211851293
chemotherapy of human african trypanosomiasis.human african trypanosomiasis or sleeping sickness is resurgent [1,2]. the disease is caused by subspecies of the parasitic haemoflagellate, trypanosoma brucei. infection starts with the bite of an infected tsetse fly (glossina spp.). parasites move from the site of infection to the draining lymphatic vessels and blood stream. the parasites proliferate within the bloodstream and later invade other tissues including the central nervous system. once they have established themselves within the cns, ...200211860365
molecular variation of trypanosoma brucei subspecies as revealed by aflp fingerprinting.genetic analysis of trypanosoma spp. depends on the detection of variation between strains. we have used the amplified fragment length polymorphism (aflp) technique to develop a convenient and reliable method for genetic characterization of trypanosome (sub)species. aflp accesses multiple independent sites within the genome and would allow a better definition of the relatedness of different trypanosome (sub)species. nine isolates (3 from each t. brucei subspecies) were tested with 40 aflp primer ...200212003059
homology modeling and molecular dynamics study of nad-dependent glycerol-3-phosphate dehydrogenase from trypanosoma brucei rhodesiense, a potential target enzyme for anti-sleeping sickness drug development.sleeping sickness and chagas disease are among the most severe diseases in africa as well as latin america. these two diseases are caused by trypanosoma spp. recently, an enzyme of a glycolytic pathway, nad-dependent glycerol-3-phosphate dehydrogenase, of leishmania mexicana was crystallized and its structure determined by x-ray crystallography. this structure has offered an excellent template for modeling of the homologous enzymes from another trypanosoma species. here, a homology model of the ...200212023213
activity of bisphosphonates against trypanosoma brucei rhodesiense.we report the results of a comparative molecular field analysis (comfa) investigation of the growth inhibition of the bloodstream form of trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. a quantitative three-dimensional structure-activity relationship comfa model for a set of 26 bisphosphonates having a range of activity spanning approximately 3 orders of magnitude (minimum ic(50) = 220 nm; maximum ic(50) = 102 microm) yielded an r(2) value of 0.87 with a cross-validated r(2) v ...200212086478
lepadins d-f: antiplasmodial and antitrypanosomal decahydroquinoline derivatives from the tropical marine tunicate didemnum sp.from a new tunicate species, belonging to the genus didemnum, three alkaloids possessing an unusual and extremely rare decahydroquinoline skeleton and showing significant and selective antiplasmodial and antitrypanosomal activity were obtained as follows: (2r*,3s*,4ar*,5r*,8as*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methylquinoline (lepadin d,1), its quaternary nitrogen derivative (2), (2r*,2"e,3s*,4ar*,5r*,8as*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic ...200212086492
case records of the massachusetts general hospital. weekly clinicopathological exercises. case 20-2002. a 37-year-old man with fever, hepatosplenomegaly, and a cutaneous foot lesion after a trip to africa. 200212087144
sleeping sickness and the brain.recent progress in understanding the neuropathological mechanisms of sleeping sickness reveals a complex relationship between the trypanosome parasite that causes this disease and the host nervous system. the pathology of late-stage sleeping sickness, in which the central nervous system is involved, is complicated and is associated with disturbances in the circadian rhythm of sleep. the blood-brain barrier, which separates circulating blood from the central nervous system, regulates the flow of ...200212088284
vsg-gpi anchors of african trypanosomes: their role in macrophage activation and induction of infection-associated immunopathology.african trypanosomes express a glycosylphosphatidyl inositol (gpi)-anchored variant-specific surface glycoprotein (vsg) as a protective coat. during infection, large amounts of vsg molecules are released into the circulation. their interaction with various cells of the immune system underlies the severe infection-associated pathology. recent results have shown that anti-gpi vaccination can prevent the occurrence of this pathology.200212106794
treatment of human african trypanosomiasis--present situation and needs for research and development.human african trypanosomiasis re-emerged in the 1980s. however, little progress has been made in the treatment of this disease over the past decades. the first-line treatment for second-stage cases is melarsoprol, a toxic drug in use since 1949. high therapeutic failure rates have been reported recently in several foci. the alternative, eflornithine, is better tolerated but difficult to administer. a third drug, nifurtimox, is a cheap, orally administered drug not yet fully validated for use in ...200212127356
alkaloids from narcissus angustifolius subsp. transcarpathicus (amaryllidaceae).seven alkaloids have been isolated from fresh bulbs of narcissus angustifolius subsp. transcarpathicus (amaryllidaceae). nangustine, reported here for the first time, is the first 5,11-methanomorphanthridine alkaloid with a c-3/c-4 substitution. the structure and stereochemistry of this new alkaloid, as well as those previously known, have been determined by physical and spectroscopic methods. spectroscopic data of pancracine have been completed. the in vitro assay activity against the parasitic ...200212150811
ancistrocongolines a-d, new naphthylisoquinoline alkaloids from ancistrocladus congolensis.four new naphthylisoquinoline alkaloids, ancistrocongolines a-d (4-7) were isolated from ancistrocladus congolensis, along with the known compound korupensamine a (8). structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. their biological activities against the pathogens of malaria, leishmaniasis, chagas disease, and african sleeping sickness were evaluated.200212193010
anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones.the anti-trypanosomal activity of six sesquiterpene lactones (helenalin, mexicanin i, 11alpha,13-dihydrohelenalin acetate, chamissonolide, ivalin and isoalantolactone) against the african trypanosoma brucei rhodesiense and american t. cruzi was investigated. all tested compounds were found active towards both parasites, the former being generally more sensitive. helenalin was the most active compound in the series with ic50 values of 0.051 and 0.695 microm against t. brucei rhodesiense and t. cr ...200212221603
genetic relatedness among trypanosoma evansi stocks by random amplification of polymorphic dna and evaluation of a synapomorphic dna fragment for species-specific diagnosis.in this study we employed randomly amplified polymorphic dna patterns to assess the genetic relatedness among 14 brazilian trypanosoma evansi stocks from domestic and wild hosts, which are known to differ in biological characteristics. these akinetoplastic stocks were compared with one another, to three old world (ethiopia, china and philippines) dyskinetoplastic stocks of t. evansi, and also with trypanosoma equiperdum, trypanosoma brucei brucei, trypanosoma brucei gambiense and trypanosoma bru ...200211796122
glutathione derivatives active against trypanosoma brucei rhodesiense and t. brucei brucei in vitro.diesters based on n-benzyloxycarbonyl-s-(2,4-dinitrophenyl) gsh (cbzgsdnp) containing linear alcohols 3 to 9, branched alcohols 10 to 20, or heteroatom linear alcohols 21 to 25, were investigated as in vitro inhibitors of pathogenic parasites. diesters 3 to 25 were better inhibitors of trypanosoma brucei rhodesiense than of t. brucei brucei and had low cytotoxicities. the most active compound had a 50% effective dose (ed(50)) of 0.2 microm. a quantitative structure activity regression equation r ...200211796354
epithelial innate immunity. a novel antimicrobial peptide with antiparasitic activity in the blood-sucking insect stomoxys calcitrans.the gut epithelium is an essential interface in insects that transmit parasites. we investigated the role that local innate immunity might have on vector competence, taking stomoxys calcitrans as a model. s. calcitrans is sympatric with tsetse flies, feeds on many of the same vertebrate hosts, and is thus regularly exposed to the trypanosomes that cause african sleeping sickness and nagana. despite this, s. calcitrans is not a cyclical vector of these trypanosomes. trypanosomes develop exclusive ...200212372834
unravelling the origins of trypanosoma brucei rhodesiense. 200212377278
synthesis and evaluation of analogues of 5'-([(z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine as inhibitors of tumor cell growth, trypanosomal growth, and hiv-1 infectivity.a well-defined series of 5'-([(z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine analogues was designed and synthesized in order to further ascertain the optimal structural requirements for s-adenosylmethionine decarboxylase inhibition and potentially to augment and perhaps separate their antiproliferative and antitrypanosomal activities. most structural modifications had a deleterious affect on both the antitrypanosomal and antineoplastic activity of 5'-([(z)-4-amino-2-butenyl]methylamino)-5' ...200212408722
evaluation of selected sudanese medicinal plants for their in vitro activity against hemoflagellates, selected bacteria, hiv-1-rt and tyrosine kinase inhibitory, and for cytotoxicity.ethnobotanical investigations led to the selection of 19 plant species, used traditionally in sudan against malaria and other similar tropical diseases, for further studies. pamianthe peruviana (amaryllidaceae) exhibited significant activity against a chloroquine-resistant plasmodium falciparum strain (k1) and a chloroquine-sensitive strain (nf54) with ic(50) values of 0.6 and 1.1 microg/ml, respectively. additionally, p. peruviana showed considerable activities against trypanosoma brucei rhodes ...200212426089
aiming to eliminate tsetse from africa.the problem of tsetse-transmitted trypanosomiasis occurs only in sub-saharan africa, where it represents a major constraint to socio-economic development. the east african form of sleeping sickness, caused by trypanosoma brucei rhodensiense, is an acute and fatal disease, whereas the west african form, caused by trypanosoma brucei gambiense, is generally more chronic and debilitating. the african governments have developed a new initiative, known as the pan african tsetse and trypanosomiasis era ...200212473355
will the real trypanosoma brucei rhodesiense please step forward?the sleeping sickness trypanosomes trypanosoma brucei rhodesiense and t. brucei gambiense are morphologically indistinguishable from each other and from t. brucei brucei, which does not infect humans. the relationships between these three subspecies have been controversial. several years ago, the characterization of t. brucei gambiense was reviewed in an attempt to clarify and draw together the results, and to put them in the context of the biology of the organism. the discovery of a gene associ ...200212473364
the human serum resistance associated gene is ubiquitous and conserved in trypanosoma brucei rhodesiense throughout east africa.the human serum resistance associated (sra) gene isolated from a ugandan strain of trypanosoma brucei rhodesiense has been shown to be capable by itself of conferring the trait of human infectivity on t.b. brucei by transfection. this gene has also been identified in several other isolates of t.b. rhodesiense, but not in the other human pathogenic trypanosome in africa, t.b. gambiense, casting doubt on its ubiquity and function. here, we show that this gene occurs in t.b. rhodesiense from sleepi ...200212798017
the serum resistance-associated gene as a diagnostic tool for the detection of trypanosoma brucei rhodesiense.in the search for new diagnostic methods that would distinguish trypanosoma brucei rhodesiense from t. b. brucei and t. b. gambiense, we have developed two polymerase chain reaction (pcr) primer sets. the first primer set was derived from the serum resistance-associated (sra) gene of t. b. rhodesiense that confers resistance to lysis by normal human serum (nhs). the specificity of the sra-based pcr was tested on 97 different trypanosome populations originating from various taxonomic groups, host ...200212518862
[three patients with african sleeping sickness following a visit to tanzania].three dutch tourists, a man aged 57 and two women aged 55 en 52 years, acquired african trypanosomiasis in the national parks of tanzania. two, without central nervous system involvement, were cured after treatment in the netherlands, albeit one after having suffered a relapse. in the third patient, involvement of the central nervous system was diagnosed in africa and she was treated with melarsoprol. after an apparently uneventful recovery she was readmitted with cerebral complaints and symptom ...200212532670
selective pressure can influence the resistance of trypanosoma congolense to normal human serum.resistance and sensitivity to normal human serum (nhs) of trypanosoma congolense, a parasite believed to cause disease in animals only, were investigated in vivo as well as in vitro. our results indicate that like trypanosoma brucei, t. congolense can be grouped into three different phenotypes according to its resistance to nhs. some strains are completely resistant to nhs, like trypanosoma brucei gambiense and the resistant form of trypanosoma brucei rhodesiense. other strains show a very low d ...200212706740
arsenicals (melarsoprol), pentamidine and suramin in the treatment of human african trypanosomiasis.human african trypanosomiasis (hat), otherwise known as sleeping sickness, has remained a disease with no effective treatment. recent progress in hat research suggests that a vaccine against the disease is far from being successful. also the emergence of drug-resistant trypanosomes makes further work in this area imperative. so far the treatment for the early stage of hat involves the drugs pentamidine and suramin which have been very successful. in the second stage of the disease, during which ...200312743807
ancistrolikokine d, a 5,8'-coupled naphthylisoquinoline alkaloid, and related natural products from ancistrocladus likoko.a new naphthylisoquinoline alkaloid, ancistrolikokine d, and the likewise 5,8'-coupled alkaloid ancistroealaine a, as well as two further, biosynthetically related, but nitrogen-free natural products, ancistronaphthoic acid b and cis-isoshinanolone, have been isolated from ancistrocladus likoko j. leacute;onard (ancistrocladaceae). the 5,8'-coupling of the new alkaloids and of the alkaloids isolated earlier hints at a close phylogenetic relationship of a. likoko to other central african ancistro ...200312560038
the origin of the serum resistance associated (sra) gene and a model of the structure of the sra polypeptide from trypanosoma brucei rhodesiense. 200312615339
trypanocidal activity of conformationally restricted pentamidine congeners.a series of conformationally restricted congeners of pentamidine in which the flexible pentyl bridge of pentamidine was replaced by trans-1,2-bismethylenecyclopropyl, phenyl, pyridinyl, piperazinyl, homopiperazinyl, and piperidinyl groups were synthesized. the compounds were evaluated for trypanocidal activity in vitro and in vivo against one drug-sensitive and three drug-resistant trypanosome isolates. the dna binding affinity of the compounds was also studied using calf thymus dna and poly(da- ...200312620080
apolipoprotein l-i is the trypanosome lytic factor of human serum.human sleeping sickness in east africa is caused by the parasite trypanosoma brucei rhodesiense. the basis of this pathology is the resistance of these parasites to lysis by normal human serum (nhs). resistance to nhs is conferred by a gene that encodes a truncated form of the variant surface glycoprotein termed serum resistance associated protein (sra). we show that sra is a lysosomal protein, and that the amino-terminal alpha-helix of sra is responsible for resistance to nhs. this domain inter ...200312621437
treatment perspectives for human african trypanosomiasis.human african trypanosomiasis (hat), or sleeping sickness, is currently on the rise. hat develops in two stages, the first involving the hemolymphatic system, and the second, the neurological system. left untreated, hat is invariably fatal. there have been no therapeutic advances in more than 40 years. stage 1 can be treated with pentamidine and suramin, but stage 2 can only be treated with melarsoprol, a toxic arsenic derivative that has a 2-12% incidence of fatal side-effects (encephalopathy). ...200312667227
antifungal, antiprotozoal, cytotoxic and piscicidal properties of justicidin b and a new arylnaphthalide lignan from phyllanthus piscatorum.using activity against candida albicans as a lead, the bioactivity-guided fractionation of the dichloromethane extract of phyllanthus piscatorum led to the isolation of the arylnaphthalide lignan justicidin b (1), which was found to be present in high amounts, and a new c-11 hydroxylated derivative that we named piscatorin (2). we provide evidence that justicidin b (1) is the main active principle of p. piscatorum, showing the same biological effects that were found for the raw extracts. justici ...200312802722
current chemotherapy of human african trypanosomiasis.human african trypanosomiasis is a fatal disease caused by trypanosoma brucei gambiense and trypanosoma brucei rhodesiense that has re-emerged in recent years. however, very little progress has been made in the development of new drugs against this disease. most drugs still in use were developed one or more decades ago, and are generally toxic and of limited effectiveness. the most recently introduced compound, eflornithine, is only useful against sleeping sickness caused by t. b. gambiense, and ...200312811544
eflornithine for the treatment of human african trypanosomiasis.eflornithine is the only new molecule registered for the treatment of human african trypanosomiasis over the last 50 years. it is the drug used mainly as a back-up for melarsoprol refractory trypanosoma brucei gambiense cases. the most commonly used dosage regimen for the treatment of t. b. gambiensesleeping sickness consists of 100 mg kg(-1) body weight at intervals of 6 h for 14 days (150 mg kg(-1) body weight in children) of eflornithine given as short infusions. its efficacy against trypanos ...200312811548
east african sleeping sickness in chennai.a traveler to east africa developed fever, an eschar on his forearm and thrombocytopenia shortly after returning home to chennai, india. trypanosoma brucei rhodesiense infection was diagnosed on examination of his peripheral smear. he made a full recovery after receiving a course of suramin.200312839358
activity of d-carnitine and its derivatives on trypanosoma infections in rats and mice.little progress has been made in the treatment of african trypanosomiasis over the past decades. l-carnitine has a major role in glycolysis-based energy supply of blood trypanosomes for it stimulates constant atp production. to investigate whether administration of the isomer d-carnitine could exert a competitive inhibition on the metabolic pathway of the l-form, possibly resulting in parasite replication inhibition, several formulations of this compound were tested on trypanosoma lewisi and t. ...200312847922
in vitro trypanocidal activity of dibutyltin dichloride and its fatty acid derivatives.searching for new compounds against pathogenic trypanosomes has been substantially accelerated by the development of in vitro screening assays. in an attempt to explore the chemotherapeutic potential of organotin compounds and to broaden the search for newer trypanocides, fatty acid derivatives of dibutyltin dichloride were synthesized and their in vitro trypanocidal profiles studied on trypanosoma brucei brucei, trypanosoma brucei gambiense and trypanosoma brucei rhodesiense. a 24-h time course ...200312851812
glycosylinositolphosphate soluble variant surface glycoprotein inhibits ifn-gamma-induced nitric oxide production via reduction in stat1 phosphorylation in african trypanosomiasis.macrophages are centrally involved in the host immune response to infection with trypanosoma brucei rhodesiense, a protozoan parasite responsible for human sleeping sickness in africa. during trypanosome infections, the host is exposed to parasite-derived molecules that mediate macrophage activation, specifically gpi anchor substituents associated with the shed variant surface glycoprotein (vsg), plus the host-activating agent ifn-gamma, which is derived from activated t cells and is essential f ...200312874239
improved trypanocidal activities of cathepsin l inhibitors.the major lysosomal cysteine proteinase of african trypanosomes is a candidate target for novel chemotherapy of sleeping sickness. this cathepsin l-like enzyme is termed rhodesain and brucipain in trypanosoma brucei rhodesiense and trypanosoma brucei brucei, respectively. three potent and selective dipeptidyl cathepsin l inhibitors have been investigated for their trypanocidal activities in vitro using culture-adapted bloodstream forms of t. b. brucei. compared with general cysteine proteinase i ...200312927956
conservation of the genomic location of the human serum resistance associated gene in trypanosoma brucei rhodesiense. 200312946855
2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase.this paper describes the synthesis of 4'-substituted and 3',4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. compounds were then assayed against the recombinant parasite and human enzymes. some of the compounds showed good activity. they were also tested against the intact parasites using in vitro assays. good activity was found against trypanosoma cruzi, moderate activity against trypanosoma brucei and leishmania d ...200314556785
synthesis and evaluation of novel 7-trifluoromethyl-4-(4-substituted anilino)quinolines as antiparasitic and antineoplastic agents.several novel derivatives bearing the 7-trifluoromethyl-4-(4-substituted anilino)-quinoline skeleton were synthesized and evaluated for their in vitro activity against the blood streaming form of the parasites trypanosoma brucei rhodesiense, the trypomastigotes of trypanosoma cruzi cultured in rat skeletal myoblasts, the amastigotes form of leishmania donovani, plasmodium falciparum (k1 strain) infected erythrocyte suspension, as well as their toxicity towards rat skeletal l-6 cells. in addition ...200314558440
synthesis and antiprotozoal activity of aza-analogues of furamidine.6-[5-(4-amidinophenyl)furan-2-yl]nicotinamidine (8a) was synthesized from 6-[5-(4-cyanophenyl)furan-2-yl]nicotinonitrile (4a), through the bis-o-acetoxyamidoxime followed by hydrogenation. compound 4a was prepared via selective bromination of 6-(furan-2-yl)nicotinonitrile (2a) with n-bromosuccinimide, followed by suzuki coupling with 4-cyanophenylboronic acid. in a similar way, diamidines 8b and 8c were prepared from the dicyano derivatives 4c and 4d, respectively. n-methoxy-6-[5-[4-(n-methoxyam ...200314561095
interactions between tsetse and trypanosomes with implications for the control of trypanosomiasis.tsetse flies (diptera: glossinidae) are vectors of several species of pathogenic trypanosomes in tropical africa. human african trypanosomiasis (hat) is a zoonosis caused by trypanosoma brucei rhodesiense in east africa and t. b. gambiense in west and central africa. about 100000 new cases are reported per year, with many more probably remaining undetected. sixty million people living in 36 countries are at risk of infection. recently, t. b. gambiense trypanosomiasis has emerged as a major publi ...200314587696
lessons learned from the emergence of a new trypanosoma brucei rhodesiense sleeping sickness focus in uganda.during the latter months of 1998, cases of sleeping sickness caused by trypanosoma brucei rhodesiense presented in soroti district, eastern uganda, a region which had not previously experienced cases of the disease. cattle are the main reservoir for t b rhodesiense, by contrast with sleeping sickness caused by trypanosoma brucei gambiense in west africa where there appears to be no epidemiologically significant animal reservoir. several factors have been identified that interacted to produce ide ...200312505033
synthesis and biological evaluation of pyrazolylnaphthoquinones as new potential antiprotozoal and cytotoxic agents.the importance of american trypanosomiasis (chagas' disease) in human pathology is widely known. the prognosis of this disease is poor and the choice of effective medicines limited, thus study of new drugs is absolutely necessary. in this work, the activities of three new pyrazolylnaphthoquinones, heterocyclic naphthoquinones bearing 3-aminopyrazole rings, were evaluated on trypanosoma cruzi, the etiological agent of chagas' disease. these activities were compared with those of three 5-aminoisox ...200312512078
synthesis and in vitro anti-protozoal activity of a series of benzotropolone derivatives incorporating endocyclic hydrazines.the preparation and evaluation as potential anti-protozoal agents of molecules bearing an endocyclic hydrazine moiety is presented. the synthetic route to this new series of compounds is straightforward, involving a hetero diels-alder reaction between different benzotropolone esters and diethyl azodicarboxylate (dead). while they show limited or no in vitro activity against leishmania donovani, plasmodium falciparum and trypanosoma brucei rhodesiense, several of the compounds have activities aga ...200314642327
drug transport and drug resistance in african trypanosomes.drug resistance in african trypanosomes has been studied for almost a hundred years. beginning with paul ehrlich's work that led to the chemoreceptor hypothesis, reduction of net drug uptake has emerged as the most frequent cause of resistance. this review, therefore, focuses on trypanosomal drug transporter genes. tbat1 encodes purine permease p2, which mediates influx of melarsoprol and diamidines. disruption of tbat1 in trypanosoma brucei reduced sensitivity to these trypanocides. tbmrpa enco ...200314643298
design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-trypanosoma brucei agents.on the basis of the structure of the cvim tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against trypanosoma brucei protein farnesyltransferase (tbpft) was evaluated. peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nm in the enzyme assay, whereas the corresponding c-4 regioisomers ...200414711313
distribution of apolipoprotein l-i and trypanosome lytic activity among primate sera. 200414747153
new 4-aminobicyclo[2.2.2]octane derivatives and their activities against plasmodium falciparum and trypanosoma b. rhodesiense.a series of new 2-substituted 4-dialkylaminobicyclo[2.2.2]octane derivatives was prepared and the compounds were investigated for their activity against causative organisms of tropical diseases. the tests were performed as microplate assays using the k1 strain of plasmodium falciparum (resistant to chloroquine and pyrimethamine) and trypanosoma brucei rhodesiense (stib 900). the results were compared to the activities of former tested compounds of the bicyclo[2.2.2]octane series and to known dru ...200414757494
antitrypanosomal and antiplasmodial activity of medicinal plants from côte d'ivoire.the antitrypanosomal activity of 101 crude ethanol extracts derived from 88 medicinal plants from côte d'ivoire was determined in vitro using trypanosoma brucei rhodesiense. of those extracts 8 showed good activity (ic50 values < or =8 microg/ml), 37 revealed a weak activity (ic50 values between 25 and 8.1 microg/ml) and 56 did not show any activity at all (ic50 values >25 microg/ml). the extracts of enantia polycarpa (annonaceae) and trichilia emetica (meliaceae) were the most promising ones. t ...200415013184
in vitro antitrypanosomal activity of ethnopharmacologically selected beninese plants.the in vitro antitrypanosomal activity of methylene chloride, methanol and aqueous extracts of the leaves and twigs of five plant species traditionally used in benin for the treatment of sleeping sickness were evaluated on trypanosoma brucei brucei and their selectivity was analysed on leishmania mexicana mexicana and j774 macrophage-like murine cells. the results showed that the four most active extracts had mic values < or =19 microg/ml (hymenocardia acida twig and leaf, strychnos spinosa leaf ...200415036465
bisguanidine, bis(2-aminoimidazoline), and polyamine derivatives as potent and selective chemotherapeutic agents against trypanosoma brucei rhodesiense. synthesis and in vitro evaluation.the in vitro screening for trypanocidal activity against trypanosoma brucei rhodesiense of an in-house library of 62 compounds [i.e. alkane, diphenyl, and azaalkane bisguanidines and bis(2-aminoimidazolines)], which were chosen for their structural similarity to the trypanocidal agents synthalin (1,10-decanediguanidine) and 4,4'-diguanidinodiphenylmethane and the polyamine n(1)-(3-amino-propyl)propane-1,3-diamine, respectively, is reported. the original synthetic procedure for the preparation of ...200415084128
detection of trypanosoma brucei rhodesiense in animals from sleeping sickness foci in east africa using the serum resistance associated (sra) gene.the human serum resistance associated (sra) gene has been found exclusively in trypanosoma brucei rhodesiense, allowing the unequivocal detection of this pathogen in reservoir hosts and the tsetse vector without recourse to laborious strain characterisation procedures. we investigated the presence of the sra gene in 264 t. brucei ssp. isolates from humans, domestic animals and glossina pallidipes from foci of human trypanosomiasis in kenya and uganda. the sra gene was present in all isolates tha ...200415099811
proinflammatory cytokine expression in the early phase of trypanosoma brucei rhodesiense infection in vervet monkeys (cercopithecus aethiops).a vervet monkey model of trypanosomiasis was used to study inflammatory cytokine responses in serum and cerebrospinal fluid (csf). gamma interferon levels were transiently up-regulated in serum between days 6 and 8 of infection, followed by a sustained up-regulation of tumor necrosis factor alpha (tnf-alpha) and soluble tnf receptor 1. at no time were these cytokines detectable in the csf.200415102822
trypanocidal activity of melamine-based nitroheterocycles.a series of nitroheterocyclic compounds were designed with linkages to melamine or benzamidine groups that are known substrates of the p2 aminopurine and other transporters in african trypanosomes of the brucei group. several compounds showed in vitro trypanotoxicity with 50% inhibitory concentrations in the submicromolar range. although most compounds interacted with the p2 transporter, as judged by their ability to inhibit adenosine transport via this carrier, uptake through this route was not ...200415105128
phyllanthus piscatorum, ethnopharmacological studies on a women's medicinal plant of the yanomamï amerindians.the shrub phyllanthus piscatorum kunth (euphorbiaceae) is cultivated by various ethnic groups of the amazon because of its piscicidal properties. during ethnobotanical fieldwork among the yanomamï amerindians in venezuela we observed that phyllanthus piscatorum was exclusively cultivated and used by the women. aerial parts of this herbaceous shrub are employed as fish poison and medicine to treat wounds and fungal infections. in addition, the leaves are used as tobacco substitute. ethnobotanical ...200415120438
history of sleeping sickness (african trypanosomiasis).infections with subspecies of the protozoan parasite trypanosoma brucei cause important wasting diseases in africa (nagana in cattle and sleeping sickness in humans). these diseases were little known until the end of the nineteenth century when serious epidemics of nagana were reported and raised concern among the colonial powers. the early history of sleeping sickness revolves around the discovery of the causative organism, its mode of transmission,and its life cycle in the tsetse fly. the hist ...200415145378
ancistrotanzanine c and related 5,1'- and 7,3'-coupled naphthylisoquinoline alkaloids from ancistrocladus tanzaniensis.three new naphthylisoquinoline alkaloids, the 7,3'-coupled ancistrotanzanine c (6), the 5,1'-coupled o-methylancistrocladinine (7), and the likewise 5,1'-coupled o,n-dimethylancistrocladine (8, previously known only as a partial-synthetic compound), have been isolated from the highland liana ancistrocladus tanzaniensis, along with the two known 7,3'-coupled naphthylisoquinoline alkaloids ancistrocladidine (4) and ancistrotectorine (5). all of the compounds are s-configured at c-3 and bear an oxy ...200415165131
synthesis, antiprotozoal and cytotoxic activities of new n-(3,4-dimethyl-5-isoxazolyl)-1,2-naphthoquinone-4-amino derivatives.three derivatives of n-(3,4-dimethyl-5-isoxazolyl)-1,2-naphthoquinone-4-amino (1), a compound which exhibits significant activity against trypanosoma cruzi and plasmodium falciparum but with cytotoxicity toward murine l-6 cells, were synthesized with the aim of ameliorating its cytotoxicity. the in vitro antiprotozoal and cytotoxic activities of the synthesized compounds were evaluated against t. cruzi, trypanosoma brucei rhodesiense, p. falciparum and murine l-6 cells. the hydroxymethyl (2) and ...200415178304
are fitness costs associated with resistance to human serum in trypanosoma brucei rhodesiense? 200415193561
novel dicationic imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines as antiprotozoal agents.2-[5-(4-amidinophenyl)-furan-2-yl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-6-carboxamidine acetate salt (7) was synthesized from 2-[5-(4-cyanophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carbonitrile (4a), through the bis-o-acetoxyamidoxime followed by hydrogenation in glacial acetic acid. compound 4a was obtained in four steps starting with two successive brominations of 2-acetylfuran first with n-bromosuccinimide, and second with bromine to form alpha-bromo-2-acetyl-5-bromofuran (2) in a mod ...200415214792
the trypanosome lytic factor of human serum and the molecular basis of sleeping sickness.trypanosoma brucei brucei infects a wide range of mammals but is unable to infect humans because this subspecies is lysed by normal human serum (nhs). the trypanosome lytic factor is associated with high density lipoproteins (hdls). several hdl-associated components have been proposed as candidate lytic factors, and contradictory hypotheses concerning the mechanism of lysis have been suggested. elucidation of the process by which trypanosoma brucei rhodesiense resists lysis and causes human slee ...200415217727
assessing the patterns of health-seeking behaviour and awareness among sleeping-sickness patients in eastern uganda.for those with sleeping sickness, the consequences of delayed diagnosis include poor prognosis at treatment and an increased risk of tsetse infection. data on their socio-demographic and clinical characteristics, health-seeking behaviour and delays in presentation and diagnosis were collected from 119 diagnosed cases of rhodesiense sleeping sickness in eastern uganda. the median total delay, from onset of the illness to diagnosis, was 60 days. the median service-provider delay (30 days) was mark ...200415228715
novel azasterols as potential agents for treatment of leishmaniasis and trypanosomiasis.this paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. azasterols are a known class of (s)-adenosyl-l-methionine: delta24-sterol methyltransferase(24-smt) inhibitors in fungi, plants, and some parasitic protozoa. the compounds prepared showed activity at micromolar and nanomolar concentrations when tested against leishmania spp. and trypanosoma spp. the enzymatic and stero ...200415273104
effect of dibutyltin(iv) on the ultrastructure of african trypanosoma spp.diorganotins (r2snx2) are compounds with a wide variety of biological properties. in an attempt to follow the morphological events and to characterize the toxic effects of diorganotins on in vitro cultured african trypanosoma spp., the ultrastructural alterations induced on the parasites by dibutyltins (bu2snx2) were followed. the data obtained indicate that these compounds induced irreparable damage to the in vitro cultured bloodstream forms of the parasites. transmission and scanning electron ...200414605876
the trypanosoma brucei reference strain treu927/4 contains t. brucei rhodesiense-specific sra sequences, but displays a distinct phenotype of relative resistance to human serum.the trypanosoma brucei reference strain treu927/4 exhibits some resistance to lysis by normal human serum (nhs), but this resistance is never complete even after selection. the genome of this strain contains a minimum of eight sequences related to the t. brucei rhodesiense-specific serum resistance-associated gene (sra), which encodes a truncated variant surface glycoprotein (vsg) conferring full resistance to lysis by nhs. we selected two sequences showing the highest similarity to sra and also ...200415287585
spatial and temporal risk factors for the early detection of trypanosoma brucei rhodesiense sleeping sickness patients in tororo and busia districts, uganda.we have carried out a study of risk factors for early detection of trypanosoma brucei rhodesiense sleeping sickness. records of sleeping sickness patients from 1987 to 2001 from tororo and busia districts in uganda were reviewed for their village of origin and clinical stage (early or late). all villages that reported sleeping sickness and fixed post-diagnostic sleeping sickness health units in tororo and busia districts were geo-referenced. the spatial distribution of early and late stage patie ...200415289093
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