In vitro and in vivo trypanocidal action of aescin and aescin liposomes against Trypanosoma evansi in experimental mice

SUMMARYThis study aimed to develop and test the in vitro and in vivo effectiveness of diminazene aceturate encapsulated into liposomes (L-DMZ) on Trypanosoma evansi. To validate the in vitro tests with L-DMZ, the efficacy of a commercial formulation of diminazene aceturate (C-DMZ) was also assessed. The tests were carried out in culture medium for T. evansi, at concentrations of 0·25, 0·5, 1, 2 and 3 μg mL−1 of L-DMZ and C-DMZ. A dose-dependent effect was observed for both formulations (L-DMZ and C-DMZ), with the highest dose-dependent mortality of trypomastigotes being observed at 1 and 3 h after the onset of tests with L-DMZ. The results of in vivo tests showed the same effects in the animals treated with L-DMZ and C-DMZ in single doses of 3·5 mg kg−1 and for 5 consecutive days (3·5 mg kg−1 day−1). It was possible to conclude that T. evansi showed greater in vitro susceptibility to L-DMZ when compared with C-DMZ. In vivo tests suggest that treatment with the L-DMZ and C-DMZ showed similar efficacy in vivo. The potential of the formulation developed in this study was clearly demonstrated, as it increased the efficacy of the treatment against trypanosomosis, but more studies are needed to increase the effectiveness in vivo.

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DSETHVASAN: A NOVEL NANODRUG AGAINST SLEEPING SICKNESS

International Journal of Nanoscience ◽

10.1142/s0219581x1100779x ◽

2011 ◽

Vol 10 (01n02) ◽

pp. 187-192

Author(s):

D. SETH ◽

R. L. BRAHMACHARY ◽

C. ULRICHS ◽

M. MONDAL ◽

S. MUKHOPADHAYAY ◽

...

Keyword(s):

Density Lipoprotein ◽

Volume Ratio ◽

Trypanosoma Evansi ◽

Sleeping Sickness ◽

Supramolecular Interactions ◽

Mitochondrial Enzymes ◽

Approved Drugs ◽

Surface Modified

Sleeping sickness (causal agent, Trypanosoma sp. parasite) causes huge morbidity and mortality in Africa (both human and livestock) in particular and zoo animals worldwide. Three of the four currently approved drugs (Pentamidine, Melarsoprol, Eflornithine, and Nifurtimox) were developed over 50 years ago. Current therapies are unsatisfactory due to unacceptable level of side effects. Pentamidine, an aromatic diamidine, safest so far, inhibits mitochondrial enzymes. Furthermore, it is effective only in early stages of infections and not on the later stage. Melarsoprol, practically insoluble in water, is very toxic and it is given intravenously (i.v.) for later stage infections only. Other drugs like eflornithine and nitfurtimox are also unsatisfactory for various reasons. Human serum derived high-density lipoprotein (HDL; not mouse or any other mammalian HDL) shows trypanolytic effect in vitro and in vivo on T. brucei. But the mechanism of action of human HDL is far from clear. In the absence of novel drug leads, nanodrugs might be valid options as nanoparticles show better accessibility to cells, supramolecular interactions due to enormous increase in surface area to volume ratio, altered partition coefficient, etc. Surface-modified hydrophobic microsilica (FS), mixture of micro- and nanosilica (Dsethvasan) and nanosilica (AL) were characterized by UV–Vis, DLS, SEM, EDAX, AFM, and XRD. Trypanosoma evansi collected from infected horses were injected in mice. Control infected mouse (n = 30) showed 100% mortality within 72±24 h of injection. Dsethvasan-treated mice (n = 30) survived for 192±24 h. FS-treated mice (n = 30) survived for 120±24 h but the AL-treated mice (n = 30) died within 72±24 h of inoculation like infected control. Hydrophobic Dsethvasan which consists of pure amorphous forms of micro- and nanosilica works better than FS (AL is not at all effective). Therefore, micro- and nanomixture of amorphous silica is best suited for treating Trypanosoma infection in mice. The possible role of ratio of higher to lower size class has been discussed.

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Suscetibilidade de Trypanosoma evansi à anfotericina B

Ciência Rural ◽

10.1590/s0103-84782009000900026 ◽

2009 ◽

Vol 39 (9) ◽

pp. 2550-2555 ◽

Cited By ~ 5

Author(s):

Aleksandro Schafer da Silva ◽

Juliano Botton ◽

Patrícia Wolkmer ◽

Régis Adriel Zanette ◽

Sonia Terezinha dos Anjos Lopes ◽

...

Keyword(s):

Trypanosoma Evansi

O objetivo deste estudo foi avaliar a suscetibilidade do Trypanosoma evansi in vitro e in vivo à anfotericina B. Nos testes in vitro, foram utilizadas quatro concentrações (0,06; 0,25; 1,0; 4,0µg mL-1) de anfotecicina B frente a uma suspensão de T. evansi em solução tampão fosfato rico em glicose (PBS - glicose). Para avaliar a eficácia in vivo, foram utilizados 15 ratos parasitados com T. evansi. Em dois grupos de cinco ratos infectados, doses únicas diárias de 1 (grupo A) e de 3mg kg-1 (grupo B) foram administradas via intraperitonial durante 10 dias, e a parasitemia foi avaliada por meio de esfregaço sanguíneo. Grupo C (n=5) foi utilizado como grupo controle positivo, infectados com T. evansi e não tratados, e o grupo D (n=5), como controle negativo. Os ensaios in vitro evidenciaram suscetibilidade de 100% do T. evansi à anfotericina B após 7h, em todas as concentrações avaliadas. Nos ratos, nem a maior dose testada curou os roedores, apesar de ter prolongado a vida destes em comparação à vida dos animais infectados, mas não tratados. Foi também investigada a função hepática e renal dos ratos após a terapia, e os parâmetros bioquímicos analisados mantiveram-se dentro da normalidade. Conclui-se que o T. evansi in vitro é suscetível à anfotericina B. A dose 3mg kg-1 testada aumentou a expectativa de vida de ratos infectados, porém não teve efeito curativo.

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In vivo and in vitro sensitivity of Trypanosoma evansi and T. equiperdum to diminazene, suramin, MelCy, quinapyramine and isometamidium

Acta Tropica ◽

10.1016/0001-706x(91)90002-2 ◽

1991 ◽

Vol 50 (2) ◽

pp. 101-110 ◽

Cited By ~ 44

Author(s):

Z.Q. Zhang ◽

C. Giroud ◽

T. Baltz

Keyword(s):

Trypanosoma Evansi ◽

In Vitro Sensitivity

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Trypanocidal action of tea tree oil (Melaleuca alternifolia) against Trypanosoma evansi in vitro and in vivo used mice as experimental model

Experimental Parasitology ◽

10.1016/j.exppara.2014.03.007 ◽

2014 ◽

Vol 141 ◽

pp. 21-27 ◽

Cited By ~ 28

Author(s):

Matheus D. Baldissera ◽

Aleksandro S. Da Silva ◽

Camila B. Oliveira ◽

Roberto C.V. Santos ◽

Rodrigo A. Vaucher ◽

...

Keyword(s):

Experimental Model ◽

Trypanosoma Evansi ◽

Tea Tree Oil ◽

Melaleuca Alternifolia ◽

Tea Tree

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Cordycepin (3′-deoxyadenosine) pentostatin (deoxycoformycin) combination treatment of mice experimentally infected withTrypanosoma evansi

Parasitology ◽

10.1017/s0031182012001990 ◽

2013 ◽

Vol 140 (5) ◽

pp. 663-671 ◽

Cited By ~ 11

Author(s):

LUCIANA DALLA ROSA ◽

ALEKSANDRO S. DA SILVA ◽

LUCAS T. GRESSLER ◽

CAMILA B. OLIVEIRA ◽

MARIA G. C. DAMBRÓS ◽

...

Keyword(s):

Liver Enzymes ◽

Trypanosoma Evansi ◽

Curative Effect ◽

Therapeutic Protocol ◽

Liver And Kidney ◽

Effect Of Treatment ◽

Dose Dependent ◽

Different Doses

SUMMARYThe aim of this study was to evaluate the anti-trypanosomal effect of treatment with 3′-deoxyadenosine (cordycepin) combined with deoxycoformycin (pentostatin: inhibitor of the enzyme adenosine deaminase)in vitroby using mice experimentally infected withTrypanosoma evansi. In vitro, a dose-dependent trypanocidal effect of cordycepin was observed against the parasite. In thein vivotrials, the two drugs were used individually and in combination of different doses. The drugs when used individually had no curative effect on infected mice. However, the combination of cordycepin (2 mg kg−1) and pentostatin (2 mg kg−1) was 100% effective in theT. evansi-infected groups. There was an increase in levels of some biochemical parameters, especially on liver enzymes, which were accompanied by histological lesions in the liver and kidneys. Based on these results we conclude that treatment using the combination of 3′-deoxyadenosine with deoxycoformycin has a curative effect on mice infected withT. evansi. However, the therapeutic protocol tested led to liver and kidney damage, manifested by hepatotoxicity and nephrotoxicity.

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In Vivo Investigations of Selected Diamidine Compounds against Trypanosoma evansi Using a Mouse Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00422-09 ◽

2009 ◽

Vol 53 (12) ◽

pp. 5074-5079 ◽

Cited By ~ 7

Author(s):

Kirsten Gillingwater ◽

Arvind Kumar ◽

Mariappan Anbazhagan ◽

David W. Boykin ◽

Richard R. Tidwell ◽

...

Keyword(s):

Mouse Model ◽

Trypanosoma Evansi ◽

Chemotherapeutic Agents ◽

Control Measures ◽

Lead Compounds ◽

Protozoan Infection ◽

Drug Doses ◽

Mouse Model Of Infection

ABSTRACT Surra is an animal pathogenic protozoan infection, caused by Trypanosoma evansi, that develops into a fatal wasting disease. Control measures rely on diagnosis and treatment. However, with the continuous emergence of drug resistance, this tactic is failing, and the pressing need for new chemotherapeutic agents is becoming critical. With the introduction of novel aromatic diamidines, a new category of antitrypanosomal drugs was discovered. Nevertheless, their efficacy within a T. evansi-infected mouse model was not known. In total, 30 compounds previously selected based on their in vitro activity were tested in a T. evansi mouse model of infection. Six of the compounds were capable of curing T. evansi-infected mice at drug doses as low as 0.5 and 0.25 mg/kg of body weight administered for 4 consecutive days, and they were more effective than the standard drugs suramin, diminazene, and quinapyramine. After all selection criteria were applied, three diamidine compounds (DB 75, DB 867, and DB 1192) qualified as lead compounds and were considered to have the potential to act as preclinical candidates against T. evansi infection.

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Single-cell transcriptome profiling and the use of AID deficient mice reveal that B cell activation combined with antibody class switch recombination and somatic hypermutation do not benefit the control of experimental trypanosomosis

PLoS Pathogens ◽

10.1371/journal.ppat.1010026 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1010026

Author(s):

Hang Thi Thu Nguyen ◽

Robin B. Guevarra ◽

Stefan Magez ◽

Magdalena Radwanska

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Somatic Hypermutation ◽

Trypanosoma Evansi ◽

Host Susceptibility ◽

B Cell Activation ◽

Wide Range

Salivarian trypanosomes are extracellular protozoan parasites causing infections in a wide range of mammalian hosts, with Trypanosoma evansi having the widest geographic distribution, reaching territories far outside Africa and occasionally even Europe. Besides causing the animal diseases, T. evansi can cause atypical Human Trypanosomosis. The success of this parasite is attributed to its capacity to evade and disable the mammalian defense response. To unravel the latter, we applied here for the first time a scRNA-seq analysis on splenocytes from trypanosome infected mice, at two time points during infection, i.e. just after control of the first parasitemia peak (day 14) and a late chronic time point during infection (day 42). This analysis was combined with flow cytometry and ELISA, revealing that T. evansi induces prompt activation of splenic IgM+CD1d+ Marginal Zone and IgMIntIgD+ Follicular B cells, coinciding with an increase in plasma IgG2c Ab levels. Despite the absence of follicles, a rapid accumulation of Aicda+ GC-like B cells followed first parasitemia peak clearance, accompanied by the occurrence of Xbp1+ expressing CD138+ plasma B cells and Tbx21+ atypical CD11c+ memory B cells. Ablation of immature CD93+ bone marrow and Vpreb3+Ly6d+Ighm+ expressing transitional spleen B cells prevented mature peripheral B cell replenishment. Interestingly, AID-/- mice that lack the capacity to mount anti-parasite IgG responses, exhibited a superior defense level against T. evansi infections. Here, elevated natural IgMs were able to exert in vivo and in vitro trypanocidal activity. Hence, we conclude that in immune competent mice, trypanosomosis associated B cell activation and switched IgG production is rapidly induced by T. evansi, facilitating an escape from the detrimental natural IgM killing activity, and resulting in increased host susceptibility. This unique role of IgM and its anti-trypanosome activity are discussed in the context of the dilemma this causes for the future development of anti-trypanosome vaccines.

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In Vitro and In Vivo Activities of Trybizine Hydrochloride against Various Pathogenic Trypanosome Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.11.2858 ◽

1998 ◽

Vol 42 (11) ◽

pp. 2858-2862 ◽

Cited By ~ 33

Author(s):

Ronald Kaminsky ◽

Reto Brun

Keyword(s):

Mammalian Cells ◽

Leishmania Donovani ◽

Central Nervous System Involvement ◽

Multidrug Resistant ◽

Trypanosoma Evansi ◽

Rodent Model ◽

Resistant Organism ◽

Intracellular Parasites

ABSTRACT Trybizine hydrochloride [O,O′-bis(4,6-diamino-1,2-dihydro-2,2-tetramethylene-s-triazine-1-yl)-1,6-hexanediol dihydrochloride] was active in vitro against the sleeping sickness-causing agents Trypanosoma brucei subsp.rhodesiense and T. brucei subsp.gambiense; against a multidrug-resistant organism, T. brucei subsp. brucei; and against animal-pathogenic organisms Trypanosoma evansi, Trypanosoma equiperdum, and Trypanosoma congolense; but not against the intracellular parasites Trypanosoma cruzi andLeishmania donovani. Cytotoxic effects against mammalian cells were observed at approximately 106-fold higher concentrations than those necessary to inhibit T. bruceisubsp. rhodesiense. Trybizine hydrochloride was able to eliminate T. brucei subsp. rhodesiense andT. brucei subsp. gambiense in an acute rodent model with four intraperitoneal doses of 0.25 mg kg of body weight−1 or four doses of 1 mg kg−1, respectively, or with four oral doses of 20 mg kg−1. The compound expressed activity against suramin-resistant T. evansi strains in mice. However, these concentrations were not sufficient to cure mice infected with multidrug-resistant T. brucei subsp. brucei. A late-stage rodent model with central nervous system involvement could not be cured, indicating that trybizine may not pass the blood-brain barrier in sufficient quantities.

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