scholarly journals Differential virulence of Trypanosoma brucei rhodesiense isolates does not influence the outcome of treatment with anti-trypanosomal drugs in the mouse model

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0229060
Author(s):  
Kariuki Ndung’u ◽  
Grace Adira Murilla ◽  
John Kibuthu Thuita ◽  
Geoffrey Njuguna Ngae ◽  
Joanna Eseri Auma ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Post Infection ◽  
Drug Resistant ◽  
Weight Changes ◽  
Cure Rate ◽  
Trypanosoma Brucei Rhodesiense ◽  
Diminazene Aceturate ◽  
Reference Drug ◽  
Western Kenya ◽  
Biotechnology Research

We assessed the virulence and anti-trypanosomal drug sensitivity patterns of Trypanosoma brucei rhodesiense (Tbr) isolates in the Kenya Agricultural and Livestock Research Organization-Biotechnology Research Institute (KALRO-BioRI) cryobank. Specifically, the study focused on Tbr clones originally isolated from the western Kenya/eastern Uganda focus of human African Trypanosomiasis (HAT). Twelve (12) Tbr clones were assessed for virulence using groups(n = 10) of Swiss White Mice monitored for 60 days post infection (dpi). Based on survival time, four classes of virulence were identified: (a) very-acute: 0–15, (b) acute: 16–30, (c) sub-acute: 31–45 and (d) chronic: 46–60 dpi. Other virulence biomarkers identified included: pre-patent period (pp), parasitaemia progression, packed cell volume (PCV) and body weight changes. The test Tbr clones together with KALRO-BioRi reference drug-resistant and drug sensitive isolates were then tested for sensitivity to melarsoprol (mel B), pentamidine, diminazene aceturate and suramin, using mice groups (n = 5) treated with single doses of each drug at 24 hours post infection. Our results showed that the clones were distributed among four classes of virulence as follows: 3/12 (very-acute), 3/12 (acute), 2/12 (sub-acute) and 4/12 (chronic) isolates. Differences in survivorship, parasitaemia progression and PCV were significant (P<0.001) and correlated. The isolate considered to be drug resistant at KALRO-BioRI, KETRI 2538, was confirmed to be resistant to melarsoprol, pentamidine and diminazene aceturate but it was not resistant to suramin. A cure rate of at least 80% was achieved for all test isolates with melarsoprol (1mg/Kg and 20 mg/kg), pentamidine (5 and 20 mg/kg), diminazene aceturate (5 mg/kg) and suramin (5 mg/kg) indicating that the isolates were not resistant to any of the drugs despite the differences in virulence. This study provides evidence of variations in virulence of Tbr clones from a single HAT focus and confirms that this variations is not a significant determinant of isolate sensitivity to anti-trypanosomal drugs.

scholarly journals Differential virulence of Trypanosoma brucei rhodesiense isolates does not influence the outcome of treatment with anti-trypanosomal drugs in the mouse model

2020 ◽  
Author(s):  
Kariuki Ndung’u ◽  
Grace Adira Murilla ◽  
John Kibuthu Thuita ◽  
Geoffrey Njuguna Ngae ◽  
Joanna Eseri Auma ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Post Infection ◽  
Drug Resistant ◽  
Weight Changes ◽  
Trypanosoma Brucei Rhodesiense ◽  
Diminazene Aceturate ◽  
Reference Drug ◽  
Western Kenya ◽  
Biotechnology Research ◽  
Cure Rates

AbstractWe assessed the virulence and anti-trypanosomal drug sensitivity patterns of Trypanosoma brucei rhodesiense (Tbr) isolates in the Kenya Agricultural and Livestock Research Organization-Biotechnology Research Institute (KALRO-BioRI) cryobank. Specifically, the study focused on Tbr clones originally isolated from the western Kenya/eastern Uganda focus of human African Trypanosomiasis (HAT). Twelve (12) Tbr clones were assessed for virulence using groups(n=10) of Swiss White Mice monitored for 60 days post infection (dpi). Based on survival time, four classes of virulence were identified: (a) very-acute: 0-15, (b) acute: 16-30, (c) sub-acute: 31-45 and (d) chronic: 46-60 dpi. Other virulence biomarkers identified included: prepatent period (pp), parasitaemia progression, packed cell volume (PCV) and body weight changes. The test Tbr clones together with KALRO-BioRi reference drug-resistant and drug sensitive isolates were then tested for sensitivity to melarsoprol (mel B) pentamidine, diminazene aceturate and suramin, using mice groups (n= 5) treated with single doses of each drug at 24 hours post infection. Our results showed that the clones were distributed among four classes of virulence as follows: 3/12 (very-acute), 3/12 (acute), 2/12 (sub-acute) and 4/12 (chronic) isolates. Differences in survivorship, parasitaemia progression and PCV were significant (P<0.001) and correlated. The isolate considered to be drug resistant at KALRO-BioRI, KETRI 2538, was confirmed to be resistant to melarsoprol, pentamidine and diminazene aceturate but it was not resistant to suramin. At least 80% cure rates of all the test isolates was achieved with melarsoprol (1mg/Kg and 20 mg/kg), pentamidine (5 and 20 mg/kg), diminazene aceturate (5 mg/kg) and suramin (5 mg/kg) indicating that the isolates were not resistant to any of the drugs despite the differences in virulence. This study provides evidence of variations in virulence of Tbr isolates from a single HAT focus and confirms that these variations are not a significant determinant of isolate sensitivity to anti-trypanosomal drugs.

The relationship between duration of infection with Trypanosoma brucei in mice and the efficacy of chemotherapy

Parasitology ◽  
1977 ◽  
Vol 75 (2) ◽  
pp. 143-153 ◽  
Author(s):  
F. W. Jennings ◽  
D. D. Whitelaw ◽  
G. M. Urquhart
Keyword(s):  
Drug Resistance ◽  
Drug Treatment ◽  
Trypanosoma Brucei ◽  
Post Infection ◽  
Drug Resistant ◽  
Diminazene Aceturate ◽  
Duration Of Infection ◽  
Permanent Cure ◽  
Dose Levels ◽  
The Relationship

Relapse of infection after drug treatment of trypanosome infections under conditions precluding re-infection has usually been ascribed to drug resistance on the part of the parasite or to under-dosage of the drug. With Trypanosoma brucei infection in mice we have obtained evidence of another type of relapse. In infections resulting from the inoculation of 1 × 105 trypanosomes, derived from a stabilate T. brucei TREU 667, treatment with diminazene aceturate (Berenil) at 40 mg/kg at either 3 or 7 days after infection elicited a permanent cure. If, however, treatment was delayed later than 14 days after infection, then all the mice relapsed. These relapses generally occurred between 20 and 50 days after treatment, but some mice remained aparasitaemic for up to 60 days. The relapsed infections were apparently not due to the survival of ‘drug-resistant’ trypanosomes, as infections derived from a stabilate isolated from a relapsed Berenil-treated mouse were also permanently cured with Berenil if treated 3 days after infection; however, if treatment was delayed until 21 days post-infection, all the mice relapsed. The cause of relapse was not related to the number of parasites inoculated, as infection resulting from initial inocula of 1 × 105 to 1 × 108 trypanosomes were all cured if treated at 3 days after infection, and all eventually relapsed if treatment was delayed until day 21. This type of relapse phenomenon was not confined to T. brucei TREU 667 but also occurred with 5 other stabi-lates of T. brucei after Berenil treatment. Treatment of T. brucei TREU 667 infections with Ethidium and Prothidium at dose levels of 7.5 and 10 mg/kg respectively was also followed by relapse if treatment was delayed for 3 weeks after infection. The possible causes of relapse under these conditions, and its implications in the study of the natural disease, are discussed.

scholarly journals Histopathological Studies on the Effects of Chloroform and Methanolic Extracts of Ilex kudingcha in Trypanosoma brucei Infected Albino Wistar Rats

2018 ◽  
Vol 04 ◽  
pp. 50
Author(s):  
Olajoju. T. Soniran ◽  
Kalu. K. Ngele ◽  
Christopher. O. Alisa ◽  
Damilola. A. Omoboyowa ◽  
Nnabude. H. Agu ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Wistar Rats ◽  
Methanolic Extract ◽  
Phytochemical Analysis ◽  
Diminazene Aceturate ◽  
Leaf Extracts ◽  
Standard Drug ◽  
Phytochemical Study ◽  
Reference Drug ◽  
Histopathological Studies

Histopathological studies of the effects of chloroform and methanolic leaf extracts of Ilex kudingcha in Trypanosoma brucei infected albino wistar rats were investigated. The toxicity and phytochemical study were also carried out using standard protocol. T. brucei infected animals were administered orally with 200 and 400 mg/kg b.w. of the extracts and 3.5 mg/kg b.w. of the standard drug (diminazene aceturate). Results on acute toxicity studies (LD50) revealed no sign of lethality up to the dose of 5,000 mg/kg body weight but the liver and kidney histology of infected animals treated with 5,000 mg/kg b.w. of I. kudingcha extracts were observed to be hepatotoxic and nephrotoxic. The methanol extracts showed appreciably high in vivo anti-trypanosomal activities compared to the reference drug. Histological examination of the organs revealed serious pathological lesions in the liver of the infected animals without treatment (negative control). In the positive control animals (infected animals administered standard drug), mild multifocal aggregate of inflammatory leucocytes was observed. In the other experimental animals, no pathological lesion was observed in the liver, kidney, brain, and heart of infected animals treated with the methanolic extract and combined methanol and chloroform extracts. The effectiveness of the methanolic extract at reducing the lesions caused by the parasite is the same compared with the standard drug. Phytochemical analysis of the plant extracts showed that methanol extract contained appreciable high levels of alkaloids, saponin, tannins, phenol, and glycoside while flavonoid was not detected. Hence, the curative properties of methanolic extract of I. kudingcha as observed in the organs indicate its anti-trypanosomal properties but it should be consumed at minimal doses.

scholarly journals Multiple Genetic Mechanisms Lead to Loss of Functional TbAT1 Expression in Drug-Resistant Trypanosomes

2009 ◽  
Vol 9 (2) ◽  
pp. 336-343 ◽  
Author(s):  
Mhairi L. Stewart ◽  
Richard J. S. Burchmore ◽  
Caroline Clucas ◽  
Christiane Hertz-Fowler ◽  
Karen Brooks ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Drug Resistant ◽  
Diminazene Aceturate ◽  
Content Type ◽  
African Trypanosomes ◽  
Genomic Location ◽  
Adenosine Uptake ◽  
Resistant Lines ◽  
The Status ◽  
Genetic Mechanisms

ABSTRACT The P2 aminopurine transporter, encoded by TbAT1 in African trypanosomes in the Trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. Loss of this transporter contributes to drug resistance. We identified the genomic location of TbAT1 to be in the subtelomeric region of chromosome 5 and determined the status of the TbAT1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), and in a Trypanosoma equiperdum clone selected for resistance to the diamidine, diminazene aceturate. In the Trypanosoma brucei gambiense STIB 386 melarsamine hydrochloride-resistant line, TbAT1 is deleted, while in the Trypanosoma brucei brucei STIB 247 melarsamine hydrochloride-resistant and T. equiperdum diminazene-resistant lines, TbAT1 is present, but expression at the RNA level is no longer detectable. Further characterization of TbAT1 in T. equiperdum revealed that a loss of heterozygosity at the TbAT1 locus accompanied loss of expression and that P2-mediated uptake of [3H]diminazene is lost in drug-resistant T. equiperdum. Adenine-inhibitable adenosine uptake is still detectable in a ΔTbat1 T. b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells.

scholarly journals Occurrence of multiple drug resistance in Trypanosoma brucei rhodesiense isolated from sleeping sickness patients

2007 ◽  
Vol 74 (1) ◽  
Author(s):  
N. Maina ◽  
J.M. Kagira
Keyword(s):  
Trypanosoma Brucei ◽  
Multiple Drug Resistance ◽  
Prepatent Period ◽  
Sleeping Sickness ◽  
Cross Resistance ◽  
Control Group ◽  
Multiple Drug ◽  
Trypanosoma Brucei Rhodesiense ◽  
Diminazene Aceturate ◽  
The Mean

The occurrence of cross-resistance among melarsoprol-resistant Trypanosoma brucei rhodesiense isolates was investigated in this study. The isolates, T. b. rhodesiense KETRI 237, 2538, 1992, 2709, 2694 and 3530, had been obtained from sleeping sickness patients in Kenya and Uganda between 1960 and 1985. Five groups consisting of six mice each were inoculated intraperitoneally with 105 parasites of each isolate, and 24 h later treated with either melarsoprol, homidium chloride, diminazene aceturate or isometamidium chloride. The control group comprised infected but untreated mice. The mice were monitored for cure for a period of 60 days post-treatment. The mean prepatent period in the control mice was 5 days while the mean survival period was 22 days. Five of the stabilates, KETRI 237, 2538, 2709, 2694, and 3530, were confirmed to be melarsoprol resistant. Cross-resistance was observed, with the majority of the isolates being resistant to homidium chloride (5/6) and diminazene aceturate (5/6), but all were sensitive to isometamidium chloride (6/6). However T. b. rhodesiense KETRI 1992, which was previously considered as melarsoprol resistant, was sensitive to all the drugs tested. In conclusion, our study has revealed the existence of cross-resistance among the melarsoprol resistant isolates which could only be cured by isometamidium.

scholarly journals Trypanocidal Activity of 8-Methyl-5′-{[(Z)-4-Aminobut-2-enyl]-(Methylamino)}Adenosine (Genz-644131), an Adenosylmethionine Decarboxylase Inhibitor

2009 ◽  
Vol 53 (8) ◽  
pp. 3269-3272 ◽  
Author(s):  
Cyrus J. Bacchi ◽  
Robert H. Barker ◽  
Aixa Rodriguez ◽  
Bradford Hirth ◽  
Donna Rattendi ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Dose Range ◽  
System Model ◽  
Drug Resistant ◽  
Trypanosoma Brucei Rhodesiense ◽  
Trypanosoma Brucei Brucei ◽  
African Trypanosomes ◽  
Adenosylmethionine Decarboxylase ◽  
Daily Dose ◽  
Purine Ring

ABSTRACT Genzyme 644131, 8-methyl-5′-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine, is an analog of the enzyme activated S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor and the trypanocidal agent MDL-7381, 5-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine. The analog differs from the parent in having an 8-methyl group on the purine ring that bestows favorable pharmacokinetic, biochemical, and trypanocidal activities. The compound was curative in acute Trypanosoma brucei brucei and drug-resistant Trypanosoma brucei rhodesiense model infections, with single-dose activity in the 1- to 5-mg/kg/day daily dose range for 4 days against T. brucei brucei and 25- to 50-mg/kg twice-daily dosing against T. brucei rhodesiense infections. The compound was not curative in the TREU 667 central nervous system model infection but cleared blood parasitemia and extended time to recrudescence in several groups. This study shows that AdoMetDC remains an attractive chemotherapeutic target in African trypanosomes and that chemical changes in AdoMetDC inhibitors can produce more favorable drug characteristics than the lead compound.

scholarly journals Virulence and pathogenicity of three Trypanosoma brucei rhodesiense stabilates in a Swiss white mouse model

2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Christopher Kariuki ◽  
John M. Kagira ◽  
Victor Mwadime ◽  
Maina Ngotho
Keyword(s):  
Trypanosoma Brucei ◽  
Late Stage ◽  
Basic Research ◽  
White Mouse ◽  
Primate Research ◽  
Survival Times ◽  
Trypanosoma Brucei Rhodesiense ◽  
Diminazene Aceturate ◽  
Blood Smears ◽  
Peak Parasitaemia

Background: A key objective in basic research on human African trypanosomiasis (HAT) is developing a cheap and reliable experimental model of the disease for use in pathogenesis and drug studies.Objective: With a view to improving current models, a study was undertaken to characterise the virulence and pathogenicity of three Trypanosoma brucei rhodesiense stabilates, labelled as International Livestock Research Institute (ILRI)-2918, ILRI-3953, and Institute of Primate Research (IPR)-001, infected into Swiss white mice.Methods: Swiss white mice were infected intraperitoneally with trypanosomes and observedfor parasitaemia using wet blood smears obtained by tail snipping. Induction of late-stagedisease was undertaken using diminazene aceturate (40 mg/kg, Berenil) with curativetreatment done using melarsoprol (3.6 mg/kg, Arsobal).Results: The prepatent period for the stabilates ranged from three to four days with mean peak parasitaemia ranging from Log10 6.40 to 8.36. First peak parasitaemia for all stabilates varied between six and seven days post infection (DPI) followed by secondary latency in ILRI-2918 (15–17 DPI) and IPR-001 (17–19 DPI). Survival times ranged from six DPI (ILRI-3953) to 86 DPI (IPR-001). Hindleg paresis was observed in both ILRI-3953 (at peak parasitaemia) and ILRI-2918 (after relapse parasitaemia). Mice infected with IPR-001 survived until 54 DPI when curative treatment was undertaken.Conclusions: This study demonstrated that the stabilates ILRI-2918 and ILRI-3953 were unsuitable for modelling late-stage HAT in mice. The stabilate IPR-001 demonstrated the potential to induce chronic trypanosomiasis in Swiss white mice for use in development of a late-stage model of HAT.

scholarly journals Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

2009 ◽  
Vol 53 (9) ◽  
pp. 3815-3821 ◽  
Author(s):  
Christophe Dardonville ◽  
Cristina Fernández-Fernández ◽  
Sarah-Louise Gibbons ◽  
Nadine Jagerovic ◽  
Lidia Nieto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Trypanosoma Cruzi ◽  
Trypanosoma Brucei ◽  
Leishmania Donovani ◽  
Antiprotozoal Activity ◽  
Protozoan Parasites ◽  
Trypanosoma Brucei Rhodesiense ◽  
Reference Drug ◽  
Axenic Amastigotes

ABSTRACT A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC50) ranging from 0.12 to 10 μM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC50 range, 0.17 to 5 μM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC50, 1.97 μM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.

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