scholarly journals Interleukin (IL)-6 and IL-10 Are Up Regulated in Late Stage Trypanosoma brucei rhodesiense Sleeping Sickness

2015 ◽  
Vol 9 (6) ◽  
pp. e0003835 ◽  
Author(s):  
Charles D. Kato ◽  
Vincent P. Alibu ◽  
Ann Nanteza ◽  
Claire M. Mugasa ◽  
Enock Matovu
Keyword(s):  
Trypanosoma Brucei ◽  
Late Stage ◽  
Sleeping Sickness ◽  
Trypanosoma Brucei Rhodesiense

scholarly journals Efficacy of the Novel Diamidine Compound 2,5-Bis(4-Amidinophenyl)- Furan-Bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense Infection in Vervet Monkeys after Oral Administration

2008 ◽  
Vol 53 (3) ◽  
pp. 953-957 ◽  
Author(s):  
R. E. Mdachi ◽  
J. K. Thuita ◽  
J. M. Kagira ◽  
J. M. Ngotho ◽  
G. A. Murilla ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Late Stage ◽  
Early Stage ◽  
Vervet Monkey ◽  
Sleeping Sickness ◽  
Vervet Monkeys ◽  
Trypanosoma Brucei Rhodesiense ◽  
Dose Rates ◽  
Group 4 ◽  
Group 5

ABSTRACT Owing to the lack of oral drugs for human African trypanosomiasis, patients have to be hospitalized for 10 to 30 days to facilitate treatment with parenterally administered medicines. The efficacy of a novel orally administered prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methlylamidoxime (pafuramidine, DB289), was tested in the vervet monkey (Chlorocebus [Cercopithecus] aethiops) model of sleeping sickness. Five groups of three animals each were infected intravenously with 104 Trypanosoma brucei rhodesiense KETRI 2537 cells. On the seventh day postinfection (p.i.) in an early-stage infection, animals in groups 1, 2, and 3 were treated orally with pafuramidine at dose rates of 1, 3, or 10 mg/kg of body weight, respectively, for five consecutive days. The animals in groups 4 and 5 were treated with 10 mg/kg for 10 consecutive days starting on the 14th day p.i. (group 4) or on the 28th day p.i. (group 5), when these animals were in the late stage of the disease. In the groups treated in the early stage, 10 mg/kg of pafuramidine completely cured all three monkeys, whereas lower doses of 3 mg/kg and 1 mg/kg cured only one of three and zero of three monkeys, respectively. Treatment of late-stage infections resulted in cure rates of one of three (group 4) and zero of three (group 5) monkeys. These studies demonstrated that pafuramidine was orally active in monkeys with early-stage T. brucei rhodesiense infections at dose rates above 3 mg/kg for 5 days. It was also evident that the drug attained only minimal efficacy against late-stage infections, indicating the limited ability of the molecule to cross the blood-brain barrier. This study has shown that oral diamidines have potential for the treatment of early-stage sleeping sickness.

scholarly journals New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients

2013 ◽  
Vol 2 (1) ◽  
Author(s):  
Natalia Tiberti ◽  
Enock Matovu ◽  
Alexandre Hainard ◽  
John Charles Enyaru ◽  
Veerle Lejon ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Sleeping Sickness ◽  
Trypanosoma Brucei Rhodesiense ◽  
New Biomarkers

scholarly journals A New NonpolarN-Hydroxy Imidazoline Lead Compound with Improved Activity in a Murine Model of Late-Stage Trypanosoma brucei brucei Infection Is Not Cross-Resistant with Diamidines

2014 ◽  
Vol 59 (2) ◽  
pp. 890-904 ◽  
Author(s):  
Carlos H. Ríos Martínez ◽  
Florence Miller ◽  
Kayathiri Ganeshamoorthy ◽  
Fabienne Glacial ◽  
Marcel Kaiser ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Late Stage ◽  
Parent Compound ◽  
Central Nervous System Infection ◽  
Sleeping Sickness ◽  
Intrinsic Activity ◽  
Cross Resistance ◽  
Content Type

ABSTRACTTreatment of late-stage sleeping sickness requires drugs that can cross the blood-brain barrier (BBB) to reach the parasites located in the brain. We report here the synthesis and evaluation of four newN-hydroxy and 12 newN-alkoxy derivatives of bisimidazoline leads as potential agents for the treatment of late-stage sleeping sickness. These compounds, which have reduced basicity compared to the parent leads (i.e., are less ionized at physiological pH), were evaluatedin vitroagainstTrypanosoma brucei rhodesienseandin vivoin murine models of first- and second-stage sleeping sickness. Resistance profile, physicochemical parameters,in vitroBBB permeability, and microsomal stability also were determined. TheN-hydroxy imidazoline analogues were the most effectivein vivo, with 4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide (14d) showing 100% cures in the first-stage disease, while 15d, 16d, and 17d appeared to slightly improve survival. In addition, 14d showed weak activity in the chronic model of central nervous system infection in mice. No evidence of reduction of this compound with hepatic microsomes and mitochondria was foundin vitro, suggesting thatN-hydroxy imidazolines are metabolically stable and have intrinsic activity againstT. brucei. In contrast to its unsubstituted parent compound, the uptake of 14d inT. bruceiwas independent of known drug transporters (i.e.,T. bruceiAT1/P2 and HAPT), indicating a lower predisposition to cross-resistance with other diamidines and arsenical drugs. Hence, theN-hydroxy bisimidazolines (14d in particular) represent a new class of promising antitrypanosomal agents.

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 Quantifying the level of under-detection of Trypanosoma brucei rhodesiense sleeping sickness cases

2005 ◽  
Vol 10 (9) ◽  
pp. 840-849 ◽  
Author(s):  
M. Odiit ◽  
P. G. Coleman ◽  
W.-C. Liu ◽  
J. J. McDermott ◽  
E. M. Fevre ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Sleeping Sickness ◽  
Trypanosoma Brucei Rhodesiense
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