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 Multiple drug resistance in hookworms infecting greyhound dogs in the USA

2021 ◽  
Author(s):  
Pablo D. Jimenez Castro ◽  
Abhinaya Venkatesan ◽  
Elizabeth Redman ◽  
Rebecca Chen ◽  
Abigail Malatesta ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multiple Drug Resistance ◽  
Infection Intensity ◽  
The United States ◽  
Post Treatment ◽  
Multiple Drug ◽  
Fecal Samples ◽  
The Usa ◽  
The Mean ◽  
Β Tubulin

AbstractThe hookworm Ancylostoma caninum is the most prevalent nematode parasite of dogs. Recently, we confirmed multiple-drug resistance (MDR) in several A. caninum isolates to all anthelmintic drug classes approved for the treatment of hookworms in dogs in the United States (USA). Cases of MDR hookworms appear to be highly overrepresented in greyhounds, suggesting that the MDR worms evolved on racing greyhound farms/kennels. The aims of this study were to evaluate the range of drug-resistant phenotypes and genotypes of the A. caninum infecting greyhounds. Fecal samples from recently retired greyhounds originating from geographically diverse areas of the USA were acquired from two greyhound adoption kennels, one active greyhound racing kennel, and three veterinary practices that work with adoption kennels. Fecal egg counts (FECs) were performed on fecal samples from 219 greyhounds, and despite almost all the dogs having been treated with one or more anthelmintics in the previous two to four weeks, the mean FEC was 822.4 eggs per gram (EPG). Resistance to benzimidazoles and macrocyclic lactones were measured using the egg hatch assay (EHA) and the larval development assay (LDA) respectively. We performed 23 EHA and 22 LDA on either individual or pooled feces, representing 81 animals. Mean and median IC50 and IC95 values for the EHA were 5.3 uM, 3.6 uM, and 24.5 uM, 23.4 uM respectively. For the LDA, mean and median IC50 values were 749.8 nM, >1000 nM respectively. These values range from 62 to 68 times higher than those we measured in our susceptible laboratory isolates. Pre-treatment fecal samples could not be obtained, however, post-treatment samples representing 219 greyhounds were collected. For samples collected <10 days post-treatment with albendazole, moxidectin, or a combination of febantel-pyrantel-moxidectin, the mean FEC were 349, 333, and 835 EPG, respectively. Samples collected 10-21 days post-treatment with albendazole, moxidectin, or pyrantel, yielded mean FEC of 1874, 335, and 600 EPG, respectively. Samples collected >21 days post-treatment with albendazole or moxidectin yielded mean FEC of 1819 and 1117 EPG, respectively. We obtained DNA from hookworm eggs isolated from 70 fecal samples, comprised of 60 individual dogs and 10 pools from multiple dogs. Deep sequencing of the isotype 1 β-tubulin gene revealed the presence of the F167Y (TTC>TAC) resistance polymorphism in 99% of these samples, with 69% having ≥75% resistant allele frequency. No resistance-associated polymorphisms were seen at any of the other β-tubulin codons previously reported as associated with benzimidazole resistance in Strongylid nematodes. These clinical, in vitro, and genetic data provide strong evidence that racing and recently retired greyhound dogs in the USA are infected with MDR A. caninum at very high levels in terms of both prevalence and infection intensity.

scholarly journals Polymorphisms of pleiotropic genes ABCC11 and ACE in Abkhazians and the longevity phenomenon

2019 ◽  
pp. 29-36
Author(s):  
С.В. Макаров ◽  
М.К. Карапетян ◽  
К.Б. Квеквескири ◽  
В.А. Спицын
Keyword(s):  
Multiple Drug Resistance ◽  
Control Group ◽  
Multiple Drug ◽  
Ace Gene ◽  
Caucasus Region ◽  
Gene Insertion ◽  
Vital Functions ◽  
Genotype Frequencies ◽  
Age Related ◽  
And Control

Изучение наследственных факторов в детерминации долголетия представляется весьма актуальным в связи с ростом средней продолжительности жизни, поиском возможностей продления «здорового» периода в позднем отногенезе. Феномен высокой продолжительности жизни всегда вызывал особый интерес исследователей, а его изучение представляется наиболее перспективным в популяциях с достаточно большой долей долгожителей. С давних времен известны случаи ярко выраженного активного долголетия в регионе Кавказа. У долгожителей Абхазии темпы соматического развития, уровень обменных процессов и меньшая интенсивность возрастной инволюции скелета указывали на относительно «здоровый» тип старения. Среди генетических факторов, которые потенциально могли бы играть важную роль в достижении долголетия, особенно перспективным представляется изучение плейотропных генов, действие которых проявляется во множественных эффектах и обладающих высокой функциональной значимостью. Среди них особый интерес представляют те, которые определяют эффективность функционирования сердечно-сосудистой системы, а также особенности, влияющие на темп созревания и старения организма. К числу таких генов можно отнести ген ангиотензин-превращающего фермента (ACE) и ген множественной лекарственной устойчивости (ABCC11). Целью исследования был поиск закономерностей в характере распределения полиморфных вариантов плеойтропных генов ABCC11 и ACE в популяции абхазов в связи с возрастом обследуемых и наличием долгожителей в выборке. В качестве материала исследования были собраны образцы клеток буккального эпителия от коренных жителей Абхазии, подразделенных на две группы: старшего возраста (75-101 год, 79 человек) и контрольную ( 97 индивидов в возрасте от 16 до 33 лет ). Анализ распределений частот генотипов и аллелей полиморфизма 538G>A (rs17822931) гена ABCC11 показал, что группы старшего возраста и контроля очень сходны между собой и достоверные различия между выборками отсутствуют. Генотипирование по инсерционно-делеционному полиморфизму гена ACE (rs1799752) осуществлялось методом ПЦР-ПДАФ. Для контрольной группы абхазов установлены следующие частоты генотипов: II = 0,186; ID = 0,412; DD = 0,402, частоты аллелей I и D оказались равны 0,392 и 0,608 соответственно. Группа старшего возраста по частотам генотипов существенно не отличалась от контроля, генотипы II/ID/DD были распределены в соотношении 0,088/0,380/0,532, а частоты аллелей I и D оказались равны 0,278 и 0,722 соответственно. В результате исследования выявлено, что частота аллеля делеции по инсерционно-делеционному полиморфизму в гене ACE в старшей возрастной группе абхазов достоверно повышена по сравнению с контрольной группой. The study of the phenomenon of longevity is the most promising in populations with a fairly large proportion of centenarians. Since old times cases of pronounced active longevity have been widely known in the Caucasus region. The complexity of age-related processes of aging assumes the involvement of multiple complex factors that have affect on life expectancy. Therefore the study of the pleiotropic genes with their multiple effects and functions could be helpful in that case. The angiotensin I-converting enzyme (ACE) gene and the multiple drug resistance gene ( ABCC11) are of great interest because of their high importance for essential vital functions. The aim of the study was the search for correlations in the frequencies distribution of polymorphic variants of pleoitropic genes ABCC11 and ACE in the population of Abkhazians with the longevity. The material included the DNA samples from indigenous residents of Abkhazia. They were divided into two groups: older age (N = 79) and control (N = 97). The differences in the frequencies distribution of 538G>A genotypes and alleles of the gene ABCC11 in the older group and control were not significant. ACE gene insertion-deletion polymorphism ( rs1799752) genotyping was performed by PCR-AFLP. The genotype frequencies were : II = 0.186; ID = 0.412; DD = 0.402, allele frequencies I and D were equal to 0.392 and 0.608 for the control group of Abkhazians. The older group did not differ significantly from the control in genotype frequencies, the ratio for II/ID/DD genotypes were as 0.088/0.380/0.532, and the frequencies of alleles I and D corresponded to 0.278 and 0.722. The obtained results revealed that the ACE gene deletion allele frequency was significantly increased in the older group of Abkhazians.

scholarly journals Anti-trypanosomal effect of Malva sylvestris (Malvaceae) extract on a Trypanosoma brucei brucei-infected mouse model of sleeping sickness

2017 ◽  
Vol 16 (10) ◽  
pp. 2373-2378
Author(s):  
Yan-Bing Ding ◽  
Jun Chen ◽  
Li-Xia Huang ◽  
Ye-Li Gong ◽  
Fa-Hu Yuan ◽  
...  
Keyword(s):  
Mouse Model ◽  
Trypanosoma Brucei ◽  
Infected Mouse ◽  
Negative Control Group ◽  
Negative Control ◽  
Sleeping Sickness ◽  
Control Group ◽  
Trypanosoma Brucei Brucei ◽  
Parasite Count ◽  
Malva Sylvestris

Purpose: To evaluate the antitrypanosomal activity of Malva sylvestris (MS) extract in a Trypanosoma brucei brucei-infected  mouse model of sleeping sickness.Methods: Sleeping sickness was induced by the intraperitoneal injection of Trypanosoma brucei brucei infected blood in mice.  Confirmation of parasitaemia was performed by estimating the parasite count in the plasma on the 12th day after inoculation. All the mice were divided into five groups: control group that received neither infection nor treatment; negative control that was  infected with the parasite but did not receive treatment; MS-treated group that receive MS extract (250 and 500 mg/kg, ip) and standard (STD) group that received levamisole (7.5 mg/kg, ip) for 7 days after the development of parasitaemia. A further parasite count was performed in the blood and cerebrospinal fluid (CSF) after the treatment period. Humoral antibody response,  delayed hypersensitivity reaction, and mobilization of leucocytes were determined after the treatment period in SRBC-sensitized mice.Results: The results indicate that treatment with MS significantly decreased body weight and parasite count in the blood and CSF of mice with Trypanosoma brucei brucei-induced sleeping sickness compared with that in the negative control group. There was a significant increase in paw swelling and decrease in secondary antibody in the MS-treated group compared with that in the  negative control group. However, treatment with MS extract also enhanced the mobilization of the total leucocyte count compared with that in the negative control group.Conclusion: The results demonstrate the anti-trypanosomal activity of Malva sylvestris extract via immunomodulation in a  Trypanosoma brucei brucei-infected mouse model of sleeping sickness.Keywords: Malva sylvestris, Trypanosoma brucei brucei, Sleeping sickness, Immunomodulatory activity, Delayed hypersensitivity reaction

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 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 Efficacy of Isometamidiumin Combination with Verapamil, Chlorpromazine ‎or Sodium-ethylenediaminetetra-acetic Acid in Treatment of Experimental ‎Diminazene Aceturate-resistant Strain of Trypanosoma brucei brucei ‎Infection in Rats

2020 ◽  
Vol 17 (4) ◽  
pp. 37-45
Author(s):  
I. C. Chukwudi ◽  
O. C. Omemgboji ◽  
B. M. Anene
Keyword(s):  
Acetic Acid ◽  
Trypanosoma Brucei ◽  
Resistant Strain ◽  
Parasite Clearance ◽  
Negative Control ◽  
Male Rats ◽  
Control Group ◽  
Sprague Dawley ◽  
Trypanosoma Brucei Brucei ◽  
Diminazene Aceturate

This study investigated the efficacy of different chemotherapeutic regimes in the treatment of rats experimentally infected with diminazene aceturate-resistant strain Trypanosoma brucei brucei. Thirty Sprague Dawley male rats used for the study were randomly assigned to six groups of five rats eachas follows: group A-uninfected untreated (negative control), group B-infected and untreated (positive control), groups C-F were infected and treated with 1.0 mg/kg isometamidum chloride, administered intramuscularly on day 11 post-infection. However, rats in groups D, E and F received further treatments with 700 mg/kg sodium-ethylenediamine tetra-acetic acid, 0.4 mg/kg verapamil and 3 mg/kg chlorpromazine, respectively, administered orally for four days. Clearance of parasite post-treatment (PT), mortality PT, relapse parasitaemia post-clearance, body weight change, rectal temperature, packed cell volume (PCV), haemoglobin (HB) concentration and red blood cell count (RBC) were determined during the experiment. Result showed parasite clearance PT of 100% in groups D and E, 80% in group F and 20% in group C by 24 hours PT. The infection relapsed on day 35 PT in 40% of rats in group C, on day 37 PT in 20% of rats in group F and lastly 20% of rats in groups D and E on day 39 PT. Rats that received drug combination showed marginal improvement in erythrocytic parameters analysed when compared with those treatment with isometamidium alone. Combination therapy showed faster clearance of parasite from the blood and also prolonged relapse post-clearance, thus had a better promising efficacy when compared to using isometamiduim chloride alone.

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