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Jennifer Keiser - One of the best experts on this subject based on the ideXlab platform.
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re infection with fasciola gigantica 6 month post treatment with Triclabendazole in cattle from mobile pastoralist husbandry systems at lake chad
Veterinary Parasitology, 2016Co-Authors: Jennifer Keiser, Jürg Utzinger, Helena Greter, Annour A Batil, Idriss O Alfaroukh, Felix Grimm, Bongo Nare Richard NgandoloAbstract:At Lake Chad in central Africa, livestock fascioliasis caused by Fasciola gigantica represents a major veterinary health problem, particularly in cattle reared in mobile pastoralist husbandry systems. We assessed re-infection after a single dose of Triclabendazole with fascioliasis in cattle in a mobile pastoralist setting towards the end of the dry season. Within the cattle herds of 14 groups of mobile pastoralists, 375 cattle were randomly selected. A faecal sample was obtained from each animal to determine the prevalence of F. gigantica. Animals were administered a single oral dose of Triclabendazole (12mg/kg). A second faecal sample was obtained 6-month post-treatment after cattle had returned from the annual migration cycle. Faecal samples were fixed in sodium acetate-acetic acid-formalin (SAF), and examined for F. gigantica using the sedimentation technique. From the 375 cattle enrolled at baseline, 198 animals (53%) in 12 groups of mobile pastoralists were re-sampled at the 6-month follow-up. Baseline prevalence did not differ noteworthy between animals lost to follow-up and those re-examined. At baseline, bovine fascioliasis prevalence in cattle with follow-up data was 41.9% (95% confidence interval (CI) 35.2-48.9%). At the 6-month post-treatment follow-up, the prevalence was 46.0% (95% CI 39.2-52.9%), ranging between 0% and 75% at the herd level. The mean faecal egg counts at the unit of the herd were higher at follow-up compared to baseline. The observed persistent high prevalence of F. gigantica infection in cattle shows that a single pre-rainy season treatment does not prevent rapid re-infection despite the partial migration away from the high-risk areas at Lake Chad into drier areas. A locally adapted strategic control package for fascioliasis in cattle in the Lake Chad area ought to integrate targeted Triclabendazole treatment and seasonal transhumance practices.
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Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials
PLoS neglected tropical diseases, 2011Co-Authors: Jennifer Keiser, Maged El-ghanam, Hoda Sabry, Saad Anani, Aly El-wakeel, Christoph Hatz, Jürg Utzinger, Sayed H. Seif El-din, Walaa H. El-maadawyAbstract:BACKGROUND: Fascioliasis is an emerging zoonotic disease of considerable veterinary and public health importance. Triclabendazole is the only available drug for treatment. Laboratory studies have documented promising fasciocidal properties of the artemisinins (e.g., artemether). METHODOLOGY: We carried out two exploratory phase-2 trials to assess the efficacy and safety of oral artemether administered at (i) 6x80 mg over 3 consecutive days, and (ii) 3x200 mg within 24 h in 36 Fasciola-infected individuals in Egypt. Efficacy was determined by cure rate (CR) and egg reduction rate (ERR) based on multiple Kato-Katz thick smears before and after drug administration. Patients who remained Fasciola-positive following artemether dosing were treated with single 10 mg/kg oral Triclabendazole. In case of treatment failure, Triclabendazole was re-administered at 20 mg/kg in two divided doses. PRINCIPAL FINDINGS: CRs achieved with 6x80 mg and 3x200 mg artemether were 35% and 6%, respectively. The corresponding ERRs were 63% and nil, respectively. Artemether was well tolerated. A high efficacy was observed with Triclabendazole administered at 10 mg/kg (16 patients; CR: 67%, ERR: 94%) and 20 mg/kg (4 patients; CR: 75%, ERR: 96%). CONCLUSIONS/SIGNIFICANCE: Artemether, administered at malaria treatment regimens, shows no or only little effect against fascioliasis, and hence does not represent an alternative to Triclabendazole. The role of artemether and other artemisinin derivatives as partner drug in combination chemotherapy remains to be elucidated
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in vivo and in vitro sensitivity of fasciola hepatica to Triclabendazole combined with artesunate artemether or oz78
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Jennifer Keiser, Urs Duthaler, Thomas J SmithAbstract:Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of Triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with Triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and Triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of Triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower Triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P = 0.07) were observed for OZ78 and Triclabendazole combinations and between the Triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent Triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.
Jürg Utzinger - One of the best experts on this subject based on the ideXlab platform.
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re infection with fasciola gigantica 6 month post treatment with Triclabendazole in cattle from mobile pastoralist husbandry systems at lake chad
Veterinary Parasitology, 2016Co-Authors: Jennifer Keiser, Jürg Utzinger, Helena Greter, Annour A Batil, Idriss O Alfaroukh, Felix Grimm, Bongo Nare Richard NgandoloAbstract:At Lake Chad in central Africa, livestock fascioliasis caused by Fasciola gigantica represents a major veterinary health problem, particularly in cattle reared in mobile pastoralist husbandry systems. We assessed re-infection after a single dose of Triclabendazole with fascioliasis in cattle in a mobile pastoralist setting towards the end of the dry season. Within the cattle herds of 14 groups of mobile pastoralists, 375 cattle were randomly selected. A faecal sample was obtained from each animal to determine the prevalence of F. gigantica. Animals were administered a single oral dose of Triclabendazole (12mg/kg). A second faecal sample was obtained 6-month post-treatment after cattle had returned from the annual migration cycle. Faecal samples were fixed in sodium acetate-acetic acid-formalin (SAF), and examined for F. gigantica using the sedimentation technique. From the 375 cattle enrolled at baseline, 198 animals (53%) in 12 groups of mobile pastoralists were re-sampled at the 6-month follow-up. Baseline prevalence did not differ noteworthy between animals lost to follow-up and those re-examined. At baseline, bovine fascioliasis prevalence in cattle with follow-up data was 41.9% (95% confidence interval (CI) 35.2-48.9%). At the 6-month post-treatment follow-up, the prevalence was 46.0% (95% CI 39.2-52.9%), ranging between 0% and 75% at the herd level. The mean faecal egg counts at the unit of the herd were higher at follow-up compared to baseline. The observed persistent high prevalence of F. gigantica infection in cattle shows that a single pre-rainy season treatment does not prevent rapid re-infection despite the partial migration away from the high-risk areas at Lake Chad into drier areas. A locally adapted strategic control package for fascioliasis in cattle in the Lake Chad area ought to integrate targeted Triclabendazole treatment and seasonal transhumance practices.
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Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials
PLoS neglected tropical diseases, 2011Co-Authors: Jennifer Keiser, Maged El-ghanam, Hoda Sabry, Saad Anani, Aly El-wakeel, Christoph Hatz, Jürg Utzinger, Sayed H. Seif El-din, Walaa H. El-maadawyAbstract:BACKGROUND: Fascioliasis is an emerging zoonotic disease of considerable veterinary and public health importance. Triclabendazole is the only available drug for treatment. Laboratory studies have documented promising fasciocidal properties of the artemisinins (e.g., artemether). METHODOLOGY: We carried out two exploratory phase-2 trials to assess the efficacy and safety of oral artemether administered at (i) 6x80 mg over 3 consecutive days, and (ii) 3x200 mg within 24 h in 36 Fasciola-infected individuals in Egypt. Efficacy was determined by cure rate (CR) and egg reduction rate (ERR) based on multiple Kato-Katz thick smears before and after drug administration. Patients who remained Fasciola-positive following artemether dosing were treated with single 10 mg/kg oral Triclabendazole. In case of treatment failure, Triclabendazole was re-administered at 20 mg/kg in two divided doses. PRINCIPAL FINDINGS: CRs achieved with 6x80 mg and 3x200 mg artemether were 35% and 6%, respectively. The corresponding ERRs were 63% and nil, respectively. Artemether was well tolerated. A high efficacy was observed with Triclabendazole administered at 10 mg/kg (16 patients; CR: 67%, ERR: 94%) and 20 mg/kg (4 patients; CR: 75%, ERR: 96%). CONCLUSIONS/SIGNIFICANCE: Artemether, administered at malaria treatment regimens, shows no or only little effect against fascioliasis, and hence does not represent an alternative to Triclabendazole. The role of artemether and other artemisinin derivatives as partner drug in combination chemotherapy remains to be elucidated
Helena Greter - One of the best experts on this subject based on the ideXlab platform.
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re infection with fasciola gigantica 6 month post treatment with Triclabendazole in cattle from mobile pastoralist husbandry systems at lake chad
Veterinary Parasitology, 2016Co-Authors: Jennifer Keiser, Jürg Utzinger, Helena Greter, Annour A Batil, Idriss O Alfaroukh, Felix Grimm, Bongo Nare Richard NgandoloAbstract:At Lake Chad in central Africa, livestock fascioliasis caused by Fasciola gigantica represents a major veterinary health problem, particularly in cattle reared in mobile pastoralist husbandry systems. We assessed re-infection after a single dose of Triclabendazole with fascioliasis in cattle in a mobile pastoralist setting towards the end of the dry season. Within the cattle herds of 14 groups of mobile pastoralists, 375 cattle were randomly selected. A faecal sample was obtained from each animal to determine the prevalence of F. gigantica. Animals were administered a single oral dose of Triclabendazole (12mg/kg). A second faecal sample was obtained 6-month post-treatment after cattle had returned from the annual migration cycle. Faecal samples were fixed in sodium acetate-acetic acid-formalin (SAF), and examined for F. gigantica using the sedimentation technique. From the 375 cattle enrolled at baseline, 198 animals (53%) in 12 groups of mobile pastoralists were re-sampled at the 6-month follow-up. Baseline prevalence did not differ noteworthy between animals lost to follow-up and those re-examined. At baseline, bovine fascioliasis prevalence in cattle with follow-up data was 41.9% (95% confidence interval (CI) 35.2-48.9%). At the 6-month post-treatment follow-up, the prevalence was 46.0% (95% CI 39.2-52.9%), ranging between 0% and 75% at the herd level. The mean faecal egg counts at the unit of the herd were higher at follow-up compared to baseline. The observed persistent high prevalence of F. gigantica infection in cattle shows that a single pre-rainy season treatment does not prevent rapid re-infection despite the partial migration away from the high-risk areas at Lake Chad into drier areas. A locally adapted strategic control package for fascioliasis in cattle in the Lake Chad area ought to integrate targeted Triclabendazole treatment and seasonal transhumance practices.
Ian Fairweather - One of the best experts on this subject based on the ideXlab platform.
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reducing the future threat from liver fluke realistic prospect or quixotic fantasy
Veterinary Parasitology, 2011Co-Authors: Ian FairweatherAbstract:The liver fluke remains an economically significant parasite of livestock and is emerging as an important zoonotic infection of humans. The incidence of the disease has increased in the last few years, as a possible consequence of changes to the World's climate. Future predictions suggest that this trend is likely to continue. Allied to the changing pattern of disease, reports of resistance to Triclabendazole (TCBZ) have appeared in the literature, although they do not all represent genuine cases of resistance. Nevertheless, any reports of resistance are a concern, because Triclabendazole is the only drug that has high activity against the migratory and damaging juvenile stages of infection. How to deal with the twin problems (of increasing incidence and drug resistance) is the overall theme of the session on "Trematodes: Fasciola hepatica epidemiology and control" and of this review to introduce the session. Greater knowledge of fluke epidemiology and population genetics will highlight those regions where surveillance is most required and indicate how quickly resistant populations of fluke may arise. Models of disease risk are becoming increasingly sophisticated and precise, with more refined data analysis programmes and Geographic Information Systems (GIS) data. Recent improvements have been made in our understanding of the action of Triclabendazole and the ways in which flukes have become resistant to it. While microtubules are the most likely target for drug action, tubulin mutations do not seem to be involved in the resistance mechanism. Rather, upregulation of drug uptake and metabolism processes appear to be more important and the data relating to them will be discussed. The information may help in the design of new treatment strategies or pinpoint potential molecular markers for monitoring fluke populations. Advances in the identification of novel targets for drugs and vaccines will be made by the various "-omics" technologies that are now being applied to Fasciola. A major area of concern in the current control of fasciolosis is the lack of reliable tests for the diagnosis of drug (TCBZ) resistance. This has led to inaccurate reports of resistance, which is hindering successful disease management, as farmers may be encouraged to switch to less effective drugs. Progress with the development of a number of new diagnostic tests will be reviewed.
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piperonyl butoxide enhances Triclabendazole action against Triclabendazole resistant fasciola hepatica
Parasitology, 2011Co-Authors: C Devine, Alan Trudgett, Elizabeth M. Hoey, G. P. Brennan, L Alvarez, C Lanusse, Ian FairweatherAbstract:A study has been carried out to determine whether the action of Triclabendazole (TCBZ) against the liver fluke, Fasciola hepatica is altered by inhibition of the cytochrome P450 (CYP 450)-mediated drug metabolism pathway. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for these experiments, the basic design of which is given in the paper by Devine et al. (2010a). Piperonyl butoxide (PB) was the CYP P450 inhibitor used. Morphological changes resulting from drug treatment and following metabolic inhibition were assessed by means of transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with PB+TCBZ, but more particularly PB+TCBZ.SO, led to greater changes to the TCBZ-resistant isolate than with each drug on its own, with blebbing of the apical plasma membrane, severe swelling of the basal infolds and their associated mucopolysaccharide masses in the syncytium and flooding in the internal tissues. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis and production of secretory bodies were badly disrupted. The mitochondria were swollen throughout the tegumental system and the somatic muscle blocks were disrupted. With the TCBZ-susceptible Cullompton isolate, there was a limited increase in drug action following co-incubation with PB. The results provide evidence that the condition of a TCBZ-resistant fluke can be altered by inhibition of drug metabolism. Moreover, they support the concept that altered drug metabolism contributes to the mechanism of resistance to TCBZ.
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time dependent changes to the tegumental system and gastrodermis of adult fasciola hepatica following treatment in vivo with Triclabendazole in the sheep host
Veterinary Parasitology, 2010Co-Authors: Emma Toner, R E B Hanna, H W J Edgar, Gerard Brennan, Ian FairweatherAbstract:Eight indoor-reared cross-bred sheep with no pre-exposure to Fasciola hepatica were infected by oral gavage with 200 metacercarial cysts of the Triclabendazole (TCBZ)-susceptible Cullompton isolate of F. hepatica. At 12 weeks post-infection, sheep were dosed with 10mg/kg Triclabendazole. Two sheep per time period were euthanized at 48 h, 72 h and 96 h post-treatment (pt). Two control sheep were euthanized alongside the 96 h Triclabendazole-treated sheep. Flukes were recovered from each of the sheeps liver and, if present, from the gall bladder and they were processed for transmission electron microscopy (TEM). Disruption to the ultrastructure of the tegument became increasingly severe over time pt. Flukes recovered at 48 h pt showed widespread blebbing of the apical plasma membrane and swelling of the mucopolysaccharide masses surrounding the basal infolds. There was evidence of reduced secretory activity in the tegumental cells and spacing between the cells. Sloughing of the tegumental syncytium was observed at 72 h pt. The subtegumental musculature, parenchyma and tegumental cells were severely disrupted. At 96 h pt, all of the flukes were totally devoid of tegument. Disruption to the subtegumental tissue and somatic musculature was severe, and was so extreme in some specimens that the tegumental cells were barely discernible. Disruption to the gastrodermis was also progressive, though not as severe as disruption to the tegument. There was a general decline of secretory activity with time pt. Autophagic activity was apparent from 48 h pt and became more widespread with increasing time, culminating in breakdown of the gastrodermal cell cytoplasm. The mitochondria were swollen and electron-lucent and the cisternae of the granular endoplasmic reticulum were dilated and fragmented from 72 h pt.
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stage specific differences in fecundity over the life cycle of two characterized isolates of the liver fluke fasciola hepatica
Parasitology, 2006Co-Authors: Stephen Walker, Elizabeth M. Hoey, Ian Fairweather, G. P. Brennan, Hugh L Fletcher, Alan TrudgettAbstract:The variability inherent in different isolates of Fasciola hepatica has been evident from reports in the literature but to date there has been no systematic examination of the relationship between these differences and the fecundity of the parasite. In this study we have attempted to remedy this situation by comparing the relative efficiencies with which 2 well-characterized isolates of the liver fluke (Oberon and Fairhurst) progress through both their definitive and intermediate hosts. We did not observe a reduction in fitness in the Oberon isolate which has been reported to be Triclabendazole-resistant, compared to the Triclabendazole-susceptible Fairhurst isolate, but considerable inter- and intra-isolate variability at different life-cycle stages was recorded. Thus the Oberon isolate gave 4-fold the number of cercariae when 100 snails were each challenged with a single miracidium and was more successful in establishing productive infections in rats. Fairhurst metacercariae excysted at a higher rate than those from the Oberon isolate and Fairhurst flukes produced 4-fold more eggs. The extent of the intra- and inter-isolate variability revealed in this work will provide a basis for the development of models of population dynamics aimed at predicting the response of the liver fluke to changing environmental conditions such as the use of anthelmintics or climatic change.
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The comparative metabolism of Triclabendazole sulphoxide by Triclabendazole-susceptible and Triclabendazole-resistant Fasciola hepatica
Parasitology Research, 2004Co-Authors: Mark W. Robinson, Jill Lawson, Alan Trudgett, Elizabeth M. Hoey, Ian FairweatherAbstract:Benzimidazole anthelmintics are widely used against nematode, cestode and trematode parasites. The drugs undergo several enzyme-mediated reactions within the host animal that produce a number of metabolites. Although it has been shown that certain helminths, including Fasciola hepatica , can metabolise albendazole, nothing is known regarding the ability of the liver fluke to metabolise Triclabendazole, which is the major flukicidal compound currently on the market. In the current study, adult Triclabendazole-susceptible flukes were treated with Triclabendazole sulphoxide in vitro, and the metabolism of the drug was monitored by high performance liquid chromatography. The data show that F. hepatica can metabolise Triclabendazole sulphoxide into its relatively inert sulphone metabolite. Parallel experiments using Triclabendazole-resistant flukes showed that the conversion of Triclabendazole sulphoxide to Triclabendazole sulphone was on average 20.29% greater in the resistant flukes compared with the susceptible flukes. The results are discussed with regard to the mechanism of Triclabendazole resistance in F. hepatica .
Alan Trudgett - One of the best experts on this subject based on the ideXlab platform.
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piperonyl butoxide enhances Triclabendazole action against Triclabendazole resistant fasciola hepatica
Parasitology, 2011Co-Authors: C Devine, Alan Trudgett, Elizabeth M. Hoey, G. P. Brennan, L Alvarez, C Lanusse, Ian FairweatherAbstract:A study has been carried out to determine whether the action of Triclabendazole (TCBZ) against the liver fluke, Fasciola hepatica is altered by inhibition of the cytochrome P450 (CYP 450)-mediated drug metabolism pathway. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for these experiments, the basic design of which is given in the paper by Devine et al. (2010a). Piperonyl butoxide (PB) was the CYP P450 inhibitor used. Morphological changes resulting from drug treatment and following metabolic inhibition were assessed by means of transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with PB+TCBZ, but more particularly PB+TCBZ.SO, led to greater changes to the TCBZ-resistant isolate than with each drug on its own, with blebbing of the apical plasma membrane, severe swelling of the basal infolds and their associated mucopolysaccharide masses in the syncytium and flooding in the internal tissues. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis and production of secretory bodies were badly disrupted. The mitochondria were swollen throughout the tegumental system and the somatic muscle blocks were disrupted. With the TCBZ-susceptible Cullompton isolate, there was a limited increase in drug action following co-incubation with PB. The results provide evidence that the condition of a TCBZ-resistant fluke can be altered by inhibition of drug metabolism. Moreover, they support the concept that altered drug metabolism contributes to the mechanism of resistance to TCBZ.
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stage specific differences in fecundity over the life cycle of two characterized isolates of the liver fluke fasciola hepatica
Parasitology, 2006Co-Authors: Stephen Walker, Elizabeth M. Hoey, Ian Fairweather, G. P. Brennan, Hugh L Fletcher, Alan TrudgettAbstract:The variability inherent in different isolates of Fasciola hepatica has been evident from reports in the literature but to date there has been no systematic examination of the relationship between these differences and the fecundity of the parasite. In this study we have attempted to remedy this situation by comparing the relative efficiencies with which 2 well-characterized isolates of the liver fluke (Oberon and Fairhurst) progress through both their definitive and intermediate hosts. We did not observe a reduction in fitness in the Oberon isolate which has been reported to be Triclabendazole-resistant, compared to the Triclabendazole-susceptible Fairhurst isolate, but considerable inter- and intra-isolate variability at different life-cycle stages was recorded. Thus the Oberon isolate gave 4-fold the number of cercariae when 100 snails were each challenged with a single miracidium and was more successful in establishing productive infections in rats. Fairhurst metacercariae excysted at a higher rate than those from the Oberon isolate and Fairhurst flukes produced 4-fold more eggs. The extent of the intra- and inter-isolate variability revealed in this work will provide a basis for the development of models of population dynamics aimed at predicting the response of the liver fluke to changing environmental conditions such as the use of anthelmintics or climatic change.
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The comparative metabolism of Triclabendazole sulphoxide by Triclabendazole-susceptible and Triclabendazole-resistant Fasciola hepatica
Parasitology Research, 2004Co-Authors: Mark W. Robinson, Jill Lawson, Alan Trudgett, Elizabeth M. Hoey, Ian FairweatherAbstract:Benzimidazole anthelmintics are widely used against nematode, cestode and trematode parasites. The drugs undergo several enzyme-mediated reactions within the host animal that produce a number of metabolites. Although it has been shown that certain helminths, including Fasciola hepatica , can metabolise albendazole, nothing is known regarding the ability of the liver fluke to metabolise Triclabendazole, which is the major flukicidal compound currently on the market. In the current study, adult Triclabendazole-susceptible flukes were treated with Triclabendazole sulphoxide in vitro, and the metabolism of the drug was monitored by high performance liquid chromatography. The data show that F. hepatica can metabolise Triclabendazole sulphoxide into its relatively inert sulphone metabolite. Parallel experiments using Triclabendazole-resistant flukes showed that the conversion of Triclabendazole sulphoxide to Triclabendazole sulphone was on average 20.29% greater in the resistant flukes compared with the susceptible flukes. The results are discussed with regard to the mechanism of Triclabendazole resistance in F. hepatica .
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Triclabendazole resistant fasciola hepatica β tubulin and response to in vitro treatment with Triclabendazole
Parasitology, 2002Co-Authors: Mark W. Robinson, Alan Trudgett, Elizabeth M. Hoey, Ian FairweatherAbstract:Resistance in Fasciola hepatica to Triclabendazole ('Fasinex') has emerged in several countries. Benzimidazole resistance in parasitic nematodes has been linked to a single amino acid substitution (phenylalanine to tyrosine) at position 200 on the beta-tubulin molecule. Sequencing of beta-tubulin cDNAs from Triclabendazole-susceptible and Triclabendazole-resistant flukes revealed no amino acid differences between their respective primary amino acid sequences. In order to investigate the mechanism of Triclabendazole resistance, Triclabendazole-susceptible and Triclabendazole-resistant flukes were incubated in vitro with Triclabendazole sulphoxide (50 microg/ml). Scanning and transmission electron microscopy revealed extensive damage to the tegument of Triclabendazole-susceptible F. hepatica, whereas Triclabendazole-resistant flukes showed only localized and relatively minor disruption of the tegument covering the spines. Immunocytochemical studies, using an anti-tubulin antibody, showed that tubulin organization was disrupted in the tegument of Triclabendazole-susceptible flukes. No such disruption was evident in Triclabendazole-resistant F. hepatica. The significance of these findings is discussed with regard to the mechanism of Triclabendazole resistance in F. hepatica.