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At least 19 recordsLinked to original sources

PubMed2003

The comparative metabolism of triclabendazole sulphoxide by triclabendazole-susceptible and triclabendazole-resistant Fasciola hepatica.

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.

Albendazole↗

PubMed2002

Triclabendazole-resistant Fasciola hepatica: beta-tubulin and response to in vitro treatment with triclabendazole.

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.

Animals↗

PubMed2003

The effect of the microtubule inhibitor tubulozole-C on the tegument of triclabendazole-susceptible and triclabendazole-resistant Fasciola hepatica.

The benzimidazole derivative, triclabendazole is the main drug used against Fasciola hepatica, although its precise mode of action remains to be fully determined. Previous studies have suggested that triclabendazole acts as a microtubule inhibitor in the same manner as tubulozole-C. Consequently, flukes from triclabendazole-susceptible and triclabendazole-resistant isolates were treated with tubulozole-C (1x10(-6 )M) in vitro and changes in tegumental morphology and tubulin distribution within the tegument were monitored by scanning and transmission electron microscopy, together with tubulin immunocytochemistry. Tubulozole-C caused severe disruption within the tegument of triclabendazole-susceptible flukes. Tubulin immunoreactivity diminished within the tegumental syncytium of the triclabendazole-susceptible flukes following treatment with tubulozole-C. In contrast, tubulozole-C caused only minor disruption of the tegument in triclabendazole-resistant F. hepatica and did not significantly alter the pattern of tubulin immunostaining within the tegumental syncytium. The results of the present study indicate that tubulozole-C and triclabendazole share the same target molecule and that triclabendazole-resistant flukes are also cross-resistant to tubulozole-C.

Animals↗

PubMed2004

Measurement of triclabendazole and its metabolites in liver flukes: method development and full validation.

The trematode parasite Fasciola hepatica is still the cause of considerable loss in livestock production all over the world. The knowledge of the pharmacological properties of the available flukicidal drugs is critical to control this parasite. Triclabendazole is an halogenated benzimidazole anthelmintic with potent flukicidal activity. A simple reversed-phase high-performance liquid chromatographic analytical method has been developed, validated and applied for the quantitative determination of the flukicidal drug triclabendazole and its sulpho- and hydroxy-metabolites in the liver fluke, F. hepatica. Triclabendazole, triclabendazole sulphoxide, triclabendazole sulphone, hydroxy-triclabendazole, hydroxy-triclabendazole sulphoxide and hydroxy-triclabendazole sulphone were measured simultaneously in this trematode parasite. Linearity, resolution, precision, accuracy, recovery, limits of detection and quantification of the method were determined. Drug extraction from the parasite's tissue homogenate was effectively performed using liquid extraction (acetonitrile), avoiding clean up by solid phase extraction, prior to analysis by reversed-phase high-performance liquid chromatography. The resolution of all the halogenated benzimidazole thiol molecules assayed was obtained on a C(18) reversed-phase (5 microm, 250 mm x 4.6 mm) column using acetonitrile and ammonium acetate as the mobile phase and ultraviolet detection at 300 nm. Regression analyses were linear over the concentration range examined (from 0.272 to 16.331 nmol/100 mg trematode protein) and the correlation coefficients of the calibration curves ranged between 0.996 and 1.000. The calculated limits of detection of the proposed method for the parent drug and its metabolites ranged between 0.007 and 0.079 nmol/100 mg trematode protein. The extraction efficiency for the different analytes from the parasite material was greater than 71%. The results obtained indicated that the developed chromatographic method was selective, accurate and easy to reproduce. The developed procedure was successfully applied to quantify triclabendazole/metabolites in F. hepatica incubated under ex vivo conditions, demonstrating to be efficient for the determination of the most extensively used flukicidal drug available for veterinary medicine, and its metabolites. The analytical method described here is an useful tool for the measurement of this flukicidal compound in different studies addresses to evaluate drug influx/eflux and metabolism in its main target parasite.

Animals↗

PubMed2006

Triclabendazole and its two main metabolites lack activity against Schistosoma mansoni in the mouse model.

Some have claimed that triclabendazole, a safe and efficacious drug for the treatment of fascioliasis, also exhibits antischistosomal properties, but results are conflicting. We assessed the effect of triclabendazole and its two main metabolites against two different strains of Schistosoma mansoni harbored in mice. Low worm burden reductions (18.6-35.9%) were observed in mice infected with an Egyptian strain of S. mansoni and treated with a single dose of 120 mg/kg 3 days before infection or single/double doses of 120-200 mg/kg 7 weeks after infection. Triclabendazole failed to significantly reduce hepatic and intestinal tissue egg loads, and eggs of all developmental stages were observed. Administration of 400 mg/kg of either triclabendazole, triclabendazole sulphone, or triclabendazole sulfphoxide to mice infected with a Liberian strain of S. mansoni resulted in worm burden reductions < 10%. In comparison, high worm burden reductions (82-100%) were observed in S. mansoni-infected mice treated with single oral doses of 400, 500, or 500 mg/kg twice a day praziquantel, regardless of the S. mansoni strain. We conclude that triclabendazole and its main metabolites display weak and inconsistent schistosomicidal activities.

Animals↗

PubMedDate not supplied

Treatment of human pulmonary paragonimiasis with triclabendazole: clinical tolerance and drug efficacy.

An open clinical trial to determine the efficacy and tolerability of postprandial doses of triclabendazole against Paragonimus mexicanus in 62 patients with pulmonary paragonimiasis from the Ecuadorian Amazon region was performed. Praziquantel was used as therapeutic control. Patients were allocated at random to the following 4 therapeutic regimens: triclabendazole, 5 mg/kg once daily for 3 d (16 patients), 10 mg/kg twice on one day (15 patients), and 10 mg/kg in a single dose (16 patients), and praziquantel, 25 mg/kg thrice daily for 3 d (15 patients). Clinical tolerance, based on the frequency and severity of adverse reactions, was superior in all 3 triclabendazole regimens to that of praziquantel. No alteration was observed in hepato-renal functions or haematological values. The clinical symptoms resolved at a comparable rate in all 4 treatment groups. A more rapid parasitological response to treatment, as determined by the reduction in the average number of parasite eggs found in sputum, was seen in patients treated with triclabendazole than with praziquantel. By day 90, 60 patients had no egg detected in their sputum; 2 patients, treated with a single dose of 10 mg/kg, had a few and were re-treated with triclabendazole (5 mg daily for 3 d). On day 365, none of the patients had eggs in their sputum. Triclabendazole can be recommended as an alternative drug of choice for the treatment of pulmonary paragonimiasis; it is as effective as praziquantel in clearing infections and better tolerated.

Adolescent↗

PubMed1997

Triclabendazole treatment in experimental goat fasciolosis: anthelmintic efficacy and influence in antibody response and pathophysiology of the disease.

A controlled test of the efficacy of triclabendazole against all stages (early immature, late immature and mature) of Fasciola hepatica has been performed in experimentally infected goats. The influence of triclabendazole treatment on the pathophysiology of the disease, in terms of haematological parameters and serum enzyme levels, and in the dynamics of production of specific antibodies to excretory/secretory products (ESP) of F. hepatica were also examined. Goats were orally infected with 200 viable metacercarie and treated at 4, 8 and 16 weeks postinfection (PI) with triclabendazole at the dose rate of 10 mg kg-1 body weight. The drug can be regarded as highly effective against mature (100%) and late immature (99.2%) flukes and effective against early immature flukes (94.9%). A moderate anaemia was found associated with the presence of late immature and mature flukes in bile ducts. Treatment with triclabendazole, by eliminating most of these flukes, largely reduced haematological alterations. Serum levels of the enzymes aspartate aminotransferase, lactate dehydrogenase and gamma-glutathione transferase reflected hepatic damage during goat fasciolosis. Early treatment (at 4 weeks PI) prevents the development of both parenchyma and bile ducts lesions; treatment at 8 weeks PI only prevents bile ducts lesions and treatment at 16 weeks PI has no appreciable effect on the development of the main hepatic lesions. The antibody response to F. hepatica ESP, as measured by enzyme-linked immunosorbent assay, was also affected by treatment with triclabendazole. In all treated animals a peak in antibody levels was observed between weeks 9 and 13, followed by a drop whose magnitude depended on the efficacy of treatment. In those animals in which triclabendazole was highly effective, antibody levels fell back to negative values similar to those recorded preinoculation at 18-21 weeks PI.

Analysis of Variance↗

PubMed1990

[Triclabendazole (Fasinex) residue in milk: determination and excretion kinetics].

The determination of triclabendazole (Fasinex) in milk is described. The excretion of triclabendazole and its two main metabolites was measured under field conditions in twenty-five cows. Triclabendazole was administered to cows in a dosage of approximately 12 mg kg-1. The maximum concentration of the main metabolites of triclabendazole (triclabendzole sulphone) measured in milk was 1.415 mg/l. Metabolites could be detected in milk during a ten-day-period. Only 1.5% (maximum) of the triclabendazole administered was eliminated as triclabendazole sulphone by way of milk.

Animals↗

PubMed2004

Response of two isolates of Fasciola hepatica to treatment with triclabendazole in vivo and in vitro.

In this study, the susceptibility of two isolates of Fasciola hepatica--the Fairhurst and Oberon isolates--to treatment with triclabendazole was investigated, both in vivo and in vitro. The Fairhurst isolate originated in England, but has since been maintained in Australia; the Oberon isolate originated in Australia. Triclabendazole had a very high efficacy against the Fairhurst isolate. In sheep (dose: 10 mg/kg), the efficacy ranged from 78.4% at 2 weeks post-infection to 98.5% at 6 weeks post-infection. In cattle (dose: 12 mg/kg) efficacy was 89% at 2 weeks post-infection and 100% at 12 weeks. In contrast, against the Oberon isolate, triclabendazole had 0% efficacy against 2-week-old flukes in sheep (dose: 10 mg/kg) and 5% against 4-week-old flukes. Surface changes to flukes of the two isolates were assessed by scanning electron microscopy following treatment in vitro for 24 h in triclabendazole sulphoxide (15 and 50 microg/ml). Disruption took the form of blebbing, swelling and furrowing of the tegument and was greater in the Fairhurst than the Oberon isolate. Surface changes generally were more severe in the anterior than posterior region of the fluke and the dorsal surface was also consistently more severely affected than the ventral surface. Disruption was more severe at the higher drug concentration for both isolates. The morphological data is consistent with the efficacy data, which indicates that the Fairhurst isolate of F. hepatica is susceptible to triclabendazole treatment, whilst the Oberon isolate is refractory.

Animals↗

PubMed2006

The effect of diet type on the plasma disposition of triclabendazole in goats.

The effect of two different diet types (concentrate feed+hay and grazing) on the pharmacokinetic profiles of triclabendazole following oral administration in goats was investigated. A total of 12 goats were randomly allocated into two groups which were either indoor and fed concentrate + hay ration (housed group) or were grazing on pasture (grazing group). Triclabendazole was administered orally to animals in two groups at 10 mg/kg bodyweight. Blood samples were collected from 1 h to 192 h post-treatment and analyzed by high performance liquid chromatography (HPLC). Feeding with different diets significantly effected the plasma disposition of triclabendazole sulphoxide. Maximum plasma concentration (C(max): 13.22+/-2.81 microg/ml), time to reach maximum plasma concentration (t(max): 18.4+/-2.19 h), area under the curve (AUC: 613+/-137 microg h/ml), half-life (t(1/2): 24.77+/-1.94 h) and mean resident time (MRT: 40.22+/-4.36 h) of triclabendazole sulphoxide in housed group were significantly different from those of grazing group (C(max): 10.17+/-1.51 microg/ml, t(max): 14.0+/-2.19 h, AUC: 406+/-98 microg h/ml), t(1/2): 16.16+/-1.17 h and MRT: 34.48+/-4.40 h). It is concluded that anthelmintically more active sulphoxide metabolite has higher plasma concentration when triclabendazole is administered to goats fed with concentrate feed + hay compared to grazing goats.

Animal Feed↗

PubMed2003

Antioxidant capacity in Fasciola hepatica patients before and after treatment with triclabendazole alone or in combination with ascorbic acid (vitamin C) and tocofersolan (vitamin E).

The aim of the present study was to investigate the effect of triclabendazole (CAS 68786-66-3) therapy alone or in combination with ascorbic acid (vitamin C, CAS 50-81-7) and tocofersolan (vitamin E, CAS 30999-06-5), in Fasciola hepatica patients, on Lipo-peroxidation (LPO) and blood antioxidant capacity. 32 Fasciola hepatica patients were divided into two groups (16 acute and 16 chronic). Each group was divided into two subgroups of 8 patients each. One subgroup was given two consecutive oral doses each of 10 mg/kg body weight of triclabendazole suspension and the other received vitamin C (1000 mg/day) and vitamin E (600 mg/day) for two months, together with the same dose of triclabendazole given to the first subgroup. Ten healthy subjects served as controls. The results revealed a significant increase in serum and erythrocyte lipid peroxide levels and a significant decrease in glutathione levels as well as in glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities in all study groups compared to their corresponding control values. After triclabendazole treatment, pronounced improvements in all studied parameters were observed which could be attributed to the fasciolicidal effect of the drug. The significant improvement of SOD and GPX activities and in lipid peroxide levels after vitamins supplementation as compared to their corresponding values after treatment with triclabendazole alone could be explained on the basis of the potent action of these vitamins in protection against oxidative damage.

Acute Disease↗

PubMed2005

Triclabendazole: new skills to unravel an old(ish) enigma.

Triclabendazole was introduced in the early 1980s for the treatment of Fasciola hepatica infections in livestock. Due to its high activity against immature flukes, it has become established as the principal anti-fluke drug on the market. More recently, triclabendazole has been used to treat human cases of fascioliasis and is now the drug of choice for this infection, too. Resistance to triclabendazole was first reported in 1995 in a field population in Australia and, since that time, resistant populations have been identified in several countries in Europe. Parallel to the spread of resistance has been a sharp increase in the prevalence of fascioliasis, which has been attributed largely to climate changes. Consequently, farmers are faced with an alarming scenario, as none of the other fasciolicides on the market possess such high activity against the damaging immature stages of fluke. The main aim of this review is to assess current understanding of the mechanism of action of triclabendazole against the fluke and the mechanism by which the fluke has become resistant to it. The use of triclabendazole against animal and human infections is summarized and suggestions are given on ways to deal with resistance. Gaps in the knowledge of various aspects of its use are highlighted and this may serve to open up future research areas.

Animals↗

PubMed2004

Randomized trial of a single, double and triple dose of 10 mg/kg of a human formulation of triclabendazole in patients with fascioliasis.

1. A study performed > 10 years ago and case reports published recently suggest that triclabendazole is effective for the treatment of patients with fascioliasis. 2. To confirm the efficacy of a human formulation of triclabendazole, we enrolled 165 patients into the present study and divided the subjects into two groups: (i) those who had fascioliasis, as evidenced by the presence of ova in their stools; and (ii) patients with clinical and laboratory data suggesting fascioliasis. 3. Patients were randomly allocated to receive 10 mg/kg, p.o., triclabendazole for 1, 2 or 3 days (single-, double- and triple-dose groups, respectively). Medical history and physical and laboratory examinations were performed at baseline and at 7, 14, 30 and 60 days after treatment. Results were based on 152 patients who completed the study. 4. A sharp decrease in the proportion of clinical signs and symptoms was observed in all groups immediately after treatment. Ova disappeared from the stools of all patients in the single- and double-dose groups. Thirty days after treatment, ova were identified in the stools of two patients in the triple-dose group who received a second course of triclabendazole. 5. All cases were cured on day 60. However, the cure rate was lower when the patients with suggestive fascioliasis were included in the analysis. The cure rate was not significantly different (P > 0.05) among the three dose groups. No cases of toxic hepatitis were observed. 6. In conclusion, oral administration of 10 mg/kg of the human pharmaceutical preparation of triclabendazole for 1-3 days is safe and effective in the treatment of human fascioliasis.

Adolescent↗

PubMed1988

Comparative efficacy of triclabendazole, nitroxynil and rafoxanide against immature and mature Fasciola hepatica in naturally infected cattle.

In two trials the fasciolicidal activities of triclabendazole, nitroxynil and rafoxanide were assessed in cattle naturally infected with predominantly immature stages of Fasciola hepatica. Tablets containing 900 mg triclabendazole were administered orally at a dose rate of 12 mg/kg bodyweight. Rafoxanide and nitroxynil were used at a dose rate of 10 mg/kg, rafoxanide being given orally and nitroxynil by subcutaneous injection. Based on faecal egg counts nine weeks after treatment the efficacies were calculated to be 100 per cent for triclabendazole and 95.0 per cent for nitroxynil in the first trial and 98.4 per cent for triclabendazole and 52.9 per cent for rafoxanide 15 weeks after treatment in the second trial. In the first trial five animals from each of the three groups were slaughtered and their fluke burdens counted. Compared with the untreated control group the reductions in the fluke burdens were 96.9 per cent in triclabendazole treated cattle and 76.4 per cent in the nitroxynil treated group.

Animals↗

PubMed2005

Triclabendazole for the treatment of fascioliasis and paragonimiasis.

Fascioliasis and paragonimiasis, which are caused by liver flukes (Fasciola) and lung flukes (Paragonimus), are emerging public health problems. Several hundred millions of people are at risk of the two diseases that cause considerable morbidity and delay socio-economic development. Triclabendazole, a benzimidazole derivative, has been routinely used since 1983 in veterinary medicine to control infections with Fasciola spp. in domestic herbivorous animals. In 1986, a veterinary formulation of triclabendazole was first administered to two human patients with fascioliasis. Clinical data obtained thus far suggest that triclabendazole is the most efficacious and best tolerated drug for the treatment of fascioliasis. Moreover, the drug holds promise as a useful therapeutic alternative to praziquantel in the treatment of paragonimiasis. This review of triclabendazole includes an overview of the pharmacodynamics and pharmacokinetics, toxicology and efficacy against the major food-borne trematodes in laboratory animals. Data from case reports and clinical trials in humans infected with Fasciola spp. and Paragonimus spp. are summarised and the current state of triclabendazole regarding treatment of human fascioliasis and paragonimiasis is described. Efforts to facilitate broader registration of this drug should go hand-in-hand with research and development on novel drugs against food-borne trematodiasis, better access to improved sanitation, sound health education and the development of new technologies for assuring food safety.

Animals↗

PubMed1990

Comparative efficacy of closantel and triclabendazole against Fasciola hepatica in experimentally infected sheep.

The effect of closantel (10 mg/kg orally) and triclabendazole (10 mg/kg orally) on the reappearance of a patent infection of Fasciola hepatica was studied in experimentally infected sheep. The treatments resulted in the interruption of faecal egg output for 11 weeks with triclabendazole and 13 weeks with closantel. Necropsy of untreated control animals revealed a mean burden of 360 flukes with a mean (+/- se) surface area of 171 +/- 64.3 mm2, whereas the fluke burdens in the closantel and triclabendazole-treated animals 14 weeks after treatment were 61 (83 per cent reduction) and 21 (94 per cent reduction), respectively. The surface areas of the flukes in the triclabendazole-group were comparable with the untreated controls (141 +/- 51.8 mm2), but the flukes in the closantel group were markedly smaller (43.1 +/- 26.9 mm2). It is concluded that closantel has, in epidemiological terms, a potency comparable with that of triclabendazole, despite its slightly lower efficacy against the very immature stages.

Animals↗

PubMed1987

Fasciola hepatica: action in vitro of triclabendazole on immature and adult stages.

Under in vitro conditions in a balanced salt solution, triclabendazole was found to accumulate in significant amounts in both immature (3 week old) and adult Fasciola hepatica. A viable parasite was needed to concentrate the drug, but a high percentage of the compound was also bound by the dead worm. The drug could penetrate into liver flukes even when the oral route had been closed off by ligation, indicating that the drug can be taken up by transtegumentary absorption. A 24 hr exposure to triclabendazole, at 10-25 microM concentrations, was found to result in a strong inhibition of the parasite's motility. This effect was paralleled by dramatic changes in the worm's resting tegumental membrane potential. The onset of these actions was found to develop very slowly, and high drug levels had to accumulate within the parasite to initiate its immobilization. In addition to drug concentration and incubation time, physiological alterations observed were also dependent on other culture conditions, such as the presence or absence of serum albumin and the drug tissue/medium ratio. Biochemical examinations showed that triclabendazole significantly stimulated glucose derived acetate and propionate formation by adult liver flukes. Adenosine triphosphate levels were not changed even in the presence of high triclabendazole concentrations (25 microM). Likewise, the activities of various membrane associated adenosine triphosphatases were not altered by the drug. However, the ability of the drug to inhibit colchicine binding to microtubular protein purified from adult liver flukes suggested an interference of the drug with microtubular structure and function.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗

PubMed1988

Pharmacokinetics and efficacy of triclabendazole in goats with induced fascioliasis.

The pharmacokinetics of triclabendazole were evaluated in normal goats and in goats artificially infected with Fasciola hepatica. Triclabendazole and its metabolites were determined using a novel high performance liquid chromatographic method with fluorimetric detection after solid-phase extraction. In normal goats triclabendazole given orally was metabolized rapidly to its sulphoxide and sulphone derivatives. The maximum plasma concentrations for the sulphoxide and sulphone were similar ranging from 9 to 19 micrograms/ml and these were attained at an average 12.8 and 25.6 h, respectively, after administration. Both metabolites were eliminated slowly from plasma with elimination half-lives of 22.4 h for the sulphoxide and 19.4 h for the sulphone. They persisted at measurable concentrations in plasma for up to seven days. In milk, the two metabolites occurred in low concentrations and none of them was detectable (sulphoxide less than 0.04 microgram/ml, sulphone less than 0.02 microgram/ml) after seven days. The pharmacokinetic behaviour of triclabendazole was not altered in animals with fascioliasis. Efficacy of the drug against immature (six-week) F. hepatica was 100%.

Animals↗