Effect of benzimidazoles on amino acid metabolism in Trichuris globulosa

L-aspartic acid C14, L-alanine C14 and L-leucine C14 uptake by Trichuris globulosa was found to be a non-linear function of time and limiting substrate concentration. The uptake was rapid initially but achieved steady state possibly owing to the saturation of transport loci. Linear transformations of substrate saturation kinetics by Lineweaver-Burk plots of L-aspartic acid C14, L-alanine C14 and L-leucine C14 gave Kt values of 6.8 X 10(3) microM, 3.4 X 10(3) microM and 6.06 X 10(3) microM and Jmax of 0.769 mumoles/mg dry weight/min, 10 mumoles/mg dry weight/min and 0.285 mumoles/mg dry weight/min, respectively. The presence of benzimidazole drugs, thiabendazole and fenbendazole, markedly inhibited the uptake of amino acids at concentrations which did not affect the motility of the parasite. The amino acid transport was also found to be pH and temperature dependent. The uptaken amino acids were readily metabolized into different tissue fractions. Thiabendazole and fenbendazole significantly inhibited the incorporation of the three amino acids into the nematode's total protein fractions and trichloroacetic acid soluble fractions. These drugs also decreased the amount of radiocarbon of 14C-amino acids incorporated into CO2.     

Lack of Cyathostomin sp. reduction after anthelmintic treatment in horses in Brazil

The increase of anthelmintic resistance in the last years in the nematode population of veterinary importance has become a major concern. The objective of the present study was to evaluate the efficacy of the main anthelmintic drugs available in the market against small strongyles of horses in Brazil. A total of 498 horses from 11 horse farms, located in the states of Paraná, São Paulo, Rio de Janeiro and Minas Gerais, in Brazil, were treated with ivermectin, moxidectin, pyrantel and fenbendazole, orally at their recommended doses. The fecal egg count reduction test (FECRT) was used to determine the product's efficacy and fecal culture was used to determine the parasite genus. Reduction on anthelmintic efficacy was found for fenbendazole in all horse farms (11/11), pyrantel in five yards (5/11) and ivermectin had low efficacy in one of the yards studied (1/11). Multidrug resistance of up to 3 drugs classes was found in one of the tested farms (1/11). Cyathostomin were the most prevalent parasite. The results showed that resistance to fenbendazole is widespread; the efficacy of pyrantel is in a critical situation. Although the macrocyclic lactones compounds still showed high efficacy on most farms, suspected resistance to macrocyclic lactones is of great concern.     

Comparative studies on the effect of fenbendazole on the liver and liver microsomal enzymes in goats,quail and rats

To compare the effect of fenbendazole on the liver and liver microsomal mono-oxygenases of goats, quail and rats, an oral dose of 25 mg/kg was administered to the animals daily for 9 consecutive days. On the tenth day, blood samples and livers were collected from both the control and the treated animals for preparation of serum and microsomes respectively. Determination of the activities of sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum samples showed that there was no significant increase in the activities of these enzymes in the treated animals as compared to their corresponding controls, suggesting no liver damage. Similarly, no significant difference in the amount of microsomal cytochrome P-450 was found between the control and the treated animals of the same species. Compared to their respective controls, the activities of microsomal benzphetamine N-demethylase and aniline hydroxylase were almost unchanged in the treated goats and rats. However, fenbendazole treatment appeared to enhance the activity of these two microsomal enzymes in quail. The results indicate that fenbendazole is not liver toxic to goats, quail or rats at a dose rate of 25 mg/kg.     

Critical tests in equids with fenbendazole alone or combined with piperazine: particular reference to activity on benzimidazole-resistant small strongyles

Seven critical tests in equids were conducted with single doses of fenbendazole (5 mg kg-1) alone (Panacur--American Hoechst, Somerville, NJ); (2 tests with paste and 1 with suspension formulation) or in combination with piperazine (American Hoechst); (40 mg base kg-1); (4 tests with paste formulation). The main purpose of the tests was evaluation of activity against benzimidazole-resistant small strongyles (Cyathostomum catinatum, Cyathostomum coronatum, Cylicocyclus nassatus, Cylicostephanus goldi, and Cylicostephanus longibursatus). Natural infections of 2 populations of benzimidazole-resistant small strongyles were evaluated; 1 was population B in 2 horses and the other was population S in 5 ponies. Removal of the 5 species of population B was 49-91% in the animal treated with fenbendazole paste alone and 100% (4 of these species present) in the animal treated with the combination. For population S, 2 of the 5 resistant species were present in small numbers in 1 animal treated with fenbendazole paste alone and all were removed; the 1 animal receiving fenbendazole suspension alone had removals of 0-70% for the 5 benzimidazole-resistant species. Also for population S, the 5 resistant species were present in 2 animals treated with the paste combination and removal was 98-100% and of 4 of the 5 resistant species in 1 animal, removal was 76-99%. Removal of large strongyles (Strongylus vulgaris and Strongylus edentatus) was 92-100% for fenbendazole paste alone or in combination with piperazine in the 5 infected animals. For Oxyuris equi, present in 1 animal treated with the combination, there was 91% removal of immature and 100% removal of mature specimens. There probHably was no activity by fenbendazole alone or the combination against bots, tapeworms, and parenteral stages of S. vulgaris and S. edentatus. The combination may have had some activity against immature Habronema spp. and mature abronema muscae.     

不同驱虫药物对奶山羊消化道线虫驱虫效果研究

本研究旨在观察不同驱虫药物对奶山羊消化道线虫的驱虫效果,为今后寄生虫病的防治筛选更好的驱虫药物。选取奶山羊96只,分3组,每组32只,分别投喂伊维菌素注射液、芬苯达唑粉和伊维菌素芬苯达唑预混剂3种驱虫药物,采用饱和盐水漂浮法和麦克马斯特法检测驱虫前后线虫的感染情况。结果发现:伊维菌素注射液组虫卵转阴率为6.25%;芬苯达唑粉剂组虫卵转阴率为31.25%;伊维菌素芬苯达唑预混剂组虫卵转阴率为50.00%。驱虫前后感染强度伊维菌素注射液组差异显著(P<0.05),芬苯达唑粉剂组差异极显著(P<0.01),伊维菌素芬苯达唑预混剂组差异极显著(P<0.01)。因此,建议采用伊维菌素芬苯达唑预混剂作为奶山羊消化道线虫首选驱虫药物。     

Effect of the antiparasitic drugs fenbendazole and ivermectin on the soil nematode Pristionchus maupasi

Pristionchus maupasi, a soil nematode, was used to elucidate the potential ecotoxic effect of the two anthelmintics fenbendazole and ivermectin in cattle dung. The population growth of P. maupasi was greater in faeces from cattle harbouring active Panacur- or Ivomec-boli, which are releasing fenbendazole and ivermectin to the rumen, respectively, compared to the growth in control faeces. In dose-response experiments it could be shown that the pure chemical compound of fenbendazole was increasingly nematocidal to P. maupasi in concentrations from 10 to 20 microg/g faeces (ww, i.e. wet weight) and the pure compound of ivermectin was effective above 3 microg/g faeces (ww). The results indicate that neither fenbendazole nor ivermectin have any acute toxic effect on P. maupasi in naturally excreted concentrations of the pure drugs, together with their metabolites in faeces from bolus-treated cattle. Both drugs are excreted in concentrations that are non-toxic to P. maupasi.     

Benzimidazole drugs and modulation of biotransformation enzymes

Benzimidazole drugs (e.g., anthelmintics albendazole, fenbendazole, oxfenbendazole, thiabendazole, mebendazole; inhibitors of proton pump omeprazole, lansoprasole, pantoprasole) represent substances used in both human and veterinary medicine; however, from the point of view of induction and inhibition of biotransformation enzymes, research has been carried out mainly due to the initiative of human pharmacologists. The purpose of the present review is to inform about inductive and inhibitive effects of benzimidazole drugs in man, animals and cell cultures. Pharmacological and toxicological consequences of modulation of biotransformation enzymes are discussed and the significance of studies in the field of modulation of biotransformation enzymes in food-producing animals is explained. Since the modulating effect of benzimidazoles strongly varies depending on structure of the individual substances, the particular attention is paid to structure-modulation relationships.     

Bioencapsulation of Fenbendazole in Adult Artemia

Fenbendazole was detected in adult brine shrimp tissue (bioencapsulation) after enrichment periods of 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours in baths that contained 2-, 4-, and 8-g/L concentrations of fenbendazole. The assays were performed using high-performance liquid chromatography. A biphasic pattern of peak concentrations at 30 minutes or 1 hour and again at 8 or 12 hours was seen in the shrimp for all treatment concentrations. Percent of fenbendazole available that was incorporated in Artemia approached 100% for all treatment groups. Survival of shrimp was not affected by any of the fenbendazole concentrations, but animal deaths increased with time in all treatment concentrations. It can be concluded that fenbendazole can be successfully bioencapsulated in adult Artemia.     

A Field Study on the Effect of Some Anthelmintics on Cyathostomins of Horses in Sweden

The objective of the study was to investigate different aspects on the efficacy of three anthelmintics on cyathostomin nematodes of Swedish horses. A faecal egg count reduction (FECR) test was performed on 26 farms. Horses were treated orally with recommended doses of ivermectin, pyrantel pamoate or fenbendazole. Faecal samples were collected on the day of deworming and 7, 14 and 21 days later. No resistance was shown against ivermectin; the FECR was constantly >99%. The effect of pyrantel was assessed as equivocal in 6 farms 14 days after treatment; the mean FECR was 99%. As many as 72% of the fenbendazole-treated groups met the criteria for resistance; the mean FECR was 86%, ranging from 56% to 100%. A re-investigation of two farms where pyrantel resistance had been suspected clearly revealed unsatisfactory efficacy of pyrantel on one of these farms; the FECR varied from 72% to 89%. Twenty-six of the horses previously dosed with pyrantel or fenbendazole, and which still excreted ≥150 eggs per gram of faeces 14 days after treatment, were dewormed with ivermectin and fenbendazole or pyrantel in order to eliminate the remaining cyathostomins. A total of 13 cyathostomin species were identified from horses that initially received fenbendazole and seven species were identified from pyrantel-treated individuals. The egg reappearance period (ERP) following treatment with ivermectin and pyrantel was investigated on two farms. The shortest ERP after ivermectin treatment was 8 weeks and after pyrantel was 5 weeks. We conclude that no substantial reversion to benzimidazole susceptibility had taken place, although these drugs have scarcely been used (<5%) in horses for the last 10 years. Pyrantel-resistant populations of cyathostomins are present on Swedish horse farms, but the overall efficacy of pyrantel is still acceptable.     

Characteristics of a flubendazole resistant isolate of Oesophagostomum dentatum from Germany.

Two controlled tests were performed to investigate the benzimidazole resistance of a nodular worm isolate "GIBZ" from a pig breeding farm in Germany. In Trial I, groups of five pigs, artificially infected with Oesophagostomum larvae isolated from that farm were treated with flubendazole at a single dose of 5 mg kg(-1) bodyweight (BW) or remained untreated. In Trial II, three groups of three pigs each infected with larvae after a further laboratory passage of this isolate were treated with flubendazole either at a single dose of 5 mg kg(-1) BW or at a divided dose of 1.5 mg kg(-1) BW daily for 5 consecutive days, or with fenbendazole at a single dose of 5 mg kg(-1) BW, the fourth infected group remained untreated. The respective doses of anthelmintics were mixed with a small amount of feed and administered to individual pigs in both trials. Fecal egg counts before and after treatment and post-mortem worm burdens 7 days after (last) treatment were examined to assess the anthelmintic efficacies. Only infections with Oesophagostomum dentatum were found in both trials. In Trial I, the mean worm count reduction by flubendazole was 30% as compared to the untreated controls. In Trial II, flubendazole administered at a single or divided dose reduced the mean worm burden by 0 and 85%, respectively, whereas fenbendazole was 100% effective. These results establish resistance to flubendazole in the isolate "GIBZ" of O. dentatum. The failure to reveal side resistance to fenbendazole may be explained by that the currently recommended dose rate of this compound is supra-optimal for porcine nodular worms.     

A study to evaluate the field efficacy of ivermectin, fenbendazole and pyrantel pamoate, with preliminary observations on the efficacy of doramectin, as anthelmintics in horses

The efficacy of ivermectin, fenbendazole, pyrantel pamoate and doramectin was evaluated under field conditions at 2 sites in the Free State Province of South Africa. The study involved 25 horses at each site, divided into 5 groups of equal size. Ivermectin, fenbendazole and pyrantel pamoate were administered orally at doses of 0.2, 10 and 19 mg/kg respectively. Doramectin was administered by intramuscular injection at a dose of 0.2 mg/kg. Treatment efficacy was based on the mean faecal egg count reduction 14 days post treatment. At site A a faecal egg count reduction of 100% was found after treatment with ivermectin, fenbendazole and doramectin. A 96.1% reduction was found after treatment with pyrantel pamoate. At site B ivermectin and doramectin produced a 100% reduction in faecal egg counts, fenbendazole produced an 80.8% reduction and pyrantel pamoate a 94.1% reduction. Doramectin produced a 100% reduction in faecal egg counts at both sites, despite not being registered for use in horses. In addition, the results indicated reduced efficacy of fenbendazole at site B, which suggested benzimidazole resistance. Larval cultures showed that cyathostomes accounted for between 86 and 96% of pre-treatment parasite burdens at both sites. Other helminths identified in the faecal samples were Strongylus spp. and Trichostrongylus axei.     

The efficacy of fenbendazole and albendazole against the lungworm Muellerius capillaris in goats

In five trials it was found that the daily administration of fenbendazole in the food for 1 or 2 weeks at dosages of 1.25, 2.5 or 5 mg kg-1 live weight was highly effective against Muellerius capillaris infection in goats. Treated animals had significantly lower numbers of larvae in the faeces for up to 223 days after treatment. There was no obvious difference between the different dose levels. Daily treatment for 2 weeks seemed to be slightly more effective than treatment for 1 week. Treatment for 1 week twice with an intervening period of 1 week seemed to be more effective than treatment for 2 weeks continuously. Goats given a single treatment with fenbendazole at 25 mg kg-1 had a significantly lower number of M. capillaris larvae in their faeces on Days 34 and 69 after treatment than the controls, but on Days 126 and 156 after treatment there was no significant difference between these two groups. Albendazole given daily for 2 weeks at a dose of 1.0 mg kg-1 showed a significant effect for up to 153 days after treatment, which was similar to the result of daily treatment with 1.25 mg kg-1 fenbendazole. Goats treated with albendazole twice at 10 mg kg-1 with a 1 week interval showed a significant reduction in the number of Muellerius larvae in the faeces on Day 41 after treatment, but not on Days 97 and 153 after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transmission studies on Trichinella species isolated from Crocodylus niloticus and efficacy of fenbendazole and levamisole against muscle L1 stages in Balb C mice

Forty-four Balb C mice, aged 18 weeks were infected with crocodile (Crocodylus niloticus)-derived Trichinella species. Of the infected mice, 32 were randomly divided into two groups each containing equal numbers of males and females; levamisole treated group and fenbendazole treated group. Each group was randomly subdivided into two subgroups as follows: levamisole group (subgroup 1: treated with levamisole on day 35 post infection, and subgroup 2: treated with levamisole on days 35 and 42 post infection) and fenbendazole group (subgroup 1: treated with fenbendazole on day 35 post infection and subgroup 2: treated with fenbendazole on days 35 and 42 post infection). The first subgroups treated on day 35 post infection were slaughtered on day 42 post infection and the second subgroups were treated on day 35 and day 42 post infection and slaughtered on day 49 post infection. Two female mice were infected a day after mating and were slaughtered together with the offspring on day 64 post-infection. Ten infected control mice were given 1 ml distilled water orally as placebo, and five of these were slaughtered on day 42 post infection. The results showed that the mean reproductive capacity index of this strain (RCI) in Balb C mice was 110. There was a significant reduction (P < 0.01) in larval counts in the single treatment groups (day 35) and in the double treatment groups (days 35 and 42) for both anthelmintics when compared the number of parasites in the control groups. After a single treatment, levamisole reduced the infection by 79.9% and fenbendazole by 76.7%. Following double treatments, levamisole reduced the infection by 95.5% and fenbendazole by 99.1%.There was evidence that the infected pregnant mice transmitted the parasite to their offspring. It is not certain whether the parasite was transmitted congenitally or transmammary Alternative ways of controlling the parasite in crocodile farms in Zimbabwe are discussed.     

Multiple anthelmintic resistance in Haemonchus contortus on a sheep farm in India

Multiple resistance to benzimidazoles (fenbendazole, albendazole and mebendazole) in a strain of Haemonchus contortus in sheep was detected on a farm where fenbendazole resistance had already been identified. Following a faecal egg count reduction test, this was confirmed by both critical and controlled anthelmintic tests. Different groups of sheep infected naturally or given an experimental infection with the fenbendazole-resistant strain were treated with the recommended doses of various anthelmintics. Compared to the control group, percentage reductions in faecal egg counts of sheep treated with fenbendazole, albendazole, mebendazole, levamisole and morantel varied between 56% and 81% and worm counts between 71% and 86%. The results indicate the presence of multiple anthelmintic resistance in this strain of H. contortus on this farm. Sheep treated with ivermectin and closantel showed 100% reductions in faecal egg and worm counts, suggesting high efficacy of these drugs against the population of H. contortus on this farm.     

Influence on the antithyroid compound methimazole on the plasma disposition of fenbendazole and oxfendazole in sheep

The influence of methimazole on the plasma disposition kinetics of fenbendazole, oxfendazole and their metabolites, was investigated in adult sheep. The two anthelmintics were administered by oral drench at 5 mg kg⁻¹ either alone (control treatments) or together with methimazole given orally at 3 mg kg⁻¹. Blood samples were taken serially for 144 hours. Fenbendazole parent drug and its sulphoxide and sulphone metabolites were the three analytes observed by high performance liquid chromatography ( ) after the administration of both anthelmintics. The disposition of each analyte followed a similar pattern after the administration of the two anthehnintics alone. Oxfendazole was the main component recovered in plasma between four and 120 to 144 hours after the administration of both anthelmintics either with or without methimazole. A modified pattern of disposition, with significantly higher C_max and values for fenbendazole parent drug, and a delayed appearance in plasma with retarded T_max values for the sulphoxide and sulphone metabolites, were the main pharmacokinetic changes observed when the drugs were administered with methimazole.     

Efficacy of fenbendazole and cambendazole against Muellerius capillaris in dairy goats

Two anthelmintics, fenbendazole and cambendazole, were used in an attempt to eliminate Muellerius capillaris infections in a group of 44 goats. During the course of this study (508 days), M capillaris larvae were found in at least one fecal specimen from each of 22 of the 44 goats. All 44 goats were dewormed with fenbendazole (30 mg/kg of body weight) at the onset of this study (day 18). Two additional dewormings with fenbendazole at 4- to 8-week intervals were restricted to the goats that continued to shed M capillaris larvae. On the basis of routine fecal examinations, fenbendazole eliminated M capillaris larvae from the feces of 8 (36%) of these 22 goats. On day 253, cambendazole (60 mg/kg) was given orally to 17 of these 22 goats (2 of the 22 had died and 3 were not available for treatment); 13 of these goats were still shedding M capillaris larvae. Cambendazole eliminated M capillaris larvae from the feces of 10 (77%) of these 13 goats chronically infected with M capillaris.     

The efficacy of fenbendazole and albendazole against immature and adult stages of benzimidazole-resistant sheep trichostrongylids

The efficacy of two recently introduced benzimidazole anthelmintics, albendazole and fenbendazole, was determined for six-day, 10-day and adult stages of resistant strains of Haemonchus contortus and Trichostrongylus colubriformis. Albendazole, at 3.8 mg/kg reduced H contortus worm counts by 92.4, 70.8 and 67.1 per cent while fenbendazole, at 5.0 mg/kg, reduced worm burdens by 51.7, 95.5 and 93.4 per cent against six-, 10- and 25-day-old parasites respectively. For T colubriformis, the corresponding reductions with albendazole were 97.7, 95.8 and 64.9 per cent and for fenbendazole 29.0, 66.3 and 33.4 per cent. Compared with susceptible strains of H contortus and T colubriformis, for which therapeutic doses of benzimidazole anthelmintics are generally highly active against all stages of development, the present results show that these drugs do not have a uniform level of activity against all developmental stages of resistant strains.     

The effects of benzimidazole anthelmintics on P4501A in rat hepatocytes and HepG2 cells

Benzimidazole anthelmintics including albendazole, fenbendazole, and mebendazole are widely used in veterinary medicine. The effects of these benzimidazoles on cytochrome P4501A were investigated in primary cultures of rat hepatocytes and in the HepG2 cell line. After incubation of rat hepatocytes and HepG2 for 24-, 48-, and 72-h cells with drugs at various concentrations (0.1-50 microM), the enzyme activities associated with P4501A1/2 (7-ethoxyresorufin O-deethylation and 7-methoxyresorufin O-demethylation) were measured. The P4501A1/2 protein levels in both model systems were determined by Western blotting. Although all benzimidazoles provoked a significant increase of P4501A1/2 protein levels and P4501A activities, large differences in the induction response were found which was dependent on drug structure, concentration, and model system used. Based on the results, relationships between induction potency and structure of drug were demonstrated, as well as differences between the in vitro systems used. Therefore, pharmacological and toxicological consequences of cytochrome P4501A induction by benzimidazole drugs should be taken into account in veterinary therapy.     

Level of benzimidazole resistance in a strain of Ostertagia circumcincta studied over several infections in lambs

A benzimidazole-resistant strain of Ostertagia circumcinta (HFRO) was used experimentally to infect lambs. The level of resistance, measured by an egg hatch assay, was studied throughout each infection and also after treatment of the lambs with fenbendazole. The HFRO strain was highly resistant to benzimidazoles. There was day-to-day variation in the level of resistance throughout a single infection with a high level of resistance in the early part of the infection, around Day 27 post-inoculation of infective larvae, falling to a lower level later in the infection. Egg hatch assays on the 3 days immediately post-treatment with fenbendazole showed the resistance level was high then resistance fell to the pre-treament level after 7 days. Selection for benzimidazole resistance using fenbendazole treatment at the normal dose rate of 5 mg kg⁻¹ over five passages of the HFRO strain in lambs failed to increase the resistance level. Storage of larvae over a 5-months period at 4°C, prior to infection of lambs, did not produce any alteration in the resistance Level. The possible reasons for the variations in resistance found with the HFRO strain are discussed along with the implications for sheep parasite control and further development of benzimidazole resistance.     

Maturational development of drug-metabolizing enzymes in sheep

A qualitative and quantitative assessment was made of the development of hepatic drug-metabolizing enzymes (DME) in sheep as part of a study of the ability of the food-producing species to metabolize drugs. The following DME and components were measured in this study: cytochromes P-450 and b5 and NADPH and NADPH-dependent reductases associated with each of these cytochromes; cytochrome P-450-mediated reactions, including aniline and coumarin hydroxylases, aminopyrine N-demethylase, and 7-ethoxycoumarin 0-deethylase; a uridine diphosphoglucuronic acid glucuronyl transferase with 4-methylumbelliferone as substrate; and glutathione-S-transferase with dinitrochlorobenzene and dichloronitrobenzene as substrates. Amounts or activities of most of these components and enzymes increased up to and beyond the time of weaning. Amount of cytochrome b5 and uridine diphosphoglucuronic acid transferase activity were not affected by age, whereas NADPH cytochrome c (P-450) reductase activity actually decreased after weaning. In some instances (eg, coumarin hydroxylase, cytochrome P-450, and dinitrochlorobenzene-glutathione-S-transferase), differences from preweaning DME values were observed only after sheep were greater than or equal to 6 months old. All other DME activities were definitely increased, compared with the values in lambs before weaning (0 to 12 weeks old). Approximately a third of the sheep studied had some type of clinical disease that might have affected the DME activities. Diseases were classified as sore mouth, pneumonia, foot rot, parasitism, and systemic bacterial infections. Except in a few instances, these diseases had minimal effect on DME activities measured in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)