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A case report of a 31 year-old woman from Paraíba State (North-Eastern Brazil) that presented severe involvement of ocular globes, ears and meninges. Diagnosis was established after enucleation of her left eye, when adult worms were seen in the midst of a granulomatous inflammatory process. Her response to the initial treatment with levamisole and cambendazole was good, but there was a relapse after the fifth month of treatment even with maintenance doses of both medications. She later received ivermectin and albendazol and responded well. Paciente do sexo feminino, com 31 anos, procedente da Paraíba, apresentava envolvimento severo de ambos os globos oculares, com perda da visão à esquerda, comprometimento da audição e das meninges. Após enucleação do olho esquerdo fragmento de helminto identificado como Lagochilascaris minor foi observado em processo inflamatório granulomatoso. Inicialmente a paciente foi tratada com levamisol e cambendazol, com bom resultado. Verificou-se, todavia, piora do quadro após cinco meses, com eliminação de larvas do ascarídeo em lesão presente na órbita esquerda, embora a medicação fosse mantida com administração periódica. Houve boa resposta terapêutica, com regressão do quadro, após substituição dos anti-helmínticos anteriores pela associação ivermectina e albendazol.

Population-S small strongyles have been studied since 1974 in central Kentucky in a closed Shetland pony breeding herd. The ponies were treated approximately every 8 weeks with cambendazole (1974-1978), oxibendazole (OBZ) (1978-1992), or pyrantel pamoate (PRT) (1992-1999). Small strongyles in the ponies have shown resistance to these compounds in field and critical tests. One purpose of this presentation was to compare different parameters for determination of effects on the small strongyle species in ponies after treatment, mainly with OBZ or PRT, from data in critical tests (n=112). Also, the objective was to report on relative changes in the composition of species of small strongyles during the period 1977 through 1999. The following entities were compared to evaluate the effect of OBZ- or PRT-treatment on the small strongyles: (1) numbers of specimens with eggs in utero--there were less gravid worms passed in the feces than recovered at necropsy for OBZ but the numbers of gravid worms were similar in both categories for PRT, (2) pre- and posttreatment counts of eggs per gram of feces (EPGs) and larvae per gram of feces (LPGs)--the reductions were greater for the counts of EPGs than LPGs for OBZ but not for PRT, and (3) pre- and posttreatment counts of EPGs versus % of worms removed--reductions of the former were greater than the latter for both compounds. As shown from data in this study, reduction of EPG counts post treatment indicated much greater drug activity than was actually demonstrated by removal of worms. One evident factor was the value of doing critical tests to verify posttreatment counts of EPGs as indicators of anthelmintic activity. Twenty-eight species of small strongyles were found. For the 20 most prevalent species in the study, two decreased, five remained unchanged, three increased and then became stationary, five increased but then decreased, and five increased progressively. Numbers of small strongyles were highest in 1987 and 1999.

Several compounds ( n = 13 single or combinations; most at therapeutic dosages) were evaluated between 1977 and 1992 in critical tests ( n = 91) against benzimidazole (BZ) resistant small strongyles (Population S) and several other species of internal parasites in Shetland ponies, mostly under 1 year old. The closed breeding herd, from which the test ponies were selected, had been treated every 8 weeks with cambendazole (CBZ) for 4 years (1974–1978) and oxibendazole (OBZ) for 14 years (1978–1992). Published field test data (1974–1992) on older ponies in the herd showed BZ resistance of small strongyles. Average efficacies in the present critical tests against small strongyles for OBZ ( n = 59 animals) were high in early years (95% or higher), but gradually declined to a low of 1% in 1991. Side-resistance of small strongyles was evident in critical tests ( n = 1–6/single drug or combination) for several other BZs and a pro-BZ; ivermectin and piperazine were highly active, but pyrantel pamoate exhibited weak activity. BZ resistance was evident for six small strongyle species ( Cyathostomum catinatum, Cyathostomum coronatum, Cylicocyclus nassatus, Cylicostephanus calicatus, Cylicostephanus goldi , and Cylicostephanus longibursatus ). Activity on bots, ascarids, large strongyles, and pinworms was essentially as expected, indicating no drug resistance.

The role of beta-tubulin genes in benzimidazole (BZ) resistance was investigated using one susceptible (S) and two resistant (Rt and Rc) strains of Haemonchus contortus. The Rt strain was isolated from the field on the basis of thiabendazole resistance. The Rc strain was derived from the S strain by treatment with cambendazole. cDNAs, derived from the S strain, encoding two isoforms of beta-tubulin (beta 12-16 and beta 8-9), alpha-tubulin and phosphofructokinase (Pfk) were used as probes for Southern hybridization analysis of genomic DNA digested by restriction enzymes. Genomic DNA was isolated from a pool of worms or single worms. The restriction-enzyme fragment length polymorphism (RFLP) differences among these strains depended on the enzyme and the probe used. When digested with Stu I or Hpa I, and probed under stringent conditions with beta 8-9 or beta 12-16, fewer fragments were seen in the Rt and Rc strains than in the S strain. Different hybridizing fragments were found in different individuals. The frequency of individuals bearing certain fragments hybridizing to beta 12-16 or beta 8-9 in the susceptible population was reduced significantly in the resistant populations. Some differences in RFLP between these strains were observed when probed with alpha-tubulin or Pfk, but the changes were not consistent with fragments being lost from the resistant strains as observed for beta-tubulin probes. These changes in RFLP pattern correlate with changes in the binding profiles of BZs and isoelectric isoform patterns reported previously for these strains. The data confirm that reduced heterogeneity within the population is associated with BZ resistance. Our results show that both the beta 8-9 and the beta 12-16 subfamilies of beta-tubulin are affected to a similar extent by this reduction in heterogeneity in a resistant population.

An enzyme-linked immunosorbent assay (ELISA) was developed for analysis of thiabendazole [2-(4-thiazolyl)-1H-benzimidazole, TBZ] residues in bovine liver. Monoclonal antibodies which bind TBZ and 5-OH-TBZ were developed using the haptens, 2-(2-succinamido-4-thiazolyl)benzimidazole and 5-succinamido-2-(4-thiazolyl)benzimidazole. The ELISA method uses monoclonal antibody in a competitive format, following a one-step, 10-min aqueous extraction of samples.Monoclonal antibodies with various specificities permit an ELISA specific for TBZ alone or for thegroup of thiazolyl compounds including TBZ, 5-OH-TBZ, and cambendazole

The treatment of chronic and massive (uncomplicated) and severe (complicated) disseminated strongyloidosis, was presented from the historical point of view. The sequence of achievements in regard of treatment of the gentian violet, dithiazine iodide, benzimidazoles (thiabendazole, mebendazole, albendazole, cambendazole), ivermectin and cyclosporin A, was described. The recommendations for treatment of strongyloidosis are also given.

A novel laboratory anticestode assay was developed using Hymenolepis diminuta in the hamster. The commercial anticestode compounds, praziquantel, bunamidine, and niclosamide were active against patent infections of Hymenolepis diminuta in golden hamsters (Mesocricetus auratus) when given orally at 3.125, 100, and 200 mg/kg, respectively. The gastrointestinal nematode anthelmintics, cambendazole and mebendazole, were active at 50 mg/kg. Rafoxanide (fasciolicide) was active at 25 mg/kg, the lowest level tested. The coccidiostat, nicarbazin, was active at experimental levels (800 mg/kg and up). The anthelmintic–ectoparasiticide (endectocide), ivermectin, was inactive against the tapeworm at 0.5 mg/kg, as expected.

Three multivariate calibration methods, Principal Component Regression (PCR), the K-matrix method and Q-mode factor analysis followed by varimax and Imbrie's oblique rotations were applied to the simultaneous spectrophotometric determinations of mebendazole (MBZ)–cambendazole (CBZ) and thiabendazole (TBZ)–mebendazole in commercial samples of Exelmin and Helmiben. The calibration set concentrations were selected to contain a ±10% variation in the quantity of active ingredients as declared by the manufacturer. The Q-mode factor analysis provides superior results for the two pharmaceutical formulations. The K-matrix method proved to be totally inadequate for these determinations. Almost all Q-mode results have relative errors much smaller than 5% of the active ingredient contents. This investigation shows that PCR and Q-mode factor analysis can be used to determine MBZ–CBZ and TBZ–MBZ in commercial drugs.

The efficacy of treatment with cambendazole was tested in 1-year-old horses on a farm in Dubrovka, Ukraine. Thirty-five horses were treated. Their egg output was compared on the day of treatment and 14 days later with that of 33 untreated horses. Before treatment the mean number of eggs g-1 faeces was 614 in the controls and 766 in horses that had been treated. After 14 days the mean egg output in the controls was 580 and in the treated horses 369. This means a reduction of 54.5%. Only cyathostome larvae could be cultured from faeces collected after treatment. It can be concluded that benzimidazole resistance in cyathostomes is present in the Ukraine.

Critical tests (91) were done between 1977 and 1992 in Shetland ponies to evaluate drug susceptibility and population dynamics (present paper) of endoparasites. The test ponies, most less than 1 year old, were from a herd where older animals were treated every 8 weeks initially with cambendazole (CBZ) (1974–1978) and then with oxibendazole (OBZ) (1978–1992). Previous field test data (1974–1992) on older ponies in the breeding herd indicated the presence of benzimidazole (BZ) resistant small strongyles. Data on population dynamics from the present critical tests indicated that 28 species of small strongyles persisted over the study period in spite of initial susceptibility and later refractiveness of six species to both CBZ and OBZ. Changes in intensities and other aspects were observed for the six BZ-resistant species ( Cyathostomum catinatum, Cyathostomum coronatum, Cylicocyclus nassatus, Cylicostephanus calicatus, Cylicostephanus goldi , and Cylicostephanus longibursatus ). Variabilities, some striking, were found in prevalence and intensity in bots, stomach worms, ascarids, eyeworms, large strongyles, pinworms and tapeworms.

The effect of sulfur-containing benzimidazoles (thiabendazole, 5-hydroxy-thiabendazole, cambendazole) and sulfur-free derivatives (benzimidazole, carbendazim and 5-hydroxycarbendazim) on cytochrome P450 enzymes was investigated in primary cultures of rabbit hepatocytes considered 72 h after plating. Thiabendazole, cambendazole and carbendazim led to a significant dose-dependent increase in both EROD activity and cytochrome P4501A1/2 proteins and mRNA expression. Experiments using actinomycin D strongly suggest that these compounds have a transcriptional control on both CYP1A1 and CYP1A2 genes in primary hepatocytes. Thiabendazole increased both COH activity and P4502A protein levels. We conclude that sulfur is not a prerequisite to the P450 induction potential of benzimidazoles, while 5-hydroxylation leads to inefficient metabolites in terms of inducibility.

Twenty-two benzimidazole compounds were tested for induction of chromosome loss (CHRL) in the diploid yeast Saccharomyces cerevisiae strain D61.M. Six compounds tested positive for CHRL induction: mebendazole, albendazole, RS-9237-000, fenbendazole, 2-benzimidazolylacetonitrile, and thiabendazole. Mebendazole, albendazole, RS-9237-000, and fenbendazole were strongly positive only after modified testing media were used to enhance solubility. The compounds that tested negative for CHRL were 2-phenylbenzimidazole, 2-(2-pyridyl)benzimidazole, benzimidazole, 2-aminobenzimidazole, 2-amino-5,6-dimethylbenzimidazole, 2-(aminomethyl)benzimidazole dihydrochloride hydrate, 5,6-dimethylbenzimidazole, 2-guanidinobenzimidazole, 2-methylbenzimidazole, 2-(methylmercapto) benzimidazole, 1-methyl-2-phenylbenzimidazole, 2-benzimidazolylurea, RS-65255-000, oxibendazole, and RS-95005-000. One chemical, cambendazole, tested negative or only marginally positive. Modified testing medium was also used to enhance the solubility of 2-phenylbenzimidazole, oxibendazole, and RS-95005-000. Because no toxicity was observed with oxibendazole or RS-95005-000, the negative results obtained with these two compounds could not be considered definitive.

Benzimidazole anthelmintics are the most common chemotherapeutic agents used to remove intestinal helminths from farm animals. The development of drug resistance within helminth populations is wide-spread and can render these drugs essentially useless. The mechanism of benzimidazole resistance appears to be common to many species ranging from fungi to nematodes and involves alterations in the genes encoding beta-tubulin. During the selection process resulting in resistance, there must be quantitative changes in the population gene pool. Knowledge of these changes would indicate the mechanisms underlying the spread of resistance in the population, which in turn could be used to design more effective drug administration strategies. To this end we have identified allelic variation at two beta-tubulin genes in Haemonchus contortus using restriction map analysis of individual adults. Extremely high levels of variation were identified at both loci within a susceptible strain. In two independently derived benzimidazole resistant strains, allele frequencies at both loci were significantly different from the susceptible strain but not from each other. The same alleles at both loci, in both resistant strains, were favored by selection with benzimidazoles, suggesting that both loci are involved in determining benzimidazole resistance. These data confirm that changes in allele frequency, rather than novel genetic rearrangements induced by exposure to the drug, explain the changes associated with benzimidazole resistance. These results also show that any DNA based test for the development of benzimidazole resistance must take into account the frequency of alleles present in the population and not simply test for the presence or absence of specific allelic types.

A 15 year old male patient was diagnosed as being infected with the nematode Lagochilascaris minor, presenting as abscesses over the left mastoid region, and invading the temporal bone, mastoid sinuses and possibly the CNS. Surgical drainage and administration of cambendazole and levamisole led to improvement, followed by an early relapse and poor tolerance to the antihelminthic drugs. Repeated doses of ivermectin (an animal preparation) were used for the first time to treat this condition and resulted in complete remission of signs of infection, maintained for 15 months after the end of drug therapy, indicating cure of the disease. Um jovem de 15 anos, masculino recebeu o diagnóstico de infecção pelo nematódeo Lagochilascaris minor, manifesta na forma de abscessos sobre a região mastoidea e invadindo o osso temporal, células mastoideas e, possivelmente, o SNC. Foi feita drenagem cirúrgica e administrado cambendazole e levamisole, seguidos de melhora e posterior recaída; ocorreu também intolerância aos anti-helmínticos. Doses repetidas de uma preparação animal de ivermectina foram utilizadas pela primeira nesta doença, levando a remissão completa dos sinais de infecção, mantida após 15 meses do final do tratamento e indicando cura do processo.

Antiparasitic activity of several compounds was evaluated over a long period (about 25 years) in the same flock of sheep. Haemonchus contortus was of special interest, including its relation to drug resistance, especially to thiabendazole and other benzimidazoles, in addition to phenothiazine. Eleven compounds were evaluated in 15 controlled tests, done between 1966 and 1989 in naturally infected lambs (n = 145) born and raised on the same pasture. Sheep were first placed on the pasture in 1962, and a few more were added thereafter. Internal parasites in these sheep were classified in 3 general categories: indeterminate exposure to parasiticides; H contortus, resistant to thiabendazole; and H contortus, resistant to phenothiazine. The parasitic infections probably became more homogeneous after several years because of few introductions of outside sheep after initial establishment of the flock. Activity against naturally acquired internal helminths was evaluated for cambendazole (CBZ: dosage, 20 mg/kg of body weight), fenbendazole (FBZ: 5 or 7.5 mg/kg), mebendazole (MBZ: 10 mg/kg); oxfendazole (OFZ: 3.5 or 10 mg/kg), oxibendazole (OBZ: 10 mg/kg); parbendazole (PBZ: 15 mg/kg), phenothiazine (PTZ: 550 mg/kg); pyrantel pamoate (PRT: 25 mg base/kg), tetramizole (TET: 15 mg/kg); thiabendazole (TBZ: 30 or 44 mg/kg), and trichlorfon (TCF: 100 mg/kg). Thiabendazole was used more often (9 tests) than the other compounds. Thiabendazole was more active against mature H contortus in later years than when first used in 1966, although it was never 100% effective. Efficacy against immature H contortus for TBZ did not exceed 86%. Activity against immature and mature stages of this parasite was good overall for the other benzimidazoles.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary A survey to determine the prevalence of anthelmintic resistance of horse strongyles was carried out with 616 horses on 22 farms. The tested drugs were cambendazole, pyrantel pamaote and ivermectin. Based on egg count reduction tests the efficacy of cambendazole varied from 0% to 93% and of pyrantel from 93% to 100%. Ivermectin treatments were 100% effective on all farms. Larval cultures after cambendazole treatments revealed exclusively cyathostome larvae. After pyrantel treatments besides cyathostome larvae other types of larvae were also found. After ivermectin treatments only a few cyathostome larvae were observed. It can be concluded that benzimidazoleresistance of cyathostomes is very common and widespread in the Netherlands. This means that benzimidazoles and pro‐benzimidazoles should be excluded for strategic use in horses.

Critical tests were completed on foals (n = 15) naturally infected with benzimidazole (BZ)-resistant population-B strongyles during the period between 1981 and 1987. Thiabendazole at a dosage of 44 mg/kg was tested in 8 foals, oxfendazole at 10 mg/kg was tested in 4 foals, and phenothiazine at 55 mg/kg, cambendazole at 20 mg/kg, and fenbendazole at 5 mg/kg were tested in 1 foal each. Efficacies of thiabendazole, cambendazole, and fenbendazole against the 5 species of BZ-resistant small strongyles (Cyathostomum catinatum, Cyathostomum coronatum, Cylicocylus nassatus, Cylicostephanus goldi, and Cylicostephanus longibursatus) were partial. Removals in the aggregate averaged 48%, 52%, and 68%, respectively, indicating continued resistance of the 5 species of small strongyles to thiabendazole, cambendazole, and fenbendazole. In contrast, oxfendazole was efficacious, removing an aggregate average of 95% of the 5 BZ-resistant species of small strongyles in the 4 foals. This apparent reversion to susceptibility to oxfendazole may be attributable to paucity of reference data (1 test foal) done in 1976. All 5 species of the BZ-resistant small strongyles had cross resistance to phenothiazine (38% aggregate removal), whereas 9 of the BZ-susceptible species were effectively (99%) removed. This suggests a similar mode of action between phenothiaznie and the BZ compounds.

Cambendazole 10(-4) M significantly reduced the level of glycogen in both the parasites. Lactic acid level was found enhanced. Oxygen consumption was suppressed by 63 and 94% in A. galli and H. gallinae, respectively, by 10(-4) M cambendazole. Haloxon did not cause any significant change in glycogen and lactic acid level in either parasite, but reduced oxygen consumption by 23 and 31% in Ascaridia galli and Heterakis gallinae, respectively.

The past two decades have seen some remarkable developments in anthelmintic chemotherapy in clinical medicine. Whereas praziquantel has revolutionized the management of many cestode and trematode infections, Gordon Cook explains how the introduction of the benzimidazoles — most importantly thiabendazole, mebendazole and recently albendazole (flubendazole, cambendazole, ciclobendazole, and triclabendazole have also been used on a very limited scale) — has had a major impact upon the safe and effective management of several important intestinal and systemic nematode and, to a leser extent, cestode infections.

Benzimidazole resistant strains of Haemonchus contortus and Ostertagia spp were subjected to selection pressure over five laboratory generations with the recommended dose rates of either cambendazolc, oxfendazole or morantel. A change in response, with larger residual worm burdens remaining after treatment at the fifth generation, was shown for both cambendazole and oxfendazole against both species of nematode. No change in response against either species was shown for morantel. The results are discussed in terms of the problem associated with inefficient removal of the adult parasites after treatment.

Electronic measurements of the motility of third stage larvae of a susceptible and a levamisole/ benzimidazole-resistant strain of Haemonchus contortus were made after incubation in solutions of anthelmintics for 24 h. Results confirmed the resistance to benzimidazoles, but failed to show differences in response to levamisole. Visual observations of paralysis of first and third stage larvae in solutions of levamisole also failed to show significant differences between the two strains. The tests as conducted failed to demonstrate levamisole resistance, suggesting that nematode strains may vary in their mechanisms of resistance to levamisole.

The prevalence of benzimidazole-resistant small strongyles was determined in a survey, conducted on 14 thoroughbred studs, which compared the faecal egg counts of groups of horses before and after treatment with the recommended doses of cambendazole (20 mg kg −1 b.w.) or febantel (6 mg kg −1 b.w.). Benzimidazole-resistant cyathostomes were found on all farms examined. Pyrantel pamoate (19 mg kg −1 b.w.), oxibendazole (10 mg kg −1 b.w.) and ivermectin (0.2 mg kg −1 b.w.) reduced the strongyle egg counts on these studs by 97–100% at 2 weeks post-treatment. However, 6 weeks after dosing the reduction of the strongyle egg output had decreased to an average of 67.8% (8.7–97.1%) with pyrantel pamoate and 51.2% (0–95.8%) with oxibendazole, whereas ivermectin still suppressed the egg counts by 98.2% (95–100%).

Rabbits infected with the ruminant parasites Trichostrongylus axei and T. colubriformis were administered eight drugs (phenothiazine, thiabendazole, haloxon, cambendazole, mebendazole, levamisole, fenbendazole, and oxibendazole) at dose rates known to be highly effective as anthelmintics in ruminants. All but phenothiazine and thiabendazole were highly active against adult T. colubriformis; mebendazole, levamisole, and fenbendazole were highly active against T. axei. When the dose rates of thiabendazole, haloxon, cambendazole, and oxibendazole were doubled, all but haloxon were highly active against T. axei adults. Efficacy against 3 and 10-day old worms was generally poor; oxibendazole showed best overall activity.

Fumarate reductase activity in a thiabendazole-resistant strain of Haemonchus contortus was found to be significantly lower than that from a susceptible strain. However, the fumarate reductase activity in a mebendazole-resistant strain did not differ from that in the susceptible strain, even though it was cross-resistant to thiabendazole. Published reports of fumarate reductase activity in strains of H. contortus susceptible or resistant to benzimidazoles were reassessed. A second, unrelated Australian thiabendazole-resistant strain also proved to have significantly diminished fumarate reductase activity, whereas two American strains, one resistant to thiabendazole and one to cambendazole, possess fumarate reductase activities indistinguishable from corresponding susceptible strains. It therefore appears that the phenomenon of benzimidazole resistance cannot be generally correlated with diminished fumarate reductase activity, although in the specific case of the Australian thiabendazole-resistant strains it may be a contributory factor.

The binding and inhibitory properties of 11 benzimidazoles for bovine brain tubulin were investigated. The effects of the benzimidazoles on the initial rates of microtubule polymerization were determined by a turbidimetric assay. The median inhibitory concentrations (I50) for nocodazole, oxibendazole, parbendazole, mebendazole and fenbendazole ranged from 1.97 . 10(-6) to 6.32 . 10(-6) M. Benomyl, cambendazole and carbendazim had I50 values from 5.83 . 10(-5) to 9.01 .10(-5) M. Thiabendazole had an I50 value of 5.49 . 10(-4) M. Inhibitor constants (Ki) were determined by the colchicine binding assay. Oxibendazole, fenbendazole, and cambendazole had Ki values of 3.20 . 10(-5), 1.73 . 10(-5) and 1.10 . 10(-4) M, respectively. Oxibendazole and fenbendazole were competitive inhibitors of colchicine. In contrast, cambendazole was a noncompetitive inhibitor of colchicine. The ability of these benzimidazoles to inhibit microtubule polymerization and the mode of action for the anthelmintic benzimidazoles is discussed.

Comley John C. W. and Wright Spdenis J. 1981. Succinate dehydrogenase and fumarate reductase activity in Aspiculuris tetraptera and Ascaris suum and the effect of the anthelmintics cambendazole, thiabendazole, and levamisole. International Journal for Parasitology11: 79–84. Succinate dehydrogenase and fumarate reductase activities from a particulate fraction of A. tetraptera and a soluble extract of A. suum have been determined using spectrophotometric methods. Fumarate reductase activity in A. suum could only be detected anaerobically. Succinate dehydrogenase activity from A. suum was partially characterized and shown to exist in several multimolecular forms (isoenzymes). The in vitro effect of the anthelmintics cambendazole, thiabendazole and levamisole on succinate dehydrogenase and fumarate reductase activity from the above nematodes are described. Significant inhibition of fumarate reductase activity of both nematodes was only achieved using 5 mM levamisole and 1 mM thiabendazole. After in vivo anthelmintic treatment of A. tetraptera only thiabendazole significantly inhibited fumarate reductase. It is suggested that the succinate dehydro-ogenase-fumarate reductase complex in these nematodes is unlikely to be the primary site chemotherapeutic attack for any of the anthelmintics tested.

In order to confirm benzimidazole resistance as recommended at a workshop of the Commission of the European Communities the isolate 'E' of cyathostome strongyles originating from a stud where benzimidazole resistance had been demonstrated by egg hatch tests and by egg count reduction tests was investigated in two series of critical tests. Each of 11 foals reared strongyle-free was infected with 130,000 third stage cyathostome larvae. One animal remained untreated, two pairs of foals were treated with paste formulations of the (pro)benzimidazoles cambendazole (20 mg/kg bodyweight) or febantel (6 mg/kg bodyweight) and two groups of three foals were given pastes containing the non-benzimidazole drugs pyrantel pamoate (19 mg/kg bodyweight) or ivermectin (0.2 mg/kg bodyweight) either at 101 days (trial 1) or at 59 to 62 days (trial 2) after infection. Strongyles were counted in faecal samples collected daily between treatment and post mortem examination five or seven days later and worm burdens were counted in the intestinal contents and mucosal digests. Nine species of the cyathostome subfamily were found in the infected foals. The numbers of luminal stages were reduced by only 3.1 and 20.2 (mean 7.9) per cent by cambendazole and by 13.6 and 32.8 (mean 21.3) per cent by febantel in the individual animals. However, pyrantel pamoate (93.6 to 98.2, mean 96.3 per cent reduction) and ivermectin (100 per cent reduction) were highly effective. These trials provide the first report of benzimidazole resistant Cylicostephanus poculatus anywhere in the world and demonstrate (pro)benzimidazole resistance in seven other species for the first time in Europe.

Treatment of rats infected with Nippostrongylus brasiliensis with a single, oral therapeutic dose of the anthelmintic benzimidazole carbamates oxfendazole or mebendazole resulted, 24 hr later, in a marked reduction (60–90%) in the secretion of a low molecular weight acetylcholinesterase from the parasites when they were incubated in vitro . This effect coincided with the expulsion of parasites from the host as a result of the therapy. When parasites were incubated in vitro with 0.1 mM oxfendazole, mebendazole, flubendazole, parbendazole, cambendazole or thiabendazole a similar effect was observed; with oxfendazole and mebendazole the effect was apparent within 1 hr and lasted for at least 4hr after removal to fresh, drug-free medium. Whether treated in the host or in vitro the reduction in secretion was balanced by an equivalent rise in acetylcholinesterase activity within the parasites. It is suggested that the inhibition of protein secretion may be a specific manifestation of a general effect of these compounds on microtubule function.

Cambendazole (CBZ), fenbendazole (FBZ), oxfendazole (OFZ) and thiabendazole (TBZ) all inhibited the fumarate stimulated oxidation of NADH in Haemonchus contortus mitochondria. These observations plus the phenomenon of cross resistance to benzimidazoles suggested that the different benzimidazole anthelmintics affect parasitic helminths in a similar manner. The variation in efficiency and spectrum of activity may therefore be due to differences in their pharmacokinetic behaviour. To test this hypothesis, the magnitude and duration of concentrations of TBZ, FBZ and OFZ in plasma and other body compartments after administration were compared with their effectiveness against parasites. The effects of similar doses against benzimidazole-resistant. Trichostrongylus colubriformis and H. contortus were found to correlate with the period high plasma concentrations were maintained. Further evidence of this relationship was obtained by infusion or multiple drenching of TBZ to cattle harbouring arrested Ostertagia ostertagi larvae, so as to maintain high circulating concentrations for an extended period. This resulted in the removal of 90% of the arrested larvae, whereas TBZ as normally administered is considered quite ineffective against these larvae. These observations suggest that the spectrum and effectiveness of benzimidazoles may be improved by extending the period during which parasites are exposed to toxic concentrations.

Extract Cambendazole, isopropy1 2-(4-thiazoly1)-5-benzimidazolecarbamate, has been reported to be a highly efficient anthelmintic against gastro-intestinal nematodes of cattle (Egerton et al., 1970; Baker and Walters, 1971; Ciordia and McCampbell, 1971; Benz, 1971a, b; Restani, 1971). Efficacy against the cattle lungworm, Dictyocaulus viviparus, has also been reported as high (Rubin, 1972; Gibbs and Gupta, 1972; Baker et al., 1972). This paperreports the results of four controlled critical efficacy trials with cambendazole against naturally acquired nematode infections in cattle.

Effects of cambendazole and mebendazole on the respiratory metabolism of the anterior portion of Moniezia expansa were investigated in vitro . Anaerobically and in the presence of glucose, both drugs inhibited glucose uptake and increased glycogen utilisation. They reduced succinate production, by inhibiting fumarate reductase and (in the case of cambendazole) phosphoenolypyruvate carboxykinase activities, and increased lactate production. The additional lactate formed was accumulated in the worms. The drugs diminished ATP synthesis and/or turnover of adenine nucleotides. Aerobically, the drugs exerted similar effects on glucose uptake, glycogen utilisation and adenine nucleotides but the formation of end products was unaffected. Hexokinase and phosphofructokinase activities were inhibited by the drugs in vitro , but were not inhibited in extracts of parasites preincubated with the drugs.

Investigations have been carried out on the multimammate rat (Mastomys natalensis), orally infected with 1000 third stage larvae of Ancylostoma caninum per animal, to evaluate the larvicidal efficacy of anthelmintics in this paratenic host. The oral or subcutaneous administration of 19 anthelmintics and filaricides revealed good activity for levamisole, cambendazole, and mebendazole against 15-day-old Ancylostoma larvae which were located in the muscular tissue. Similarly, good results were obtained with levamisole and cambendazole against the migrating third stage larvae, by treatment two to six days after infection. The benzimidazole derivatives, thiabendazole, oxibendazole, parbendazole, and fenbendazole showed marked activity only at high dosage rates. The anthelmintics methyridine, amoscanate, pyrantel tartrate, morantel tartrate; the microfilaricidal organophosphates dichlorvos, fenthion, and haloxon; as well as the micro- or macrofilaricidal drugs diethylcarbamazine, nitrofurantoin, nifurtimox, suramin sodium, and thiacetarsamide sodium failed to show larvicidal activity even in high dosages. The average larval recovery rate after oral infection with 1000 third stage larvae, in untreated control animals, was 14.85%.

SUMMARY The anthelmintic action of cambendazole against 10-day-old Hyostrongylus rubidis and Oesophagostomum spp. larvae was evaluated in a controlled test using artificially-infected pigs. Twenty-two pigs divided into four groups were orally infected with 3000 H. rubidis and 38,000 Oesophagostomum spp. larvae. Three groups of pigs were given cambendazole orally at dose rates of 15, 20 and 25 mg/kg bodyweight respectively 10 days after infection. The fourth group remained untreated as controls. Two control “indicator” pigs were killed on the day of treatment to determine the number and location of the larvae. Anthelmintic efficiency was estimated by comparing faecal egg counts and numbers of worms in the stomach and large intestine at post-mortem examination 46 days after infection. At the dose rates given cambendazole had little or no effect against immature 10-day-old Hyostrongylus larvae found both in the stomach wall and lumen, or against 10-day-old Oesophagostomum spp. larvae, the majority of which were found to be in the fourth stage in the large intestinal contents and in the third and fourth stages in the large intestinal wall.

O autor tratou 50 pacientes portadores de infestações parasitárias múltiplas (ascaríase, tricocefalfase, ancilostomíase e estrongiloidíase) com uma nova associação medicamentosa composta de Cambendazol e Mebendazol Os enfermos foram divididos em dois grupos: Grupo A: composto por 25 doentes adultos e portadores de ascaríase, tricocefalfase e ancilostomíase em 100% dos casos e em 80% havia estrongiloidíase associada (20 pacientes). A associação medicamentosa foi administrada na forma de comprimidos, na seguinte posologia: Cambendazol: 3mg x Kg de peso x 3 dias Mebendazol: 5mg x Kg de peso x 3 dias Tanto para o diagnóstico, como para o controle de cura parasitológica, utilizamos as técnicas de Hoffman, Baerman-Moraes ea de Willis. Obtivemos cura parasitológica em 96% para ascaríase, 90% para estrongiloidíase, 72% para tricuríase e 60% para ancilostomíase. Em quatro doentes (16%) surgiram sintomas colaterais, tais como, náuseas, cefaléia e epigastralgia. Grupo B: Também constituído por 25 enfermos, todos crianças e portadoras de ascaríase, tricocefalfase, ancilostomíase e estrongiloidíase em 100% dos casos. Estes doentes receberam a referida associação, na forma de suspensão na seguinte dose: Cambendazol: 3mg x Kg de peso em dose única Mebendazol: 5mg x Kg de peso em dose única. Efetuamos as mesmas técnicas para o diagnóstico e controle de cura parasitológica, conforme referido no Grupo A. Conseguimos as seguintes taxas de cura parasitológica: estrongiloidíase - 96%; ascaríase - 92%; tricuríase - 68% e ancilostomíase - 60%. Apenas três crianças (12%) referiram náuseas, cefaléia e sensação de plenitude pós- prandial.The author report his experience with a new drug combination: Cambendazole and Mebendazole, in multiple helminthiasis infections, including strongyloidiasis, in 50 patients, divided in two groups: Group A: Composed of the 25 patients adults, who received the new drug in a dosage of: Cambendazole - 3 mgm x Kgm of body weight, and Mebendazole - 5 mgm x Kgm of b.w., during three consecutive days. Group B - Composed of the 25 children who received the new drug-compound in a single dose: Cambendazole - 3 mgm x Kgm of b.w., and Mebendazole - 5 mgm x Kgm of b.w. After treatment, parasitological cure rate obtained was: Group A - Roundworm :96% (24 cases) Whipworm: 72% (18 cases) Hookworm: 60% (15 cases) Strongyloidiasis: 90% (18 cases) Group B - Roundworm:92% (23 cases) Whipworm: 68% (17 cases) Hookworm: 60% (15 cases) Strongyloidiasis: 96% (24 cases) In general, the new drug was well tolerated by all patients, and no important side - effects were observed.

The susceptibility of a known thiabendazole-resistant population of small strongyles to anthelmintics of both benzimidazole and non-benzimidazole groups, was determined. In the first study, 42 horses infected with thiabendazole-resistant small strongyles were allocated to 6 groups. Treatment groups received one of the following anthelmintics: mebendazole, febantel, febantel plus trichlorphon, morantel tartrate, or a combination of thiabendazole, piperazine and trichlorphon. Morantel tartrate and the thiabendazole/piperazine/trichlorphon combination produced highly significant (p less than 0.001) reductions in faecal strongyle egg counts 20 days post-treatment. Mebendazole, febantel and febantel plus trichlorphon failed to reduce strongyle egg counts significantly. Larval culture and differentiation indicated that in all cases of anthelmintic failure, small strongyles of the sub-family Cyathostominae were involved. Eighteen horses from groups in which treatment had failed were re-allocated to 3 groups. Treatment with either morantel tartrate or haloxon was highly efficient in reducing faecal strongyle egg counts. In the final study, fifty-four horses, infected with benzimidazole-resistant small strongyles were allocated to 10 groups. On day zero, each treatment group received one of the following anthelmintics: thiabendazole, cambendazole, mebendazole, oxibendazole, piperazine, thiabendazole/piperazine, cambendazole/piperazine, mebendazole/piperazine or oxibendazole/piperazine. Oxibendazole, piperazine and the benzimidazole/piperazine combinations produced highly significant reductions in faecal strongyle egg counts 20 days post-treatment (p less than 0.001). When administered alone, benzimidazole anthelmintics failed to reduce strongyle egg counts significantly, with the exception of oxibendazole. Larval culture and differentiation indicated that in all cases of anthelmintic failure, the species involved were small strongyles of subfamily Cyathostominae. There was no significant increase in benzimidazole resistance level (based on in vitro assay) as a result of drug treatment, over one generation.

SUMMARY: Thiabendazole and cambendazole induced mitotic arrest and isogenic diploid formation through chromosome doubling in amoebae of the cellular slime mould Dictyostelium discoideum grown either axenically or in a bacterial suspension. The effect of nocodazole on axenically grown cells was similar to that of thiabendazole and cambendazole, but with cells grown on bacteria nocodazole was a much less effective inducer of mitotic arrest and did not lead to isogenic diploid formation. Benomyl, the active ingredient of ben late, had little or no effect on the induction of mitotic arrest and was a poor inducer of isogenic diploids in cells grown either axenically or on bacteria. All four benzimidazole derivatives were effective in haploidizing pre-existing diploids.

Systematic dose- and time-response trials were first conducted to determine a treatment regimen with cambdendazole (CBZ, 2-[4′-thiazolyl]-5- iso propoxycarbonylaminobenzimidazole) that would be therapeutically effective against adult Trichinella spiralis in experimentally-infected mice. CBZ proved to be highly effective against adult Trichinella in a 3-day treatment course during the enterai phase of experimental trichinellosis. When treatment began 72 h after the mice were inoculated with parasites, the number of adult worms recovered from the host intestine was greatly reduced by twice-daily oral doses of CBZ at 25 mg kg −1 body wt. The efficacy of the divided daily oral dosage treatment regimen that was effective against adult T. spiralis during the enteral phase of infection was then tested during the parenteral phases of trichinellosis. Gavage administration of CBZ at 25 mg kg −1 bis m die for 3 consecutive days during the invasive (days 14–16) and encystment (days 28–30) phases of infection significantly reduced (29 and 90 %, respectively) the number of larvae subsequently recovered from the host musculature on day 44 postinoculation.

An in vitro egg development assay was used to test the resistance of eggs from a benzimidazole susceptible and a resistant strain of Haemonchus contortus to four benzimidazoles. Storage of eggs contained in faecal samples at 4°C for four, 24 or 72 hours did not appear to impair the results from the in vitro egg development assay or alter the LD50. Storage for one week, however, proved to be lethal for the eggs. The average LD50 values for thiabendazole, albendazole, mebendazole and cambendazole were 0·06, 0·07, 0·96 and 2·47 ppm for the susceptible strain. For the resistant strain the values averaged 0·26, 0·24, 1·07 and 5·11 ppm.

Two trials were conducted to determine the effect of cambendazole against natural infections of the swine kidneyworm, Stephanurus dentatus, in sows. In the first trial, nine sows were given a single dose of 20 mg cambendazole/kg body weight, in the feed, and eight sows were not treated. In the second trial, five sows were given 40 mg cambendazole/kg body weight and four were untreated. Urine volume, S. dentatus eggs per milliliter of urine, egg hatchability, and larval survival to the third stage were determined pre and post treatment. Adult kidneyworms were counted at necropsy, 14 days after treatments. Only a temporary decline in egg hatchability was observed on the day after treatment in each trial, and cambendazole was not found to be effective against adults of S. dentatus.

Summary Horses with a history of frequent benzimidazole (BZD) treatment were used in a trial to assess the effectiveness of oxibendazole (OBZ). Initial investigations established that these animals were infected with small strongyles resistant to thiabendazole (TBZ), mebendazole (MBZ), cambendazole (CBZ), oxfendazole (OXF) and fenbendazole (FBZ). The herd was subsequently divided into four groups and received TBZ, CBZ, OBZ, or no treatment. OBZ effectly reduced fecal egg counts. Similar reductions were not observed with TBZ or CBZ.

Gavage administration of cambendazole at 50 mg/kg was found to eliminate a 7 hour Trichinella spiralis infection in mice. Cambendazole was also found to be highly active against the muscle phase of trichinosis. Partial activity was also indicated against migratory larvae and adult worms. Cambendazole appears to have a sterilising effect on adult T. spiralis. It is postulated that cambendazole has potential therapeutic value.

An outbreak of dictyocauliasis among a captive herd of black-tailed deer fawns (Odocoileus hemionus columbianus) occurred in January, 1971. A transient decrease in output of Dictyocaulus viviparus larvae in feces occurred after treatment with levamisole hydrochloride given as a drench at the rate of 16 mg/kg of body weight. Lungworm larvae were not recovered in feces 6 days after cambendazole, 2-(4-thiazolyl)-5-isopropoxycarbonylaminobenzimidazole, was given as a drench at 40 and 50 mg/kg of body weight. Larvae were again recovered in feces from these fawns between post-treatment days 15 and 23. Output of larvae in feces increased when fawns were confined on a contaminated grass pasture that was intensively grazed. Deteriorating physical condition of the fawns necessitated additional treatment with cambendazole and movement to a woodlot where reinfection by ingestion of larvae was probably minimized. A noninfected deer was placed on the contaminated pasture 75 days after the infected herd was removed. Aft...

Cambendazole, 5-isopropoxycarbonyl-amino-2-(4-thiazolyl)bcuzimidazole, was given at dosages of 11 to 44 mg./kg. to cattle with naturally acquired helminth infectious. A single oral dose of 22 mg./kg. was highly effective in removing mature Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Strongyloides and Oesophagostomum, as well as various lumen dwelling immature trichostrongylids.

Cambendazole was used for the treatment of strongyloidiasis in 40 hospitalized patients, given in a single dose of 5 mg/kg body weight. According to the criteria adopted, parasitological cure was obtained in 100% of cases. Side effects were negligible, and did not require interruption of treatment. We therefore conclude that cambendazole is at present the most effective agent for the therapy of human strongyloidiasis.

A new anthelmintic 5-isopropoxy- carbonylamino-2-(4-thiazolyl)benzimidazole, was highly effective against immature and mature helminths of sheep, when given orally at 20 mg./kg. Helminths removed by this dosage, or even lower dosages, included the genera Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Ncmatodirus, Strongyloides and Chabertia.