Benzimidazole Drugs Research Articles

Characteristics of the K+-competitive H+,K+-ATPase inhibitor AZD0865 in isolated rat gastric glands

The gastric H+,K+-ATPase of the parietal cell is responsible for acid secretion in the stomach and is the main target in the pharmacological treatment of acid-related diseases. Omeprazole and other benzimidazole drugs, although having delayed efficacy if taken orally, have high success rates in the treatment of peptic ulcer disease. Potassium competitive acid blockers (P-CAB) compete with K+ for binding to the H+,K+-ATPase and thereby they inhibit acid secretion. In this study, the in vitro properties of AZD0865, a reversible H+,K+-ATPase inhibitor of gastric acid secretion, are described. We used a digital-imaging system and the pH sensitive dye BCECF to observe proton efflux from hand-dissected rat gastric glands. Glands were stimulated with histamine (100 microM) and exposed to a bicarbonate- and Na+-free perfusate to induce an acid load. H+,K+-ATPase inhibition was determined by calculating pHi recovery (dpH/dT) in the presence of omeprazole (10-200 microM) or AZD0865 (0.01-100 microM). The efficacies of both drugs were compared. Our data show that acid secretion is inhibited by both the proton pump inhibitor omeprazole and the P-CAB AZD0865. Complete inhibition of acid secretion by AZD0865 had a rapid onset of activation, was reversible, and occurred at a 100-fold lower dose than omeprazole (1 microM AZD0865 vs. 100 microM omeprazole). This study demonstrates that AZD0865 is a potent, fast-acting inhibitor of gastric acid secretion, effective at lower concentrations than drugs of the benzimidazole class. Therefore, these data strongly suggest that AZD0865 has great potential as a fast-acting, low-dose inhibitor of acid secretion.

Efficacy of Orally Administered Febantel against Monogenean Heterobothrium okamotoi infection of Cultured Tiger Puffer Takifugu rubripes

We examined the efficacy of febantel against the infection of the diclidophorid monogenean Heterobothrium okamotoi in cultured tiger puffer Takifugu rubripes. Febantel is a prodrug of fenbendazole, a benzimidazole drug, which is widely used in the field of veterinary medicine. Febantel was metabolized to fenbendazole in tiger puffer just like veterinary animals for oral administration. At the doses of 12.5 mg/kg and 25 mg/kg for 5 days, and 50 mg/kg for 3 days, 88%, 96% and 94%, respectively, of mature worms, and 97%, 95% and 97%, respectively, of immature worms were eradicated at 22-23°C. These results suggest that febantel has high anti-H. okamotoi activity.

Determination of the relative amounts of three crystal forms of a benzimidazole drug in complex finished formulations by FT-Raman spectroscopy

A 5% (m/m) premix for animal use was quantitatively characterized for the polymorph composition of its benzimidazole drug substance. Raman spectra of reference samples (pure polymorphs A, B and C in lactose at a concentration of 5%, m/m) were compared with the spectra of benzimidazole samples with a known polymorph composition and with the spectra of uncharacterized premixes. The raw intensities of 78 selected wavenumbers were vector-normalized and application of stepwise linear regression models estimated the relative quantities of the benzimidazole-drug polymorphs A, B and C in the different samples. Modelling results of the samples with known polymorph composition were in compliance with the expected concentrations, validating the proposed methodology. The benzimidazole drug substance in the premixes was predominantly polymorph B. Although statistically not significant, some traces of polymorph A could not be ruled out. Similar analyses were performed to evaluate the solid-state stability of the benzimidazole drug substance in another drug formulation, i.e. a suspension-emulsion. Suspension-emulsions originally determined as containing polymorph B benzimidazole drug substance were stored for 12 months at 25 °C/60%RH. FT-Raman spectroscopy revealed that no polymorph transformations occurred during this storage.

Mutation detection on isotype-1 β tubulin genes of Haemonchus contortus resistant strain to benzimidazole using single strand conformation polymorphism

Evidence of anthelmintic resistance of Haemonchus contortus to benzimidazole groups based on Larval development assay (LDA) and Fecal egg count reduction test (FECRT) test has been reported in some areas in Indonesia. Studies on sheep parasite H. contortus have shown that resistance to benzimidazole drugs is correlated with selection for individuals in the population possesing a spesific isotype-1 β tubulin gene. The aim of this study was to determine mutation on central part of isotype-1 β tubulin gene of benzimidazole resistant strain H. contortus using Single Strand Conformation Polymorphism (SSCP). H. contortus worms were isolated from four sheep from two government farms that resistance to benzimidazole have been occurred (SPTD Trijaya, Kuningan, West Java and UPTD Pelayanan Kesehatan Hewan, Bantul, Yogyakarta) and one sheep that susceptible from Cicurug, Bogor, West Java as a kontrol. Resistance status to benzimidazole was reexamined individually with LDA and FECRT before sheep slaughtered. DNA was extracted from female H. contortus worms . A fragment of 520 bp isotype- 1 β tubulin gene was amplified using Polymerase chain reaction ( PCR) and then analyze using SSCP. The results showed that there were polymorphism in isotype-1 β tubulin gene among H. contortus susceptible (Cicurug, Bogor, Jawa Barat) and two H. contortus resistant strains from SPTD Trijaya, Kuningan, West Java and UPTD Pelayanan Kesehatan Hewan, Bantul, Yogyakarta. Mutation occurred in the different nucleotide of the two resistant strain. Key Words: Haemonchus contortus , Benzimidazole, Isotype-1 β tubulin gene, SSCP

Multi-residue method for the determination of benzimidazoles in bovine liver

A method has been developed to analyse for 12 benzimidazole drug residues in bovine liver. Liver samples were extracted with ethyl acetate, sample extracts were defatted with hexane and cleaned-up by automated SPE on C 18 solid phase extraction cartridges. Aliquots of the extracts were analysed by LC with UV detection (298 nm). The method was validated in bovine liver, according to the criteria defined in Commission Decision 2002/657/EC. The decision limit (CC α) was between MRL + 12% and MRL + 25% and the detection capability (CC β) was between MRL + 25% and MRL + 45% for the range of benzimidazoles investigated. The results of the inter-assay study, which was performed by fortifying bovine liver samples ( n = 6) in three separate assays, show the mean recovery to be between 60% and 100% for albendazole sulphoxide, albendazole sulphone, thiabendazole, oxfendazole/fenbendazole sulphoxide, hydroxy-mebendazole, fenbendazole sulphone, oxibendazole, mebendazole and flubendazole. Lower mean recovery was obtained for amino-flubendazole and albendazole (approximately 50%) and amino-albendazole sulphone (approximately 25%). The precision of the method, expressed as R.S.D. values for the within-laboratory repeatability, was generally below 25%.

Differential Kinetochore Requirements for Establishment and Maintenance of the Spindle Checkpoint Are Dependent on the Mechanism of Checkpoint Activation in Saccharomyces cerevisiae

The spindle checkpoint in the yeast Saccharomyces cerevisiae is an intracellular signal transduction pathway comprised of two branches that inhibit two different mitotic transitions in cells treated with benzimidazole drugs such as nocodazole. The kinetochore is an integral component of the MAD2 branch of the spindle checkpoint pathway. Current models propose that the kinetochore is required for both the establishment and maintenance of the spindle checkpoint but a role for the kinetochore in the maintenance of spindle checkpoint in yeast has never been directly tested. We used a temperature sensitive ndc10-1 mutant to inactivate kinetochores before and after arresting cells in mitosis to determine the role of kinetochores in the establishment and maintenance of the spindle checkpoint. We show that both establishment and maintenance requires kinetochore function in response to spindle damage induced by benzimidazole drugs. Excess expression of the Mps1 protein kinase causes wild type cells and ndc10-1 cells to arrest in mitosis. Unlike the spindle checkpoint arrest activated by benzimidazoles, this arrest can be maintained independently of kinetochores. The arrest induced by excess Mps1p is independent of BUB2. Therefore, mitotic arrest induced by excess Mps1p expression is due to the action of the MAD2 branch of the spindle checkpoint pathway and excess Mps1p acts downstream of the kinetochore.

Characterisation of a beta-tubulin gene from the monogenean parasite, Gyrodactylus salaris Malmberg, 1957.

The cDNA and two partial genomic sequences of beta-tubulin genes have been isolated from the monogenean parasite Gyrodactylus salaris. The cDNA sequence is not represented by either of the genomic sequences, implying that at least three isotypes of the gene exist in G. salaris. The sequences show regions of high homology with other helminth beta-tubulin genes. This represents the first isolation of a beta-tubulin gene from a monogenean and contributes to the overall characterisation of these genes within the helminths. This is an important area, as anthelmintic resistance is increasing against benzimidazole drugs that target the beta-tubulin gene. Benzimidazole drugs have been tested successfully against Gyrodactylus parasites, but their use is not widespread. Should it increase, analysis of the beta-tubulin gene may provide a tool for monitoring resistance development and improving management practises. Use of the beta-tubulin gene in the identification of Gyrodactylus species may prove complex due to the presence of different isotypes.

Assaying the spindle checkpoint in the budding yeast Saccharomyces cerevisiae.

The spindle checkpoint is assayed in Saccharomyces cerevisiae using several criteria. Sensitivity to benzimidazole drugs is assayed in cells grown in liquid medium and cells grown on solid medium on petri plates. Cell cycle delays are measured using cells synchronized by treatment with mating pheromone alpha-factor, and the population is monitored by flow cytometry measuring DNA content in cells. There are two different transitions that are monitored, and cytological assays for individual cells and biochemical assays for populations of cells are presented. The metaphase to anaphase transition is assayed by monitoring sister chromatid separation using GFP-tagged chromosomes, Pds1 stability using immunofluorescence, and Mcd1/Scc1 association with chromatin using chromosome spreads. Pds1 and Mcd1/Scc1 stability is measured in populations by Western blots. The exit from mitosis is monitored by Cdc14 immunofluorescence and Clb2 Western blots.

The effects of albendazole and its metabolites on hepatic cytochromes P450 activities in mouflon and rat

Albendazole (ABZ) is a benzimidazole anthelmintic widely used in veterinary medicine. The effects of ABZ on cytochromes P450 were investigated in primary cultures of mouflon ( Ovis musimon) and rat ( Rattus norvegicus) hepatocytes. Besides ABZ, its two main metabolites (albendazole-sulphoxide, ABZSO and albendazole-sulphone, ABZSOO) were tested to clarify which compound is responsible for the induction potency of this benzimidazole drug. After 48 h incubation of hepatocytes with benzimidazoles (0.2–25 μM), ethoxyresorufin O-deethylation (EROD) and benzoxyresorufin O-dearylation (BROD) were measured and the P4501A and 3A protein levels were determined by Western blotting. All benzimidazoles provoked a significant increase of EROD and BROD activities in rat hepatocytes. ABZSO and ABZSOO seemed to be responsible for the induction effect of ABZ on P450s in rat. In mouflon, no pharmacologically significant induction of EROD and BROD activities by benzimidazoles tested was observed. From this point of view, anthelmintic therapy of mouflons with ABZ seems to be safe.

Effect of clotrimazole on microsomal metabolism and pharmacokinetics of albendazole.

Albendazole is a broad spectrum anthelmintic drug widely used in human and veterinary medicine. Intestinal and hepatic albendazole metabolism leads to albendazole sulfoxide (active metabolite) and albendazole sulfone (inactive metabolite) formation. Microsomal sulfonase activity can be abolished by in-vitro interaction with clotrimazole and pharmacokinetic studies confirm this interaction. After albendazole incubation, albendazole sulfone formation was completely inhibited by 50 microM clotrimazole in intestinal incubations and a 50% inhibition was observed in hepatic incubations. The lower inhibition constant (K(i)) value observed in the intestinal incubations (9.4 +/- 1.0 microM) compared with the hepatic counterparts (23.3 +/- 15.8 microM) pointed to a greater affinity of the enzymatic systems in the intestine. Regarding the formation of albendazole sulfoxide, an inhibition close to 50% was observed in liver and intestine at 10 microM clotrimazole. The pharmacokinetic parameters obtained following the oral co-administration of albendazole sulfoxide and clotrimazole corroborated the in-vitro inhibition of albendazole sulfone formation, since the ratio of the area under the plasma concentration-time curves for the sulfoxide/sulfone (AUC(ABZSO)/AUC(ABZSO2)) was significantly higher (38.1%). In addition, the AUC and C(max) for albendazole sulfone were significantly lower. The effect of clotrimazole was also studied after prolonged treatment. Hepatic microsomal metabolism of albendazole was induced after 10 days of clotrimazole administration, with significant increases in formation of albendazole sulfoxide (40%) and sulfone (27%). These results offer further insight into the metabolism of benzimidazole drugs and highlight the difficulty involved in human therapy with these anthelmintics, since after prolonged treatment the drug interactions are affected differentially.

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.

Development and optimisation of a method for the extraction of benzimidazoles from animal liver using supercritical carbon dioxide

A multi-residue supercritical fluid extraction (SFE) method has been developed for extraction of 10 benzimidazole drug residues from animal liver. The method may be applicable also to some other benzimidazoles, but recovery was not quantitative. An oven dried sample-hydromatrix mixture was packed into an extraction vessel and rehydrated with water (1 ml). The sample was extracted at 80 °C using 60 l unmodified supercritical carbon dioxide (690 bar). Residues were trapped off-line on a neutral alumina trap, which was eluted with methanol + water (60+40, v/v, 18 ml). Sample extracts were acidified and cleaned-up using strong cation exchange solid phase extraction. After elution, sample extracts were evaporated to dryness under nitrogen, reconstituted in 400 μl methanol + water (50+50, v/v) and analysed by HPLC with UV photodiode array detection. The method was validated using ovine liver fortified at levels of 50, 100, 250 and 500 μg kg −1 with the drugs. Mean recovery ranged between 51 and 115% for the various benzimidazoles. The intra- and inter-assay variations showed R.S.D. values of <10 and <32%, respectively. The procedure was applied, also, to avian, bovine and porcine liver, giving similar results. The validated limit of determination of the method is 50 μg kg −1.

Anthelmintic resistance in nematodes of horses.

Suppressive anthelmintic treatment strategies originally designed to control Strongylus vulgaris in horses were extremely successful in reducing morbidity and mortality from parasitic disease. Unfortunately, this strategy has inadvertently resulted in the selection of drug-resistant cyathostomes (Cyathostominea), which are now considered the principal parasitic pathogens of horses. Resistance in the cyathostomes to benzimidazole drugs is highly prevalent throughout the world, and resistance to pyrantel appears to be increasingly common. However, there are still no reports of ivermectin resistance in nematode parasites of horses despite 20 years of use. It is unknown why resistance to ivermectin has not yet emerged, but considering that ivermectin is the single most commonly used anthelmintic in horses most parasitologists agree that resistance is inevitable. The fecal egg count reduction test is considered the gold standard for clinical diagnosis of anthelmintic resistance in horses, but diagnosis is complicated by lack of an accepted standard for the performance of this test or for the analysis and interpretation of data. Presently there is very little data available on the molecular mechanisms of anthelmintic resistance in cyathostomes; beta-tubulin gene is the only anthelmintic-resistance associated gene that has been cloned. The increasingly high prevalence of anthelmintic-resistant cyathostomes must be taken into account when designing worm control programs for horses. Strategies to decelerate further selection for drug resistance thereby extending the lifetime of currently effective anthelmintics should be implemented whenever possible. Considering the nature of the equine industry in which horses often graze shared pastures with horses from diverse locations, transmission and widespread dispersal of resistant parasites is virtually assured. A proactive approach to this problem centered on understanding the molecular basis of anthelmintic resistance in cyathostomes is required if we are to expect chemical control of nematodes in horses to remain a viable element of parasite control in the future.

Sequence variation in the Trichuris trichiura β-tubulin locus: implications for the development of benzimidazole resistance

Benzimidazole resistance has evolved in a variety of organisms and typically results from mutations in the β-tubulin locus at specific amino acid sites. Despite widespread treatment of human intestinal nematodes with benzimidazole drugs, there have been no unambiguous reports of resistance. However, since β-tubulin mutations conferring resistance are generally recessive, frequencies of resistance alleles less than 30% would be difficult to detect on the basis of drug treatment failures. Here we investigate sequence variation in a 1,079 bp segment of the β-tubulin locus in the human whipworm Trichuris trichiura from 72 individual nematodes from seven countries. We did not observe any alleles with amino acid mutations indicative of resistance, and of 40 point mutations there were only four non-synonymous mutations all of which were singletons. Estimated effective population sizes are an order of magnitude lower than those from another nematode species in which benzimidazole resistance has developed ( Haemonchus contortus). Both the lower diversity and reduced population sizes suggest that benzimidazole resistance is likely to evolve less rapidly in Trichuris than in trichostrongyle parasites of livestock. We observed moderate levels of population subdivision ( Φ ST=0.26) comparable with that previously observed in Ascaris lumbricoides, and identical alleles were frequently found in parasites from different continents, suggestive of recent admixture. A particularly interesting feature of the data is the high nucleotide diversities observed in nematodes from the Caribbean. This genetic complexity may be a direct result of extensive admixture and complex history of human populations in this region of the world. These data should encourage (but not make complacent) those involved in large-scale benzimidazole treatment of human intestinal nematodes.

Prevalence of anthelmintic resistance in gastrointestinal nematodes of dairy goats under extensive management conditions in southwestern France

The occurrence of benzimidazole (BZ) and levamisole resistance was investigated in 18 randomly selected dairy goat herds located in southwestern France and characterized by extensive management. On each of the 18 farms, 45 adult goats were randomly allocated into three groups of 15 animals each: an untreated control group, a group that was orally administered fenbendazole (10 mg kg-1 body weight) and a group that received orally a levamisole drench (12 mg kg-1 body weight). Individual faecal egg counts and pooled larval cultures were done 10 days after anthelmintic treatment. Naive lambs were infected with larvae obtained from control and fenbendazole treated groups and were necropsied 35 days after infection for worm recovery. Faecal egg count reductions (FERC) were calculated for fenbendazole and levamisole and, when less than 95 per 100, were considered as indicative of anthelmintic resistance. An in vitro egg hatch test (EHT) was conducted with thiabendazole on eggs isolated from pooled faeces of fenbendazole treated goats in nine farms. Faecal egg count reductions indicated the occurrence of benzimidazole resistance in 15 out of 18 farms. Among these farms, nine had EHT values above 0.1 μg thiabendazole ml-1 confirming the benzimidazole resistance status. Levamisole resistance was detected in two farms through FECR. Based on necropsy results, the prevalence of benzimidazole resistance was higher in Trichostrongylus colubriformis, medium in Haemonchus contortus and lower in Teladorsagia circumcincta. In nine farms the benzimidazole resistance was monospecific whereas multispecific resistance was found in the six remaining farms. A negative relationship was found between FECR for fenbendazole and the average number of anthelmintic treatments given per year on the farm. Despite extensive management including a low number of treatments, the prevalence of benzimidazole resistance was very high suggesting that the repeated and sometimes exclusive use of benzimidazole drugs, even at low frequency, is probably the main cause in developing nematode resistance in dairy goat herds. The importance of other factors such as under-dosing or buying animals already carrying resistant nematodes are discussed.

Pharmacokinetic behaviour of albendazole sulphoxide enantiomers in male and female sheep.

Benzimidazole anthelmintic drugs are widely used in veterinary practice. Albendazole sulphoxide (ABZSO) is a benzimidazole drug with two enantiomers, as a consequence of a chiral centre in the sulphoxide group. The kinetics of these enantiomers were studied in male and female sheep. Plasma samples were obtained from the animals between 0.5 and 72 h after oral administration of 7.5 mg/kg of a racemic formulation of ABZSO (total-ABZSO). After a liquid-liquid extraction, the samples were analysed by HPLC to determine the concentrations of total-ABZSO and of the sulphone metabolite (ABZSO2). During the chromatographic analysis, the ABZSO peak was collected and reanalysed by an HPLC technique using a Chiral AGP column to quantify the enantiomeric proportion therein. After kinetic analysis, the AUCs obtained for the (+)-ABZSO were 5.8 and 4.0 times higher than those for the (-)-ABZSO in male and female animals, respectively. The mean residence times were 23.4 and 16.1 h for (+)-ABZSO and 22.2 and 17.4 h for (-)-ABZSO for male and female animals, respectively. The only significant difference between the sexes (p < 0.05) was in the Tmax of the (-)-ABZSO. Comparing both enantiomers within each sex, significant differences were found in all the kinetic parameters. Finally, no kinetic differences were found between sex for total-ABZSO or ABZSO2.

Multiple anthelmintic resistance in a goat herd

Anthelmintic resistance was monitored over a 30 month period within a goat herd in eastern Virginia, USA. Resistance to ivermectin, levamisole and benzimidazole drugs was detected in Haemonchus contortus using the fecal egg count reduction test (FECRT). When levamisole use was discontinued for 1 year, susceptibility to levamisole appeared to return. Although a single treatment with fenbendazole was able to reduce fecal egg counts by only 50%, two doses administered in a 12 h interval increased efficacy to 92%, however, confidence intervals indicated that resistance was still present. When fecal egg counts were determined the following year after several treatment using this protocol, the efficacy of fenbendazole had fallen again to 57% reduction in fecal egg counts. The predominant genus present in cultured composite fecal samples was Haemonchus. Trichostrongylus, Cooperia and Teladorsagia were also present in smaller numbers.

Review article: rabeprazole's tolerability profile in clinical trials.

Rabeprazole is a new member of a class of substituted benzimidazole drugs known as proton pump inhibitors. Comparative trials have demonstrated that it is at least as effective as omeprazole for the treatment of gastrooesophageal reflux disease (GERD), duodenal ulcers, or gastric ulcers. It is significantly more effective than histamine2-receptor antagonists for acid suppression, GERD healing and pain relief, and duodenal ulcer healing and pain relief. Adverse events reported during clinical trials provide an important indication of a medication's tolerability. We demonstrate that rabeprazole has a favourable adverse events profile. It is well tolerated in placebo-controlled studies and comparative trials with omeprazole and H2-receptor antagonists. Moreover, no dose adjustments are required for special populations, such as the elderly or patients with renal or mild-to-moderate hepatic disease. Adverse events data from clinical trials support the use of rabeprazole as a treatment for acid-related diseases.

Comparative efficacy of ivermectin pour-on, albendazole, oxfendazole and fenbendazole against Ostertagia ostertagi inhibited larvae, other gastrointestinal nematodes and lungworm of cattle

An experiment was conducted to evaluate the current efficacy of albendazole (ABZ), oxfendazole (OXF) and fenbendazole (FBZ) compared with ivermectin pour-on (IVM-PO) against inhibited early fourth-stage larvae (IEL 4) of Ostertagia ostertagi, other gastrointestinal nematodes and lungworm of cattle during spring in Louisiana. Twenty-five crossbred beef heifer calves of 235 kg average weight and 10–12 months of age were acquired in late winter and grazed for 9 weeks on pasture contaminated with O. ostertagi and other nematodes until May 15. The cattle were weighed and randomly allotted into 5 groups of 5 calves on May 16 (day 0) and treatments were as follows: group 1, nontreated controls (CONT); group 2, IVM-PO on mid-backline at 500 μg/kg; group 3, ABZ suspension (oral) at 10 mg/kg; group 4, OXF suspension (oral) at 4.5 mg/kg; group 5, FBZ suspension (oral) at 5 mg/kg. After treatment and confinement in separate pens for each group, approximately equal numbers of cattle from each group were necropsied daily between days 29–31. Mean numbers of O. ostertagi developmental stages present in CONT were: adult, 5234; developing (DL 4), 3130; IEL 4, 44 077. The mean percentage of IEL 4 was 84.1. Cooperia spp. were the second most prevalent in CONT (20 307) and smaller numbers of abomasal and intestinal species and Dictyocaulus viviparus were present in nearly all CONT. Percent reductions for the four compounds against O. ostertagi adult, DL 4 and IEL 4, respectively, were IVM-PO: 99.7, 98.3, 98.1; ABZ: 74.1, 76.5, 75.3; OXF: 78.5, 42.1, 32.0; FBZ: 63.6 17.7, 39.7. Efficacy of IVM-PO was greater ( P < 0.05) against all O. ostertagi stages than the benzimidazole (BZ) drugs, except for ABZ (DL 4). There were no significant differences in group means (except for C. punctata adult males, P < 0.05 lower for IVM-PO) or wide variation in reduction percentages for other abomasal and intestinal species and D. viviparus between IVM-PO and BZ drugs. The low efficacy of all three BZ drugs for O. ostertagi, but especially for OXF and FBZ, under conditions of this experiment, were suggestive of drug tolerance to dosages employed or resistance. However, problems of drug availability/concentration in the abomasum, and the factor of IEL 4 and DL 4 replacing adult worms after treatment cannot be excluded. Efficacy of the BZ drugs against all other species were essentially similar to that of IVM-PO.

The efficacy of benzimidazole drugs against Plasmodium falciparum in vitro

The sensitivities in vitro of Plasmodium falciparum to the benzimidazoles, albendazole, thiabendazole, mebendazole, omeprazole and 2 albendazole metabolites, albendazole sulphone and albendazole sulphoxide, were investigated and compared to those of the commonly used antimalarial drugs chloroquine and quinine. Quinine and chloroquine were the most potent drugs tested (EC 50 values of 8 × 10 −9–6 × 10 −8 mol/L and 5–7 × 10 −9 mol/L, respectively). Thiabendazole, mebendazole, albendazole sulphone and albendazole sulphoxide reached maximum growth inhibitions of 13–36% at the highest concentration tested (1 × 10 −4 mol/L). Albendazole (EC 50 range: not achieved-2 × 10 −6 mol/L) and omeprazole (EC 50 range: 2–4 × 10 −5 mol/L) were the most effective benzimidazoles. The activity of albendazole was pH dependent, as was that of chloroquine, and variable. Albendazole has its primary mode of action on trophozoites, suggesting that the drug may target parasite tubulin polymerization. Omeprazole, although also primarily effective against trophozoites, had additional activity against schizonts and ring forms, suggesting a distinct or additional parasitic target. Given the variable activity of albendazole and its rapid metabolism in vivo into compounds with even less antimalarial activity, it appears unlikely that this benzimidazole will be useful in the treatment of malaria. The rapid activity and different stage-specific profile of the more soluble benzimidazole omeprazole warrants further investigation.