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Drug-metabolizing enzymes represent the main defense system against xenobiotics in all organisms. Long-term exposure to drugs can lead to changes in the expression of specific enzymes and to development of drug resistance. The previous studies have shown that increased anthelmintics inactivation via increased expression of certain drugmetabolizing enzymes belongs to a significant mechanism of drug resistance in Haemonchus contortus. H. contortus, a gastrointestinal parasite of ruminants, has developed resistance to all used anthelmintics. As short-chain dehydrogenases/reductases (SDRs) catalyze the deactivation of carbonyl-containing anthelmintics (e.g. flubendazole, mebendazole), the increased expression of these SDRs could promote decreased susceptibility of H. contortus to these anthelmintics. For these reasons, the present study was designed to follow the changes in the relative expression of selected SDR genes in adults of H. contortus exposed to different concentrations of flubendazole (FLU). FLU-mediated responses in adults from drug-susceptible strain (ISE) and drug-resistant strain (IRE) were compared. The adult nematodes were incubated ex vivo with or without FLU (0.01 μM, 0.1 μM, 1 μM, and 5 μM) in a culture medium for 4 h or 12 h. After incubation, total RNA was isolated and the expression level of individual SDRs were analyzed using qPCR. The results have shown the variability in the expression of individual SDR genes in H. contortus adults after contact with sub lethal doses of FLU. [ABSTRACT FROM AUTHOR]

Taenia crassiceps is often used as experimental model for T. solium cysticercosis studies. Currently cysticercosis antiparasitic treatment is based on albendazole and praziquantel which may present side effects and parasitic resistance. The search for other antiparasitic drugs is necessary. Nitazoxanide (NTZ) and flubendazole (FLB) are broad spectrum antiparasitic drugs that present anti-cysticercosis effect. Metabolic analyses help to determine the impact of these drugs on parasites. The aim of this study was to determine the impact on the production and excretion of organic metabolites in T. crassiceps cysticerci after in vitro exposure to NTZ and FLB, isolated or in combination. T. crassiceps cysticerci were culture in RPMI medium and exposed to 10 μg/mL of NTZ, 10 μg/mL of FLB or 10 μg/mL of NTZ +10 μg/mL of FLB. 24 h after exposure, the parasites were chromatographic analyzed to determine the impact of these drugs on glycolysis, homolactic fermentation, tricarboxylic acid cycle, fatty acids oxidation and proteins catabolism. It was possible to determine that the drugs combination induced greater metabolic impact on cysticerci in comparison to the isolated drugs exposure. The drugs combination induced gluconeogenesis, metabolic acidosis, increase in tricarboxylic acid cycle and in proteins catabolism. While the NTZ isolated exposure induced metabolic acidosis and protein catabolism and the FLB isolate exposure induced gluconeogenesis and protein catabolism. These results show that the combination of drugs with different modes of action increase the antiparasitic effect and may be indicated as alternative cysticercosis treatments. [Display omitted] • NTZ + FLB combination enhances metabolic acidosis. • NTZ + FLB combination enhances protein catabolism. • NTZ + FLB combination enhances TCA cycle. • NTZ + FLB combination induces greater metabolic impact than isolated drugs. [ABSTRACT FROM AUTHOR]

Benzimidazole anthelmintics, the drugs against parasitic worms, are widely used in human as well as veterinary medicine. Following excretion, these substances may persist in the environment and impact non-target organisms. In order to test phytoremediation as a possible tool for detoxification of anthelmintics in environment, the biotransformation pathways of albendazole (ABZ) and flubendazole (FLU) were studied in reed ( Phragmites australis ) in vitro . Reed cells were able to uptake and biotransform both anthelmintics. Ten ABZ metabolites and five FLU metabolites were found. Some atypical biotransformation reactions (formation of glucosylglucosides, acetylglucosides and xylosylglucosides), which have not been described previously, were identified. Based on the obtained results, the schemes of metabolic pathways of ABZ and FLU in reed were proposed. Most of ABZ and FLU metabolites can be considered as anthelmintically less active; therefore uptake and biotransformation of these anthelmintics by reed could be useful for decrease of their toxicity in environment. [ABSTRACT FROM AUTHOR]

Highlights: [•] ABZ and FLBZ efficacy against cystic echinococcosis (CE) was assessed. [•] ABZ metabolites reached a higher systemic exposure compared to FLBZ/metabolites. [•] Both ABZ and FLBZ markedly decreased protoscoleces’ vitality/viability. [•] Hepatotoxicity due to the long standing treatment was not observed. [•] Enhancing FLBZ bioavailability may improve the efficacy against CE. [Copyright &y& Elsevier]

Abstract: Filarial diseases affect millions of people in poverty-stricken areas. In 2011, an investigation of the potential of flubendazole as a safe, highly efficacious, and field-usable macrofilaricidal drug was begun by Drug for Neglected Diseases initiative. As part of the preclinical development program, whole embryo culture was used to investigate the potential embryotoxicity of flubendazole and its metabolites, reduced and hydrolyzed flubendazole. Albendazole was included as a comparator. Flubendazole and albendazole showed similar potency in affecting rat embryonic development in vitro, inducing retardation of growth and dysmorphogenic effects at concentrations ≥0.5μg/mL. The head, optic and otic systems, branchial arches and posterior body portion were affected. Diffuse areas of cell death were seen in various embryonic districts. The No Observed Effect Level (NOEL) was 0.25μg/mL for both drugs. Reduced and hydrolyzed flubendazole were less embryotoxic than the parent compound, with NOELs 4-fold and >40-fold higher than that of flubendazole, respectively. [Copyright &y& Elsevier]

Introduction: Breast cancer (BC) accounts for the majority of cancers among the female population. Anomalous activation of various signaling pathways has become an issue of concern. The JAK-STAT signaling pathway is activated in numerous cancers, including BC. STAT3 is widely involved in BCs, as 40 % of BCs display phosphorylated STAT3. JAK-STAT signaling is crucial for proliferation, survival, metastasis and other cellular events associated with the tumor microenvironment. Hence, targeting this pathway has become an area of interest among researchers., Key Findings: This review article focuses on the role of STAT3 in the initiation, proliferation, progression and metastasis of BC. The roles of various phytochemicals, synthetic molecules and biologicals against JAK-STAT and STAT3 in various cancers have been discussed, with special emphasis on BC., Significance: JAK and STAT3 are involved in various phases from initiation to metastasis, and targeting this pathway is a promising approach to inhibit the various stages of BC development and to prevent metastasis. A number of phytochemicals and synthetic and biological molecules have demonstrated potential inhibitory effects on JAK and STAT3, thereby paving the way for the development of better therapeutics against BC., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound. The parent FLBZ is metabolized to its reduced (R-FLBZ) and hydrolyzed (H- FLBZ) metabolites. There are no data on the potential nematodicidal activity of R-FLBZ, the main plasma metabolite found in sheep and mice. The goal of the current work was to assess the efficacy of FLBZ and R-FLBZ against Trichinella spiralis in a mouse model. Methods: Both compounds were administered to Balb/c miceinfected with T. spiralis as either a cyclodextrin aqueous solution or as a carboxymethylcellulose suspension. Treatments were performed orally (5 mg/kg) at 1 day after infection with T. spiralis. The efficacy of the treatments was assessed at day 6 after infection. Results: While the efficacy obtained for FLBZ and R-FLBZ administered as a solution was 94 and 98%, respectively, the efficacies obtained after the treatment with FLBZ suspensions were 38% (FLBZ) and 64% (R-FLBZ). Conclusion: Under the current experimental conditions, a high nematodicidal efficacy of both FLBZ and R-FLBZ administered as solution preparations was observed. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Different therapeutic regimes using flubendazole for the treatment of Trichostrongylus tenuis infection in experimentally infected grey partridges Perdix perdix were examined. Flubendazole dosages of 4, 8 and 20 mg/kg were administered orally as a single dose or split into 3 or 9 parts given over 9 days. The efficacy against adult worms in the caeca improved with dose rate. Split doses were at least as effective as single doses, which removed up to 83% of adult T. tenuis. A dose of 20 mg/kg administered on a daily basis over 3 or 9 days gave the best clearance of T. tenuis, resulting in a reduction of at least 95% in worm burden. [ABSTRACT FROM PUBLISHER]

Residues of veterinary drugs and feed additives used extensively in animal husbandry are sometimes found in edible matrices. In this study, broilers received experimental feed, containing either flubendazole or tylosin, at crosscontamination levels of 2.5%, 5%, and 10% of the therapeutic dose to determine the transfer ratio of these molecules from feed to poultry matrices. Breast and thigh muscle and liver samples were collected during treatment and depletion periods and then analyzed using liquid chromatographytandem mass spectrometry. The parent molecule flubendazole and its 2 major metabolites were quantified. After 3 to 5 d, a plateau phase was reached, and a few days after withdrawal of the experimental feed, a depletion of residues was noted. Significant difference between both muscle types was noted for flubendazole. Strong metabolization of flubendazole in the liver was seen. For tylosin, no residue concentrations above the limit of quantification could be detected in muscle. None of the residue concentrations for either molecule exceeded the corresponding maximum residue limits. [ABSTRACT FROM AUTHOR]

Chemical residues may be present in eggs from laying hens' exposure to drugs or contaminants. These residues may pose risks to human health. In this study, laying hens received experimental feed containing flubendazole or tylosin at cross contamination levels of 2.5, 5, and 10% of the therapeutic dose. Eggs were collected daily and analysis of the whole egg, egg white, and egg yolk was performed using liquid chromatography tandem mass spectrometry. Highest concentrations of the parent molecule flubendazole, as well as the hydrolyzed and the reduced metabolite, were detected in egg yolk. Residue concentrations of the parent molecule were higher compared with those of the metabolites in all egg matrices. No tylosin residue concentrations were detected above the limit of quantification for all concentration groups and in all egg matrices. Neither molecule exceeded the set maximum residue limits. [ABSTRACT FROM AUTHOR]

The drug-metabolizing enzymes of some helminths can deactivate anthelmintics and therefore partially protect helminths against these drugs' toxic effect. The aim of our study was to assess the activity of the main drug-metabolizing enzymes and evaluate the metabolism of selected anthelmintics (albendazole, flubendazole, mebendazole) in the rat tapeworm Hymenolepis diminuta, a species often used as a model tapeworm. In vitro and ex vivo experiments were performed. Metabolites of the anthelmintics were detected and identified by HPLC with spectrofluorometric or mass–spectrometric detection. The enzymes of H. diminuta are able to reduce the carbonyl group of flubendazole, mebendazole and several other xenobiotics. Although the activity of a number of oxidation enzymes was determined, no oxidative metabolites of albendazole were detected. Regarding conjugation enzymes, a high activity of glutathione S-transferase was observed. A methyl derivative of reduced flubendazole was the only conjugation metabolite identified in ex vivo incubations of H. diminuta with anthelmintics. The results revealed that H. diminuta metabolized flubendazole and mebendazole, but not albendazole. The biotransformation pathways found in H. diminuta differ from those described in Moniezia expanza and suggest the interspecies differences in drug metabolism not only among classes of helminths, but even among tapeworms. [ABSTRACT FROM AUTHOR]

Abstract: The infection dynamics of Ascaridia galli in laying hens was investigated in six commercial non-caged flocks. Three flocks were managed in accordance with the regulations for organic production and had outdoor access, whereas three flocks were housed indoors in aviaries or traditional floor systems. Faecal egg counts and total worm burdens were determined at specified intervals during the first 50 weeks of the production period. In two conventional flocks the efficacy of flubendazole on lumenal stages was investigated. All flocks became infected following the arrival of the birds (post placement) with residual infective eggs derived from the previous flock. In four flocks (two organic and two conventional) parasite eggs were first detected in faeces 6–7 weeks post placement, whereas parasite eggs were not detected until after 17–18 weeks in two flocks. This delay was observed in two of three flocks that were housed in barns that had been thoroughly cleaned and disinfected by chlorocresol. In three flocks (two conventional and one organic) flubendazole was administered to the birds in the drinking water for approximately one week. Both conventional flocks were dewormed twice approximately 20 weeks apart, whereas the organic flock was dewormed only once about 40 weeks post placement. Parasite eggs reappeared after deworming in all flocks, often within 2–4 weeks, followed by a rapid increase in parasite egg expulsion. Our results suggested impairment of host immunity post treatment, as the egg counts exceeded pre-treatment levels after 7–8 weeks on both conventional farms. Accordingly, the way by which anthelmintics and/or disinfectants are used in non-caged chicken flocks must be refined. [Copyright &y& Elsevier]

Background. The European eel, Anguilla anguilla (L.), is considered an endangered species and a series of protective measures have been implemented within the European community in order to enhance natural stocks. Restocking natural habitats with larger eels reared from the glass-eel stage in recirculated farming systems may be one solution. Gill diseases caused by monogenean parasites of the genus Pseudodactylogyrus are currently causing morbidity and mortality in these farms and previously applied standard treatments have recently failed. Therefore the applied control methods should be verified and novel solutions proposed. Materials and methods. Eels infected by Pseudodactylogyrus anguillae were obtained from a typical recirculated eel-culture system which had been treated regularly but recently unsuccessfully with benzimidazole anthelmintics. In the laboratory infected eels were subjected to bath treatments with flubendazole (5 or 10 mg · L-1) or praziquantel (5 or 10 mg · L-1) for 24 h at 25°C and parasite infections were recorded three days post-treatment. Results. Gill monogeneans, Pseudodactylogyrus anguillae, were not controlled by the anthelmintic flubendazole at any of the dosages tested whereas praziquantel showed a significant effect when used as bath (5 and 10 mg · L-1). Conclusion. The failure of flubendazole for control of pseudodactylogyrosis may result from selection of anthelmintic resistant parasite strains due to use of benzimidazoles for decades. Future treatment regimes during acute outbreaks may be based on praziquantel. A risk for future continued selection for anthelmintic resistance exists and supplementary non-chemical methods (mechanical and biological) in rearing of European eel should be emphasized in the future management practice of eel. [ABSTRACT FROM AUTHOR]

Background: Cystic echinococcosis (CE) is an important public health problem worldwide. Flubendazole, administered in tablets, has shown poor in vivo efficacy against CE in humans. However, flubendazole prepared as a solution caused a marked reduction in hydatid cysts developed in mice. The goal of the current work was to compare the chemoprophylactic effect of flubendazole formulated either as a hydroxypropyl-β-cyclodextrin solution or as a carboxymethylcellulose suspension in secondary CE in mice. Methods: Balb/C mice were infected with Echinococcus granulosus protoscoleces. One day after infection, the animals were allocated into 3 different experimental groups: unmedicated control and treated at the time point of infection with flubendazole either prepared as a solution or suspension given twice a day during 15 days. Six months after infection, the animals were sacrificed to collect and weight parasitic cysts. Cyst samples recovered from infected mice of each experimental group were prepared for both scanning and transmission electron microscopy. Results: Both flubendazole formulations induced a significant reduction in cyst weight compared to the cysts recovered from the unmedicated control animals. Both formulations showed similar flubendazole-induced ultrastructural morphological changes. Conclusion: Flubendazole offers a great potential to become a drug of choice in the preventive treatment of cystic echinococcosis. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Copepods are well known to be the optimal live feed for most species of marine fish larvae. Still copepods are rarely used in marine hatcheries worldwide. Lack of efficient production techniques are among the reasons for this. Consequently, Artemia and rotifers are utilized in commercial settings. One problem in intensive production of copepods is contamination with rotifers. Rotifers have higher growth rates than copepods and consequently will compete out the copepods when accidentally introduced to the copepod production systems. Once contamination has occurred, the only cure has been to shut down production and subsequently use a therapeutic agent to eliminate all zooplankton in the system before restart with a stock culture free of rotifers. We tested flubendazole as a mean of controlling rotifers ( Brachionus plicatilis) in intensive laboratory cultures of the harpacticoid copepod ( Tisbe holothuria). Flubendazole was lethal to rotifers in concentrations as low as 0.05 mg L−1. There was no significant effect on the concentration of copepods, even at the highest concentration tested, i.e. 5.0 mg L−1 flubendazole. We conclude that flubendazole is an effective drug for control of B. plicatilis in T. holothuriae batch cultures. [ABSTRACT FROM AUTHOR]

Abstract: Cystic echinococcosis (CE) caused by the parasite Echinococcus granulosus is an important public health problem worldwide. Flubendazole has shown poor in vivo efficacy against CE in humans and mice. However, flubendazole causes marked in vitro damage on E. granulosus protoscoleces. The goals of the current work were: a) to compare the plasma pharmacokinetic behaviour of flubendazole formulated as a hydroxipropyl-β-cyclodextrin aqueous solution or as a carboxymethyl celullose suspension, both given by the oral route to mice, b) to compare flubendazole clinical efficacy in secondary CE in mice after its administration as both formulations, c) to evaluate the flubendazole-induced morphological changes in hydatid cysts recovered from infected mice treated with both drug formulations. Flubendazole administration as a solution resulted in significantly higher plasma maximum concentration (C max) and area under the concentration–time curve (AUC) values compared to those obtained after the flubendazole-suspension treatment. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the flubendazole-solution formulation, while the suspension formulation did not reach differences with the untreated control group. Similar ultrastructural changes were observed in cysts recovered from flubendazole (both formulations) treated mice after 3, 6 and 9months of infection, although the damage extension was greater after treatment with the flubendazole-solution formulation. [Copyright &y& Elsevier]

Abstract: The problem of chemotherapeutic treatments for human echinococcosis has not been completely solved. The benzimidazole–methylcarbamates (BZD), broad-spectrum antihelminthic agents, such as mebendazole and albendazole are the only drugs licensed for treatment of hydatid cysts. These drugs bind directly to β-tubulin causing the disruption of microtubule-based processes in helminths. However, the molecular bases of their multiple biological activities are poorly understood. Recently, the effect of halogenated derivative flubendazole (FLBZ), against E. granulosus larvae has been conclusively demonstrated. The comparative effectiveness of FLBZ, among other BZDs, was shown by means of vitality tests and time of appearance of morphological damage of larvae. In the present study, we examined biochemical and molecular changes on protoscoleces treated with FLBZ. We show that FLBZ induces: 1) an increase in cytosolic free calcium, 2) a decrease in tubulin transcripts, 3) a reduction of mMDH expression and 4) a significant decrease in glycogen levels. These results are consistent with the existence of multiple targets for FLBZ, such as calcium signaling and energy metabolism, and contribute to the understanding of the pharmaceutical properties of FLBZ. [Copyright &y& Elsevier]

Abstract: Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound used in pigs, poultry and humans. Its potential for parasite control in ruminant species is under investigation. The objective of the work described here was to identify the main enzymatic pathways involved in the hepatic and extra-hepatic biotransformation of FLBZ in sheep. Microsomal and cytosolic fractions obtained from sheep liver and duodenal mucosa metabolised FLBZ into a reduced FLBZ metabolite (red-FLBZ). The keto-reduction of FLBZ led to the prevalent (∼98%) stereospecific formation of one enantiomeric form of red-FLBZ. The amounts of red-FLBZ formed in liver subcellular fractions were 3–4-fold higher (P <0.05) compared to those observed in duodenal subcellular fractions. This observation correlates with the higher (P <0.05) carbonyl reductase (CBR) activities measured in the liver compared to the duodenal mucosa. No metabolic conversion was observed following FLBZ or red-FLBZ incubation with sheep ruminal fluid. Sheep liver microsomes failed to convert red-FLBZ into FLBZ. However, this metabolic reaction occurred in liver microsomes prepared from phenobarbital-induced rats, which may indicate a cytochrome P450-mediated oxidation of red-FLBZ. A NADPH-dependent CBR is proposed as the main enzymatic system involved in the keto-reduction of FLBZ in sheep. CBR substrates such as menadione and mebendazole (a non-fluoride analogue of FLBZ), inhibited this liver microsomal enzymatic reaction, which may confirm the involvement of a CBR enzyme in FLBZ metabolism in sheep. This research is a further contribution to the understanding of the metabolic fate of a promissory alternative compound for antiparasitic control in ruminant species. [Copyright &y& Elsevier]

Abstract: Basal activities of certain pheasant hepatic and intestinal biotransformation enzymes and modulation of their activities by anthelmintics flubendazole (FLBZ) and mebendazole (MBZ) were investigated in subcellular fractions that were prepared from liver and small intestine of control and FLBZ or MBZ treated birds. Several oxidation, reduction and conjugation enzyme activities were assessed. In the liver, treatment of pheasants by FLBZ or MBZ caused very slight or no changes in monooxygenase activities and conjugation enzymes. More significative changes were detected in small intestine. Metyrapone and daunorubicin reductase activities were increased by both substances in the liver. This is the first evidence that certain benzimidazoles modulate reductases of carbonyl group. With respect to the relatively slight extent of the changes caused by FLBZ or MBZ we can assume that repeated administration of therapeutic doses of both FLBZ and MBZ has probably no serious influence on pheasant biotransformation enzyme system. [Copyright &y& Elsevier]

Fenbendazole (FEN) and flubendazole (FLU) are benzimidazole anthelmintics often used in pig management for the control of nematodoses. The in vivo study presented here was designed to test the influence of FLU and FEN on cytochrome P4501A and other cytochrome P450 (CYP) isoforms, UDP-glucuronosyl transferase and several carbonyl reducing enzymes. The results indicated that FEN (in a single therapeutic dose as well as in repeated therapeutic doses) caused significant induction of pig CYPIA, while FLU did not show an inductive effect towards this isoform. Some of the other hepatic and intestinal biotransformation enzymes that were assayed were moderately influenced by FEN or FLU. Strong CYPIA induction following FEN therapy in pigs may negatively affect the efficacy and pharmacokinetics of FEN itself or other simultaneously or consecutively administered drugs. From the perspective of biotransformation enzyme modulation, FLU would appear to be a more convenient anthelmintic therapy of pigs than FEN. [ABSTRACT FROM AUTHOR]

Abstract: A rapid and very effective analytical procedure for the simultaneous HPLC determination of two anthelmintics, Flubendazole (FLUB) and Febantel (FEBA), in swine and poultry feeds was developed and tested. The ground feed samples were extracted using dimethylformamide. The extracts were directly analyzed, without any purification, on a reversed-phase ODS column (150mm×4.6mm, 5μm) with acetonitrile–phosphate buffer (pH 3; 0.017M) as mobile phase. Ultraviolet detection of FLUB and FEBA was carried out at 300nm. The method was validated for specificity, linearity, accuracy, repeatability, limit of detection and limit of quantification. The limits of detection (LOD) of FLUB and FEBA in feeds, based on a detector signal-to-noise ratio of 3, were 3mgkg−1 and the lowest levels tested in feeds by this procedure (limit of quantification, LOQ) were 10mgkg−1. The mean recovery of FLUB and FEBA from spiked samples, in a concentration range of 10–200mgkg−1, was 98% with a CV% of 4% and 99% with a CV% of 2%, respectively. [Copyright &y& Elsevier]

The voltammetric behavior of flubendazole was studied using direct current (DCt), differential pulse (DPP) and alternating current (ACt) polarography. The drug manifests a cathodic wave in 20% v/v formic acid solution. The wave was characterized as being irreversible, diffusion-controlled with limited adsorption properties. The diffusion current–concentration relationship was found to be rectilinear over the range 3.2–14.4 μg/ml and 0.1 to 12.8 μg/ml, using DCt and DPP modes, respectively, with minimum detectability of 0.161 μg/ml (5.14×10−7 M) and 0.0.057 μg/ml (1.82×10−8 M) using DCt and DPP modes, respectively. Furthermore, the proposed method was applied to the in-vitro determination of flubendazole in spiked human urine and plasma adopting the DPP technique. The percentage recoveries were 100.20±0.62 and 97.42±0.95, respectively. [Copyright &y& Elsevier]

Flubendazole was suspended in deionized water or olive oil and administered by gavage once daily to pregnant rats on Days 8–15 of pregnancy to examine if the embryolethal and teratogenic doses were affected by the vehicles used. Flubendazole in olive oil caused a statistically significant increase in embryolethality at doses of 7.83 mg/kg per day and higher, with complete resorption in all dams at 31.33 mg/kg per day. When flubendazole was suspended in deionized water, a significant increase in embryolethality occurred only at a maternal dose of 125.32 mg/kg per day. The proportion of litters with anomalous fetuses was significantly increased at doses of 31.33 mg/kg per day and above when flubendazole was administered in deionized water, but increased at doses at four times lower when flubendazole was administered as in olive oil. Administered as a single dose in olive oil on any one of Days 6–12 of pregnancy, a flubendazole dose of 31.33 mg/kg caused significant increases in embryolethality and decreased fetal body weights on Days 7–9, with an 82.7% incidence of embryolethality on Day 8, with complete resorption in 5 of the 8 dams. The critical periods for teratogenic effects were between Days 8 and 11 of pregnancy, with Day 9 being the most critical. Fetuses with gross, skeletal, or internal anomalies were seen in dams given a single dose of as low as 7.83 mg/kg. [Copyright &y& Elsevier]

A trial was undertaken to assess the efficacy of flubendazole against experimentally induced trichinellosis in pigs when given mixed with food at different dose rates. At the start of the experiment, 48 pigs were infected with approximately 35,000 larvae of Trichinella spiralis, afterwhat the animals were distributed in six groups. The first three groups were used to test the activity of the drug against adult stages. Other three groups served to define the efficacy against muscle larvae. The dose rate of flubendazole varied according to the purpose of the experiment (from 8 mg/kg up to 62 mg/kg). At the end of the trial, the pigs were necropsied and the number of adults and larvae in predilection muscles were determined. At a dose rate of 8 mg/kg flubendazole supplied with food during eight days was 100 % effective against adults. At a dose rate of 31 mg/kg flubendazole administered for 14 days was 72.35 % effective. Treatment with higher dosages of flubendazole (62 mg/kg) resulted in increased efficacy (87.77 %) against the parasites. The biological assay performed with larvae from the muscle samples originating from the pigs treated with 62 mg/kg showed that at least half of the larvae were not infective.

Efficacy of flubendazole and albendazole against Trichinella spiralis in mice were studied. ICR mice were experimentally infected with Trichinella spiralis and treated with either flubendazole (FBZ) or albendazole (ABZ) at four different stages of the parasite life-cycle. Oral administration of either FBZ or ABZ at 20 mg/kg and 50 mg/kg on 2 h, 8 h and 24 h (pre-adult stage) after infection eliminated 94.7 - 100 % of adults as determined at necropsy on day 7 post infection (p.i.) and 96.9 ~ 100 % of larvae on day 45 p.i. FBZ was more effective than ABZ against adult T. spiralis (at 2 to 6 days p.i.), when treated with a dosage of 20 mg/kg for 5 consecutive days (99.4 % and 46.0 % reduction with respect to the control group). Against migrating larval T. spiralis, FBZ was more effective than ABZ at 20 mg/kg for five consecutive days (on days 11 ~ 15 p.i.), and the reduction rate of recovered larvae were 99.6 % (FBZ) and 80.8 % (ABZ) respectively. FBZ was more effective against early encapsulated larval T. spiralis (at 21 to 25 days p.i.), than ABZ when both were given at 20 mg/kg for five consecutive days (99.8 % and 45.4 % reduction, respectively). In conclusion, flubendazole was more effective than albendazole against adult and parenteral stages of Trichinella spiralis in mice.

[Display omitted] • Flubendazole amorphous solid dispersions were hot-melted extruded. • Copovidone, magnesium stearate and hydroxypropylcelullose were evaluated. • Mixtures statiscally designed were extruded in a twin-screw extruder. • Flubendazole:copovidone was highly extrudable, except when drug load was >40%. • Extruded materials had improved dissolution results compared with pure drug. The FDA-approved anthelmintic flubendazole has shown potential to be repositioned to treat cancer and dry macular degeneration; however, its poor water solubility limits its use. Amorphous solid dispersions may overcome this challenge, but the balance of excipients may impact the preparation method and drug release. The purpose of this study was to evaluate the influence of adjuvants and drug loading on the development of an amorphous solid dispersion of flubendazole-copovidone by hot-melt extrusion. The drug, copovidone, and adjuvants (magnesium stearate and hydroxypropyl cellulose) mixtures were statistically designed, and the process was performed in a twin-screw extruder. The study showed that flubendazole and copovidone mixtures were highly extrudable, except when drug loading was high (>40%). Furthermore, magnesium stearate positively impacted the extrusion and was more effective than hydroxypropyl cellulose. The extruded materials were evaluated by modulated differential scanning calorimetry and X-ray powder diffraction, obtaining positive amorphization and physical stability results. Pair distribution function analysis indicated the presence of drug-rich domains with medium-range order structure and no evidence of polymer-drug interaction. All extrudates presented faster dissolution (HCl, pH 1.2) than pure flubendazole, and both adjuvants had a notable influence on the dissolution rate. In conclusion, hot-melt extrusion may be a viable option to obtain stable flubendazole:copovidone amorphous dispersions. [ABSTRACT FROM AUTHOR]

The efficacy of commercially available anthelmintics against mature and immature stages (including ovicidal effects) of two Australian field isolates of Ascaridia galli was evaluated in two separate experiments. The anthelmintics tested were levamisole (LEV), piperazine (PIP) and flubendazole (FBZ) plus LEV-PIP. A total of 192 artificially trickle-infected young cockerels (96 birds per isolate) were randomized into sixteen experimental groups of 12 cockerels each (7 treatments and 1 untreated control per isolate). Chickens received label-recommended doses of LEV (28 mg/kg), PIP (100 mg/kg) or LEV-PIP co-administered at their full individual doses as a single oral dose or in group drinking water at recommended concentrations of 0.8 mg/ml or 2.5 mg/ml over eight hours for 1 and 2 days respectively and FLBZ (30 ppm) in the feed over 7 days. Anthelmintic efficacies were assessed by worm count reduction (WCR%) and excreta egg count reduction (EECR%) estimated by two methods. Ten days post treatment, all untreated control birds harboured mixed worm population of 10.1 and 12.3/bird for each isolate respectively which was significantly higher (P < 0.0001) than counts in all treatment groups. Luminal or histotrophic larvae comprised 50–57 % of the total worm count. For LEV, PIP and LEV-PIP, individual oral administration provided a somewhat higher efficacy than group medication in drinking water. EECR% values were inconsistent with WCR% and found to be only an indicator of efficacy against adult worms. All developmental stages of the two A. galli isolates were highly susceptible to FLBZ (100 %) followed by LEV-PIP (92.4–100 %) and LEV (87.7–100 %). PIP exhibited good efficacy against adult worms (92–97 %) but reduced efficacy against luminal (79–84 %) and histotrophic (61–72 %) larvae. Embryonation capacity of eggs recovered from worms expelled after treatment with LEV (47–54 %), PIP (44–54 %) or LEV-PIP (45–48 %) did not differ from those from untreated birds (50–51 %) whereas eggs from FLBZ treated worms had a significantly lower (P < 0.05) capacity to embryonate (≤ 2 %). Put together, our results demonstrate no evidence of resistance of the test A. galli isolates to the tested anthelmintics but a significant advantage of FLBZ, followed by LEV-PIP and LEV over PIP in the control of A. galli, specifically with regard to immature stages. A. galli worms expelled after treatment with LEV, PIP or their combination, but not FLBZ contain viable eggs. This has epidemiological implications and may also provide an option for isolating eggs from mature worms for A. galli propagation experiments without having to sacrifice birds. [ABSTRACT FROM AUTHOR]

Flubendazole, belonging to benzimidazole, is a broad-spectrum insect repellent and has been repurposed as a promising anticancer drug. In recent years, many studies have shown that flubendazole plays an anti-tumor role in different types of cancers, including breast cancer, melanoma, prostate cancer, colorectal cancer, and lung cancer. Although the anti-tumor mechanism of flubendazole has been studied, it has not been fully understood. In this review, we summarized the recent studies regarding the anti-tumor effects of flubendazole in different types of cancers and analyzed the related mechanisms, in order to provide the theoretical reference for further studies in the future. [ABSTRACT FROM AUTHOR]

This study investigated worm control practices by free-range egg farmers and the efficacy of the commercial anthelmintics levamisole (LEV), piperazine (PIP), flubendazole (FLBZ) and fenbendazole (FBZ) against gastrointestinal nematodes on two free-range layer farms in Australia. An online survey comprising 36 questions was designed and implemented using SurveyMonkey. The survey contained questions about participant demographics, farm and flock characteristics, perceived intestinal worm importance, infection monitoring, deworming and other worm control practices. A link for the survey was emailed to free range egg producers from their industry body in December 2019. The anthelmintic efficacy trial was conducted in a total of 229 layers naturally infected with Ascaridia galli, Hetarakis gallinarum, Capillaria spp. and/or tape worms. Chickens received a single oral dose of LEV (28 mg/kg), PIP (100 mg/kg), FBZ (10 mg/kg) or LEV-PIP co-administered at their full individual doses, and FLBZ (Flubenol®), 30 ppm or 60 ppm) in the feed over 7 days. Anthelmintic efficacies were estimated by both worm count reduction (WCR %) and excreta egg count reduction (EECR %) tests 10 days after start of treatment. The survey with a response rate of 16/203, revealed that worm infection was of moderate concern to the producers and the majority (68%) felt that the current anthelmintics work effectively. The level of understanding of worms, monitoring and control practices did not reveal any major deficiencies of concern. The most commonly used anthelmintic was LEV (73%) followed by PIP (45%). Based on a standard cut-off value (≥90%), LEV, LEV-PIP, and FBZ attained the desired efficacy but PIP exhibited reduced efficacy against immature A. galli (61-85%), all stages of H. gallinarum (42-77%) and Capillaria spp. (25-44%). FLBZ was highly effective against all stages of roundworms and tapeworm infections. Even though there was some association between the efficacies estimated by WCR % and EECR % the latter was poorly associated in the natural infection model and hence does not provide a reasonable alternative for assessing anthelmintic efficacy when immature stages of the lifecycle are included. These results show no evidence of loss of susceptibility to the tested anthelmintics on these farms supporting the perception of producers that participated in the survey that current treatments work effectively. The reduced efficacy of PIP against some species and immature stages is related to its spectrum of activity rather than providing evidence of emerging resistance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mebendazole and flubendazole are antihelmintic drugs that have re-entered the research spotlight due to their exhibited anticancer effects, thus making them strong candidates as repurposed drugs. However, these benzimidazole derivatives exhibit poor solubility in water and various organic solvents, which limits their bioavailability. With the aim of obtaining an improved drug solubility and increased biological effect, mebendazole and flubendazole were complexed with 2-hydroxypropyl-β-cyclodextrin (HPBCD). The binary 1:1 conjugates were physicochemically evaluated by X-ray diffraction, thermal analysis, and FTIR spectroscopy, revealing the formation of physical mixtures. The increased aqueous solubility of the binary 1:1 conjugates vs. pure benzimidazole compounds was demonstrated by performing dissolution tests. The in vitro antiproliferative activity of mebendazole and flubendazole, as well as their combination with HPBCD, was tested on two cancer cell lines, human melanoma—A375 and pulmonary adenocarcinoma—A549 by the MTT assay. The cytotoxic activity manifested in a dose-dependent manner while the presence of HPBCD increased the antiproliferative activity against the targeted cells. Treatment of A375 and A549 cell lines with the binary conjugates induced a significant inhibition of mitochondrial respiration, as revealed by high-resolution respirometry studies. Molecular docking analysis showed that one of the mechanisms related to MEB and FLU cytotoxic activity may be due to the inhibition of MEK/ERK proteins. [ABSTRACT FROM AUTHOR]