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Due to limited non-clinical and clinical data, European guidance recommends to discontinue breastfeeding when taking albendazole. The aim of this study was to consider the use of PBPK modeling to support the expected exposure in breastfed infants. A fully mechanistic PBPK approach was used to provide quantitative predictions of albendazole and its main active metabolite, albendazole sulfoxide, concentrations in plasma and breast milk of lactating women. The model predicted the exposure in adults and the large food effect, however, it does not predict all the clinical data for the exposure in children. Milk/plasma ratio predictions were also largely over-predicted for this lipophilic compound, but not for the less lipophilic metabolite. Predictions using the observed ratio and a worse-case exposure based on C max predictions, suggest doses to children through milk will be low. However, more clinical data are required before full exposure predictions can be made to breastfed infants., (© 2024 Crown copyright. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.)

Background and Objective: Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d'Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate., Methods: Pharmacokinetic data from studies in Tanzania and Côte d'Ivoire in adolescents (aged 12-19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 µg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis., Results: Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d'Ivoire study population. Exposure-efficacy response analyses indicated that peak concentration and the time-above-exposure threshold were associated with the egg reduction rate., Conclusions: Study population but not co-administered ivermectin showed an effect on apparent clearance of albendazole sulfoxide and albendazole sulfone. Polymorphisms in drug-metabolizing enzymes and host-parasite interaction may explain this result. Difference in drug exposure did not explain the disparate efficacy responses in Tanzania and Côte d'Ivoire. Peak concentration and time-above-threshold were exposure measures associated with the egg reduction rate. Further studies evaluating genetic and resistance patterns in various regions in Africa are warranted., (© 2024. The Author(s).)

Purpose: 3D printing (3DP) makes it possible to obtain systems that are not achievable with current conventional methods, one of them, sustained release floating systems. Floating systems using ricobendazole (RBZ) as a model drug and a combination of polymers were designed and obtained by melt solidification printing technique (MESO-PP)., Methods: Four different MESO-PP inks were formulated based on combinations of the polymers Gelucire 43/01 and Gelucire 50/13 in different ratios. For each of the formulated inks, physicochemical characterization was performed by thermal analysis (thermogravimetric analysis [TGA] and differential scanning calorimetry [DSC]), fourier transform infrared spectrophotometer (FTIR) and X-ray diffraction (XRD). Pharmaceutical characterization was performed by in vitro assays to determine pharmaceutically relevant parameters. These parameters were calculated by applying mathematical models developed to evaluate in vitro drug release profiles. On the other hand, a physiologically based pharmacokinetic (PBPK) model was developed to predict the in vivo performance of RBZ loaded in the different inks by determining the C max , and the AUC 0-∞ ., Results: By increasing the proportion of Gelucire 50/13 co-surfactant in the mixtures (the proportion in Ink 1 was 33%, while the proportion in Ink 4 was 80%), the dissolution capacity of RBZ increases substantially, decreasing flotation times., Conclusion: MESO-PP produced ink 1 (50% Gelucire 43/01, 25% Gelucire 50/13 and 25% RBZ), which has a zero-order release (RR = 0.180%/min) and the longest flotation time (545 ± 23 min), and in turn would produce a significant increase in oral absorption of the drug, with an AUC 0-∞ 2.16-fold higher than that obtained in animals treated with RBZ loaded in conventional tablets., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

At present, the use of benzimidazole drugs in veterinary medicine is strongly limited by both pharmacokinetics and formulative issues. In this research, the possibility of applying an innovative semi-solid extrusion 3D printing process in a co-axial configuration was speculated, with the aim of producing a new gastro-retentive dosage form loaded with ricobendazole. To obtain the drug delivery system (DDS), the ionotropic gelation of alginate in combination with a divalent cation during the extrusion was exploited. Two feeds were optimized in accordance with the printing requirements and the drug chemical properties: the crosslinking ink, i.e., a water ethanol mixture containing CaCl 2 at two different ratios 0.05 M and 0.1 M, hydroxyethyl cellulose 2% w / v , Tween 85 0.1% v / v and Ricobendazole 5% w / v ; and alginate ink, i.e., a sodium alginate solution at 6% w / v . The characterization of the dried DDS obtained from the extrusion of gels containing different amounts of calcium chloride showed a limited effect on the ink extrudability of the crosslinking agent, which on the contrary strongly influenced the final properties of the DDS, with a difference in the polymeric matrix toughness and resulting effects on floating time and drug release.

Sheep and goats are sharing different helminth parasites including Haemonchus contortus. Control of these helminths is based mainly on the use of anthelmintics. However, in goats, the application of anthelmintics is often carried out mainly at dosages determined for sheep without knowing the real effects and metabolism features. One of the several anthelmintic classes used against these parasites is (pro) benzimidazoles which are still widely in use in small ruminants in many countries. The objective of this study was to determine (i) the correlation between plasma and tissue or gastrointestinal content dispositions of ricobendazole (RBZ) in goats and (ii) the in vivo exposure of ricobendazole by H. contortus. Ten goats were experimentally infected with 10,000 larvae of H. contortus. Four weeks of post-infection, the animals received RBZ subcutaneously at 5 mg/kg body weight. Two goats were sacrificed per time at 1, 2, 4, 6 and 12 h after drug administration and, blood, bile, urine, liver, lung, muscle and kidney gastrointestinal tissues/fluids were collected. Adult H. contortus were collected from abomasum, and all samples were analysed by HPLC system. Ricobendazole (RBZ) and its sulphone metabolite were extensively excreted by urine and distributed to all tissues and digestive tract, mainly into the abomasum fluid. RBZ concentration in the lung and ABZSO 2 in the kidney were relatively higher than those of other tissues, respectively. The parent drug and its metabolite were recovered in both male and female H. contortus. This study indicates that in goats the plasma concentration profiles of RBZ are strongly correlated with those achieved in different target tissues or fluids, which in turn, reflect the amount of drug taken up by parasites., (© 2021 John Wiley & Sons Ltd.)

The aim of this study was to use a combined in vitro-in silico approach to develop a physiologically based pharmacokinetic model (PBPK) that predicts the bioavailability of albendazole (ABZ), a BCS class II/IV lipophilic weak base, and simulates its main metabolite albendazole sulphoxide (ABZSO) after oral administration of the current marketed dose of 400 mg in the fasted state. In vitro data was collected from solubility and dissolution tests performed with biorelevant media and transfer tests were carried out to evaluate the supersaturation and precipitation characteristics of ABZ upon gastric emptying. These in vitro results were used as biopharmaceutical inputs together with ABZ physicochemical properties including also permeability and in vitro metabolism data and information gathered from different clinical trials reported in the literature, were used to enable PBPK models to be developed using GastroPlus™ (version 9.7). As expected for this weak base with pKa = 3.6, ABZ exhibited a pronounced pH dependent solubility, with the solubility and extent of dissolution being greater at gastric pH and dropping significantly in the intestinal environment suggesting supersaturation and precipitation upon gastric emptying, which was confirmed by the transfer model experiments. PBPK models were set up for heathy volunteers using a full PBPK modeling approach and by implementing dynamic fluid volumes in the ACAT gut physiology in GastroPlus™. When coupling in vitro data (solubility values, dissolution rate and precipitation rate constant, etc.) for ABZ and with fitted values for the Vdss and liver systemic clearance of the sulfoxide metabolite to the PBPK model, the simulated profiles successfully predicated plasma concentrations of ABZ at 400 mg dose and simulated ABZSO at different ABZ dose levels and with different study populations, indicating the usefulness of combing in vitro biorelevant tools with PBPK modeling for the accurate prediction of ABZ bioavailability. The results obtained in this study also helped confirm that ABZ behaves as a BCS class IV compound., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Albendazole is known as the drug of choice for medical treatment of cystic echinococcosis (CE). Albendazole sulfoxide (ABZ-SO), as the main active metabolite of albendazole, has low efficacy in the disease due to low water solubility and poor absorptivity. PLGA nanoparticles (NPs) enhance the dissolution of poorly soluble drugs, and chitosan (CS) coating enhances oral drug delivery of NPs. In this study, the efficacy of ABZ-SO-loaded CS-PGLA NPs in the treatment of CE was evaluated in laboratory mice. ABZ-SO-loaded CS-PGLA NPs were prepared by nanoprecipitation and characterized by dynamic light scattering method and scanning electron microscopy. Thirty mice were intraperitoneally infected by 1000 protoscoleces of Echinococcus granulosus. Ten months later, the mice were allocated into 3 groups: groups 1 and 2 were treated with ABZ-SO and ABZ-SO-loaded CS-PGLA NPs, respectively, and the mice in group 3 remained untreated as the control group. The drugs were administered by gavage for 45 days at a daily dose of 10 mg/kg. Finally, all mice were opened and the cysts were collected, counted, weighed, and measured separately. The therapeutic effect of ABZ-SO in the number, weight, and volume of the cysts were not statistically significant compared with those in ABZ-SO-loaded CS-PGLA NPs and the control group. However, the therapeutic effect of ABZ-SO-loaded CS-PGLA NPs in the weight and volume of cysts were statistically significant when compared with that in the control group (p ˂ 0.05). In conclusions, this study revealed that ABZ-SO-loaded CS-PGLA NPs could enhance the therapeutic efficacy of ABZ-SO in the treatment of CE in laboratory mice.

In this research study, a method of dispersive-micro-solid phase extraction (D-µ-SPE) combined with molecularly imprinted polymer nanoparticles (MIP-NPs) with HPLC-UV was developed for the fast and selective detection of the trace amount of albendazole sulfoxide (ABZSO) in the biological samples. To investigate the effective factors on ABZSO microextraction by the method, central composite design (CCD) was utilized, and the optimum conditions for ABZSO microextraction were sample pH of 8.0, MIP-mass of 15 mg, sonication time of 12 min, and eluent (methanol) volume of 0.25 mL. Under the obtained optimal extraction conditions, the value for the limit of detection (LOD) and limit of quantification (LOQ) was respectively showed to be 0.074 and 0.246 ng mL -1 . In addition, the calculated peak areas exhibited a linear relationship with the ABZSO concentration ranging from 0.4 to 4200 ng mL -1 . The analyses of the samples including human plasma and urine, and water were successfully performed by the usage of the D-µ-SPE method, which was a simple and sensitive technique and a suitable alternative for the analysis of ABZSO. In the analysis of ABZSO in various samples, the recoveries at various levels of ABZSO concentrations (50, 300, and 500 ng mL -1 ) were in the range of 95.7-103.0 %, and the relative standard deviations (RSDs; n = 3) varied from 2.2 to 4.4%., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, we evaluated the efficacy, expressed as a mean weight decrease of the whole echinococcal cyst mass, of novel benzimidazole salt formulations in a murine Echinococcus granulosus infection model. BALB/c mice were intraperitoneally infected with protoscoleces of E. granulosus (genotype G1). At 9 months post-infection, treatment with albendazole (ABZ), ricobendazole (RBZ) salt formulations, and RBZ enantiomer salts (R)-(+)-RBZ-Na and (S)-(-)-RBZ-Na formulations were initiated. Drugs were orally applied by gavage at 10 mg kg-1 body weight per day during 30 days. Experimental treatments with benzimidazole sodium salts resulted in a significant reduction of the weight of cysts compared to conventional ABZ treatment, except for the (S)-(-)-RBZ-Na enantiomer formulation. Scanning electron microscopy and histological inspection revealed that treatments impacted not only the structural integrity of the parasite tissue in the germinal layer, but also induced alterations in the laminated layer. Overall, these results demonstrate the improved efficacy of benzimidazole salt formulations compared to conventional ABZ treatment in experimental murine cystic echinococcosis.

This paper describes a melting solidification printing process (MESO-PP) capable of obtaining printed oral solid dosage forms in a safe, versatile, and robust manner avoiding the use of solvents and high temperatures. MESO-PP and Gelucire® 50/13 (fatty polyethylene glycol esters) as ink can be used to obtain a floating sustained-release system with the aim of improving the dissolution and absorption of drugs, such as ricobendazole (RBZ), which have a low and erratic bioavailability. Gelucire 50/13 can be considered a good material to formulate inks using MESO-PP. As a model, the RBZ allowed us to assess that there were no changes in crystallinity and the API-ink interactions were ruled out using TGA, DSC, XRD and FT-IR assays. A batch of printlets, obtained using MESO-PP, fulfilled USP requirements regarding uniformity of mass (827 ± 9 mg) and drug content (211 ± 5 mg). Hardness and friability were 39.23 ± 9.65 N and 1.07 ± 0.5% respectively, just above the 1% USP tablet-friability limit. It was possible to obtain tablets of different sizes with high precision (r 2  = 0.995). In vitro dissolution test showed that the printlet had a sustained-release of RBZ (only 7% after 15 min), that erosion was the predominant mechanism for drug release (n-value of Korsmeyer-Peppas equation = 0.991; r 2  = 0.99) and that changes in the internal structures modify the release. Consequently, MESO-PP can be considered an excellent alternative to obtain solid pharmaceutical dosage forms with variable geometries for different pharmaceutical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Helminthic infections are produced by different types of worms and affect millions of people worldwide. Benzimidazole compounds such as ricobendazole (RBZ) are widely used to treat helminthiasis. However, their low aqueous solubility leads to poor gastrointestinal dissolution, absorption and potential lack of efficacy. The formulation of nanocrystals (NCs) have become the strategy of preference for hydrophobic drugs. In this work, we prepared RBZ NCs (RBZ-NCs) by an optimized combination of bead milling and spray-drying. Following the physicochemical characterization, a comparative pharmacokinetic evaluation of RBZ-NCs was performed in dogs using as controls a micronized powdered form of RBZ (mRBZ) and a physical mixture of drug and stabilizer 1:1 (PM). The particle size of the redispersed RBZ-NCs was 181.30 ± 5.93 nm, whereas DSC, PXRD and FTIR analyses demonstrated that the active ingredient RBZ remained physicochemically unchanged after the manufacture process. RBZ-NCs exhibited improved in vitro biopharmaceutical behaviour when compared to mRBZ. Consequently, the pharmacokinetic trial demonstrated a significant increase in the drug oral absorption, with an AUC 0-∞ 1.9-fold higher in comparison to that obtained in animals treated with mRBZ. This novel formulation holds substantial potential for the development of new/alternative treatments for helminth infections both in human and veterinary medicine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3, cyp-6, cyp-7, cyp-8, UGT10B1, UGT24C1, UGT26A2, UGT365A1, UGT366C1, UGT368B2, UGT367A1, UGT371A1, UGT372A1 and pgp-3, pgp-9.1, pgp-9.2, pgp-10. This induction led to increased formation of ABZ metabolites (especially glycosides) and their increased export from the helminths' body into the medium. The present study demonstrates for the first time that contact of H. contortus with sub-lethal doses of ABZ (e.g. during underdose treatment) improves the ability of H. contortus adults to deactivate ABZ in consequent therapy.

ABSTRACT Aims: The main goal of the current study was to evaluate, on a commercial beef cattle farm, the impact of infection with gastrointestinal nematodes resistant to both ivermectin (IVM) and moxidectin (MXD) on the productivity of calves. Methods: Male Aberdeen Angus calves, aged 9-11 months, with faecal nematode egg counts (FEC) ≥200 epg and body weight ≥190 kg, were allocated to two herds. Herd A (n = 90) grazed a maize-winter forage crop rotation and Herd B (n = 90) grazed a 2-year-old Agropyrum pasture. On Day 0 in each herd, calves were randomly allocated into five groups (n = 18), which were treated with 0.2 mg/kg IVM; 0.2 mg/kg MXD; 3.75 mg/kg ricobendazole (RBZ), both IVM and RBZ, or remained untreated. Faecal samples collected on Days -1 and 19 were used to determine the percentage reduction in FEC, and genera of the nematodes were determined by the identification of the third-stage larvae recovered from faecal cultures. Total weight gain was determined from body weights recorded on Days -1 and 91. Results: Overall mean reduction in FEC was 42% for IVM, 67% for MXD, 97% for RBZ and 99% for IVM + RBZ. The reduction in FEC for Cooperia spp. was ≤78% for IVM and MXD, and for Haemonchus spp. was 0 and 36% for IVM and MXD, respectively, confirming the presence of parasites resistant to both anthelmintics. Only IVM + RBZ treatment resulted in 100% efficacy against Haemonchus spp. The overall estimated mean total weight gain for calves treated with IVM was 15.7 (95% CI = 11.9-19.7) kg and for calves treated with IVM + RBZ was 28.8 (95% CI = 25-32.5) kg (p < 0.001). Mean total weight gain for calves treated with MXD was 23.5 (95% CI = 19.7-27.2) kg. Conclusions and clinical relevance: In calves naturally infected with resistant nematodes, under the production system assessed here, weight gains were lower in calves treated with anthelmintics that were moderately or highly ineffective compared to those treated with highly effective anthelmintics. These results demonstrate to farmers and veterinarians the importance of a sustainable and effective nematode control under field conditions.

Nitazoxanide (NTZ) is a broad-spectrum drug used in intestinal infections, but still poorly explored in the treatment of parasitic tissular infections. This study aimed to evaluate the in vitro responses of the energetic metabolism of T. crassiceps cysticerci induced by NTZ. The organic acids of the tricarboxylic acid cycle, products derived from fatty acids oxidation and protein catabolism were analyzed. These acids were quantified after 24 h of in vitro exposure to different NTZ concentrations. A positive control group was performed with albendazole sulfoxide (ABZSO). The significant alterations in citrate, fumarate and malate concentrations showed the NTZ influence in the tricarboxylic acid (TCA) cycle. The non-detection of acetate confirmed that the main mode of action of NTZ is effective against T. crassiceps cysticerci. The statistical differences in fumarate, urea and beta-hydroxybutyrate concentrations showed the NTZ effect on protein catabolism and fatty acid oxidation. Therefore, the main energetic pathways such as the TCA cycle, protein catabolism and fatty acids oxidation were altered after in vitro NTZ exposure. In conclusion, NTZ induced a significant metabolic stress in the parasite indicating that it may be used as an alternative therapeutic choice for cysticercosis treatment. The use of metabolic approaches to establish comparisons between anti parasitic drugs mode of actions is proposed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Internet-facilitated self-diagnosis and treatment is becoming more prevalent, putting individuals at risk of toxicity when drugs are acquired without medical oversight. We report a patient with delusional parasitosis who consumed veterinary albendazole purchased on the Internet, leading to pancytopenia, transaminase elevation, and alopecia. A 53-year-old man was sent to the emergency department (ED) by his gastroenterologist because of abnormal laboratory results. The patient had chronic abdominal pain and believed he was infected with parasites. He purchased two bottles of veterinary-grade albendazole on the Internet, and over the 3 weeks before his ED visit, he consumed 113.6 g of albendazole (a normal maximal daily dose is 800 mg). Five days before admission, he noticed hair loss and a rash on his face. His examination was notable for significant scalp hair loss and hyperpigmentation along the jaw line. Laboratory studies were remarkable for pancytopenia (most notably a white blood cell count (WBC) of 0.4 × 10 3 cells/mm 3 , with an absolute neutrophil count (ANC) of 0 × 10 3 cells/mm 3 ) and transaminase elevation (aspartate aminotransferase [AST] 268 IU/L, alanine aminotransferase [ALT] 89 IU/L). He developed a fever and was treated with antibiotics and colony-stimulating factors for presumed neutropenic bacteremia. Over the course of 1 week, his hepatic function normalized and his ANC increased to 3,000 × 10 3 cells/mm 3 . Serial albendazole and albendazole sulfoxide concentrations were measured in serum and urine by liquid chromatography-quadruple time-of-flight mass spectrometry. On day 2, his serum concentrations were 20.7 ng/mL and 4,257.7 ng/mL for albendazole and albendazole sulfoxide, respectively. A typical peak therapeutic concentration for albendazole sulfoxide occuring at 2-5 hours post-ingestion is 220-1,580 ng/mL. Known adverse effects of albendazole include alopecia, transaminase elevation, and neutropenia. Pancytopenia leading to death from septic shock is reported. In our patient, prolonged use of high-dose albendazole resulted in a significant body burden of albendazole and albendazole sulfoxide, leading to pancytopenia, transaminase elevation, and alopecia. He recovered with supportive therapy.

Background: The efficacy of albendazole therapy in patients with parenchymal neurocysticercosis (NCC) is suboptimal. Plasma levels of albendazole sulfoxide (ASOX), the active metabolite of albendazole, are highly variable among patients. We hypothesized that high ASOX plasma levels during albendazole therapy may be associated with an increased antiparasitic efficacy., Methods: ASOX plasma levels were measured at treatment day 7 in 118 patients with parenchymal NCC enrolled in a treatment trial. The relationships between increasing ASOX plasma levels with the proportion of cysts resolved and the proportion of patients with complete cyst resolution (evaluated by 6-month brain magnetic resonance) were assessed., Results: There was a trend toward a higher proportion of cysts resolved and a higher proportion of patients cured with increasing quartiles of ASOX plasma levels. In patients with 3 or more brain cysts, the regression analysis adjusted by the concomitant administration of praziquantel (PZQ) showed a 2-fold increase in the proportion of cysts resolved (risk ratio [RR], 1.98; 95% confidence interval [CI], 1.01-3.89; P = .048) and 2.5-fold increase in the proportion of patients cured (RR, 2.45; 95% CI, .94-6.36; P = .067) when ASOX levels in the highest vs the lowest quartile were compared. No association was found in patients with 1-2 brain cysts., Conclusions: We suggest an association between high ASOX plasma levels and increased antiparasitic efficacy in patients with parenchymal NCC. Nonetheless, this association is also influenced by other factors including parasite burden and concomitant administration of PZQ. These findings may serve to individualize and/or adjust therapy schemes to avoid treatment failure., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

A sensitive and relatively fast, cost-effective high-performance liquid chromatographic method coupled with mass spectrometer (HPLC-MS) is herein reported for the first time for a simultaneous quantification of plasma and organs concentration of three therapeutic agents that are widely used in treatment of lymphatic filariasis (LF), namely, doxycycline (DOX), diethylcarbamazine (DEC) and albendazole (ABZ) metabolites. The method was developed and validated as per ICH and FDA guidelines and successfully employed to quantify DOX, DEC and ABZ metabolites (albendazole sulfoxide (ABZ-OX) and albendazole sulfone (ABZ-ON)) in the plasma and organs of Sprague Dawley rats after oral concomitant administration of the above mentioned therapeutic agents. Importantly, a simple, one-step protein precipitation and extraction method was used to extract the four compounds efficiently with a recovery in the range of 79.88 ± 5.02%-90.71 ± 5.13%, 85.72 ± 7.22%-93.17 ± 5.55%, 94.38 ± 7.35%-101.00 ± 8.88% and 94.38 ± 7.35%-99.87 ± 10.22% in plasma and organs for DOX, DEC, ABZ-OZ and ABZ-ON, respectively. Separation of all analytes was performed on a Xselect CSH™ C18 HPLC column (Waters, 3.0 x 150 mm, 3.5 μm particle size) with gradient elution employing a mobile phase consisting of 0.1% v/v formic acid in water and methanol with a run time of 20 min. Quantification was carried out employing a single, quadruple MS detector operated with single ion monitoring (SIM) mode and the ion transitions at m/z of 445.4, 200.2, 282.3 and 298.3 for DOX, DEC, ABZ-OX and ABZ-ON respectively. The MS response for plasma samples was linear across the concentration range of 2.5-2500 ng/mL for DOX, 0.5-500 ng/mL for DEC, 1-1000 ng/mL for ABZ-OX and ABZ-ON with a correlation coefficient (r 2 ) ≥ 0.998. The method was selective, precise and accurate. This method allowed us to get an insight into the pharmacokinetics and biodistribution of the three therapeutic agents after simultaneous oral administration to Sprague Dawley rats. This bioanalytical method could provide a reliable, reproducible and excellent tool for routine therapeutic drug monitoring of the above mentioned therapeutic agents and also support other clinical pharmacokinetic-based studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Extraparenchymal neurocysticercosis is the most severe form of cysticercosis, and response to treatment is suboptimal. We sought to determine how demographic and clinical characteristics and albendazole sulfoxide concentrations were related to cysticidal treatment response. We conducted a longitudinal study of 31 participants with extraparenchymal vesicular parasites who received the same treatment, albendazole 30 mg/kg/day for 10 days with dexamethasone 0.4 mg/kg/day for 13 days, followed by a prednisone taper. Response to treatment was determined by parasite volumes before and 6 months after treatment. Eight participants (25.8%) had a complete treatment response, 16 (51.6%) had a treatment response > 50% but < 100%, and 7 (22.6%) had a treatment response < 50%. Complete treatment response was significantly associated with higher concentrations of albendazole sulfoxide (P = .032), younger age (P = .032), fewer cysts (P = .049) and lower pretreatment parasite volume (P = .037). Higher number of previous cysticidal treatment courses was associated with a noncomplete treatment response (P = .023). Although the large proportion of participants with less than a complete response emphasizes the need to develop more efficacious pharmacologic regimens, the association of albendazole sulfoxide concentrations with treatment response highlights the importance of optimizing existing therapeutic regimens. In addition, the association of treatment response with parasite volume emphasizes the importance of early diagnosis., (© 2018, The American College of Clinical Pharmacology.)

Albendazole is an effective anthelmintic intensively used for decades. However, profound pharmacokinetic (PK) characterization is missing in children, the population mostly affected by helminth infections. Blood microsampling would facilitate PK studies in pediatric populations but has not been applied to quantify albendazole's disposition. Quantification methods were developed and validated using liquid chromatography-tandem mass spectrometry to analyze albendazole and its metabolites albendazole sulfoxide and albendazole sulfone in wet samples (plasma and blood) and blood microsamples (dried-blood spots [DBS]; Mitra). The use of DBS was limited by a matrix effect and poor recovery, but the extraction efficiency was constant throughout the concentration range. Hookworm-infected adolescents were venous and capillary blood sampled posttreatment with 400 mg albendazole and 25 mg/kg oxantel pamoate. Similar half-life ( t 1/2 = ∼1.5 h), time to reach the maximum concentration ( t max = ∼2 h), and maximum concentration ( C max = 12.5 to 26.5 ng/ml) of albendazole were observed in the four matrices. The metabolites reached C max after ∼4 h with a t 1/2 of ca. 7 to 8 h. A statistically significant difference in albendazole sulfone's t 1/2 as determined by using DBS and wet samples was detected. C max of albendazole sulfoxide (288 to 380 ng/ml) did not differ among the matrices, but higher C max of albendazole sulfone were obtained in the two microsampling devices (22 ng/ml) versus the wet matrices (14 ng/ml). In conclusion, time-concentration profiles and PK results of the four matrices were similar, and the direct comparison of the two microsampling devices indicates that Mitra extraction was more robust during validation and can be recommended for future albendazole PK studies., (Copyright © 2019 American Society for Microbiology.)

Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-β-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.

The drug albendazole (ABZ) has a positive effect against Trichinella spiralis infection and has been used for the treatment and prevention of trichinellosis in humans and animals. However, the molecular mechanism ofthe effects of ABZ on T. spiralis remains unknown. Albendazole sulfoxide (ABZSO) is the main intermediary metabolic product of ABZ, and it is often used as a substitute for ABZ in metabolism and bioavailability research. Herein, isobaric tagging reagents for relative and absolute quantification (iTRAQ)-based LC-MS/MS analysis was used to identify the effect of ABZSO on the proteome of T. spiralis muscle larvae in vitro. 3795 proteins were quantified from 22974 unique peptides. Comparative proteomics analysis displayed that 417 proteins were remarkably differentially expressed in ABZSO-treated larvae, of which 213 proteins were up-regulated and 204 proteins were down-regulated. Quantitative real-time PCR of ten randomly-selected genes verified the proteomic data. Gene ontology annotation and KEGG pathway analysis showed that most of the differentially expressed proteins were involved in cell apoptosis, signal pathway, amino acid metabolism, protein synthesis/assembly/degradation and other biological processes. This study firstly provided the comprehensive proteomics data of T. spiralis in response to ABZSO, and would help us to deeply understand the molecular mechanism of ABZSO effects on T. spiralis., (Copyright © 2017. Published by Elsevier B.V.)

Albendazole (ABZ) and ricobendazole (RBZ) are referred to as class II compounds in the Biopharmaceutical Classification System. These drugs exhibit poor solubility, which profoundly affects their oral bioavailability. Micellar systems are excellent pharmaceutical tools to enhance solubilization and absorption of poorly soluble compounds. Polysorbate 80 (P80), poloxamer 407 (P407), sodium cholate (Na-C), and sodium deoxycholate (Na-DC) have been selected as surfactants to study the solubilization process of these drugs. Fluorescence emission was applied in order to obtain surfactant/fluorophore (S/F) ratio, critical micellar concentration, protection efficiency of micelles, and thermodynamic parameters. Systems were characterized by their size and zeta potential. A blue shift from 350 to 345 nm was observed when ABZ was included in P80, Na-DC, and Na-C micelles, while RBZ showed a slight change in the fluorescence band. P80 showed a significant solubilization capacity: S/F values were 688 for ABZ at pH 4 and 656 for RBZ at pH 6. Additionally, P80 micellar systems presented the smallest size (10 nm) and their size was not affected by pH change. S/F ratio for bile salts was tenfold higher than for the other surfactants. Quenching plots were linear and their constant values (2.17/M for ABZ and 2.29/M for RBZ) decreased with the addition of the surfactants, indicating a protective effect of the micelles. Na-DC showed better protective efficacy for ABZ and RBZ than the other surfactants (constant values 0.54 and 1.57/M, respectively), showing the drug inclusion into the micelles. Entropic parameters were negative in agreement with micelle formation.

Haemonchus contortus (family Trichostrongylidae, Nematoda), a hematophagous gastrointestinal parasite found in small ruminants, has a great ability to develop resistance to anthelmintic drugs. We studied the biotransformation of the three benzimidazole anthelmintics: albendazole (ABZ), ricobendazole (albendazole S-oxide; RCB) and flubendazole (FLU) in females and males of H. contortus in both a susceptible ISE strain and resistant IRE strain. The ex vivo cultivation of living nematodes in culture medium with or without the anthelmintics was used. Ultrasensitive UHPLC/MS/MS analysis revealed 9, 7 and 12 metabolites of ABZ, RCB and FLU, respectively, with most of these metabolites now described in the present study for the first time in H. contortus. The structure of certain metabolites shows the presence of biotransformation reactions not previously reported in nematodes. There were significant qualitative and semi-quantitative differences in the metabolites formed by male and female worms. In most cases, females metabolized drugs more extensively than males. Adults of the IRE strain were able to form many more metabolites of all the drugs than adults of the ISE strain. Some metabolites were even found only in adults of the IRE strain. These findings suggest that increased drug metabolism may play a role in resistance to benzimidazole drugs in H. contortus., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The goals of the current study were to evaluate the potential pharmacokinetic (PK) interactions and the clinical efficacy occurring after the subcutaneous (s.c.) administration of ricobendazole (RBZ) and levamisole (LEV) given both separately and co-administered to calves naturally infected with susceptible gastrointestinal nematodes. The clinical efficacy was shown in two seasons, winter and spring, with predominance of different nematode populations. Groups of 15 calves were treated with RBZ alone, LEV alone and RBZ + LEV combination, and an untreated group was kept as a Control. RBZ and LEV plasma concentrations were quantified by HPLC. The clinical efficacy was determined by the faecal egg count reduction test. RBZ and LEV have similar plasma persistence, being detected in plasma over 24 hr post-treatment. No PK interactions were observed after the combined treatment, with similar PK parameters (p > .05) obtained for the single-drug and the combination-based strategy. In winter, the observed clinical efficacies were 96%, 99% and 100% for groups treated with RBZ, LEV and RBZ + LEV, respectively; however, in spring, the efficacies were 95%, 93% and 96% for the same groups. Remarkably, the combination was the only treatment that achieved 100% clinical efficacy against both Haemonchus spp and Ostertagia spp in winter; but the increased presence of Ostertagia spp. in spring (28% in untreated group) determined a tendency to reduced efficacies compared to winter time (only 10% of Ostertagia spp. in untreated group), even for the combined treatment. Overall, in a scenario where the nematode population is susceptible, the RBZ + LEV treatment may be a valid combination in cattle to delay the development of resistance, especially in winter when this combination achieved 100% of efficacy. Thus, selection of anthelmintic resistance will never occur. In fact, this is one of the greatest challenges for the whole cattle production system: to be one step ahead of anthelmintic resistance., (© 2017 John Wiley & Sons Ltd.)

Background: The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites., Objective: The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites., Methods: In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method., Results: CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasidone sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was inhibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfoxide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by montelukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sulfoxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (approximately 56% of total) in the metabolic fate experiments., Conclusion: Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The emergence of resistance to albendazole has encouraged the search for effective alternatives for cysticercosis and other parasitosis treatment. RCB15 is a benzimidazole derivative that may be used against such diseases. The aim of this study was to determine the in vitro effect of RCB15 on the alternative energetic pathways of Taenia crassiceps cysticerci. The cysticerci were in vitro exposed to albendazole sulphoxide (ABZSO) or RCB15 at different concentrations during 24h. The cysticerci extract and the culture medium were analyzed through spectrophotometry and high performance liquid chromatography as to detect glucose, urea, creatinine and organic acids of the energetic metabolism. The drugs did not influence the protein catabolism. Fatty acids oxidation was enhanced through significantly higher acetate concentrations in the groups treated with RCB15 and ABZSO. Beta-hydroxybutyrate concentrations were decreased which indicates the use of fatty acids towards acetyl-CoA synthesis. There was a decrease in glucose uptake and pyruvate concentrations. The absence of lactate indicates the use of pyruvate in gluconeogenesis. Therefore it is possible to conclude that RCB15 enhanced the alternative energetic pathways of cysticerci in vitro exposed to different concentration, with emphasis on the fatty acids catabolism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

1. Precision-cut liver slices (PCLS) from food-producing animals have not been extensively used to study xenobiotic metabolism, and thus information on this field of research is sparse. 2. The aims of the present work were to further validate the technique of production and culture of bovine PCLS and to characterize the metabolic interaction between the anthelmintic albendazole (ABZ) and the flavin-monooxygenase (FMO) inhibitor methimazole (MTZ). 3. Nine steers were used as donors. PCLS were produced and incubated under two methods: a dynamic organ culture (DOC) incubator and a well-plate (WP) system. 4. Tissue viability, assessed through both structural and functional markers, was preserved throughout 12 h of incubation. ABZ was metabolized to its (+) and (-) albendazole sulfoxide stereoisomers (ABZSO) in bovine PCLS. The interaction between ABZ and MTZ resulted in a reduction (p < 0.001) in the rates of appearance of (+) ABZSO. Conversely, in presence of MTZ, the rates of appearance of (-) ABZSO increased under both systems (p < 0.05). 5. Both culture systems were suitable for assessing the interaction between ABZ and MTZ. 6. Overall, the results presented herein show that PCLS are a useful and reliable tool for short-term studies on metabolic drug-drug interactions in the bovine species.

A new, simple, accurate and precise high-performance thin-layer chromatographic method has been developed and validated for simultaneous determination of an anthelmintic drug, albendazole, and its active metabolite albendazole, sulfoxide. Planar chromatographic separation was performed on aluminum-backed layer of silica gel 60G F 254 using a mixture of toluene-acetonitrile-glacial acetic acid (7.0:2.9:0.1, v/v/v) as the mobile phase. For quantitation, the separated spots were scanned densitometrically at 225 nm. The retention factors (R f ) obtained under the established conditions were 0.76 ± 0.01 and 0.50 ± 0.01 and the regression plots were linear (r 2  ≥ 0.9997) in the concentration ranges 50-350 and 100-700 ng/band for albendazole and albendazole sulfoxide, respectively. The method was validated for linearity, specificity, accuracy (recovery) and precision, repeatability, stability and robustness. The limit of detection and limit of quantitation found were 9.84 and 29.81 ng/band for albendazole and 21.60 and 65.45 ng/band for albendazole sulfoxide, respectively. For plasma samples, solid-phase extraction of analytes yielded mean extraction recoveries of 87.59 and 87.13% for albendazole and albendazole sulfoxide, respectively. The method was successfully applied for the analysis of albendazole in pharmaceutical formulations with accuracy ≥99.32%., (Copyright © 2017 John Wiley & Sons, Ltd.)

Millions of people are treated with anthelmintics to control soil-transmitted helminth infections; yet, drug distribution in the plasma and gastrointestinal tract compartments and the pathway of drug uptake into gastrointestinal nematodes responsible for the pharmacological effect are unknown. We assessed the distribution and uptake of albendazole, albendazole sulfoxide, albendazole sulfone in the hookworm Heligmosomoides polygyrus in vitro and in vivo as well as the distribution and uptake of albendazole, mebendazole, and oxantel pamoate in the whipworm Trichuris muris in vitro and in vivo. Oral and intraperitoneal treatments (100 mg/kg) were studied. Drug quantities in helminths and host compartments (stomach, the contents and mucosa of the small and large intestine, and the plasma) were determined using HPLC-UV/vis and anthelmintic activities were recorded using phenotypic readout. The influence of 1-aminobenzotriazole (ABT), an irreversible and unspecific cytochrome P450 inhibitor, on albendazole disposition in mice harboring H. polygyrus was evaluated. In vivo, albendazole was found in quantities up to 10 nmol per ten H. polygyrus and up to 31 nmol per ten T. muris. ABT did not change the levels of albendazole or its metabolites in the plasma of mice harboring H. polygyrus or in H. polygyrus, whereas drug levels in the gastrointestinal tract of host mice doubled. Mebendazole and oxantel pamoate quantities per ten T. muris were as high as 21 nmol and 34 nmol, respectively. Albendazole revealed a very dynamic distribution and high rate of metabolism, hence, H. polygyrus and T. muris are exposed to albendazole and both metabolites via multiple pathways. Diffusion through the cuticle seems to be the crucial pathway of oxantel pamoate uptake into T. muris, and likely also for mebendazole. No relationship between concentrations measured in helminths and concentrations in plasma, intestinal content and mucosa of mice, or drug efficacy was noted for any of the drugs studied., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Albendazole (ABZ) is a sulfanyl-benzimidazole anthelmintic drug used worldwide in the treatment and prevention of parasitic diseases in animals and humans. Following oral administration, ABZ is rapidly oxidized into the pharmacologically active chiral sulfoxide metabolite known as ricobendazole (RBZ). As its achiral precursor, RBZ shows very low intestinal absorption due to its poor solubility in water (0.06mgmL -1 ). To the best of our knowledge, there is no known example in human medicine of a water-soluble salt form of racemic or enantiomerically pure RBZ. In the present study, we describe in detail the preparation of the sodium (Na) salt of the enantiomers of RBZ through a two-step process: i) the multi-milligram resolution of RBZ by HPLC on the amylose-based Chiralpak IG chiral stationary phase under polar organic mode; ii) the salification of the isolated enantiomers of RBZ by reaction with sodium hydroxide solution. The spectroscopic and chiroptical properties of the RBZ-Na enantiomers were determined. Due to their unique solubility in 0.01M phosphate buffer at physiological pH (14.49mgmL -1 ) and the high sample throughput obtained on semipreparative separation of the non-salified form, it is potentially possible to develop new anthelmintic enantiopure formulations with improved pharmacokinetic properties and lower toxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The purpose of this study was to enhance the dissolution properties of albendazole (ABZ) by the use of amorphous solid dispersions. Phase diagrams of ABZ-polymer binary mixtures generated from Flory-Huggins theory were used to assess miscibility and processability. Forced degradation studies showed that ABZ degraded upon exposure to hydrogen peroxide and 1 N NaOH at 80 °C for 5 min, and the degradants were albendazole sulfoxide (ABZSX), and ABZ impurity A, respectively. ABZ was chemically stable following exposure to 1 N HCl at 80 °C for one hour. Thermal degradation profiles show that ABZ, with and without Kollidon ® VA 64, degraded at 180 °C and 140 °C, respectively, which indicated that ABZ could likely be processed by thermal processing. Following hot melt extrusion, ABZ degraded up to 97.4%, while the amorphous ABZ solid dispersion was successfully prepared by spray drying. Spray-dried ABZ formulations using various types of acids (methanesulfonic acid, sulfuric acid and hydrochloric acid) and polymers (Kollidon ® VA 64, Soluplus ® and Eudragit ® E PO) were studied. The spray-dried ABZ with methanesulfonic acid and Kollidon ® VA 64 substantially improved non-sink dissolution in acidic media as compared to bulk ABZ (8-fold), physical mixture of ABZ:Kollidon ® VA 64 (5.6-fold) and ABZ mesylate salt (1.6-fold). No degradation was observed in the spray-dried product for up to six months and less than 5% after one-year storage. In conclusion, amorphous ABZ solid dispersions in combination with an acid and polymer can be prepared by spray drying to enhance dissolution and shelf-stability, whereas those made by melt extrusion are degraded.

This paper describes the development of analytical methods for the quantification of albendazole (ABZ) in fish feed and ABZ and its main known metabolites (albendazole sulfoxide, albendazole sulfone and albendazole aminosulfone) in fish fillet employing LC-MS/MS. In order to assess the reliability of the analytical methods, evaluation was undertaken as recommended by related guides proposed by the Brazilian Ministry of Agriculture for analytical method validation. The calibration curve for ABZ quantification in feed showed adequate linearity (r > 0.99), precision (CV < 1.03%) and trueness ranging from 99% to 101%. The method for ABZ residues in fish fillet involving the QuEChERS technique for sample extraction had adequate linearity (r > 0.99) for all analytes, precision (CV < 13%) and trueness around 100%, with CCα < 122 ng g - 1 and CCβ < 145 ng g - 1 . Besides, by aiming to avoid the risk of ABZ leaching from feed into the aquatic environment during fish medication via the oral route, a promising procedure for drug incorporation in the feed involving coating feed pellets with ethyl cellulose polymer containing ABZ was also evaluated. The medicated feed had good homogeneity (CV < 3%) and a lower release of ABZ (< 0.2%) from feed to water when the medicated feed stayed in the water for up to 15 min.

Albendazole (ABZ), a widely used anthelmintic, attributes its primary metabolite-albendazole sulfoxide (ABZSO)-as an effective agent against helminthes. For a purpose of long-lasting releasing ABZSO in a special lesion, the present study successfully manufactured ABZSO-loaded thermo-sensitive hydrogel, which was proved by FTIR and 1 H NMR, in the interim; in vitro and in vivo behaviors of the thermo-sensitive hydrogel containing ABZSO were studied too. The in vivo pharmacokinetics parameters indicated ABZSO-loaded hydrogel as a better choice for sustained release compared with simple ABZSO. Additionally, the effect of the prepared hydrogels against helminth was investigated by the lethality of Caenorhabditis elegans, the results indicated that the lethality of ABZSO-loaded hydrogel (1, 2, and 4 mg/ml, respectively) on C. elegans was higher than that of PLGA-PEG-PLGA group (P < 0.05). It suggested that the hydrogels loaded with albendazole sulfoxide could be considered highly effective against the nematode C. elegans.

Nematodicidal combinations have been proposed as a valid strategy to achieve effective nematode control in the presence of drug resistance. The goals of this study were: (1) to compare the clinical efficacy (therapeutic response) of ivermectin (IVM) and ricobendazole (RBZ) given subcutaneously either by separate or combined administration to calves naturally infected with gastrointestinal nematodes resistant to IVM, and (2) to evaluate the potential pharmacokinetic (PK) and/or pharmacodynamic (PD) interactions occurring after the co-administration of both anthelmintics. Sixty male calves naturally infected with gastrointestinal nematodes resistant to IVM were randomly allocated into four groups (n=15). Untreated control: animals not receiving anthelmintic treatment; IVM alone: animals treated with IVM by subcutaneous (SC) injection (0.2mg/kg); RBZ alone: animals received RBZ by the SC route (3.75mg/kg); IVM+RBZ: animals treated with IVM and RBZ (0.2 and 3.75mg/kg, respectively), by SC injection in two separates sites. Eight animals of each treated group were randomly selected to perform the PK study. Plasma samples were taken from those animals up to 28days post-treatment. IVM and RBZ plasma concentrations were quantified by HPLC. The therapeutic response was determined by faecal egg count reduction test (FECRT). The proportions of third-stage larvae (L3) recovered from coprocultures were used to calculate the efficacy against the main parasite genera. The daily total egg deposition for each experimental group was estimated. Similar pharmacokinetic trends were obtained for both IVM and RBZ allying the single-drug and the combined treatments, which indicates the absence of PK interactions between both anthelmintics. The observed overall clinical drug efficacies were 48% (IVM alone), 94% (RBZ alone) and 98% (IVM+RBZ). Haemonchus spp. and Cooperia spp. were recovered in the coproculture after IVM treatment, suggesting that resistance to IVM includes both genera. In fact, the efficacy against Cooperia spp. was 83% (IVM), 98% (RBZ) and 98% (IVM+RBZ), while the efficacy against Haemonchus spp. was 0% (IVM), 97% (RBZ) and 100% (IVM+RBZ). The combination was the only treatment that achieved 100% clinical efficacy against IVM-resistant Haemonchus spp. The total egg excretion was reduced to 49.9% (IVM alone group), 6.3% (RBZ alone group) and 1.8% (IVM+RBZ combined group) compared to the untreated control. Although the combined treatment did not significantly increase the overall clinical efficacy in the current natural field conditions, an additive effect was achieved against IVM-resistant nematodes. In fact, the combination obtained significantly higher efficacy against IVM-resistant Haemonchus spp. than RBZ alone. Additionally, the epidemiological relevance of the reduction in the number of eggs excreted following the combined treatment is not negligible and should be taken into account in future studies. Further work is required to understand the advantages of nematodicidal combinations in different natural anthelmintic resistance scenarios., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Human cysticercosis caused by Taenia crassiceps is unusual; however, it is an useful experimental model for cysticercosis studies. Benzimidazole derivatives are important antihelminthic drugs widely used against helminths. A novel compound 6-chloro-5-(1-naphthyloxy) -2-(trifluoromethyl)-1H-benzimidazole (RCB20) is a benzimidazole derivative less polar and more lipophilic. The aim of this study was to detect the effect of the RCB20 on the in vitro energetic metabolism of T. crassiceps cysticerci. For this, products of the metabolism both produced and secreted/excreted (S/E) by the parasite were detected through spectrophotometry and high performance liquid chromatography after exposure to 6.5 and 13 μM of RCB20 and albendazole sulfoxide (ABZSO). There was a gradual increase in the concentrations of glucose not uptaken by parasites exposed to both concentrations RCB20 and ABZSO. There was a higher concentration of all the organic acids related to the tricarboxilic acid cycle int the parasites exposed to RCB20. The structural differences between RCB20 and ABZSO result in different targets within the parasite and in a greater induction of the energetic pathways, such as the glycolysis and the TCA cycle. RCB20 is a good candidate as a substitute for anthelminthic benzimidazoles due to a differentiated site of action with similar outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Treatment failures of human cystic echinococcosis (CE) with albendazole (ABZ) have attributed to its low solubility and poor drug absorption rate, resulting in low drug level in plasma. The scolicidal effects of ABZ-loaded liposome nanoparticles have recently evaluated; however, these particles have several challenges due to their low encapsulated load. This investigation was designed to evaluate and compare in vitro apoptotic activities of ABZ sulfoxide (ABZs) and ABZs-loaded poly(lactic-co-glycolic acid) (PLGA)-PEG against protoscoleces (PSCs). ABZs-loaded PLGA-PEG was prepared by a double-emulsion method (W1/O/W2). Various concentrations of ABZs and ABZs-loaded PLGA-PEG (50, 100, 150, and 200 μg/ml) were experimentally tested against PSC of CE at different exposure times (5, 10, 20, 30, and 60 min). ABZs-loaded PLGA-PEG at concentrations of 150 and 200 μg/ml was able to act at a 100 % scolicidal rate in all exposure times (5 to 60 min), while ABZs at a concentration of 200 μg/ml demonstrated 94, 100, and 100 % mortality rates following 20, 30, and 60 min of exposure times, respectively. The messenger RNA (mRNA) expression of caspase-3 was assessed by semi-quantitative RT-PCR after 15 h of exposure. Caspase-3 mRNA expression was higher in both PSC treated with ABZs and PSC treated with ABZs-loaded PLGA-PEG than that in control groups (P < 0.05). No significant difference was observed between the apoptotic intensity of PSC treated with ABZs and that of PSC treated with ABZs-loaded PLGA-PEG (P > 0.05). DNA fragmentation assay and ultrastructural changes revealed that ABZs and ABZs-loaded PLGA-PEG induced the apoptosis of PSC by activation of caspase-3. The higher permeability and scolicidal rate of ABZs-loaded PLGA-PEG can be addressed as an effectual alternative strategy to improve the treatment of human CE.

Nitazoxanide (NTZ) is a broad-spectrum anti-parasitic drug used against a wide variety of protozoans and helminthes. Albendazole, its active metabolite albendazole sulfoxide (ABZSO), is one of the drugs of choice to treat both intestinal and tissue helminth and protozoan infections. However little is known regarding their impact on the metabolism of parasites. The aim of this study was to compare the in vitro effect of NTZ and ABZSO in the glycolysis of Taenia crassiceps cysticerci. The cysticerci were treated with 1.2; 0.6; 0.3 or 0.15 μg/mL of NTZ or ABZSO. Chromatographic and spectrophotometric analyses were performed in the culture medium and in the cysticerci extract. Regarding the glucose concentrations was possible to observe two responses: impair of the uptake and gluconeogenesis. The pyruvate concentrations were increased in the ABZSO treated group. Lactate concentrations were increased in the culture medium of NTZ treated groups. Therefore it was possible to infer that the metabolic acidosis was greater in the group treated with NTZ than in the ABZSO treated group indicating that this is one of the modes of action used by this drug to induce the parasite death., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Fasciolosis, a parasitic disease caused by the trematode Fasciola hepatica underreported is expanding both in human and animal population, throughout the world. The constant use of synthetic drugs to treat this condition has led to the natural selection of resistant strains of the parasite. Hence, there is a growing focus on the potential anti-helminthic properties of medicinal plants and phytopharmaceuticals. The current study assessed the potential anti-fasciolicide action of Momordica charantia leaf extracts and fractions on the eggs of F. hepatica parasites. The lyophilized crude extract (CE) of M. charantia leaves and its sub-fractions, obtained from liquid-liquid partitioning with organic solvents, were analysed by High Performance Liquid Chromatography (HPLC), suspended in 1% DMSO and used in in vitro tests. Quadruplicates of 50F. hepatica eggs were incubated at 23°C with M. charantia leaf CE in different concentrations. After 12days no larvae were formed in eggs incubated with CE concentrations above 12.5mg/mL. Eggs incubated with CE sub-fractions at concentrations of 1000, 100, 10, 1, 0.1, 0.01μg/mL affected embryonic development, with n-butanol presenting the strongest inhibition of miracidia formation. In contrast, on the 12th day, 90% of the miracidia hatched in the control experiments using 0.03% DMSO whereas embryogenesis was completely abolished with any concentration of albendazole sulphoxide ABZ(SO). Chemical analysis of the CE and sub-fractions revealed a prominent presence of flavonoids. HPLC-MS confirmed Quercetin to be one of the main flavonoids present in the CE and the n-butanol subfraction. This is the first study to analyse the potential anti-fasciolicide action of M. charantia leaf CE and subfractions., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Cystic echinococcosis (CE) is a widespread zoonosis caused by the species complex Echinococcus granulosus. Albendazole (ABZ)-the first-line anthelminthic drug for medical treatment of CE-is metabolized in vivo to the active derivative ABZ-sulphoxide (ABZ-SO). Target-site ABZ-SO concentrations in the hydatid cyst mediate the anthelminthic effect in CE. Primary outcome of this systematic review of individual patient data was the intra-cystic ABZ-SO concentration stratified by cyst size, location, calcification status and use of praziquantel. Studies reporting intra-cystic ABZ-SO concentrations in humans were identified by a systematic search. A pooled analysis of individual patient data was performed to assess intra-cystic concentrations. Pharmacokinetic data of 121 individual cysts were analysed. There was no correlation between plasma and intra-cystic ABZ-SO concentrations (rho = -0.03, p = 0.76). Intra-cystic drug concentrations were also not associated with sex and treatment duration. Use of praziquantel in combination with ABZ was associated with higher plasma (median 540 vs. 240 μg/L; p = 0.04) but not intra-cystic ABZ-SO concentrations (median 220 vs. 199 μg/L; p = 0.36). Relative drug concentrations in hepatic cysts were higher than in other cysts (0.8 vs. 0.4; p = 0.05). Intra-cystic concentrations were higher in calcified than non-calcified cysts (median 897 vs. 245 μg/L; p = 0.03). There was a trend towards higher intra-cystic concentrations in smaller sized cysts (β = -17.2 μg/L/cm; 95th CI, -35.9 to 1.6; p = 0.07). This study demonstrates that mean intra-cystic drug concentrations are similar to plasma concentrations on a population level. However, in individual patients plasma concentrations are not directly predictive for intra-cystic concentrations. The use of booster drugs was not associated with higher intra-cystic ABZ-SO concentrations in this analysis.

Anthelmintic resistance (AR) of gastrointestinal nematodes to macrocyclic lactones is an increasingly common worldwide phenomenon limiting cattle production. This has motivated the search for alternatives, such as new active compounds, added drug synergisms, different doses, and alternate administration routes. The aim of this study was the assessment of moxidectin (MXD) performance in feedlot calves with a history of AR to ivermectin (IVM). Crossbred female calves aged 6-7 months and weighing 163kg (SD=34kg) were divided into 3 groups of 35 animals each. They were assigned to the following antiparasitic treatment groups: IVM group (0.2mg/kg IVM); MXD group (0.2mg/kg MXD), and ricobendazole+levamisole (RBZ+LEV) group (7.5mg/kg RBZ+8mg/kg LEV). On days 0, 26, and 47, fecal samples were taken and the weight of each animal was registered. Anthelmintic efficacy (by fecal egg count reduction), total weight gain (TWG) and average daily weight gain (AWG) were compared between the groups. A mixed SAS procedure was used for statistical analysis. Fecal egg count reduction 26 days post-treatment (PT) was calculated at 28% for the IVM group, 85% for the MXD group, and 99% for the RBZ+LEV group. AWGs (Standard Error) of 1.095g (56), 1.264g (49), and 1.340g (52) were registered for the IVM, MXD, and RBZ+LEV groups, respectively (p<0.05). Coprocultures revealed that MXD more effectively reduced Haemonchus spp. and Cooperia spp. egg counts than IVM. This resulted in higher AWGs and TWGs for this group; similar results were seen for the RBZ+LEV group as well. In this study, animals treated with MXD gained about 160 more g/day than animals treated with IVM. This represents a gain of 16 USD per animal over the 47 day trial., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A rapid, simple and sensitive method was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for determination of albendazole sulfoxide (ABZOX) in human plasma. The plasma samples were extracted by protein precipitation using albendazole sulfoxide-d3 as internal standard (IS). The chromatographic separation was performed on Waters Xbridge C18Column (100×4.6mm, 3.5μm) with a mobile phase consisting of ammonia solution, water and methanol at a flow rate of 0.70mL/min. ABZOX was detected and identified by mass spectrometry with electrospray ionization (ESI) in positive ion and multiple-reaction monitoring (MRM) mode. The method was linear in the range of 3-1500ng/mL for ABZOX. This method was successfully applied to the bioequivalence study in human plasma samples., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Biochemical studies of benzimidazole derivatives are important to determine their mode of action and activity against parasites. The lack of antihelminthic alternatives to treat parasitic infections and albendazole resistance cases make the search for new antiparasitary drugs of utmost importance. The 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20) is a benzimidazole derivative with promising effect. This study evaluated the effect of different concentrations of RCB20 in the alternative energetic pathway of in vitro Taenia crassiceps cysticerci. The parasites were in vitro exposed to 6.5 and 13 µM of RCB20 and albendazole sulfoxide (ABZSO). The quantification of acetate, acetoacetate, β-hydroxybutyrate, fumarate and propionate was performed by high-performance liquid chromatography. The quantification of urea, creatinine and total proteins was performed by spectrophotometry. The increase in β-hydroxybutyrate reflects the enhancement of the fatty acid oxidation in the treated groups. Volatile fatty acids secretion, acetate and propionate, was increased in the treated groups. The secretion mechanisms of the treated parasites were impaired due to organic acids increased concentrations in the cysticerci. It is possible to conclude that the metabolic effect on alternative energetic pathways is slightly increased in the parasites treated with RCB20 than the ones treated with ABZSO.

The comparative pharmacokinetic behavior of albendazole (ABZ) and its new benzimidazol prodrug [1-tert-butyloxycarbonyl-5-propylthio-1-H-benzimidazol-2ylcarbamate of methyl] (ABZBoc), following their oral administration (10mg/kg) to healthy dogs was explored. Blood samples were obtained serially over a 24h period after treatment, then the plasma was analyzed by high-performance liquid chromatography (HPLC) to search the albendazole metabolites (ABZSO and ABZSO2). However, the albendazole parent drug was not detectable at any time after both treatments (ABZ and ABZBoc). By albendazole metabolites (ABZSO and ABZSO2) were the analytes recovered in the plasma after oral administration of ABZ and ABZBoc. Furthermore, some amounts of ABZBoc were also available in the plasma samples treated with this new produg. The plasma profile of each analyte followed a similar pattern after both treatments, the active metabolite (ABZSO) was the major analyte recovered in plasma (between 1 and 24h post-treatment). The pharmacokinetic parameters of both groups were calculated (Cmax, Tmax, t1/2, AUC0-›∞), and analyzed using the Student's t-test, P<0.05. Thus,the pharmacokinetic analysis indicated four statistically significant changes in the pharmacokinetic parameters defined above of the albendazole metabolites (ABZSO, ABZSO2) between the group treated with albendazole (group A) and that treated with ABZBoc prodrug (group B). Hence, the levels of the various pharmacokinetics parameters were low in the group treated with prodrug, as well they did not reach equivalent concentrations to that of albendazole. These differences between albendazole and its new prodrug may be explained by the fact that ABZBoc prodrug was not effectively reduced in the intestine of dogs., (Copyright © 2015 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The aims of this study were to compare the pharmacokinetics of albendazole sulfoxide (ABZ-SO, ricobendazole) in goats and sheep at a dose of 5 g/kg bodyweight (BW), after intravenous (IV) and subcutaneous (SC) administrations, and to investigate the effects of increased doses (10 and 15 mg/kg BW) on the plasma disposition of ABZ-SO in goats following SC administration. A total of 16 goats (Capra aegagrus hircus, eight males and eight females) and 8 sheep (Ovis aries, four males and four females) 12-16 months old and weighing 20-32 kg, were used. The study was designed according to two-phase crossover study protocol. In Phase-1, eight sheep were assigned as Group I and 16 goats were allocated into two groups (Group II and Group III). ABZ-SO was applied to Group I (sheep) and Group II (goats) animals subcutaneously, and to Group III (goats) animals intravenously, all at a dose rate of 5 mg/kg BW. In Phase-2, the sheep in the Group I received ABZ-SO intravenously in a dose of 5 mg/kg BW; the goats in Group II and Group III received ABZ-SO subcutaneously at a dose of 10 mg/kg and 15 mg/kg BW, respectively. Blood samples were collected from the jugular vein at different times between 1 and 120 h after drug administrations. The plasma concentrations of ABZ-SO and its metabolites were analysed by high performance liquid chromatography., Results: In goats, the area under the curve, terminal half-life and plasma persistence of ABZ-SO were significantly smaller and shorter, respectively, compared with those observed in sheep following both IV and SC administrations at a dose of 5 mg/kg BW. On the other side, dose-dependent plasma dispositions of ABZ-SO were observed following SC administration at increased doses (10 and 15 mg/kg) in goats., Conclusions: Consequently, ABZ-SO might be used at higher doses to provide higher plasma concentration and thus to achieve greater efficacy against the target parasites.

This work presents an in vitro investigation of the effect of protein restriction on the metabolism of albendazole (ABZ). This study was conducted using liver microsomal fractions obtained from Wistar rats. For the quantitative analysis, a multidimensional High Performance Liquid Chromatography (2D HPLC) method was fully validated for the determination of the ABZ metabolites: albendazole sulfoxide, albendazole sulfone and albendazole 2-aminesulfone. The target compounds were directly extracted using a C8-RAM-BSA column (5.0x0.46 cm i.d.) and analyzed on a chromatographic chiral column containing amylose tris(3,5-dimethylphenylcarbamate) (150x4.6 mm i.d.). The in vitro biotransformation results showed that the protein restriction influenced the oxidative metabolism of ABZ. The production of R-(+)-ABZ-SO (1309 nmol/L) and S-(-)-ABZ-SO (1456 nmol/L) was higher in the control animals than in the animals fed with a diet containing 6% protein, which produced 778.7 nmol/L and 709.5 nmol/L for R-(+) and S-(-)-ABZ-SO enantiomers, respectively. These results were statistically inspected by Student´s t test and the results showed a significant difference between the two means (p<0.05). Moreover, the production of ABZ-SO enantiomers was enantioselective where the S-(-)-ABZ-SO was formed in greater amounts than the R-(+)-ABZ-SO in control animals (p=0.0231). However, the enantioselectivity was not observed when the in vitro biotransformation of ABZ was conducted using the microsomal fractions obtained from protein restriction animals (p>0.05). Furthermore, animal nutritional condition could affect the pattern of ABZ sulphoxidation indicating that the protein nutrition affect primarily the formation of R-(+)-ABZSO and S-(-)-ABZ-SO enantiomers.

The aim of this study was to evaluate, in a commercial feedlot, the effect of different anthelmintic drugs on the productivity of naturally infected calves from a cow-calf operation, where resistance to ivermectin (IVM) has been previously detected. The study began with the random selection of 80 calves whose weight was 132 ± 12 kg. Four groups were made: IVM, ricobendazole (RBZ), ricobendazole plus levamisol (RBZ + LEV) and a control group (CG) without treatment. On days 0, 21, 42, 70, 98 and 126, manual collection of fecal matter and individual weight were registered. Mixed SAS procedure was used for statistical analysis. The percentages of fecal egg count reduction test (FECRT) calculated 21 days post treatment (PT) were 18%, 96% and 100% for the IVM, RBZ and RBZ + LEV groups, respectively. Body weight (± SEM) at the end of the trial was 266 kg (± 0.9), 269 kg (± 1.1), 276 kg (± 1.3), 280 kg (± 1.9) for CG, IVM, RBZ and RBZ + LEV groups, respectively. The effect on live weight was highly significant (p < 0001). After 126 days of fattening, the deleterious effect of the combination of Cooperia and Haemonchus in the IVM group on body weight was evident. Undetected animals carrying anthelmintic resistant (AR) worms entering the feedlot, could cause major productivity losses., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A strain, designated as FM-6, was isolated from fish. Based on the results of phenotypic, physiological characteristics, genotypic and phylogenetic analysis, strain FM-6 was finally identified as Paenibacillus sp. When albendazole was provided as the sole carbon source, strain FM-6 could grow and transform albendazole. About 82.7 % albendazole (50 mg/L) was transformed by strain FM-6 after 5 days incubation at 30 °C, 160 rpm. With HPLC-MS method, the transforming product of albendazole was researched. Based on the molecular weight and the retention time, product was identified as albendazole sulfoxide and the transforming pathway of albendazole by strain FM-6 was proposed finally. The optimum temperature and pH for the bacterium growth and albendazole transformation by strain FM-6 were both 30 °C and 7.0. Moreover, the optimum concentration of albendazole for the bacterium growth was 50 mg/L. Coupled with practical production, 50 mg/L was the optimum concentration of albendazole transformation for strain FM-6. This study highlights an important potential use of strain FM-6 for producing albendazole sulfoxide.

Albendazole is a broad-spectrum parasiticide with high effectiveness and low host toxicity. No method is currently available for measuring albendazole and its metabolites in silkworm hemolymph. This study describes a rapid, selective, sensitive, synchronous and reliable detection method for albendazole and its metabolites in silkworm hemolymph using ultrafast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-MS/MS). The method is liquid-liquid extraction followed by UFLC separation and quantification in an MS/MS system with positive electrospray ionization in multiple reaction monitoring mode. Precursor-to-product ion transitions were monitored at 266.100 to 234.100 for albendazole (ABZ), 282.200 to 208.100 for albendazole sulfoxide (ABZSO), 298.200 to 159.100 for albendazole sulfone (ABZSO2) and 240.200 to 133.100 for albendazole amino sulfone (ABZSO2-NH2). Calibration curves had good linearities with R2 of 0.9905-0.9972. Limits of quantitation (LOQs) were 1.32 ng/mL for ABZ, 16.67 ng/mL for ABZSO, 0.76 ng/mL for ABZSO2 and 5.94 ng/mL for ABZSO2-NH2. Recoveries were 93.12%-103.83% for ABZ, 66.51%-108.51% for ABZSO, 96.85%-105.6% for ABZSO2 and 96.46%-106.14% for ABZSO2-NH2, (RSDs <8%). Accuracy, precision and stability tests showed acceptable variation in quality control (QC) samples. This analytical method successfully determined albendazole and its metabolites in silkworm hemolymph in a pharmacokinetic study. The results of single-dose treatment suggested that the concentrations of ABZ, ABZSO and ABZSO2 increased and then fell, while ABZSO2-NH2 level was low without obvious change. Different trends were observed for multi-dose treatment, with concentrations of ABZSO and ABZSO2 rising over time.

Cystic echinococcosis is a chronic, complex, and still neglected disease. Although albendazole has demonstrated efficacy, only about one-third of patients experience complete remission or cure and 30-50% of treated patients develop some evidence of a therapeutic response. Different strategies have been developed in order to improve the albendazole water solubility and dissolution rate. The aim of the current work was to investigate the chemoprophylactic and clinical efficacy of an albendazole:poloxamer 188 solid dispersion formulation on mice infected with Echinococcus granulosus metacestodes. Albendazole formulated as solid dispersion had greater chemoprophylactic and clinical efficacy than albendazole alone. The improved in therapeutic efficacy could be a consequence of the increase in the systemic availability of albendazole sulfoxide. The work reported here demonstrates that in vivo treatment with albendazole:poloxamer 188 impairs the development of the hydatid cysts. This new pharmacotechnically based strategy could be a suitable alternative for treating cystic echinococcosis in humans., (Copyright © 2014 Elsevier B.V. All rights reserved.)