Pharmacokinetics and tissue residues of albendazole sulphoxide and its metabolites in donkey after intramuscular injection.

BACKGROUND: Various anti-parasitic drugs are used to control donkey parasitic diseases. The abuse of donkey drugs leads to the disposition of residues in the edible parts of treated donkeys. OBJECTIVES: The aim of this study was to (1) analyse the pharmacokinetics of ABZSO to serve as reference for the dosage regimen in donkey; and (2) calculate the withdrawal times of the ABZSO in the tissue of the donkey. METHODS: The concentrations of ABZSO and its metabolites in plasma and tissues were determined using high-performance liquid chromatography with an ultraviolet detector. Pharmacokinetic analysis was performed by the programme 3p97. RESULTS: The plasma concentrations of ABZSO and ABZSO2 concentration-time data in donkey conformed to the absorption one-compartment open model. The t 1 / 2 k e ${{{t1}} \!\mathord{/ {\vphantom { {2{{k}_{\mathrm{e}}}}}}}}$ of ABZSO was 0.67 h, whereas the t1/2 k e was 12.93 h; the Cmax and the Tp were calculated as 0.58 µg mL-1 and 3.01 h. The Vd/F of ABZSO was estimated to be 10.92 L kg-1; the area under the curve (AUC) was 12.81 µg mL-1 h. The Cmax and AUC values of ABZSO were higher than those of ABZSO2; however, t1/2 K e and Vd/F were lower. Other pharmacokinetics parameters were similar between the two metabolites. CONCLUSIONS: The results revealed that ABZSO2 was the main metabolite of ABZSO in donkey plasma. The concentrations of ABZSO and its chief metabolite (ABZSO2) were detected in liver, kidney, skin and muscle; however, ABZ-SO2NH2 was only detected in liver and kidney. The results also revealed that the depletion of ABZSO and its metabolite in donkey was longer, especially in skin.

Mathematical and Pharmacokinetic Approaches for the Design of New 3D Printing Inks Using Ricobendazole.

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 Cmax, and the AUC0-∞. 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 AUC0-∞ 2.16-fold higher than that obtained in animals treated with RBZ loaded in conventional tablets.

Floating Ricobendazole Delivery Systems: A 3D Printing Method by Co-Extrusion of Sodium Alginate and Calcium Chloride.

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 CaCl2 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.

In vivo exposure of Albendazole sulphoxide by Haemonchus contortus and correlation between plasma and target tissue or gastrointestinal content dispositions in goats.

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 ABZSO2 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.

A new approach for microextraction of trace albendazole sulfoxide drug from the samples of human plasma and urine, and water by the molecularly imprinted polymer nanoparticles combined with HPLC.

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%.

Evaluation of the efficacy of albendazole sulfoxide (ABZ-SO)-loaded chitosan-PLGA nanoparticles in the treatment of cystic echinococcosis in laboratory mice.

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.

A combined in vitro in-silico approach to predict the oral bioavailability of borderline BCS Class II/IV weak base albendazole and its main metabolite albendazole sulfoxide.

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.

Efficacy of novel albendazole salt formulations against secondary cystic echinococcosis in experimentally infected mice.

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.

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults.

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.

Design of novel oral ricobendazole formulation applying melting solidification printing process (MESO-PP): An innovative solvent-free alternative method for 3D printing using a simplified concept and low temperature.

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 (r2 = 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; r2 = 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.

Ricobendazole nanocrystals obtained by media milling and spray drying: Pharmacokinetic comparison with the micronized form of the drug.

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 AUC0-∞ 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.

Impact on beef cattle productivity of infection with anthelmintic-resistant nematodes.

ABSTRACTAims: 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.

Case Report: Analytically Confirmed Severe Albenzadole Overdose Presenting with Alopecia and Pancytopenia.

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 × 103 cells/mm3, with an absolute neutrophil count (ANC) of 0 × 103 cells/mm3) 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 × 103 cells/mm3. 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.

In vitro nitazoxanide exposure affects energetic metabolism of Taenia crassiceps.

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.

New HPLC-MS method for rapid and simultaneous quantification of doxycycline, diethylcarbamazine and albendazole metabolites in rat plasma and organs after concomitant oral administration.

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 (r2) ≥ 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.

Pharmacokinetics of Albendazole, Albendazole Sulfoxide, and Albendazole Sulfone Determined from Plasma, Blood, Dried-Blood Spots, and Mitra Samples of Hookworm-Infected Adolescents.

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 (t1/2 = ∼1.5 h), time to reach the maximum concentration (tmax = ∼2 h), and maximum concentration (Cmax = 12.5 to 26.5 ng/ml) of albendazole were observed in the four matrices. The metabolites reached Cmax after ∼4 h with a t1/2 of ca. 7 to 8 h. A statistically significant difference in albendazole sulfone's t1/2 as determined by using DBS and wet samples was detected. Cmax of albendazole sulfoxide (288 to 380 ng/ml) did not differ among the matrices, but higher Cmax 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.

Albendazole Sulfoxide Plasma Levels and Efficacy of Antiparasitic Treatment in Patients With Parenchymal Neurocysticercosis.

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.

Factors Associated With Cysticidal Treatment Response in Extraparenchymal Neurocysticercosis.

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.

Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer.

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-ß-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.

In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole , Aldicarb, Methiocarb, Montelukast and Ziprasidone.

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.