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.

Metabolic mechanism and pharmacological study of albendazole in secondary hepatic alveolar echinococcosis (HAE) model rats.

Albendazole (ABZ) is the primary treatment for alveolar echinococcosis (AE); however, its limited solubility impacts oral bioavailability, affecting therapeutic outcomes. In this study, various ABZ-solubilizing formulations, including albendazole crystal dispersion system (ABZ-CSD), albendazole hydrochloride-hydroxypropyl methylcellulose phthalate composite (TABZ-HCl-H), and albendazole hydroxyethyl sulfonate-hydroxypropyl methylcellulose phthalate composite (TABZ-HES-H), were developed and evaluated. Physicochemical properties as well as liver enzyme activity were analyzed and their pharmacodynamics in an anti-secondary hepatic alveolar echinococcosis (HAE) rat model were investigated. The formulations demonstrated improved solubility, exhibiting enhanced inhibitory effects on microcysts in HAE model rats compared to albendazole tablets. However, altered hepatic drug-metabolizing enzymes in HAE model rats led to increased ABZ levels and reduced ABZ-SO production, potentially elevating drug toxicity. These findings emphasize the importance of dose adjustments in patient administration, considering the impact of alveolar echinococcosis on rat hepatic drug metabolism.

1,3-Substituted ß-Carboline Derivatives as Potent Chemotherapy for the Treatment of Cystic Echinococcosis.

Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted ß-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.

The Use of Cyclodextrin Inclusion Complexes to Increase the Solubility and Pharmacokinetic Profile of Albendazole.

Albendazole is the preferred deworming drug and has strong insecticidal effects on human and animal helminth parasites, showing remarkable activity against hepatocellular carcinoma and colorectal cancer cells. However, it is classified as being in class II in the Biopharmaceutics Classification System due to its poor water solubility (0.2 mg/L) and high permeability, which make the clinical application of albendazole impractical. Through complexation with methyl-ß-cyclodextrin, as the best result so far, albendazole's water solubility was increased by 150,000 times, and albendazole could be 90% released during the first 10 min. In an in vivo pharmacokinetic study, the Cmax and Tmax of the active metabolized sulfoxide were changed from 2.81 µg/mL at 3 h to 10.2 µg/mL at 6 h and the AUC0-48 was increased from 50.72 h⁎µg/mL to 119.95 h⁎µg/mL, indicating that the inclusion complex obtained can be used as a new oral therapeutic anti-anthelmintic and anti-tumor agent formulation.

Population pharmacokinetics of ivermectin after mass drug administration in lymphatic filariasis endemic communities of Tanzania.

Ivermectin (IVM) is a drug of choice used with albendazole for mass drug administration (MDA) to halt transmission of lymphatic filariasis. We investigated IVM pharmacokinetic (PK) variability for its dose optimization during MDA. PK samples were collected at 0, 2, 4, and 6 h from individuals weighing greater than 15 kg (n = 468) receiving IVM (3-, 6-, 9-, or 12 mg) and ALB (400 mg) during an MDA campaign in Tanzania. Individual characteristics, including demographics, laboratory/clinical parameters, and pharmacogenetic variations were assessed. IVM plasma concentrations were quantified by liquid-chromatography tandem mass spectrometry and analyzed using population-(PopPK) modeling. A two-compartment model with transit absorption kinetics, and allometrically scaled oral clearance (CL/F) and central volume (Vc /F) was adapted. Fitting of the model to the data identified 48% higher bioavailability for the 3 mg dose compared to higher doses and identified a subpopulation with 97% higher mean transit time (MTT). The final estimates for CL/F, Vc /F, intercompartment clearance, peripheral volume, MTT, and absorption rate constant for a 70 kg person (on dose other than 3 mg) were 7.7 L/h, 147 L, 20.4 L/h, 207 L, 1.5 h, and 0.71/h, respectively. Monte-Carlo simulations indicated that weight-based dosing provides comparable exposure across weight bands, but height-based dosing with capping IVM dose at 12 mg for individuals with height greater than 160 cm underdoses those weighing greater than 70 kg. Variability in IVM PKs is partly explained by body weight and dose. The established PopPK model can be used for IVM dose optimization. Height-based pole dosing results in varying IVM exposure in different weight bands, hence using weighing scales for IVM dosing during MDA is recommended.

Giardia duodenalis: Flavohemoglobin is involved in drug biotransformation and resistance to albendazole.

Giardia duodenalis causes giardiasis, a major diarrheal disease in humans worldwide whose treatment relies mainly on metronidazole (MTZ) and albendazole (ABZ). The emergence of ABZ resistance in this parasite has prompted studies to elucidate the molecular mechanisms underlying this phenomenon. G. duodenalis trophozoites convert ABZ into its sulfoxide (ABZSO) and sulfone (ABZSOO) forms, despite lacking canonical enzymes involved in these processes, such as cytochrome P450s (CYP450s) and flavin-containing monooxygenases (FMOs). This study aims to identify the enzyme responsible for ABZ metabolism and its role in ABZ resistance in G. duodenalis. We first determined that the iron-containing cofactor heme induces higher mRNA expression levels of flavohemoglobin (gFlHb) in Giardia trophozoites. Molecular docking analyses predict favorable interactions of gFlHb with ABZ, ABZSO and ABZSOO. Spectral analyses of recombinant gFlHb in the presence of ABZ, ABZSO and ABZSOO showed high affinities for each of these compounds with Kd values of 22.7, 19.1 and 23.8 nM respectively. ABZ and ABZSO enhanced gFlHb NADH oxidase activity (turnover number 14.5 min-1), whereas LC-MS/MS analyses of the reaction products showed that gFlHb slowly oxygenates ABZ into ABZSO at a much lower rate (turnover number 0.01 min-1). Further spectroscopic analyses showed that ABZ is indirectly oxidized to ABZSO by superoxide generated from the NADH oxidase activity of gFlHb. In a similar manner, the superoxide-generating enzyme xanthine oxidase was able to produce ABZSO in the presence of xanthine and ABZ. Interestingly, we find that gFlHb mRNA expression is lower in albendazole-resistant clones compared to those that are sensitive to this drug. Furthermore, all albendazole-resistant clones transfected to overexpress gFlHb displayed higher susceptibility to the drug than the parent clones. Collectively these findings indicate a role for gFlHb in ABZ conversion to its sulfoxide and that gFlHb down-regulation acts as a passive pharmacokinetic mechanism of resistance in this parasite.

Quantitative Analysis of Abamectin, Albendazole, Levamisole HCl and Closantel in Q-DRENCH Oral Suspension Using a Stability-Indicating HPLC-DAD Method.

Combination therapy of many anthelmintic drugs has been used to achieve fast animal curing. Q-DRENCH is an oral suspension, containing four different active drugs against GIT worms in sheep, commonly used in Australia and New Zeeland. The anti-parasitic drugs are Albendazole (ALB), Levamisole HCl (LEV), Abamectin (ABA), and Closantel (CLO). The main purpose of this study is to present a new simultaneous stability-indicting HPLC-DAD method for the analysis of the four drugs. The recommended liquid system was 1 mL of Triethylamine/L water, adjusting the pH to 3.5 by glacial acetic acid: acetonitrile solvent (20:80, v/v). Isocratic elusion achieved the desired results of separation at a 2 mL/min flow rate using Zorbax C-18 as a stationary phase. Detection was performed at 210 nm. The linearity ranges were 15.15 to 93.75 µg/mL for ALB, 25 to 150 µg/mL for LEV, 30 to 150 µg/mL for ABA, and 11.7 to 140.63 µg/mL for CLO. Moreover, the final greenness score was 0.62 using the AGREE tool, which reflects the eco-friendly nature. Moreover, the four drugs were determined successfully in the presence of their stressful degradation products. This work presents the first chromatographic method for simultaneous analysis for Q-DRENCH oral suspension drugs in the presence of their stressful degradation products.

Depletion study and estimation of the withdrawal period for albendazole in tambaqui (Colossoma macropomum) parasitised by acanthocephalan (Neoechinorhynchus buttnerae) treated with albendazole-containing feed.

This study provides the first data related to albendazole (ABZ) and its main metabolites [albendazole sulphoxide (ABZSO), albendazole sulphone (ABZSO2), and albendazole-2-amino sulphone (ABZ-2-NH2-SO2)] residue depletion in tambaqui (Colossoma macropomum) parasitised by acanthocephalan (Neoechinorhynchus buttnerae). The ABZ withdrawal period was also calculated. The fish received a daily dose of 10 mg ABZ kg-1 body weight (b.w.) via medicated feed for 34 days. Samples of target tissue (muscle plus skin in natural proportions) were collected 24, 48, 72, 120, 168, 240, and 336 h after the end of ABZ administration. The quantitation of ABZ residues and its metabolites in the target tissue was performed using a validated ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analytical method. After treatment, ABZ in the target tissue was rapidly metabolised over time, and ABZSO was the most persistent metabolite and was shown to be at the highest levels in the target tissue. Considering the maximum residue limit (MRL) established by Codex Alimentarius in the muscle (100 µg kg-1, species not specified), a withdrawal period of 4 days (112 °C-day) was estimated for the total residue (sum of ABZ and its metabolite residues). Considering data reported in the literature and data obtained in this study, it is suggested that the total residue be considered as marker residue to be adopted for fish in the legislative framework.

Albendazole Nanocrystal-Based Dissolving Microneedles with Improved Pharmacokinetic Performance for Enhanced Treatment of Cystic Echinococcosis.

Cystic echinococcosis (CE) is a zoonosis caused by Echinococcus spp., affecting both humans and animals' lives. Current treatment of CE by oral administration of albendazole (ABZ) is hampered by several limitations. The poor aqueous solubility and the rapid metabolism of ABZ in the liver are the main issues, leading to lack of efficacy of the treatment. In the present study, we developed a nanocrystalline (NC) formulation of ABZ to be delivered intradermally using dissolving microneedles (DMNs). The NC formulation was developed using milling in an ultrasmall-scale device. Following several screenings, Pluronic F127 was selected as a suitable stabilizer, producing NCs with around 400 nm in size with narrow particle distribution. The crystallinity of ABZ was maintained as observed by DSC and XRD analysis. The NC approach was able to improve the dissolution percentage of ABZ by approximately three-fold. Furthermore, the incorporation of NCs into DMNs using the combination of poly(vinylpyrrolidone) and poly(vinyl alcohol) formed sharp needles with sufficient mechanical strength and insertion properties. Dermatokinetic studies revealed that >25% of ABZ was localized in the dermis of excised neonatal porcine skin up to 48 h after DMN administration. In in vivo pharmacokinetic studies, the AUC and relative bioavailability values of ABZ delivered by NC-loaded DMNs were found to be significantly higher than those obtained after oral administration of coarse suspension of ABZ or ABZ-NCs, as well as DMNs delivering coarse ABZ as indicated by the relative bioavailability values of >100%. Therefore, the combination approach developed in this study could maintain the systemic circulation of ABZ, which could be possibly caused by avoiding the first-pass metabolism in the liver. This could be beneficial to improve the efficacy of ABZ in CE treatment.

Albendazole-loaded cubosomes interrupt the ERK1/2-HIF-1α-p300/CREB axis in mice intoxicated with diethylnitrosamine: A new paradigm in drug repurposing for the inhibition of hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.

Solid Polymeric Nanoparticles of Albendazole: Synthesis, Physico-Chemical Characterization and Biological Activity.

Albendazole is a benzimidazole derivative with documented antitumor activity and low toxicity to healthy cells. The major disadvantage in terms of clinical use is its low aqueous solubility which limits its bioavailability. Albendazole was incorporated into stable and homogeneous polyurethane structures with the aim of obtaining an improved drug delivery system model. Spectral and thermal analysis was used to investigate the encapsulation process and confirmed the presence of albendazole inside the nanoparticles. The in vitro anticancer properties of albendazole encapsulated in polyurethane structures versus the un-encapsulated compound were tested on two breast cancer cell lines, MCF-7 and MDA-MB-231, in terms of cellular viability and apoptosis induction. The study showed that the encapsulation process enhanced the antitumor activity of albendazole on the MCF-7 and MDA-MB-23 breast cancer lines. The cytotoxic activity manifested in a concentration-dependent manner and was accompanied by changes in cell morphology and nuclear fragmentation.

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.

Albendazole solid dispersions prepared using PEG6000 and Poloxamer188: formulation, characterization and in vivo evaluation.

This study aimed to optimize the preparation process of albendazole (ABZ) solid dispersion (SD) and enhance its dissolution rate and oral bioavailability in dogs. The ABZ-SD formulations were prepared by a fusion method with ABZ and polyethylene glycol 6000 (PEG 6000), poloxamer 188 (P 188) polymers at various weight ratios or the combination of PEG 6000&P 188. The characterizations of the optimal formulations were performed by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), in vitro dissolution test and molecular docking. The in vivo pharmacokinetic study was conducted in beagle dogs. As a result, ABZ solid dispersion based on PEG 6000&P 188 (1:2) was successfully prepared. The ABZ-SD formulation could significantly improve the apparent solubility and dissolution rate of ABZ compared with commercial tablets. Furthermore, the water solubility of ABZ-SD was improved mainly based on hydrogen bond association. Besides, at an oral dosage of 15 mg/kg ABZ, the SDs had higher Cmax values and areas under the curve (AUCs) compared to those of commercial ABZ tablets. Preparation of ABZ-loaded SDs by PEG 6000&P 188 is a promising strategy to improve the oral bioavailability of ABZ.

Effect of Genotype and Sex of the Host on the Bioavailability of Novel Albendazole Microcrystals Based on Chitosan and Cellulose Derivatives.

Albendazole (ABZ), an anthelmintic compound widely used in the treatment of systemic nematode infections, is included in the list of class II drugs based on the Biopharmaceutical Classification System. ABZ has limited effectiveness due to its poor water solubility and consequent low bioavailability. Bioavailability of novel ABZ microcrystals based on hydroxyethylcellulose (S4A) or chitosan (S10A) was studied in male and female mice of two inbred lines, from the murine CBi-IGE model of trichinellosis, differing in susceptibility to this parasitosis (line CBi/L, resistant; line CBi+, susceptible). ABZ microcrystals were administered orally, and albendazole sulfoxide (ABZSO) was quantified in plasma by high-performance liquid chromatography. Mice given the microcrystals showed a significant increase in maximum plasmatic concentration (Cmax) compared with those receiving pure ABZ (P < 0.01). In both genotypes, males and females given S4A had higher Cmax than those receiving S10A (P < 0.05). CBi/L showed a greater Cmax than CBi+ (significantly different only in females treated with S4A (P = 0.001)). CBi/L females attained a higher Cmax than males (P < 0.05). No sex effect was observed for this variable in CBi+ (P > 0.05). The results of the pharmacokinetic analysis indicate that the microcrystalline formulations optimize ABZ bioavailability, both in males and females, S4A being the best system in CBi/L mice and S10A in CBi+. In summary, the microcrystals increased ABZ bioavailability, and under the conditions of this investigation, both host genotype and sex influenced the pharmacokinetic parameters measured.

Pharmacokinetics and tissue distribution study of liposomal albendazole in naturally Echinococcus granulosus infected sheep by a validated UPLC-Q-TOF-MS method.

Albendazole (ABZ) is the first-line drug in treating echinococcosis, which is recommended by WHO. To address the poor bioavailability of albendazole, liposomal albendazole was formulated and is available in our hospital for many years. In this study, a sensitive, reliable and accurate UPLC-Q-TOF-MS method was developed and validated for the determination of albendazole and its metabolites, albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO2) and albendazole-2-aminosulfone (ABZSO2NH2) in naturally echinococcus granulosus (E. granulosus) infected sheep plasma and tissues with mebendazole (MBZ) as the internal standard (IS). Plasma and tissues samples were prepared by protein precipitation method. The separation was performed on an ACQUITY UPLC® BEH C18 column (2.1 × 50 mm, 1.7 µm) with a gradient mobile phase consisting of methanol and water containing 0.1% formic acid at 0.4 mL/min. The detection was performed on a quadrupole time-of-flight (Q-TOF) high-resolution mass spectrometer using positive electrospray ionization (ESI) source with a chromatographic run time of 6.0 min. The detection was operated using target ions of [M + H]+ at m/z 266.096 for ABZ, m/z 282.091 for ABZSO, m/z 298.086 for ABZSO2, m/z 240.081 for ABZSO2NH2 and m/z 296.104 for IS in selective ion mode, respectively. This method was validated in terms of selectivity, linearity, precision, accuracy, recovery, matrix effect, dilution effect, carryover effects, stability, calibration curve and LLOQ. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. This method has been successfully applied to the pharmacokinetic study following single and multiple oral dose of 10 mg/kg liposomal albendazole, and tissue distribution study following multiple oral dose of 10 mg/kg, with emulsion albendazole as the reference preparation. The results in the article will provide valuable information for use in clinical applications of liposomal albendazole and also be beneficial for further development of liposomal albendazole in future studies.

Recent advances in surgical strategies for alveolar echinococcosis of the liver.

Liver resection is the safest intervention for alveolar echinococcosis (AE), because the only potentially curative treatment is complete removal of the lesion. In combination with medical anthelmintic treatment, a safe distance of at least 1 mm is permissible in this procedure. Even when liver resection does not cure AE, good long-term survival outcomes can be achieved if most of the lesion has been removed and the disease is controlled with lifelong benzimidazole treatment. If the residual lesion is comparatively small and does not contain a closed space that may adhere to the surrounding tissue and form an abscess, complications such as sepsis arising from an abscess on the cut surface can be prevented and the required biliary drainage might be relatively simple. Larger AE lesions that invade the inferior vena cava can be treated effectively with the recent advances in reduction surgical techniques. An effective concentration of albendazole (ABZ) is found only in the periphery of AE lesions, because this drug penetrates the lesions passively. Liver transplantation, with adjuvant ABZ and the administration of appropriate immunosuppressive agents such as cyclosporin A, is indicated for patients with end-stage AE.

Do albendazole-loaded lipid nanocapsules enhance the bioavailability of albendazole in the brain of healthy mice?

Neurocysticercosis is a neglected tropical disease that affects the central nervous system and is the most common cause of human epilepsy acquired in developing countries. Therapeutic failures attributed to medical management of neurocysticercosis with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and brain tissue. The aim of the current work was to characterize and compare the brain pharmacokinetic behavior of ABZ formulated as a suspension or lipid nanocapsules (ABZ-LNCs) in healthy mice. The relative availability in brain tissue of the active metabolite ABZ sulphoxide increased 183% when ABZ was administered as LNCs, in relation to ABZ suspension. The parent drug was also detected for a short period of time. The bioavailability of ABZ in ABZ-LNCs treated mice increased more than 2 fold compared with ABZ suspension group. The enhanced drug brain exposure observed after administration of ABZ-LNCs to healthy mice has potential usefulness for the treatment of human neurocysticercosis.

Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Côte d'Ivoire.

BACKGROUND: A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa. METHODS: In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d'Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants' infection status. FINDINGS: There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment. CONCLUSIONS: Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845713.

In Vitro Assessment of Supersaturation/Precipitation and Biological Membrane Permeation of Poorly Water-Soluble Drugs: A Case Study With Albendazole and Ketoconazole.

This study aimed to elucidate the relationship between supersaturation and precipitation and the effect of a supersaturated state on drug membrane permeation. Stock solutions of albendazole (ALB) and ketoconazole (KTZ) dissolved in dimethyl sulfoxide (0.1-50 mg/mL) were diluted 100-fold with buffer solution (pH 6.8, 37°C). In the case of ALB, a supersaturated state and immediate precipitation were observed at 10 µg/mL or less and 20 µg/mL or higher, respectively. When KTZ was used, at an initial concentration of 200 µg/mL or higher, precipitation was observed, although the dissolved concentration remained at approximately 120 µg/mL for at least 30 min. These dissolved concentrations of ALB and KTZ related to approximately 10-fold and 14-fold over the saturated solubility from respective bulk powder. An in vitro permeation study implied that the rate of drug permeation across a biological membrane increased with increasing supersaturation. These results suggested favorable strategies for development of a supersaturable formulation could depend on the precipitation properties of the drug. Immediate- and controlled-release forms might be suitable for supersaturable formulations for KTZ and ALB, respectively.