RESUMEN
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.
Asunto(s)
Antihelmínticos , Giardia lamblia , Albendazol/química , Albendazol/farmacocinética , Animales , Antihelmínticos/farmacología , Biotransformación , Cromatografía Liquida , Citocromos/metabolismo , Flavinas/metabolismo , Giardia lamblia/genética , Giardia lamblia/metabolismo , Hemo/metabolismo , Humanos , Hierro , Metronidazol/farmacología , Oxigenasas de Función Mixta/metabolismo , Simulación del Acoplamiento Molecular , ARN Mensajero/metabolismo , Sulfonas , Sulfóxidos/metabolismo , Superóxidos , Espectrometría de Masas en Tándem , Trofozoítos/metabolismo , Xantina Oxidasa/metabolismo , XantinasRESUMEN
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.
Asunto(s)
Acantocéfalos , Albendazol/farmacocinética , Albendazol/uso terapéutico , Characiformes , Enfermedades de los Peces/tratamiento farmacológico , Helmintiasis Animal/tratamiento farmacológico , Administración Oral , Albendazol/metabolismo , Alimentación Animal , Animales , Antihelmínticos/farmacocinética , Antihelmínticos/uso terapéutico , Residuos de Medicamentos , Helmintiasis Animal/parasitología , Reproducibilidad de los ResultadosRESUMEN
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.
Asunto(s)
Albendazol/análogos & derivados , Nanopartículas/química , Tamaño de la Partícula , Secado por Pulverización , Albendazol/síntesis química , Albendazol/farmacocinética , Animales , Antihelmínticos/síntesis química , Antihelmínticos/farmacocinética , Estudios Cruzados , Perros , Femenino , MasculinoRESUMEN
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.
Asunto(s)
Albendazol/farmacocinética , Celulosa/análogos & derivados , Quitosano/química , Albendazol/química , Animales , Área Bajo la Curva , Disponibilidad Biológica , Celulosa/química , Femenino , Genotipo , Masculino , Ratones , Caracteres SexualesRESUMEN
AIM: Solid dispersions using Poloxamer 407 as carrier were developed to improve albendazole (ABZ) solubility and dissolution profiles. METHODS: ABZ/poloxamer solid dispersions were prepared, and dissolution profiles were mathematically modeled and compared with physical mixtures, pharmaceutical ABZ and a commercial formulation. RESULTS: Poloxamer 407 increased exponentially ABZ solubility, in about 400% when 95% w/w of polymer compared with its absence. Solid dispersions initial dissolution rate was three to 20-fold higher than physical mixtures, the drug and the commercial formulation. All the solid dispersions required less than 2.2 min to reach an 80% of ABZ dissolution, while the commercial formulation needed around 40 min. CONCLUSION: Solid dispersions improved ABZ solubility and dissolution rate, which could result in a faster absorption and an increased bioavailability.
Asunto(s)
Albendazol/farmacocinética , Portadores de Fármacos/química , Liberación de Fármacos , Poloxámero/química , Absorción Fisicoquímica , Albendazol/administración & dosificación , Albendazol/química , Disponibilidad Biológica , Química Farmacéutica , Composición de Medicamentos/métodos , SolubilidadRESUMEN
This work characterized the egg residual concentrations of albendazole (ABZ) and its sulphoxide (ABZSO) and sulphone (ABZSO2 ) metabolites and evaluated their effect on egg fertility and hatchability after ABZ treatments to laying hens. Seventy hens were allocated in groups: Group-1 was the control without treatment; Group-2 received a single ABZ oral dose (10 mg/kg); Group-3, -4 and -5 were treated with ABZ in medicated feed over 7 days at 10, 40, or 80 mg kg-1 day-1 , respectively. Eggs were analyzed to determine the ABZ/metabolite level by HPLC or subjected to incubation to evaluate the fertility and hatchability. Only ABZSO and ABZSO2 metabolites were quantified in egg after ABZ single oral administration with maximum concentrations of 0.47 ± 0.08 and 0.30 ± 0.07 µg/ml, respectively. ABZ and its metabolites were found in eggs after 7-day ABZ treatments. The egg residue exposure estimated as AUCs (areas under the concentration vs. time curve) were 100.5 (ABZ), 56.3 (ABZSO) and 141.3 µg hr g-1 (ABZSO2 ). ABZ administration did not affect the egg fertility at any dosages. Egg hatchability was not affected by ABZ treatment at 10 mg/kg in medicated feed, but it decreased when the dose was 4-8 times higher. These results should be considered when ABZ is used for deworming laying hens.
Asunto(s)
Albendazol/farmacología , Antihelmínticos/farmacología , Residuos de Medicamentos/análisis , Fertilidad/efectos de los fármacos , Óvulo/efectos de los fármacos , Administración Oral , Albendazol/análisis , Albendazol/farmacocinética , Animales , Antihelmínticos/análisis , Antihelmínticos/farmacocinética , Embrión de Pollo/efectos de los fármacos , Pollos , Cromatografía Líquida de Alta Presión/veterinaria , Femenino , Óvulo/químicaRESUMEN
Parasitic diseases have a significant impact on livestock production. Nematodicidal drugs, such as fenbendazole (FBZ) or its oxidized metabolite oxfendazole (OFZ), can be used along with the trematodicidal triclabendazole (TCBZ), to broaden the spectrum of anthelmintic activity. However, co-exposure to these compounds could lead to drug-drug (D-D) interactions and eventually alter the clinical profile of each active principle. The aim of this study was to assess the presence of such interactions by means of two in vitro models, namely bovine liver microsomal fractions and bovine precision-cut liver slices (PCLSs). To this end, an in vitro assessment involving incubation of FBZ and TCBZ or a combination of FBZ and TCBZ was carried out. Results with microsomal fractions showed a 78.4% reduction (p = .002) in the rate of OFZ production upon co-incubation, whereas the sulfoxide metabolite of TCBZ (TCBZSO) exhibited a decreasing tendency. With PCLS, OFZ accumulation in the incubation medium increased 1.8-fold upon co-incubation, whereas TCBZSO accumulation decreased by 28%. The accumulation of FBZ and OFZ in the liver tissue increased upon 2-hr co-incubation, from 2.1 ± 1.5 to 18.2 ± 6.1 (p = .0009) and from 0.4 ± 0.1 to 1.3 ± 0.3 nmol (p = .0005), respectively. These results confirm the presence of D-D interactions between FBZ and TCBZ. Further studies are needed to determine the extent of involvement of drug-metabolizing enzymes and membrane transporters in interactions between compounds largely used in livestock production systems.
Asunto(s)
Bencimidazoles/farmacocinética , Bovinos , Fenbendazol/farmacocinética , Hígado/metabolismo , Microsomas Hepáticos/metabolismo , Albendazol/farmacocinética , Animales , Antihelmínticos/farmacocinética , Interacciones Farmacológicas , Manejo de Especímenes , TriclabendazolRESUMEN
Albendazole (ABZ), a benzimidazole widely used to control gastrointestinal parasites, is poorly soluble in water, resulting in variable and incomplete bioavailability. This has favored the appearance ABZ-resistant nematodes and, consequently, an increase in its clinical ineffectiveness. Among the pharmaceutical techniques developed to increase drug efficacy, cyclodextrins (CDs) and other polymers have been extensively used with water-insoluble pharmaceutical drugs to increase their solubility and availability. Our objective was to prepare ABZ formulations, including ß-cyclodextrin (ßCD) or hydroxypropyl-ß-cyclodextrin (HPßCD), associated or not to the water-soluble polymer polyvinylpyrrolidone (PVP). These formulations had their solubility and anthelmintic effect both evaluated in vitro. Also, their anthelmintic efficacy was evaluated in lambs naturally infected with gastrointestinal nematodes (GIN) through the fecal egg count (FEC) reduction test. In vitro, the complex ABZ/HPßCD had higher solubility than ABZ/ßCD. The addition of PVP to the complexes increased solubility and dissolution rates more effectively for ABZ/HPßCD than for ABZ/ßCD. In vivo, 48 lambs naturally infected with GIN were divided into six experimental groups: control, ABZ, ABZ/ßCD, ABZ/ßCD-PVP, ABZ/HPßCD, and ABZ/HPßCD-PVP. Each treated animal received 10 mg/kg of body weight (based on the ABZ dose) for three consecutive days. After 10 days of the last administered dose, treatment efficacy was calculated. The efficacy values were as follows: ABZ (70.33%), ABZ/ßCD (85.33%), ABZ/ßCD-PVP (82.86%), ABZ/HPßCD (78.37%), and ABZ/HPßCD-PVP (43.79%). In vitro, ABZ/HPßCD and ABZ/HPßCD-PVP had high solubility and dissolution rates. In vivo, although the efficacies of ABZ/ßCD, ABZ/ßCD-PVP, and ABZ/HPßCD increased slightly when compared to pure ABZ, this increase was not significant (P > 0.05).
Asunto(s)
Albendazol/farmacocinética , Antiparasitarios/farmacocinética , Ciclodextrinas/farmacocinética , Nanopartículas/química , Povidona/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Albendazol/química , Animales , Antihelmínticos/química , Antihelmínticos/farmacocinética , Antiparasitarios/química , Disponibilidad Biológica , Ciclodextrinas/química , Composición de Medicamentos , Parasitosis Intestinales/tratamiento farmacológico , Parasitosis Intestinales/veterinaria , Masculino , Nematodos , Infecciones por Nematodos/tratamiento farmacológico , Infecciones por Nematodos/veterinaria , Povidona/química , Ovinos , Enfermedades de las Ovejas/tratamiento farmacológico , Enfermedades de las Ovejas/parasitología , Solubilidad , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinéticaRESUMEN
AIM: Albendazole (ABZ) is a broad-spectrum antiparasitic agent with poor aqueous solubility, which leads to poor/erratic bioavailability and therapeutic failures. Here, we aimed to produce a novel formulation of ABZ nanocrystals (ABZNC) and assess its pharmacokinetic performance in mice. Results/methodology: ABZNC were prepared by high-pressure homogenization and spray-drying processes. Redispersion capacity and solid yield were measured in order to obtain an optimized product. The final particle size was 415.69±7.40 nm and the solid yield was 72.32%. The pharmacokinetic parameters obtained in a mice model for ABZNC were enhanced (p < 0.05) with respect to the control formulation. CONCLUSION: ABZNC with improved pharmacokinetic behavior were produced by a simple, inexpensive and potentially scalable methodology.
Asunto(s)
Albendazol/farmacocinética , Antihelmínticos/farmacocinética , Nanopartículas/metabolismo , Tamaño de la Partícula , Albendazol/química , Animales , Antihelmínticos/química , Masculino , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , SolubilidadRESUMEN
BACKGROUND: Soil Transmitted Helminth (STH) infections negatively impact physical and mental development in human populations. Current WHO guidelines recommend morbidity control of these infections through mass drug administration (MDA) using albendazole (ABZ) or mebendazole. Despite major reductions in STH associated morbidity globally, not all programs have demonstrated the expected impact on prevalence of parasite infections. These therapeutic failures may be related to poor programmatic coverage, suboptimal adherence or the exposure of parasites to sub-therapeutic drug concentrations. As part of the DeWorm3 project, we sought to characterize the serum disposition kinetics and pattern of urinary excretion of ABZ and its main metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) in humans, and the assessment of the duration and optimal time point where ABZ and/or its metabolites can be measured in urine as an indirect assessment of an individual's adherence to treatment. METHODOLOGY/PRINCIPAL FINDINGS: Consecutive venous blood and urine samples were collected from eight (8) human volunteers up to 72 h post-ABZ oral administration. ABZ/metabolites were quantified by HPLC. The ABZSO metabolite was the main analyte recovered both in serum and urine. ABZSO Cmax in serum was 1.20 ± 0.44 µg/mL, reached at 4.75 h post-treatment. In urine, ABZSO Cmax was 3.24 ± 1.51 µg/mL reached at 6.50 h post-ABZ administration. CONCLUSION/SIGNIFICANCE: Pharmacokinetic data obtained for ABZ metabolites in serum and urine, including the recovery of the ABZ sulphoxide derivative up to 72 h in both matrixes and the recovery of the amino-ABZ sulphone metabolite in urine samples, are suggesting the possibility of developing a urine based method to assess compliance to ABZ treatment. Such an assay may be useful to optimize ABZ use in human patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03192449.
Asunto(s)
Albendazol/farmacocinética , Antihelmínticos/farmacocinética , Antiprotozoarios/farmacocinética , Suero/química , Orina/química , Albendazol/administración & dosificación , Antihelmínticos/administración & dosificación , Antiprotozoarios/administración & dosificación , Cromatografía Líquida de Alta Presión , Voluntarios Sanos , Humanos , Factores de TiempoRESUMEN
OBJECTIVES: Here, we aimed to assess the pharmacokinetic performance and therapeutic response (anthelmintic efficacy) of an albendazole (ABZ) nano-sized formulation in dogs. METHODS: In the pharmacokinetic study, ABZ self-dispersible nanocrystals (SDNCS) and a control formulation were administered orally to healthy dogs (n = 6). The concentrations of the sulphoxide metabolite in plasma were determined by high-performance liquid chromatography. For the anthelmintic efficacy trial, SDNCS and a commercially available formulation of ABZ were given to naturally parasitised dogs. The number of Ancylostoma caninum eggs in the faeces was determined using the McMaster technique. KEY FINDINGS: The area under the curve, Tmax and Cmax for the SDNCS were improved compared to the control. The efficacy study showed no statistical differences between the SDNCS and the commercial formulation at the doses of 25 and 12.5 mg/kg. However, significant differences (P < 0.05) between the treatments were found at 6.25 mg/kg (a quarter of the reference dose) with a reduction in the faecal nematode egg counts of 62.0 ± 21.1% and 100 ± 0% for the control and SDNCS, respectively. CONCLUSIONS: The improved pharmacokinetic performance observed for the novel formulation of ABZ correlated with an improved in vivo therapeutic response against a model intestinal nematode parasite in dogs.
Asunto(s)
Albendazol/administración & dosificación , Anquilostomiasis/tratamiento farmacológico , Antihelmínticos/administración & dosificación , Nanopartículas , Albendazol/farmacocinética , Albendazol/farmacología , Ancylostoma/efectos de los fármacos , Anquilostomiasis/parasitología , Anquilostomiasis/veterinaria , Animales , Antihelmínticos/farmacocinética , Antihelmínticos/farmacología , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/parasitología , Perros , Relación Dosis-Respuesta a Droga , Heces/parasitología , Femenino , Masculino , Resultado del TratamientoRESUMEN
The oral route has notable advantages to administering dosage forms. One of the most important questions to solve is the poor solubility of most drugs which produces low bioavailability and delivery problems, a major challenge for the pharmaceutical industry. Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its extended spectrum activity and low cost. Nevertheless, the main disadvantage is the poor bioavailability due to its very low solubility in water. The main objective of this study was to prepare microcrystal formulations by the bottom-up technology to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. Thus, 20 novel microstructures based on chitosan, cellulose derivatives, and poloxamer as a surfactant were produced and characterized by their physicochemical properties and in vitro biological activity. To determine the significance of type and concentration of polymer, and presence or absence of surfactant in the crystals, the variables area under the curve, albendazole microcrystal solubility, and drug released (%) at 30 min were analyzed with a three-way ANOVA. This analysis indicated that the microcrystals made with hydroxyethylcellulose or chitosan appear to be the best options to optimize oral absorption of the active pharmaceutical ingredient. The in vitro evaluation of anthelmintic activity on adult forms of Trichinella spiralis identified system S10A as the most effective, of choice for testing therapeutic efficacy in vivo.
Asunto(s)
Albendazol , Trichinella spiralis/efectos de los fármacos , Triquinelosis/tratamiento farmacológico , Administración Oral , Albendazol/administración & dosificación , Albendazol/farmacocinética , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/farmacocinética , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Disponibilidad Biológica , Celulosa/análogos & derivados , Celulosa/química , Celulosa/farmacología , Quitosano/química , Quitosano/farmacología , Sistemas de Liberación de Medicamentos , SolubilidadRESUMEN
Therapeutic failures attributed to medical management of cystic echinococcosis (CE) with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and hydatid cysts. Lipid nanocapsules (LNCs) represent nanocarriers designed to encapsulate lipophilic drugs, such as ABZ. The goals of the current work were: (i) to characterize the plasma and cyst drug exposure after the administration of ABZ as ABZ-LNCs or ABZ suspension (ABZ-SUSP) in mice infected with Echinococcus granulosus, and ii) to compare the clinical efficacies of both ABZ formulations. Enhanced ABZ sulphoxide (ABZ-SO) concentration profiles were obtained in plasma and cysts from ABZ-LNC treated animals. ABZSO exposure (AUC0-LOQ) was significantly higher in plasma and cyst after the ABZ-LNC treatments, both orally and subcutaneously, compared to that observed after oral administration of ABZ-SUSP. Additionally, ABZSO concentrations measured in cysts from ABZ-LNC treated mice were 1.7-fold higher than those detected in plasma. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the ABZ-LNCs, while ABZ-SUSP did not reach differences with the untreated control group. This new pharmacotechnically-based strategy could be a potential alternative to improve the treatment of human CE.
Asunto(s)
Albendazol/administración & dosificación , Antihelmínticos/administración & dosificación , Equinococosis/tratamiento farmacológico , Echinococcus granulosus , Administración Oral , Albendazol/farmacocinética , Animales , Disponibilidad Biológica , Química Farmacéutica , Sistemas de Liberación de Medicamentos , Femenino , Lípidos/administración & dosificación , Ratones , NanocápsulasRESUMEN
1. To optimise the use of albendazole (ABZ) as an anthelmintic in hens, the effects of fasting and type of diet on the plasma kinetics of ABZ and its metabolites were evaluated. 2. Twenty-four hens were distributed into 4 groups: In experiment I the Fed group were fed ad libitum, while the Fasted group was fasted over a 12-h period. In experiment II the Pelleted group was fed with pelleted commercial food, while the Grain group was fed with cereal grains. All the groups were treated with ABZ by oral route. Blood samples were taken and plasma analysed by HPLC. 3. ABZ and its metabolites albendazole-sulphoxide (ABZSO) and albendazole-sulphone (ABZSO2) were recovered in plasma in all the groups. The 12-h fasting period did not modify the disposition kinetics of ABZ in hens. The type of feed affected ABZ kinetics. ABZSO concentration profile was higher and detected for longer in the Grain group compared to the Pelleted group. Statistical differences were not found for AUC0-∞ values, whereas the T1/2for and T1/2el were different between groups. 4. Factors affecting ABZ kinetic behaviour should be taken into account to optimise its use to ensure the sustainability of the limited available anthelmintic therapeutic tools in avian parasite control.
Asunto(s)
Albendazol/farmacocinética , Antihelmínticos/farmacocinética , Pollos/metabolismo , Albendazol/análogos & derivados , Albendazol/sangre , Animales , Antihelmínticos/sangre , Pollos/sangre , Pollos/fisiología , Dieta/veterinaria , Femenino , Privación de Alimentos/fisiologíaRESUMEN
The goals of the current trial were (a) to characterize the plasma disposition kinetics of levamisole (LEV), albendazole (ABZ) and ivermectin (IVM), each administered either alone (single active ingredient) or as a combined formulation to lambs; (b) to compare the clinical anthelmintic efficacy of the same drugs given either separately or co-administered to lambs infected with resistant nematodes. Fifty Corriedale lambs naturally infected with multiple resistant gastrointestinal nematodes were involved in the following experimental trials: (a) "Pharmacokinetic trial": the animals were allocated into five groups (n=10 each) and intraruminally treated with either LEV (8 mg/kg), ABZ (5mg/kg), IVM (0.2mg/kg), or with a LEV+ABZ+IVM combined formulation, where each active ingredient was administered at the same dose. Blood samples were collected over 15 days post-treatment and drug plasma concentrations measured by HPLC. (b) "Efficacy trial": the same treated groups plus an untreated control group were used to assess the comparative anthelmintic efficacy by the faecal egg count reduction test (FECRT). Although the overall LEV disposition kinetics was unaffected, significantly lower (61%) ABZ-sulphoxide and higher (71%) IVM systemic availabilities were obtained after administration of the combined formulation in comparison to those obtained after treatment with each drug alone. A multiple drug resistance situation was observed for Haemonchus spp. The observed efficacies were 52% (LEV), 72% (ABZ), 80% (IVM) and 87% (triple combined formulation). The results reported here contribute to the pharmaco-therapeutic knowledge on drug combinations. This type of research is crucial before further development of combined anthelmintic preparations reaches the market to deal with resistant nematode control. The co-administration of LEV+ABZ+IVM did not result in a significant advantageous anthelmintic effect compared to the treatment with IVM alone. The simultaneous/combined administration of LEV, ABZ and IVM may account for a drug-drug pharmacological interaction in infected lambs. The pharmacokinetic interaction accounted for a reduced ABZ-sulphoxide and enhanced IVM systemic exposure following the combined treatment.
Asunto(s)
Antihelmínticos/administración & dosificación , Antihelmínticos/farmacocinética , Infecciones por Nematodos/veterinaria , Enfermedades de las Ovejas/tratamiento farmacológico , Albendazol/administración & dosificación , Albendazol/análogos & derivados , Albendazol/sangre , Albendazol/farmacocinética , Animales , Antihelmínticos/sangre , Antihelmínticos/farmacología , Área Bajo la Curva , Interacciones Farmacológicas , Resistencia a Medicamentos/efectos de los fármacos , Heces/parasitología , Femenino , Ivermectina/administración & dosificación , Ivermectina/sangre , Ivermectina/farmacología , Levamisol/administración & dosificación , Levamisol/sangre , Levamisol/farmacocinética , Masculino , Nematodos/efectos de los fármacos , Infecciones por Nematodos/tratamiento farmacológico , Recuento de Huevos de Parásitos/veterinaria , Ovinos , TiempoRESUMEN
The main objectives of this study were (a) to evaluate the in vitro performance of the rapid disintegration tablets as a way to improve the solid dispersions and (b) to study the in vivo pharmacokinetics of the albendazole modified formulation in dogs. Rapid disintegration of tablets seems to be a key factor for efficiency of solid dispersions with regard to improvement of the albendazole bioavailability. The in vivo assays performed on dogs showed a marked increase in drug plasma exposure when albendazole was given in solid dispersions incorporated into rapid disintegration tablets compared with conventional solid dosage form.
Asunto(s)
Albendazol/administración & dosificación , Albendazol/sangre , Administración Oral , Albendazol/farmacocinética , Animales , Disponibilidad Biológica , Química Farmacéutica , Perros , Femenino , Dureza , ComprimidosRESUMEN
Cyst echinococcosis (CE) is a zoonotic disease caused by the larval stage of the Echinococcus granulosus helminth parasite. The work reported here aimed to compare the efficacy of albendazole (ABZ) and flubendazole (FLBZ) against CE in naturally infected sheep. Additionally, their comparative pharmacokinetic behaviour and the assessment of serum liver enzymes activities were studied. Twelve (12) naturally infected sheep were allocated to the following experimental groups: unmedicated control group, FLBZ-treated and ABZ-treated. Treatments were orally performed every 48 h, over 55 days at dose rate of 10 (FLBZ) and 8.5 (ABZ) mg/kg (equimolar dose rates). The efficacy of the drug treatments was based on protoscoleces' vitality/viability. The kinetic disposition assessment included the Initial and Final Kinetic Studies which implicated the collection of blood samples after both the first and the last drug administration. Blood samples were processed to measure drug concentrations by HPLC. The protoscoleces' vitality observed in the untreated control group (98%) was significantly reduced in the presence of both ABZ and FLBZ. 90% of mice inoculated with protoscoleces in the control group developed hydatid cysts in their peritoneal cavity (viability study). However, only 25% (FLBZ) and 33% (ABZ) of mice inoculated with protoscoleces recovered from treated sheep, developed hydatid cysts in their abdominal cavity. Reduced FLBZ (R-FLBZ) was the main metabolite recovered in the bloodstream after oral administration of FLBZ to sheep. Low plasma concentrations of FLBZ parent drug were measured up to 48 h post-administration. ABZ was not detected in plasma at any time post-treatment, being its metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) recovered in plasma. Hepatotoxicity due to the continued treatment with either ABZ or FLBZ was not observed. A 3-fold increase ethoxyresorufin O-deethylase activity, a cytochrome P450 1A (CYP1A)-dependent enzyme reaction, was observed in liver microsomes obtained from sheep receiving ABZ, compared to those of the unmedicated and FLBZ-treated animals. In conclusion, FLBZ is an available anthelmintic which may be developed into an effective and safe drug for the human CE treatment. Despite the low plasma concentrations measured by FLBZ/R-FLBZ, an important reduction in protoscoleces' vitality was observed in cysts located in sheep liver. Modern pharmaceutical technology may help to greatly improve FLBZ systemic exposure improving its efficacy against CE.
Asunto(s)
Albendazol/uso terapéutico , Equinococosis/veterinaria , Echinococcus granulosus , Mebendazol/análogos & derivados , Enfermedades de las Ovejas/tratamiento farmacológico , Albendazol/sangre , Albendazol/metabolismo , Albendazol/farmacocinética , Animales , Antihelmínticos/sangre , Antihelmínticos/metabolismo , Antihelmínticos/farmacocinética , Antihelmínticos/uso terapéutico , Área Bajo la Curva , Equinococosis/tratamiento farmacológico , Equinococosis/parasitología , Semivida , Mebendazol/sangre , Mebendazol/metabolismo , Mebendazol/farmacocinética , Mebendazol/uso terapéutico , OvinosRESUMEN
An increasing prevalence of roundworm parasites in poultry, particularly in litter-based housing systems, has been reported. However, few anthelmintic drugs are commercially available for use in avian production systems. The anthelmintic efficacy of albendazole (ABZ) in poultry has been demonstrated well. The goal of this work was to characterize the ABZ and metabolites plasma disposition kinetics after treatment with different administration routes in laying hens. Twenty-four laying hens Plymouth Rock Barrada were distributed into three groups and treated with ABZ as follows: intravenously at 10 mg/kg (ABZ i.v.); orally at the same dose (ABZ oral); and in medicated feed at 10 mg/kg·day for 7 days (ABZ feed). Blood samples were taken up to 48 h posttreatment (ABZ i.v. and ABZ oral) and up to 10 days poststart feed medication (ABZ feed). The collected plasma samples were analyzed using high-performance liquid chromatography. ABZ and its albendazole sulphoxide (ABZSO) and ABZSO2 metabolites were recovered in plasma after ABZ i.v. administration. ABZ parent compound showed an initial concentration of 16.4 ± 2.0 µg/mL, being rapidly metabolized into the ABZSO and ABZSO2 metabolites. The ABZSO maximum concentration (Cmax ) (3.10 ± 0.78 µg/mL) was higher than that of ABZSO2 Cmax (0.34 ± 0.05 µg/mL). The area under the concentration vs time curve (AUC) for ABZSO (21.9 ± 3.6 µg·h/mL) was higher than that observed for ABZSO2 and ABZ (7.80 ± 1.02 and 12.0 ± 1.6 µg·h/mL, respectively). The ABZ body clearance (Cl) was 0.88 ± 0.11 L·h/kg with an elimination half-life (T1/2el ) of 3.47 ± 0.73 h. The T1/2el for ABZSO and ABZSO2 were 6.36 ± 1.50 and 5.40 ± 1.90 h, respectively. After ABZ oral administration, low ABZ plasma concentrations were measured between 0.5 and 3 h posttreatment. ABZ was rapidly metabolized to ABZSO (Cmax , 1.71 ± 0.62 µg/mL) and ABZSO2 (Cmax , 0.43 ± 0.04 µg/mL). The metabolite systemic exposure (AUC) values were 18.6 ± 2.0 and 10.6 ± 0.9 µg·h/mL for ABZSO and ABZSO2 , respectively. The half-life values after ABZ oral were similar (5.91 ± 0.60 and 5.57 ± 1.19 h for ABZSO and ABZSO2 , respectively) to those obtained after ABZ i.v. administration. ABZ was not recovered from the bloodstream after ABZ feed administration. AUC values of ABZSO and ABZSO2 were 61.9 and 92.4 µg·h/mL, respectively. The work reported here provides useful information on the pharmacokinetic behavior of ABZ after both i.v. and oral administrations in hens, which is a useful first step to evaluate its potential as an anthelmintic tool for use in poultry.
Asunto(s)
Albendazol/farmacocinética , Antihelmínticos/farmacocinética , Pollos/metabolismo , Administración Oral , Albendazol/administración & dosificación , Albendazol/sangre , Albendazol/metabolismo , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/sangre , Antihelmínticos/metabolismo , Área Bajo la Curva , Pollos/sangre , Femenino , Semivida , Inyecciones Intravenosas , Oviposición , Reproducibilidad de los ResultadosRESUMEN
Solid dispersions (SDs) containing the anthelmintic compound albendazole (ABZ) and either Pluronic 188 (P 188) or polyethylene glycol 6000 (PEG 6000) as hydrophilic carriers were formulated. Drug-polymers interactions in solid state were investigated using different techniques. Only a 4% of total ABZ was dissolved at 5 min post-incubation, reaching dissolution rates of 32.8% (PEG 6000) and 69.4% (P 188) in SDs. In this way, P 188 was substantially more efficient as ABZ dissolution promoter in comparison to PEG 6000, especially at the initial stages of the dissolution processes (<30 min). An increased systemic availability (p < 0.001) was obtained when ABZ was administered as ABZ-P 188 SDs, with a 50% enhancement in systemic exposure (AUC values) compared to treatment with an ABZ suspension. Consistently, the Cmax increased 130% (p < 0.001) following treatment with P 188 based SD ABZ formulation. For the ABZ-PEG 6000 SD formulation, the favorable effect on ABZ systemic availability did not reached statistical significance compared to the control group. The study reported here showed the utility of pharmacokinetic assays performed on mice as a model for preliminary drug formulation screening studies.
Asunto(s)
Albendazol/química , Albendazol/farmacocinética , Portadores de Fármacos/química , Albendazol/administración & dosificación , Animales , Área Bajo la Curva , Disponibilidad Biológica , Química Farmacéutica/métodos , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Evaluación Preclínica de Medicamentos/métodos , Masculino , Ratones , Ratones Endogámicos BALB C , Polietilenglicoles/química , Solubilidad , Suspensiones/administración & dosificación , Suspensiones/química , Suspensiones/farmacocinéticaRESUMEN
BACKGROUND: Flubendazole (FLBZ) is a poor water solubility broad-spectrum BZD methylcarbamate anthelmintic compound. Cyclodextrins (CDs) are usually used to increase aqueous solubility of poor hydrosoluble compounds. The comparative in vitro aqueous solubility of FLBZ and other BZD anthelmintics in the presence of hydroxypropyl-ß-cyclodextrin (HPßCD) was evaluated in the current work. Additionally, the comparative pharmacokinetic behaviour of FLBZ (and its metabolites) administered by the intraruminal (i.r.) or intraabomasal (i.a.) routes to sheep as either an aqueous CDs-based solution or a conventional carboximethylcellulose (CMC) suspension was assessed. Drug solubility studies involving albendazole, mebendazole, oxfendazole and FLBZ were performed in an aqueous solution (pH 1.2 or 7.4) with or without HPßCD (10%, w/v). The pharmacokinetic study involved two experiments. Experiment 1: In a crossover study, sheep received either a FLBZ-CDs solution (n = 3) or a FLBZ-CMC suspension (n = 3) by the i.r. route (3.8 mg/kg). The treatment Groups were reversed after a 21-days washout period. Experiment 2: sheep (n = 4) were treated by the i.a. route with the FLBZ-CDs solution (3.8 mg/kg). Plasma and abomasal fluid samples were collected between 0 and 72 h post-treatment. Samples were analysed by HPLC. RESULTS: Improvement of FLBZ aqueous solubility due to CDs resulted markedly higher than that observed for mebendazole and albendazole. However, oppositely to what was expected, the absorption-related pharmacokinetic parameters did not show any marked formulation-dependant effect. After the i.a. administration of FLBZ, the AUC and the Tmax of the parent compound were significantly (P < 0.05) reduced, which is consistent with ruminal bypass. CONCLUSION: The administration of FLBZ as a CDs-based solution, does not seem to achieve great practical relevance for parasite control in sheep.