Feeding Management and Albendazole Pharmacokinetics in Pigs.

Albendazole (ABZ) is a methylcarbamate benzimidazole anthelmintic used to control gastrointestinal parasites in several animal species and humans. The type of diet has been identified as a major determinant for ABZ pharmacokinetics in different animal species and humans. The work described here assesses the pattern of the absorption and the systemic availability of ABZ and its metabolites after its oral administration to pigs under different feed management plans. Eighteen pigs (5 months old, local ecotype breeds) were distributed into three experimental groups. In the fasting group, the animals fasted for 8 h prior to treatment. In the pellet + oil and pellet groups, the animals were fed ad libitum with a commercial pelleted-based diet with or without the addition of soya oil. An ABZ suspension was orally administered at 10 mg/kg. Blood samples were taken over the 48 h post-treatment. The plasma samples were analyzed by HPLC. Under the described experimental conditions, the ingestion of the pellet-based diet with or without the soya oil before ABZ treatment did not significantly (p < 0.05) modify the plasma disposition kinetics of the ABZ sulfoxide (ABZSO, the main ABZ metabolite) compared to that observed in the fasting pigs. Both ABZ metabolites (ABZSO and ABZ sulphone) reached similar peak concentrations and systemic exposures in all the experimental groups regardless of the feeding management. However, the addition of oil to the pelleted food enhanced the pattern of ABZ absorption, which was reflected in the higher (p < 0.05) concentration profiles of the active ABZSO metabolite measured between 12 and 48 h post-treatment compared to the pigs fed with the pelleted food alone. Although this effect may not be therapeutically relevant after ABZ administration as a single oral dose, the overall impact of the type and feeding conditions when ABZ is supplemented with food for several days should be cautiously evaluated.

Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model

High ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray (N-IVM-spray) administration may contribute to attaining high drug concentrations in nasopharyngeal (NP) tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performance of a new N-IVM spray formulation in a piglet model were assessed. Crossbred piglets (10-12 kg) were treated with either one or two (12 h apart) doses of N-IVM-spray (2 mg, 1 puff/nostril) or orally (0.2 mg/kg). The overall safety of N-IVM-spray was assessed (clinical, haematological, serum biochemical determinations), and histopathology evaluation of the application site tissues performed. The IVM concentration profiles measured in plasma and respiratory tract tissues (nasopharynx and lungs) after the nasal spray treatment (one and two applications) were compared with those achieved after the oral administration. Animals tolerated well the novel N-IVM-spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in NP and lung tissues. Significant increases in IVM concentration profiles in both NP-tissue and lungs were observed after the 2-dose nasal administrations. The nasal/oral IVM concentration ratios in NP and lung tissues (at 6 h post-dose) markedely increased by repeating the spray application. The fast attainment of high and persistent IVM concentrations in NP tissue is the main advantage of the nasal over the oral route. These original results are encouraging to support the undertaking of further clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the treatment and/or prevention of COVID-19.

Combined flubendazole-nitazoxanide treatment of cystic echinococcosis: Pharmacokinetic and efficacy assessment in mice.

The current chemotherapy of cystic echinococcosis (CE) is mainly based on the use of albendazole, and the results have been shown to be highly variable. Thus, new and more efficient treatment options are urgently needed. The goals of the current study were: a) to compare the ex vivo activity of flubendazole (FLBZ) and nitazoxanide (NTZ), given either separately or co-administered, against Echinococcus granulosus protoscoleces and cysts, b) to characterize the plasma disposition kinetics of FLBZ administered alone or combined with NTZ in mice; (c) to compare the in vivo activity of FLBZ and NTZ (either each alone or as a combined treatment) against secondary CE developed in mice. Ex vivo drug activity study: E. granulosus protoscoleces and cysts were incubated either with FLBZ, NTZ, or the FLBZ-NTZ combination. Protoscoleces and cyst viability was monitored by the methylene blue exclusion test and scanning electron microscopy (SEM). Pharmacokinetic study: Balb/C mice received FLBZ (5 mg/kg) orally either alone or co-administered with NTZ (100 mg/kg). Blood samples were collected up to 12 h post treatment and plasma analyzed for FLBZ/metabolites by HPLC. Clinical Efficacy study: following secondary infection, meaning i.p. injection of 1500 E. granulosus protoscoleces/animal (n=40), the both drugs were administered by intragastric inoculation on a daily basis for a period of 25 days. Balb/C mice received FLBZ (5 mg/kg, twice a day) alone, NTZ (100 mg/kg, once daily) alone or a combination of both molecules (FLBZ, 5mg/kg twice a day and NTZ, 100 mg/kg, once daily). Ten untreated animals were used as a control. All animals were killed and the weight of the cysts collected from each animal was recorded. The presence of NTZ did not markedly affect the FLBZ kinetic parameters in mice. FLBZ alone or combined with NTZ induced a reduction (P<0.05) of cyst weight in comparison to the untreated control and NTZ-treated treated mice. The data obtained here indicate that NTZ did not affect hydatid cyst development in mice. Conversely, FLBZ shows an excellent efficacy against CE.

Gender-related differences on P-glycoprotein-mediated drug intestinal transport in rats.

OBJECTIVES: Evidence of sex-related differences on drug pharmacokinetics and pharmacodynamics are markedly increasing. The aim of this study was to characterize the influence of gender on P-glycoprotein (P-gp)-mediated drug intestinal transport using two ex-vivo methodological approaches. METHODS: To study the comparative tissue uptake of ivermectin, intestinal sacs (distal jejunum/ileum) of male and female Wistar rats were incubated with ivermectin (0.5 µm) (a P-gp substrate) in the presence or absence of PSC833 (10 µm) (a P-gp inhibitor). Additionally, sex-based differences in the bidirectional transport of Rhodamine 123 (Rho 123; 5 µm) incubated either alone or with PSC833 (10 µm) were examined in diffusion chambers. KEY FINDINGS: The ivermectin accumulation in the everted gut sacs was higher in female compared with male intestine. The presence of PSC833 increased ivermectin accumulation profiles both in male and female rats. However, a greater response to transport modulation was observed in male compared with female animals. Similar results were obtained for Rho 123, where a higher absorption was measured in the intestine of females. PSC833 decreased Rho 123 intestinal secretion in animals of both sexes with a greater inhibition in male. CONCLUSIONS: Substantial sex-related differences were observed on the ivermectin and Rho 123 active intestinal transport. Likewise, the PSC833-mediated modulation had a differential impact between male and female animals. Further work is needed to clarify the mechanisms underlying this phenomenon, which may have considerable pharmacological and clinical relevance.