Journal of veterinary pharmacology and therapeutics最新文献

Alprazolam is used to facilitate mare–foal bonding in aggressive or anxious postpartum mares. In humans, alprazolam crosses the blood–milk barrier, but the amount transferred into milk is minor and compatible with breastfeeding as the relative infant dose is < 10%. Similar data are not available for horses. The aim of this study was to measure alprazolam in serum and milk of mares (milk: serum ratio) administered alprazolam, and to determine alprazolam serum concentrations in nursing foals to estimate the extent of absorption. This was a prospective observational study involving 7 healthy postpartum mares and foals. Mares received alprazolam (0.04 mg/kg PO, q12h) for 6 days. Venous blood and milk samples were collected on days 3,4,5 and 6, just before the next dose, and were used to calculate milk: serum ratios and estimate the extent of absorption of alprazolam by foals. A validated liquid chromatography–tandem mass spectrometry assay was used to measure alprazolam and α-hydroxyalprazolam. There were no significant differences in concentrations of alprazolam or α-hydroxyalprazolam in mare serum, milk, or foal serum over time, consistent with steady state and a lack of accumulation. Milk:serum ratios were similar to slightly higher than those reported in humans (median: 0.64; range: 0.42–3.0). Relative foal dose (RFD) based on 12 h concentrations was < 10% in all foals and in 96% of total samples. Foal serum concentrations of alprazolam were 6.6% ± 4.1% of those in mare serum at the same time points. This study shows that milk:serum ratios of alprazolam in mares are variable. Foal serum concentrations and RFD suggest that alprazolam is safe for use in mares with nursing foals.

Seresto by Elanco (formerly Bayer Animal Health) is a collar for cats and dogs that provides long-lasting antiparasitic protection through the gradual release of imidacloprid and flumethrin onto the animal's skin. Although the EPA has deemed Seresto safe, their assessment is based on laboratory data, which may not fully reflect real-world exposure. Furthermore, recent reports of over 900 adverse human health events between 2012 and 2022 underscore the need for further safety investigations. We measured these chemicals' concentrations from the fur of eight dogs over 9 months to evaluate how daily interactions with pets could expose humans to toxic levels. Flumethrin was mostly undetectable, and imidacloprid levels were well below the toxicity threshold, suggesting low risks. However, factors like cumulative exposure and individual characteristics warrant consideration. Concentration levels were highest right after collar application, potentially reaching up to 11.6% of an 8 kg child's acceptable daily intake. We recommend limiting prolonged contact with pets, especially for young children, in the first 48 h post-application. We detected residual imidacloprid prior to collar application and 1 month after removal, raising questions as to the potential contamination risks that roaming pets could pose to ecosystems, given the known environmental impacts of these chemicals.

Previous research has shown that azotemic dogs have a lower clearance and higher drug plasma concentrations of ampicillin compared to healthy dogs. The objective of this study was to determine the pharmacokinetics of ampicillin-sulbactam after multiple intravenous doses in hospitalized azotemic and non-azotemic dogs. This prospective study included 29 client-owned dogs; 19 azotemic and 10 non-azotemic. Ampicillin-sulbactam was administered at a combined dose of 22 mg/kg intravenously every 8 h for up to 5 days. Blood samples were obtained at baseline (prior to administration of the first dose of ampicillin-sulbactam), and 1-, 4-, and 8-h post-ampicillin-sulbactam administration each day. Plasma ampicillin was measured using LC-MS and non-compartmental pharmacokinetic modeling and dose interval modeling were performed. Plasma ampicillin exposure (azotemic mean 214.5 ug/mL × h ± 110.8, non-azotemic mean 60.3 ± 35.7; p < 0.0009) and half-life (azotemic mean 3.9 h ± 2.4, non-azotemic mean 1.5 h ± 0.3; p < 0.00001) were statistically greater in azotemic dogs compared to non-azotemic dogs. Single dose interval modeling predicted that 100% of azotemic dogs would have > 50% of the dosing interval with plasma concentrations > MIC (MIC = 2) with q12 h dosing and 79% of azotemic dogs would have > 50% of the dosing interval with plasma concentrations > MIC (MIC = 8) with q12 h dosing. Comparatively, 20% of non-azotemic dogs were predicted to have > 50% of the dosing interval with plasma concentrations > MIC (MIC = 2) with q12 h dosing and 0 non-azotemic dogs would have > 50% of the dosing interval with plasma concentrations > MIC (MIC = 8) with q12 h dosing. This study demonstrated that q12-h dosing of ampicillin-sulbactam in azotemic dogs over multiple days of administration is sufficient to reach the PK-PD target (> 50% of dosing interval > MIC) against susceptible bacteria.

This study assesses the pharmacokinetics (PK) of published methylprednisolone (MPL) data in horses following intra-articular (IA) administration of MPL acetate (MPA) and the associated adrenal suppression. The concentrations of MPL/MPA in synovial fluid, blood, and urine, as well as hydrocortisone (HC) in plasma, were digitized from multiple sources in the literature. A minimal physiologically based pharmacokinetic model and a linked indirect response model with a circadian rhythm baseline were applied. Concentrations of MPA in joints followed a triexponential decay, converting to MPL. The clearance of MPL was 797 mL/h/kg via hepatic metabolism (93%) and renal excretion (7%). The persistence of MPL in synovium and plasma for over 500 h was primarily ascribed to slow prodrug dissolution. The formation of MPL from available MPA in SF was rapid. A transit step was needed between the synovium and plasma for MPL absorption. The MPA to MPL bioavailability was dose and/or study dependent; 100% for dosages below 100 mg and 58% for 200 mg. The MPL inhibition of HC production was potent, with an IC₅₀ of 0.83 ng/mL, and lasted over 50 h. This meta-analysis utilizing a mechanistic modeling approach provided advanced and comprehensive insights on IA MPL PK in horses and was translatable for the PK appreciation of IA MPA dosing in man.

Diazepam (DZP), a benzodiazepine medication, is extensively utilized in both human and veterinary medicine and has been frequently detected in fish populations. The use of DZP-laced bait is identified as a predominant contributor to drug residue contamination in fish. Nonetheless, our understanding of the residue profile of DZP in fish and its potential implications for human health remains constrained. This study investigated the residue behavior and dietary intake risks of DZP and its primary metabolites in crucian carp (Carassius auratus) following oral administration. A rapid and sensitive UHPLC–MS/MS method was developed and validated for the reliable quantification of DZP and its identified metabolites. The findings revealed rapid absorption and extensive distribution of DZP in crucian carp, with peak concentrations in plasma and tissues occurring at 1 h. The distribution pattern of DZP, based on calculated AUC, was kidney > liver > plasma > gill > muscle plus skin. The distribution of DZP in plasma and tested tissues followed the decreasing order of kidney > liver > plasma > gill > muscle plus skin according to the calculated AUC. DZP elimination was notably slow, particularly in muscle plus skin, with an elimination half-life of 619.31 h, necessitating at least 70 days for concentrations to fall below the limit of quantitation, suggesting a high likelihood of residue formation in fish from oral DZP administration. DZP was metabolized into nordiazepam and temazepam in crucian carp; nordiazepam is the main metabolite of DZP, which is gradually higher than the parent drug in the elimination phase. The dietary risk assessment suggested that a possible health risk (HQ ≥ 0.1) was found within 1 day via ingestion of crucian carp after an oral dose of DZP, suggesting that frequent consumption of high-residue crucian carp may cause harm to human health.