Egg residue and depletion of meloxicam in Jing Hong laying hens following multiple oral doses.

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) commonly used in an extra-label manner in commercial laying hens for the treatment of foot lesions, which are a common issue in this species. The present study aimed to determine the depletion profiles of meloxicam in eggs with multiple oral administration under 2 different dosing regimens and to further recommend reasonable withdrawal intervals (WDIs). Meloxicam (1 mg/kg) was administered orally to laying hens under 2 dosing schedules: 10 doses at 24-h intervals and 15 doses at 12-h intervals. Eggs were collected daily after the first dosing, and meloxicam concentrations in both yolk and white were determined by a high-performance liquid chromatography (HPLC) method. The weight ratio of white to yolk in the whole egg was 1.54 (the mean of 20 eggs with repeated tests), and this value combined with the meloxicam concentrations in white and yolk were used to calculate the drug concentrations in whole eggs. Meloxicam was quickly eliminated from egg white, and its concentrations could only be quantified at 2 time points during the elimination phase. The elimination half-lives in yolk and whole egg were 3.07 ± 1.00 and 2.98 ± 0.88 d, respectively, after 10 repeated doses. And the corresponding elimination half-lives were 2.30 ± 0.83 and 2.18 ± 0.67 d, respectively, after repeated 15 doses. Considering the time when meloxicam was not detectable in eggs with the time of ovum development and maturation, a withdrawal interval (WDI) was suggested as 17 d for both dosing schedules. The current results enriched the study on the residue of meloxicam in domestic Jing Hong laying hens and provided WDIs to help ensure animal-derived food safety.

Pharmacokinetics of danofloxacin after single oral and intravenous administration in non-laying hens.

The current study aimed to explore the pharmacokinetics of danofloxacin in non-laying hens after a single oral (PO) and intravenous (IV) dose, both at 5 mg/kg body weight (BW). Eighteen 13-week-old healthy hens were equally and randomly divided into two groups. After both doses, blood samples (approximately 1 ml) were collected at different time points. Danofloxacin concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method followed by a non-compartmental analysis using the software of WinNonLin. The elimination half-lives (t1/2λz s) after PO and IV routes were determined as 8.15 ± 3.37 and 7.69 ± 3.40 h, respectively. After IV administration, danofloxacin had an initial concentration (C0 ) of 3.62 µg/ml, a volume of distribution at steady state (VSS ) of 3579.72 ± 454.29 ml/kg, and a total body clearance (Cl) of 0.49 ml/h/g. After PO administration, the absolute bioavailability and absorption half-life (t1/2ka ) were calculated as 100.99% ± 23.10% and 0.82 ± 0.58 h, respectively. Based on the calculated ratio values of AUC/MIC and Cmax /MIC, an oral dose of 5 mg/kg danofloxacin would be expected to successfully treat hens infected with strains with MIC values ≤0.1 µg/ml.

The Incidence of Acute Pancreatitis After Device Assisted Enteroscopy: a Systematic Review and Meta-analysis.

Background: The diagnosis of small bowel diseases is challenging and device assisted enteroscopy (DAE) is a technique for visualizing the entire small bowel. DAE is considered as a safe procedure and the reported rate of adverse events associated with DAE in the literature is low. Objective: The present study tried to investigate the actual incidence of AP after DAE with a systematic review and meta-analysis of available relevant studies. Methods: Studies were searched through the PubMed, EMBASE, and Cochrane library databases. The following data were extracted from all eligible studies: author, country, publication year, publication type, study design, type of DAE used, route of DAE, number of patients with AP after DAE, and number of patients with hyperamylasemia after DAE.A random-effects model with RStudio version 4.2.0 was performed in all analyses. Heterogeneity was assessed using the I2 test. The risk of bias was assessed by the Newcastle-Ottawa Scale criteria and the publication bias was assessed by the Egger test. Results: Twenty three studies involving a total of 11145 patients were included in the analysis. The overall, pooled AP rate after DAE was 1% (95% CI:0-1%). There was significant heterogeneity among the studies (I2 = 65%; P < 0.01).The pooled AP rate was 1% (95% CI:0-2 %)in peroral route group. The pooled proportion of patients having hyperamylasemia after DAE was 29% (95% CI: 16-46%).Among the patients who had hyperamylasemia AP were identified in 2% (95% CI: 0-6%) of patients. Conclusion: The incidence of AP after DAE is about 1%. Hyperamylasemia is a common change in the patients undergoing DAE and only 2% of the patients with hyperamylasemia present with AP.

Pharmacokinetics of meloxicam in laying hens after single intravenous, oral, and intramuscular administration.

The objective of this study was to determine the pharmacokinetics of meloxicam after a single intravenous (IV), intramuscular (IM), and oral (PO) dose at 1 mg/kg body weight in Jing Hong laying hens. Blood samples were collected at predetermined time points. Plasma meloxicam concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay method and then subjected to a non-compartmental analysis. After IV administration, meloxicam had a mean (±SD) volume of distribution at steady-state (Vdss ) of 206.50 ± 25.23 ml/kg, a terminal half-life (t1/2λ ) of 5.45 ± 0.53 h, and a total body clearance (Cl) of 26.48 ± 4.13 ml/h/kg. After PO and IM administration, meloxicam was absorbed relatively rapidly: the peak concentrations (Cmax s) of 3.04 ± 0.56 and 8.94 ± 2.31 µg/ml were observed at 3.08 and 0.80 h, respectively. After PO and IM administration, the absolute bioavailability (F) was determined as 70.13% and 125.50%, respectively. Assuming that hens shared the same analgesic threshold of meloxicam (0.5 µg/ml) with humans, the plasma concentrations after three different routes (PO, IM, and IV) of administration were above this value for 16.7, 19.2, and 14.9 h, respectively.

Population Pharmacokinetics of Danofloxacin in Yellow River Carp (Cyprinus carpio haematopterus) After One Single Oral Dose.

This study aimed to determine the population pharmacokinetics of danofloxacin in healthy Yellow River carp (Cyprinus carpio Haematopterus) after single oral administration at 10 mg/kg body weight (BW). A sparse sampling was applied in this study and plasma samples were randomly collected from the tail veins of six carp at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 and 144 h after administration. A maximum of four plasma samples was collected from each carp. Then the concentrations of danofloxacin in plasma samples were determined through an HPLC method. Danofloxacin could be quantified in plasma up to 144 h after administration. The corresponding population pharmacokinetic modeling was developed according to the non-linear mixed effect method, including covariate and covariance models to explain some variations from unknown sources and improve the prediction ability. On the premise of sparse sampling, the typical values of the population (fixed effect) and inter-individual variation (random effect) were described by the current population pharmacokinetic model. The estimated typical values and coefficient of variation between individuals (CV%) of absorption rate constant (tvKa), apparent distribution volume (tvV) and clearance (tvCL) were 2.48 h-1 and 0.203%, 47.8 L/kg and 8.40%, 0.694 L/h/kg and 4.35%, respectively. The current danofloxacin oral dosing (10 mg/kg BW) can provide suitable plasma concentrations to inhibit those pathogens with MIC values below 0.016 µg/ml based on the calculated PK/PD indices of AUC/MIC or Cmax/MIC. Further studies are still needed to determine the in vitro and in vivo antibacterial efficacy of danofloxacin against pathogens isolated from Yellow River carp and finally draw a reasonable dosing regimen.

Clinical Outcomes of Negative Balloon-Assisted Enteroscopy for Obscure Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.

Background: For patients with obscure gastrointestinal bleeding (OGIB), finding the bleeding site is challenging. Balloon-assisted enteroscopy (BAE) has become the preferred diagnostic modality for OGIB. The long-term outcome of patients with negative BAE remains undefined. The present study aimed to evaluate the long-term outcomes of patients with negative BAE results for OGIB and to clarify the effect of further investigations at the time of rebleeding with a systematic review and meta-analysis of the available cohort studies. Methods: Studies were searched through the PubMed, EMBASE, and Cochrane library databases. The following indexes were analyzed: rebleeding rate after negative BAE, rebleeding rate after different follow-up periods, the proportion of patients who underwent further evaluation after rebleeding, the percentage of patients with identified rebleeding sources, and the percentage of patients with rebleeding sources in the small intestine. Heterogeneity was assessed using the I2 test. Results: Twelve studies that involved a total of 407 patients were included in the analysis. The pooled rebleeding rate after negative BAE for OGIB was 29.1% (95% CI: 17.2-42.6%). Heterogeneity was significant among the studies (I2 = 88%; p < 0.0001). The Chi-squared test did not show a difference in rebleeding rates between the short and long follow-up period groups (p = 0.142). The pooled proportion of patients who underwent further evaluation after rebleeding was 86.1%. Among the patients who underwent further evaluation, rebleeding sources were identified in 73.6% of patients, and 68.8% of the identified rebleeding lesions were in the small intestine. Conclusion: A negative result of BAE in patients with OGIB indicates a subsequently low risk of rebleeding. Further evaluation should be considered after rebleeding.

Development and application of a physiologically based pharmacokinetic model for orbifloxacin in crucian carp (Carassius auratus).

A flow-limited physiologically based pharmacokinetic (PBPK) model consisting of seven compartments was established for orbifloxacin in crucian carp to predict drug concentrations after intravenous or intramuscular injections. Physiological and anatomical parameters, including tissue weights and blood flow through different tissues, were obtained from previous literature. The tissue/plasma partition coefficients for orbifloxacin were calculated using the area method or parameter optimization. In addition, their values were 0.9326, 1.1204, 1.1644, 1.3514, and 2.0057 in the liver, skin, muscle, kidney, and the rest of the body compartment, respectively. Based on the current PBPK model, orbifloxacin concentrations were predicted and compared with those previously reported for further validation. In addition, the mean absolute percentage error (MAPE) values were also calculated, with values ranging from 10.21% in plasma to 42.37% in kidneys, indicating acceptable predictions for all tissues and plasma. A local sensitivity analysis was performed, which showed that the parameters related to elimination and distribution were most influential on orbifloxacin concentrations in muscle. This model was finally used to predict plasma and tissue concentrations after multiple intramuscular dosing. The current PBPK model provided a valuable tool for predicting the tissue residues of orbifloxacin in crucian carp following intramuscular injection.

Pharmacokinetics and Tissue Distribution of Enrofloxacin Following Single Oral Administration in Yellow River Carp (Cyprinus carpio haematoperus).

The pharmacokinetics and tissue distribution of enrofloxacin were determined in Yellow River carp (Cyprinus carpio haematopterus) reared at 20°C after single oral administration of enrofloxacin at 10 mg·kg-1 body weight (BW). Plasma, bile, and different tissue samples, including liver, kidney, gill, gut, and skin-muscle, were collected at predetermined times points. An HPLC method was developed to simultaneously determine the concentrations of enrofloxacin and its metabolite, ciprofloxacin. However, ciprofloxacin was only detectable in some liver samples with trace levels. Then the average enrofloxacin concentrations vs. time data were subjected to a non-compartmental analysis using WinNonLin 5.2 software. Multiple peaking profiles were observed in all enrofloxacin concentration-time curves. The peak concentration (Cmax) values were observed as 0.79, 1.01, 2.09, 2.85, 4.34, 10.78, and 13.07 µg·ml-1 (or g-1) in plasma, skin-muscle, gill, kidney, liver, bile, and gut, respectively, and the corresponding time to reach peak concentration (Tmax) was 8, 8, 1, 8, 1, 72, and 4 h, respectively. The values of elimination half-life (T1/2λZ ) of enrofloxacin in different tissues was in the following order: gill (291.13 h) > liver (222.29 h) > kidney (157.22 h) > plasma (129.44 h) > gut (91.47 h) > skin-muscle (87.77 h) > bile (86.22 h). The present results showed that enrofloxacin had a wide distribution in different tissues, however slow absorption and elimination in Yellow River carp. Additionally, enrofloxacin exhibited large distribution in bile, indicating that bile excretion might be the primary elimination route of enrofloxacin in Yellow River carp. A withdrawal period was calculated as 379.2 °C-day for single oral dosing of enrofloxacin at 10 mg/kg BW. Based on the calculated PK/PD indices of AUC/MIC or Cmax/MIC, the current enrofloxacin dosing regimen might have a positive therapeutic effect on the infection of Flavobacterium columnare, Aeromonas sobria, or Aeromonas hydrophila. However, the depletion study following multiple oral doses should be carried out in Yellow River carp reared at lower temperatures, and the withdrawal period should also be further calculated.

The influence of immune stress induced by Escherichia coli lipopolysaccharide on the pharmacokinetics of danofloxacin in broilers.

This study aimed to determine whether the challenge from Escherichia coli (E. coli) lipopolysaccharide (LPS) affects the pharmacokinetics of danofloxacin in broilers. Twenty 1-day-old Arbor Acres (AA) broilers were equally and randomly divided into 2 groups. When the chickens were 23, 25, 27, and 29 days old, E. coli LPS (1 mL; 0.5 mg/kg body weight [BW]) and sterile saline (1 mL) were intraperitoneally injected into the two groups. After the last injection, danofloxacin was given to all chickens by gavage at the dose of 5 mg/kg BW. Then serum and plasma samples at each time point were collected through the wing vein. Danofloxacin concentrations in plasma were detected through the high-performance liquid chromatography (HPLC) method and subjected to noncompartmental analysis using Phoenix software. The levels of chicken interleukin-1ß (IL-1ß) and corticosterone (CORT) in serum were measured by the Enzyme-linked immunosorbent assay (ELISA) kit. In addition, after the collection of plasma or serum samples, 7 chickens (31 days of age) in each group were killed to calculate the organ indices. Compared with the control group, the challenge of LPS significantly decreased the parameters of AUC0-∞, Cmax, and t1/2λz and increased the parameters of Tmax and λz. Additionally, in the LPS group, the absorption time of danofloxacin was prolonged; however, the elimination was accelerated, which resulted in reduced internal exposure.

Influence of Escherichia coli endotoxemia on danofloxacin pharmacokinetics in broilers following single oral administration.

As a fluoroquinolone antimicrobial agent, danofloxacin is mainly used to treat avian bacterial and mycoplasma infections. The pharmacokinetic characteristics of danofloxacin are usually explored in healthy animals, while those in endotoxemic broilers are still rare. This study aimed to investigate the pharmacokinetics of danofloxacin in endotoxemic broilers induced by Escherichia coli (E. coli) lipopolysaccharide (LPS) after single oral administration. Ten healthy 5-week-old Arbor Acres (AA) broilers with similar body weight (BW) were randomly and equally divided into LPS and control groups. The LPS group was intravenously injected with an LPS of E. coli O55: B5 at 2.5 mg/kg BW, and the control group was intravenously injected with the same volume of sterile saline. Danofloxacin was administered orally at a dose of 5 mg/kg BW immediately 1 h after the intravenous injection of LPS or sterile saline. Rectal temperature was measured at predetermined times points in all broilers, and plasma and serum samples were taken. The interleukin-6 (IL-6) levels in serum samples were detected by the enzyme-linked immunosorbent assay (ELISA) kits, and danofloxacin concentrations in plasma were detected through the high-performance liquid chromatography (HPLC) method and subjected to a compartmental analysis using Phoenix software. The LPS challenge led to biphasic adaptive changes in broiler body temperature and increased the levels of IL-6. Compared with the control group, LPS treatment significantly prolonged the time to the peak concentration (LPS: 8.75 ± 3.88 h; Control: 3.20 ± 2.20 h). However, there were no significant differences in the other pharmacokinetic parameters between both groups.

Pharmacokinetics of ceftiofur sodium in Peekapoo dogs following a single intravenous and subcutaneous injection.

The present study aimed to determine the pharmacokinetic profiles of ceftiofur (as measured by ceftiofur and its active metabolites concentrations) in a small-size dog breed, Peekapoo, following a single intravenous or subcutaneous injection of ceftiofur sodium. The study population comprised of five clinically healthy Peekapoo dogs with an average body weight (BW) of 3.4 kg. Each dog received either intravenous or subcutaneous injection, both at 5 mg/kg BW (calculated as pure ceftiofur). Plasma samples were collected at different time points after the administration. Ceftiofur and its active metabolites were extracted from plasma samples, derivatized, and further quantified by high-performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetic parameters. The terminal half-life (t1/2 λz ) was calculated as 7.40 ± 0.79 and 7.91 ± 1.53 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady-state (VSS ) were determined as 39.91 ± 4.04 ml hr-1  kg-1 and 345.71 ± 28.66 ml/kg, respectively. After subcutaneous injection, the peak concentration (Cmax ; 10.50 ± 0.22 µg/ml) was observed at 3.2 ± 1.1 hr, and the absorption half-life (t1/2 ka ) and absolute bioavailability (F) were calculated as 0.74 ± 0.23 hr and 91.70%±7.34%, respectively. The pharmacokinetic profiles of ceftiofur and its related metabolites demonstrated their quick and excellent absorption after subcutaneous administration, in addition to poor distribution and slow elimination in Peekapoo dogs. Based on the time of concentration above minimum inhibitory concentration (T > MIC) values calculated here, an intravenous or subcutaneous dose at 5 mg/kg of ceftiofur sodium once every 12 hr is predicted to be effective for treating canine bacteria with a MIC value of ≤4.0 µg/ml.

Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout.

Enrofloxacin (ENR) has been approved for the treatment of infections in aquaculture, but it may cause tissue residue. This research aimed to develop and validate a water temperature related PBPK model, including both ENR and ciprofloxacin (CIP), in rainbow trout, and to predict further their residue concentrations and the withdrawal periods for ENR at different water temperatures. With the published concentrations data, a flow-limited PBPK model including both ENR and CIP sub-models was developed to predict ENR and CIP concentrations in tissues and plasma/serum after intravenous, oral, or immersion administration. A Monte Carlo simulation including 500 iterations was further incorporated into this model. Based on the model and Monte Carlo analysis, the withdrawal intervals were estimated for different dosage regimens and at different water temperatures, ranging from 80 to 272 degree-days. All of these values were shorter than the labeled withdrawal period (500 degree-days) in fish. This model provided a useful tool for predicting the tissue residues of ENR and CIP in rainbow trout under different dosage regimens and at different water temperatures.