Dispositions and residue depletion of enrofloxacin and its metabolite ciprofloxacin in muscle tissue of giant freshwater prawns (Macrobrachium rosenbergii)

Fates and residue depletion of enrofloxacin (ER) and its metabolite ciprofloxacin (CP) were examined in giant freshwater prawns, Macrobrachium rosenbergii, following either single oral (p.o.) administration of ER at a dosage of 10 mg/kg body weight (b.w.) or medicated‐feed treatment at the feeding concentration of 5 g/kg of feed for five consecutive days. The concentrations of ER and CP in prawn muscle tissues were measured simultaneously using high‐performance liquid chromatography (HPLC) equipped with a fluorescence detector. Muscle tissue concentrations of ER and CP were below the detection limit (LOD, 0.015 μg/g for ER; 0.025 μg/g for CP) after 360 and 42 h, following single p.o. administration respectively. Peak muscle concentration (C_max) of ER was 1.98 ± 0.22 μg/g whereas CP was measurable at concentrations close to the detection limit of the analytical method after p.o. administration at a single dosage of 10 mg/kg b.w. The concentration of ER in prawn muscle tissue with respect to time was analyzed with a non‐compartmental pharmacokinetic model. The elimination half‐life and area under the curve of ER were 39.33 ± 7.27 h and 168.7 ± 28.7 μg·h/g after p.o. administration at a single dose of 10 mg/kg·b.w. respectively. In medicated‐feed treated group, ER was detectable in prawn muscle tissue 11 days postdosing at the dose of 5 g/kg of feed for five consecutive days, which is the value corresponding to the maximum residue limit (MRL) of ER in animal products. The maximum concentrations of ER and CP were 2.77 ± 0.91 and 0.06 ± 0.006 μg/g during medicated‐feed treatment and postdosing respectively. The values of elimination half‐life and absorption half‐life of ER after single p.o. administration at a dosage of 10 mg/kg b.w. corresponded well with the values determined from medicated‐feed treated group, showing 41.01 ± 6.62 and 11.36 ± 3.15 h respectively in M. rosenbergii. Based on data derived from this study, to avoid the ER residue in prawn muscle, it should take at least 11 days postcessation of medicated feed containing ER at the dose concentration of 5 g/kg of feed twice a day at a rate of 1% of total body weight for five consecutive days to wash out the drug from the muscle of M. rosenbergii.     

Muscle tissue kinetics of oxytetracycline following intramuscular and oral administration at two dosages to giant freshwater shrimp (Macrobrachium rosenbergii)

The giant river shrimp (Macrobrachium rosenbergii), a native species of Thailand, is either exported for commercial purposes or supplied to meet the local requirements in Thailand. Limited pharmacokinetic information of the major antibiotic, oxytetracycline (OTC), is available for this freshwater shrimp. The purpose of the present study was to investigate the muscle tissue kinetics of OTC in M. rosenbergii following either intramuscular (i.m.) or oral (p.o.) administration at two dosages of 11 and 22 mg/kg body weight (b.w.). The concentration of OTC in shrimp tissues was measured using high‐performance liquid chromatography (HPLC) equipped with a fluorescence detector. Muscle tissue concentrations were below the detection limit (LOD, 0.1 μg/g) after 96 and 120 h, following i.m. and p.o. administration, respectively. Peak muscle concentrations (C_max) were 3.47 and 1.73 μg/g after i.m. and p.o. administration at a single dose of 11 mg/kg b.w. whereas they were 6.03 and 2.51 μg/g at a single dose of 22 mg/kg b.w., respectively. A noncompartment model was developed to describe the pharmacokinetics of OTC in the giant freshwater shrimp. The terminal half‐lives of OTC were 28.68 and 28.09 h after i.m. and p.o. administration at a single dose of 11 mg/kg b.w., but 29.95 and 27.03 h at a single dose of 22 mg/kg b.w., respectively. The relative bioavailability was 82.32 and 64.67% following i.m. and p.o. administration, respectively. Based on the pharmacokinetic data, i.m. and p.o. administration with OTC at a dose of 11 mg/kg b.w. would be appropriate for use in giant freshwater shrimp farming. To avoid the OTC residue in shrimp muscle, it should take at least seven half‐lives (8 days) to wash out the drug from the muscle of M. rosenbergii.     

Determination and kinetics of enrofloxacin and ciprofloxacin in Tra catfish (Pangasianodon hypophthalmus) and giant freshwater prawn (Macrobrachium rosenbergii) using a liquid chromatography/mass spectrometry method

Determination and kinetics of enrofloxacin and ciprofloxacin in Tra catfish (Pangasianodon hypophthalmus) and giant freshwater prawn (Macrobrachium rosenbergii) using a liquid chromatography/mass spectrometry method. J. vet. Pharmacol. Therap. 34, 142-152. The fluoroquinolones enrofloxacin (EF) and ciprofloxacin (CF) residues were investigated in the edible tissues of two important Asian aquacultured species such as Tra catfish (Pangasianodon hypophthalmus) and giant freshwater prawn (Macrobrachium rosenbergii) using a sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry method. Fish and prawn were treated with medicated feed with multiple doses of EF, in field conditions. A validation study of the analytical method was realized in terms of linearity, specificity, precision (repeatability and within-laboratory reproducibility), recovery and decision limit (CCα). The time needed before the antibiotic disappears from animal tissues or reach the maximum residue limit (MRL, 100μg/kg) was assessed. The concentration values of EF detected in Tra catfish tissue were between the MRL and 2×MRL concentrations, according to the fish density, 7days following the end of the enrofloxacin treatment (20mg/kg body weight per day, for seven consecutive days). The concentration value of ER in prawn tissue was lower than the MRL and the limit of quantification (LOQ, 14μg/kg) 5 and 7days after the stop of the EF treatment (50mg/kg body weight per day, for five consecutive days), respectively. The mean detected levels of CF was much lower in comparison with that of EF, indicating that only a small part of EF is metabolized into CF (<5%) in both Tra catfish and prawn.     

How to extrapolate a withdrawal time from an EHSLC published detection time: A Monte Carlo simulation appraisal

Reason for performing study: For legitimate medications, veterinarians must advise the owners or trainers of horses on appropriate withholding times after a treatment, to avoid the risk of incurring a positive drug test. Objective: To explore the safety span to select that a veterinarian may extrapolate a tailored withdrawal time (WT) from a generic detection time (DT) as published by the European Horserace Scientific Liaison Committee (EHSLC). Methods: Using Monte Carlo simulations, it was shown that for a low variability of pharmacokinetic parameters (CV = 20%), an uncertainty span of about 40% may be selected to transform a mean DT into a WT (i.e. WT = 1.4 DT), which covers 90% of the horse population. In contrast for a highly variable drug (CV = 40%), an uncertainty factor of about 2.1–2.2 needs to be selected, i.e. a WT that is twice the DT. Results: The relative impact of the different factors of variability on the final WT was documented by a so‐called sensitivity analysis. It was shown that the parameters that have the greatest influence on the value of a DT are those that control the terminal half‐life of the drug disposition. In contrast, parameters controlling the level of urine (or plasma) concentrations (i.e. the actual administered dose, the urine‐to‐plasma ratio and the bioavailability) collectively have a minimal influence on the DT. Conclusions and potential relevance: In practice, this means that the main sources of uncertainty are of biological origin and cannot be reduced by any managerial options. The influence of the number of experimental horses that are used by EHSLC to establish a DT was shown that with the standard EHLSC protocol of 6 horses, half of the trials lead to a proposed DT that is equal to or higher than the population 90^th percentile. Increasing the number of investigated horses to 8 and 10 would increase this last probability to 85 and 90%, respectively.     

Use of population pharmacokinetic modeling and Monte Carlo simulation to capture individual animal variability in the prediction of flunixin withdrawal times in cattle

The objective of this study was to develop a population pharmacokinetic (PK) model and predict tissue residues and the withdrawal interval (WDI) of flunixin in cattle. Data were pooled from published PK studies in which flunixin was administered through various dosage regimens to diverse populations of cattle. A set of liver data used to establish the regulatory label withdrawal time (WDT) also were used in this study. Compartmental models with first‐order absorption and elimination were fitted to plasma and liver concentrations by a population PK modeling approach. Monte Carlo simulations were performed with the population mean and variabilities of PK parameters to predict liver concentrations of flunixin. The PK of flunixin was described best by a 3‐compartment model with an extra liver compartment. The WDI estimated in this study with liver data only was the same as the label WDT. However, a longer WDI was estimated when both plasma and liver data were included in the population PK model. This study questions the use of small groups of healthy animals to determine WDTs for drugs intended for administration to large diverse populations. This may warrant a reevaluation of the current procedure for establishing WDT to prevent violative residues of flunixin.     

Interindividual variability in plasma concentrations after systemic exposure of swine to dietary doxycycline supplied with and without paracetamol: a population pharmacokinetic approach

Anorexigenic substances released during infection may hinder the therapeutic efficacy of in-feed antibiotics. Paracetamol (acetaminophen; PARA) inhibits the anorexia of infection and seems to improve the clinical efficacy of doxycycline (DOX) against bacterial respiratory disease in swine herds. In order to verify whether PARA selectively stimulates intake of DOX-medicated feed in diseased pigs, we documented the pharmacokinetics (PK) of DOX when coadministered with PARA and examined the effect of in-feed PARA on the interindividual variability in plasma concentrations after systemic exposure to in-feed DOX in swine herds with respiratory disease. Systemic exposure to DOX was measured with the area under the curve (AUC) of its plasma concentrations over time. First, a rich-sampling PK study of in-feed and i.v. DOX (10 mg/kg of BW) and PARA (30 and 10 mg/kg of BW, respectively) was performed on 5 pigs. The PK profiles of in-feed DOX were used in mathematical simulations to determine 5 optimal sampling times for the farm-based population PK study. A randomized, blind, parallel PK study was performed in 2 herds with bacterial respiratory disease, where liquid feed was fortified with DOX alone (5 mg x kg of BW(-1) x meal(-1)) or combined with PARA (15 mg x kg of BW(-1) x meal(-1)). Medicated meals were given twice, 12 h apart, to group-housed growing pigs (n > 50 pigs x treatment(-1) x herd(-1), totaling 215 pigs). Plasma concentrations of DOX and PARA were measured with HPLC. At variance with our expectations, PARA decreased (P = 0.069) mean AUC of in-feed DOX and did not decrease its variability (P > 0.34). Mean AUC of DOX increased with feed intake and with initial exposure to DOX, and was greater in sick animals. Therefore, symptomatic PARA-induced improvement in bacterial respiratory disease control with DOX is more likely caused by its analgesic/antipyretic effects than by its orexigenic effect. Interindividual variation in the AUC of DOX was large in pigs given group medication, even when sufficient feeding space was allowed and the amount of feed offered was greater than their requirements. Therefore, future studies to improve the efficacy of group antibiotic therapy should focus on feeding behavior characteristics as well as biopharmaceutical properties of medicated feeds.     

Description of a microfilaria from an umbrella cockatoo (Cacatua alba) and an unsuccessful attempt to infect mosquitoes (Culex pipiens pipiens).

Unidentified microfilariae circulating in the blood of an umbrella cockatoo (Cacatua alba) are described. They are ensheathed, measure 102-152 microns long and 2-3 microns in diameter, and have four distinct and consistent gaps in the nuclear column. Attempts to infect mosquitoes (Culex pipiens pipiens) with the microfilariae were unsuccessful.     

South-western extension of the known range of two freshwater shrimps,Caridina nilotica (Roux) and Macrobrachium petersi (Hilgendorf), in South Africa

Two freshwater shrimps, Caridina nilotica (Roux) and Macrobrachium petersi (Hilgendorf), were collected in the Gamtoos River in the eastern Cape, representing a southwestern range extension for both. This is the first known record of these species west of Port Elizabeth, and also the first record of an overlap of their distribution ranges with that of the Cape river shrimp, Palaemon capensis (de Man).     

Propofol as an induction agent in the goat: a pharmacokinetic study

Reid, J., Nolan, A.M., Welsh, E. Propofol as an induction agent in the goat: a pharmacokinetic study. J. vet. Pharmacol. Therap. 16, 488–493.
The pharmacokinetics of propofol, 4 mg/kg, administered as a bolus dose intravenously (i.v.) prior to the maintenance of anaesthesia with halothane in oxygen, were determined in five goats, and a clinical impression of its use as an induction agent was made. Induction of anaesthesia was rapid and smooth, providing satisfactory conditions for intubation in all animals. Post-induction apnoea occurred in one goat and minimal regurgitation of ruminal contents was recorded in two animals. Recovery times were rapid with a mean time to standing after halothane inhalation ceased of 13.7 min. The blood propofol concentration time profile was best described by a bi-exponential decline in all five goats. The mean elimination half-life was short (15.5 min), the volume of distribution at steady state large (2,56 1/kg) and the clearance rapid (275 ml/min.kg). Propofol was shown to be a very satisfactory induction agent in the goat.     

A linear programming approach to estimate the economic impact of bovine viral diarrhoea (BVD) at the whole-farm level in Scotland

We combined epidemiological and economic concepts and modelling techniques, to integrate animal health into whole-farm business management. This allowed us to assess the relative contribution that disease prevention could make to whole-farm income and to the variability in farm income (risk). It also allowed us to assess disease losses in the context of a farm business rather than as a disease outbreak in isolation. A linear program ("MOTAD") establishes the combination of decision maker's activities that minimise risk for a given level of income within farm-business constraints. The MOTAD model was applied to farm-management decision making in Scottish cow-calf herds and was linked to an epidemiological model of bovine viral diarrhoea (BVD). When BVD was considered in isolation (i.e. without taking into account risk), the minimum expected total cost of BVD (sum of output losses plus expenditure on prevention) was similar whether the herd was susceptible to BVD or of unknown BVD-status at the outset. However, the expected total cost of BVD fell in response to increasing expenditure on prevention in 'susceptible' herds. This relationship was not apparent in herds of unknown BVD-status. As a consequence of this difference, 'susceptible' herds were better able to use investment in BVD biosecurity as a means to increase farm income at minimum risk than herds of unknown BVD-status. 'Susceptible' herds therefore were able to achieve high income targets with less-intensive production than herds of unknown BVD-status. This suggested that maintaining a cow-calf herd free of BVD contributes to farm income and risk management indirectly through its effect on the management of the whole farm. It follows that measurement of the economic impact of BVD requires a whole-farm perspective that includes a consideration of risk. Because farmers generally are considered to be risk adverse, this means that the least-cost disease-control option might not always be the preferred option.     

The non-linear effect (determined by the penalised partial-likelihood approach) of milk-protein concentration on time to first insemination in Belgian dairy cows

The time to first insemination in dairy cows depends partly on the energy balance of the cow. Because milk-protein concentration is related to the energy balance, we investigated whether milk-protein concentration predicted the hazard of being inseminated. The main objective of the paper is to demonstrate that the relationship between milk-protein concentration and the hazard of being inseminated was not linear and that this non-linear relationship was modelled adequately using cubic–splines. The semiparametric Cox model was used to introduce protein concentration into the model as a time-varying covariate and additionally herd was added to the model as a frailty term to adjust for the clustering of the cows within a herd. We extended the penalised partial-likelihood technique to fit the frailty model with cubic–splines for the effect of the protein concentration. The model was fitted for a large database consisting of 5114 multiparous cows from 181 different farms. Low milk-protein concentration (<2.7%) was associated with a negative energy balance and this probably led to the decreased hazard. On the other hand, high milk-protein concentration (>4.0%) was linked with low milk production and it was probably a farmer’s decision not to inseminate such cows, leading to the observed decreased hazard.     

Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study

Bakker, J., Thuesen, L. R., Braskamp, G., Skaanild, M. T., Ouwerling, B., Langermans, J. A. M., Bertelsen, M. F. Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study. J. vet. Pharmacol. Therap. 34 , 464–468. Cefovecin is a third‐generation cephalosporin approved for antibacterial treatment with a 14‐day dosing interval in dogs and cats. This antibiotic may also be useful for zoo and wildlife veterinary medicine, because of its broad spectrum and long duration of activity. The aim of the study was to determine whether cefovecin is a suitable antibiotic to prevent skin wound infection in rhesus monkeys. Therefore, the pharmacokinetics (PK) of cefovecin after a single subcutaneous injection at 8 mg/kg bodyweight in four rhesus monkeys (Macaca mulatta) and sensitivity of bacterial isolates from fresh skin wounds were determined. After administration, blood, urine, and feces were collected, and concentrations of cefovecin were determined. Further, the minimum inhibitory concentrations (MIC) for bacteria isolated from fresh skin wounds of monkeys during a health control program were determined. The mean maximum plasma concentration (C_max) of cefovecin was 78 μg/mL and was achieved after 57 min. The mean apparent long elimination half‐life (t½) was 6.6 h and excretion occurred mainly via urine. The MIC for the majority of the bacteria examined was >100 μg/mL. The PK of cefovecin in rhesus monkeys is substantially different than for dogs and cats. Cefovecin rapidly reached C_max which however was lower than most of the MIC levels and with a very short t½. Therefore, cefovecin is not recommended for treating skin wounds in rhesus monkeys.     

A pharmacokinetic/clinical approach to postulate a local action of intra‐articular xylazine administration in the horse: a preliminary study

The study aims to evaluate whether the analgesic effect of intra‐articular (IA) route of xylazine administered to horses following arthroscopic surgery is due to a local or a systemic action. Two connected studies were performed. In the first, 1 mg/kg b.w. of xylazine was injected IA, and blood samples were taken to assess drug systemic absorption. In addition, systemic effects of the drug (sedation, ataxia or reduction of respiratory and cardiac rate) were registered. Control horses injected with saline IA were included in the study to exclude the influence of anaesthesia in the occurrence of these manifestations. In the second study, 1 mg/kg b.w. of xylazine was administered intravenously (i.v.) in healthy horses. Blood samples were collected to determine the concentrations of xylazine, and the same signs of systemic effects of the drug were recorded. By correlating these parameters, a systemic ‘no effect’ concentration was defined. Pharmacokinetic data after IA administration resulted in some xylazine absorption (bioavailability equal to 58.12%) with values above the systemic ‘no effect’ concentration. The occurrence of some signs related to systemic effects in horses receiving IA xylazine was significant compared with horses receiving saline. In conclusion, a systemic action of the drug after IA administration cannot be excluded.     

Ovarian biopsy: a non-terminal method to determine reproductive status in giant kokopu,Galaxias argenteus (Gmelin 1789)

AIM: To establish a method of gonad biopsy for ovarian tissue collection in the declining giant kokopu Galaxias argenteus (Gmelin 1789) as an alternative to lethal sampling in order to understand the species' reproductive biology.

METHODS: Six female giant kokopu weighing between 200 and 350 g were caught from the wild in early December of 2009 and transferred to a holding facility (Department of Zoology, University of Otago, Dunedin) where they were kept under a simulated natural photo-thermal regime for 10 months. Fish were repeatedly biopsied for ovarian tissue at near-monthly intervals (mean number of days between biopsies = 33) until ovulation.

RESULTS AND CONCLUSIONS: Ovarian samples were successfully collected from giant kokopu by biopsy for use in downstream analyses. Among a total of 23 biopsy events, a single death occurred when a two-layered suturing approach was used, highlighting the value of this method for study of the reproductive biology of valuable fish.

CLINICAL RELEVANCE: This biopsy method may have implications for veterinary research on fish physiology, pathology, conservation and development, when repeated tissue samples need to be collected over a prolonged period of time or for general surgical manipulations on fish when accessing the coelom. Furthermore, this approach allows the implementation of a more powerful experimental design, as repeated measures reduces the variability of estimates due to the removal of inherent stage differences among individuals.     

A new dosing schedule for gentamicin in blood pythons (Python curtus): a pharmacokinetic study

Gentamicin is frequently used in the treatment of aerobic Gram-negative infections in reptiles. Pharmacokinetic data to ensure proper dosing are scant, especially for large snakes. A pharmacokinetic study of gentamicin was therefore conducted in four blood pythons. Snakes were given intramuscular injections of either 2.5 mg kg-1 or 3.0 mg kg-1 loading dose followed by 1.5 mg kg-1 at 72 and 96 hours. A linear pharmacokinetic relationship between gentamicin serum concentrations and time was demonstrated in each of the four snakes studied. Peak serum concentrations occurred six to 10 hours after injection and ranged from 4.6 to 8.9 micrograms ml-1. Half-life was variable and ranged from 32 to 110 hours. Total body clearance and apparent volume of distribution varied little between the individual snakes studied. There was no evidence of renal toxicity. For blood pythons a loading dose of 2.5 mg kg-1 followed by 1.5 mg kg-1 at 96 hour intervals is recommended. If higher concentrations are desired, a loading dose of 3.0 mg kg-1 followed by 1.5 mg kg-1 at 96 hours can be given. These dosing schedules will provide serum concentrations in excess of the minimum inhibitory concentrations for most aerobic Gram-negative bacilli that are pathogenic in snakes; gentamicin accumulation with subsequent renal dysfunction should not occur.     

Use of a pharmacokinetic/pharmacodynamic approach in the cat to determine a dosage regimen for the COX-2 selective drug robenacoxib

This study investigated the analgesic, anti-inflammatory and antipyretic efficacy of the new COX-2 selective inhibitor robenacoxib in the cat and established pharmacodynamic (PD) parameters for these effects. Robenacoxib, at a dosage of 2 mg/kg administered subcutaneously, was evaluated in a kaolin-induced paw inflammation model in 10 cats, using both clinically relevant endpoints (lameness scoring, locomotion tests) and other indicators of inflammation (body and skin temperature, thermal pain threshold) to establish its pharmacological profile. A pharmacokinetic/pharmacodynamic (PK/PD) modelling approach, based on indirect response models, was used to describe the time course and magnitude of the responses to robenacoxib. All endpoints demonstrated good responsiveness to robenacoxib administration and both the magnitude and time courses of responses were well described by the indirect pharmacodynamic response models. Pharmacokinetic and clinically relevant pharmacodynamic parameters were used to simulate dosage regimens that will assist the planning of clinical trials and the selection of an optimal dosage regimen for robenacoxib in the cat.     

Analysis of blood gases,serum fat and serum protein: a new approach to estimate survival chances of stranded Harbor seal (Phoca vitulina) pups from the German North Sea

Background

Facing numerous challenges, such as illness, storms or human disturbance, some harbor seal (Phoca vitulina) pups lose contact to their dams and are found abandoned along the North Sea coast. In Schleswig-Holstein, pups with the prospect of surviving rehabilitation are admitted to the Seal Center Friedrichskoog. Despite elaborate clinical health assessments on admission, including differential hematology, in 2010, 17% of 108 admitted pups did not survive the first 20 days. The death rate during the years 2006 and 2009 varied between 9 and 19%. To broaden the spectrum of variables which could be predictive for survival, blood gas and serum analyses were performed for 99 pups using venous blood. Variables included total CO₂, pH, partial CO₂, HCO₃^–, base excess and anion gap as well as glucose, urea nitrogen, sodium, potassium and chloride. Moreover, total serum protein and fat (triglyceride) concentrations were measured for all pups on admission.

Results

Repeated measurements of 12 randomly selected individuals revealed a significant (p = 0.002) positive influence of time in rehabilitation on triglyceride concentrations. This trend probably shows the improvement of the pups’ nutritional status as a consequence of the shift from milk replacer formula to fish. No such positive influence was detected for total protein concentrations though. Hematologic values, including blood gases, were not predictive for survival.

Conclusions

For the first time blood gas values are reported in this study for a large sample size (N = 99) of seal pups (regardless of their health status). The ranges and medians calculated from the data can serve as a stepping stone towards the establishment of reference values for neonate harbor seals. However, future investigations on the development of blood gases in harbor seals with different health conditions and ages over time are necessary to allow for a better understanding of acid–base regulation in harbor seals.