PK/PD modeling of flunixin meglumine in a kaolin‐induced inflammation model in piglets

Flunixin is marketed in several countries for analgesia in adult swine but little is known about its efficacy in piglets. Thirty‐two piglets (6–8 days old) were randomized to receive placebo saline (n = 11, group CONTROL) or flunixin meglumine intravenously at 2.2 (n = 11, group MEDIUM) or 4.4 (n = 10, group HIGH) mg/kg, 10 hr after subcutaneous injection of kaolin in the left metacarpal area. A hand‐held algometer was used to determine each piglet’s mechanical nociceptive threshold (MNT) from both front feet up to 50 hr after treatment (cut‐off value of 24.5 newton). Serial venous blood samples were obtained to quantify flunixin in plasma using LC‐MS/MS. A PKPD model describing the effect of flunixin on the mechanical nociceptive threshold was obtained based on an inhibitory indirect response model. A two‐compartmental PK model was used. A significant effect of flunixin was observed for both doses compared to control group, with 4.4 mg/kg showing the most relevant (6–10 newton) and long‐lasting effect (34 hr). The median IC50 was 6.78 and 2.63 mg/ml in groups MEDIUM and HIGH, respectively. The ED50 in this model was 6.6 mg/kg. Flunixin exhibited marked antinociceptive effect on kaolin‐induced inflammatory hyperalgesia in piglets.     

Anesthetic interaction in cardiovascular research models: effects of xylazine and pentobarbital in cats

The effects of xylazine given to cats before anesthetization was induced with pentobarbital were determined. Cardiac hemodynamic variables and regional blood flow rates in the heart and other organs were measured, using radiolabeled microspheres. Two groups, each of 10 cats, were included in the study: one group (group 1) was anesthetized with pentobarbital given intraperitoneally and subsequently given xylazine; the other group (group 2) was first given 1 mg of xylazine/kg, IM, and then anesthetized with pentobarbital given IV. Anesthesia was maintained in both groups with nitrous oxide. The preanesthetic administration of xylazine decreased the amount of pentobarbital used for surgical anesthesia by approximately 50%. It also resulted in decreased heart rate, cardiac contractility, and cardiac output and increased left ventricular end-diastolic pressure, compared with those values in cats given pentobarbital (group 1). After the latter cats (anesthetized with pentobarbital) were given xylazine, heart rate, cardiac contractility, and cardiac output decreased and left ventricular end-diastolic pressure increased to values similar to those found in group 2 (given xylazine before anesthetization). Myocardial tissue blood flow rates in the left and right ventricles were lower in the cats of group 2. In group 1 cats, myocardial blood flow rates decreased when xylazine was subsequently added. Blood flow rates in the kidneys and gastrointestinal tract were generally decreased by xylazine. Xylazine profoundly changed cardiac hemodynamic function and perfusion in the heart, as well as several other organ systems, because of marked cardiodepression.     

Comparison of various anesthetic regimens in the domestic fowl

Three anesthetic agents (equithesin, metomidate, and ketamine) combined with diazepam were tested in the domestic fowl. Laparotomy and thoractomy were possible with the equithesin/diazepam combination, but only laparotomy was possible with the metomidate/diazepam combination. The combination of ketamine/diazepam did not result in the depth of anesthesia required for surgical procedures. Repeated blood pressure and heart rate measurements were recorded by use of a modified noninvasive Doppler technique. Equithesin/diazepam was our combination of choice for long-duration surgical anesthesia. The depth of anesthesia could be modulated by increasing the dose of diazepam. Metomidate/diazepam was useful when short-term anesthesia was required. In contrast to equithesin/diazepam, the metomidate/diazepam combination provided unstable anesthesia of varying depth and duration. Adverse reactions with metomidate indicated caution when using this drug in chickens; the drug also caused marked bradycardia. Ketamine/diazepam combination cannot be recommended as an anesthetic agent for use in chickens. The combination may be useful for minor surgical procedures or treatment, but not for experimental procedures that involve major surgery. Diazepam alone had a slight tranquilizing effect.     

Pharmacokinetics and pharmacodynamics of meloxicam in piglets

The pharmacokinetics and pharmacodynamics of meloxicam in piglets (16–23 days old) were studied using a stratified parallel group design. One group ( n  = 13) received 0.4 mg/kg meloxicam intravenously, while the other group ( n  = 12) received physiological saline solution. A carrageenan-sponge model of acute inflammation was used to evaluate the effects of meloxicam. The plasma clearance was low (0.061 L/kg/h), the volume of distribution was low (0.19 L/kg) and the elimination half-life was short (2.7 h). At most time points, the mean concentration of meloxicam in plasma exceeded the concentrations in exudate indicating a limited accumulation of the drug at the site of the inflammation. There were significant differences between the groups in the exudate prostaglandin E₂ (PGE₂) concentration, but the inhibition of PGE₂ in the meloxicam group was limited. The inhibition of thromboxane B₂ (TXB₂) production in serum in the meloxicam group was extensive, but of shorter duration than the PGE₂ inhibition in exudate.     

Biochemical analysis of uterine fluid for identification of indicators for subclinical endometritis in the water buffalo (Bubalus bubalis)

Alterations in biochemical constituents of uterine fluid have been suggested for diagnosis of subclinical uterine infection in the bovine. This study was undertaken to investigate whether uterine fluid biomolecules could act as tool for diagnosis of subclinical endometritis in the buffalo. Uterine fluid samples from normal (n = 22) and subclinical endometritis (n = 18; diagnosed based on uterine cytology)‐affected buffaloes were subjected to biochemical analysis. Among the different biochemical constituents estimated, urea, urea N, cholesterol, total bilirubin and alkaline phosphatase (ALP) concentrations were significantly (p < 0.05) higher in uterine fluid obtained from subclinical endometritis‐affected buffaloes. The extent of difference between normal and subclinical endometritis‐affected buffaloes was highest in ALP (69%) followed by cholesterol (55%), bilirubin (48%), urea (30%) and urea N (30%) concentrations. Receiver operating characteristic (ROC) analysis indicated that the likelihood ratio (LR) was 3.63 for urea, indicating that buffaloes having less than the threshold concentration (47.5 mg/dl) of urea in their uterine fluid were at 3.6 times more risk to be affected with SE. The LRs for urea N, cholesterol, ALP and bilirubin were 2.33, 2.54, 2.12 and 1.65, respectively. It was concluded that ALP, urea, urea N and cholesterol concentrations in uterine fluid may serve as an aid for diagnosing subclinical endometritis in the buffalo.     

Prevalence and Risk Factors for Bacterial Food‐Borne Zoonotic Hazards in Slaughter Pigs: A Review

The Hygiene Package and Regulation EC‐2160/2003 require information flow from farm to slaughterhouse to enhance European consumers protection in a ‘farm to fork’ approach. This obligation especially concerns food‐borne zoonotic hazards transmitted to humans through pork consumption, such as thermophilic Campylobacter spp., Listeria monocytogenes, Salmonella enterica and Yersinia enterocolitica. Prevalence estimates of these four hazards are affected by the sampling strategy and diagnostic procedure. Individual prevalence estimates for pig carriage (from digestive contents or lymph nodes collected at slaughterhouse) were higher than individual prevalence estimates for pig shedding (from faeces). Among risk factors described in the literature, poor pen cleaning and disinfection after pig departure to slaughterhouse and poor bio‐security measures are of major significance. Moreover, whereas wet feed increases the risk of pig infection by L. monocytogenes, dry feed is a risk factor for Salm. enterica. Mixing batches of pigs, notably in fattening herds, represents a risk for the transmission of Salm. enterica and Y. enterocolitica. Whereas small herds are more infected by thermophilic campylobacters and Y. enterocolitica, higher prevalence of Salmonella is observed in large herds due to a more frequent mixing of batches. Antibiotic treatment during the finishing period increases the risk of transmission of Salm. enterica. The forenamed elements should be taken into account to characterize farms in a risk assessment approach and to improve zoonotic hazard management in the pork food chain.     

Enantioselective pharmacokinetics of ketoprofen in piglets: the significance of neonatal age

Following intravenous dose of 6mg/kg racemic ketoprofen, the chiral pharmacokinetics of ketoprofen was investigated in eight piglets aged 6 and 21days old. S-ketoprofen predominated over R-ketoprofen in plasma of the piglets in both age groups. The volumes of distribution of S-ketoprofen for the 6- and 21-day-old piglets were 241.7 (211.3-276.5) mL/kg and 155.0 (138.7-173.1) mL/kg, respectively, while the corresponding parameters for R-ketoprofen were 289.2 (250.3-334.2) mL/kg and 193.0 (168.7-220.8) mL/kg. The clearances of R-ketoprofen [948.4 (768.0-1171.2) mL/h/kg and 425 (319.1-566.0) mL/h/kg for the 6- and 21-day-old piglets, respectively] were significantly higher compared to the clearances of S-ketoprofen [57.3 (46.6-70.4) mL/h/kg and 33.8 (27.0-42.2) mL/h/kg for 6- and 21-day-old piglets, respectively]. The elimination half-life of S-ketoprofen was 3.4h for both age groups, while the elimination half-life of R-ketoprofen was 0.2h for the 6-day-old and 0.4h for the 21-day-old piglets. The clearances of both R- and S-ketoprofen were significantly higher in the 6-day-old piglets compared to when they were 21 days old. Furthermore, the volumes of distribution were larger in the youngest age group.     

Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling

The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen-treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 μg/mL and an IC(50) for R-ketoprofen of 1.6 μg/mL. This indicates that R-ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg.     

On-farm multi-contamination of pigs by food-borne bacterial zoonotic hazards: An exploratory study

Application of risk analysis to control pork-borne zoonoses on farms is a major aim of the current European food safety legislation. The prevalence, levels of contamination and variations in pig contaminations according to herds and batches must therefore be studied to define relevant methods for control of zoonoses. The aims of this exploratory study were to provide information on the prevalence and levels of infection of finisher/fattening pigs by Campylobacter spp., Clostridium perfringens, Listeria monocytogenes, Salmonella enterica and Staphylococcus aureus, and to quantify the respective effects of batches and herds. One hundred and twenty-seven pooled fresh feces samples and 120 pooled cutaneous swab samples were tested from 37 batches in 14 farrowing-to-finishing farms. Campylobacter spp. was identified in all fecal samples on farms whereas L. monocytogenes was never found. C. perfringens was identified in 48% of samples, Salmonella in 2%, and S. aureus in 48%. The decomposition of variance of on-farm prevalence and levels of contamination and a general linear model showed a systematically significant effect of herd, and an effect of batch only for levels of contamination with Campylobacter and C. perfringens and for prevalence of S. aureus. The contamination status of pigs seems to be mainly explained by herd status linked to poor biosecurity measures. Further studies are needed to explain such correlations in order to define farm indicators for food-borne zoonotic hazards.