Surgical treatment of epiploic foramen entrapment in 142 horses (2008-2016).

OBJECTIVE: To report the clinical features, outcomes, and prognostic factors associated with the surgical treatment of epiploic foramen entrapment (EFE). STUDY DESIGN: Retrospective study at a single referral hospital. ANIMALS: Horses (n = 142) undergoing surgery (n = 145) for EFE. METHODS: Preoperative, perioperative, and postoperative data of surgeries on horses that underwent exploratory laparotomy for EFE were obtained. The postoperative outcome was assessed by follow-up telephone calls with the owners/caregivers. Factors associated with postoperative reflux (POR), relaparotomy, hospital discharge, colic after hospital discharge, and survival after discharge were assessed. RESULTS: In total, 145 surgeries were performed on 142 horses (recurrence rate, 3%). Warmblood horses represented 85% of the horses that underwent surgery. Windsucking/crib-biting was confirmed in 60% of these surgery cases. Left-to-right entrapment was diagnosed in all horses. Ileal involvement was recorded in 74% of the cases. Uncontrollable intraoperative hemorrhage was encountered in 6% of the surgeries. One hundred seven (74%) horses recovered from surgery, and 65% of those survived to discharge. The rate of survival to discharge of all surgeries was 48%. The median survival of the cases that were discharged exceeded 3193 days. Horses requiring intestinal resection were predisposed to POR, and those undergoing jejunoileostomy were more prone to POR than those undergoing jejunojejunostomy. Horses with POR were less likely to be discharged than those without POR, and those that underwent resection had shorter life expectancy after hospital discharge than those that did not undergo resection. CONCLUSION: Surgical treatment of EFE was associated with high morbidity and mortality, with recurrence in at least 3% of surviving horses. CLINICAL SIGNIFICANCE: Owners of horses with EFE should be informed of the guarded prognosis associated with current surgical treatment.

A preliminary study of pulmonary vein implant applicability and safety as a potential ablation platform in a follow-up study in pigs.

BACKGROUND: Recurrence of atrial fibrillation after an ablation procedure remains a major problem which emphasizes the need for improved pulmonary vein isolation techniques. AIMS: The aim of this study was to describe an implantation procedure of a pulmonary vein-stent which may possibly serve as an ablation technique in the future and to examine stent safety in a follow-up study in pigs. METHODS AND RESULTS: Eight pigs were catheterized and nine self-expanding nitinol stents were implanted through a transfemoral or transatrial approach into the antra of the pulmonary veins. After 3 months' follow-up, the animals were euthanized for further examination. During the follow-up phase, no complications were observed. Absence of thrombus formation or pulmonary vein wall dissection was noticed during anatomical and histological evaluation of the heart-lung packages. All implants were almost completely covered by neo-intima, of which thickness varied between 0.2 and 3.9 mm. CONCLUSIONS: Stents can safely be positioned and deployed into the antra of the pulmonary veins without any acute or long-term (3 months) adverse effects. In the future, these implants could function as a permanently implanted ablation device and provide new therapeutic strategies for pulmonary vein isolation in patients with atrial fibrillation.

In vivo contribution of deoxynivalenol-3-ß-D-glucoside to deoxynivalenol exposure in broiler chickens and pigs: oral bioavailability, hydrolysis and toxicokinetics.

Crossover animal trials were performed with intravenous and oral administration of deoxynivalenol-3-ß-D-glucoside (DON3G) and deoxynivalenol (DON) to broiler chickens and pigs. Systemic plasma concentrations of DON, DON3G and de-epoxy-DON were quantified using liquid chromatography-tandem mass spectrometry. Liquid chromatography coupled to high-resolution mass spectrometry was used to unravel phase II metabolism of DON. Additionally for pigs, portal plasma was analysed to study presystemic hydrolysis and metabolism. Data were processed via tailor-made compartmental toxicokinetic models. The results in broiler chickens indicate that DON3G is not hydrolysed to DON in vivo. Furthermore, the absolute oral bioavailability of DON3G in broiler chickens was low (3.79 ± 2.68 %) and comparable to that of DON (5.56 ± 2.05 %). After PO DON3G administration to pigs, only DON was detected in plasma, indicating a complete presystemic hydrolysis of the absorbed fraction of DON3G. However, the absorbed fraction of DON3G, recovered as DON, was approximately 5 times lower than after PO DON administration, 16.1 ± 5.4 compared with 81.3 ± 17.4 %. Analysis of phase II metabolites revealed that biotransformation of DON and DON3G in pigs mainly consists of glucuronidation, whereas in chickens predominantly conjugation with sulphate occurred. The extent of phase II metabolism is notably higher for chickens than for pigs, which might explain the differences in sensitivity of these species to DON. Although in vitro studies demonstrate a decreased toxicity of DON3G compared with DON, the species-dependent toxicokinetic data and in vivo hydrolysis to DON illustrate the toxicological relevance and consequently the need for further research to establish a tolerable daily intake.

Laparoscopic Evaluation of the Epiploic Foramen after Celiotomy for Epiploic Foramen Entrapment in the Horse.

OBJECTIVES: To evaluate the epiploic foramen using laparoscopy in horses previously treated for epiploic foramen entrapment to determine if spontaneous epiploic foramen closure had occurred. STUDY DESIGN: Non-consecutive case series. ANIMALS: Seven horses. METHODS: The epiploic foramen was inspected by right flank laparoscopy between 35 and 71 days after successful surgical treatment for epiploic foramen entrapment. Data were collected on the presence of behavior vices, details of surgery for epiploic foramen entrapment (time from colic onset to surgery, site and length of entrapped intestine, direction of entrapment, compromise of the intestine, intestine resected), the time between surgery for epiploic foramen entrapment and laparoscopy, and the laparoscopic appearance of the epiploic foramen. If the epiploic foramen was open, a mesh was introduced to obliterate the epiploic foramen (Foramen Epiploicum Mesh Closure [FEMC]). Clinical progress of the horses was followed by owner telephone interview at 1 and 4 months after laparoscopy, and a final interview between 135 and 282 days after laparoscopy. Owners were questioned on specific postoperative complications and the exercise level of the horse. RESULTS: At laparoscopy, 3/7 horses had complete closure of the epiploic foramen by dense fibrous tissue. The FEMC was performed in 4 horses without major complications. Postoperative colic episodes were recorded in 3 horses, all of them displaying windsucking/cribbing behavior. CONCLUSION: Laparoscopic evaluation after celiotomy for epiploic foramen entrapment revealed spontaneous closure of the epiploic foramen in 3/7 horses. This finding could explain the reported low recurrence rate after surgical treatment for epiploic foramen entrapment.

Equine colic associated with small intestinal epiploic foramen entrapment.

Intestinal epiploic foramen entrapment (EFE) is an important differential diagnosis in horses with colic, but disappointing short- and long-term outcomes are reported in the scientific literature. Many horses are euthanased during surgery due to a predicted poor prognosis or due to uncontrollable intraoperative haemorrhage. The ileum is involved in the majority of cases. Several risk factors for the development of EFE are described; crib-biting/windsucking being the most important one. The recurrence rate of EFE is low despite the described risk factors, probably due to spontaneous closure of the EF after EFE colic surgery in about 40% of the cases. Safe laparoscopic techniques to obliterate the EF preventively in horses at risk or as part of surgical management of EFE at laparotomy are described. Methods for improved outcomes including utilising recently gained anatomical insights of the region while manipulating entrapped intestines, critical revision of anastomosis techniques and avoiding the occurrence of post-operative reflux are discussed.

Gastrostomy tube placement via a laparotomic procedure in growing conventional piglets to perform multi-dose preclinical paediatric drug studies.

The use of juvenile conventional pigs as a preclinical animal model to perform pharmacokinetic (PK), pharmacodynamic (PD) and safety studies for the paediatric population is increasing. Repetitive oral administration of drugs to juvenile pigs is however challenging. A representative method which can be used from birth till adulthood is necessary. The current study presents the placement and use of a gastrostomy button in pigs with a weight ranging from 2.4 to 161 kg. The surgical placement was performed via a laparotomic procedure on, each time, 12 pigs (six male, six female) of 1 week, 4 weeks, 8 weeks and 6-7 months old. For every age category, eight pigs were part of a PK study with a non-steroidal anti-inflammatory drug (NSAID) and four pigs served as a control group. No severe complications were observed during surgery. The button remained functional for 10 days in 40 out of 48 pigs. No significant differences in body temperature or white blood cell count were observed during the trial. Three control pigs showed signs of inflammation indicating a NSAID might be warranted. Autopsy revealed minimal signs of major inflammation in the abdominal cavity or the stomach. A limited number of pigs showed mucosal inflammation, ulcers or abscesses in the stomach or around the fistula. These results indicate that the laparotomic placement of a gastrostomy button might be considered safe and easy in growing pigs to perform repetitive oral dosing preclinical studies. However, the method is not advised in pigs weighing more than 100 kg.

Developmental Pharmacokinetics and Safety of Ibuprofen and Its Enantiomers in the Conventional Pig as Potential Pediatric Animal Model.

Pediatric drug development, especially in disease areas that only affect children, can be stimulated by using juvenile animal models not only for general safety studies, but also to gain knowledge on the pharmacokinetic and pharmacodynamic properties of the drug. Recently, the conventional growing piglet has been suggested as juvenile animal model. However, more studies with different classes of drugs are warranted to make a thorough evaluation whether the juvenile pig might be a suitable preclinical animal model. Ibuprofen is one of the most widely used non-steroidal anti-inflammatory drugs in human. The present study determined the PK parameters, gastro-intestinal and renal safety of 5 mg/kg BW ibuprofen after single intravenous, single oral and multiple oral administration to each time eight pigs (four males, four females) aging 1, 4, 8 weeks and 6-7 months. Oral administration was performed via a gastrostomy button. A jugular catheter was used for intravenous administration and blood sampling. To assess NSAID induced renal toxicity, renal function was evaluated using iohexol and p-aminohippuric acid as markers for glomerular filtration rate and renal plasma flow, respectively. After the trial, necropsy and histology was performed to evaluate macroscopic and microscopic gastro-intestinal as well as renal lesions. Both enantiomers, R-ibuprofen and S-ibuprofen, were determined in plasma using an in-house developed and validated UHPLC-MS/MS method. Pharmacokinetic parameters were estimated using compartmental analysis. Clearance and volume of distribution of total ibuprofen and both enantiomers increased with age as was observed in human. The rate of stereochemical conversion decreased with age. Multiple oral dosing decreased the absolute oral bioavailability and maximum plasma concentration of R-ibuprofen and food consumption did not influence drug absorption. Based on the limited available pediatric literature, the current study might suggest the conventional pig as suitable animal model to evaluate NSAIDs for pediatric use.

Population Pharmacokinetic Modeling of a Desmopressin Oral Lyophilisate in Growing Piglets as a Model for the Pediatric Population.

Desmopressin is used to treat primary nocturnal enuresis in children. Over the years, various formulations of desmopressin were commercialized of which the sublingual melt tablet is preferred in the pediatric population, despite the lack of full PK studies in this population. A full PK study was performed in growing conventional piglets to evaluate if this juvenile animal model can provide supplementary information to complement the information gap in the pediatric population. A desmopressin sublingual melt tablet (120 µg) was administered to 32 male piglets aged 8 days, 4 weeks, 7 weeks, and 6 months (each group n = 8). Population PK (pop-PK) analysis was performed to derive the PK parameters, the between- and within-subject variabilities and the effects of covariates. Desmopressin demonstrated two-compartmental PK, with a dual, sequential absorption process, and linear elimination. Body weight was the only significant covariate on clearance and on apparent volume of distribution of the central compartment. In human pediatric trials, no double peak in the absorption phase was observed in the plasma concentration-time curves, possibly due to the sparse sampling strategy applied in those pediatric studies. Therefore, it is recommended to perform additional studies, based on the sampling protocol applied in the current study.

Repetitive urine and blood sampling in neonatal and weaned piglets for pharmacokinetic and pharmacodynamic modelling in drug discovery: a pilot study.

Piglets are considered to be suitable animal models for predicting the pharmacokinetics and pharmacodynamics (PK/PD) of test drugs for potential use in the paediatric population. Such PK/PD studies require multiple blood and urine samplings. The goal of the present study was to determine a suitable blood collection strategy applicable in the youngest age categories of six days, four weeks and eight weeks of age, as well as a urine collection technique for male piglets in the same age categories. Blood was collected either by a surgically-placed jugular vein catheter (six days old [ n = 4] and four weeks old [ n = 2] piglets) or by direct venepuncture of the jugular vein (four weeks old [ n = 2] and eight weeks old [ n = 4] piglets). A non-invasive method for total volume urine collection in male piglets was also developed using a urine pouch. No specific complications were encountered during anaesthesia or surgery for jugular catheter placement. After a 24 h recovery period, urine and blood were easily collected without technical complications. One piglet was humanely killed at week 2 because of septicaemia. Histological analysis of both veins in all four piglets revealed negligible damage to the blood vessel wall. In conclusion, the presented techniques for blood (jugular catheter and direct venepuncture) and urine collection (pouches) are suitable for PK/PD studies in piglets.

Modulation by gamithromycin and ketoprofen of in vitro and in vivo porcine lipopolysaccharide-induced inflammation.

The immunomodulatory properties of gamithromycin (GAM), ketoprofen (KETO) and their combination (GAM-KETO) were investigated after both in vitro and in vivo lipopolysaccharide (LPS)-induced inflammation. The influence of these drugs was measured on the production of prostaglandin E2 (PGE2) and the pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß in both LPS-stimulated porcine peripheral blood mononuclear cells (PBMCs) and LPS-challenged pigs. Additionally, effects on the production of acute phase proteins (APPs), including pig major acute phase protein (pig-MAP) and C-reactive protein (CRP), as well as on the development of fever, pulmonary symptoms and sickness behaviour were investigated. Dexamethasone was included as a positive control in the in vitro research. Following an 18h-incubation period with 1.25µg/mL LPS, the levels of TNF-α, IL-1ß and IL-6 (p<0.05) measured in the PBMC supernatants were significantly increased. Incubation with a high concentration of both GAM and KETO significantly reduced the in vitro levels of all three cytokines. Maximal plasma concentrations of TNF-α and IL-6 were observed at 1h and 2.5h following LPS challenge in pigs, respectively. Neither GAM, nor KETO nor the combination GAM-KETO was able to inhibit the in vivo LPS-induced cytokine production. Furthermore, none of the drugs influenced the subsequent APPs production. In contrast, administration of KETO significantly reduced PGE2 production both in vitro and in vivo (p<0.05 and p<0.001, respectively) and prevented the development of fever and severe symptoms, including dyspnoea, anorexia, vomiting and lateral decubitus.