Noncompartmental pharmacokinetics of three intravenous mycophenolate mofetil concentrations in healthy Standardbred mares.

BACKGROUND: Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA) which acts as an immunosuppressive agent. During the biotransformation of MMF to MPA, additional metabolites including MPA phenol glucuronide (MPAG), MPA acyl glucuronide (AcMPAG) and MPA phenol glucoside (MPG) are formed. OBJECTIVE: To define the noncompartmental pharmacokinetic (PK) parameters of three single doses of intravenous (i.v.) MMF and its downstream metabolites in healthy horses. ANIMALS: Six healthy Standardbred mares. MATERIALS AND METHODS: Generic MMF (Par Pharmaceuticals; Chestnut Ridge, NY, USA) was reconstituted and administered as a single i.v. bolus at 1.0 mg/kg, 5.0 mg/kg and 10.0 mg/kg with an eight day washout between treatments. Blood samples were collected immediately before MMF administration and over 24 h. A liquid chromatography-tandem mass spectrometry assay was developed following FDA guidance to determine plasma MMF, MPA, MPAG, AcMPAG and MPG concentrations. Plasma concentrations were analysed independently, followed by calculation of geometric mean and coefficient of variation. RESULTS: Noncompartmental PK parameters were determined for MMF and all metabolites at all doses. MMF was rapidly converted to MPA in all horses. Each incremental dose of MMF resulted in increases in Cmax and AUCinf _obs for MPA and the three additional metabolites. Within the 10-fold dose range, the increase in Cmax and AUCinf _obs for MMF and its metabolites was nonlinear. CONCLUSIONS AND CLINICAL RELEVANCE: Horses biotransform MMF into MPA, MPAG, AcMPAG and MPG via the glucuronidation and glucosidation clearance pathways. Equine reference PK profiles for MPA and the metabolites, MPAG, AcMPAG and MPG were established.

Pathophysiology of intraabdominal hypertension and abdominal compartment syndrome and relevance to veterinary critical care.

BACKGROUND: Increased intraabdominal pressure, termed intraabdominal hypertension (IAH), is reported as an independent cause of morbidity and mortality in the human ICU but, until recently, has been rarely described in veterinary species outside of experimental models. Failure to identify severe IAH leads to organ dysfunction, termed abdominal compartment syndrome, and rapidly becomes fatal without therapeutic intervention. Although the veterinary community has been slow to address the concept of IAH and associated comorbidities, recent companion and large animal case series and experimental studies suggest IAH may also be common in veterinary species and correlates well with risk factors and grading systems already described in the human literature. PATHOPHYSIOLOGY: Increasing abdominal pressures exert deleterious local effects through visceral ischemia and reperfusion injury as well as systemic effects on the cardiovascular, pulmonary, renal, and central nervous systems. Even mild grades of IAH increase systemic vascular resistance, impede venous return, increase pulmonary wedge pressure, and decrease pulmonary function. More severe grades cause azotemia, oliguria, decreased coronary blood flow, hypoxia, increased intracranial pressure, and death. IMPORTANCE: Many of the common diseases in veterinary patients are associated with IAH, including gastric dilatation-volvulus, colon volvulus, closed pyometra, hemoperitoneum, ascites, uroperitoneum, and hydrops. Monitoring of the veterinary patient is difficult, but several experimental studies validate both the presence of IAH and the ability to monitor abdominal pressures in large and small animal species. Moreover, prompt recognition of IAH and subsequent treatment is feasible in the veterinary ICU. KEY POINTS: Increasing abdominal pressures exert deleterious local effects through visceral ischemia and reperfusion injury as well as systemic effects on the cardiovascular, pulmonary, renal, and central nervous systems. Increases in central venous pressure, systemic vascular resistance, pulmonary wedge pressure, and a decreased cardiac output by way of both decreased preload and increased afterload have been documented as a result of intraabdominal hypertension (IAH). Direct diagnosis of IAH is achieved by blind or ultrasound-guided abdominal needle puncture attached to a water manometer or direct pressure monitoring transducer. Transvesicular measurement of intraabdominal pressure (IAP) is relatively noninvasive, and many patients that would benefit from rapid diagnosis of IAH and abdominal compartment syndrome already have indwelling bladder catheters. Recommendations for interventions are based on the assigned grade of IAH (mild, moderate, severe). KEY POINTS: If IAH is strongly suspected or diagnosed, abdominal wall compliance may be improved through judicious use of neuromuscular blockers and sedation. Decompression, either minimally invasive or surgical, is absolutely recommended for IAPs consistently above 20 mm Hg, especially in the presence of signs attributed to secondary organ dysfunction.

How to perform a percutaneous cecal or colonic trocarization in horses with severe abdominal tympany.

BACKGROUND: Cecal or colonic gas tympany of any cause may result in increased intraabdominal pressure, causing a significant decrease in venous return and cardiac output. Trocarization of the large colon or cecum in the event of large intestinal tympany may resolve gas distension and accompanying increased intraabdominal pressures sufficiently enough to promote resolution of a displaced large colon. Furthermore, trocarization of the medical colic may decrease morbidity and mortality associated with severe intraabdominal hypertension. DESCRIPTION: This how-to description details the technique of transcutaneous trocarization of the large colon and cecum in the standing horse using a 14-gauge catheter. SUMMARY: Trocarization is not a substitute for surgery in the severely gas-distended painful horse exhibiting signs of colic that require surgery; however, it is a viable medical therapy with minimal risk that alleviates gas distention and may assist with correction of a colonic displacement in the horse. KEY POINTS: The majority of colic episodes involving the large colon can be managed medically without surgical intervention. Auscultation and percussion of the paralumbar fossa area will solicit an audible "ping" (gas/fluid interface), thus targeting the appropriate site for trocarization. Percutaneous trocarization allows for rapid controlled decompression of colonic or cecal tympany, permitting improvement of both ventilation and perfusion. In situations where a displacement or primary colonic or cecal tympany is suspected, trocarisation is deemed successful if the horse has resolution of colic signs and the physical examination parameters return to normal. Trocarization may be clinically advantageous by requiring less pain medication, decreased time in the hospital, decreased costs, and avoidance of surgical intervention; yet, this therapy should not take place of surgical intervention if deemed necessary.

Multicenter Placebo-Controlled Randomized Study of Ethyl Pyruvate in Horses Following Surgical Treatment for ≥ 360° Large Colon Volvulus.

Identifying therapies that mitigate ischemic colonic injury and improve mucosal healing and intestinal viability are crucial to improving survival in horses with ≥360° large colon volvulus (LCV). Ethyl pyruvate is the ethyl ester of pyruvate with diverse pharmacologic effects that limit ischemic injury and hasten intestinal mucosal repair in preclinical rodents, sheep and swine models. The objective of this study was to determine the effects of ethyl pyruvate on systemic indices of colon viability, expression of inflammatory genes in whole blood, morbidity and survival after surgical correction of LCV compared to controls. Horses received either 150 mg/kg ethyl pyruvate in 1 liter lactated Ringer's solution (LRS) or 1 liter LRS intravenously (IV) every 6 h for 24 h following surgical recovery for correction of LCV. Colic duration, perioperative heart rate (HR), packed cell volume (PCV), total solids (TS), blood L-lactate concentration, surgical time, intraoperative episodes of hypoxemia and hypotension, expression of inflammatory cytokine genes, fecal consistency and survival to hospital discharge were compared between ethyl pyruvate treated horses and controls. Twenty-two horses, 12 receiving ethyl pyruvate and 10 controls, were enrolled in the study. Ethyl pyruvate was safely administered to horses following surgical correction of LCV. No significant effects of ethyl pyruvate on post-operative variables, including survival, were found. Seven of 12 ethyl pyruvate treated horses and 5/10 controls survived to hospital discharge. Higher HR, PCV and blood L-lactate concentration at the time of hospital admission, P = 0.005, 0.01, 0.04, respectively, 24 h after surgery, P = 0.001, 0.03, 0.02, respectively, were associated with death. Heart rate, P = 0.005, 48 h after surgery was associated with death. Ethyl pyruvate was safely administered to horses following correction of LCV with no apparent adverse events but was not associated with improved post-operative outcomes including survival. A larger, randomized control trial is needed to fully evaluate the effectiveness of ethyl pyruvate. A major limitation of this investigation is the small sample size, making the study underpowered and creating a high possibility of type II error.

The effect of hypothermia on influx of leukocytes in the digital lamellae of horses with oligofructose-induced laminitis.

Sepsis-related laminitis (SRL) is a common complication in the septic/endotoxemic critically-ill equine patient, in which lamellar injury and failure commonly lead to crippling distal displacement of the distal phalanx. Similar to organ injury in human sepsis, lamellar injury in SRL has been associated with inflammatory events, including the influx of leukocytes into the lamellar tissue and markedly increased expression of a wide array of inflammatory mediators at the onset of Obel grade 1 (OG1) laminitis. The only treatment reported both clinically and experimentally to protect the lamellae in SRL, local hypothermia ("cryotherapy"), has been demonstrated to effectively inhibit lamellar expression of multiple inflammatory mediators when initiated at the time of administration of a carbohydrate overload in experimental models of SRL. However, the effect of hypothermia on leukocyte influx into affected tissue has not been assessed. We hypothesized that cryotherapy inhibits leukocyte emigration into the digital lamellae in SRL. Immunohistochemical staining using leukocyte markers MAC387 (marker of neutrophils, activated monocytes) and CD163 (monocyte/macrophage-specific marker) was performed on archived lamellar tissue samples from an experimental model of SRL in which one forelimb was maintained at ambient temperature (AMB) and one forelimb was immersed in ice water (ICE) immediately following enteral oligofructose administration (10g/kg, n=14 horses). Lamellae were harvested at 24h post-oligofructose administration (DEV, n=7) or at the onset of OG1 laminitis (OG1, n=7). Both MAC387-positive and CD163-positive cells were counted by a single blinded investigator on images [n=10 (40× fields/digit for MAC387 and 20x fields/digit for CD163)] obtained using Aperio microscopy imaging analysis software. Data were assessed for normality and analyzed with a paired t-test and one-way ANOVA with significance set at p<0.05. MAC387-positive cells were present in low numbers in the lamellar tissue and were decreased in the hypothermic limbs (vs. AMB limbs, p<0.05) in the OG1 group; no change in CD163-positive cell numbers was noted across the conditions of the model. This study demonstrated that hypothermia of the distal limbs instituted early in the disease process in the horse at risk of SRL significantly attenuates the increase of MAC387-positive leukocytes in the digital lamellae, but has minimal effect on increases in lamellar concentrations of the major leukocyte cell type present in that tissue, CD163-positive mononuclear cells.