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.

Assessment and comparison of microcirculation and macrocirculation in horses undergoing emergency exploratory celiotomy versus elective surgical procedures.

OBJECTIVE: To assess oral buccal microcirculation by hand-held videomicroscopy in horses during colic surgery, comparing microcirculation values with macrocirculatory parameters and with those of healthy elective surgical horses. STUDY DESIGN: Clinical prospective study. ANIMALS: Client-owned horses (nine in the colic group; 11 in the elective group). METHODS: In the colic group, buccal mucosal side stream dark-field microscopy (DFM) videos, cardiac output (CO), mean arterial pressure (MAP), and lactate were obtained at three timepoints under general anesthesia (30, 90, and 150 min after induction). Video analysis was used to determine total vessel density, proportion of perfused vessels, perfused vessel density, and heterogeneity index. Dark-field microscopy videos, MAP, and lactate were obtained at a single timepoint under general anesthesia (45 min after induction) in the elective group. RESULTS: There were no differences in microcirculatory parameters between colic and elective horses, nor was there a difference across timepoints in the colic group. There was a weak negative correlation between microvascular parameters and CO (rho = -0.23). CONCLUSION: The colic group did not have decreased microcirculation in comparison with the healthy elective group. Dark-field microscopy did not correlate well with macrocirculatory parameters in the colic group. IMPACT: Dark-field microscopy may not be a sensitive enough indicator to detect differences in microcirculation between colic and elective groups. The lack of difference in microcirculation may be due to sample size, probe location, or variation in disease severity.

Ingesta-associated choledocholithiasis in horses: 2 cases and literature review.

Equine ingesta-associated choledocholithiasis is a rare cause of morbidity and mortality. We describe here the clinical, gross, histologic, and microbiologic features of this condition in 2 horses and compare the features to 2 previous cases. Case 1 was a 4-y-old Thoroughbred mare with colic. Case 2 was an 18-y-old American Paint Horse mare with colic, chronic weight loss, and inappropriate mentation. Both had elevated biochemical markers of hepatocellular injury and cholestasis and were euthanized given a poor prognosis. Case 1 had a well-formed 5-cm choledocholith surrounding a piece of hay, and had chronic neutrophilic cholangiohepatitis, bridging fibrosis, and extrahepatic obstruction. Case 2 had an ill-formed choledocholith with occasional hay fragments, wood stick, and twigs, and had regionally extensive hepatocellular necrosis with mild neutrophilic cholangiohepatitis and bridging fibrosis. Enterococcus casseliflavus and Escherichia coli were isolated in both cases; Clostridium spp. were also isolated from case 2. All 4 reported cases had increased activity of cholestatic enzymes, hyperbilirubinemia, portal inflammation, and bridging fibrosis. Colic, pyrexia, leukocytosis with neutrophilia, and elevated hepatocellular enzyme activity were documented in 3 cases. Foreign material in all 4 cases was plant origin (choledochophytolithiasis), including hay (n = 2), sticks/twigs (n = 2), and grass awns (n = 1). Ingesta-associated choledocholithiasis may be considered as a cause of colic, pyrexia, and elevated cholestatic biomarkers in horses.

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.

Pembrolizumab activity in patients with Fanconi anemia repair pathway competent and deficient tumors.

BACKGROUND: Given the observed antitumor activity of immune-checkpoint-inhibitors in patients with mismatch-repair deficient (MSI-H) tumors, we hypothesized that deficiency in homologous-recombination-repair (HRR) can also influence susceptibility. METHODS: Patients with disease progression on standard of care and for whom pembrolizumab had no FDA approved indication received pembrolizumab. Patients with MSI-H tumors were excluded. Objectives included immune-related objective response rate (iORR), progression-free survival (PFS) and 20-weeks-PFS. Pembrolizumab was given every 3 weeks and scans performed every six. We evaluated a triple-stain (FANCD2foci/DAPI/Ki67) functional assay of the Fanconi Anemia (FA) pathway: FATSI, in treated patients' archived tumors. The two-stage sample size of 20/39 patients evaluated an expected iORR≥20% in the whole population vs. the null hypothesis of an iORR≤5%, based on an assumed iORR≥40% in patients with functional FA deficiency, and < 10% in patients with intact HRR. An expansion cohort of MSI stable endometrial cancer (MS-EC) followed. Exploratory stool microbiome analyses in selected patients were performed. RESULTS: Fifty-two patients (45F,7M;50-evaluable) were enrolled. For the 39 in the two-stage cohort, response evaluation showed 2CR,5PR,11SD,21PD (iORR-18%). FATSI tumor analyses showed 29 competent (+) and 10 deficient (-). 2PR,9SD,17PD,1NE occurred among the FATSI+ (iORR-7%) and 2CR,3PR,2SD,3PD among the FATSI(-) patients (iORR-50%). mPFS and 20w-PFS were 43 days and 21% in FATSI+, versus 202 days and 70% in FATSI(-) patients. One PR occurred in the MS-EC expansion cohort. CONCLUSIONS: Pembrolizumab has meaningful antitumor activity in malignancies with no current FDA approved indications and FA functional deficiency. The results support further evaluation of FATSI as a discriminatory biomarker for population-selected studies.

Equine inflammatory response to abdominal surgery in the absence of gastrointestinal disease.

OBJECTIVE: To investigate the, equine inflammatory response to ventral midline celiotomy in the absence of gastrointestinal disease in horses of varying body condition scores primarily using serial measurements of serum amyloid A (SAA). DESIGN: Experimental clinical study. SETTING: University teaching hospital. ANIMALS: Ten adult light breed horses free of any clinical disease, 5 with body condition score (BCS) 3-4/9 and 5 with BCS 7-8/9. INTERVENTIONS: Horses had a ventral midline celiotomy performed under general anesthesia, including manual decompression of the small intestine. SAA, semiquantitative fibrinogen, plasma lactate, and WBC count were measured in the blood preoperatively and at 12, 24, 48, 72, 120, and 168 hours postoperatively. Complete serum biochemistry was performed preoperatively and 24 and 72 hours postoperatively. Serial abdominocentesis was also performed with peritoneal fluid analysis of SAA, total protein, lactate, WBC count, and cytology. MEASUREMENTS AND MAIN RESULTS: Significant (P < 0.05) increases in serum SAA were noted at 12, 24, and 48 hours postoperatively (124.6 ± 68.6, 390.8 ± 209.0, 568.6 ± 197.7 µg/mL), and most horses had values approaching normal at 168 hours postoperatively (174.4 ± 307.7 µg/mL). Other values such as fibrinogen also increased in response to surgery but did not return to normal within the measured time points. Horses with high BCS did not have significantly different serum SAA compared to horses with low BCS. Peritoneal fluid SAA did not increase significantly at 12 hours postoperatively. CONCLUSIONS: The information from this study can be used to help determine the effect of anesthesia and surgical intestinal manipulation resulting in increased SAA when a comparison to clinical or experimental cases is needed.

Secondary Cytoreduction and Carboplatin Hyperthermic Intraperitoneal Chemotherapy for Platinum-Sensitive Recurrent Ovarian Cancer: An MSK Team Ovary Phase II Study.

PURPOSE: The purpose of this phase II study was to evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin for recurrent ovarian cancer during secondary cytoreductive surgery. MATERIALS AND METHODS: Patients were intraoperatively randomly assigned to carboplatin HIPEC (800 mg/m2 for 90 minutes) or no HIPEC, followed by five or six cycles of postoperative IV carboplatin-based chemotherapy, respectively. Based on a binomial single-stage pick-the-winner design, an arm was considered winner if ≥ 17 of 49 patients were without disease progression at 24 months post-surgery. Secondary objectives included postoperative toxicity and HIPEC pharmacokinetics. RESULTS: Of 98 patients, 49 (50%) received HIPEC. Complete gross resection was achieved in 82% of the HIPEC patients and 94% of the standard-arm patients. Bowel resection was performed in 37% of patients in the HIPEC arm compared with 65% in the standard (P = .008). There was no perioperative mortality and no difference in use of ostomies, length of stay, or postoperative toxicity. At 24 months, eight patients (16.3%; 1-sided 90% CI, 9.7 to 100) were without progression or death in the HIPEC arm and 12 (24.5%; 1-sided 90% CI, 16.5 to 100) in the standard arm. With a medium follow-up of 39.5 months, 82 patients progressed and 37 died. The median progression-free survival in the HIPEC and standard arms were 12.3 and 15.7 months, respectively (hazard ratio, 1.54; 95% CI, 1 to 2.37; P = .05). There was no significant difference in median overall survival (52.5 v 59.7 months, respectively; hazard ratio, 1.39; 95% CI, 0.73 to 2.67; P = .31). These analyses were exploratory. CONCLUSION: HIPEC with carboplatin was well tolerated but did not result in superior clinical outcomes. This study does not support the use of HIPEC with carboplatin during secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer.

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.

Double outlet right ventricle with subpulmonary ventricular septal defect (Taussig-Bing anomaly) and other complex congenital cardiac malformations in an American Quarter Horse foal.

A 4-week-old American Quarter Horse colt presented with a recent history of diarrhea and decreased activity level. On initial physical examination, the animal was bright and alert and major findings were limited to a loud systolic heart murmur radiating widely over both sides of the thorax. While in the hospital, the clinical condition of the foal warranted further imaging to determine the cause and extent of cardiac disease. A variety of congenital cardiac malformations were identified during echocardiographic examination and autopsy, including a double outlet right ventricle and a subpulmonary interventricular septal defect (Taussig-Bing anomaly), ventricular inversion with atrioventricular discordance, tricuspid valve atresia, a septum primum interatrial septal defect, mitral valve dysplasia with a cleft in the septal mitral valve cusp, aortic, and subaortic stenosis, tubular hypoplasia of the ascending aorta and the aortic arch, a patent ductus arteriosus, an aberrant circumflex coronary artery, and aberrant left and right subclavian arteries. Echocardiographic and postmortem findings of the cardiac defects in this foal are presented and discussed.

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.

Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study.

OBJECTIVE: Doripenem is a new carbapenem that has broad-spectrum activity against bacterial pathogens commonly responsible for nosocomial pneumonia (NP). It has several advantages over currently available carbapenems and other classes of drugs used in this indication. This prospective, randomized, open-label, multicenter study was designed to establish whether doripenem was noninferior to piperacillin/tazobactam in NP. METHODS: Adults (n=448) with signs and symptoms of NP, including non-ventilated patients and those ventilated for <5 days, were stratified by ventilation mode, illness severity (Acute Physiology and Chronic Health Evaluation II score), and geographic region and then randomly allocated to treatment with doripenem 500 mg every 8 h by a 1-h intravenous (IV) infusion or piperacillin/tazobactam 4.5 g every 6 h by 30-min IV infusion. After receiving IV study drug for at least 72 h, eligible patients could be switched to oral levofloxacin 750 mg once daily. Antibiotic therapy was continued for a total of 7-14 days. The primary endpoint was the clinical cure rate, assessed 7-14 days after treatment completion, in clinically evaluable patients and in the clinical modified intent-to-treat population (cMITT). TRIAL REGISTRATION: ClinicalTrials.gov, NCT00211003. RESULTS: Doripenem was noninferior to piperacillin/tazobactam. Clinical cure rates in clinically evaluable patients (n=253) were 81.3% in the doripenem arm and 79.8% in the piperacillin/tazobactam arm (between-treatment difference: 1.5%; 95% confidence interval [CI], -9.1 to 12.1%) and in the cMITT population 69.5% and 64.1%, respectively, (between-treatment difference: 5.4%; 95% CI, -4.1 to 14.8%). Baseline resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa to piperacillin/tazobactam was 44% and 26.9%, respectively; a doripenem minimum inhibitory concentration (MIC) >8 mug/mL occurred in 0% and 7.7%, respectively. Favorable microbiological outcome rates against Gram-negative pathogens were numerically higher with doripenem than with piperacillin/tazobactam, but the difference was not statistically significant. Both study drugs were generally well tolerated, as only 16.1% and 17.6% of patients receiving doripenem and piperacillin/tazobactam, respectively, had a drug-related adverse event. Study limitations included the open-label design, the low rate of monotherapy (adjunctive use of aminoglycoside was required when P. aeruginosa was suspected), and the exclusion of the most critically ill and immunocompromized patients. CONCLUSIONS: Doripenem was clinically and microbiologically effective in patents with NP, including those with early-onset ventilator-associated pneumonia, and was therapeutically noninferior to piperacillin/tazobactam.