Pharmacokinetic characterization of fluorocoxib D, a cyclooxygenase-2-targeted optical imaging agent for detection of cancer.

SIGNIFICANCE: Fluorocoxib D, N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, is a water-soluble optical imaging agent to detect cyclooxygenase-2 (COX-2)-expressing cancer cells. AIM: We evaluated the pharmacokinetic and safety properties of fluorocoxib D and its ability to detect cancer cells in vitro and in vivo. APPROACH: Pharmacokinetic parameters of fluorocoxib D were assessed from plasma collected at designated time points after intravenous administration of 1 mg / kg fluorocoxib D in six research dogs using a high-performance liquid chromatography analysis. Safety of fluorocoxib D was assessed for 3 days after its administration using physical assessment, complete blood count, serum chemistry profile, and complete urinalysis in six research dogs. The ability of fluorocoxib D to detect COX-2-expressing cancer cells was performed using human 5637 cells in vitro and during rhinoscopy evaluation of specific fluorocoxib D uptake by canine cancer cells in vivo. RESULTS: No evidence of toxicity and no clinically relevant adverse events were noted in dogs. Peak concentration of fluorocoxib D (114.8 ± 50.5 ng / ml) was detected in plasma collected at 0.5 h after its administration. Pretreatment of celecoxib blocked specific uptake of fluorocoxib D in COX-2-expressing human 5637 cancer cells. Fluorocoxib D uptake was detected in histology-confirmed COX-2-expressing head and neck cancer during rhinoscopy in a client-owned dog in vivo. Specific tumor-to-normal tissue ratio of detected fluorocoxib D signal was in an average of 3.7 ± 0.9 using Image J analysis. CONCLUSIONS: Our results suggest that fluorocoxib D is a safe optical imaging agent used for detection of COX-2-expressing cancers and their margins during image-guided minimally invasive biopsy and surgical procedures.

Effect of site of sample collection and prandial state on blood glucose concentrations measured with a portable blood glucose meter in healthy dogs.

OBJECTIVE: To compare glucose concentrations in peripheral venous and capillary blood samples collected from dogs before and after consumption of a meal and measured with a veterinary-specific portable blood glucose meter (PBGM). ANIMALS: 12 dogs (96 blood samples). PROCEDURES: A veterinary-specific PBGM was used to measure blood glucose concentrations. Glucose concentrations in capillary blood samples obtained from the carpal pad, medial aspect of a pinna, and oral mucosa were compared with glucose concentrations in blood samples obtained from a lateral saphenous vein. Samples were collected after food was withheld for 12 hours and again 2 hours after consumption of a meal. RESULTS: Location of capillary blood collection had a significant effect on glucose concentrations measured with the PBGM. Glucose concentration in capillary blood collected from the medial aspect of the pinna did not differ significantly from the glucose concentration in peripheral venous blood samples, whereas glucose concentrations in blood samples collected from the carpal pad and oral mucosa differed significantly from the glucose concentration in peripheral venous blood samples. There was no significant difference between preprandial and postprandial blood glucose concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Glucose concentrations in capillary blood collected from the medial aspect of the pinna of dogs better reflected glucose concentrations in venous blood than concentrations measured in capillary blood collected from the carpal pad or oral mucosa.

Effects of a synbiotic on the fecal microbiome and metabolomic profiles of healthy research cats administered clindamycin: a randomized, controlled trial.

Reduction in antibiotic-associated gastrointestinal signs (AAGS) in people co-administered probiotics is believed to result from shifts in the microbiome and metabolome. Amelioration of AAGS in cats secondary to synbiotic administration has recently been demonstrated. Thus, the aim of this randomized, double-blinded, placebo-controlled trial was to characterize associated changes in the fecal microbiome and metabolome. Sixteen healthy research cats received clindamycin with food, followed 1 h later by either a placebo or synbiotic, daily for 21 days. Fecal samples were collected during baseline, antibiotic administration, and 6 weeks after antibiotic discontinuation. Sequencing of 16S rRNA genes was performed, and mass spectrometry was used to determine fecal metabolomic profiles. Results were compared using mixed-model analyses, with P < 0.05 considered significant. Alpha and beta diversity were altered significantly during treatment, with persistent changes in the Shannon and dysbiosis indices. The relative abundance of Actinobacteria (Adlercreutzia, Bifidobacterium, Collinsella, Slackia), Bacteroidia (Bacteroides, Prevotella), Ruminococcaceae (Faecalibacterium, Ruminococcus), Veillonellaceae (Megamonas, Megasphaera, Phascolarctobacterium) and Erysipelotrichaceae ([Eubacterium]) decreased and relative abundance of Clostridiaceae (Clostridium) and Proteobacteria (Enterobacteriaceae) increased during treatment, followed by variable return to baseline relative abundances. Derangements in short-chain fatty acid (SCFA), bile acid, tryptophan, sphingolipid, polyamine, benzoic acid, and cinnaminic acid pathways occurred with significant group by time, group, and time interactions for 10, 5, and 106 metabolites, respectively. Of particular note were changes related to polyamine synthesis. Further investigation is warranted to elucidate the role of these alterations in prevention of AAGS in cats, people, and other animals treated with synbiotics.

Short and long-term effects of a synbiotic on clinical signs, the fecal microbiome, and metabolomic profiles in healthy research cats receiving clindamycin: a randomized, controlled trial.

BACKGROUND: Antibiotic-associated gastrointestinal signs (AAGS) occur commonly in cats. Co-administration of synbiotics is associated with decreased AAGS in people, potentially due to stabilization of the fecal microbiome and metabolome. The purpose of this double-blinded randomized-controlled trial was to compare AAGS and the fecal microbiome and metabolome between healthy cats that received clindamycin with a placebo or synbiotic. METHODS: 16 healthy domestic shorthair cats from a research colony were randomized to receive 150 mg clindamycin with either a placebo (eight cats) or commercially-available synbiotic (eight cats) once daily for 21 days with reevaluation 603 days thereafter. All cats ate the same diet. Food consumption, vomiting, and fecal score were recorded. Fecal samples were collected daily on the last three days of baseline (days 5-7), treatment (26-28), and recovery (631-633). Sequencing of 16S rRNA genes and gas chromatography time-of-flight mass spectrometry was performed. Clinical signs, alpha and beta diversity metrics, dysbiosis indices, proportions of bacteria groups, and metabolite profiles were compared between treatment groups using repeated measures ANOVAs. Fecal metabolite pathway analysis was performed. P < 0.05 was considered significant. The Benjamini & Hochberg's False Discovery Rate was used to adjust for multiple comparisons. RESULTS: Median age was six and five years, respectively, for cats in the placebo and synbiotic groups. Hyporexia, vomiting, diarrhea, or some combination therein were induced in all cats. Though vomiting was less in cats receiving a synbiotic, the difference was not statistically significant. Bacterial diversity decreased significantly on days 26-28 in both treatment groups. Decreases in Actinobacteria (Bifidobacterium, Collinsella, Slackia), Bacteriodetes (Bacteroides), Lachnospiraceae (Blautia, Coprococcus, Roseburia), Ruminococcaceae (Faecilobacterium, Ruminococcus), and Erysipelotrichaceae (Bulleidia, [Eubacterium]) and increases in Clostridiaceae (Clostridium) and Proteobacteria (Aeromonadales, Enterobacteriaceae) occurred in both treatment groups, with incomplete normalization by days 631-633. Derangements in short-chain fatty acid, bile acid, indole, sphingolipid, benzoic acid, cinnaminic acid, and polyamine profiles also occurred, some of which persisted through the terminal sampling timepoint and differed between treatment groups. DISCUSSION: Cats administered clindamycin commonly develop AAGS, as well as short- and long-term dysbiosis and alterations in fecal metabolites. Despite a lack of differences in clinical signs between treatment groups, significant differences in their fecal metabolomic profiles were identified. Further investigation is warranted to determine whether antibiotic-induced dysbiosis is associated with an increased risk of future AAGS or metabolic diseases in cats and whether synbiotic administration ameliorates this risk.

Continuous radiotelemetric monitoring of intragastric pH in a dog with peptic ulceration.

CASE DESCRIPTION A 6-year-old castrated male Boxer was evaluated for a 5-week history of frequent vomiting, melena, and signs of abdominal pain following accidental ingestion of 5 to ten 15-mg meloxicam tablets (approx ingested dose, 3.1 to 6.2 mg/kg [1.4 to 2.8 mg/lb]). CLINICAL FINDINGS Clinical signs persisted despite 3 weeks of treatment with sucralfate (41.8 mg/kg [19 mg/lb], PO, q 8 h) and omeprazole (0.8 mg/kg [0.36 mg/lb], PO, q 24 h). Results of a CBC and serum biochemical analysis were unremarkable. Abdominal ultrasonography revealed peptic ulceration, and esophagogastroduodenoscopy confirmed the presence of severe proximal duodenal ulceration. TREATMENT AND OUTCOME A radiotelemetric pH-monitoring capsule was placed in the gastric fundus under endoscopic guidance for continuous at-home monitoring of intragastric pH and response to treatment. Treatment was continued with sucralfate (as previously prescribed) and omeprazole at an increased administration frequency (0.8 mg/kg, PO, q 12 h). Intragastric pH was consistently ≥ 3.0 for > 75% of the day during treatment, with the exception of 1 day when a single dose of omeprazole was inadvertently missed. Ulceration and clinical signs completely resolved. CLINICAL RELEVANCE Continuous radiotelemetric monitoring of intragastric pH in the dog of this report was useful for confirming that treatment achieved a predetermined target pH and for demonstrating the impact of missed doses. Duodenal ulceration resolved with twice-daily but not once-daily omeprazole administration. Findings suggested that twice-daily administration of omeprazole may be necessary to achieve this target pH and that a pH ≥ 3.0 for 75% of the day may promote healing of peptic ulcers in dogs.

Cryopreserved platelet concentrate transfusions in 43 dogs: a retrospective study (2007-2013).

OBJECTIVE: To clinically characterize a group of thrombocytopenic dogs that received cryopreserved platelet concentrate (cPC) transfusion, assess efficacy of cPC treatment in improving patient outcome, and compare treated dogs to a control population of thrombocytopenic dogs that did not receive cPC transfusions. DESIGN: Retrospective study. SETTING: University teaching hospital. ANIMALS: Eighty-six client-owned dogs (43 in treatment group, 43 in control group). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records of thrombocytopenic dogs that received cPC transfusions and those of thrombocytopenic dogs that did not receive cPC (control population) from January 2007 through March 2013 were reviewed. Dogs receiving cPC were statistically more likely than controls to have a platelet trigger for cPC transfusion (P = 0.01), lower platelet count (P = 0.009) and hematocrit at presentation (P = 0.001), and lower hematocrit after cPC (P = 0.02). Although there was a statistically significant increase in platelet count from pre- to post-cPC transfusion (P = 0.002), cPC was not found to be effective in improving clinical bleeding or increasing survival compared to the control group. No other characteristics were statistically different between groups. No dogs receiving cPC had an acute transfusion reaction during hospitalization. CONCLUSIONS: In the population described in this study, cPC was not found to increase survival, but was well tolerated. Controlled, prospective studies are necessary to determine indications for and efficacy of cPC transfusions.

Effects of gadoxetate disodium (Eovist(®)) contrast on magnetic resonance imaging characteristics of the liver in clinically healthy dogs.

Gadoxetate disodium (Gd-EOB-DTPA; gadolinium-ethoxybenzyl-diethylene triamine penta-acetic acid) is a newly developed paramagnetic contrast agent reported to have a high specificity for the hepatobiliary system in humans. The purpose of this prospective study was to describe effects of Gd-EOB-DTPA contrast administration on MRI characteristics of the liver in eight clinically healthy dogs. Precontrast dorsal and transverse T1-weighted spin echo, T2-weighted fast spin echo, and transverse T1-weighted 3D gradient echo (VIBE; volume-interpolated body examination) pulse sequences were acquired for each dog. Dogs were assigned to four groups based on contrast dose administered (0.0125 mmol/kg or 0.025 mmol/kg), and pulse sequences acquired after contrast administration (T1-weighted spin echo and T1-weighted 3D gradient echo). Liver signal intensity ratios were calculated and compared between the two contrast dose groups and two postcontrast pulse sequence groups using ANOVA. No adverse effects of contrast administration were observed. All dogs exhibited homogeneous contrast enhancement of the liver with no statistical difference in enhancement between the two different contrast doses. Contrast enhancement in all dogs peaked between 1 and 10 min after intravenous injection. There was a significant difference in mean signal intensity ratios between sequences (P = 0.035) but not between doses (P = 0.421). Postcontrast signal intensities of the liver parenchyma were significantly higher for the T1-weighted 3D gradient echo images when compared to the T1-weighted spin echo sequences. Findings indicated that Gd-EOB-DTPA contrast administration is safe in healthy dogs and causes homogeneous enhancement of the liver that is more pronounced in T1-weighted 3D gradient echo MRI pulse sequences.

Ultrasonographic observation of secretin-induced pancreatic duct dilation in healthy cats.

Secretin is a polypeptide hormone that stimulates secretion of bicarbonate from the exocrine pancreas and, in healthy human subjects, causes transient pancreatic duct dilation observable sonographically. In humans with chronic pancreatitis, secretin administration fails to cause pancreatic duct dilation, theoretically due to the restrictive effects of periductal fibrosis. We characterized the effect of exogenous secretin administration on the width of the pancreatic duct in nine healthy domestic cats. Cats were given a commercially available secretin product (ChiRho Stim) while the pancreatic duct was monitored sonographically. Mean pancreatic duct diameter increased from 0.77 +/- 0.33 to 1.42 +/- 0.40 mm after secretin administration (P = 0.0017). The mean percent increase in pancreatic duct diameter over basal diameter for all time points up to 15 min postsecretin administration was 101.9 +/- 58.8%. Applicability of this technique to diagnose chronic pancreatitis in cats will need to be investigated.

Prevalence of serum antibodies against six Leptospira serovars in healthy dogs.

OBJECTIVE: To determine the prevalence of antibodies against 6 Leptospira serovars and determine risk factors associated with positive Leptospira titers in healthy client-owned dogs in Michigan. DESIGN: Cross-sectional study. ANIMALS: 1,241 healthy dogs at least 4 months of age. PROCEDURES: Dogs were examined by veterinarians at private practices. Vaccinated and unvaccinated dogs were enrolled in the study, which occurred prior to the availability of a 4-serovar (Canicola, Grippotyphosa, Icterohaemorrhagiae, and Pomona) Leptospira vaccine. Sera were tested by use of the microscopic agglutination test to determine antibody titers against Leptospira serovars Bratislava, Canicola, Grippotyphosa, Hardjo, Icterohaemorrhagiae, and Pomona. A questionnaire was used to collect demographic information about each dog to identify risk factors associated with seropositive status. RESULTS: 309 of 1,241 (24.9%) dogs had antibody titers against at least 1 of the 6 Leptospira serovars, which suggested exposure to Leptospira spp. Prevalence of antibodies was highest to serovar Grippotyphosa, followed by Bratislava, Canicola, Icterohaemorrhagiae, and Pomona. Age, travel outside Michigan, exercise outside fenced yards, and exposure to livestock and wildlife were significant risk factors for positive titers. CONCLUSIONS AND CLINICAL RELEVANCE: Among healthy dogs from the lower peninsula of Michigan, > 20% have antibodies against leptospiral serovars historically considered uncommon but more recently incriminated as causing clinical canine leptospirosis. Wildlife and livestock may be of increasing importance as reservoirs for canine leptospirosis as urbanization continues to occur. Expanded vaccination strategies may partially mitigate these trends.

New and unusual causes of acute renal failure in dogs and cats.

This article provides a source for easy reference, summarizing in one location newly recognized and unusual causes of acute renal failure (ARF) in dogs and cats. Several of the causes discussed in this article have been described previously. New or unusual causes of ARF in dogs and cats include infectious diseases (leptospirosis,borreliosis, and babesiosis), nephrotoxicants (aminoglycosides,vitamin D, and nonsteroidal anti-inflammatory drugs), and plant material (lilies and raisins/grapes).