Investigation into the causes of aspirin resistance in healthy dogs

Antiplatelet effects of acetylsalicylic acid (ASA, aspirin) may be poor in some individuals. Additionally, no method exists for predicting poor ASA response (resistance) in individual dogs. This study's main objective was to determine whether poor ASA response results from pharmacodynamic or pharmacokinetic causes. ASA concentrations causing 50% inhibition of platelet aggregation (in vitro IC50) were determined using whole blood collected from 21 drug‐free healthy dogs to evaluate intrinsic sensitivity of platelets to ASA. Dogs were then administered ASA at 4 mg/kg once orally. Percent decrease in platelet aggregation from baseline, and plasma ASA and salicylic acid (SA) concentrations (expressed as AUC values) were measured for up to 3 hr. By 3 hr, 13/21 (62%) dogs showed >50% aggregation inhibition, while 8/21 (38%) dogs showed <50% inhibition. Aggregation inhibition values were negatively correlated with in vitro IC50 values (Rs = ?0.49; p = 0.028) and positively correlated with ASA concentrations (Rs = 0.48; p = 0.03). Furthermore, ASA concentrations were strongly negatively correlated (Rs = ?0.88; p < 0.001) with SA/ASA concentration ratios, an index of ASA metabolism to SA by esterase enzymes. Multiple linear regression analysis indicated that 59% (p < 0.001) of interindividual variability in aggregation inhibition was explained by in vitro IC50 values (29% of variability) and ASA concentrations (29% of variability). Consequently, poor in vivo ASA response in these dogs resulted from both pharmacodynamic (decreased platelet sensitivity) and pharmacokinetic (lower ASA concentrations) causes. Lower ASA concentrations may be explained by reduced bioavailability associated with higher esterase activities.     

Pulmonary vasculature in dogs assessed by three‐dimensional fractal analysis and chemometrics

Fractal analysis of canine pulmonary vessels could allow quantification of their space‐filling properties. Aims of this prospective, analytical, cross‐sectional study were to describe methods for reconstructing three dimensional pulmonary arterial vascular trees from computed tomographic pulmonary angiogram, applying fractal analyses of these vascular trees in dogs with and without diseases that are known to predispose to thromboembolism, and testing the hypothesis that diseased dogs would have a different fractal dimension than healthy dogs. A total of 34 dogs were sampled. Based on computed tomographic pulmonary angiograms findings, dogs were divided in three groups: diseased with pulmonary thromboembolism (n = 7), diseased but without pulmonary thromboembolism (n = 21), and healthy (n = 6). An observer who was aware of group status created three‐dimensional pulmonary artery vascular trees for each dog using a semiautomated segmentation technique. Vascular three‐dimensional reconstructions were then evaluated using fractal analysis. Fractal dimensions were analyzed, by group, using analysis of variance and principal component analysis. Fractal dimensions were significantly different among the three groups taken together (P = 0.001), but not between the diseased dogs alone (P = 0.203). The principal component analysis showed a tendency of separation between healthy control and diseased groups, but not between groups of dogs with and without pulmonary thromboembolism. Findings indicated that computed tomographic pulmonary angiogram images can be used to reconstruct three‐dimensional pulmonary arterial vascular trees in dogs and that fractal analysis of these three‐dimensional vascular trees is a feasible method for quantifying the spatial relationships of pulmonary arteries. These methods could be applied in further research studies on pulmonary and vascular diseases in dogs.     

Ex vivo binding of the immunosuppressant mycophenolic acid to dog and cat plasma proteins and the effect of co‐incubated dexamethasone and prednisolone

Mycophenolic acid (MPA) has been shown to be promising for the treatment of autoimmune diseases in dogs and cats. In humans, MPA is highly bound to plasma proteins (~97%). It has been recommended to monitor free drug plasma concentrations because the free MPA correlates with its immunosuppressive effect. However, it is unknown if MPA is highly bound to plasma proteins in dogs and cats. The objectives of this study were to determine the extent of plasma protein binding of MPA and evaluate the effect of prednisolone and dexamethasone on the extent of protein binding of MPA in dogs and cats. The extent of plasma protein binding of MPA was determined in plasma collected from clinically healthy adult cats (n = 13) and dogs (n = 14) by combining high‐throughput dialysis and ultra‐high‐liquid chromatography. This study reveals that MPA is highly bound to plasma proteins (>90%) in dogs and cats, mean extent of binding of MPA at 15 μg/ml to plasma proteins being 96% (range, 95%–97%) and 92% (range, 90%–93%) for dogs and cats, respectively. In dog plasma, MPA is primarily bound to albumin. In vitro, prednisolone increased the unbound MPA in dogs (p < .01) but not in cats (p = .07) while dexamethasone had no effect on MPA plasma binding in either species (p > .05). Results of this study provide valuable information for designing future pharmacokinetic and pharmacodynamic studies and also therapeutic monitoring programs for dogs and cats.     

The curative and antioxidative efficiency of ivermectin and ivermectin + vitamin E-selenium treatment on canine <Emphasis Type="Italic">Sarcoptes scabiei</Emphasis> infestation

The objective of the present study was to investigate the curative and antioxidative efficacy of ivermectin and ivermectin + vitamin E-selenium, and the influence of these agents on oxidative stress parameters in canines infested by Sarcoptes scabiei. Twenty two sarcoptic mites infested dogs and nine healthy dogs of 6 months to 2 years of age were divided into three groups. Group I comprised of healthy dogs (n = 9) whereas animals in group II (n = 11) and III (n = 11) were positive for scabies. Group II animals were treated with only 1% ivermectin @ 0.2 mg/kg SC whereas group III were additionally treated with Vitamin E and selenium (tocopherol 50 mg + Se 1.5 mg/ml) @0.5 ml/20 kg IM at weekly intervals for three times. Blood samples were collected on day 0 and 28 post therapy. The values for hemato-biochemical parameters and activities of antioxidant enzymes were significantly decreased (P < 0.05) whereas level of lipid peroxidation was significantly increased in all the infested dogs in comparison to the healthy dogs on day 0 which approached normalcy by day 28 post therapy. The dogs of group III showed better clinical recovery in comparison to group II at the end of therapy. Thus, administration of vitamin E and selenium in addition to standard therapy can alleviate these alterations hastening the clinical recovery of diseased dogs and can be recommended as an adjunct therapy with miticides for canine sarcoptic mange.     

Single‐voxel and multi‐voxel spectroscopy yield comparable results in the normal juvenile canine brain when using 3 Tesla magnetic resonance imaging

Conventional magnetic resonance imaging (MRI) characteristics of canine brain diseases are often nonspecific. Single‐ and multi‐voxel spectroscopy techniques allow quantification of chemical biomarkers for tissues of interest and may help to improve diagnostic specificity. However, published information is currently lacking for the in vivo performance of these two techniques in dogs. The aim of this prospective, methods comparison study was to compare the performance of single‐ and multi‐voxel spectroscopy in the brains of eight healthy, juvenile dogs using 3 Tesla MRI. Ipsilateral regions of single‐ and multi‐voxel spectroscopy were performed in symmetric regions of interest of each brain in the parietal (n = 3), thalamic (n = 2), and piriform lobes (n = 3). In vivo single‐voxel spectroscopy and multi‐voxel spectroscopy metabolite ratios from the same size and multi‐voxel spectroscopy ratios from different sized regions of interest were compared. No significant difference was seen between single‐voxel spectroscopy and multi‐voxel spectroscopy metabolite ratios for any lobe when regions of interest were similar in size and shape. Significant lobar single‐voxel spectroscopy and multi‐voxel spectroscopy differences were seen between the parietal lobe and thalamus (P = 0.047) for the choline to N‐acetyl aspartase ratios when large multi‐voxel spectroscopy regions of interest were compared to very small multi‐voxel spectroscopy regions of interest within the same lobe; and for the N‐acetyl aspartase to creatine ratios in all lobes when single‐voxel spectroscopy was compared to combined (pooled) multi‐voxel spectroscopy datasets. Findings from this preliminary study indicated that single‐ and multi‐voxel spectroscopy techniques using 3T MRI yield comparable results for similar sized regions of interest in the normal canine brain. Findings also supported using the contralateral side as an internal control for dogs with brain lesions.     

Human tularaemia associated with exposure to domestic dogs—United States, 2006–2016

Dogs have been implicated in the zoonotic transmission of numerous pathogens. Whereas cats are known to transmit Francisella tularensis to humans via bite and other routes, the role of dogs in facilitating infection is much less understood. We reviewed tularaemia case investigation records collected through national surveillance during 2006–2016 to summarize those with dog involvement, characterize the nature of dog‐related exposure and describe associated clinical characteristics. Among 1,814 human tularaemia cases, 735 (41%) supplemental case investigation records were available for review; and of those, 24 (3.3%) were classified as dog‐related. Median age of patients was 51 years (range: 1–82); 54% were female. Two thirds (67%) of cases presented with ulceroglandular/glandular tularaemia; pneumonic (13%) and oropharyngeal (13%) illness occurred less frequently. Dog‐related exposures were classified as follows: direct contact via bite, scratch or face snuggling/licking (n = 12; 50%); direct contact with dead animals retrieved by domestic dogs (n = 8; 33%); and contact with infected ticks acquired from domestic dogs (n = 4; 17%). Prevention of dog‐related tularaemia necessitates enhanced tularaemia awareness and tick avoidance among pet owners, veterinarians, health care providers and the general public.     

Contrast‐enhanced ultrasonography is a feasible technique for quantifying hepatic microvascular perfusion in dogs with extrahepatic congenital portosystemic shunts

Extrahepatic‐congenital portosystemic shunt is a vascular anomaly that connects the portal vein to the systemic circulation and leads to a change in hepatic microvascular perfusion. However, an assessment of hepatic microvascular perfusion is limited by conventional diagnostic modalities. The aim of this prospective, exploratory study was to assess hepatic microvascular perfusion in dogs with extrahepatic‐congenital portosystemic shunt using contrast‐enhanced ultrasonography (CEUS) using perfluorobutane (Sonazoid^®). A total of 17 dogs were included, eight healthy dogs and nine with extrahepatic‐congenital portosystemic shunt. The time‐to‐peak (TTP), rising time (RT), and rising rate (RR) in the hepatic artery, portal vein, and hepatic parenchyma, as well as the portal vein‐to‐hepatic parenchyma transit time (ΔHP‐PV) measured from time‐intensity curve on CEUS were compared between healthy and extrahepatic‐congenital portosystemic shunt dogs. The RT of the hepatic artery in extrahepatic‐congenital portosystemic shunt dogs was significantly earlier than in healthy dogs (P = 0.0153). The TTP and RT of the hepatic parenchyma were significantly earlier in extrahepatic‐congenital portosystemic shunt dogs than in healthy dogs (P = 0.0018 and P = 0.0024, respectively). ΔHP–PV was significantly shorter in extrahepatic‐congenital portosystemic shunt dogs than in healthy dogs (P = 0.0018). CEUS effectively revealed changes in hepatic microvascular perfusion including hepatic artery, portal vein, and hepatic parenchyma simultaneously in extrahepatic‐congenital portosystemic shunt dogs. Rapid hepatic artery and hepatic parenchyma enhancements may reflect a compensatory increase in hepatic artery blood flow (arterialization) caused by a decrease in portal vein blood flow and may be used as an additional diagnostic test to distinguish extrahepatic‐congenital portosystemic shunt dogs from healthy dogs.     

Evaluation of platelet function in dogs with cardiac disease using the PFA‐100 platelet function analyzer

Background: Cardiac disease has the potential to alter platelet function in dogs. Evaluation of platelet function using the PFA‐100 analyzer in dogs of multiple breeds and with a broad range of cardiac conditions would help clarify the effect of cardiac disease on platelets. Objectives: The objective of this study was to assess differences in closure time (CT) in dogs with cardiac disease associated with murmurs, when compared with that of healthy dogs. Methods: Thirty‐nine dogs with cardiac murmurs and turbulent blood flow as determined echocardiographically were included in the study. The dogs represented 23 different breeds. Dogs with murmurs were further divided into those with atrioventricular valvular insufficiency (n=23) and subaortic stenosis (n=9). Fifty‐eight clinically healthy dogs were used as controls. CTs were determined in duplicate on a PFA‐100 analyzer using collagen/ADP cartridges. Results: Compared with CTs in the control group (mean±SD, 57.6±5.9 seconds; median, 56.5 seconds; reference interval, 48.0–77.0 seconds), dogs with valvular insufficiency (mean±SD, 81.9±26.3 seconds; median, 78.0 seconds; range, 52.5–187 seconds), subaortic stenosis (71.4±16.5 seconds; median, 66.0 seconds; range, 51.5–95.0 seconds), and all dogs with murmurs combined (79.6±24.1 seconds; median, 74.0 seconds; range, 48.0–187 seconds) had significantly prolonged CTs (P<.01). Conclusions: The PFA‐100 analyzer is useful in detecting platelet function defects in dogs with cardiac murmurs, most notably those caused by mitral and/or tricuspid valvular insufficiency or subaortic stenosis. The form of turbulent blood flow does not appear to be an important factor in platelet hypofunction in these forms of cardiac disease.     

A cross‐sectional study of intestinal parasitoses in dogs and children of the periurban area of La Plata (Buenos Aires,Argentina): Zoonotic importance and implications in public health

A cross‐sectional study was performed between school term dates 2014 and 2015 to diagnose intestinal parasites in dogs and children living with them. The socio‐environmental characteristics and hygiene practices of the children were also evaluated in terms of risk factors for parasitic infection of periurban neighbourhoods of La Plata (Buenos Aires, Argentina). Serial coproparasitological samples of 78 dogs and 211 children were analysed by means of concentration and flotation techniques. Socio‐environmental variables and hygiene practices of children were evaluated through semi‐structured questionnaires which were answered by every family. The study showed that 82.1% of dogs were parasitized. The specific richness was of 11 species; Ancylostoma caninum (69.2%), Uncinaria stenocephala (41.0%), Trichuris vulpis (28.2%) and Toxocara canis (21.8%) were the most prevalent. The study also revealed that 67.8% of children were positive. Also, 11 species were identified and the most prevalent were Blastocystis sp. (36.0%), Enterobius vermicularis (27.5%) and Giardia lamblia (21.3%). The risk for parasitosis was higher in 6‐year‐old children and older (OR = 1.9, 95% IC: 1.0–3.7) and in those who did not wash their hands or did it occasionally after playing with their pets (OR = 2.8, 95% IC: 1.4–5.5). Blastocystis sp. and Entamoeba coli infection risks were greater in children whose parents had a basic level of education (OR = 3.4, 95% IC: 1.3–8.7 and OR = 3.6, 95% IC: 0.8–15.9, respectively). In addition, the risk of infection for E. coli was higher in children who lived in floodable houses (OR = 4.4, 95% IC: 0.9–16.6). Likewise, the risk of infection for E. vermicularis was greater in children with onychophagia (OR = 1.6, 95% IC: 0.7–3.7) and in 6 year olds and older whose parents completed only primary studies (OR = 3.6, 95% IC: 1.4–9.1). The results obtained show the existence of a worrying epidemiological scenario that stresses the importance of zoonotic parasitosis as a serious problem of public health.     

Congenital heart disease in boxer dogs: results of 6 years of breed screening

This prospective study was conducted to evaluate the prevalence and severity of ocular lesions in dogs with anemia (packed cell volume  20%) and/or thrombocytopenia (platelet count < 150,000/μL). Dogs were divided into four groups: (1) anemic (n = 17); (2) thrombocytopenic (n = 36); (3) anemic and thrombocytopenic (n = 24); and (4) healthy controls (n = 26). The prevalence of ophthalmic lesions in these four groups was 12%, 42%, 42% and 0%, respectively. Anemia was not associated with the presence of ocular lesions (P = 0.41) or their severity. Thrombocytopenia was significantly associated with the presence of ocular lesions (P = 0.0016) and with their severity (P = 0.017). We conclude that thrombocytopenia, but not anemia, is associated with ocular lesions in dogs.     

Effects of food intake on pharmacokinetics of mosapride in beagle dogs

This study was performed to determine the pharmacokinetic profile of mosapride in fasting and fed states. A single 5‐mg oral dose of mosapride was administered to fasted (n = 15) and fed (n = 12) beagle dogs, and the plasma concentrations of mosapride were measured by liquid chromatography–tandem mass spectrometry. The resultant data were analyzed by noncompartmental analysis (NCA). Mosapride was absorbed in fasted and fed dogs with similar T_max. Both C_max and AUC were significantly higher in the fasting group than in fed dogs, being four times (10.51 μg/mL vs. 2.76 μg/mL) and 3.5 times higher (38.53 h·μg/mL vs. 10.22 h·μg/mL), respectively. These findings suggest that food intake affects the pharmacokinetics of mosapride and that the dosage regimen for this drug need to be reconsidered.     

Fluoroquinolone levels in healthy dog urine following a 20‐mg/kg oral dose of enrofloxacin exceed mutant prevention concentration targets against Escherichia coli isolated from canine urinary tract infections

A 3‐day course of oral enrofloxacin is effective for treating uncomplicated urinary tract infection (UTI) in dogs when administered 20 mg/kg Q24H. However, emergence of fluoroquinolone‐resistant mutants of uropathogens is a concern. Urine concentrations of enrofloxacin and ciprofloxacin were measured in six healthy dogs following dose of enrofloxacin 20 mg/kg. Mutant prevention concentrations of Escherichia coli isolated from canine UTI were also determined against ciprofloxacin. Urine AUC(24)/MPC ratios considering ciprofloxacin concentrations ranged 3819–7767, indicating that selection of resistant E. coli mutants in dogs with uncomplicated UTIs is unlikely in the bladder given that an AUC(24)/MPC = 39 is considered to be protective against mutant selection for ciprofloxacin. However, additional studies are required to evaluate the effects of this enrofloxacin treatment protocol on bacteria that colonize anatomic sites where fluoroquinolones achieve lower concentrations compared to the urinary bladder.     

Computed tomographic bronchial collapsibility values over 50% may be detected in healthy dogs

Bronchomalacia and bronchial collapse are important causes of chronic coughing in dogs. The current reference standard diagnostic tests for these problems are flexible bronchoscopy and biopsy. Previous human studies have also supported inspiration/expiration computed tomography (CT) as a diagnostic test. The current prospective, pilot study aimed to determine whether inspiration/expiration CT is also a feasible test for quantifying bronchial collapsibility in dogs. Thoracic CT images were acquired using a 64‐row multidetector CT for 10 healthy Beagle dogs during maximal inspiration and expiration. For each scan, one observer measured transverse sectional areas of the mainstem and lobar bronchi, and the dorsal and ventral segmental bronchi of the left cranial lobar bronchus. Diameters for each bronchus were also measured in transverse, sagittal, and dorsal planes. Bronchial collapsibility (%) was calculated as the difference between inspiration/expiration transverse sectional areas divided by the inspiration transverse sectional areas. Mean bronchial collapsibility of all bronchi was 38.20 ± 15.17%. A collapsibility of over 50% was found in the dorsal (n = 7) and ventral (n = 4) segmental bronchi of the left cranial lobar bronchus, and the left caudal (n = 5) and right middle (n = 2) lobar bronchus. Bronchial collapsibility measurements were greater in the dorsal and ventral segmental bronchi of the left cranial lobar bronchus and the left caudal lobar bronchus (P < 0.001). Findings supported inspiration/expiration CT as a modality to noninvasively assess bronchial collapse in dogs and a bronchial collapsibility value greater than 50% for detecting pathologic bronchial collapse in clinically affected dogs.     

18F‐FDG‐PET/CT as adjunctive diagnostic modalities in canine fever of unknown origin

Fever of unknown origin (FUO) is a persistent or recurrent fever for which the underlying source has not been identified despite diagnostic investigation. In people, ¹⁸F‐fluoro‐2‐deoxyglucose positron emission tomography (¹⁸F‐FDG‐PET) alone or in combination with computed tomography (CT) is often beneficial in detecting the source of fever when other diagnostics have failed. Veterinary reports describing use of these modalities in animals with fever of unknown origin are currently lacking. Aims of this retrospective case series were to describe ¹⁸F‐FDG‐PET or ¹⁸F‐FDG‐PET/CT findings in a group of dogs with fever of unknown origin. Dogs presenting to a single center between April 2012 and August 2015 were included. A total of four dogs met inclusion criteria and underwent either positron emission tomography (n = 2) or positron emission tomography/CT (n = 2) as a part of their diagnostic investigation. All subjects underwent extensive diagnostic testing prior to ¹⁸F‐FDG‐PET/CT. Initial diagnostic evaluation failed to identify either a cause of fever or an anatomic location of disease in these four dogs. In each dog, positron emission tomography or positron emission tomography/CT was either able to localize or rule out the presence of focal lesion thereby allowing for directed sampling and/or informed disease treatment. Follow up ¹⁸F‐FDG‐PET/CT scans performed in two patients showed improvement of observed abnormalities (n = 1) or detected recurrence of disease allowing for repeated treatment before clinical signs recurred (n = 1). Fever resolved after specific treatment in each dog. Findings from the current study supported the use of positron emission tomography or positron emission tomography/CT as adjunctive imaging modalities for diagnosis and gauging response to therapy in dogs with fever of unknown origin.     

Evaluation of the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs after a single dose and at steady‐state

The aim of the study was to describe the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs when investigated as a single dose and at steady‐state. Five healthy adult dogs were used in the study in a crossover design receiving either 5 mg/kg of cyclosporin A (CsA) alone or 5 mg/kg of fluconazole with 2.5 mg/kg of cyclosporin A (CsA/Flu) for 35 days. Pharmacokinetic curves were performed on day 1 and day 35 in addition to sampling trough and suspected peak concentrations (C2) twice weekly with LC/MS/MS. There was no statistically significant difference noted in any pharmacokinetic value (AUC_0‐inf. [day 1, P = 0.225], AUC_tau [day 35, P = 0.225], t_½ [day 1, P = 0.279; day 35, P = 0.686], and C_max [day 1, P = 0.225; day 35, P = 0.225]) between the treatment groups by sampling day. There was a statistically significant increase in AUC (CsA P = 0.043; CsA/Flu P = 0.043) and t_½ (CsA P = 0.042, CsA/Flu P = 0.042) over time within each group_. There were no significant differences in the C_max (CsA P = 0.08; CsA/Flu P = 0.08) when comparing day 1 vs. day 35. Steady‐state cyclosporine concentrations were achieved by day 10 in both groups. Subjectively, individual variability was noted among the dogs and a much larger sample size would be beneficial in a future study.     

Plasma and platelet serotonin concentrations in healthy dogs and dogs with myxomatous mitral valve disease

ObjectivesSerotonin has been implicated in canine myxomatous mitral valve disease (MMVD); however, the sources of serotonin have not been fully elucidated. This study compared the concentration of serotonin in plasma and platelets of normal healthy small breed dogs with predisposition to MMVD and dogs with naturally occurring MMVD.Animals43 small-breed client-owned dogs with an approximate weight of <10 kg and age of 6 years or above were divided into 2 groups: a healthy control group (n = 20) and a group with echocardiographic evidence of MMVD (n = 23).Methods5 ml samples of blood were collected. Plasma and platelets were separated by centrifugation and assayed for serotonin measured by enzyme linked immunosorbent assay (ELISA).ResultsMedian plasma serotonin concentration was not significantly different (p = 0.3630) between normal healthy dogs (3.7 ng/ml) and dogs with MMVD (4.3 ng/ml). Males had higher plasma serotonin concentration than females (4.7 and 2.9 ng/ml respectively, p = 0.0043). Platelet serotonin concentration was not different between healthy dogs and dogs with MMVD (128.6 ng/10⁹ platelets and 176.6 ng/10⁹ platelets respectively, p = 0.4575). Age, echocardiographic indices and platelet count showed no correlation with plasma or platelet serotonin concentration.ConclusionsCirculating plasma serotonin is unlikely a major source of serotonin signaling in canine MMVD. Platelets could be a source of serotonin in canine MMVD through platelet adhesion to the mitral valve; however, the amount of serotonin stored in platelets of healthy dogs and dogs with MMVD is not different.     

Canine orosomucoid (alpha‐1 acid glycoprotein) variants and their influence on drug plasma protein binding

Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed‐breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography–mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann‐Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated.     

Plasma and serum concentrations of cytarabine administered via continuous intravenous infusion to dogs with meningoencephalomyelitis of unknown etiology

The objective of this study was to evaluate the plasma and serum concentrations of cytarabine (CA) administered via constant rate infusion (CRI) in dogs with meningoencephalomyelitis of unknown etiology (MUE). Nineteen client‐owned dogs received a CRI of CA at a dose of 25 mg/m²/h for 8 h as treatment for MUE. Dogs were divided into four groups, those receiving CA alone and those receiving CA in conjunction with other drugs. Blood samples were collected at 0, 1, 8, and 12 h after initiating the CRI. Plasma (n = 13) and serum (n = 11) cytarabine concentrations were measured by high‐pressure liquid chromatography. The mean peak concentration (C_MAX) and area under the curve (AUC) after CRI administration were 1.70 ± 0.66 μg/mL and 11.39 ± 3.37 h·μg/mL, respectively, for dogs receiving cytarabine alone, 2.36 ± 0.35 μg/mL and 16.91 + 3.60 h·μg/mL for dogs administered cytarabine and concurrently on other drugs. Mean concentrations for all dogs were above 1.0 μg/mL at both the 1‐ and 8‐h time points. The steady‐state achieved with cytarabine CRI produces a consistent and prolonged exposure in plasma and serum, which is likely to produce equilibrium between blood and the central nervous system in dogs with a clinical diagnosis of MUE. Other medications commonly used to treat MUE do not appear to alter CA concentrations in serum and plasma.     

Evaluation of peripheral blood neutrophil function in tumor‐bearing dogs

Background: Peripheral blood neutrophils of untreated human cancer patients have been shown to have normal, increased, and decreased phagocytic activity, killing capacity, and/or oxidative burst activities. Objectives: The objectives of this study were to evaluate oxidative burst and phagocytic activities of peripheral blood neutrophils from tumor‐bearing dogs before therapy and compare them with neutrophil function of healthy control dogs. Methods: Heparinized whole blood was obtained from dogs with high‐grade lymphoma (n=23), sarcoma (n=13), or carcinoma (n=11), and healthy control dogs (n=11) for flow cytometric evaluation of oxidative burst and phagocytic activities. Percentage of bursting cells and amount of oxidative burst activity were determined after stimulation with phorbol 12‐myristate 13‐acetate (PMA) or Escherichia coli. Percentage of phagocytic cells and amount of phagocytic activity were determined after incubation with fluorescent E. coli. Results: Compared with control dogs, dogs with sarcoma (P=.004) and carcinoma (P=.05) had a lower percentage of neutrophils exhibiting oxidative burst activity after stimulation with PMA. Phagocytic activity was significantly lower in dogs with sarcomas compared with control dogs (P<.0001) and dogs with lymphoma (P=.01). Conclusions: Untreated carcinomas and sarcomas in dogs may suppress the percentage of neutrophils capable of oxidative burst when stimulated by PMA. Furthermore, sarcomas also may suppress the amount of phagocytic activity per neutrophil. Until further studies can be performed, the clinical significance of these findings is unknown.     

The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs

Pimobendan is a benzimidazole‐pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavailability have not been described in dogs. The aim of this study was to describe pharmacokinetics of three formulations of pimobendan in healthy dogs: the licensed capsule product, and novel liquid and intravenous formulations. A three‐period, nested randomized two‐treatment crossover design was used. Pimobendan was administered p.o. at 0.25 and i.v. at 0.125 mg/kg. Blood and plasma samples were analysed by liquid chromatography–mass spectrometry. Noncompartmental modelling was used to describe the pharmacokinetics. Parameters were compared between formulations using a general linear model. Bioequivalence of the oral formulations was tested using CI90 for AUC_(0–∞) and C_max. Bioavailability of pimobendan after oral dosing was 70%. Liquid and capsule formulations were bioequivalent only for AUC. The positive enantiomer of pimobendan (PE) had a larger volume of distribution than the negative enantiomer (NE) (281 ± 48 vs. 215 ± 68 mL/kg; P = 0.003) and a shorter half‐life (21.7 vs. 29.9 min; P = 0.004). The NE was distributed more quickly than the PE into blood cells. Enantiomers of pimobendan have differing absorption, distribution and elimination. The pharmacokinetics of pimobendan in healthy dogs was described.