Preliminary Investigation of the Area Under the l‐Lactate Concentration–Time Curve (LACAREA) in Critically Ill Equine Neonates

Background

A variety of measures of l‐lactate concentration ([LAC]) in the blood of critically ill neonatal foals have shown utility as prognostic indicators. These measures, evaluating either the severity of hyperlactatemia or the duration of exposure to hyperlactatemia, perform fairly well and have correctly classified 75–80% of foals examined in several studies. The area under the l‐lactate concentration versus time curve (LAC _Area) encompasses both severity and duration of hyperlactatemia and should improve correct classification of patient survival.

Hypothesis/Objectives

LAC _Area is larger in nonsurviving critically ill neonatal foals.

Animals

Forty‐nine foals admitted for critical illness to 1 of 4 referral hospitals.

Methods

Whole blood was obtained at admission and 6, 12, 18, and 24 hours after admission for measurement of l‐lactate using a handheld lactate meter. LAC _Area was calculated for: admission–6, 6–12, 12–18, 18–24 hours, and admission–24 hours using the trapezoidal method and summing the 6‐hours interval areas to determine total 24 hours area. Differences between survivors and nonsurvivors were determined using robust regression and Kruskal–Wallis testing, P < .05.

Results

LAC _Area was significantly larger in nonsurviving foals (n = 9) than in surviving foals (n = 40) at all time periods examined.

Conclusions and Clinical Importance

Differences in LAC _Area between surviving and nonsurviving critically ill neonatal foals are large and support further investigation of this method as an improved biomarker for survival in critically ill neonatal foals is indicated.     

Effect of Trilostane and Mitotane on Aldosterone Secretory Reserve in Dogs with Pituitary‐Dependent Hyperadrenocorticism

Background

Maximal aldosterone secretion in healthy dogs occurs 30 minutes postadrenocorticotropin (ACTH; 5 μg/kg IV) stimulation. The effect of trilostane and mitotane on aldosterone at that time is unknown.

Objectives

To assess the effect of trilostane and mitotane in dogs with pituitary‐dependent hyperadrenocorticism on aldosterone secretory reserve. To determine if aldosterone concentration correlates with electrolyte concentrations.

Animals

Serum collected from 79 client‐owned dogs and 33 stored samples.

Methods

Client‐owned dogs had ACTH stimulation tests with cortisol concentrations measured at 0 and 60 minutes and aldosterone concentrations measured at 0, 30, and 60 minutes. Stored samples had aldosterone concentrations measured at 0 and 60 minutes. Ten historical clinically healthy controls were included. All had basal sodium and potassium concentrations measured.

Results

The aldosterone concentrations in the mitotane‐ and trilostane‐treated dogs at 30 and 60 minutes post‐ACTH were significantly lower than in clinically healthy dogs; no significant difference was detected in aldosterone concentration between 30 and 60 minutes in treated dogs. However, a significantly higher percentage of dogs had decreased aldosterone secretory reserve detected at 30 minutes than at 60 minutes. At 30 minutes, decreased secretory reserve was detected in 49% and 78% of trilostane‐ and mitotane‐treated dogs, respectively. No correlation was detected between aldosterone and serum electrolyte concentrations.

Conclusions and Clinical Importance

Decreased aldosterone secretory reserve is common in trilostane‐ and mitotane‐treated dogs; it cannot be predicted by measurement of serum electrolyte concentrations. Aldosterone concentration at 30 minutes post‐ACTH stimulation identifies more dogs with decreased aldosterone secretory reserve than conventional testing at 60 minutes.     

Autologous Peripheral Blood Hematopoietic Cell Transplantation in Dogs with T‐Cell Lymphoma

Background

Peripheral blood hematopoietic cell transplantation (PBHCT) is a feasible treatment option for dogs with B‐cell lymphoma.

Objective

To examine apheresis and PBHCT outcomes in dogs diagnosed with T‐cell lymphoma (TCL).

Animals

Fifteen client‐owned dogs diagnosed with high‐grade TCL.

Methods

After high‐dose cyclophosphamide and rhG‐colony‐stimulating (rhG‐CSF) factor treatment, peripheral blood mononuclear cells were collected using cell separators. The harvested cells then were infused after varying doses of total body irradiation (TBI). Postirradiation adverse effects were managed symptomatically and dogs were discharged upon evidence of hematopoietic engraftment.

Results

More than 2 × 10⁶ CD34+ cells/kg were harvested from 15/15 dogs. Thirteen of 15 (87%) dogs engrafted appropriately, whereas 2 (13%) of the dogs died in the hospital. One dog developed cutaneous B‐cell lymphoma 120 days post‐PBHCT. The median disease‐free interval and overall survival (OS) of the 13 dogs transplanted in first remission from the time of PBHCT were 184 and 240 days, respectively. Stage and substage of disease at diagnosis had no effect on OS. Two of 13 (15%) dogs were alive 741 and 772 days post‐PBHCT.

Conclusions and Clinical Importance

PBHCT may be considered as a treatment option for dogs with TCL.     

Dobutamine Stress Echocardiography for Assessment of Systolic Function in Dogs with Experimentally Induced Mitral Regurgitation

Background

Systolic dysfunction is associated with poor outcomes in dogs with myxomatous mitral valve disease. However, assessment of systolic variables by conventional echocardiographic methods is difficult in these dogs because of mitral regurgitation (MR).

Hypothesis

We hypothesized that assessment of systolic function by dobutamine stress may identify systolic dysfunction in dogs with MR, and that 2‐dimensional speckle‐tracking echocardiography (2D‐STE) could quantitatively evaluate myocardial function.

Animals

Anesthetized dogs with experimentally induced MR.

Methods

Dogs were examined for systolic myocardial deformations using 2D‐STE during dobutamine infusion before and 3 and 6 months after MR induction. We evaluated peak systolic rotation and rotation rate in each basal and apical view; peak systolic torsion and torsion rate were also calculated.

Results

Invasive peak positive first derivatives of left ventricular pressure (dp/dt) were significantly decreased in dogs 6 months after induction of MR compared with pre‐MR results. After 3 and 6 months of MR, dogs had diminished peak systolic torsion values and torsion rates in response to dobutamine infusion compared with pre‐MR results (3 months, P < .001 and P = .006; 6 months, P = .003 and P = .021). These results were significantly correlated with overall invasive dp/dt (r = 0.644, P < .001; r = 0.696, P < .001).

Conclusions and Clinical Importance

Decreased torsion during dobutamine infusion in dogs with MR may reflect latent systolic dysfunction. Dobutamine infusion, therefore, may be useful for the assessment of systolic function in dogs with MR.     

Chiari‐Like Malformation and Syringomyelia in American Brussels Griffon Dogs

Background

Although Chiari‐like malformation (CM) and syringomyelia (SM) have been described in many small breed dogs, the prevalence and clinical manifestations of this complex have not been documented in a large cohort of American Brussels Griffon (ABG) dogs.

Objectives

To characterize the clinical and magnetic resonance imaging (MRI) features of CM and SM in the ABG breed.

Animals

Eighty‐four American Kennel Club registered ABG dogs were recruited.

Methods

Prospective study. Complete histories and neurologic examinations were obtained before MRI. Images were blindly reviewed and calculations were made by using OsiriX. All analyses were performed by Student''s t‐test, Spearman''s correlation, ANOVA, and chi‐square test where appropriate.

Results

Chiari‐like malformation and SM were present in 65% and 52% of dogs, respectively. Twenty‐eight percent of dogs had neurologic deficits and 20% had neck pain. Mean central canal (CC) transverse height was 2.5 mm with a mean length of 3.6 cervical vertebrae. Neurologic deficits were significantly associated with a larger syrinx (P = .04, P = .08) and syrinx size increased with age (P = .027). SM was associated with a smaller craniocervical junction (CCJ) height (P = .04) and larger ventricles (P = .0001; P < .001).

Conclusions and Clinical Importance

Syringomyelia and CM are prevalent in American Brussels Griffon dogs. Syrinx size is associated with neurologic deficits, CM, larger ventricles, a smaller craniocervical junction height, neurologic deficits, and cerebellar herniation. Fifty‐two percent of dogs with a SM were clinically normal.     

The Impact of Demographic,Social, and Environmental Factors on the Development of Steroid‐Responsive Meningitis‐Arteritis (SRMA) in the United Kingdom

Background

Steroid‐responsive meningitis‐arteritis (SRMA) is an inflammatory disease of dogs that is suspected to be immune‐mediated. The development of other immune‐mediated diseases has been linked to vaccinations, time of the year, geographic location, sex, neuter status, and breed.

Hypothesis/Objectives

To identify if the development of SRMA is associated with time of year, vaccination, geographic location, sex, neuter status, and breed.

Animals

Sixty SRMA cases and 180 controls, all ≤24 months of age and matched for year of presentation, from a referral hospital population in the United Kingdom.

Methods

Retrospective case‐control study with unconditional logistic regression analysis.

Results

Beagles (P = .001), Border Collies (P = .001), Boxers (P = .032), Jack Russell Terriers (P = .001), Weimaraners (P = .048), and Whippets (P < .001) had significantly greater odds of developing SRMA in this population of dogs. Vaccination, time of year, geographic category, sex, and neuter status did not increase the odds of developing SRMA.

Conclusions and Clinical Importance

Only breed increased the odds of developing SRMA. It would be prudent to investigate the genetics of the identified breeds to help elucidate the etiopathogenesis of SRMA.     

Immunohistochemical Expression of Potential Therapeutic Targets in Canine Thyroid Carcinoma

Background

Thyroid carcinoma is a common endocrine tumor in the dog. Local invasive growth frequently precludes surgical excision and, in up to 38% of dogs, the tumor has already metastasized by the time of diagnosis. Therefore, it is important to investigate new treatment modalities that may be useful for the large number of dogs with inoperable tumors or metastatic disease.

Hypothesis/Objectives

To investigate the immunohistochemical expression of potential therapeutic targets in canine thyroid tumors.

Animals

74 dogs with thyroid neoplasia.

Methods

Immunohistochemistry was performed for thyroglobulin, calcitonin, vascular endothelial growth factor (VEGF), p53, cycloxygenase‐2 (cox‐2), and P‐glycoprotein (P‐gp).

Results

Fifty‐four (73%) tumors were classified as follicular cell thyroid carcinomas (FTCs) and 20 (27%) as medullary thyroid carcinomas (MTCs). Eighty percent of FTCs and all MTCs had a high percentage (76–100%) of neoplastic cells immunopositive for VEGF. Thirteen percent of FTCs and 50% of MTCs expressed cox‐2. Seven percent of FTCs and 70% of MTCs expressed P‐gp. No tumor was immunopositive for p53 expression. Expression of VEGF (P = .034), cox‐2 (P = .013), and P‐gp (P < .001) was significantly higher in MTCs compared to FTCs.

Conclusions and Clinical Importance

VEGF is a potential therapeutic target in both FTC and MTC in dogs. Cox‐2 and P‐gp may be useful molecular targets in canine MTC.     

Prognostic Value of Left Atrial Function in Dogs with Chronic Mitral Valvular Heart Disease

Background

A strong correlation between left atrial (LA) dysfunction and the severity of cardiac disease has been described in human patients with various cardiac diseases. The role of LA dysfunction in dogs with chronic mitral valvular heart disease (CMVHD) has not been addressed.

Objectives

To investigate the correlation between LA function and the prognosis of dogs with CMVHD.

Animals

Thirty‐eight client‐owned dogs with CMVHD.

Methods

Prospective clinical cohort study. Dogs were divided into 2 groups (survivors and nonsurvivors) based on the onset of cardiac‐related death within 1 year. Physical examination and echocardiographic variables were compared between the groups. For the assessment of the comparative accuracy in identifying patients with cardiac‐related death, receiver operating characteristic (ROC) curves and multivariate logistic analysis were used.

Results

The highest accuracy was obtained for the LA active fractional area change (LA‐FAC _act), with an area under the ROC curve (AUC) of 0.95, followed by the left atrial to aortic root ratio (LA/Ao), with an AUC of 0.94; peak early diastolic mitral inflow velocity (E), with an AUC of 0.85; and LA total fractional area change (LA‐FAC _total), with an AUC of 0.85. In the multivariate logistic regression analysis, LA‐FAC _act emerged as the only independent correlate of cardiac‐related death within 1 year (odds ratio = 1.401, P = .002).

Conclusions and Clinical Importance

Regarding both the size and function, the LA has a strong correlation with the prognosis of dogs with CMVHD. The most significant independent predictor of mortality in this study was LA‐FAC _act.     

Short‐ and Long‐Term Cure Rates of Short‐Duration Trimethoprim‐Sulfamethoxazole Treatment in Female Dogs with Uncomplicated Bacterial Cystitis

Background

Long‐duration beta‐lactam antibiotics are used for empirical treatment in female dogs with uncomplicated bacterial cystitis. However, women with bacterial cystitis are treated with short‐duration potentiated sulfonamides because longer courses of beta‐lactams result in lower cure and higher recurrence rates.

Hypothesis/Objectives

Short‐duration potentiated sulfonamide treatment is more efficacious than long‐duration beta‐lactam treatment in achieving clinical and microbiological cures in female dogs with uncomplicated bacterial cystitis.

Animals

Thirty‐eight client‐owned female dogs.

Methods

Randomized, double‐blinded, placebo‐controlled clinical trial. Dogs were treated with TMP‐SMX (15 mg/kg PO q12h for 3 days followed by a placebo capsule PO q12h for 7 days; Group SDS; n = 20) or cephalexin (20 mg/kg PO q12h for 10 days; Group LDBL; n = 18). Dogs were monitored for clinical and microbiological cure during treatment and at short‐ and long‐term follow‐up.

Results

No statistically significant differences were found between treatment groups in clinical cure rates after 3 days of treatment (89% SDS, 94% LDBL; P = 1.00) and 4 days (85% SDS, 72% LDBL; P = .44) or >30 days (50% SDS, 65% LDBL; P = .50) after conclusion of treatment or in microbiological cure rates 4 days (59% SDS, 36% LDBL; P = .44) or >30 days (44% SDS, 20% LDBL; P = .40) after conclusion of treatment.

Conclusions and Clinical Importance

We did not identify a difference in cure rates between short‐duration sulfonamide and long‐duration beta‐lactam treatments in female dogs with uncomplicated cystitis. Long‐term cure rates in both treatment groups were low. In some female dogs, “uncomplicated” bacterial cystitis may be more complicated than previously recognized.     

Comparative Analysis of mRNA Expression of Surface Antigens between Histiocytic and Nonhistiocytic Sarcoma in Dogs

Background

Definitive diagnosis of histiocytic sarcoma (HS) in dogs is relatively difficult by conventional histopathological examination because objective features of HS are not well defined.

Hypothesis

Quantitative analysis of mRNA expression of selected cellular surface antigens (SAs) specific to HS in dogs can facilitate objective and rapid diagnosis.

Animals

Dogs with HS (n = 30) and dogs without HS (n = 36), including those with other forms of lymphoma (n = 4), inflammatory diseases (n = 6), and other malignant neoplasias (n = 26).

Methods

Retrospective clinical observational study. Specimens were collected by excisional biopsy, needle core biopsy, or fine needle aspiration. To determine HS detection efficacy, mRNA expression levels of selected SAs specific to HS in dogs, including MHC class IIα, CD11b, CD11c, and CD86, were quantitatively analyzed using real‐time quantitative polymerase chain reaction.

Results

Each SA mRNA expression level was significantly higher in HS dogs than in non‐HS dogs (P = .0082). Cutoff values for discriminating between HS and non‐HS dogs based on these expression levels were calculated on the basis of receiver‐operating characteristic analysis. Accuracy of the cutoff values, including MHC class IIα, CD11b, CD11c, and CD86, was 87.9, 86.4, 86.4, and 84.8%, respectively.

Conclusions and Clinical Importance

Our results suggest that quantitative analysis of mRNA expression of the selected SAs could be an adjunctive diagnostic technique with high diagnostic accuracy for HS in dogs. Substantial investigation is required for exclusion of diseases with similar cell types of origin to lymphoma.     

Tumor Necrosis Factor‐α and Interleukin‐6 Concentrations in Cerebrospinal Fluid of Dogs After Seizures

Background

Idiopathic and acquired epilepsy are common in dogs. Up to 30% of these dogs are refractory to pharmacological treatment. Accumulating experimental evidence indicates that brain immune response and presence of inflammatory mediators decrease the threshold for individual seizures and contribute to epileptogenesis.

Hypothesis

Dogs with seizures have higher cerebrospinal interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNF‐α) concentrations compared to dogs with no seizures.

Methods

A prospective double blinded study; cerebrospinal fluid (CSF) and serum IL‐6, TNF‐α and total protein (TP) concentrations were measured by a blinded investigator for the study group and CSF IL‐6 and TNF‐α levels and TP concentrations were measured in the control group (CG).

Animals

Dogs presented with seizures that had enough CSF collected to allow analysis were included in the study group. Twelve apparently healthy, quarantined, stray dogs served as control (CG).

Results

Cerebrospinal fluid TNF‐α and IL‐6 concentrations were significantly higher (P = .011, P = .039) in dogs with seizures (0 ± 70.66, 0.65 ± 10.93 pg/mL) compared to the CG (0 ± 19, 0.73 ± 0.55 pg/mL). When assessing cytokine concentrations of specifically the idiopathic epilepsy (IE) dogs compared to the CG, only TNF‐α concentrations (8.66 ± 62, 0 ± 19 pg/mL) were significantly higher (P = .01). CSF TP concentrations were not significantly higher in the study dogs compared to the CG.

Conclusions and Clinical Importance

Higher TNF‐α and IL‐6 concentration in the CSF of dogs with naturally occurring seizures. The higher supports the hypothesis that inflammatory processes through certain mediators play a role in the pathogenesis of seizures in dogs.     

Wireless Ambulatory Esophageal pH Monitoring in Dogs with Clinical Signs Interpreted as Gastroesophageal Reflux

Background

Although gastroesophageal reflux (GER) often is assumed to be causative for upper gastrointestinal and respiratory signs in dogs, no attempts have been made to verify this assumption.

Objectives

To monitor esophageal pH with the Bravo pH system in healthy dogs and client‐owned dogs displaying signs commonly attributed to GER.

Animals

Seven healthy and 22 client‐owned dogs.

Methods

After routine esophagogastroduodenoscopy, radiotelemetric pH capsules were placed in distal esophagus for continuous pH recording. Reflux was defined as single pH measurement <4. At discharge, owners were instructed to press individually predefined clinical sign‐buttons on the receiver whenever indicated. Results between groups were compared using Mann–Whitney U‐test.

Results

The median (range) number of refluxes in client‐owned and healthy dogs, respectively, was 17 (1–205) and 10 (1–65), the number of refluxes >5 minutes in duration was 1 (0–14), and 1 (0–4), duration of longest reflux (min) was 10 (0–65) and 8 (0–27), and fractional time pH <4 (%) was 0.76% (0.01–6.28), and 0.3% (0–3.1). No differences were found between groups. The median of 7 (1–35) clinical sign‐button pushes were recorded in 21 dogs. Median of 12.5% (2.8% [1/35]–50% [2/4]) reflux‐positive clinical sign‐button pushes was found in 10 dogs with reflux‐positive pushes. Five (22.7%) dogs had increased esophageal acid exposure, and mild esophagitis was noted in 1 dog.

Conclusion and Clinical Importance

Despite evidence of increased GER in some dogs, the clinical sign‐reflux association remained poor. Future investigation should focus on dogs with esophagitis.     

Serum Adipokine Concentrations in Dogs with Naturally Occurring Pituitary‐Dependent Hyperadrenocorticism

Background

An excess of intra‐abdominal fat is observed frequently in dogs with hyperadrenocorticism (HAC). Adipokine dysregulation is a possible cause of complications related to visceral obesity, but little information is available on adipokine in dogs with naturally occurring HAC.

Objectives

To examine the differences in the circulating adipokines concentrations in overweight dogs with and without pituitary‐dependent HAC (PDH).

Animals

Thirty healthy dogs and 15 client‐owned dogs with PDH.

Methods

Case–controlled observational study, which enrolled 15 overweight dogs diagnosed with PDH and 30 otherwise healthy dogs of similar body condition score. Nine of 15 dogs with PDH were treated with low‐dose trilostane twice daily and reassessed after treatment.

Results

The serum leptin (P < .0001) and insulin (P < .0001) concentrations were significantly higher in the PDH group (leptin, 22.8 ± 8.8 [mean ± SD]; insulin, 9.1 ± 6.1) than the healthy group (leptin, 4.9 ± 3.7; insulin, 1.9 ± 0.9). However, there were no significant differences in the adiponectin, resistin, tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, IL‐10, and IL‐18 levels between the 2 groups. In the PDH group, the serum cortisol concentrations had a linear association with the leptin concentrations, and there were significant decreases in the leptin (P = .0039) and insulin (P = .0039) levels after trilostane treatment. However, the leptin and insulin levels remained higher after trilostane treatment than in healthy control dogs with similar body condition score.

Conclusions and Clinical Importance

Hypercortisolemia in dogs with PDH might upregulate the circulating leptin levels. However, a large population‐based study will be necessary to determine whether the upregulation of leptin is involved directly with the complications caused by HAC.     

Phase II Evaluation of VDC‐1101 in Canine Cutaneous T‐Cell Lymphoma

Background

Canine cutaneous T‐cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies are lacking. The novel anticancer nucleotide prodrug VDC‐1101 (formerly known as GS‐9219) has shown efficacy in dogs with multicentric lymphoma. One of the observed adverse effects with this drug was a skin change characterized by hair loss, erythema, and pruritus, implying delivery of VDC‐1101 to the skin.

Hypothesis/Objectives

The primary study objective was to identify the objective response rate (ORR) to VDC‐1101 in canine CTCL; secondary objectives included characterization of progression‐free survival (PFS) and adverse events (AEs).

Animals

Twelve dogs with chemotherapy‐naïve or relapsed, histologically and immunohistochemically confirmed CTCL.

Methods

Dogs received VDC‐1101 as a 30‐minute IV infusion once every 21 days. Prednisone (1 mg/kg PO q48h) was administered concurrently.

Results

In 11 evaluable patients, responses included 1 complete response (CR), 4 partial responses (PR), 2 stable disease (SD), and 4 progressive disease for an ORR of 45% and biologic response rate (CR/PR/SD) of 64%. The median PFS was 37.5 days (26 to >399 days), which includes 1 durable and ongoing CR (>1 year). Gastrointestinal and hematologic AEs were mild; no dogs developed grade 3 or 4 AEs. Three dogs developed dermatopathies and 1 of these dogs was removed from the study as a result of this AE.

Conclusions and Clinical Importance

VDC‐1101 has activity against canine CTCL and could provide another treatment option in a disease process with a poor prognosis.     

Effect of Trilostane on Hormone and Serum Electrolyte Concentrations in Dogs with Pituitary‐Dependent Hyperadrenocorticism

Background

The effects of trilostane on key hormones and electrolytes over 24 hours in dogs with pituitary‐dependent hyperadrenocorticism (PDH) are unknown.

Objectives

To determine the plasma concentration of cortisol, endogenous adrenocorticotropic hormone (ACTH), aldosterone, sodium, potassium, and ionized calcium concentrations, and plasma renin activity over a 24‐hour period after administration of trilostane to dogs with well‐controlled PDH.

Animals

Nine dogs (mean age 9.3 ± 0.67 years, mean weight 31.9 ± 6.4 kg) with confirmed PDH.

Methods

Prospective study. Thirty days after the first administration of trilostane, blood samples were taken at −30, 0 (baseline), 15, 30, 60, and 90 minutes, and 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after administration of trilostane and plasma concentration of cortisol, endogenous ACTH, aldosterone, sodium, potassium, ionized calcium, and renin activity were determined.

Results

Cortisol concentrations decreased significantly (P < .001) 2–4 hours after trilostane administration. From baseline, there was a significant (P < .001) increase in endogenous ACTH concentrations between hours 3–12, a significant increase (P < .001) in aldosterone concentration between hours 16–20, and a significant (P < .001) increase in renin activity between hours 6–20. Potassium concentration decreased significantly (P < .05) between hours 0.5–2.

Conclusion and Clinical Importance

Treatment with trilostane did not cause clinically relevant alterations in plasma aldosterone and potassium concentration. Results suggest that in dogs with PDH, the optimal time point for an ACTH‐stimulation test to be performed is 2–4 hours after trilostane dosing. Future studies are necessary to establish interpretation criteria for a 2‐ to 4‐hour postpill ACTH‐stimulation test.     

Bioequivalence of Orally Administered Generic,Compounded, and Innovator‐Formulated Itraconazole in Healthy Dogs

Background

Itraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost.

Objective

To determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs.

Animals

Nine healthy, adult research Beagle dogs.

Methods

A randomized, 3‐way, 3‐period, crossover design with an 8‐day washout period. After a 12‐hour fast, each dog received 100 mg (average: 10.5 mg/kg) of either innovator itraconazole, an approved human generic capsule, or compounded itraconazole (compounded using a commercially available compounding vehicle) with a small meal. Plasma was collected at predetermined intervals for high pressure liquid chromatography analysis. Concentration data were analyzed using noncompartmental pharmacokinetics to determine area under the curve (AUC), peak concentration (C_MAX), and terminal half‐life. Bioequivalence tests compared generic and compounded itraconazole to the reference formulation.

Results

Average ratios of compounded and generic formulations to the reference formulation of itraconazole for AUC were 5.52% and 104.2%, respectively, and for C_MAX were 4.14% and 86.34%, respectively. A test of bioequivalence using 2 one‐sided tests and 90% confidence intervals did not meet bioequivalence criteria for either formulation.

Conclusion and Clinical Importance

Neither generic nor compounded itraconazole is bioequivalent to the reference formulation in dogs. However, pharmacokinetic data for generic formulation were similar enough that therapeutic concentrations could be achieved. Compounded itraconazole produced such low plasma concentrations, it is unlikely to be effective; therefore, compounded itraconazole should not be used in dogs.     

Phenotypic Characterization of Canine Intestinal Intraepithelial Lymphocytes in Dogs with Inflammatory Bowel Disease

Background

Many dogs suffering from inflammatory bowel disease (IBD) are presented to veterinary clinics. These patients are diagnosed based on a history of chronic gastrointestinal signs and biopsy‐confirmed histopathologic intestinal inflammation. Intestinal intraepithelial lymphocytes (IEL) are part of the first line of defense in the gastrointestinal immune system. Alterations in IEL subsets may play a role in the pathogenesis of IBD.

Hypothesis

The aim of this study was to characterize the phenotypes of IEL in dogs with IBD compared with healthy control dogs.

Animals

Intestinal intraepithelial lymphocytes subpopulations of control dogs (n = 5) obtained from endoscopic biopsies (EB) were compared to those obtained from full thickness biopsies (FTB) on the same day. In addition, the phenotypes of IEL from FTB of control dogs (n = 10) were compared with EB of IBD dogs (n = 10). Each participant was scored clinically using the canine inflammatory bowel disease activity index (CIBDAI), and all samples were graded histopathologically. Three‐color flow cytometry of isolated IEL was performed using monoclonal antibodies against T‐ and B‐lymphocyte subpopulations.

Results

No significant differences in the composition of IEL subpopulations were found in control dogs based on method of biopsy. The IBD dogs had significantly higher CIBDAI and histopathologic scores compared with control dogs and their IEL contained a significantly higher frequency TCRγδ T‐cells.

Conclusions and Clinical Importance

Endoscopic biopsies provide suitable samples for 3‐color flow cytometry when studying canine intestinal IEL and IBD patients show significant changes of major T‐cell subsets compared to healthy control dogs.     

Simpson's Method of Discs for Measurement of Echocardiographic End‐Diastolic and End‐Systolic Left Ventricular Volumes: Breed‐Specific Reference Ranges in Boxer Dogs

Background

Boxer dogs are predisposed to congenital and adult onset cardiac diseases. Breed‐specific reference values for M‐mode and Doppler echocardiographic measurements previously have been established. Left ventricular (LV) end‐systolic (ESV) and end‐diastolic volumes (EDV) can be measured by M‐mode or two‐dimensional methods, such as Simpson''s method of discs (SMOD). Reference ranges for SMOD‐derived LV volumes are lacking.

Objectives

To determine reference intervals for EDV and ESV in Boxer dogs.

Animals

Previously collected data from 85 healthy Boxers (37 males and 48 females) were used for analysis.

Methods

Simpson''s method of discs‐derived EDV and ESV were measured using offline analysis by 1 observer, in both the right parasternal and the left apical views. Measurements were compared between both views and between male and female dogs using a t‐test. Reference intervals were established using the mean + 2 × SD.

Results

Measurements obtained from both views showed good agreement, and mean EDVI and ESVI, indexed to body surface area (BSA), were calculated. Reference intervals were 49–93 mL/m² for EDVI, and 22–50 mL/m² for ESVI. EDV and ESV were significantly higher in males compared with females, when indexing to BSA, but not when indexing to body weight.

Conclusion and Clinical Importance

The upper limit for ESVI exceeds the previously suggested cut‐off of 30 mL/m² for detection of systolic dysfunction. The reference intervals generated in this study should be useful clinically in the assessment of LV size and function in Boxer dogs.     

N‐Terminal Pro‐C‐Natriuretic Peptide and Cytokine Kinetics in Dogs with Endotoxemia

Background

Serum N‐terminal pro‐C‐natriuretic peptide (NT‐proCNP) concentration at hospital admission has sufficient sensitivity and specificity to differentiate naturally occurring sepsis from nonseptic systemic inflammatory response syndrome (SIRS). However, little is known about serum NT‐proCNP concentrations in dogs during the course of sepsis.

Objective

To determine serum NT‐proCNP and cytokine kinetics in dogs with endotoxemia, a model of canine sepsis.

Samples

Eighty canine serum samples.

Methods

Eight healthy adult Beagles were randomized to receive Escherichia coli lipopolysaccharide (LPS, 5 μg/kg) or placebo (0.9% NaCl) as a single IV dose in a randomized crossover study. Serum collected at 0, 1, 2, 4, and 24 hours was stored at −80°C for batch analysis. Serum NT‐proCNP was measured by ELISA and 13 cytokines and chemokines by multiplex magnetic bead‐based assay.

Results

Serum NT‐proCNP concentrations did not differ significantly between LPS‐ and placebo‐treated dogs at any time. When comparing serum cytokine concentrations, LPS‐treated dogs had higher interleukin‐6 (IL‐6), IL‐10, TNF‐α and KC‐like at 1, 2, and 4 hours; higher CCL2 at 1, 2, 4, and 24 hours; and higher IL‐8 and CXCL10 at 4 hours compared to placebo‐treated dogs. There were no differences in serum GM‐CSF, IFN‐γ, IL‐2, IL‐7, IL‐15 or IL‐18 between LPS‐ and placebo‐treated dogs.

Conclusions and Clinical Importance

Serum NT‐proCNP concentration does not change significantly in response to LPS administration in healthy dogs. Certain serum cytokine and chemokine concentrations are significantly increased within 1–4 hours after LPS administration and warrant further investigation as tools for the detection and management of sepsis in dogs.     

Clinical Features and Treatment Outcomes of 41 Dogs with Sublingual Ectopic Thyroid Neoplasia

Background

Thyroid neoplasia is common in dogs, but there are few reports of dogs with ectopic, sublingual thyroid tumors.

Objectives

To describe clinical features and outcomes of dogs with ectopic, sublingual thyroid neoplasia.

Animals

Five hundred and forty‐four dogs with thyroid neoplasia.

Methods

This retrospective study reviewed the medical records of dogs referred for thyroid neoplasia between 1995 and 2013. Data extracted included signalment, extent of thyroid disease (eutopic or ectopic; metastasis), serum thyroxine (T₄) concentration, treatment, and survival.

Results

Of 544 dogs with thyroid neoplasia, 41 (7.5%) dogs had ectopic sublingual thyroid tumors. The clinical features of these 41 dogs were similar to the cohort group of 503 dogs with eutopic or ectopic mediastinal thyroid tumors, but dogs with sublingual tumors were younger and less likely to have metastatic disease (15% versus 30%, P < .05). Of the 41 dogs, 28 received treatment: 21 with surgery (which included partial hyoidectomy in 13), 7 with radioiodine alone, and 13 with surgery followed by administration of radioiodine. Overall median survival was 562 days (range, 1‐1,850 days).

Conclusions and Clinical Importance

When compared with eutopic thyroid carcinomas, ectopic sublingual thyroid tumors generally have a less aggressive biologic behavior. Many dogs have prolonged survival, even without treatment, although death because of local tumor invasiveness or metastasis can develop in some dogs. Surgical thyroidectomy, including partial hyoidectomy, is generally effective for control of local disease. Administration of radioiodine, alone or in combination with surgical treatment, is recommended for multifocal disease or metastasis.