The Intravenous Xylitol Tolerance Test in Non-Lactating Cattle

Xylitol is a five-carbon sugar alcohol that is often used for treatment of ketosis in dairy cattle in Japan. An intravenous xylitol tolerance test (IVXTT, 0.1 g/kg, bolus injection through the jugular vein) was performed in 4 non-lactating cows (n = 4) and the results were compared with those of an intravenous glucose tolerance test (IVGTT) performed under equivalent conditions. The serum xylitol concentration reached a peak value (41.4±9.0 mg/dl) at 5 min, and then rapidly decreased and almost disappeared within 2 h. The C ₀ for xylitol was 56.9±16.6 mg/dl and the t _1/2was 8.5±0.9 min. The administration of xylitol appeared to cause similar secretion of insulin to that caused by glucose. There was also a reduction in the concentration of free fatty acids. It seems that xylitol has value for the treatment of ketosis. However, rapid administration of xylitol appeared to have an osmotic diuretic action and might be a cause of dehydration.     

Xylitol

Xylitol is a prevalent sugar substitute found in a wide variety of foods, particularly those labeled as “low carb.” It is found in many medicines and dental products both for its antibacterial activity and to increase palatability. Originally, this toxin was recognized as a problem in dogs following sugarless gum ingestions. Xylitol is generally nontoxic to mammals except for dogs. In the dog, xylitol induces marked increases in insulin production and occasionally hepatopathy. The clinical syndrome is manifested with signs consistent with profound hypoglycemia, hypokalemia, hypophosphatemia, and acute hepatic failure. Treatment relies upon administration of intravenous glucose, hepatic support, and general supportive care.     

Experimental acute toxicity of xylitol in dogs

The Cases of xylitol poisoning in dogs are increasing as a result of ingestion of xylitol-containing products. Eighteen adult, clinically normal Pekingese dogs were orally dosed with 1 or 4 g/kg xylitol in aqueous solution. Blood samples were collected before and after dosing. Plasma insulin concentrations of both treated groups rose sharply from 20 min after xylitol dosing, peaking at 40 min. Hypoglycemia followed the increase in insulin concentration, with blood glucose values started to decrease 30 min after dosing. Other plasma biochemistry changes associated with xylitol administration were increased alanine aminotransferase and aspartate aminotransferase activities, hypophosphatemia, hypokalemia, and hypercalcemia. Plasma sodium and chloride concentrations remained normal. This study established a biochemical basis for diagnosis and treatment of xylitol poisoning in dogs.     

Effects of supplementation of chromium histidinate on glucose,lipid metabolism and oxidative stress in cats

In recent years, two meta‐analyses of chromium (Cr) supplementation have shown beneficial effects on glucose metabolism. Chromium histidinate (CrHis) reduces serum glucose levels in rats fed a high‐fat diet but no study has been conducted on cats until now. The aim of this study was to examine the effects of CrHis on glucose and lipid metabolism in cats. To challenge the glucose metabolism, 16 cats were fed a high‐carbohydrate high‐fat diet for three months. One group (n = 8) received 800 ug CrHis per day for two months, while the other group (n = 8) served as control group. An oral glucose tolerance test was conducted, blood samples were taken, and biochemical parameters and oxidative stress were measured. CrHis serum levels were significantly increased (p = 0.027) in the treatment group, while fructosamine levels were significantly lower (p = 0.029) in the control group. In both groups, glucose (p < 0.01), b‐hydroxy‐butyrate (p = 0.024) and 8‐hydroxy‐deoxyguanosine (p = 0.028) levels decreased significantly and cholesterol levels increased significantly (p < 0.01). In conclusion, CrHis did not improve glucose or lipid metabolism and did not affect oxidative stress in healthy cats.     

Clinical pharmacokinetics and outcomes of oral fluconazole therapy in dogs and cats with naturally occurring fungal disease

This multi-institutional study was designed to determine the clinical pharmacokinetics of fluconazole and outcomes in client-owned dogs (n = 37) and cats (n = 35) with fungal disease. Fluconazole serum concentrations were measured. Pharmacokinetic analysis was limited to animals at steady state (≥72 hr of treatment). The mean (range) body weight in 31 dogs was 25.6 (2.8–58.2) kg and in 31 cats was 3.9 (2.4–6.1) kg included in pharmacokinetic analyses. The dose, average steady-state serum concentrations (C_SS), and oral clearance in dogs were 14.2 (4.5–21.3) mg/kg/d, 26.8 (3.8–61.5) µg/mL, and 0.63 ml min⁻¹ kg⁻¹, respectively, and in cats were 18.6 (8.2–40.0) mg/kg/d, 32.1 (1.9–103.5) µg/mL, and 0.61 ml min⁻¹ kg⁻¹, respectively. Random inter-animal pharmacokinetic variability was high in both species. Two dogs had near twofold increases in serum fluconazole when generic formulations were changed, suggesting lack of bioequivalence. Median C_SS for dogs and cats achieving clinical remission was 19.4 and 35.8 µg/ml, respectively. Starting oral doses of 10 mg/kg q12h in dogs and 50–100 mg total daily dose in cats are recommended to achieve median C_SS associated with clinical remission. Due to the large pharmacokinetic variability, individualized dose adjustments based on C_SS (therapeutic drug monitoring) and treatment failure should be considered.     

Influence of type of starch and feeding management on glycaemic control in diabetic dogs

The present study evaluated the effects of two diets with different starch sources and two feeding methods on the glycaemic control in dogs with diabetes mellitus. The diets had similar nutrient contents (40% starch and 16% dietary fibre), one formulated with 46% of broken rice and the other with 42% sorghum and 10% lentils (as-fed). Ten client-owned diabetic dogs were fed with each diet for 2 months, in a crossover design. Five dogs received NPH human insulin and food every 12 h (feeding method 1), and the other five received insulin every 12 h but were fed three times a day (feeding method 2). In feeding method 2, morning insulin was higher than the evening dose and dogs received the second meal after 4 to 5 h of the morning insulin and meal. Parameters evaluated included insulin dosage, 12- and 8-h glycaemic curves, complete blood count, biochemical profile and urinalysis. Glycaemic curves were analysed by ANOVA with repeated measures. Glycaemic control parameters (fasting, mean, minimum and maximum glycaemia and serum fructosamine) and glucose area under the curve (AUC) were calculated and analysed by paired t test (p < 0.05). In feeding method 1, dogs fed the sorghum-based diet presented lower mean (p = 0.04) and minimum blood glucose concentrations (p = 0.03), and a tendency to lower maximum blood glucose (p = 0.06) and glucose AUC (p = 0.08) than when fed the rice-based diet. When food was provided twice a day, the ingestion of the rice-based diet resulted in higher post-prandial glucose response than the diet with sorghum and lentil. In feeding method 2, there was no effect of diet on the assessed parameters (p > 0.05). No differences in insulin dosage were observed between groups or feeding methods (p > 0.05). Providing two meals a day followed by insulin administration associated with the sorghum- and lentil-based diet improved glycaemic control in diabetic dogs.     

Use of the gonadotropin‐releasing hormone (GnRH) stimulation test to monitor gonadal function in intact adult male cats

The gonadotropin‐releasing hormone (GnRH) stimulation test is a common procedure used to investigate normality of the pituitary‐gonadal axis in mammals. There is very little information on the technique, its efficacy and side effects in small animals and in particular no information for male cats. In dogs, such test is performed by intravenous (IV) administration. With cats, the number of times the animal needs to be restrained for blood sampling should be the least possible. The purpose of this study was to assess efficacy and side effects of the GnRH stimulation test in tomcats comparing the IV with the intramuscular (IM) route of administration. A GnRH stimulation test was performed in eight adult tomcats through IM or IV administration of 50 μg gonadorelin. The response of the pituitary‐gonadal axis was assessed by measuring serum testosterone on blood samples collected prior to and 1 hr following treatment. When considering each single group of cats, the post‐stimulation serum testosterone values were significantly higher than the pre‐treatment ones (p < .05). When comparing the two groups of cats, basal testosterone concentrations did not differ, and also post‐GnRH testosterone concentrations did not differ. In conclusion, in the cats of our study, the GnRH stimulation test produced the same results following the IM or the IV route of administration. Therefore, in tomcats, the IM route can be considered as effective as the IV one and should be preferred when doing a GnRH test.     

Pharmacokinetics of single doses of maropitant citrate in adult horses

The neurokinin‐1 (NK) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood and likely under‐recognized in horses. Use of NK‐1 receptor antagonists in horses has not been reported. The purpose of this study was to determine the pharmacokinetic profile of maropitant in seven adult horses after single intravenous (IV; 1 mg/kg) and intragastric (IG; 2 mg/kg) doses. A randomized, crossover design was performed. Serial blood samples were collected after dosing; maropitant concentrations were measured using LC‐MS/MS. Pharmacokinetic parameters were determined using noncompartmental analysis. The mean plasma maropitant concentration 3 min after IV administration was 800 ± 140 ng/ml, elimination half‐life was 10.37 ± 2.07 h, and volume of distribution was 6.54 ± 1.84 L/kg. The maximum concentration following IG administration was 80 ± 40 ng/ml, and elimination half‐life was 9.64 ± 1.27 hr. Oral bioavailability was variable at 13.3 ± 5.3%. Maropitant concentrations achieved after IG administration were comparable to those in small animals. Concentrations after IV administration were lower than in dogs and cats. Elimination half‐life was longer than in dogs and shorter than in cats. This study is the basis for further investigations into using maropitant in horses.     

Pharmacokinetics of the novel COX‐2 selective inhibitor vitacoxib in cats: The effects of feeding and dose

The purpose of this study was to determine the pharmacokinetics and dose‐scaling model of vitacoxib in either fed or fasted cats following either oral or intravenous administration. The concentration of the drug was quantified by UPLC‐MS/MS on plasma samples. Relevant parameters were described using noncompartmental analysis (WinNonlin 6.4 software). Vitacoxib is relatively slowly absorbed and eliminated after oral administration (2 mg/kg body weight), with a T_max of approximately 4.7 hr. The feeding state of the cat was a statistically significant covariate for both area under the concentration versus time curve (AUC) and mean absorption time (MAT_fed). The absolute bioavailability (F) of vitacoxib (2 mg/kg body weight) after oral administration (fed) was 72.5%, which is higher than that in fasted cats (F = 50.6%). Following intravenous administration (2 mg/kg body weight), Vd (ml/kg) was 1,264.34 ± 343.63 ml/kg and Cl (ml kg^?1 hr^?1) was 95.22 ± 23.53 ml kg^?1 hr^?1. Plasma concentrations scaled linearly with dose, with C_max (ng/ml) of 352.30 ± 63.42, 750.26 ± 435.54, and 936.97 ± 231.27 ng/ml after doses of 1, 2, and 4 mg/kg body weight, respectively. No significant undesirable behavioral effects were noted throughout the duration of the study.     

Evaluation of the safety of daily administration of capromorelin in cats

Capromorelin is a ghrelin receptor agonist that is FDA approved for appetite stimulation in dogs. The objective of this study was to evaluate the safety of daily oral administration of capromorelin to cats over a range of doses and for an extended period. Two randomized, controlled studies were conducted: in Study 1, cats (n = 6 per group) received placebo or capromorelin at a dose of 9, 15, 30 or 60 mg/kg once daily for 14 days; and in Study 2, cats received capromorelin at 6 mg/kg (n = 8) or placebo (n = 4) once daily for 91 days. Cats were evaluated using clinical observations and clinical pathology test results for both studies, with the addition of postmortem examination in Study 1 and measurements of growth hormone and insulin‐like growth factor 1 in Study 2. Abnormal clinical observations were limited to emesis, hypersalivation, lethargy/depression, head shaking and lip smacking, which occurred more frequently in the capromorelin‐treated groups than in the placebo group. There were no clinically relevant differences in clinical pathology test results between the capromorelin and placebo groups in either study.     

Pharmacometabolomics with a combination of PLS-DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles

Repeated administration of meloxicam to cats is often limited by the potential damage to multiple organ systems. Identifying molecules that predict the adverse effects of meloxicam would help to monitor and individualize its administration, maximizing meloxicam's beneficial effects. The objectives of this study were to (a) determine if the repeated administration of meloxicam to cats alters the plasma metabolome and (b) identify plasma metabolites that may serve to monitor during the administration of meloxicam in cats. Purpose bred young adult cats (n = 12) were treated with meloxicam at 0.3 mg/kg or saline subcutaneously once daily for up to 17 days. An untargeted metabolomics approach was applied to plasma samples collected prior to and at designated time points after meloxicam or saline administration. To refine the discovery of biomarkers, the machine-learning algorithms, partial least squares discriminant analysis (PLS-DA) and random forest (RF), were trained and validated using a separate unrelated group of meloxicam- and saline-treated cats (n = 8). A total of 74 metabolites were included in the statistical analysis. Metabolomic analysis shows that the repeated administration of meloxicam alters multiple substances in plasma, including nonvolatile organic acids, aromatic amino acids, monosaccharides, and inorganic compounds as early as four days following administration of meloxicam. Seventeen plasma molecules were able to distinguish meloxicam-treated from saline-treated cats. The metabolomic changes discovered in this study may help to unveil unknown mechanisms of NSAID-induced side effects. In addition, some metabolites could be valuable for individualizing the administration of meloxicam to cats to mitigate adverse effects.     

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.     

Changes in blood profile in sheep receiving raw garlic,garlic oil or monensin

This study aimed to evaluate the effects of supplementing a basal diet (CTR) with raw garlic (GAR) or garlic oil (GAO) on blood profile in sheep. Monensin (MON, 33 mg/kg DM) was used as positive control. Four ruminally fistulated rams were used in three experiments each arranged in a 4 × 4 Latin square design with 28‐day periods. Experiments 1 and 2 differed in the dose of GAR (75 vs. 100 g/kg DM) and GAO (500 vs. 750 mg/kg DM), while experiment 3 was designed to compare the two doses of each additive (GAR and GAO). The animals were fed a basal diet as TMR consisting of 77.83% forage (alfalfa hay and corn silage) and 22.17% concentrate, providing 10.50 MJ/kg DM (metabolizable energy) and 16.5% crude protein to cover maintenance energy and protein requirements. Supplementation of monensin decreased (P < 0.05) β‐hydroxybutyrate (BHB) and non‐esterified fatty acid (NEFA) concentrations in the blood compared with other treatments. There was no significant effect of additives on serum concentration of glucose, total triglycerides, cholesterol, total protein, albumin and blood urea nitrogen (BUN). Although the serum insulin concentration was elevated in sheep receiving MON and GAO (P < 0.01), no change was observed in blood glucose concentration. No significant effect of GAO and GAR was observed in key energy and protein‐related blood metabolites. However, administration of monensin had a positive influence on energy indices. In conclusion, whereas parameters characterizing the energy balance did not show a significant effect of GAR supplementation, a higher insulin concentration in GAO‐treated animals was observed.     

Oral,subcutaneous, and intravenous pharmacokinetics of ondansetron in healthy cats

Ondansetron is a 5‐HT₃ receptor antagonist that is an effective anti‐emetic in cats. The purpose of this study was to evaluate the pharmacokinetics of ondansetron in healthy cats. Six cats with normal complete blood count, serum biochemistry, and urinalysis received 2 mg oral (mean 0.43 mg/kg), subcutaneous (mean 0.4 mg/kg), and intravenous (mean 0.4 mg/kg) ondansetron in a cross‐over manner with a 5‐day wash out. Serum was collected prior to, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18, and 24 h after administration of ondansetron. Ondansetron concentrations were measured using liquid chromatography coupled to tandem mass spectrometry. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Repeated measures anova was used to compare parameters between administration routes. Bioavailability of ondansetron was 32% (oral) and 75% (subcutaneous). Calculated elimination half‐life of ondansetron was 1.84 ± 0.58 h (intravenous), 1.18 ± 0.27 h (oral) and 3.17 ± 0.53 h (subcutaneous). The calculated elimination half‐life of subcutaneous ondansetron was significantly longer (P < 0.05) than oral or intravenous administration. Subcutaneous administration of ondansetron to healthy cats is more bioavailable and results in a more prolonged exposure than oral administration. This information will aid management of emesis in feline patients.     

Nodules and masses are associated with malignant pleural effusion in dogs and cats but many other intrathoracic CT features are poor predictors of the effusion type

Thoracic CT may be used in the workup of patients with pleural effusion. In humans, certain pleural features on CT aid in diagnosing an underlying cause for pleural effusion, whereas this is not well studied in veterinary medicine. This retrospective cross‐sectional analytical study assessed pleural and other intrathoracic abnormalities on CT in dogs and cats with pleural effusion and explored potential discriminatory features between effusion types. Eighty‐nine dogs and 32 cats with pleural cytology and/or histopathology were categorized into malignant pleural disease (15 dogs and 11 cats), pyothorax (34 dogs and 7 cats), chylothorax (20 dogs and 11 cats), transudative (11 dogs and 2 cats), and hemorrhagic effusion (9 dogs and 1 cat). Multivariable logistic regression analysis comparing malignancy to other effusions found that older patient age (dogs: odds ratio 1.28, P = 0.015; cats: odds ratio 1.53, P = 0.005), nodular diaphragmatic pleural thickening (dogs: odds ratio 7.64, P = 0.021; cats: odds ratio 13.67, P = 0.031), costal pleural masses (dogs: odds ratio 21.50, P = 0.018; cats: odds ratio 32.74, P = 0.019), and pulmonary masses (dogs: odds ratio 44.67, P = 0.002; cats: odds ratio 18.26, P = 0.077) were associated with malignancy. In dogs, any costal pleural abnormality (odds ratio 47.55, P = 0.002) and pulmonary masses (odds ratio 10.05, P = 0.004) were associated with malignancy/pyothorax, whereas any costal pleural abnormality (odds ratio 0.14, P = 0.006) and sternal lymphadenopathy (odds ratio 0.22, P = 0.040) were inversely associated with transudates. There were, however, many overlapping abnormalities between effusion types, so further diagnostic testing remains important for diagnosis.     

Glycosylated Hemoglobin Concentration for Assessment of Glycemic Control in Diabetic Cats

Blood glycosylated hemoglobin (GHb) concentration was quantified in 84 healthy cats, 9 cats with stress-induced hyperglycemia, 37 cats with newly diagnosed diabetes mellitus, and 122 diabetic cats treated with insulin or glipizide. Diabetic control was classified as good or poor in insulin-treated or glipizide-treated cats based on review of history, physical examination findings, changes in body weight, and measurement of blood glucose concentrations. Blood GHb concentration was determined using an affinity chromatography assay. Mean blood GHb concentration was similar for healthy normoglycemic cats and cats with transient, stress-induced hyperglycemia, but was significantly (P < .001) higher in untreated diabetic cats when compared with healthy normoglycemic cats. Mean blood GHb concentration was significantly (P < .001) higher in 84 cats with poorly controlled diabetes mellitus when compared with 38 cats in which the disease was well controlled. Mean blood GHb concentration decreased significantly (P < .01) in 6 cats with untreated diabetes mellitus after insulin and dietary treatment. A similar significant (P < .01) decrease in mean blood GHb concentration occurred in 7 cats with poorly controlled diabetes mellitus after diabetic control was improved by an increase in insulin dosage from 1.1 ± 0.9 to 1.4 ± 0.6 U/kg/ 24 h and by feeding a diet containing increased fiber content and in 6 cats with transient diabetes mellitus 8.2 ± 0.6 weeks after discontinuing insulin treatment. There was a significant (P< .01) stress-induced increase in mean fasting blood glucose concentration and mean blood glucose concentration for 12 hours after administration of insulin or glipizide but no change in mean blood GHb concentration in 5 docile diabetic cats 12.2 ± 0.4 weeks after the cats became fractious as a result of frequent hospitalizations and blood samplings. Results of this study suggest that evaluation of blood GHb concentration may be a clinically useful tool for monitoring glycemic control of diabetes in cats.     

The pharmacokinetics of DPH after the administration of a single intravenous or intramuscular dose in healthy dogs

The objective of this study was to determine the pharmacokinetics of diphenhydramine (DPH) in healthy dogs following a single i.v. or i.m. dose. Dogs were randomly allocated in two treatment groups and received DPH at 1 mg/kg, i.v., or 2 mg/kg, i.m. Blood samples were collected serially over 24 h. Plasma concentrations of DPH were determined by high‐performance liquid chromatography, and noncompartmental pharmacokinetic analysis was performed with the commercially available software. Cardio‐respiratory parameters, rectal temperature and effects on behaviour, such as sedation or excitement, were recorded. Diphenhydramine Cl_area, Vd_area and T_1/2 were 20.7 ± 2.9 mL/kg/min, 7.6 ± 0.7 L/kg and 4.2 ± 0.5 h for the i.v. route, respectively, and Cl_area/F, Vd_area/F and T_1/2 20.8 ± 2.7 mL/kg/min, 12.3 ± 1.2 L/kg and 6.8 ± 0.7 h for the i.m. route, respectively. Bioavailability was 88% after i.m. administration. No significant differences were found in physiological parameters between groups or within dogs of the same group, and values remained within normal limits. No adverse effects or changes in mental status were observed after the administration of DPH. Both routes of administration resulted in DPH plasma concentrations which exceeded levels considered therapeutic in humans.     

Pharmacokinetics and pharmacodynamics of suberoylanilide hydroxamic acid in cats

Suberoylanilide hydroxamic acid (SAHA), or vorinostat, is a histone deacetylase inhibitor approved for use as chemotherapy for lymphoma in humans. The goal of this study was to establish pharmacological parameters of SAHA in cats. Our interest in treating cats with SAHA is twofold: as an anticancer chemotherapeutic and as antilatency therapy for feline retroviral infections. Relying solely on data from studies in other animals would be inappropriate as SAHA is partially metabolized by glucuronidation, which is absent in feline metabolism. SAHA was administered to cats intravenously (2 mg/kg) or orally (250 mg/m², ~17 mg/kg) in a cross‐over study design. Clinically, SAHA was well tolerated at these dosages as no abnormalities were noted following administration. The pharmacokinetics of SAHA in cats was found to be similar to that of dogs, but the overall serum drug exposure was much less than that of humans at an equivalent dose. The pharmacodynamic effect of an increase in acetylated histone proteins in blood was detected after both routes of administration. An increased oral dose of 60 mg SAHA/kg administered to one animal resulted in a surprisingly modest increase in peak drug concentration, suggesting possible saturation of absorption kinetics. This study provides a foundation for future studies of the clinical efficacy of SAHA in treating feline disease.     

Repetitive propofol administration in dogs and cats

A bolus of propofol was administered to 10 dogs (6 mg/kg intravenously [IV]) and 10 cats (10 mg/kg IV) on three consecutive days. The occurrence of apnea, heart and respiratory rates, blood pressure, time to movement, and changes in a complete blood count and biochemical profile were recorded. Apnea was not seen in the dogs but was seen in three cats. Slight increases in the number of Heinz bodies were seen in six cats, but the increases were not considered clinically significant. No apparent cumulative adverse effects were seen from a bolus of bisulfite-containing propofol, administered on three consecutive days.