Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder

OBJECTIVE-To evaluate the antitumor activity and toxic effects of deracoxib, a selective cyclooxygenase-2 inhibitor, in dogs with transitional cell carcinoma (TCC) of the urinary bladder. DESIGN-Clinical trial. Animals-26 client-owned dogs with naturally occurring, histologically confirmed, measurableTCC of the urinary bladder. PROCEDURES-Dogs were treated PO with deracoxib at a dosage of 3 mg/kg/d (1.36 mg/lb/d) as a single-agent treatment for TCC. Tumor response was assessed via radiography, abdominal ultrasonography, and ultrasonographic mapping of urinary bladder masses. Toxic effects of deracoxib administration in dogs were assessed through clinical observations and hematologic and biochemical analyses. RESULTS-Of 24 dogs for which tumor response was assessed, 4 (17%) had partial remission, 17 (71%) had stable disease, and 3 (13%) had progressive disease; initial response could not be assessed in 2 of 26 dogs. The median survival time was 323 days. Median time to progressive disease was 133 days. Renal, hepatic, and gastrointestinal abnormalities attributed to deracoxib administration were noted in 4% (1/26), 4% (1/26), and 19% (5/26) of dogs, respectively. CONCLUSIONS AND CLINICAL RELEVANCE-Results indicated that deracoxib was generally well tolerated by dogs and had antitumor activity against TCC.     

Evaluation of cisplatin administered with piroxicam in dogs with transitional cell carcinoma of the urinary bladder

OBJECTIVE: To evaluate the antitumor activity and toxic effects of a conservative dose of cisplatin administered in combination with piroxicam to dogs with transitional cell carcinoma (TCC) of the urinary bladder. DESIGN: Clinical trial (nonrandomized, noncontrolled). ANIMALS: 14 client-owned dogs with histologically confirmed TCC of the urinary bladder. PROCEDURES: Each dog was treated with cisplatin (50 mg/m(2), i.v., q 21 d [reduced to 40 mg/m(2), i.v., q 21 d because of toxic effects]) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h). A CBC, serum biochemical analyses, and urinalysis were performed prior to each cisplatin treatment. Tumor staging (determined from thoracic and abdominal radiographic and urinary bladder ultrasonographic findings) was performed before treatment and at 6-week intervals during treatment. RESULTS: 5 dogs received only 1 dose of cisplatin because of the rapid progression of disease (n = 2) or toxic effects (3). With regard to the neoplastic disease among the other 9 dogs, 1 had partial remission, 5 had stable disease, and 3 had progressive disease after 6 weeks of treatment. Median progression-free interval was 78 days (range, 20 to 112 days). Median survival time was 307 days (range, 29 to 929 days). Moderate to severe renal toxicosis and moderate to severe gastrointestinal toxicosis developed in 5 and 8 dogs, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Because of minimal efficacy and associated renal and gastrointestinal toxicosis, administration of cisplatin (40 to 50 mg/m(2)) with piroxicam cannot be recommended for treatment of dogs with TCC of the urinary bladder.     

Antitumor Activity of Mycobacterial Cell Wall‐DNA Complex (MCC) Against Canine Urinary Bladder Transitional Cell Carcinoma Cells

Introduction:  Mycobacterial cell wall‐DNA complex (MCC) is a bifunctional anticancer agent that induces cancer cell apoptosis and stimulates cytokine synthesis by immune cells. Intravesical MCC is currently being evaluated in humans with high‐grade urinary bladder cancer. Evaluation of MCC in dogs with transitional cell carcinoma (TCC) will allow mechanistic studies in a natural animal model of TCC, and a potentially beneficial therapy for dogs with this cancer. In this study, we have determined the anticancer activity of MCC against canine TCC cells in vitro .
Methods:  Canine TCC cells (K9TCC cell line) were incubated with MCC (0.05–100 μg/ml, 0.5–72 hours). Cellular proliferation was measured by MTT reduction. Cell cycle was analyzed by flow cytometry with propidium iodide. Apoptosis was identified by flow cytometry using anti‐active‐caspase‐3/PE and anti‐cleaved‐PARP/FITC antibodies. Apoptosis‐inducing activity of 100 μg/ml MCC in combination with piroxicam (0.1–1.0 uM) was evaluated.
Results:  MCC inhibited K9TCC cell proliferation in a concentration‐dependent manner (maximal activity – 45% at 100 μg/ml MCC) in association with the presence of activated caspase‐3 and cleaved PARP. Inhibition of proliferation and apoptosis‐inducing activities of MCC were independent of cell cycle phase. A thirty‐minute exposure of MCC was sufficient for optimal activity. Piroxicam (0.5 uM) enhanced apoptosis‐inducing activity of MCC.
Conclusions:  MCC induces apoptosis in K9TCC cells. This activity is potentiated by piroxicam. Following positive results in vitro , in vivo studies have been initiated. One dog, treated to date, has had a minor reduction in tumor volume following the first course of treatment with no treatment‐related toxicity.     

Estimated plasma bupivacaine concentration after single dose and eight-hour continuous intra-articular infusion of bupivacaine in normal dogs

Objective— To estimate maximum plasma concentration (C_max) and time to maximum plasma (t_max) bupivacaine concentration after intra‐articular administration of bupivacaine for single injection (SI) and injection followed by continuous infusion (CI) in normal dogs. Study Design— Cross‐over design with a 2‐week washout period. Animals— Healthy Coon Hound dogs (n=8). Methods— Using gas chromatography/mass spectrometry, canine plasma bupivacaine concentration was measured before and after SI (1.5 mg/kg) and CI (1.5 mg/kg and 0.3 mg/kg/h). Software was used to establish plasma concentration–time curves and estimate C_max, T_max and other pharmacokinetic variables for comparison of SI and CI. Results— Bupivacaine plasma concentration after SI and CI best fit a 3 exponential model. For SI, mean maximum concentration (C_max, 1.33±0.954 μg/mL) occurred at 11.37±4.546 minutes. For CI, mean C_max (1.13±0.509 μg/mL) occurred at 10.37±4.109 minutes. The area under the concentration–time curve was smaller for SI (143.59±118.390 μg/mL × min) than for CI (626.502±423.653 μg/mL × min, P=.02) and half‐life was shorter for SI (61.33±77.706 minutes) than for CI (245.363±104.415 minutes, P=.01). The highest plasma bupivacaine concentration for any dog was 3.2 μg/mL for SI and 2.3 μg/mL for CI. Conclusion— Intra‐articular bupivacaine administration results in delayed absorption from the stifle into the systemic circulation with mean C_max below that considered toxic and no systemic drug accumulation. Clinical Relevance— Intra‐articular bupivacaine can be administered with small risk of reaching toxic plasma concentrations in dogs, though toxic concentrations may be approached. Caution should be exercised with multimodal bupivacaine administration because plasma drug concentration may rise higher than with single intra‐articular injection.     

The Influence of High‐Intensity Moderate Duration Exercise on Cardiac Troponin I and C‐Reactive Protein in Sled Dogs

Background: C‐reactive protein (CRP) and cardiac troponin I (cTnI) are biomarkers of systemic inflammation and cardiac damage, respectively. Objective: To investigate the effects of short‐duration high‐intensity exercise on plasma cTnI and serum CRP concentrations in sprint racing sled dogs. Animals: Twenty‐two Alaskan sled dogs of 2 different teams participating in a 2‐day racing event. Methods: In this prospective field study, cephalic venipuncture was performed on all dogs before racing and immediately after racing on 2 consecutive days. Plasma cTnI and serum CRP concentrations were evaluated at each time point. Results: There was a mild, significant rise (P < .01) in median cTnI concentrations from resting (0.02 ng/mL; 0.0–0.12 ng/mL) on both days after racing (day 1 = 0.06, 0.02–0.2 ng/mL; day 2 = 0.07, 0.02–0.21 ng/mL). Serum CRP concentrations showed a mild significant increase (P < .01) on day 2 after racing mean (9.2 ± 4.6 μg/mL) as compared with resting (6.5 + 4.3 μg/mL) and day 1 after racing (5.0 + 2.9 μg/mL). Neither cTnI or CRP concentrations exceeded the upper reference range for healthy dogs. Conclusions and Clinical Relevance: Strenuous exercise of short duration did not result in cTnI concentrations above the reference range for healthy dogs. Although increased after 2 days of short‐duration strenuous exercise, CRP did not reach concentrations suggestive of inflammation, as reported previously in the endurance sled dogs. Therefore, we surmise that moderate exercise does not present a confounding variable in the interpretation of cTnI and CRP concentrations in normal dogs.     

The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs

Different doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, with or without dexmedetomidine were compared in conscious dogs. Eight animals received either dexmedetomidine (10 μg/kg [D]), MK-467 (250 μg/kg [M250] or dexmedetomidine (10 μg/kg) with increasing doses of MK-467 (250 μg/kg [DM250], 500 μg/kg [DM500] and 750 μg/kg [DM750], respectively). Treatments were given intravenously (i.v.) in a randomized, crossover design with a 14-day washout period. Systemic hemodynamics and arterial blood gas analyses were recorded at baseline and at intervals up to 90 min after drugs administration. Dexmedetomidine alone decreased heart rate, cardiac index and tissue oxygen delivery and increased mean arterial pressure and systemic vascular resistance 5 min after administration. DM250 did not completely prevent these early effects, while DM750 induced a decrease in mean arterial pressure. With DM500, systemic hemodynamics remained stable throughout the observational period. MK-467 alone increased cardiac index and tissue oxygen delivery and had no deleterious adverse effects. No differences in arterial blood gases were observed between treatments that included dexmedetomidine. It was concluded that MK-467 attenuated or prevented dexmedetomidine's systemic hemodynamic effects in a dose-dependent manner when given simultaneously i.v. but had no effect on the pulmonary outcome in conscious dogs. A 50:1 dose ratio (MK-467:dexmedetomidine) induced the least alterations in cardiovascular function.     

Pharmacokinetics of single-dose intravenous levetiracetam administration in normal dogs

Objective: To determine plasma pharmacokinetics of levetiracetam after a single intravenous dose (60 mg/kg) in normal dogs using a high‐performance liquid chromatography assay validated for canine plasma. Design: Pharmacokinetic study. Setting: A university‐based canine research facility. Animals: Six healthy adult dogs. Interventions: Intravenous drug administration, multiple blood sample procurement. Measurements and main results: There were no obvious adverse effects associated with the intravenous (IV) bolus administration of levetiracetam in any of the dogs. Plasma levetiracetam concentrations remained above or within the reported therapeutic range for humans (5–45 μg/mL) for all dogs, for all time periods evaluated. Mean and median (in parentheses) values for pharmacokinetic parameters included the following: maximum plasma concentration, 254 μg/mL (254 μg/mL); half‐life, 4.0 hours (4.0 hours); volume of distribution at steady state, 0.48 L/kg (0.48 L/kg); clearance, 1.4 mL/kg/min (1.5 mL/kg/min); and median residence time, 6.0 hours (6.0 hours). Conclusions: In normal dogs, a 60 mg/kg IV bolus dose of levetiracetam is well tolerated and achieves plasma drug concentrations within or above the therapeutic range reported for humans for at least 8 hours after administration. Based on the favorable pharmacokinetics and tolerability demonstrated for IV levetiracetam in this study, in addition to previously demonstrated efficacy of oral levetiracetam, IV levetiracetam may be a useful treatment option for emergency management of canine seizure activity.     

Pharmacokinetics of cyclophosphamide after oral and intravenous administration to dogs with lymphoma

Background: Cyclophosphamide is an alkylating chemotherapeutic drug administered IV or PO. It is currently assumed that exposure to the active metabolite, 4‐hydroxycyclophosphamide (4‐OHCP), is the same with either route of administration.

Objectives:

To characterize the pharmacokinetics of cyclophosphamide and 4‐OHCP in dogs with lymphoma when administered PO or IV. Animals: Sixteen client‐owned dogs with substage A lymphoma were enrolled in the study. Eight dogs received cyclophosphamide IV and 8 received it PO. Methods: Prospective randomized clinical trial was performed. Blood was collected from each dog at specific time points after administration of cyclophosphamide. The serum was evaluated for the concentration of cyclophosphamide and 4‐OHCP with mass spectrometry and liquid chromatography. Results: Drug exposure to cyclophosphamide measured by area under the curve (AUC)_0–inf is significantly higher after intravenous administration (7.14 ± 3.77 μg/h/mL) compared with exposure after oral administration (P‐value < .05). No difference in drug exposure to 4‐OHCP was detected after IV (1.66 ± 0.36 μg/h/mL) or PO (1.42 ± 0.64 μg/h/mL) administered cyclophosphamide. Conclusions and Clinical Importance: Drug exposure to the active metabolite 4‐OHCP is equivalent after administration of cyclophosphamide either PO or IV.     

Evaluation of cisplatin combined with piroxicam for the treatment of oral malignant melanoma and oral squamous cell carcinoma in dogs

OBJECTIVE: To determine the maximum tolerated dose (MTD) of cisplatin administered with piroxicam, the antitumor activity and toxicity of cisplatin combined with piroxicam in dogs with oral malignant melanoma (OMM) and oral squamous cell carcinoma (SCC), and the effects of piroxicam on the pharmacokinetics of cisplatin in dogs with tumors. DESIGN: Prospective nonrandomized clinical trial. ANIMALS: 25 dogs. PROCEDURE: Dogs were treated with a combination of cisplatin (escalating dose with 6 hours of diuresis with saline [0.9% NaCI] solution) and piroxicam (0.3 mg/kg 10.14 mg/lb], PO, q 24 h).The initial cisplatin dose (50 mg/m2) was increased by 5 mg/m2 until the MTD was reached. Tumor stage and size were determined at 6-week intervals during treatment. The pharmacokinetics of cisplatin were determined in dogs receiving a combination of cisplatin and piroxicam during the clinical trial and dogs that were treated with cisplatin alone. RESULTS: 11 dogs with OMM and 9 dogs with SCC were included in the clinical trial. The MTD of cisplatin when administered in combination with piroxicam was 50 mg/m2. Tumor remission occurred in 5 of 9 dogs with SCC and 2 of 11 dogs with OMM. The most common abnormality observed was renal toxicosis. Clearance of cisplatin in dogs that were treated with cisplatin alone was not significantly different from that in dogs treated with a combination of cisplatin and piroxicam. CONCLUSIONS AND CLINICAL RELEVANCE: Cisplatin administered in combination with piroxicam had antitumor activity against OMM and SCC. The level of toxicity was acceptable, although renal function must be monitored carefully.     

Evaluation of a bladder tumor antigen test as a screening test for transitional cell carcinoma of the lower urinary tract in dogs

OBJECTIVE: To evaluate the veterinary version of the bladder tumor antigen (V-BTA) test as a screening test for transitional cell carcinoma (TCC) of the lower urinary tract of dogs. ANIMALS: 229 client-owned dogs. PROCEDURE: Urine samples from dogs were shipped overnight to a single laboratory to facilitate testing within 48 hours of collection by use of the V-BTA rapid latex agglutination urine dipstick test. Groups of dogs included the following: 1) dogs with TCC of the lower urinary tract, 2) healthy control dogs, 3) unhealthy control dogs with non-TCC urinary tract disease, and 4) unhealthy control dogs without urinary tract disease. Test sensitivity and specificity were calculated by use of standard methods. Logistic models were developed to assess the effect of disease status, test conditions, urine composition, and signalment on the performance of the V-BTA test. RESULTS: A total of 229 urine samples were analyzed, including 48 from dogs with suspected (n = 3) or confirmed (45) TCC. Test sensitivities were 88, 87, and 85% for all dogs with (suspected and confirmed) TCC, dogs with confirmed TCC at any site, and dogs with confirmed TCC of the urinary bladder, respectively. Test specificities were 84, 41, and 86% for healthy control dogs, unhealthy control dogs with non-TCC urinary tract disease, and unhealthy control dogs without urinary tract disease, respectively. The test performed slightly better on centrifuged urine samples than on uncentrifuged urine samples. CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate that the V-BTA test is useful in screening for urinary tract TCC in dogs.     

Susceptibility of bacteria from feline and canine urinary tract infections to doxycycline and tetracycline concentrations attained in urine four hours after oral dosage

OBJECTIVES: To measure urinary concentrations of doxycycline in cats and dogs and tetracycline in dogs 4 h after conventional oral dosing and determine whether these antibiotics were present in sufficient concentrations to be effective against common feline and canine urinary tract pathogens as assessed in vitro by Epsilometer and disc diffusion antimicrobial susceptibility methods. DESIGN: A prospective study involving oral administration to clinically normal cats and dogs of doxycycline or tetracycline (dogs only) and culture of bacteria from dogs and cats with urinary tract infections to determine their susceptibility to both doxycycline and tetracycline in vitro. PROCEDURE: In the first study, nine cats and eight dogs were administered doxycycline monohydrate (5 mg/kg every 12 h) and a further eight dogs were administered tetracycline hydrochloride (20 mg/kg every 8 h) for 72 h. Blood was collected at 2 and 4 h, and urine at 4 h, after the last dose. The concentration of each agent in serum and urine was determined by modified agar diffusion. In the second study, 45 urine samples from cats and dogs with urinary tract infections were cultured. Every bacterial isolate was tested in vitro using both Epsilometer (doxycycline and tetracycline) and disc diffusion (doxycycline, tetracycline or amoxycillin-clavulanate) tests. RESULTS: Serum doxycycline concentrations in sera of cats and dogs at 2 h were 4.2 +/- 1.0 mg/mL and 3.4 +/- 1.1 mg/mL, respectively. The corresponding concentrations at 4 h were 3.5 +/- 0.7 mg/mL and 2.8 +/- 0.6 mg/mL. Urinary doxycycline concentrations at 4 h (53.8 +/- 24.4 mg/mL for cats and 52.4 +/- 24.1 mg/mL for dogs) were substantially higher than corresponding serum values. Serum tetracycline concentrations in dogs at 2 and 4 h, and in urine at 4 h, were 6.8 +/- 2.8, 5.4 +/- 0.8, 144.8 +/- 39.4 mg/mL, respectively. Most of the urinary tract pathogens (35/45) were susceptible to urinary concentrations of doxycycline and 38/45 were susceptible to tetracycline. In contrast 41/45 of all isolates were susceptible to amoxycillin-clavulanate. CONCLUSION: This is the first report of urinary concentrations of doxycycline after conventional oral administration. Concentrations attained in the urine of normal cats and dogs were sufficient to inhibit the growth of a significant number of urinary tract pathogens and thus doxycycline may be a useful antimicrobial agent for some urinary tract infections.     

Canine transitional cell carcinoma

Transitional cell carcinoma (TCC) of the urinary bladder, the most common malignancy of the urinary tract in dogs, is challenging to both diagnose and treat effectively. The prevalence of this disease may be increasing. The etiology of canine TCC is likely multifactorial. Epidemiological studies of TCC in the dog have revealed a number of risk factors, including breed and female gender, as well as environmental factors, such as insecticide exposure. This tumor is difficult to remove surgically and responds poorly to chemotherapy. The efficacy of radiotherapy and other treatment modalities needs further investigation. Cyclooxygenase-inhibiting drugs have some activity against TCC, and studies to further define these effects are ongoing. Use of the tumor/node/ metastasis (TNM) classification scheme for bladder cancer has allowed for the identification of prognostic factors. Urinary tract obstruction and metastatic disease remain challenges to treat. Work with canine TCC has demonstrated how closely this disease resembles human invasive urinary bladder cancer. Therefore, future research has the potential to benefit both dogs and humans with TCC.     

C‐reactive protein concentration in dogs with primary immune‐mediated hemolytic anemia

Background: Canine primary immune-mediated hemolytic anemia (IMHA) is associated with a high-mortality rate. C-reactive protein (CRP) is the most important acute-phase protein in dogs and may have value as a marker of prognosis or response to treatment in IMHA. Objective: The objectives of this study were to evaluate serum CRP concentration in dogs with primary IMHA at presentation and during treatment, to assess potential differences based on survival time, and to compare CRP with other laboratory parameters of inflammation and prognosis. Methods: Inclusion criteria for primary IMHA were anemia (PCV<0.30 L/L), a positive Coombs' test or persistent autoagglutination of erythrocytes, and the exclusion of underlying diseases by other diagnostic tests. Dogs were divided into 2 groups based on survival: dogs that were still alive 14 days after start of treatment (group 1) and dogs that died or were euthanized before day 14 (group 2). Serum CRP concentration, a CBC, and a biochemistry profile were performed on days 0, 3, 8, and 14. Serum CRP also was determined in 25 clinically healthy dogs. Results: CRP concentration in the 25 clinically healthy dogs ranged from 0–8.9 μg/mL (median 2.2 μg/mL). Thirty dogs were diagnosed with primary IMHA, 24 in group 1 and 6 in group 2. On day 0, CRP concentration in dogs in both groups (median 224 μg/mL) was increased above the reference interval. In group 1 dogs, median CRP concentration was 242 μg/mL on day 0, 69 μg/mL on day 3, 35 μg/mL on day 8, and 2 μg/mL on day 14. In group 2 dogs, median CRP concentration was 194 μg/mL on day 0, 119 μg/mL on day 3, and 41 μg/mL on day 8; only 1 dog in group 2 survived to day 8. There was a significant correlation between CRP and total WBC concentrations on days 0 and 3 (r=−.598, P=.003). Conclusions: Serum CRP concentration was markedly increased in dogs with primary IMHA. CRP concentration did not differ based on patient survival, but might be a marker for long-term monitoring of these patients.     

Effect of sucralfate on oral minocycline absorption in healthy dogs

Sucralfate and minocycline may be administered concurrently to dogs. The relative bioavailability of tetracyclines may be reduced if administered with sucralfate, but studies confirming these interactions in dogs are not available. This study evaluated the pharmacokinetics of oral minocycline in dogs (M), determined the effects of concurrent administration of sucralfate and minocycline (MS) on minocycline pharmacokinetics, determined the effects of delaying sucralfate administration by 2 h (MS+2) on minocycline pharmacokinetics, and established dosing recommendations based on pharmacodynamic indices. Oral minocycline (300 mg) and sucralfate suspension (1 g) were administered to five greyhounds in a randomized crossover design. Minocycline plasma concentrations were evaluated using liquid chromatography with mass spectrometry. The maximum plasma concentration (C_MAX) and area under the curve (AUC) of minocycline were 1.15 μg/mL and 8.0 h* μg/mL, respectively. The C_MAX and AUC were significantly lower (P < 0.05) in the MS group (C_MAX = 0.33 μg/mL, AUC 3.0 h*μg/mL) compared with M or MS+2 (C_MAX = 0.97 μg/mL, AUC 10.3 h*μg/mL). Delaying sucralfate by 2 h did not decrease oral minocycline absorption, but concurrent administration significantly decreased minocycline absorption. A dose of 7.5 mg/kg p.o. q12 h achieves the pharmacodynamic index for a bacterial minimum inhibitory concentration (MIC) of 0.25 μg/mL (AUC:MIC≥33.9).     

Preclinical evaluation of 5-aminolevulinic acid-based photodynamic therapy for canine transitional cell carcinoma

As a prelude to photodynamic therapy, 5‐aminolevulinic acid (ALA) was given orally to healthy dogs. ALA‐induced protoporphyrin IX (PpIX) fluorescence significantly increased in the mucosa of the urinary bladder in an ALA dose‐dependent fashion. Vomiting occurred after ALA administration in 70% of the dogs but did not affect PpIX fluorescence. ALA‐based photodynamic therapy (PDT) of the urinary bladder in healthy dogs caused only submucosal oedema within the bladder wall. No haematologic or serum biochemistry abnormalities were observed after ALA administration. Microscopic haematuria was observed in all the dogs after PDT but was mild and self limiting. ALA‐based PDT was administered to six dogs with transitional cell carcinoma (TCC) of the lower urinary tract. ALA‐based PDT resulted in tumour progression‐free intervals from 4 to 34 weeks in five dogs; one dog with pre‐existing hydronephrosis died shortly after PDT. Dogs with TCC represent an outbred, spontaneous, tumour model for developing PDT protocols for humans with bladder cancer.     

Selenium status in adult cats and dogs fed high levels of dietary inorganic and organic selenium

Cats (Felis catus) maintain greater blood Se concentrations compared with dogs (Canis familiaris) and, unlike dogs, show no signs of chronic Se toxicity (selenosis) when fed dietary organic Se (selenomethionine) concentrations of 10 μg/g DM. This study investigated the response of cats and dogs to high dietary concentrations of sodium selenite and organic Se to determine differences in metabolism between both species. In 2 consecutive studies, 18 adult cats and 18 adult dogs of with equal numbers of each sex were fed a control diet (0.6 μg Se/g DM) or the control diet supplemented to 8 to 10 μg Se/g DM from Na(2)SeO(3) or organic Se for 3 wk. All animals were fed the control diet 1 mo before the start of the study and blood samples were taken on d 0 and 21. The Se balance was assessed during the final week and a liver biopsy was obtained on the final day of the study. Measurements included plasma Se concentrations, plasma glutathione peroxidise (GPx) activities, plasma Se clearance, Se intake, and urinary Se excretion. No clinical signs of selenosis were observed in the cats or dogs, and apart from Se clearance, form of Se had no effect on any of the measurements. Apparent fecal Se absorption was greater in the dogs fed both forms of Se, while greater plasma Se concentrations were observed in the cats on both the control and supplemented diet (P = 0.034). Cats fed the supplemented diets had lower hepatic Se concentrations (P < 0.001) and excreted more Se in urine (P < 0.001) compared with dogs. Furthermore, cats fed the Na(2)SeO(3) supplement had greater Se clearance rates than dogs (P < 0.001). There was no effect of species on plasma GPx activity. We conclude that cats can tolerate greater dietary Se concentrations as they are more efficient at excreting excess Se in the urine and storing less Se in the liver.     

Effects of urine alkalization and activated charcoal on the pharmacokinetics of orally administered carprofen in dogs

OBJECTIVE: To investigate the effects of oral administration of activated charcoal (AC) and urine alkalinization via oral administration of sodium bicarbonate on the pharmacokinetics of orally administered carprofen in dogs. ANIMALS: 6 neutered male Beagles. PROCEDURES: Each dog underwent 3 experiments (6-week interval between experiments). The dogs received a single dose of carprofen (16 mg/kg) orally at the beginning of each experiment; after 30 minutes, sodium bicarbonate (40 mg/kg, PO), AC solution (2.5 g/kg, PO), or no other treatments were administered. Plasma concentrations of unchanged carprofen were determined via high-performance liquid chromatography at intervals until 48 hours after carprofen administration. Data were analyzed by use of a Student paired t test or Wilcoxon matched-pairs rank test. RESULTS: Compared with the control treatment, administration of AC decreased plasma carprofen concentrations (mean +/- SD maximum concentration was 85.9 +/- 11.9 mg/L and 58.1 +/- 17.6 mg/L, and area under the time-concentration curve was 960 +/- 233 mg/L x h and 373 +/- 133 mg/L x h after control and AC treatment, respectively). The elimination half-life remained constant. Administration of sodium bicarbonate had no effect on plasma drug concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: After oral administration of carprofen in dogs, administration of AC effectively decreased maximum plasma carprofen concentration, compared with the control treatment, probably by decreasing carprofen absorption. Results suggest that AC can be used to reduce systemic carprofen absorption in dogs receiving an overdose of carprofen. Oral administration of 1 dose of sodium bicarbonate had no apparent impact on carprofen kinetics in dogs.     

Disposition of creatine kinase activity in dog plasma following intravenous and intramuscular injection of skeletal muscle homogenates

The fate of skeletal muscle-derived creatine kinase (CK) was investigated in six dogs. After i.m. and i.v. injections of 3000 g and 105 000 g supernatants of dog muscle homogenates, plasma CK activity was measured up to 48 h. There was no significant difference in pharmacokinetic parameters dependent on the type of supernatant injected. After i.v. injection, the volume of distribution of CK was equal to the plasma volume, CK clearance was relatively low (about 0.5 mL/kg/min) and its terminal half-life of elimination was about 2.5 h. After i.m. injection, the CK terminal half-life was about 6.5 h, demonstrating a flip-flop mechanism, i.e. a limiting absorption process from the site of injection. Bioavail-ability after i.m. injection was about 65%, and the rate of absorption from muscle injection site was relatively slow: peak activity occurred at the second hour post administration, and most CK activity had been absorbed by 24 h. These pharmacokinetic parameters can be used as a basis for a minimally invasive means of quantitating muscle damage either after intramuscular drug administration or in canine sports medicine.     

Terbinafine pharmacokinetics after single dose oral administration in the dog

Terbinafine is an allylamine antifungal prescribed for the treatment of mycoses in humans. It is increasingly being used in veterinary patients. The purpose of this study was to evaluate the pharmacokinetic properties of terbinafine in dogs after a single oral dose. Ten healthy adult dogs were included in the study. A single dose of terbinafine (30–35 mg/kg) was administered orally, and blood samples were periodically collected over a 24 h period during which dogs were monitored for adverse effects. Two of 10 dogs developed transient ocular changes. A high‐performance liquid chromatography assay was developed and used to determine plasma terbinafine concentrations. Pharmacokinetic analysis was performed using PK Solutions^® computer software. Area under the curve (AUC) from time 0 to 24 h was 15.4 μg·h/mL (range 5–27), maximal plasma concentration (C_max) was 3.5 μg/mL (range 3–4.9 μg/mL) and time to C_max (T_max) was 3.6 h (range 2–6 h). The time above minimal inhibitory concentration (T > MIC) as well as AUC/MIC was calculated for important invasive fungal pathogens and dermatophytes. The T > MIC was 17–18 h for Blastomyces dermatitidis, Histoplasma capsulatum and dermatophytes (Microsporum spp. and Trichophyton mentagrophytes), while the MIC for Sporothrix schenckii and Coccidioides immitis was exceeded for 9.5–11 h. The AUC/MIC values ranged from 9 to 13 μg h/mL for these fungi. Our results provide evidence supporting the use of terbinafine as an oral therapeutic agent for treating systemic and subcutaneous mycoses in dogs.