Disposition of levetiracetam in healthy adult horses.

Nine horses received 20 mg/kg of intravenous (LEVIV ); 30 mg/kg of intragastric, crushed immediate release (LEVCIR ); and 30 mg/kg of intragastric, crushed extended release (LEVCER ) levetiracetam, in a three-way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEVCIR and LEVCER were 50.72 ± 10.60 and 53.58 ± 15.94 µg/ml, respectively. The y-intercept for IV administration was 64.54 ± 24.99 µg/ml. The terminal half-life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEVCIR , LEVCER, and LEVIV , respectively. Volume of distribution at steady-state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg-1  hr-1 . Bioavailability was 96 ± 10, and 98 ± 13% for LEVCIR and LEVCER , respectively. A single dose of Levetiracetam (LEV) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.

Pharmacokinetics and dynamics of mycophenolate mofetil after single-dose oral administration in juvenile dachshunds.

Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young-aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose-bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole-blood mitogen-stimulated T-cell proliferation was determined using a flow cytometric assay. Plasma MPA Cmax (mean ± SD, 9.33 ± 7.04 µg/ml) occurred at <1 hr. The AUC0-∞ (mean ± SD, 12.84±6.62 hr*µg/ml), MRTinf (mean ± SD, 11.09 ± 9.63 min), T1/2 (harmonic mean ± PseudoSD 5.50 ± 3.80 min), and k/d (mean ± SD, 0.002 ± 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets.

Pharmacokinetics of tramadol and its major metabolites in alpacas following intravenous and oral administration.

Tramadol, a centrally acting opioid analgesic with monamine reuptake inhibition, was administered to six alpacas (43-71 kg) randomly assigned to two treatment groups, using an open, single-dose, two-period, randomized cross-over design at a dose of 3.4-4.4 mg/kg intravenously (i.v.) and, after a washout period, 11 mg/kg orally. Serum samples were collected and stored at -80°C until assayed by HPLC. Pharmacokinetic parameters were calculated. The mean half-lives (t(1/2)) i.v. were 0.85±0.463 and 0.520±0.256 h orally. The Cp(0) i.v. was 2467±540 ng/mL, and the C(max) was 1202±1319 ng/mL orally. T(max) occurred at 0.111±0.068 h orally. The area under the curve (AUC(0-∞)) i.v. was 895±189 and 373±217 ng*h/mL orally. The volume of distribution (V(d[area])) i.v. was 5.50±2.66 L/kg. Total body clearance (Cl) i.v. was 4.62±1.09 h; Cl/F for oral administration was 39.5±23 L/h/kg. The i.v. mean residence time (MRT) was 0.720±0.264. Oral adsorption (F) was low (5.9-19.1%) at almost three times the i.v. dosage with a large inter-subject variation. This may be due to binding with the rumen contents or enzymatic destruction. Assuming linear nonsaturable pharmacokinetics and absorption processes, a dosage of 6.7 times orally would be needed to achieve the same i.v. serum concentration of tramadol. The t(1/2) of all three metabolites was longer than the parent drug; however, O-DMT, N-DMT, and Di-DMT metabolites were not detectable in all of the alpacas. Because of the poor bioavailability and adverse effects noted in this study, the oral administration of tramadol in alpacas cannot be recommended without further research.

Antimicrobial resistance profiles and clonal relatedness of canine and feline Escherichia coli pathogens expressing multidrug resistance in the United States.

BACKGROUND: Antimicrobial resistance is increasing among Escherichia coli isolates associated with spontaneous infection in dogs and cats. OBJECTIVES: To describe E. coli resistance phenotypes and clonal relatedness and their regional prevalence. ANIMALS: Isolates of E. coli (n = 376) collected from dogs and cats in the United States between May and September 2005. METHODS: Isolates submitted from the South, West, Northeast, and Midwest regions of the United States were prospectively studied. Phenotype was based on E-test susceptibility to 7 antimicrobials. Isolates were classified as no (NDR), single (SDR), or multidrug resistance (MDR). Clonal relatedness was determined by pulsed-field gel electrophoresis (PFGE). RESULTS: One hundred and ninety-three (51%) isolates expressed resistance to at least 1 drug, yielding 42 phenotypes. SDR isolates (n = 84; 44%, 8 phenotypes), expressed resistance most commonly to amoxicillin (30%, n = 25) and least commonly to cefpodoxime (1%, n = 1). MDR isolates (n = 109; 56%, 31 phenotypes) were resistant to amoxicillin (96%, n = 105), amoxicillin-clavulanate (85%, n = 93), and enrofloxacin (64%, n = 70); 18% (n = 20) were resistant to all drugs tested. The frequency of MDR did not differ regionally (P = .066). MDR minimum inhibitory concentrations (MICs) were 6-fold higher than SDR MICs (P < .0001). Dendrograms of 91 isolates representing 25 phenotypes revealed 62 different PFGE profiles. CONCLUSIONS AND CLINICAL IMPORTANCE: E. coli strains spontaneously infecting dogs and cats are genetically and phenotypically diverse. Given the current prevalence of MDR among clinical isolates of E. coli in United States, implementation of a robust surveillance program is warranted.

Evaluation of the distribution of enrofloxacin by circulating leukocytes to sites of inflammation in dogs.

OBJECTIVE: To determine the effect of WBC accumulation on the concentration of enrofloxacin in inflamed tissues in dogs. ANIMALS: 6 adult Bloodhounds. PROCEDURES: Dogs were instrumented bilaterally with tissue chambers. Peripheral WBCs collected from each dog were exposed in vitro to radiolabeled enrofloxacin ((14)C-ENR). Inflammation was induced with carrageenan in 1 chamber. Ten hours later, treated cells were administered IV to each dog such that (14)C-ENR was delivered at a mean +/- SD dosage of 212 +/- 43 microg. Samples of extracellular fluid from inflammation and control chambers and circulating blood were then collected before (baseline) and for 24 hours after WBCs were administered. Samples were centrifuged to separate WBCs from plasma (blood) or chamber fluid. Radiolabeled enrofloxacin was scintigraphically detected and pharmacokinetically analyzed. Comparisons were made between extra- and intracellular chamber fluids by use of a Student paired t test. RESULTS: (14)C-ENR was not detectable in plasma, peripheral WBCs, control chambers, or baseline samples from inflammation chambers. However, (14)C-ENR was detected in extra- cellular fluid from inflammation chambers (mean +/- SD maximum concentration, 2.3 +/- 0.5 ng/mL) and WBCs (maximum concentration, 7.7 +/- 1.9 ng/mL). Mean disappearance half-life of (14)C-ENR from extracellular fluid and WBCs from inflammation chambers was 26 +/- 10 hours and 17 +/- 6 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: WBCs were responsible for the transport and release of (14)C-ENR at sites of inflammation. Accumulation of drug by WBCs might increase the concentration of drug at the site of infection, thus facilitating therapeutic success.

Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs.

The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady-state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross-over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one-way anova; P

Pharmacokinetics of Single Oral Dose Extended-Release Levetiracetam in Healthy Cats.

BACKGROUND: Repeated PO dosing of anti-epileptic drugs may contribute to poor compliance in treated cats. Intermediate-release levetiracetam has been used safely in cats, but must be given q8h to maintain serum concentrations in the therapeutic interval for humans (5-45 µg/mL). Approved extended-release levetiracetam (XRL) for human use may require less frequent dosing, but the large dosing unit has limited its use in cats. HYPOTHESES: In healthy cats, serum levetiracetam concentration will remain above 5 µg/mL for at least 24 hours after administration of a single dose of XRL PO and will be well tolerated. ANIMALS: 7 healthy cats. METHODS: Extended-release levetiracetam (500 mg) was administered PO. Blood was collected and neurologic examination findings recorded at scheduled times over 30 hours. Serum levetiracetam concentration was quantitated by an immunoassay validated in cats. Data were subjected to noncompartmental analysis. Descriptive statistics were reported. RESULTS: The median dosage of 86.2 mg/kg, (range, 80-94.3) achieved a mean maximum concentration (Cmax ) of 89.8 ± 25.8 µg/mL at 4.9 ±1.57 hours. Serum levetiracetam was >5 µg/mL in all cats by 90 minutes. Mean concentrations were 43.7 ± 18.4 and 4.9 ± 3.4 µg/mL at 12 and 24 hours, respectively. The half-life was 4.1 ± 1.0 hours. The drug was well tolerated. CONCLUSIONS AND CLINICAL IMPORTANCE: A single 500 mg PO dose of XRL safely maintained serum levetiracetam concentration ≥5 µg/mL in healthy cats for at least 21 hours. Clinical efficacy studies in epileptic cats receiving XRL are indicated; however, monitoring should be implemented for individual cats.

Disposition of Extended Release Levetiracetam in Normal Healthy Dogs After Single Oral Dosing.

BACKGROUND: Levetiracetam is an anticonvulsant used for control of canine epilepsy. An extended release preparation should improve dosing convenience. OBJECTIVES: To determine the disposition of extended release levetiracetam in normal dogs after single dosing. ANIMALS: Pharmacokinetic study: 16 healthy, adult dogs. METHODS: Using a partially randomized crossover study, levetiracetam (30 mg/kg) was administered intravenously (i.v.) and orally (p.o.) as extended release preparation with or without food. Blood was collected for 24 hours (i.v.) or 36 hours (p.o.). Serum levetiracetam was quantitated by immunoassay and data were subjected to noncompartmental analysis. RESULTS: Pharmacokinetic parameters for fasted versus fed animals, respectively, were (mean ± SEM): Cmax = 26.6 ± 2.38 and 30.7 ± 2.88 µ/mL, Tmax = 204.3 ± 18.9 and 393.8 ± 36.6 minutes, t1/2 = 4.95 ± 0.55 and 4.48 ± 0.48 hours, MRT = 9.8 ± 0.72 and 10 ± 0.64 hours, MAT = 4.7 ± 0.38 and 5.6 ± 0.67 hours, and F = 1.04 ± 0.04 and 1.26 ± 0.07%. Significant differences were limited to Tmax (longer) and F (greater) in fed compared to fasted animals. Serum levetiracetam concentration remained above 5 µ/mL for approximately 20 hours in both fasted and fed animals. CONCLUSIONS AND CLINICAL IMPORTANCE: Extended release levetiracetam (30 mg/kg q12h), with or without food, should maintain concentrations above the recommended minimum human therapeutic concentration.

A canine model of multiple portosystemic shunting.

The objective of this study was to develop and describe an experimental canine model of multiple acquired portosystemic shunts (PSS) similar in nature to spontaneously occurring PSS. Sixteen dogs were used and were divided into a control (n = 6) and a diseased group (n = 10). Dogs of the diseased group were administered dimethylnitrosamine (2 mg/kg of body weight, po) twice weekly, and clinicopathologic, ultrasonographic, and hepatic scintigraphic findings were recorded during the development of hepatic disease and PSS. Surgery was then performed to permit visual verification of multiple shunts, catheter placement for portography examination, and biopsy of the liver. All diseased dogs developed severe hepatic disease and multiple PSS as documented visually at surgery and on portography. Based on this study, dimethylnitrosamine-induced portosystemic shunting appears to be an appropriate model for spontaneously occurring multiple PSS secondary to portal hypertension.

Effects of serum separation tubes on serum benzodiazepine and phenobarbital concentrations in clinically normal and epileptic dogs.

OBJECTIVE: To characterize the effects of serum separation tubes (SST) on serum drug concentrations. SAMPLE POPULATION: Clinically normal dogs (clorazepate, n = 7) or dogs with epilepsy (phenobarbital, n = 7) were studied in experiment 1, and samples submitted for therapeutic drug monitoring (n = 87) were studied in experiment 2. PROCEDURE: In experiment 1, blood containing either drug was placed in 2 types of 4-ml SST (SST-A and SST-B) and in nonserum separation tubes (non-SST [control]). Samples were processed, then stored at 20 to 22 C (both drugs) or 10 C (phenobarbital only). Aliquots were collected for 96 hours. The rate constant of disappearance and the percentage decrease of each drug over time were determined for each tube. For experiment 2, paired samples were collected in non-SST and SST and submitted by mail for therapeutic drug monitoring. The SST samples were either decanted from SST prior to shipment (group 1; n = 30) or mailed in SST with serum in contact with the silica gel (group 2; n = 57). Drug concentrations and drug elimination half-life were compared between groups. For both experiments, drugs were detected in samples, using polarized immunofluorescence. RESULTS: For experiment 1, the rate constant of drug disappearance for both drugs was greater in the 4-ml SST-A (P < 0.0001). This SST also caused the greatest percentage decrease (20% for phenobarbital and 35% for benzodiazepines) at 96 hours. Refrigeration reduced the mean decrease in phenobarbital at 96 hours to 11%. For experiment 2, phenobarbital concentration was lower for both SST, compared with non-SST (P < 0.0005). Phenobabital had decreased a mean 6.4 +/- 0.5% in group-1 and a mean 30.5 +/- 11.1% in group-2 (P < 0.0005) samples. CONCLUSION: The SST should be avoided when collecting serum for monitoring of either phenobarbital or benzodiazepines. CLINICAL RELEVANCE: The SST can falsely decrease serum drug concentrations and should be avoided when collecting blood for therapeutic drug monitoring.

Itraconazole disposition after single oral and intravenous and multiple oral dosing in healthy cats.

OBJECTIVE: To determine the disposition of itraconazole in cats after single IV and oral dosing (as a solution or capsule) and multiple oral (capsule) dosing, and to establish bioavailability after oral administration of the solution. ANIMALS: 6 healthy cats for experiment 1 (E1), and 12 cats for experiment 2 (E2). PROCEDURE: For E1 (nonrandomized crossover design), each cat received a single dose of itraconazole solution (5 mg/kg of body weight) orally, and 1 month later, another dose i.v.. Blood samples were collected for 96 hours. For E2, each cat was given either 5 (group [G] 1) or 10 (G2) mg of itraconazole/kg (capsules) twice daily for 6 weeks. Samples were collected for 96 hours after the first and last dose. Itraconazole was detected by use of high-performance liquid chromatography. RESULTS: For E1, itraconazole plasma drug concentration extrapolated to time zero (IV dose) was 5.2 +/- 1.4 micrograms/ml, and mean residence time (MRT) was 37 +/- 16 hours. For oral dosing, maximal itraconazole concentration was 1.69 +/- 0.864 micrograms/ml, MRT was 48 +/- 17 hours, and bioavailability was 78.8 +/- 28%. For the multiple oral dosing study, MRT (at last dose: 81.1 +/- 97.4 hours for G1, and 63.1 +/- 15.1 hours for G2) was shorter (P = 0.02) at first dose, compared with last dose, for both groups but did not differ between groups. Maximal concentration did not differ between groups at either time. Steady state was achieved at 14 to 21 days. All cats tolerated itraconazole with no evidence of adverse effects. CONCLUSIONS: The oral itraconazole solution is preferred to capsules; a 24-hour dosing interval should be sufficient; 10 mg/kg given daily should generate therapeutic concentrations in most cats; steady-state concentrations may take up to 3 weeks to achieve; and cats appear to tolerate itraconazole well.

Endotoxemia associated with experimentally induced multiple portosystemic shunts in dogs.

OBJECTIVE: To document presence of endotoxin in portal and systemic blood in a model of canine multiple portosystemic shunts (PSS), and compare values in clinically normal dogs, before and after vena caval banding. ANIMALS: 6 control dogs and 10 dogs with dimethylnitrosamine-induced multiple PSS that were subjected to vena caval banding. PROCEDURE: Dimethylnitrosamine was administered orally (2 mg/kg of body weight, twice weekly) to the 10 dogs in the diseased group until multiple PSS developed. Surgery was then performed on all 16 dogs (both groups), and shunts were confirmed in the diseased dogs. Blood was collected from the portal vein, hepatic vein, and caudal vena cava baseline endotoxin determination and aerobic and anaerobic blood culturing. Baseline pressure measurements were taken from the portal venous catheter; then vena caval banding was performed. Blood for endotoxin determinations was taken from all vessels 20, 40, 60, 120, 240, and 360 minutes after banding; portal pressure measurements were taken at the same time as sample acquisition. Blood for culturing was taken from the portal and hepatic venous catheters at 120, 240, and 360 minutes after banding. RESULTS: Dogs in the diseased group had significantly greater overall presence of endotoxin in the portal vein (P < or = 0.0002), hepatic vein (P < or = 0.0001), and caudal vena cava (P < or = 0.0004) than did control dogs. With respect to time, endotoxin presence was greater in the diseased group before banding (P < or = 0.0002), and at 20 (P < or = 0.0008), 40 (P < or = 0.002), 60 (P < or = 0.006), and 120 (P < or = 0.01) minutes after banding. CONCLUSIONS: Endotoxemia is more frequently present in catheterized dogs with dimethylnitrosamine-induced hepatic disease and multiple PSS, compared with clinically normal dogs. Additionally, portal pressure changes induced by vena caval banding did not affect endotoxemia. CLINICAL RELEVANCE: Endotoxemia may exist in dogs with hepatic disease and multiple PSS, and should be kept in mind when formulating treatment (particularly antimicrobial selection) for dogs with suspected endotoxemia.

Detection of portal and systemic bacteremia in dogs with severe induced hepatic disease and multiple portosystemic shunts.

OBJECTIVE: To determine existence of portal and systemic bacteremia in dogs with induced severe hepatic disease, compared with clinically normal dogs, before and after vena caval banding. ANIMALS: 6 control dogs and 10 dogs with induced severe hepatic disease and multiple portosystemic shunts (PSS). PROCEDURE: Dogs of the diseased group were given dimethylnitrosamine (2 mg/kg of body weight, PO) twice weekly until multiple PSS developed. Surgery was performed on dogs of both groups, and blood for baseline aerobic and anaerobic bacterial culture was collected from catheters placed in the portal and hepatic veins and caudal vena cava. All dogs underwent vena caval banding, and blood for aerobic and anaerobic bacterial culture was collected from the portal and hepatic venous catheters at 120, 240, and 360 minutes after banding. RESULTS: Compared with control dogs (16% gram-positive and 84% gram-negative bacteria), diseased dogs had significantly higher percentage of gram-positive bacteria (42% of positive culture results, P < or = 0.01) and significantly lower percentage of gram-negative bacteria (58% of positive culture results, P < or = 0.01) isolated. Pseudomonas aeruginosa was isolated most frequently from dogs of both groups; more than 1 organism was isolated from 5 dogs of each group. Antimicrobial susceptibility included that to aminoglycosides (particularly amikacin), fluorinated quinolones, and imipenem. CONCLUSION: Portal and systemic, predominantly gram-negative, bacteremia is present in catheterized, clinically normal dogs and dogs with dimethylnitrosamine-induced hepatic disease and multiple PSS.

Tracheal mucociliary transport rate in awake dogs.

To measure tracheal mucociliary transport rate (TMTR) in awake dogs, restrained in dorsal recumbency, 99mtechnetium-labeled macroaggregated albumin was administered by tracheal injection, and the cephalic movement of boluses containing the radiopharmaceutical was detected by a gamma camera positioned lateral to the dog's head and neck. The distance traveled by each bolus was measured, relative to external markers placed a known distance apart. Tracheal mucociliary transport rates were calculated by dividing the measured distance of radiopharmaceutical movement by elapsed time. The technique was efficient and well tolerated. Mean (+/- SD) TMTR was 35.3 +/- 15.9 mm/min. Significant (P = 0.029) difference in TMTR was found between males and females, but significant difference attributable to age of the dog was not detected. This method of measuring TMTR in awake dogs has potential for evaluation of clinical animal patients with suspected tracheal mucociliary abnormalities.

Effects of vena caval banding in experimentally induced multiple portosystemic shunts in dogs.

Effects of vena caval banding on portal venous and vena caval hemodynamics were examined in 6 control dogs and in 10 dogs that had undergone attenuation (banding) of the abdominal part of the caudal vena cava and had dimethylnitrosamine-induced multiple portosystemic shunts (PSS). Additionally, indocyanine green (ICG) extraction and clearance after infusion to steady state were used to calculate hepatic plasma flow in these dogs. Sixteen dogs were randomly assigned to 2 groups: control (n = 6) or diseased (n = 10). Diseased dogs were administered dimethylnitrosamine (2 mg/kg, PO, twice weekly) until multiple PSS developed, as assessed by results of clinical laboratory tests, ultrasonography, and hepatic scintigraphy. Shunts were confirmed visually at celiotomy and by contrast portography. Venous pressures (caudal vena caval, portal, and hepatic) were recorded before and after vena caval banding for up to 7 days in dogs from both groups. Peritoneal cavity pressures were recorded in all dogs after closure of the body wall. To determine ICG extraction and clearance, a bolus injection of ICG (0.5 mg/kg, i.v.) was administered, followed by steady-state infusion of 0.097 mg/min. Extractions and clearances of ICG were measured, and from these, hepatic plasma flow rates were determined immediately before and after banding and at 6 hours, 48 hours, and 7 days after banding. The gradient (caudal vena caval pressure within 1 to 2 mm of Hg of portal pressure) between caudal vena cava and portal venous pressures established at banding was maintained after the first hour in both groups. Caudal vena cava pressures established at banding were maintained throughout the study, with the exception of the first hour in diseased dogs. Extraction ratios were higher in control dogs at all times, except at 48 hours. Clearance was higher in control dogs at all times. Hepatic plasma flow did not differ between groups, except immediately after banding, when flow was greater in diseased dogs, and differences were not found over time in either group. This study indicated that vena caval banding in this model of experimentally induced multiple PSS increases and maintains caudal vena cava pressure, relative to portal venous pressure (after the first hour) for 7 days, and that calculated hepatic plasma flow is not persistently improved by vena caval banding.

Nitric oxide generation in a rat model of acute portal hypertension.

OBJECTIVE: To document blood nitric oxide concentrations in the portal vein and systemic circulation in a rat model of acute portal hypertension and compare values with a control group and a sham surgical group. ANIMALS: 30 rats; 10 controls (group 1), 10 sham surgical (group 2), and 10 rats with surgically induced acute portal hypertension (group 3). PROCEDURE: Following induction of anesthesia, catheters were placed surgically in the carotid artery, jugular, and portal veins of group 2 and 3 rats and in the carotid artery and jugular vein of group 1 rats. Baseline heart and respiratory rates, rectal temperature, and vascular pressure measurements were obtained, and blood was drawn from all catheters for baseline nitric oxide (NO) concentrations. Acute portal hypertension was induced in the group 3 rats by tying a partially occluding suture around the portal vein and a 22-gauge catheter. The catheter was then removed, resulting in a repeatable degree of portal vein impingement. After catheter placement, all variables were remeasured at 15-minute intervals for 3 hours. RESULTS: Blood nitric oxide concentrations were greater in all vessels tested in group 3 than in group 2 rats. CONCLUSIONS AND CLINICAL RELEVANCE: Acute portal hypertension in this experimental model results in increased concentrations of NO in the systemic and portal circulation. On the basis of information in the rat, it is possible that increased NO concentrations may develop in dogs following surgical treatment of congenital portosystemic shunts if acute life-threatening portal hypertension develops. Increased NO concentrations may contribute to the shock syndrome that develops in these dogs.

Pharmacokinetics of fentanyl after intravenous and transdermal administration in goats.

OBJECTIVE: To evaluate disposition of fentanyl in goats after IV and transdermal administration. ANIMALS: 8 healthy 2-year-old goats weighing 31.8 to 53.6 kg (mean+/-SD, 40.4+/-7.5 kg). PROCEDURE: Each goat was given 2 treatments consisting of fentanyl administered IV (2.5 microg/kg of body weight) and via a transdermal patch (50 microg/h). There was a 2-month interval between treatments. Blood samples were collected at specified times and analyzed in duplicate to determine plasma fentanyl concentrations. Pharmacokinetic values were calculated, using a computerized modeling program. RESULTS: Administration of fentanyl was tolerated by all goats. Intravenous administration of fentanyl resulted in a transitory increase in rectal temperature that was not clinically important. Terminal elimination half-life after IV administration was 1.20+/-0.78 h, volume of distribution at steady state was 1.51+/-0.39 L/kg, and systemic clearance was 2.09+/-0.62 L/kg/h. Transdermal administration of fentanyl resulted in variable plasma concentrations, with peak plasma concentrations ranging from 1.12 to 16.69 ng/ml (mean+/-SD, 6.99+/-6.03 ng/ml) and time to peak concentration ranging from 8 to 18 hours (mean+/-SD, 13+/-4.5 hours). After removal of the transdermal patch, mean+/-SD terminal elimination half-life was 5.34+/-5.34 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous administration of fentanyl (2.5 microg/kg) in goats results in a relatively short half-life that will limit its use for management of pain. Transdermal administration of fentanyl (50 microg/h) in goats results in variable plasma concentrations that may exceed those anticipated on the basis of a theoretical delivery rate, but stable plasma concentrations of fentanyl may not be achieved.

Disposition of cyproheptadine in cats after intravenous or oral administration of a single dose.

OBJECTIVE: To determine disposition of cyproheptadine hydrochloride in cats after intravenous or oral administration of a single dose. ANIMALS: 6 healthy cats. PROCEDURE: A randomized crossover design was used, and each cat was studied after intravenous (2 mg) and oral (8 mg) administration of cyproheptadine. Blood samples were collected at fixed time intervals after drug administration, and serum cyproheptadine concentration was determined by means of polarized immunofluorescence. RESULTS: Mean (+/- SD) residence time was significantly longer after oral (823 +/- 191 minutes) than after intravenous (339 +/- 217 minutes) administration, but no significant differences were detected between other pharmacokinetic parameters after oral and intravenous administration. Mean +/- SD oral bioavailability was 1.01 +/- 0.36. Mean elimination half-life after oral administration was 12.8 +/- 9.9 hours. Peak extrapolated cyproheptadine concentration was 669 +/- 206 ng/ml. Only 1 cat developed adverse effects (transient vocalization). CONCLUSIONS: Cyproheptadine appeared to be well tolerated in cats and had high bioavailability after oral administration. The mean elimination half-life of 12 hours indicated that approximately 2.5 days must elapse to achieve steady-state concentrations of cyproheptadine after oral administration of multiple doses. A 12-hour dosing interval is acceptable, but an 8-hour interval may be indicated for some cats. CLINICAL RELEVANCE: On the basis of pharmacokinetic parameters determined in this study, the oral form of cyproheptadine appears to be suitable for use in clinical trials to treat anorexia in cats. Its half-life is compatible with once or twice daily dosing.

Indocyanine green disposition in healthy dogs and dogs with mild, moderate, or severe dimethylnitrosamine-induced hepatic disease.

Disposition kinetics of indocyanine green (ICG) were used to evaluate hepatic function in healthy Beagles (group 1; n = 6) and Beagles with progressive hepatic disease induced by oral administration of dimethylnitrosamine, a hepatospecific toxin. Three classes of hepatic disease were defined by histologic features: mild (group 2; n = 5), moderate (group 3; n = 6), and severe (group 4; n = 5). Disposition of ICG was studied 3 weeks following the last dose of toxin. A rapid IV injection of 0.5 mg of ICG/kg was administered and serum samples were obtained at certain intervals during 60-minute periods. Serum ICG was analyzed by use of visible spectrophotometry. Disposition kinetics were determined from serum ICG concentrations vs 15- and 60-minute time curves and compared between one another and among groups. Data based on 60-minute time curves were not significantly different from those based on 15-minute curves. Area under the curve for ICG was greatest in group 3. Clearance of ICG was decreased and mean resident time was increased in groups 3 and 4, compared with those in groups 1 and 2. When disposition data (60 minutes) were normalized for differences in hepatic weight among dogs, group-3 mean resident time was significantly greater than that of group 4. This study supports the diagnostic benefits of using ICG disposition kinetics as a method of evaluating hepatic function in dogs with progressive liver disease.

Dimethylnitrosamine-induced hepatotoxicosis in dogs as a model of progressive canine hepatic disease.

A model of toxin-induced progressive hepatitis is described in Beagles. The toxin, dimethylnitrosamine, was administered orally to 18 Beagles; 6 dogs comprised a control group. Clinical signs and laboratory test results were monitored as disease progressed and were used to determine the end point of disease. Following euthanasia, histologic lesions were scored and used to derive a total severity score for each dog. Severity scores were then used to allot the 18 dogs to 3 groups of hepatic disease, defined as mild, moderate, or severe. Changes in clinical laboratory test results, including tests of hepatic function, and clinical signs indicative of liver disease were described chronologically for all dogs. Group means of clinical laboratory test results and quantifiable clinical signs (eg, weight loss and ascitic fluid accumulation) were compared. This model offers several advantages, compared with other experimental models of canine hepatic disease. These include hepatospecificity, similarity to natural disease (eg, the development of multiple extrahepatic portosystemic shunts), and the ability to titrate the disease to a desired end point. The major disadvantages of this model were the toxic nature of the drug to human beings and the variation in individual animal response to the toxin, which precludes preassignment of animals into groups.