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SUMMARY

Clorazepate dipotassium was administered orally to 8 healthy dogs at a dosage of 2 mg/kg of body weight, q 12 h, for 21 days. Serum disposition of nordiazepam, the principle metabolite of clorazepate, was determined after the first and last dose of clorazepate. Disposition variables were analyzed by use of model-independent pharmacokinetics by the predictive equations method and the trapezoidal rule method. Complete blood counts, serum chemical analyses, and urinalyses were performed before administration of clorazepate and at 10 and 21 days after administration of clorazepate.

Maximal nordiazepam concentrations ranged from 446 to 1,542 ng/ml (814 ± 334 ng/ml), at 59 to 180 minutes (97.9 ± 42.0 minutes) after a single oral dose of clorazepate. Maximal nordiazepam concentrations ranged from 927 to 1,460 ng/ml (1,308 ± 187.6 ng/ml), at 120 to 239 minutes (153 ± 57.9 minutes) after multiple oral doses of clorazepate. Serum disposition was significantly altered after multiple doses of clorazepate. Using data determined by the predictive equations method, the mean residence time after multiple doses (712 ± 214 minutes) was longer (P < 0.05) than after a single dose (527 ± 95.8 minutes). Oral volume of distribution after multiple doses of clorazepate (1.76 ± 0.647 L/kg) was smaller (P < 0.02) than after a single dose (3.18 ± 1.52 L/kg). Oral clearance after multiple doses of clorazepate (3.09 ± 0.726 ml/min/kg) was less (P < 0.001) than after a single dose (6.54 ± 2.15 ml/min/kg). Absorption half-life after multiple doses (72 minutes) was longer (P < 0.01) than after a single dose (33 minutes). The elimination half-life after a single dose (284 minutes) was not significantly different after multiple doses (355 minutes).

Significant changes (P < 0.05) in serum chemical values after multiple doses of clorazepate included decreased concentrations of albumin, total protein, and calcium and increased concentrations of urea nitrogen and glucose. Serum activities of alkaline phosphatase and alanine transaminase increased after multiple doses of clorazepate. Significant changes (P < 0.05) in the hemogram included increased total wbc count, segmented neutrophils, lymphocytes, and eosinophils. Urine pH after multiple doses (5.88 ± 0.641) was lower (P < 0.01) than after a single dose (7.44 ± 1.29). All changes in laboratory values remained within our reference ranges.

Mild sedation and ataxia developed in only 1 dog after the first dose of clorazepate. These effects were transient and did not redevelop with additional dosing.

An oral clorazepate dosage of 2 mg/kg, q 12 h, maintains serum nordiazepam concentrations considered to be therapeutic in human beings (500 to 1,900 ng/ml).

Free access
in American Journal of Veterinary Research
in Journal of the American Veterinary Medical Association

Abstract

Objective—To determine the effect of meloxicam and flunixin meglumine on recovery of ischemia-injured equine jejunum.

Animals—18 horses.

Procedures—Horses received butorphanol tartrate; were treated IV with saline (0.9% NaCl) solution (SS; 12 mL; n = 6), flunixin meglumine (1.1 mg/kg; 6), or meloxicam (0.6 mg/kg; 6) 1 hour before ischemia was induced for 2 hours in a portion of jejunum; and were allowed to recover for 18 hours. Flunixin and SS treatments were repeated after 12 hours; all 3 treatments were administered immediately prior to euthanasia. Selected clinical variables, postoperative pain scores, and meloxicam pharmacokinetic data were evaluated. After euthanasia, assessment of epithelial barrier function, histologic evaluation, and western blot analysis of ischemia-injured and control jejunal mucosa samples from the 3 groups were performed.

Results—Meloxicam- or flunixin-treated horses had improved postoperative pain scores and clinical variables, compared with SS-treated horses. Recovery of transepithelial barrier function in ischemia-injured jejunum was inhibited by flunixin but permitted similarly by meloxicam and SS treatments. Eighteen hours after cessation of ischemia, numbers of neutrophils in ischemia-injured tissue were higher in horses treated with meloxicam or flu-nixin than SS. Plasma meloxicam concentrations were similar to those reported previously, but clearance was slower. Changes in expression of proteins associated with inflammatory responses to ischemic injury and with different drug treatments occurred, suggesting cy-clooxygenase-independent effects.

Conclusions and Clinical Relevance—Although further assessment is needed, these data have suggested that IV administration of meloxicam may be a useful alternative to flunixin meglumine for postoperative treatment of horses with colic.

Full access
in American Journal of Veterinary Research

Summary

Dexamethasone pharmacokinetics was studied in 10 healthy dogs receiving high-dose administration of dexamethasone (dosage, 0.1 mg/kg of body weight, iv), alone or combined with acth (dosage, 0.5 U/kg, iv), or low-dose administration of dexamethasone (dosage, 0.01 mg/kg, iv) in an incomplete cross-over design. Serum samples were obtained at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 720, 1,080, 1,440, 1,920, 2,400, and 2,880 minutes after dexamethasone administration; dexamethasone was measured by radioimmunoassay validated for use in dogs. Dexamethasone pharmacokinetics was adequately described by a two-compartment first-order open model.

Comparison of pharmacokinetics for the low- and high-dose protocols revealed dose dependence; area under the curve, mean residence time, clearance, and volume of distribution increased significantly when dexamethasone dosage increased. The elimination rate constant was significantly (P < 0.05) less, and the elimination half-life significantly greater for the high-dose protocols; however, the distribution rate constant and distribution half-life were not significantly different when high-dose protocols were compared with the low-dose protocol. Dose-dependent increases in volume of distribution and clearance may be related to saturation of protein-binding sites. Concurrent administration of acth did not affect dexamethasone disposition.

Free access
in American Journal of Veterinary Research

SUMMARY

Four methods of evaluating renal function were performed in 6 cats anesthetized with halothane in oxygen. Glomerular filtration rate (gfr) was measured simultaneously in each cat by exogenous creatinine clearance (ecc), bolus inulin clearance, and 99mTc(Sn)-diethylenetriaminepentaacetic acid (dtpa) clearance determined by 2 different methods. In the first dtpa clearance method (dtpa-1), we measured radioactivity in serial blood specimens to construct plasma disappearance curves for calculation of gfr. In the second dtpa clearance method (dtpa-2), we used serial external head counts of radioactivity and a single blood specimen to construct plasma disappearance curves for calculation of gfr. Bolus inulin clearance was calculated from plasma disappearance curves using a 1-compartment open pharmacokinetic model (IN- 1) and a 2-compartment open pharmacokinetic model (IN- 2). Glomerular filtration rates were measured over 3 hours, for creatinine and dtpa methods, and over 4 hours for the inulin methods.

The gfr obtained with the reference method (ecc) was 2.56 ± 0.61 ml/min/kg of body weight (mean ± SD). Values for gfr determined by ecc and dtpa-1 were significantly correlated (r = 0.852; P ≤ 0.05). Correlation between ecc and dtpa 2 was not as good (r = 0.783; P ≤ 0.10), but the 2 dtpa methods significantly correlated with one another (r = 0.897; P ≤ 0.05). Regardless of the method of calculation, bolus inulin clearance was poorly correlated with ecc (IN-1: r = 0.538, P ≥ 0.10; in-2: r = 0.430, P ≥ 0.10) and dtpa-1 in-1: r = 0.601, P ≥ 0.10; in-2: r = 0.625, P ≥ 0.10). The 2 methods of calculating inulin clearance were highly correlated (r = 0.927; P ≤ 0.01). The dtpa clearance calculated from directly measured plasma disappearance curves (dtpa-1) compared favorably with ecc as an estimate of gfr and appears to be a safe, reliable, and less invasive method of determining gfr in cats.

Free access
in American Journal of Veterinary Research

SUMMARY

The absorption kinetics of porcine regular insulin following iv, im, and sc administration were evaluated in 10 dogs with alloxan-induced diabetes mellitus. Plasma immunoreactive insulin (iri) concentrations were evaluated immediately prior to and at 10, 20, 30, 45, 60, 90, 120, 180, and 240 minutes following iv administration; and immediately prior to and every 30 minutes for 2 hours and then every hour for 6 hours following im and sc administration of 0.55 U of porcine regular insulin/kg of body weight. Model-independent pharmacokinetic analysis was performed on each data set.

Plasma iri concentration declined rapidly after iv administration of regular insulin and then returned to baseline iri concentration by 3.2 ± 0.8 hours. The absorption kinetics following iv administration of regular insulin were similar to those found in earlier studies in healthy dogs and human beings.

The im and sc routes of regular insulin administration resulted in a pharmacologic concentration of iri at 30 minutes. The peak mean (± SD) plasma iri concentration was significantly (P < 0.05) greater following sc administratin than it was following im administration of regular insulin (263 ± 185 and 151 ± 71 IμU/ml, respectively). The time of the peak plasma iri concentration (68 ± 31 minutes and 60 ± 30 minutes) and the time to return to baseline plasma iri concentration (5.8 ± 1.2 hours and 5.8 ± 1.3 hours) were not significantly different following sc and im administration of regular insulin, respectively. The absorption kinetics following sc administration of regular insulin were similar to those found in earlier studies in healthy dogs and human beings. The absorption kinetics following im administration of regular insulin differed from those found in earlier studies and was similar to the absorption kinetics of regular insulin administered sc in this study. The reasons for this similarity were not readily apparent.

Free access
in American Journal of Veterinary Research

SUMMARY

Norfloxacin was given to 6 healthy dogs at a dosage of 5 mg/kg of body weight iv and orally in a complete crossover study, and orally at dosages of 5, 10, and 20 mg/kg to 6 healthy dogs in a 3-way crossover study. For 24 hours, serum concentration was monitored serially after each administration. Another 6 dogs were given 5 mg of norfloxacin/kg orally every 12 hours for 14 days, and serum concentration was determined serially for 12 hours after the first and last administration of the drug. Complete blood count and serum biochemical analysis were performed before and after 14 days of oral norfloxacin administration, and clinical signs of drug toxicosis were monitored twice daily during norfloxacin administration. Urine concentration of norfloxacin was determined periodically during serum acquisition periods. Norfloxacin concentration was determined, using high-performance liquid chromatography with a limit of detection of 25 ng of norfloxacin/ml of serum or urine.

Serum norfloxacin pharmacokinetic values after single iv dosing in dogs were best modeled, using a 2-compartment open model, with distribution and elimination half-lives of 0.467 and 3.56 hours (harmonic means), respectively. Area-derived volume of distribution (Vd area) was 1.77 ± 0.69 L/kg (arithmetic mean ± sd), and serum clearance (ClS) was 0.332 ± 0.115 L/h/kg. Mean residence time was 4.32 ± 0.98 hour. Comparison of the area under the curve (AUC; derived, using model-independent calculations) after iv administration (5 mg/kg) with AUC after oral administration (5 mg/kg) in the same dogs indicated bioavailability of 35.0 ± 46.1%, with a mean residence time after oral administration of 5.71 ± 2.24 hours.

Urine concentration was 33.8 ± 15.3 μg/ml at 4 hours after a single dose of 5 mg/kg given orally, whereas concentration after 20 mg/kg was given orally was 56.8 ± 18.0 μg/ml at 6 hours after dosing. Twelve hours after drug administration, urine concentration was 47.4 ± 20.6 μg/ml after the 5-mg/kg dose and 80.6 ± 37.7 μg/ml after the 20-mg/kg dose.

Absorption lag time after oral administration ranged from 0.186 ± 0.103 hour after multiple doses (5 mg/kg) to 0.385 ± 0.254 hour after a single dose of 10 mg/kg. The AUC increased (P < 0.01) as the dose increased. However, AUC per unit dose decreased linearly with dose (P < 0.05), most probably because of a dose-dependent decrease in absorption from the gastrointestinal tract.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine clinical characteristics and clinicopathologic findings, including results of pericardial fluid analysis, and determine the outcome associated with pericardial effusion caused by cardiac lymphoma in dogs.

Design—Retrospective case series.

Animals—12 dogs.

Procedure—Medical records of affected dogs were reviewed for echocardiographic findings, radiographic findings, results of pericardial fluid analysis, clinicopathologic findings, treatment protocols, and outcomes.

Results—Pericardial effusion was detected by echocardiography in all 12 dogs, and lymphoma was detected by cytologic examination of the effusion (11/12 dogs) or histologic examination of pericardium (3/12). Large-breed dogs were overrepresented; median weight was 40.5 kg (89.1 lb). Most hematologic and biochemical changes were mild and nonspecific. Survival time for dogs treated with combination chemotherapeutic agents was 157 days and for dogs that did not receive chemotherapy survival time was 22 days. This difference was not significant, but several dogs had long-term survival.

Conclusions and Clinical Relevance—Cardiac lymphoma is an uncommon cause of pericardial effusion, and results suggest that cardiac lymphoma does not always warrant the poor prognosis of other stage V, substage b lymphomas. (J Am Vet Med Assoc 2005; 227:1449–1453)

Full access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To determine the interobserver variability of assessment of exercise-induced pulmonary hemorrhage (EIPH) during tracheobronchoscopic examination in horses.

Animals—747 Thoroughbred racehorses.

Procedure—850 tracheobronchoscopic examinations were performed within 2 hours of racing for the horses. Examinations were recorded on videotape, and EIPH and its severity were assessed independently by 3 veterinarians. Concordance was determined by calculation of the Cohen weighted κ statistic and tabulation of scores assigned by each observer.

Results—Weighted κ statistics ranged from 0.75 to 0.80. In 99.4% of observations, all observers agreed or 2 of 3 agreed and the third differed by ≤ 1 grade.

Conclusions and Clinical Relevance—Results indicated that interobserver reliability of tracheobronchoscopic assessment of EIPH in Thoroughbred racehorses is high when the examination is conducted by experienced veterinarians. Concordance among investigators is sufficient to justify use of this grading system for further studies and clinical descriptions of EIPH. (Am J Vet Res 2005;66:596–598)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether exercise-induced pulmonary hemorrhage (EIPH) was associated with racing performance in Thoroughbred horses not medicated with furosemide and not using nasal dilator strips.

Design—Observational cross-sectional study.

Animals—744 two- to 10-year-old Thoroughbred horses racing in Melbourne, Australia.

Procedure—Horses were enrolled prior to racing, and a tracheobronchoscopic examination was performed after 1 race. Examinations were recorded on videotape, and presence and severity (grade 0 to 4) of EIPH were subsequently determined by 3 observers blinded to the horses' identity. Race records were abstracted for each horse examined.

Results—Overall, 52.1% of horses eligible for participation in the study were examined, and horses that were examined did not differ from horses that were not examined in regard to age, sex distribution, or proportion of horses that won or finished in the first 3 positions. Horses with EIPH grades ≤ 1 were 4.0 times as likely to win, 1.8 times as likely to finish in the first 3 positions, and 3.03 times as likely to be in the 90th percentile or higher for race earnings as were horses with grades ≥ 2. Horses with EIPH grades ≥ 1 finished significantly farther behind the winner than did horses without EIPH. However, odds that horses with grade 1 EIPH would win or finish in the first 3 positions were not significantly different from odds for horses without EIPH.

Conclusions and Clinical Relevance—Results suggest that EIPH is associated with impaired performance in Thoroughbred racehorses not medicated with furosemide and not using nasal dilator strips. ( J Am Vet Med Assoc 2005;227:768–774)

Full access
in Journal of the American Veterinary Medical Association