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in Journal of the American Veterinary Medical Association

Objective

To determine the pharmacokinetics of gentamicin sulfate in healthy llamas after IV administration of a single bolus and after repeated parenteral administration.

Design

Prospective clinical trial.

Animals

19 clinically normal, adult male llamas for the single-dose trial and 10 of the 19 llamas for the multiple-dose trial.

Procedure

In the first trial, llamas were given gentamicin (5 mg/kg of body weight, IV) as a single bolus, and serum gentamicin concentration was monitored over the next 48 hours. 2 months later, llamas were given gentamicin (2.5 mg/kg) IV for the first day, then IM every 8 hours for 7 days. Serum gentamicin concentration and indices of renal function and damage were monitored during the 7 days.

Results

There were no significant dose- or time-related differences in clearance of the drug; volume of distribution; apparent coefficients of the distribution and elimination phases, α and β, respectively; mean residence time; or distribution (t½α) and elimination phase (tt/2β) half-lives. The 5 mg/kg IV kinetic study revealed t½β, of 14.5 ± 5.06 minutes and t½β of 166 ± 20.5 minutes. The 2.5 mg/kg IV kinetic study revealed t½α of 17.7 ± 6.59 minutes and t½β of 165 ± 40.3 minutes. Peak serum gentamicin concentration averaged 10.10 μg/ml in the multiple-dose trial, and trough concentration averaged 1.50 μg/ml.

Conclusions

Dose effects were not observed for gentamicin clearance, volume of distribution, or half-lives. Multiple dosing at 2.5 mg/kg every 8 hours does not appear to cause renal impairment in healthy llamas.

Clinical Relevance

Gentamicin pharmacokinetic variables in llamas appear to resemble those in other ruminant species. (Am J Vet Res 1996;57:1193–1199)

Free access
in American Journal of Veterinary Research

Objective—

Comparison of diagnostic accuracy of results of low-dose dexamethasone suppression (LDDS) and ACTH stimulation tests with necropsy findings in 81 dogs.

Design—

Retrospective study.

Animals—

81 dogs that had undergone screening tests for hyperadrenocorticism and that had a complete necropsy report.

Procedure—

Medical records were evaluated for results of CBC, serum biochemical analysis, urinalysis, endocrine testing, signalment, treatment, and necropsy findings. Each dog was definitively classified as having true-positive, true-negative, false-positive, or false-negative results. Statistical analyses included determination of prevalence, apparent prevalence, accuracy, number of dogs misclassifled, sensitivity, specificity, and posltive-and negative-predictive values.

Results—

Of the 81 dogs that fit the criteria for selection, 40 (49%) were confirmed as having hyperadreno-corticism (30 had pituitary-dependent disease and 10 had adrenal gland tumors). Forty-one dogs had illnesses attributable to a cause other than disease of the adrenal glands. Sensitivity of ACTH stimulation and LDDS tests were 95 and 96%, respectively. Specificity for the ACTH stimulation test was higher (91%) than that of the LDDS test (70%). When prevalence of the disease in the study population was taken into consideration, the positive-predictive value for the ACTH stimulation test was 91%, compared with 76% for the LDDS test.

Clinical Implications—

The ACTH stimulation test was more specific than the LDDS test, although sensitivity was similar for both tests. The ACTH stimulation test also had a significantly higher positive-predictive value than the LDDS test when a prevalence of 25% was taken into consideration. (J Am Vet Med Assoc 1997;211:322–325)

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in Journal of the American Veterinary Medical Association

Summary

Systolic, diastolic, and mean arterial blood pressure were measured by femoral artery puncture every other day in 2 groups (n = 4) of partially nephrectomized (approx 75%) dogs fed 2 concentrations of dietary sodium beginning 9 weeks after partial nephrectomy was completed. In a double crossover design, dogs were fed a low-sodium (0.18% sodium on a dry-weight basis) or high-sodium (1.3% sodium on a dry-weight basis) diet in 2 sequences (l/h/l or h/l/h) for 3 consecutive 4-week observation periods. Significant effect of sequence was found in dogs fed the l/h/l sequence, compared with those fed the h/l/h sequence. Systolic blood pressure was significantly (P < 0.05) increased in dogs fed the l/h/l sequence (175 ± 16 mm of Hg), compared with dogs fed the h/l/h sequence (156 ± 14 mm of Hg). Mean arterial blood pressure was higher, but not significantly different, for the l/h/l sequence (116 ± 8 mm of Hg) vs the h/l/h sequence (109 ± 6 mm of Hg). Significant difference in diastolic pressure was not observed between the l/h/l (86 ± 10 mm of Hg) and h/l/h (86 ± 10 mm of Hg) sequences. Restricted sodium intake (0.18% sodium on a dry-weight basis) was associated with moderate systolic hypertension in dogs with experimentally induced chronic renal disease. Acute fluctuations in dietary sodium intake had no apparent immediate effect on blood pressure in dogs with this mild to moderate degree of renal dysfunction.

Free access
in American Journal of Veterinary Research

Summary

Eighteen 6-month-old male Beagles with normal renal function were allotted at random to 3 groups of 6 dogs each. For 21 days, each group was fed a diet that was similar except for protein content (high protein, 27.3%; medium protein, 13.7%; and low protein, 9.4%). After the conditioning period, gentamicin was administered at a dosage of 10 mg/kg of body weight, IM, every 8 hours for 8 days, and the respective diet was continued. Clearance of endogenous creatinine, 24-hour urinary excretion of protein and enzymes (γ-glutamyltransferase, and N-acetyl- β-d-glucosaminidase, and fractional clearance of sodium and potassium (%) were determined before and after dietary protein conditioning and on days 2, 4, 6, and 8 of gentamicin administration. Additionally, trough serum gentamicin concentration was determined on days 2, 4, 6, and 8 of gentamicin administration. At the end of the study, all dogs were euthanatized; renal histologic features were graded, using a continuous ranking scale, and renal cortical gentamicin concentrations were measured. Data were ranked and analyzed, using a nonparametric equivalent of a two-way anova; P < 0.05 was considered significant.

After the dietary conditioning period (prior to gentamicin), dogs fed the high-protein diet had higher endogenous creatinine clearance and urinary excretion of protein, compared with dogs fed the low-protein diet. Differences existed among groups after 8 days of gentamicin administration. Dogs fed the high-protein diet had higher creatinine clearance, lower serum creatinine concentration, lower fractional clearance of sodium, lower urinary excretion of N-acetyl-β-d-glucosaminidase and lower trough serum gentamicin concentration, compared with dogs fed the medium- and low-protein diets. Dogs fed the high-protein diet also had lower urinary excretion of protein and lower fractional clearance of potassium, compared with dogs fed the low-protein diet. There was no difference in urinary excretion of γ-gluta-myltransferase among groups on day 8 of the study. Proximal tubular necrosis was more severe in dogs fed the medium-protein diet, compared with dogs fed the high-protein diet; however, there were no differences in renal cortical gentamicin concentrations among groups. In conclusion, feeding the high-protein diet prior to and during gentamicin administration reduced nephrotoxicosis in these dogs.

Free access
in American Journal of Veterinary Research

Summary

Exogenous creatinine clearance rate was determined in 8 partially (approx 75%) nephrectomized dogs fed 2 concentrations of dietary sodium, beginning 9 weeks after partial nephrectomy was performed. In a double crossover design, dogs were then fed low-sodium diet (0.18% sodium on a dry-weight basis) or high-sodium diet (1.3% sodium on a dry-weight basis) in 2 sequences (l/h/l or h/l/h) for 3 consecutive 4-week observation periods. Glomerular filtration rate (gfr) was measured by exogenous creatinine clearance before and after partial nephrectomy, and every 2 weeks during the experimental diet periods. Initial mean ± sd gfr (3.76 ± 0.78 ml/min/kg of body weight) decreased precipitously after nephrectomy (1.25 ± 0.45 ml/min/kg); however, during the postnephrectomy and experimental diet periods, gfr gradually increased in all dogs to nearly half the prenephrectomy values (1.87 ± 0.22 ml/min/kg). Significant differences ingfr were not observed when dogs were fed the l/h/l or the h/l/h sequence. Therefore, it was concluded that abrupt change from high dietary sodium (1.3%) to restricted dietary sodium (0.18%), or vice versa, does not cause deterioration of renal function in dogs with moderate renal impairment. However, caution should be used in extrapolating these findings to dogs with clinically evident (azotemia, isosthenuria) renal failure.

Free access
in American Journal of Veterinary Research

Objective

To describe the clinicopathologic characteristics of dogs with hyperadrenocorticism and concurrent pituitary and adrenal tumors.

Design

Retrospective study.

Animals

17 client-owned dogs.

Procedure

Signalment, response to treatment, and results of CBC, serum biochemical analysis, urinalysis, endocrine testing, and histologic examinations were obtained from medical records of dogs with hyperadrenocorticism and concurrent adrenal and chromophobe pituitary tumors.

Results

On the basis of results of adrenal function tests and histologic examination of tissue specimens collected during surgery and necropsy, concurrent pituitary and adrenal tumors were identified in 17 of approximately 1,500 dogs with hyperadrenocorticism. Twelve were neutered females, 5 were males (3 sexually intact, 2 neutered); and median age was 12 years (range, 7 to 16 years). Hyperadrenocorticism had been diagnosed by use of low-dose dexamethasone suppression tests and ACTH stimulation tests. During high-dose dexamethasone suppression testing of 16 dogs, serum cortisol concentrations remained high in 11 dogs but decreased in 5 dogs. Plasma concentrations of endogenous ACTH were either high or within the higher limits of the reference range (12/16 dogs), within the lower limits of the reference range (2/16), or low (2/16). Adrenal lesions identified by histologic examination included unilateral cortical adenoma with contralateral hyperplasia (10/17), bilateral cortical adenomas (4/17), and unilateral carcinoma with contralateral hyperplasia (3/17). Pituitary lesions included a chromophobe microadenoma (12/17), macroadenoma (4/17), and carcinoma (1/17).

Clinical Implications

Pituitary and adrenal tumors can coexist in dogs with hyperadrenocorticism, resulting in a confusing mixture of test results that may complicate diagnosis and treatment of hyperadrenocorticism. (J Am Vet Med Assoc 1999;214:1349–1353)

Free access
in Journal of the American Veterinary Medical Association

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

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 effects of various diets on the pharmacokinetics of phenobarbital and the interactive effects of changes in body composition and metabolic rate.

Design—Prospective study.

Animals—27 healthy sexually intact adult female Beagles.

Procedure—Pharmacokinetic studies of phenobarbital were performed before and 2 months after dogs were fed 1 of 3 diets (group 1, maintenance diet; group 2, protein-restricted diet; group 3, fat- and protein-restricted diet) and treated with phenobarbital (approx 3 mg/kg [1.4 mg/lb] of body weight, PO, q 12 h). Pharmacokinetic studies involved administering phenobarbital (15 mg/kg [6.8 mg/lb], IV) and collecting blood samples at specific intervals for 240 hours. Effects of diet and time were determined by repeated-measures ANOVA.

Results—Volume of distribution, mean residence time, and half-life (t1/2) of phenobarbital significantly decreased, whereas clearance rate and elimination rate significantly increased with time in all groups. Dietary protein or fat restriction induced significantly greater changes: t1/2 (hours) was lower in groups 2 (mean ± SD; 25.9 ± 6.10 hours) and 3 (24.0 ± 4.70) than in group 1 (32.9 ± 5.20). Phenobarbital clearance rate (ml/kg/min) was significantly higher in group 3 (0.22 ± 0.05 ml/kg/min) than in groups 1 (0.17 ± 0.03) or 2 (0.18 ± 0.03). Induction of serum alkaline phosphatase activity (U/L) was greater in groups 2 (192.4 ± 47.5 U/L) and 3 (202.0 ± 98.2) than in group 1 (125.0 ± 47.5).

Conclusions and Clinical Relevance—Clinically important differences between diet groups were observed regarding pharmacokinetics of phenobarbital, changes in CBC and serum biochemical variables, and body composition. Drug dosage must be reevaluated if a dog's diet, body weight, or body composition changes during treatment. Changes in blood variables that may indicate liver toxicosis caused by phenobarbital may be amplified by diet-drug interactions. (J Am Vet Med Assoc 2000;217:847–852)

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in Journal of the American Veterinary Medical Association