Estimation of Quantitative Enzymuria in Dogs With Gentamicin-Induced Nephrotoxicosis Using Urine Enzyme/Creatinine Ratios From Spot Urine Samples

The correlation between 24-hour urinary excretion of N -acetyl-β- d -glucosaminidase (NAG) and γ-glutamyl transferase (GGT) with urine NAG and GGT/creatinine ratios was assessed in dogs with gentamicin-induced nephrotoxicosis. Eighteen 6-month-oid male Beagles with normal renal function were randomly divided into 3 groups of 6. Each group was fed a different concentration of protein (high protein, 27.3%; medium protein, 13.7%; and low protein, 9.4%) for 21 days. After dietary conditioning, gentamicin was administered at a dose of 10 mg/kg IM tid for 8 days and each group was continued on its respective diet. Endogenous creatinine clearance and 24-hour urinary excretion of NAG and GGT were determined after dietary conditioning (day 0) and on days 2, 4, 6, and 8 of gentamicin administration. In addition, urine NAG and GGT/creatinine ratios (IU/L ± mg/dL) were determined from catheterized spot urine samples obtained between 7 and 10 am on the same days. The correlation between 24-hour urinary enzyme excretion and urine enzyme/creatinine ratio in the spot urine samples was evaluated by simple linear regression analysis. Spot sample urine enzyme/creatinine ratios were significantly correlated with 24-hour urinary enzyme excretion through day 4 for dogs on low dietary protein, through day 6 for those on medium protein, and through day 8 for those on high dietary protein. Mean ± SD baseline values for urine NAG/creatinine ratio and 24-hour urinary NAG excretion were 0.06 ± 0.04 and 0.19 ± 0.14 IU/kg/24 hr, respectively. Baseline values for urine GGT/creatinine ratio and 24-hour urinary GGT excretion were 0.39 ± 0.18 and 1.42 ± 0.82 IU/kg/24 hr, respectively.     

Effect of diet on gentamicin-induced nephrotoxicosis in horses.

Gentamicin sulfate-induced nephrotoxicosis was compared in 2 groups of horses fed different rations. Four horses were fed only alfalfa hay, and 4 other horses were fed only whole oats. Seven days after initiation of the diet, all horses were given gentamicin IV (5 mg/kg of body weight) every 12 hours for 22 days. Urinary gamma-glutamyl-transferase to urinary creatinine (UGGT:UCr) ratio was calculated daily, and serum concentration of gentamicin was measured at 1 and 12 hours after drug administration. Results indicated that horses fed oats had greater renal tubular damage than did horses fed alfalfa. Mean UGGT:UCr for horses fed alfalfa was 47.1 +/- 18.8 and was 100.0 +/- 19.0 for horses fed oats (P = 0.007). The UGGT:UCr in horses fed oats was greater than 100 for a total of 54 days; horses fed alfalfa had UGGT:UCr greater than 100 for only 7 days. Two horses not given gentamicin were fed only oats and 2 were fed only alfalfa. These horses had mean UGGT:UCr of 17.6 +/- 2.2 and 30.5 +/- 3.0, respectively. Mean peak and trough concentrations of gentamicin were statistically different for horses fed oats and those fed alfalfa (peak 23.16 +/- 1.87 and 14.07 +/- 1.79 micrograms/ml, respectively [P = 0.0001], and trough, 1.81 +/- 0.69 and 0.71 +/- 0.70 micrograms/ml, respectively [P = 0.0270]). Mean half-lives of gentamicin (estimated from peak and trough concentrations) for horses fed alfalfa (2.58 +/- 0.26 hours) and horses fed oats (2.88 +/- 0.27 hours) were not significantly different. Horses fed only oats had greater degree of gentamicin-induced nephrotoxicosis than did those fed only alfalfa.     

Effect of time of cisplatin administration on its toxicity and pharmacokinetics in dogs.

Cisplatin (90 mg/m2) was administered in a 5-minute bolus IV infusion to dogs at 8 AM (n = 6) or 4 PM (n = 6). Blood and urine samples were collected over a 4-hour period for statistical moment pharmacokinetic analysis. Mean urinary excretion rate of total platinum was increased, whereas mean plasma residence time of ultrafilterable platinum was decreased, in the group treated at 4 PM (PM group), compared with those treated at 8 AM (AM group). Over a 2-week postinfusion-monitoring period, both groups of dogs developed decreases in creatinine clearance, urine/serum osmolality ratio (UOsm/SOsm), specific gravity, and increase in BUN, serum creatinine concentration, urine gamma-glutamyltranspeptidase/urine creatinine ratio (UGGT/UCr), fractional excretion of magnesium, and fractional excretion of phosphate. Urine specific gravity and UOsm/SOsm were significantly decreased, whereas UGGT/UCr and BUN were significantly increased in the AM group, compared with the PM group. The time of administration had a significant effect on the pharmacokinetics of cisplatin, which resulted in significant differences in cisplatin-induced renal toxicosis.     

The Effects of Cyclosporine Versus Standard Care in Dogs With Naturally Occurring Glomerulonephritis

Glomerulonephritis (GN) is a leading cause of chronic renal failure in dogs. However, little is known about the efficacy of available treatment options for GN in this species. The purpose of this study was to determine the effects of cyclosporine (Cy) administration on the outcome of naturally occurring GN in dogs. Thirteen dogs from 4 institutions were included in the study. Randomization of dogs into placeboversus Cy-treated groups was stratified according to initial morphological diagnosis and contributing institution. Seven and 6 dogs were assigned to be given placebo or Cy, respectively. The initial Cy dose of 10 mg/kg every 24 hours was adjusted to maintain 24-hour trough, whole blood Cy concentrations between 250 and 400 ng/mL. There were no statistically significant differences between placebo-and Cy-treated groups with respect to serum total protein, albumin, urea nitrogen and creatinine, and plasma protein concentrations; platelet count; urine protein-creatinine ratio; endogenous creatinine clearance; 24-hour urine protein concentrations; or 24-hour urine protein—endogenous creatinine clearance ratio. However, PCV was significantly lower in the Cy-treated group. Decreased appetite, diarrhea, vomiting, weight loss, involuntary shaking, and thrombocytopenia were noted in both treatment groups; however, clinical signs in Cy-treated dogs subjectively were more severe. One Cy-treated dog developed gingival hyperplasia. After entry into the study, the median survival times for placebo-and Cy-treated dogs were 16 and 11 months, respectively. Considering the expense and the frequency of adverse effects related to Cy administration, the use of Cy in the treatment of dogs with GN does not seem warranted.     

Effects of general anesthesia and surgery on renal function in healthy dogs

OBJECTIVES: To evaluate renal function in healthy dogs undergoing general anesthesia and ovariohysterectomy without concurrent IV administration of fluids. ANIMALS: 35 healthy client-owned dogs. PROCEDURE: Dogs were medicated with promazine hydrochloride (0.05 mg/kg of body weight, SC) approximately 45 minutes before induction of anesthesia with thiopental sodium (10 to 15 mg/kg, IV). Anesthesia was maintained with 2% halothane in oxygen. Ovariohysterectomies were performed by senior veterinary students under the direct supervision of a veterinary surgeon. Renal function was assessed (serum urea and creatinine concentrations, fractional clearance of sodium, urine alkaline phosphatase [ALP] and gamma-glutamyltransferase [GGT] activities, urine specific gravity, and enumeration of renal tubular epithelial cells in urine sediment) prior to and 24 and 48 hours after surgery. RESULTS: Duration of general anesthesia ranged from 80 to 310 minutes. Urine specific gravity and ALP activity and serum urea and creatinine concentrations did not change over time. Fractional clearance of sodium decreased 24 and 48 hours after surgery, whereas urine GGT activity and the ratio of urine GGT activity to urine creatinine concentration increased 24 hours after surgery, compared with presurgery values. Renal tubular epithelial cells increased in number in urine sediment from 11 of 35 (31.4%) dogs and 5 of 35 (14.3%) dogs 24 and 48 hours after surgery, respectively. However, this increase was not clinically relevant. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous administration of fluids to healthy dogs undergoing general anesthesia and elective surgery may not be necessary for maintenance of renal homeostasis.     

QUANTITATIVE AND QUALITATIVE SCINTIGRAPHIC MEASUREMENT OF RENAL FUNCTION IN DOGS EXPOSED TO TOXIC DOSES OF GENTAMICIN

Five, 3-month-old mongrel dogs weighing between 4.5 to 5.5 kg were studied to evaluate and compare the efficiency of 99mTc-DTPA, 99mTc-MAG3, and 99mTc-DMSA in detecting gentamicin-induced renal tubular injury. After baseline renograms using all three methods, all dogs received daily intramuscular injections of gentamicin at a dose of 30-45 mg/kg. Additional studies were obtained after a cumulative dose of 450, 1,575, and 2,250 mg of gentamicin was reached. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and percentage of total renal uptake measurements were calculated. Baseline and post-gentamicin injection blood urea nitrogen (BUN) and serum creatinine values were determined. A Duncan test revealed significant renal function impairment at 450 mgs of cumulated gentamicin with 99mTc-DMSA and at 1,575 mgs of cumulated gentamicin for 99mTc-DTPA and 99mTc-MAG3. There was no correlation between BUN and serum creatinine values when compared to gentamicin (p > 0.05). The images obtained with 99mTc-MAG3 were of better quality than those obtained with 99mTc-DTPA even under severe renal dysfunction. Percentage of 99mTc-DMSA uptake indicated renal damage, before than GFR and ERPF. BUN and serum creatinine measurements were poor indicators of gentamicin-induced renal failure.     

Effects of dietary protein/phosphate restriction in normal dogs and dogs with chronic renal failure

The effects of three dietary protein intakes (1–9, 1–3, and 0–6 g protein/kg bodyweight/day) on selected aspects of protein, mineral and electrolyte balance as well as renal functions was studied in normal dogs with moderate chronic renal failure. Dietary phosphate levels varied according to the quantity of phosphate in protein sources. Within the ranges of protein intake examined in this study, protein intake did not have a significant effect on glomerular filtration rates as measured by inulin clearance or 24-hour creatinine clearance. Restricting protein intake to less than 1–9 g protein/kg bodyweight/day further reduced retention of nitrogenous waste products as measured by serum urea nitrogen concentrations, but at the expense of adequate protein nutrition. Diets providing less than 1–9 g protein/kg bodyweight/day promoted protein malnutrition characterised by hypoproteinaemia and hypoalbuminaemia in both normal dogs and dogs with renal failure. Serum protein concentrations were similar in normal and renal failure dogs, suggesting that, under the conditions of this study, normal and renal failure dogs may have similar protein requirements. Progressive dietary protein/phosphate restriction improved but did not normalise phosphate balance in renal failure dogs.     

Plasma exogenous creatinine clearance test in dogs: comparison with other methods and proposed limited sampling strategy

Plasma clearance of creatinine was evaluated for assessment of glomerular filtration rate (GFR) in dogs. In 6 healthy dogs (Experiment 1), we determined 24-hour urine clearance of endogenous creatinine, plasma, and urine clearances of exogenous creatinine administered at 40, 80, and 160 mg/kg in a crossover design (linearity study), plasma iothalamate clearance, and plasma and urine clearances of 14C-inulin. In Experiment 2, plasma creatinine and iothalamate clearances were compared, and a linearity study was performed as for Experiment 1 in 6 dogs with surgically induced renal impairment. Experiment 3 compared plasma creatinine clearance with plasma iothalamate clearance before and 3 weeks after induction of moderate renal impairment in 6 dogs. Plasma creatinine clearances were calculated by both noncompartmental and compartmental analyses. In Experiment 1, plasma inulin clearance was higher (P < .001) than other clearance values. Plasma creatinine clearances at the 3 dose rates did not differ from urine inulin clearance and each other. In Experiment 2, plasma creatinine clearances were about 14% lower than plasma iothalamate clearance (P < .05). In Experiment 3, decreases in GFR assessed by plasma clearances of iothalamate and creatinine were similar. Renal failure decreased the daily endogenous input rate of creatinine by 25%. Limiting sampling strategies for optimizing GFR calculation were proposed, allowing an error lower than 6.5% with 4 blood samples. These results suggest that determination of plasma creatinine clearance by a noncompartmental approach offers a reliable, inexpensive, rapid, and convenient means of estimating GFR in routine practice.     

Phenolsulfonphthalein pharmacokinetics and renal morphologic changes in adult pony mares with gentamicin-induced nephrotoxicosis

Changes in renal function, determined by pharmacokinetics of phenolsulfonphthalein (PSP), and renal morphologic features were examined in adult pony mares given 20 mg of gentamicin sulfate/kg of body weight, IV, q 8 h (group A) n = 7 or isotonic saline solution, IV, q 8 h, n = 5 (group B) for 14 days. Susceptibility of ponies to gentamicin-induced nephrotoxicosis was varied. Two group-A ponies developed acute renal failure and were euthanatized before treatment day 14, whereas 5 group-A A ponies did not develop physical or behavioral abnormalities after 14 days of gentamicin administration. All group-A ponies but none of group-B ponies developed ultrastructural abnormalities of the proximal tubular epithelium, consistent with gentamicin-induced nephrotoxicosis. Significant (P less than 0.05) differences were not detected in pharmacokinetic values of either group. Clearance of PSP was reduced in 4 group-A ponies that developed the most severe gentamicin-induced nephrotoxicosis. Changes in clearance of PSP were significantly (P less than 0.05) correlated with changes in the serum creatinine concentration.     

Clinical evaluation of glomerular function: 24-hour creatinine clearance in dogs.

Methods of renal clearance to measure glomerular filtration rate (GFR) were compared with plasma creatinine concentration in clinically normal and partially nephrectomized dogs. Glomerular filtration rate was measured by use of a simple 24-hour creatinine clearance method in 36 normal female Beagles. Mean values were 57.6 +/- 9.3 ml/minute/m2 of body surface or 3.7 +/- 0.77 ml/minute/kg of body weight. Variability of this measurement was considerable, as determined in 4 dogs studied on 4 consecutive days. Glomerular filtration rate was measured in the same 36 dogs while they were under anesthesia, using short clearance periods to compare inulin and endogenous creatinine clearance. Mean values for inulin were 41.8 +/- 13.9 ml/minute/m2 of body surface. A close agreement with creatinine clearance was found (correlation coefficient, 0.998). Mean plasma creatinine concentration was 0.82 (range, 0.5--1.0) mg/100 ml. The value of GFR measurement compared with plasma creatinine concentration was determined in 10 dogs after 75% nephrectomy. Sixty days after partial nephrectomy, GFR was reduced to 61% of normal. Mean plasma creatinine and blood urea nitrogen were 1.2 +/- 0.14 mg/100 ml and 20.4 +/- 7.1 mg/100 ml, respectively. Thus, the detection of reduced renal function may be uncertain when plasma creatinine or blood urea nitrogen are used as a means of evaluating renal function. It was concluded that a simple method of creatinine clearance is a sensitive and useful measurement to detect early or borderline reduction in glomerular function.     

Evaluation of a one-hour saline diuresis protocol for administration of cisplatin to dogs.

A study was undertaken to determine the toxic effects of cisplatin, an antineoplastic agent, when administered immediately after a 1-hour saline diuresis. Four treatments with cisplatin (70 mg/m2 of body surface, q 3 wk) were administered IV to 6 healthy dogs over a 20-minute period after 0.9% NaCl (saline) solution was administered IV for 1 hour at a volume of 132 ml (kg)0.75. Each dog vomited at least once within 8 hours after each treatment was administered. Clinical status, body weight, and food consumption were normal throughout the 12-week study for 5 of the 6 dogs. The sixth dog developed acute renal failure and became acutely blind and deaf within 3 days after the fourth treatment with cisplatin. Serum electrolyte, creatinine, and urea nitrogen values remained within established normal limits in all dogs immediately prior to each treatment, and in 5 of 6 dogs evaluated 3 weeks after the final treatment. The serum creatinine value (3.3 mg/dl) obtained from the Beagle euthanatized 2 weeks after the fourth treatment was above established normal values. Despite normalcy for all but 1 of the creatinine values, serum creatinine concentration obtained 3 weeks after the final treatment with cisplatin was significantly (P = 0.0001) higher than pretreatment values. When compared with data from all other evaluation periods, significant decreases in glomerular filtration rate, as determined by exogenous (P less than or equal to 0.0001) and endogenous (P less than or equal to 0.0001) creatinine clearance testing, were identified 3 weeks after the fourth treatment with cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of renal function in cats, using quantitative urinalysis

Two consecutive 24-hour quantitative urinalyses were performed on each of 12 healthy adult cats to evaluate the technique and obtain reference values for measurements of urinary excretion of several substances. Endogenous creatinine clearance (2.31 +/- 0.47 ml/min/kg) and urinary protein excretion (17.43 +/- 9.05 mg/kg/day) were determined. Additionally, clearances and ratios to creatinine clearances were calculated for phosphate, sodium, potassium, and chloride. The endogenous creatinine clearance value was compared with another estimate of glomerular filtration rate that was based on 99mTc(Sn) diethylene-triaminepentaacetic acid clearance (2.52 +/- 0.58 ml/min/kg). Evaluation of feline renal function, using 24-hour quantitative urinalysis techniques, has potential for clinical application, but has several important limitations as well.     

Effects of Glucocorticoid Therapy on Urine Protein-to-Creatinine Ratios and Renal Morphology in Dogs

Glomerulonephritis has been associated with exogenous glucocorticoid administration and spontaneous hyperadrenocorticism in the dog. The purpose of this study was to determine the effects of long-term glucocorticoid therapy on urine protein:creatinine ratios (UP/Cs) and renal morphology. Nine young-adult male dogs were determined to be healthy and have normal renal function as assessed by physical examination, CBC, serum biochemistry analysis, Knott's test for Dirofilaria immitis , urinaly-sis, urine culture, urine protein electrophoresis, endogenous creatinine clearance, 24-hour urinary protein excretion, and UP/C. Prednisone was administered to each dog at a dosage of 2.2 mg/kg PO bid for 42 days. Urinalysis and UP/C were performed on days 0, 7, 14, 21, 28, and 42 of treatment. Mean UP/C on day 0 was 0.29 ± 0.10. Mean UP/C increased progressively to a maximum of 1.27 ± 1.02 on day 28. Mean UP/C on day 42 decreased slightly (0.92 ± 0.56) but remained significantly increased above baseline.
The most consistent renal light microscopic finding on necropsy examination was generalized hypercellular glomerular tufts, suggestive of mesangial cell proliferation. Four dogs also had occasional adhesions of glomerular tufts to Bowman's capsule, accompanied by thickening of the capsule. Direct immunofluorescence for immunoglobulin deposition was negative in all dogs. Electron microscopy, evaluated in 7 dogs, was characterized by occasional mild segmental thickening of basement membranes, fusion of visceral cell foot processes, and glomerular adhesions. The results of this study indicate that long-term administration of glucocorticoids results in significant proteinuria and glomerular changes in the dog.     

Effect of Experimental Hypothyroidism on Glomerular Filtration Rate and Plasma Creatinine Concentration in Dogs

Background: Hypothyroidism affects renal function in a manner opposite the effects of hyperthyroidism.
Objective: To evaluate the effects of experimentally induced hypothyroidism on glomerular filtration rate (GFR) and basal plasma creatinine concentration in dogs.
Animals: Sixteen anestrous, female dogs.
Methods: Hypothyroidism was induced by administration of ¹³¹I in 8 dogs, and 8 healthy euthyroid dogs acted as controls. Exogenous plasma creatinine clearance (an estimate of GFR) was measured in all dogs before (control period) and 43–50 weeks after induction of hypothyroidism (posttreatment period). Other pharmacokinetic parameters of creatinine were also determined.
Results: No significant difference was observed for basal plasma creatinine concentration and creatinine clearance between control and hypothyroid dogs in the control period. In the posttreatment period, mean ± SD creatinine clearance in the hypothyroid group (2.13 ± 0.48 mL/min/kg) was lower ( P < .001) than that of the control group (3.20 ± 0.42 mL/kg/min). Nevertheless, basal plasma creatinine concentrations were not significantly different between the hypothyroid and control groups (0.74 ± 0.18 versus 0.70 ± 0.08 mg/dL, respectively) because endogenous production of creatinine was decreased in hypothyroid dogs (22 ± 3 versus 32 ± 5 mg/kg/d, P =.001).
Conclusion and Clinical Importance: Hypothyroidism causes a substantial decrease in GFR without altering plasma creatinine concentrations, indicating that GFR evaluation is needed to identify renal dysfunction in such patients.     

Drug disposition and dosage determination of once daily administration of gentamicin sulfate in horses after abdominal surgery.

OBJECTIVE: To evaluate pharmacokinetics of once daily i.v. administration of gentamicin sulfate to adult horses that had abdominal surgery. DESIGN: Prospective study. ANIMALS: 28 adult horses that underwent abdominal surgery for colic. PROCEDURE: 14 horses were treated with each dosage of gentamicin (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) and blood samples were collected for pharmacokinetic analysis. Plasma gentamicin concentrations were measured by use of a fluorescence polarization immunoassay. Pharmacokinetic analysis measured the elimination half-life, volume of distribution, and gentamicin total systemic clearance. Treatment outcome, CBC, and serum creatinine concentrations were recorded. RESULTS: 1 horse in the high-dosage group died. All other horses successfully recovered, and did not develop bacterial infection or have evidence of drug toxicosis resulting in renal injury. Mean pharmacokinetic variables for gentamicin administration at a high or low dosage (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) were half-life of 1.47 and 1.61 hours, volume of distribution of 0.17 and 0.17 L/kg, and systemic clearance of 1.27 and 1.2 ml/kg/min, respectively. Mean serum creatinine concentration was 1.74 and 1.71 for the high and low dosages, respectively, and serum creatinine concentration was not correlated with gentamicin clearance. CONCLUSIONS AND CLINICAL RELEVANCE: Gentamicin administration at a dosage of 4 mg/kg, i.v., every 24 hours, will result in plasma concentrations that are adequate against susceptible bacteria with a minimum inhibitory concentration (MIC) of < or = 2.0 micrograms/ml. Gentamicin administration at a calculated dosage of 6.8 mg/kg, i.v., every 24 hours will result in optimum plasma concentrations against susceptible bacteria with a MIC of < or = 4.0 micrograms/ml.     

Dose-dependent pharmacokinetics of gentamicin in sheep

Dose-related changes in the pharmacokinetics of gentamicin sulfate were investigated in 9 sheep given 3, 10, or 20 mg/kg of body weight IV in a crossover design with a 24-day washout period. The pharmacokinetics of the 3 mg/kg single dose were compared with that of the terminal phase pharmacokinetics of 3 mg of gentamicin/kg IV every 8 hours for 7 days in 8 additional sheep. Serum concentrations were monitored for 21 to 24 days after the dose. Polyexponential equations were fit to each data set. The number of exponential terms was determined by optimizing the fit for each data set. The pharmacokinetics of the 3 mg/kg single dose were mainly described by triexponential equations. The 10 mg/kg and the 20 mg/kg single doses and the 3 mg/kg multiple-dose data were described by a tetraexponential equation. The elimination rate constant was significantly smaller (P less than 0.05) after the larger single doses, and the serum gentamicin clearance increased as the dose increased (P less than 0.05). The crossover design sequence had a significant effect on serum gentamicin clearance and the area under the curve normalized to unit dose (P less than 0.01). The final exponential phase was not detectable with the present assay sensitivity under the 3 mg/kg single dose. The triexponential equation underpredicted the terminal serum concentrations determined after the 3 mg/kg multiple dose, whereas the 4 phase equation overpredicted the same terminal serum concentrations, perhaps reflecting saturation of the tissue pools that were mirrored by the serum gentamicin concentrations after 24 hours. The present study emphasized the complexity of the terminal phase gentamicin. pharmacokinetics and acknowledged the need for a long-term washout period when using the crossover design for gentamicin pharmacokinetic studies.     

Effects of dose and duration of therapy on gentamicin tissue residues in sheep

The effects of different doses and dosage regimens on gentamicin pharmacokinetics and tissue residues were determined. Five groups of 12 sheep each were given gentamicin IM: group I, 2 mg of gentamicin sulfate/kg once; group II, 6 mg/kg once; group III, 18 mg/kg once; group IV, 6 mg/kg every 24 hours for 3 doses; and group V, 2 mg/kg every 8 hours for 9 doses. Serum concentrations were determined serially until sheep were killed and necropsied. Three sheep from each group were killed at 1, 4, 8, and 12 days after the last dose was administered. Renal cortex, renal medulla, liver, spleen, lung, skeletal muscle, and skeletal muscle at the injection site were assayed for gentamicin. An exponential equation was fitted to the serum concentrations, and various pharmacokinetic variables were determined. Serum clearance tended to increase as the single dose increased (P = 0.0588). Steady-state volume of distribution increased as the single dose was increased (P less than 0.05). Renal cortex contained the highest concentration of gentamicin which decreased in a biexponential manner. Concentrations in all tissues, except the injection site, were dependent upon the amount of the total dose, not the size of the injected dose (P less than 0.05). Concentrations at the injection site were up to 29 micrograms/g of tissue at 1 day after the last dose was given and were dependent upon the amount of total dose from multiple injections, not on the amount of each injected dose (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Uric acid and phosphorus excretion in dogs with lymphosarcoma

Serum uric acid and phosphorus concentrations were determined for 27 dogs with multicentric lymphosarcoma before and after chemotherapy. Mean serum uric acid values in dogs before treatment were significantly higher (P less than 0.05) than those of a control group of healthy dogs. Serum uric acid values did not change after treatment. Of the 27 dogs, 13 had 24-hour urine collections to determine endogenous creatinine clearance and quantitation of uric acid and phosphorus excretion before and after treatment for lymphosarcoma. Mean values for 24-hour creatinine clearance before and after treatment were statistically similar in dogs with lymphosarcoma, although the values were lower than those in a normal range. Total urinary phosphorus excretions were increased significantly (P less than 0.01) after treatment without change in fractional excretion. Chemotherapeutic agents used accounted for the significant (P less than 0.05) increase in urine volume after treatment and may have affected the excretion of uric acid and phosphorus. Seemingly, dogs with uncomplicated lymphosarcoma rarely have renal dysfunction or clinically important alterations in uric acid or phosphorus excretion secondary to rapid tumor lysis. However, preexisting renal disease or systemic complications, such as hypercalcemia, may be associated with increased risk of further renal impairment during treatment.     

Multiple once-daily dose pharmacokinetics and renal safety of gentamicin in dogs

In this study the pharmacokinetics and renal safety of gentamicin in healthy dogs was investigated after multiple dosing. Six adult male dogs received once-daily gentamicin (6 mg/kg) intramuscularly for 5 days. Serial blood samples were taken on days 1 and 5 of treatment, and at predose, 1 and 6 h on days 2, 3 and 4. Urinalysis, hematology and serum biochemistry evaluation were carried out before, 7 and 14 days after the first gentamicin administration. Mean value of the main pharmacokinetic parameters were: AUC (microg.h/mL), 97.4 and 100.2; terminal half-life (harmonic mean), 0.76 and 1.01 h; ClB/F (mL/min.kg), 1.24 and 1.10; VD(area)/F (L/kg), 0.084 and 0.10; MRT (h), 1.48 and 1.77; Cmax (microg/mL), 54.5 and 49.2; tmax (h), 0.40 and 0.48 for the first and last dose, respectively. Accumulation was determined as R1 = 0.97 and R2 = 1.22. Mean trough gentamicin serum concentrations were 0.06, 0.07, 0.09, 0.1 and 0.1 microg/mL for the first, second, third, fourth and fifth dose, respectively. Statistically significant increases (P < 0.05) were found for last dose MRT and fourth and fifth trough gentamicin serum concentrations. Laboratory tests detected a slight increase in serum creatinine and urea nitrogen concentrations (one dog), decreased specific urine gravity (one dog) and presence of few granular casts (two dogs). It is concluded that once-daily administration of gentamicin may provide adequate serum levels to treat most susceptible gram-negative infections with little or no nephrotoxicity in dogs.     

Effect of NSAID administration on creatinine clearance in healthy dogs undergoing anaesthesia and surgery

Thirty healthy male dogs were randomly assigned to receive carprofen (4 mg/kg intravenously), ketoprofen (2 mg/kg intravenously) or saline (0.2 ml/kg intravenously) at induction of anaesthesia for castration surgery. A routine castration was undertaken and a buccal mucosal bleeding time was assessed at the completion of surgery. Twenty-four hours after surgery a 24-hour endogenous creatinine clearance study was undertaken. Buccal mucosal bleeding time was not significantly different between the three groups. Creatinine clearance was significantly lower (P ≤ 0.01) in the two groups of dogs that received a non-steroidal anti-inflammatory drug compared with that in the dogs that received sterile saline. There was no significant difference between the carprofen and ketoprofen groups with respect to creatinine clearance.