Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model.

INTRODUCTION: Diuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide. ANIMALS: Six healthy male dogs. METHODS: Raw data and stored samples from one arm of a previously published study were further analyzed to mechanistically investigate causes of diuretic braking in these dogs. Urine volume was recorded hourly during a 5-h furosemide CRI. Urine and blood samples were collected hourly to measure serum and urine electrolytes, urine aldosterone, and plasma and urine furosemide. Serum electrolyte fractional excretion was calculated. Urine sodium concentration was indexed to urine potassium (uNa:uK) and urine furosemide (uNa:uFur) concentrations, plasma furosemide concentration was indexed to urine furosemide concentration (pFur:uFur), and urine aldosterone was indexed to urine creatinine (UAldo:C). Temporal change and the relationship to urine volume were evaluated for these measured and calculated variables. RESULTS: Urine volume was significantly correlated with urine electrolyte amounts and with uNa:uK. The ratio of pFur:uFur decreased during the infusion, whereas furosemide excretion was unchanged. CONCLUSIONS: There was a strong relationship between urine volume and absolute urine electrolyte excretion. Urine volume was strongly correlated to uNa:uK, giving it potential as a spot indicator of urine production during diuresis. The decrease in uNa:uK over time during the infusion is consistent with mineralocorticoid modification of urinary electrolyte excretion, supporting renin-angiotensin-aldosterone activation as a cause of diuretic braking in this model.

Ciprofloxacin Pharmacokinetics in Clinical Canine Patients.

BACKGROUND: Ciprofloxacin generic tablets approved for human use frequently are administered to dogs for treatment of bacterial infections because they are inexpensive and readily available. However, previous work indicated low and variable oral absorption in healthy research dogs. OBJECTIVE: To examine orally administered ciprofloxacin in a group of clinical canine patients using population pharmacokinetics in order to identify minimum inhibitory concentrations (MIC) that potentially could be achieved with orally administered ciprofloxacin in dogs. ANIMALS: Thirty-four clinical canine patients; mean weight, 22.95 kg (range, 4.6-57 kg). METHODS: Ciprofloxacin generic tablets intended for human use were administered to dogs in a prospective study (mean dose, 23.5 mg/kg). Sparse blood sampling was used to obtain population pharmacokinetic results with nonlinear mixed-effects modeling. These data were used to estimate a breakpoint for susceptible bacteria. Monte Carlo simulations were used to determine the probability of target attainment (PTA) for an area under the curve (AUC)/MIC ratio of ≥100, the pharmacokinetic-pharmacodynamic target for fluoroquinolones. RESULTS: The values for volume of distribution, peak concentration, and half-life were 10.7 L/kg (11.7%), 1.9 µg/mL (11.66%), and 4.35 hours (7.62%), respectively (mean, % coefficient of variation [CV]). The size of the dog was an important covariate with larger dogs achieving lower plasma drug concentrations than smaller dogs, despite a similar mg/kg dose. Ninety percent PTA was obtained for a MIC ≤ 0.06 µg/mL. CONCLUSIONS AND CLINICAL IMPORTANCE: A breakpoint (susceptible) of ≤0.06 µg/mL should be considered when ciprofloxacin tablets are administered to dogs at a dose of 25 mg/kg once daily, which is much lower than the breakpoint of ≤1 µg/mL in humans.

Pharmacokinetics of ibuprofen after intravenous and oral administration and assessment of safety of administration to healthy foals.

OBJECTIVE: To determine pharmacokinetics of ibuprofen in healthy foals and to determine clinical effects after oral administration for 6 days. ANIMALS: 7 healthy 5- to 10-week-old foals. PROCEDURE: Serum concentrations of ibuprofen were measured after IV and oral (nasogastric tube) administration at dosages of 10 and 25 mg/kg of body weight. Foals were given ibuprofen (25 mg/kg, PO, q 8 h) as a paste for 6 days. Serum and urine were obtained before and after the 6-day period. RESULTS: Half-life of elimination (Kel t1/2) of IV-administered ibuprofen (ie, 10 and 25 mg/kg), was 79 and 108 minutes, maximal serum concentration (C(MAX)) was 82 and 160 microg/ml, and clearance was 0.003 and 0.002 L/kg/min, respectively. At the higher dosage, clearance was significantly lower and C(MAX) was significantly higher. Ibuprofen given via nasogastric tube resulted in Kel t1/2 of 81 and 100 minutes and C(MAX) of 22 and 52 microg/ml for 10 and 25 mg/kg, respectively. The absorption half-life was 13 minutes, and bioavailability ranged from 71 to 100%. Foals remained healthy during oral administration of ibuprofen. Serum urea nitrogen, creatinine, and L-iditol dehydrogenase values increased significantly, and gamma-glutamyltransferase (GGT) activity and osmolality decreased, but all measurements remained within reference ranges. Urine GGT activity doubled. Necropsy did not reveal gross or histologic renal lesions attributable to ibuprofen. Acute gastric ulcers were evident in 1 foal, although clinical signs of ulcers were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Ibuprofen can be given safely to healthy foals at dosages < or = 25 mg/kg every 8 hours for up to 6 days.