Comparison of the effect of hypertonic hydroxyethyl starch and mannitol on the intraocular pressure in healthy normotensive dogs and the effect of hypertonic hydroxyethyl starch on the intraocular pressure in dogs with primary glaucoma

PURPOSE: The purpose of this study was to determine if intravenous hypertonic hydroxyethyl starch (7.5%/6%) (HES) could decrease the intraocular pressure (IOP) in healthy normotensive dogs, and compare its effect with that of mannitol (20%) (experimental study). In addition, the potential IOP-lowering effect of hypertonic HES was evaluated in six dogs with primary glaucoma (clinical study). MATERIAL AND METHODS: Experimental study: eight male ophthalmoscopically and clinically healthy Beagles were included in this study. The IOP of each dog was measured by applanation tonometry in both eyes to obtain control values at 10:00, 10:15, 10:30, 10:45, 11:00 a.m., and then every hour until 6:00 p.m. prior to the first treatment (control period). Each dog received, with at least 2-week intervals and in a random order, an intravenous (IV) infusion of 4 mL/kg hypertonic HES (1.2 g/kg NaCl; 0.96 g/kg HES) and 4 mL/kg mannitol 20% (1 g/kg) over a period of 15 min starting at 10:00 a.m. IOP was measured oculus uterque (OU) at the same time intervals as in the control study. The differences in IOP between the treatment groups and the baseline IOP (before the start of infusion), between oculus sinister (OS) and oculus dexter (OD) and between the same time points of all groups were determined with a Student's t-test for paired samples (P = 0.05). Clinical study: six dogs with primary glaucoma (representing seven eyes) received an IV infusion of 4 mL/kg hypertonic HES over a period of 15 min. IOP was measured before and 15 and 30 min after starting the infusion. RESULTS: Experimental study: no significant difference between IOP of both eyes was found. A significant decrease in IOP from baseline value was recorded at 15, 30, 45, and 60 min after the start of mannitol infusion (mean amplitude in IOP decrease 3.21 mmHg; P < 0.05) and at 15 and 30 min in dogs treated with HES (mean amplitude in IOP decrease 2.43 mmHg; P < 0.05). At 120 and 180 min there was a significantly higher IOP (P < 0.05) in HES treatment group compared to the values of the control group. Clinical study: in 5/7 eyes diagnosed with primary glaucoma a maximum decrease in IOP of an average of 24% from the baseline value (IOP before start of the infusion) was observed (range of decrease 2-21 mmHg). In three of these five cases the maximum decrease was reached at 15 min and in two cases at 30 min. In one case an increase in IOP of 35% (+ 18 mmHg) was seen after 15 min and 26% (+ 13 mmHg) after 30 min. Case 4 showed an increase in IOP of 5% (+ 3 mmHg) after 15 min and a decrease of 6% (- 4 mmHg) after 30 min. CONCLUSIONS: Intravenous hypertonic HES is comparable to intravenous mannitol 20% in lowering the intraocular pressure in healthy normotensive dogs. But this effect lasted half an hour longer after mannitol. In 6/7 eyes with primary glaucoma, hypertonic HES decreased IOP.     

Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogs

Dextromethorphan is an N-methyl-D-aspartate (NMDA) noncompetitive antagonist which has been used as an antitussive, analgesic adjunct, probe drug, experimentally to attenuate acute opiate and ethanol withdrawal, and as an anticonvulsant. A metabolite of dextromethorphan, dextrorphan, has been shown to behave pharmacodynamically in a similar manner to dextromethorphan. The pharmacokinetics of dextromethorphan were examined in six healthy dogs following intravenous (2.2 mg/kg) and oral (5 mg/kg) administration in a randomized crossover design. Dextromethorphan behaved in a similar manner to other NMDA antagonists upon injection causing muscle rigidity, ataxia to recumbency, sedation, urination, and ptyalism which resolved within 90 min. One dog repeatedly vomited upon oral administration and was excluded from oral analysis. Mean +/- SD values for half-life, apparent volume of distribution, and clearance after i.v. administration were 2.0 +/-0.6 h, 5.1 +/- 2.6 L/kg, and 33.8 +/- 16.5 mL/min/kg. Oral bioavailability was 11% as calculated from naive pooled data. Free dextrorphan was not detected in any plasma sample, however enzymatic treatment of plasma with glucuronidase released both dextromethorphan and dextrorphan indicating that conjugation is a metabolic route. The short half-life, rapid clearance, and poor bioavailability of dextromethorphan limit its potential use as a chronic orally administered therapeutic.     

Pharmacokinetics of ibafloxacin following intravenous and oral administration to healthy Beagle dogs

The pharmacokinetics of ibafloxacin, a new veterinary fluoroquinolone antimicrobial agent, was studied following intravenous (i.v.) and oral administration to healthy dogs. The mean absolute bioavailability of ibafloxacin after oral doses of 7.5, 15 and 30 mg/kg ranged from 69 to 81%, indicating that ibafloxacin was well absorbed by dogs. Ibafloxacin was also absorbed rapidly [time of maximum concentration (t(max)) 1.5 h], reaching a mean maximum concentration (C(max)) of 6 microg/mL at 15 mg/kg, well distributed in the body [large volume of distribution at steady state (V(ss)) and V(area) of 1.1 L/kg and 4 L/kg, respectively], and exhibited an elimination half-life of 5.2 h and a low total body clearance (8.7 mL/min/kg). Both C(max) and area under the concentration-time curve (AUC) showed dose proportionality over the dose range tested (7.5-30 mg/kg). The pharmacokinetics of ibafloxacin was similar following single and repeated dosage regimens, implying no significant accumulation in plasma. Food promoted the absorption of ibafloxacin by increasing C(max) and AUC, but did not change t(max). High amounts of the metabolites, mainly 8-hydroxy- and, 7-hydroxy-ibafloxacin were excreted in urine and faeces, either unchanged or as glucuronide conjugates. Following oral administration of 15 mg ibafloxacin/kg, the total recovery of ibafloxacin, its metabolites and conjugates in urine and faeces was 61.9-99.9% of the dose within 48 h.     

Effect of hydroxyethyl starch infusion on colloid oncotic pressure in hypoproteinemic horses

OBJECTIVE: To determine the effect of hydroxyethyl starch (HES) on colloid oncotic pressure (pi) during fluid resuscitation of hypoproteinemic horses and to evaluate the clinical usefulness of direct and indirect methods for determination of pi before and after infusion of a synthetic colloid. DESIGN: Prospective clinical study. ANIMALS: 11 hypoproteinemic horses. PROCEDURE: Horses received IV infusions of 8 to 10 ml of a 6% solution of HES/kg (3.6 to 4.5 ml/lb) of body weight during fluid resuscitation. Blood samples were obtained for determination of plasma measured colloid oncotic pressure (pi meas) and plasma total protein and albumin (A) concentrations. Plasma globulin concentration (G) was calculated as the difference between plasma total protein and albumin concentrations. Calculated values for colloid oncotic pressure (piA + G) were determined by use of a predictive nomogram previously developed for horses. RESULTS: There was no significant difference between the means of pi meas and piA + G at the beginning of HES infusion. After HES infusion, the mean of pi meas was increased significantly from baseline for 6 hours. Mean plasma total protein and albumin concentrations and piA + G were decreased significantly from baseline for 24 hours. Differences between mean pi meas and piA + G after HES infusion were significant for 24 hours. CONCLUSIONS AND CLINICAL RELEVANCE: There was good agreement between plasma pi meas and piA + G in blood samples obtained from hypoproteinemic horses immediately before infusion of HES. Use of a predictive nomogram did not, however, account for the oncotic effect of HES. Results of comparison of pi meas to piA + G after HES infusion suggest that a significant oncotic effect was maintained for 24 hours in the study horses.     

Plasma L-carnitine concentration in healthy dogs and dogs with hepatopathy

BACKGROUND: L-Carnitine has an essential role in lipid metabolism. Disturbances of L-carnitine metabolism can influence the energy supply of the organism. L-Carnitine is synthesized exclusively in the liver. Hence, we hypothesized that liver disease can influence L-carnitine metabolism. OBJECTIVES: The goal of this study was to compare plasma L-carnitine concentrations in dogs with different liver diseases of differing severity with the plasma L-carnitine concentrations of healthy dogs. METHODS: Sixteen dogs with inflammatory liver disease and 12 dogs with liver neoplasia were included in the study. Liver disease was diagnosed by clinical chemistry, ultrasonography, and histology of liver biopsy specimens. L-Carnitine concentration was measured in plasma samples using mass spectrometry, and compared among groups using unpaired Student's t-tests. RESULTS: Compared with healthy controls (24.4 +/- 8.4 micromol/L), the plasma L-carnitine concentration in dogs with liver disease (44.2 +/- 23.7 micromol/L) was significantly higher (P<.0001). The difference in L-carnitine concentration between dogs with moderate (n=8; 33.6 +/- 13.7 micromol/L) and severe (n=8; 57.4 +/- 22.9 micromol/L) hepatitis was also significant (P=.02). No difference in plasma L-carnitine concentration was found between dogs with hepatitis and those with liver tumors. CONCLUSIONS: Liver disease in dogs was accompanied by elevated plasma L-carnitine concentration. The severity of hepatitis appears to influence L-carnitine concentration.     

Effect of intravenous infusion of a 7.2% hypertonic saline solution on serum electrolytes and osmotic pressure in healthy beagles.

The effect of an intravenous (i.v.) infusion of hypertonic saline solution (HSS; 7.2%, 2,400 mOsmol/kg.H2O) was evaluated by serum electrolyte concentrations and osmotic pressure in the anesthetized beagles. Sixteen beagles were assigned to 3 experimental groups (2.5, 5 or 15 ml/kg of HSS i.v. infusion) or a control group (5 ml/kg of isotonic saline solution (ISS) i.v. infusion) and were monitored for 120 min after the initiation of fluid infusion. The relative plasma volume (rPV) in the 5 ml/kg and 15 ml/kg HSS groups progressively expanded to 143.1 +/- 7.4% at 3 min and 156.4 +/- 5.9% at 5 min after the initiation of the fluid infusion, respectively. Significant increases were not produced by ISS and 2.5 ml/kg HSS infusion. The serum sodium and chloride concentrations in the ISS group were not altered. The 5 ml/kg HSS infusion induced transient high osmotic and sodium levels, and the serum sodium concentration remained under the 160 mM/l after the completion of the HSS infusion. However, the 15 ml/kg HSS infusion induced a constant high osmotic level (340.5-352.8 mOsmol/kg.H2O) and hypernatremia (161.4-174.5 mM/l) from 10 to 90 min after the initiation of the fluid infusion. The 15 ml/kg HSS infusion induced significant decreases in the partial pressure of oxygen (PaO2), reaching 63.7 +/- 8.0 mmHg at 120 min after the initiation of the fluid infusion compared with an immediately before fluid infusion value. On the basis of these findings, 5 ml/kg HSS infusion can be safely administered to healthy beagles for expanding the plasma volume without inducing hypernatremia. A 5 ml/kg HSS infusion is thus recommended for the initial field resuscitation of dogs.     

Plasma cortisol concentrations following cortisone infusion in dogs before and after treatment with cortisone acetate

OBJECTIVE: To evaluate effects of iatrogenic hyperadrenocorticism on plasma cortisol concentrations produced by an infusion of hydrocortisone in dogs. PROCEDURE: Plasma cortisol concentrations were measured regularly during a 6 h infusion of hydrocortisone sodium succinate at two dose rates. The infusions were performed before and after treatment for 30 d with oral cortisone acetate at 10 mg/kg/24 h, divided thrice daily. Adrenal activity during the experimental period was assessed by weekly ACTH stimulation tests. RESULTS: Both infusion rates produced lower plasma cortisol concentrations after treatment for 30 d with cortisone. CONCLUSION: Prior exposure to high concentrations of glucocorticoids may result in accelerated metabolism of glucocorticoids administered subsequently. This may necessitate increased dosages when using glucocorticoids to support inadequate adrenal function.     

Comparison of the pharmacokinetics of two formulations of hydroxyethyl starch in healthy horses

A lower molecular weight and molar substitution formulation (130/0.4) of hydroxyethyl starch solution has been shown to have a more sustained effect on COP and similar hemodynamic effects as a higher molecular weight and molar substitution formulation (600/0.75) in healthy horses. In humans, these pharmacodynamic characteristics are coupled with more rapid clearance and decreased adverse coagulation effects and accumulation. The objective of this study was to determine and compare the pharmacokinetics of these two formulations in horses. Eight healthy horses were given a 10 mL/kg bolus of each formulation (600/0.75 and 130/0.4) of hydroxyethyl starch solution in a randomized crossover design. Blood was collected, and plasma was harvested for plasma levels over 24 h. Pharmacokinetic parameters for each horse were estimated from a noncompartmental analysis. Treatment with 600/0.75 resulted in a higher initial plasma concentration (C₀), systemic half‐life (t_1/2), and overall drug exposure (AUC_0–inf) in addition to decreased elimination rate (β), volume of distribution (Vd), and clearance (CL), compared to treatment with 130/0.4 (P < 0.001). The pharmacokinetic findings combined with previous pharmacodynamics findings suggest that 130/0.4 can provide similar benefits to 600/0.75 with a lower risk of accumulation in the circulation.     

Plasma pharmacokinetics and milk levels of ceftriaxone following single intravenous administration in healthy and endometritic cows

Pharmacokinetics and milk levels of ceftriaxone were studied in healthy and endometritic cows following single intravenous administration. The drug was detected up to 8 h of dosing in plasma of healthy and endometritic cows and the drug disposition followed three-compartment open model. The values of Vd_area, AUC, t_1/2β, Cl_B, MRT and P/C ratio were 0.50 ± 0.19 L.kg⁻¹, 62.2 ± 23.3 μg.ml⁻¹.h, 1.02 ± 0.07 h, 0.30 ± 0.09 L.kg⁻¹.h⁻¹, 1.55 ± 0.25 h and 0.52 ± 0.27, respectively, in healthy and 1.55 ± 0.52 L.kg⁻¹, 37.0 ± 17.1 μg.ml⁻¹.h, 1.56 ± 0.25 h, 0.56 ± 0.14 L.kg⁻¹.h⁻¹, 2.14 ± 0.34 h and 1.44 ± 0.60, respectively, in endometritic cows. The drug was detected in milk for 36 h after administration. For MIC₉₀ of 0.5 μg.ml⁻¹ the most appropriate dosage for ceftriaxone, would be 9.0 mg.kg⁻¹ repeated at 6 h intervals for the treatment of endometritis in cows.     

Comparison of plasma and interstitial fluid concentrations of doxycycline and meropenem following constant rate intravenous infusion in dogs

OBJECTIVE: To compare plasma (total and unbound) and interstitial fluid (ISF) concentrations of doxycycline and meropenem in dogs following constant rate IV infusion of each drug. ANIMAL: 6 adult Beagles. PROCEDURE: Dogs were given a loading dose of doxycycline and meropenem followed by a constant rate IV infusion of each drug to maintain an 8-hour steady state concentration. Interstitial fluid was collected with an ultrafiltration device. Plasma and ISF were analyzed by high performance liquid chromatography. Protein binding and lipophilicity were determined. Plasma data were analyzed by use of compartmental methods. RESULTS: Compared with meropenem, doxycycline had higher protein binding (11.87% [previously published value] vs 91.75 +/- 0.63%) and lipophilicity (partition coefficients, 0.02 +/- 0.01 vs 0.68 +/- 0.05). A significant difference was found between ISF and plasma total doxycycline concentrations. No significant difference was found between ISF and plasma unbound doxycycline concentrations. Concentrations of meropenem in ISF and plasma (total and unbound) were similar. Plasma half-life, volume of distribution, and clearance were 4.56 +/- 0.57 hours, 0.65 +/- 0.82 L/kg, and 1.66 +/- 2.21 mL/min/kg, respectively, for doxycycline and 0.73 +/- 0.07 hours, 0.34 +/- 0.06 L/kg, and 5.65 +/- 2.76 mL/min/kg, respectively, for meropenem. The ISF half-life of doxycycline and meropenem was 4.94 +/- 0.67 and 2.31 +/- 0.36 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The extent of protein binding determines distribution of doxycycline and meropenem into ISF. As a result of high protein binding, ISF doxycycline concentrations are lower than plasma total doxycycline concentrations. Concentrations of meropenem in ISF can be predicted from plasma total meropenem concentrations.     

Plasma and serum concentrations of cytarabine administered via continuous intravenous infusion to dogs with meningoencephalomyelitis of unknown etiology

The objective of this study was to evaluate the plasma and serum concentrations of cytarabine (CA) administered via constant rate infusion (CRI) in dogs with meningoencephalomyelitis of unknown etiology (MUE). Nineteen client‐owned dogs received a CRI of CA at a dose of 25 mg/m²/h for 8 h as treatment for MUE. Dogs were divided into four groups, those receiving CA alone and those receiving CA in conjunction with other drugs. Blood samples were collected at 0, 1, 8, and 12 h after initiating the CRI. Plasma (n = 13) and serum (n = 11) cytarabine concentrations were measured by high‐pressure liquid chromatography. The mean peak concentration (C_MAX) and area under the curve (AUC) after CRI administration were 1.70 ± 0.66 μg/mL and 11.39 ± 3.37 h·μg/mL, respectively, for dogs receiving cytarabine alone, 2.36 ± 0.35 μg/mL and 16.91 + 3.60 h·μg/mL for dogs administered cytarabine and concurrently on other drugs. Mean concentrations for all dogs were above 1.0 μg/mL at both the 1‐ and 8‐h time points. The steady‐state achieved with cytarabine CRI produces a consistent and prolonged exposure in plasma and serum, which is likely to produce equilibrium between blood and the central nervous system in dogs with a clinical diagnosis of MUE. Other medications commonly used to treat MUE do not appear to alter CA concentrations in serum and plasma.     

The effect of intravenous mannitol or oral glycerol on intraocular pressure in dogs

The effect of IV mannitol (1.5 gm/kg) or oral glycerol (1.4 and 2.0 gm/kg) on intraocular pressure (IOP) and serum osmolality (SOSM) was investigated in 24 normal dogs. Mean IOPs were significantly decreased from baseline values from 0.5 through 5.5 hours following mannitol administration with a mean maximum depression of 8.7 +/- 1.8 mm Hg whereas mean SOSM was significantly increased from baseline values. Mean IOPs were significantly decreased from baseline values from 1.0 through 10 hours following oral administration of 1.4 gm/kg glycerol with a mean maximal depression of 5.4 +/- 2.7 mm Hg. Mean SOSM increased initially followed by a significant decrease. The change in IOP following mannitol administration showed less variation (smaller standard deviations) than glycerol (1.4 gm/kg). Five of the 6 dogs that received the 2.0 gm/kg glycerol vomited; the mean IOP and SOSM values were not significantly altered from baseline values in these dogs. Four of 5 dogs given cooled (10C) 2.0 gm/kg glycerol vomited. The incidence of vomiting appeared to be dose related. Both mannitol and glycerol (1.4 gm/kg) are effective for decreasing IOP in normal dogs.     

Pharmacokinetics of buprenorphine following intravenous administration in dogs

OBJECTIVE: To determine pharmacokinetics of buprenorphine in dogs after i.v. administration. ANIMALS: 6 healthy adult dogs. PROCEDURES: 6 dogs received buprenorphine at 0.015 mg/kg, i.v. Blood samples were collected at time 0 prior to drug administration and at 2, 5, 10, 15, 20, 30, 40, 60, 90, 120, 180, 240, 360, 540, 720, 1,080, and 1,440 minutes after drug administration. Serum buprenorphine concentrations were determined by use of double-antibody radioimmunoassay. Data were subjected to noncompartmental analysis with area under the time-concentration curve to infinity (AUC) and area under the first moment curve calculated to infinity by use of a log-linear trapezoidal model. Other kinetic variables included terminal rate constant (k(el)) and elimination half-life (t(1/2)), plasma clearance (Cl), volume of distribution at steady state (Vd(ss)), and mean residence time (MRT). Time to maximal concentration (T(max)) and maximal serum concentration (C(max)) were measured. RESULTS: Median (range) values for T(max) and MRT were 2 minutes (2 to 5 minutes) and 264 minutes (199 to 600 minutes), respectively. Harmonic mean and pseudo SD for t(1/2) were 270+/-130 minutes; mean +/- SD values for remaining pharmacokinetic variables were as follows: C(max), 14+/-2.6 ng/mL; AUC, 3,082+/-1,047 ng x min/mL; Vd(ss), 1.59+/-0.285 L/kg; Cl, 5.4+/-1.9 mL/min/kg; and, k(el), 0.0026+/-0.0,012. CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetic variables of buprenorphine reported here differed from those previously reported for dogs. Wide variations in individual t(1/2) values suggested that dosing intervals be based on assessment of pain status rather than prescribed dosing intervals.     

Disposition of ciprofloxacin following intravenous administration in dogs

The pharmacokinetics of ciprofloxacin (CIP) following intravenous administration m dogs nave been mvestisated. The drug was administered at three doses (2.5,5 and 10 mg/kg body weight) and was assayed in biological fluid samples (plasma and urine) by an HPLC method. The plasma concentration-time curves ere best described by a two-compartment open pharmacokinetic model. The was widely distributed (V_d(area) almost 3 1/kg), being distributed in the dog more rapidly than in other species (t_1/2(λ1) 3 min approximately). The elimination half-life (t_1/2λ2)) was 129–180 min which is similar to values obtaine in other species. The unchanged drug eliminated in urine was less than 37% of the administered dose, which is less than the values obtained in humans, calves and pigs. The glomerular filtration rate and the renal clearance of CIP in the dog suggest that renal elimination probably occurs mainly by glomerular filtration. The results showed that the pharmacokinetics of CIP, as in other species, was linear in dogs in the dose range studied.     

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs

The purpose of this study was to compare the pharmacokinetics of two highly protein‐bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half‐life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol–water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95–98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs.