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SUMMARY

Eight adult horses were used in a study to determine ketamine's ability to reduce halothane requirement. To obtain steady-state plasma concentrations of 0.5, 1.0, 2.0, 4.0, and 8.0 μg/ml, loading doses and constant infusions for ketamine were calculated for each horse on the basis of data from other studies in which the pharmacokinetic properties of ketamine were investigated. Blood samples for determination of plasma ketamine concentrations were collected periodically during each experiment. Plasma ketamine concentrations were determined by capillary gas chromatography/mass spectrometry under electron-impact ionization conditions, using lidocaine as the internal standard. Halothane minimal alveolar concentration (mac; concentration at which half the horses moved in response to an electrical stimulus) and plasma ketamine concentration were determined after steady-state concentrations of each ketamine infusion had been reached. Plasma ketamine concentrations > 1.0 μg/ml decreased halothane mac. The degree of mac reduction was correlated directly with the square root of the plasma ketamine concentration, reaching a maximum of 37% reduction at a plasma ketamine concentration of 10.8 ± 2.7 μg/ml. Heart rate, mean arterial blood pressure, and the rate of increase of right ventricular pressure did not change with increasing plasma ketamine concentration and halothane mac reduction. Cardiac output increased significantly during ketamine infusions and halothane mac reduction. Our findings suggest that plasma ketamine concentrations > 1.0 μm/ml reduce halothane mac and produce beneficial hemodynamic effects.

Free access
in American Journal of Veterinary Research

Summary

Age and species reportedly affect the pharmacokinetic variables of nonsteroidal anti-inflammatory drugs. We determined the effect of age on flunixin pharmacokinetic variables in foals during the first month of life. We also estimated the physiologic activity of the drug in neonatal foals by determining the effect of flunixin on thromboxane production during clotting of blood taken from the foals. Flunixin disposition and clearance were determined after iv administration of 1.1 mg of drug/kg of body weight to 5 healthy foals when they were 24 to 28 hours, 10 to 11 days, and 27 to 28 days old. The area under the curve (2,471 μg·min/ml), mean residence time (477 minutes), and zero-time intercept of the elimination phase (4,853 ng/ml) were significantly (P = 0.05) greater, the elimination half-life (339 minutes) and slope of the elimination phase (0.002 L/min) were significantly (P = 0.05) longer, and total body clearance (0.482 ml/min/kg) and zero-time intercept for the distribution phase (2,092 ng/ml) were significantly (P = 0.05) lower at 24 to 28 hours. At each age, a biexponential equation was best fitted to the plasma flunixin concentration from each foal. Thromboxane B2 production during clotting of blood was significantly (P = 0.05) suppressed for 12 hours after flunixin meglumine administration at all ages. Therefore, it appears that although age does alter the disposition and elimination of flunixin in neonatal foals, this effect may be of little consequence because the drug's physiologic activity in foals appears similar to that in mature horses.

Free access
in American Journal of Veterinary Research

Summary

Flunixin meglumine and phenylbutazone are nonsteroidal anti-inflammatory drugs commonly used for the management of colic, endotoxemia, and musculoskeletal disorders in equids. Although it is not usually recommended, there appears to be an increasing trend to use nonsteroidal anti-inflammatory drugs in combination to enhance or prolong their effects. Therefore, we studied the effect of concurrent administration of flunixin (1.1 mg/kg of body weight, iv) as flunixin meglumine and phenylbutazone (2.2 mg/kg, iv) on the pharmacokinetics of each drug and on in vitro thromboxane B2 production.

Pharmacokinetic variables calculated for each drug when given alone and in combination were similar to those reported. Serum thromboxane B2 production was significantly (P = 0.05) suppressed for 12, 8, and 24 hours after administration of flunixin, phenylbutazone, and the drugs in combination, respectively. These results indicate that although concurrent administration of these drugs at the aforementioned dosages does not alter either drug disposition or clearance, it prolongs their pharmacologic effect.

Free access
in American Journal of Veterinary Research

Summary

Single doses (2.2 mg/kg of body weight) of phenylbutazone (pbz) were administered iv to 6 neonatal horses (5 to 17 hours old at time of dosing). Plasma concentrations of pbz and its metabolite oxyphenbutazone were monitored serially for 120 hours after drug administration. Pharmacokinetic variables were calculated, using 1- and 2-compartment open models. Descriptive equations from the best model for each foal were then used to derive model-independent variables describing pbz disposition. Median volume of distribution at steady-state was 0.274 L/ kg (range, 0.190 to 0.401 L/kg). Median terminal half-life was 7.4 (6.4 to 22.1) hours, and median total plasma clearance of pbz for foals in this study was 0.018 L/kg/h (range, 0.013 to 0.038 L/kg/h). Volume of distribution was larger, half-life was longer, and total clearance was lower, compared with similar values reported for administration of pbz to adult horses.

Free access
in American Journal of Veterinary Research

Summary

Age, species, and disease state may substantially alter the disposition and clearance of pharmacologic agents. This is particularly important when drugs with low therapeutic index are used in ill neonates. Pharmacokinetic variables for phenylbutazone were determined in 24- to 32-hour-old healthy and endotoxemic calves after iv administration of a single dose (5 mg/kg of body weight, iv). Elimination halflife was 207 and 168 hours, and clearance was 0.708 and 0.828 ml/kg/h in healthy and endotoxemic calves, respectively. Intravenous infusion of endotoxin at the dose (2 μg/kg over 4 hours) given did not significantly alter any of the calculated pharmacokinetic variables. Serum thromboxane B2 concentration was significantly (P = 0.05) suppressed for 3 hours after phenylbutazone administration in healthy calves and for 4 hours in endotoxin-challenged calves. Daily administration of phenylbutazone (10 mg/kg loading, then 5 mg/kg for 9 days) to healthy and endotoxemic calves failed to induce any lesions consistent with nonsteroidal anti-inflammatory drug toxicosis.

Free access
in American Journal of Veterinary Research

Abstract

Objective

To determine pharmacokinetic variables that describe disposition of ketoprofen after its IV administration to foals < 24 hours old.

Animals

6 healthy foals (1 male and 5 females); mean age, 12.5 (range, 8.5 to 17) hours at time of dose administration.

Procedure

Ketoprofen was administered IV to foals at a dosage of 2.2 mg/kg of body weight. Ketoprofen concentration in plasma samples was analyzed, using high-performance liquid chromatography. Concentration versus time profiles were analyzed according to standard pharmacokinetic techniques. Blood samples were obtained from foals by jugular venipuncture at defined times during a 48-hour period. Samples were centrifuged, and plasma was frozen at −70 C until analyzed. One-, two-, and three-compartment analyses were conducted. The most appropriate model was determined by use of Akaike's information criterion analysis.

Results

Plasma concentration versus time profiles were best described, using a two-compartment open model. Clearance (normalized for body weight) was significantly lower than that determined for adult horses. Volume of distribution (normalized for body weight) was larger than that determined for adult horses. Mean (harmonic) plasma half-life for healthy foals < 24 hours old was 4.3 hours.

Clinical Relevance

Although additional factors, such as dehydration or sepsis, must be considered on a case-by-case basis, the dose of ketoprofen administered to foals < 24 hours old should be different from the dose administered to adult horses. Under similar clinical circumstances, doses in foals should be increased by as much as 1.5 times to produce comparable therapeutic concentrations; longer dose intervals, based on clinical response, would be necessary to avoid drug toxicity. (Am J Vet Res 1998;59:290–292)

Free access
in American Journal of Veterinary Research

Abstract

Objective

To determine pharmacokinetic variables that describe the disposition of flunixin after IV administration of flunixin meglumine to foals < 24 hours old.

Animals

6 healthy foals, 2 males and 4 females (mean age, 11.6 hours; range, 6 to 22.5 hours).

Procedure

Flunixin (as flunixin meglumine) was administered to foals at a dosage of 1.1 mg/kg of body weight. Flunixin concentration in plasma samples was analyzed, using gas chromatography/mass spectroscopy. Concentration versus time profiles were analyzed according to standard pharmacokinetic techniques. Blood samples were obtained from foals by jugular venipuncture at defined intervals over a 48-hour period. Samples were centrifuged, and plasma was frozen at −70 C until analyzed. One-, two-, and three-compartment analyses were conducted. The most appropriate model was determined by Akaike's information criterion analysis.

Results

Plasma concentration versus time profiles were best described, using a two-compartment open model. Clearance was significantly lower than that determined for older foals and adult horses. Volume of distribution was larger than that determined for adults. Mean plasma halflife for healthy foals < 24 hours old was 8.5 hours.

Conclusions and Clinical Relevance

Although additional factors (eg, dehydration or sepsis) must be considered on a case-by-case basis, flunixin meglumine should be administered differently to foals < 24 hours old, compared with adults. Under similar clinical circumstances, doses in foals should be increased by as much as 1.5 times to induce comparable therapeutic concentrations; longer dose intervals, on the basis of clinical response, would be necessary to avoid drug toxicity. (Am J Vet Res 1996;57:1759–1761)

Free access
in American Journal of Veterinary Research

Abstract

Objective

To examine the pharmacokinetic profile of propranolol in cats before and during experimentally induced hyperthyroidism.

Animals

8 conditioned, random-source, young adult, female cats.

Procedure

Propranolol was administered IV as a single bolus and 72 hours later by mouth. Thereafter, the cats were dosed for 5 weeks with L-thyroxine (50 μg/kg of body weight, SC, once daily) to induce hyperthyroidism (serum thyroxine concentration, 217 ± 17 nmol/L). Blood samples were obtained at appropriate intervals before and during hyperthyroidism and were analyzed for plasma propranolol concentration by use of high-performance liquid chromatography.

Results

In all cats, a two-compartment model best described the control and hyperthyroid intravenous data. The change in thyroid status from euthyroid to hyperthyroid caused a significant (P < 0.05), but small reduction in propranolol area under the curve (19,932 ± 7,900 min·μg/L vs 15,911 ± 1,400 min · μg/L) after IV administration. In contrast, after oral administration during the hyperthyroid state, a twofold increase (P < 0.05) in propranolol area under the curve (105,430 ± 57,600 min·μg/L vs 226,811 ± 112,000 min·μg/L) and peak serum propranolol concentration (651 ± 247 μg/L vs 1191 ± 590 μg/L) were attributed to significant (P < 0.05) increase in propranolol bioavailability caused by increased fractional absorption (57 ± 28% vs 137 ± 73%) and decreased total body clearance (58 ± 27 ml/min/kg vs 30 ± 19 ml/min/kg). Mean arrival time after oral dosing was significantly lengthened by hyperthyroidism (100 ± 38 minutes vs 157 ± 71 minutes).

Clinical Relevance

Hyperthyroidism-induced changes in propranolol pharmacokinetics may signal the need to reduce doses of propranolol when they are orally administered to hyperthyroid cats. (Am J Vet Res 1997;58:398–403)

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetic disposition of IV administered caffeine in healthy Lama spp camelids.

Animals—4 adult male alpacas and 4 adult female llamas.

Procedures—Caffeine (3 mg/kg) was administered as an IV bolus. Plasma caffeine concentrations were determined by use of high-performance liquid chromatography in 6 animals and by use of liquid chromatography-mass spectrometry in 2 llamas.

Results—Median elimination half-life was 11 hours (range, 9.3 to 29.8 hours) in alpacas and 16 hours (range, 5.4 to 17 hours) in llamas. The volume of distribution at steady state was 0.60 L/kg (range, 0.45 to 0.93 L/kg) in alpacas and 0.75 L/kg (range, 0.68 to 1.15 L/kg) in llamas. Total plasma clearance was 44 mL/h/kg (range, 24 to 56 mL/h/kg) in alpacas and 42 mL/h/kg (range, 30 to 109 mL/h/kg) in llamas.

Conclusions and Clinical Relevance—High-performance liquid chromatography and liquid chromatography-mass spectrometry were suitable methods for determination of plasma caffeine concentrations in alpacas and llamas. Plasma caffeine concentration-time curves were best described by a 2-compartment model. Elimination half-lives, plasma clearance, volume of distribution at steady state, and mean residence time were not significantly different between alpacas and llamas. Intravenous administration of caffeine at a dose of 3 mg/kg did not induce clinical signs of excitement.

Full access
in American Journal of Veterinary Research

SUMMARY

Pharmacokinetics and bioavailability of rifampin in adult sheep were investigated by use of high-performance liquid chromatography for determination of serum concentrations. Eight adult ewes were given rifampin po at the rate of 50 mg of rifampin/kg of body weight. Three weeks after the first experiment, the sheep were given rifampin po and iv at the rate of 20 mg/kg in a cross-over design, with 1 week between treatments. Serum obtained over a 36-hour period was analyzed for rifampin and a potential metabolite, 25-desacetyl-rifampin, using reverse-phase chromatography with uv detection at 254 nm. Data were analyzed by compartmental and noncompartmental models. Analysis by the noncompartmental model of rifampin serum concentrations after iv administration yielded a mean ± sd total body clearance of 1.16 ± 0.21 ml/min/kg, apparent volume of distribution at steady state of 0.45 ± 0.06 L/kg, and terminal elimination rate constant of 0.15 ± 0.04 hour−1. The harmonic mean of the elimination half-life was 4.56 hours. Because of incomplete and continuing absorption, bioavailability was extremely variable after oral administration. Desacetylrifampin was not detected. On the basis of pharmacokinetic values, serum concentrations measured in this study, and published minimal inhibitory concentrations, the dosage of 20 mg of rifampin/kg, po, every 24 hours should provide adequate serum concentrations for treatment of rifampin-susceptible bacterial infections in sheep.

Free access
in American Journal of Veterinary Research