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Abstract

Objective—To determine the pharmacokinetics of carvedilol administered IV and orally and determine the dose of carvedilol required to maintain plasma concentrations associated with anticipated therapeutic efficacy when administered orally to dogs.

Animals—8 healthy dogs.

Procedures—Blood samples were collected for 24 hours after single doses of carvedilol were administered IV (175 µg/kg) or PO (1.5 mg/kg) by use of a crossover nonrandomized design. Carvedilol concentrations were detected in plasma by use of high-performance liquid chromatography. Plasma drug concentration versus time curves were subjected to noncompartmental pharmacokinetic analysis.

Results—The median peak concentration (extrapolated) of carvedilol after IV administration was 476 ng/mL (range, 203 to 1,920 ng/mL), elimination half-life (t1/2) was 282 minutes (range, 19 to 1,021 minutes), and mean residence time (MRT) was 360 minutes (range, 19 to 819 minutes). Volume of distribution at steady state was 2.0 L/kg (range, 0.7 to 4.3 L/kg). After oral administration of carvedilol, the median peak concentration was 24 µg/mL (range, 9 to 173 µg/mL), time to maximum concentration was 90 minutes (range, 60 to 180 minutes), t1/2 was 82 minutes (range, 64 to 138 minutes), and MRT was 182 minutes (range, 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range, 0.4% to 54%).

Conclusions and Clinical Relevance—Although results suggested a 3-hour dosing interval on the basis of MRT, pharmacodynamic studies investigating the duration of β-adrenoreceptor blockade provide a more accurate basis for determining the dosing interval of carvedilol. (Am J Vet Res 2005;66:2172–2176)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To evaluate the correlation between halftime of liquid-phase gastric emptying (T50), determined with nuclear scintigraphy using technetium Tc 99m pentetate, and absorption variables of orally administered acetaminophen.

Animals—6 mature horses.

Procedure—Technetium Tc 99m pentetate (10 mCi) and acetaminophen (20 mg/kg of body weight) were administered simultaneously in 200 ml of water. Serial left and right lateral images of the stomach region were obtained with a gamma camera, and T50 determined separately for counts obtained from the left side, the right side and the geometric mean. Power exponential curves were used for estimation of T50 and modified R2 values for estimation of goodness of fit of the data. Serial serum samples were taken, and acetaminophen concentration was determined, using fluorescence polarization immunoassay. Maximum serum concentration (Cmax), time to reach maximum serum concentration (Tmax), area under the curve for 240 minutes and the absorption constant (Ka) were determined, using a parameter estimation program. Correlations were calculated, using the Spearman rank correlation coefficient.

Results—Correlations between T50 and Tmax and between T50 and Ka were significant.

Conclusions and Clinical Relevance—Tmax and Ka are valuable variables in the assessment of liquidphase gastric emptying using acetaminophen absorption. Acetaminophen absorption may be a valuable alternative to nuclear scintigraphy in the determination of gastric emptying rates in equine patients with normally functioning small intestine. (Am J Vet Res 2000;61:310–315)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To evaluate the correlation between the half-time of liquid-phase gastric emptying (T50) determined by use of nuclear scintigraphy, using technetium Tc 99m pentetate, and absorption variables of orally administered acetaminophen in horses with experimentally delayed gastric emptying.

Animals—6 mature horses.

Procedure—Delayed gastric emptying was induced by IV injection of atropine sulfate. Twenty minutes later, acetaminophen and technetium Tc 99m pentetate were administered simultaneously via nasogastric tube. Serial lateral images of the stomach region were obtained, using a gamma camera. Power exponential curves were used for estimation of T50 and modified R2 values for estimation of goodness-of-fit of the data. Serial serum samples were obtained, and acetaminophen concentration was determined, using fluorescence polarization immunoassay. Maximum serum concentration (Cmax), time to reach maximum serum concentration (Tmax), area under the curve for 480 minutes, and the appearance rate constant were determined, using a parameter estimation program. Correlations were calculated, using a Spearman rank correlation coefficient.

Results—A significant correlation was detected between T50 determined by use of scintigraphy and Tmax determined by use of acetaminophen absorption. Correlation between T50 and other absorption variables of acetaminophen was not significant.

Conclusions and Clinical Relevance—The acetaminophen absorption method was a valid technique in this model of delayed gastric emptying in horses. The method may be a valuable tool for use in research as well as in clinical evaluation of gastric emptying in horses. (Am J Vet Res 2002;63:170–174)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetics of tramadol and its metabolites O-desmethyltramadol (ODT) and N-desmethyltramadol (NDT) in adult horses.

Animals—12 mixed-breed horses.

Procedures—Horses received tramadol IV (5 mg/kg, over 3 minutes) and orally (10 mg/kg) with a 6-day washout period in a randomized crossover design. Serum samples were collected over 48 hours. Serum tramadol, ODT, and NDT concentrations were measured via high-performance liquid chromatography and analyzed via noncompartmental analysis.

Results—Maximum mean ± SEM serum concentrations after IV administration for tramadol, ODT, and NDT were 5,027 ± 638 ng/mL, 0 ng/mL, and 73.7 ± 12.9 ng/mL, respectively. For tramadol, half-life, volume of distribution, area under the curve, and total body clearance after IV administration were 2.55 ± 0.88 hours, 4.02 ± 1.35 L/kg, 2,701 ± 275 h•ng/mL, and 30.1 ± 2.56 mL/min/kg, respectively. Maximal serum concentrations after oral administration for tramadol, ODT, and NDT were 238 ± 41.3 ng/mL, 86.8 ± 17.8 ng/mL, and 159 ± 20.4 ng/mL, respectively. After oral administration, half-life for tramadol, ODT, and NDT was 2.14 ± 0.50 hours, 1.01 ± 0.15 hours, and 2.62 ± 0.49 hours, respectively. Bioavailability of tramadol was 9.50 ± 1.28%. After oral administration, concentrations achieved minimum therapeutic ranges for humans for tramadol (> 100 ng/mL) and ODT (> 10 ng/mL) for 2.2 ± 0.46 hours and 2.04 ± 0.30 hours, respectively.

Conclusions and Clinical Relevance—Duration of analgesia after oral administration of tramadol might be < 3 hours in horses, with ODT and the parent compound contributing equally.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE To evaluate the pharmacokinetics of zonisamide following rectal administration of 20 or 30 mg/kg suspended in sterile water or polyethylene glycol (PEG) to healthy dogs and determine whether either dose resulted in plasma zonisamide concentrations within the recommended therapeutic target range (10 to 40 μg/mL).

ANIMALS 8 healthy mixed-breed dogs.

PROCEDURES Each dog received each of 2 doses (20 or 30 mg/kg) of zonisamide suspended in each of 2 delivery substrates (sterile water or PEG) in a randomized crossover study with a 7-day washout period between phases. A blood sample was collected from each dog immediately before and at predetermined times for 48 hours after zonisamide administration. Plasma zonisamide concentrations were determined by high-performance liquid chromatography, and data were analyzed with a noncompartmental model.

RESULTS Mean maximum plasma concentration, time to maximum plasma concentration, mean residence time, and elimination half-life did not differ significantly among the 4 treatments. The mean maximum plasma concentration for all 4 treatments was less than the therapeutic target range. The mean ± SD area under the concentration-time curve for the 30 mg/kg-in-water treatment (391.94 ± 237.00 h•μg/mL) was significantly greater than that for the 20 mg/kg-in-water (146.19 ± 66.27 h•μg/mL) and 20 mg/kg-in-PEG (87.09 ± 96.87 h•μg/mL) treatments.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that rectal administration of zonisamide at doses of 20 and 30 mg/kg failed to achieve plasma zonisamide concentrations within the recommended therapeutic target range. Therefore, rectal administration of zonisamide cannot be recommended as a suitable alternative to oral administration.

Full access
in American Journal of Veterinary Research
in Journal of the American Veterinary Medical Association

Abstract

Objective—To assess pharmacokinetics, efficacy, and tolerability of oral levetiracetam administered as an adjunct to phenobarbital treatment in cats with poorly controlled suspected idiopathic epilepsy.

Design—Open-label, noncomparative clinical trial.

Animals—12 cats suspected to have idiopathic epilepsy that was poorly controlled with phenobarbital or that had unacceptable adverse effects when treated with phenobarbital.

Procedures—Cats were treated with levetiracetam (20 mg/kg [9.1 mg/lb], PO, q 8 h). After a minimum of 1 week of treatment, serum levetiracetam concentrations were measured before and 2, 4, and 6 hours after drug administration, and maximum and minimum serum concentrations and elimination half-life were calculated. Seizure frequencies before and after initiation of levetiracetam treatment were compared, and adverse effects were recorded.

Results—Median maximum serum levetiracetam concentration was 25.5 μg/mL, median minimum serum levetiracetam concentration was 8.3 μg/mL, and median elimination half-life was 2.9 hours. Median seizure frequency prior to treatment with levetiracetam (2.1 seizures/mo) was significantly higher than median seizure frequency after initiation of levetiracetam treatment (0.42 seizures/mo), and 7 of 10 cats were classified as having responded to levetiracetam treatment (ie, reduction in seizure frequency of ≥ 50%). Two cats had transient lethargy and inappetence.

Conclusions and Clinical Relevance—Results suggested that levetiracetam is well tolerated in cats and may be useful as an adjunct to phenobarbital treatment in cats with idiopathic epilepsy.

Full access
in Journal of the American Veterinary Medical Association

Abstract

OBJECTIVE To determine pharmacokinetics after oral administration of single and multiple doses and to assess the safety of zonisamide in Hispaniolan Amazon parrots (Amazona ventralis).

ANIMALS 12 adult Hispaniolan Amazon parrots.

PROCEDURES Zonisamide (30 mg/kg, PO) was administered once to 6 parrots in a single-dose trial. Six months later, a multiple-dose trial was performed in which 8 parrots received zonisamide (20 mg/kg, PO, q 12 h for 10 days) and 4 parrots served as control birds. Safety was assessed through monitoring of body weight, attitude, and urofeces and comparison of those variables and results of CBC and biochemical analyses between control and treatment groups.

RESULTS Mean ± SD maximum plasma concentration of zonisamide for the single- and multiple-dose trials was 21.19 ± 3.42 μg/mL at 4.75 hours and 25.11 ± 1.81 μg/mL at 2.25 hours after administration, respectively. Mean plasma elimination half-life for the single- and multiple-dose trials was 13.34 ± 2.10 hours and 9.76 ± 0.93 hours, respectively. Pharmacokinetic values supported accumulation in the multiple-dose trial. There were no significant differences in body weight, appearance of urofeces, or appetite between treated and control birds. Although treated birds had several significant differences in hematologic and biochemical variables, all variables remained within reference values for this species.

CONCLUSIONS AND CLINICAL RELEVANCE Twice-daily oral administration of zonisamide to Hispaniolan Amazon parrots resulted in plasma concentrations known to be therapeutic in dogs without evidence of adverse effects on body weight, attitude, and urofeces or clinically relevant changes to hematologic and biochemical variables.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To describe misoprostol pharmacokinetics and anti-inflammatory efficacy when administered orally or per rectum in endotoxin-challenged horses.

ANIMALS

6 healthy geldings.

PROCEDURES

A randomized 3-treatment crossover design was performed with a minimum washout period of 28 days between treatment arms. Prior to endotoxin challenge (lipopolysaccharide, 30 ng/kg IV over 30 minutes), horses received misoprostol (5 µg/kg once) per os (M-PO) or per rectum (M-PR) or water as control (CON). Clinical parameters were evaluated and blood samples obtained to measure plasma misoprostol free acid concentration, leukocyte counts, and tumor necrosis factor-α (TNFα) and interleukin 6 (IL-6) leukocyte gene expression and serum concentrations.

RESULTS

In the M-PO treatment arm, maximum plasma concentration and area under the concentration-versus-time curve (mean ± SD) were higher (5,209 ± 3,487 pg/mL and 17,998,254 ± 13,194,420 h·pg/mL, respectively) and median (interquartile range) time to maximum concentration (25 min [18 to 34 min]) was longer than in the M-PR treatment arm (854 ± 855 pg/mL; 644,960 ± 558,866 h·pg/mL; 3 min [3 to 3.5 min]). Significant differences in clinical parameters, leukocyte counts, and TNFα or IL-6 gene expression or serum protein concentration were not detected. Downregulation of relative gene expression was appreciated for individual horses in the M-PO and M-PR treatment arms at select time points.

CLINICAL RELEVANCE

Considerable variability in measured parameters was detected among horses within and between treatment arms. Misoprostol absorption and systemic exposure after PO administration differed from previous reports in horses not administered LPS. Investigation of multidose administration of misoprostol is warranted to better evaluate efficacy as an anti-inflammatory therapeutic.

Open access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To compare the pharmacokinetics between repeated doses and to characterize changes in the fecal microbiome after oral and rectal multidose misoprostol administration.

ANIMALS

6 healthy university-owned geldings.

PROCEDURES

In a randomized, crossover study, misoprostol (5 μg/kg) was administered orally or rectally every 8 hours for 10 doses, or not administered (control), with a 21-day washout between treatments. Concentration-versus-time data for dose 1 and dose 10 were subject to noncompartmental analysis. For microbiota analysis using 16S rRNA amplicon sequencing, manure was collected 7 days before study onset, immediately before dose 1, and 6 hours, 7 days, and 14 days after dose 10, with time-matched points in controls.

RESULTS

Repeated dosing-related differences in pharmacokinetic parameters were not detected for either administration route. The area under the concentration-versus-time curve was greater (P < .04) after oral versus rectal administration. The relative bioavailability of rectal administration was 4 to 86% of that of oral administration. Microbial composition, richness, and β-diversity differed among subjects (P < .001 all) while only composition differed between treatments (P ≤ .01). Richness was decreased 6 hours after dose 10 and at the control-matched time point (P = .0109) in all subjects. No other differences for time points, treatments, or their interactions were observed.

CLINICAL RELEVANCE

Differences in systemic exposure were associated with the route of administration but were not detected after repeated administration of misoprostol. Differences in microbiota parameters were primarily associated with interindividual variation and management rather than misoprostol administration.

Open access
in American Journal of Veterinary Research