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Abstract

Objective—To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.

Animals—6 healthy Greyhounds, 3 male and 3 female.

Procedures—Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 ± 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software.

Results—Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds.

Conclusions and Clinical Relevance—Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.

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in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetics of tramadol, the active metabolite O-desmethyltrcamadol, and the metabolites N-desmethyltramadol and N,O-didesmethyltramadol after oral tramadol administration and to determine the antinociceptive effects of the drug in Greyhounds.

Animals—6 healthy 2- to 3-year-old Greyhounds (3 male and 3 female), weighing 25.5 to 41.1 kg.

Procedures—A mean dose of 9.9 mg of tramadol HCl/kg was administered PO as whole tablets. Blood samples were obtained prior to and at various points after administration to measure plasma concentrations of tramadol and its metabolites via liquid chromatography with mass spectrometry. Antinociceptive effects were determined by measurement of pain-pressure thresholds with a von Frey device.

Results—Tramadol was well tolerated, and a significant increase in pain-pressure thresholds was evident 5 and 6 hours after administration. The mean maximum plasma concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol were 215.7, 5.7, 379.1, and 2372 ng/mL, respectively. The mean area-under-the-curve values for the compounds were 592, 16, 1,536, and 1,013 h·ng/mL, respectively. The terminal half-lives of the compounds were 1.1, 1.4, 2.3, and 3.6 hours, respectively. Tramadol was detected in urine 5 days, but not 7 days, after administration.

Conclusions and Clinical Relevance—Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and O-desmethyltramadol were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower O-desmethyltramadol plasma concentrations in Greyhounds.

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in American Journal of Veterinary Research

Abstract

OBJECTIVE To determine drug content (potency) of compounded doxycycline formulations for veterinary use and of US FDA–approved doxycycline formulations for human use < 24 hours after receipt (day 1) and after 21 days of storage under recommended conditions (day 21).

DESIGN Evaluation study.

SAMPLE FDA-approved doxycycline tablets (100 mg), capsules (100 mg), and liquid suspension (10 mg/mL) and compounded doxycycline formulations from 3 pharmacies (tablets [25, 100, and 150 mg; 1 product/source], chews [100 mg; 1 product/source], and liquid suspensions or solution [6 mg/mL {2 sources} and 50 mg/mL {1 source}]).

PROCEDURES Doxycycline content was measured in 5 samples of each tablet, chew, or capsule formulation and 5 replicates/bottle of liquid formulation on days 1 and 21 by liquid chromatography and compared with US Pharmacopeia acceptable ranges.

RESULTS All FDA-approved formulations had acceptable content on days 1 and 21. On day 1, mean doxycycline content for the 3 compounded tablet formulations was 89%, 98%, and 116% (3/5, 5/5, and 1/5 samples within acceptable ranges); day 21 content range was 86% to 112% (1/5, 5/5, and 4/5 samples within acceptable ranges). Day 1 content of chews was 81%, 78%, and 98% (0/5, 0/5, and 5/5 samples within acceptable ranges), and that of compounded liquids was 50%, 52%, and 85% (no results within acceptable ranges). No chews or compounded liquid formulations met USP standards on day 21.

CONCLUSIONS AND CLINICAL RELEVANCE FDA-approved doxycycline should be prescribed when possible. Whole tablets yielded the most consistent doxycycline content for compounded formulations.

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in Journal of the American Veterinary Medical Association

Abstract

OBJECTIVE

To determine the effects of coadministration of naltrexone, a human opioid abuse deterrent, on the pharmacokinetics and pharmacodynamics of a methadone-fluconazole combination administered orally to dogs.

ANIMALS

12 healthy Beagles.

PROCEDURES

Dogs (body weight, 10.7 to 13.9 kg) were randomly allocated to 2 groups in a parallel design study. All dogs received fluconazole (100 mg [7.19 to 9.35 mg/kg], PO). Twelve hours later (time 0), dogs were administered methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.62 to 4.22 mg/kg]; methadone-fluconazole) or methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.60 to 4.67 mg/kg]) and naltrexone (2.5 mg [0.18 to 0.23 mg/kg]; methadone-fluconazole-naltrexone), PO, in a gelatin capsule. Blood samples were collected for pharmacokinetic analysis, and rectal temperature and sedation were assessed to evaluate opioid effects at predetermined times up to 24 hours after treatment.

RESULTS

Most dogs had slight sedation during the 12 hours after drug administration; 1 dog/group had moderate sedation at 1 time point. Mean rectal temperatures decreased significantly from baseline (immediate pretreatment) values from 2 to ≥ 12 hours and 2 to ≥ 8 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Geometric mean maximum observed concentration of methadone in plasma was 35.1 and 33.5 ng/mL and geometric mean terminal half-life was 7.92 and 7.09 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Naltrexone was sporadically detected in 1 dog. The active naltrexone metabolite, β-naltrexol, was not detected. The inactive metabolite, naltrexone glucuronide, was detected in all dogs administered methadone-fluconazole-naltrexone.

CONCLUSIONS AND CLINICAL RELEVANCE

Opioid effects were detected after oral administration of methadone-fluconazole or methadone-fluconazole-naltrexone. Further studies assessing additional opioid effects, including antinociception, are needed.

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in American Journal of Veterinary Research

Abstract

OBJECTIVE

To compare hematologic results for juvenile versus adult dogs from shelters that outwardly appeared healthy and were presented for ovariohysterectomy or castration.

ANIMALS

138 dogs from 13 regional shelters.

PROCEDURES

Each dog underwent a physical examination (including use of a flea comb), age estimation by dental eruption characteristics, PCV, CBC, and tests for Dirofilaria immitis antigen and Anaplasma phagocytophilum, Borrelia burgdorferi, and Ehrlichia canis antibodies. Additional diagnostic tests were performed as needed. Dogs were grouped by age as < 3, ≥ 3 to ≤ 6, or > 6 months of age, with dogs ≤ 6 months of age considered juveniles and dogs > 6 months of age considered adults. Hematologic results were compared across groups.

RESULTS

There were 138 dogs, of which 56 were juveniles (34 dogs < 3 months old; 22 dogs ≥ 3 to ≤ 6 months old) and 82 were adults. Juvenile (vs adult) dogs had lower mean calculated Hct and mean PCV whether dogs with infectious agents or parasites were included or excluded. The mean PCV and mean cell hemoglobin concentration were lower and the reticulocyte count higher for juvenile dogs < 3 months old (35.8%, 33.1 g/dL, and 135,000 reticulocytes/μL) versus adults (44.9%, 34.7 g/dL, and 68,500 reticulocytes/ μL). Most (98.6%) dogs underwent surgery as scheduled; 2 dogs had surgery postponed because of thrombocytopenia or parvovirus infection.

CONCLUSIONS AND CLINICAL RELEVANCE

Our findings indicated that outwardly healthy-appearing juvenile shelter dogs often have results for PCV and calculated Hct that are lower than those for adult shelter dogs and adult dog reference intervals but rarely require postponement of ovariohysterectomy or castration.

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in Journal of the American Veterinary Medical Association

Abstract

Objective—To evaluate the pharmacokinetics and pharmacodynamics of morphine after IV administration as an infusion or multiple doses in dogs by use of a von Frey (vF) device.

Animals—6 dogs.

Procedure—In the first 2 crossover experiments of a 3-way crossover study, morphine or saline (0.9%) solution was administered via IV infusion. Loading doses and infusion rates were administered to attain targeted plasma concentrations of 10, 20, 30, and 40 ng/mL. In the third experiment, morphine (0.5 mg/kg) was administered IV every 2 hours for 3 doses. The vF thresholds were measured hourly for 8 hours. Plasma concentrations of morphine were measured by highpressure liquid chromatography.

Results—No significant changes in vF thresholds were observed during infusion of saline solution. The vF thresholds were significantly increased from 5 to 8 hours during the infusion phase, corresponding to targeted morphine plasma concentrations > 30 ng/mL and infusion rates ≥ 0.15 ± 0.02 mg/kg/h. The maximal effect (EMAX) was 78 ± 11% (percentage change from baseline), and the effective concentration to attain a 50% maximal response (EC50) was 29.5 ± 5.4 ng/mL. The vF thresholds were significantly increased from 1 to 7 hours during the multiple-dose phase; the EC50 and EMAX were 23.9 ± 4.7 ng/mL and 173 ± 58%, respectively. No significant differences in half-life, volume of distribution, or clearance between the first and last dose of morphine were detected.

Conclusions and Clinical Relevance—Morphine administered via IV infusion (0.15 ± 0.02 mg/kg/h) and multiple doses (0.5 mg/kg, IV, every 2 hours for 3 doses) maintained significant antinociception in dogs. (Am J Vet Res 2005;66:1968–1974)

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in American Journal of Veterinary Research

Abstract

Objective—To assess the use of a von Frey device as a mechanical nociceptive stimulus for evaluation of the antinociceptive effects of morphine in dogs and its potential application in the pharmacodynamic modeling of morphine in that species.

Animals—6 healthy Beagles.

Procedure—von Frey thresholds were measured in all dogs before and at intervals after they received no treatment (control dogs) and IV administration of morphine sulfate (1 mg/kg; treated dogs) in a crossover study. The von Frey device consisted of a rigid tip (0.5 mm in diameter) and an electronic load cell; the operator was unaware of recorded measurements.

Results—Application of the von Frey device was simple and well tolerated by all dogs and caused no apparent tissue damage. No significant changes in thresholds were detected in the control dogs at 8 hourly measurements, indicating a lack of acquired tolerance, learned aversion, or local hyperalgesia. When assessed as a group, treated dogs had significantly high thresholds for 4 hours following morphine administration, compared with baseline values; individually, thresholds decreased to baseline values within (mean ± SE) 2.8 ± 0.6 hours. The maximal effect (change from baseline values) was 213 ± 43%, and the plasma morphine concentration to achieve 50% maximal effect was 13.92 ± 2.39 ng/mL.

Conclusions and Clinical Relevance—Data suggest that, in dogs, evaluation of the antinociceptive effect and pharmacodynamic modeling of a dose of morphine sulfate (1 mg/kg, IV) can be successfully achieved by use of a von Frey device. (Am J Vet Res 2005;66:1616–1622)

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in American Journal of Veterinary Research

Abstract

OBJECTIVE To determine pharmacokinetics of butorphanol delivered via osmotic pumps in common peafowl (Pavo cristatus) as a method for analgesic administration to avian species.

ANIMALS 14 healthy adult male common peafowl.

PROCEDURES A preliminary experiment was conducted with 2 birds to establish time point and concentration requirements. Then, the remaining 12 birds were anesthetized, and 2 osmotic pumps containing butorphanol (volume, 2 mL; mean dosage, 247 μg/kg/h) were implanted subcutaneously in each bird for 7 days prior to removal. Blood samples were collected before pump implantation (time 0); 3, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours after pump implantation; and 3 and 6 hours after pump removal. Plasma butorphanol concentrations were measured via liquid chromatography–mass spectrometry.

RESULTS Plasma concentrations peaked (mean, 106.4 μg/L; range, 61.8 to 133.0 μg/L) at a mean of 39.0 hours, with no evidence of sedation in any bird. After pump removal, butorphanol was rapidly eliminated (half-life, 1.45 hours; range, 1.31 to 1.64 hours; n = 5). Mean clearance per fraction of dose absorbed was 2.89 L/kg/h (range, 2.00 to 5.55 L/kg/h). Mean amount of time the plasma butorphanol concentration was ≥ 60 μg/L was 85.6 hours (range, 3.5 to 155.3 hours).

CONCLUSIONS AND CLINICAL RELEVANCE Plasma concentrations of butorphanol in common peafowl were maintained at or above reported efficacious analgesic concentrations. This study established a method for administering analgesics to avian patients without the need for frequent handling or injections. Use of these osmotic pumps may provide options for avian analgesia.

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in American Journal of Veterinary Research

Abstract

OBJECTIVE To determine plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin following single-dose SC administration to black-tailed prairie dogs (Cynomys ludovicianus).

ANIMALS 8 captive healthy 6-month-old sexually intact male black-tailed prairie dogs.

PROCEDURES Enrofloxacin (20 mg/kg) was administered SC once to 6 prairie dogs and IV once to 2 prairie dogs. A blood sample was collected from each animal immediately before (0 hours) and 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin. Plasma enrofloxacin and ciprofloxacin concentrations were quantified with ultraperformance liquid chromatography–mass spectrometry, and noncompartmental pharmacokinetic analysis was performed.

RESULTS Enrofloxacin was biotransformed to ciprofloxacin in the prairie dogs used in the study. For total fluoroquinolones (enrofloxacin and ciprofloxacin), the mean (range) of peak plasma concentration, time to maximum plasma concentration, and terminal half-life after SC administration were 4.90 μg/mL (3.44 to 6.08 μg/mL), 1.59 hours (0.5 to 2.00 hours), and 4.63 hours (4.02 to 5.20 hours), respectively.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that administration of enrofloxacin (20 mg/kg, SC, q 24 h) in black-tailed prairie dogs may be appropriate for treatment of infections with bacteria for which the minimum inhibitory concentration of enrofloxacin is ≤ 0.5 μg/mL. However, clinical studies are needed to determine efficacy of such enrofloxacin treatment.

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in American Journal of Veterinary Research

Abstract

Objective—To determine pharmacokinetics, efficacy, and adverse effects of topically administered selamectin in flea-infested rabbits.

Animals—18 healthy 5-month-old New Zealand White rabbits.

Procedures—On day 0, rabbits (n = 6/group) received topically applied selamectin at doses of 10 or 20 mg/kg or received no treatment. Each rabbit was infested with 50 fleas (Ctenocephalides felis) on days −1, 7, and 14. Live and dead flea counts were performed on days 2, 9, and 16, and treatment efficacy was calculated. Blood samples were collected prior to drug administration and at 6 and 12 hours and 1, 2, 3, 5, 7, 10, 14, 21, and 28 days after treatment for determination of plasma selamectin concentrations via high-performance liquid chromatography with mass spectrometry. Pharmacokinetic parameters were determined.

Results—On day 2, efficacy of selamectin against flea populations of rabbits in the 10 and 20 mg/kg treatment groups was 91.3% and 97.1%, respectively, but by day 9, these values decreased to 37.7% and 74.2%, respectively. Mean terminal half-life and maximum plasma concentrations of selamectin were 0.93 days and 91.7 ng/mL, respectively, for rabbits in the 10 mg/kg group and 0.97 days and 304.2 ng/mL, respectively, for rabbits in the 20 mg/kg group. No adverse effects were detected.

Conclusions and Clinical Relevance—Selamectin was rapidly absorbed transdermally and was rapidly eliminated in rabbits. Results suggested that topical administration at a dosage of 20 mg/kg every 7 days is efficacious for treatment of flea infestation in rabbits. Further studies are needed to assess long-term safety in rabbits following repeated applications.

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in American Journal of Veterinary Research