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Abstract

Objective—To characterize pharmacokinetics and pharmacodynamics of detomidine gel administered sublingually in accordance with label instructions to establish appropriate withdrawal guidelines for horses before competition.

Animals—12 adult racehorses.

Procedures—Horses received a single sublingual administration of 0.04 mg of detomidine/kg. Blood samples were collected before and up to 72 hours after drug administration. Urine samples were collected for 5 days after detomidine administration. Plasma and urine samples were analyzed via liquid chromatography–mass spectrometry, and resulting data were analyzed by use of noncompartmental analysis. Chin-to-ground distance, heart rate and rhythm, glucose concentration, PCV, and plasma protein concentration were also assessed following detomidine administration.

Results—Mean ± SD terminal elimination half-life of detomidine was 1.5 ± 1 hours. Metabolite concentrations were below the limit of detection (0.02, 0.1, and 0.5 ng/mL for detomidine, carboxydetomidine, and hydroxydetomidine, respectively) in plasma by 24 hours. Concentrations of detomidine and its metabolites were below the limit of detection (0.05 ng/mL for detomidine and 0.10 ng/mL for carboxydetomidine and hydroxydetomidine) in urine by 3 days. All horses had various degrees of sedation after detomidine administration. Time of onset was ≤ 40 minutes, and duration of sedation was approximately 2 hours. Significant decreases, relative to values at time 0, were detected for chin-to-ground distance and heart rate. There was an increased incidence and exacerbation of preexisting atrioventricular blocks after detomidine administration.

Conclusions and Clinical Relevance—A 48-hour and 3-day withdrawal period for detection in plasma and urine samples, respectively, should be adopted for sublingual administration of detomidine gel.

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

Abstract

Objective—To estimate the probability of concurrently exceeding thresholds for plasma concentration of furosemide and urine specific gravity after IV administration of furosemide in horses.

Animals—12 mature healthy Thoroughbred (n = 6) or Quarter Horse (6) mares.

Procedure—Venous blood was collected from each horse prior to and 0.25, 0.5, 0.75, 1, 2, 3, 4, 4.5, 5, and 6 hours after IV administration of 250 mg (first experiment) or 500 mg (second experiment) of furosemide. Urine was collected hourly between 1 and 6 hours after administration of furosemide at both doses. Concentrations of furosemide were determined by use of an ELISA. Concentration of furosemide and urine specific gravity was modeled as a function of time, accounting for inter- and intrahorse variabilities. On the basis of pharmacokinetic and specific gravity data, the probability of exceeding a concentration of 100 ng of furosemide/ml as a function of time was determined, using a semiparametric smooth functional averaging method. A bootstrap approach was used to assess the inherent variation in this estimated probability.

Results—The estimated probability of exceeding the threshold of 100 ng of furosemide/ml and urine specific gravity < 1.012 was approximately 0% between 4.0 and 5.5 hours after IV administration of 250 mg of furosemide/horse, and ranged from 0 to 1% between 4 and 5.5 hours after IV administration of 500 mg of furosemide/horse. The probability of a horse being falsely identified as in violation of regulatory concentrations was inversely associated with time.

Conclusions and Clinical Relevance—Coupling plasma furosemide concentration with urine specific gravity testing will greatly reduce the chance that some horses are misclassified as being in violation of regulatory concentrations. (Am J Vet Res 2001;62:1349–1353)

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in American Journal of Veterinary Research

Abstract

Objective—To estimate the probability for exceeding a threshold concentration of furosemide commonly used for regulatory purposes after IV administration of furosemide in horses.

Animals—12 mature healthy horses (6 Thoroughbreds and 6 Quarter Horses).

Procedure—Venous blood was collected from each horse prior to and 0.25, 0.5, 0.75, 1, 2, 3, 4, 4.5, 5, and 6 hours after administration of 250 or 500 mg of furosemide. Concentrations of furosemide were determined, using an ELISA. Concentration of furosemide was modeled as a function of time, accounting for inter- and intrahorse variabilities. On the basis of pharmacokinetic data, the probability for exceeding a concentration of 100 ng/ml as a function of time was determined, using a semiparametric smooth functional averaging method. A bootstrap approach was used to assess inherent variation in this estimated probability.

Results—The estimated probability of exceeding the threshold of 100 ng of furosemide/ml ranged from 11.6% at 4 hours to 2.2% at 5.5 hours after IV administration of 250 mg of furosemide/horse and 34.2% at 4 hours to 12.3% at 5.5 hours after IV administration of 500 mg of furosemide/horse. The probability of a horse being falsely identified in violation of regulatory concentrations was inversely associated with time and positively associated with dose.

Conclusions and Clinical Relevance—Interhorse variability with respect to pharmacokinetics of furosemide will result in misclassification of some horses as being in violation of regulatory concentrations. (Am J Vet Res 2001;62:320–325)

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in American Journal of Veterinary Research

Abstract

Objective—To determine effects of cisapride and 5-hydroxytryptamine (5-HT) on the jejunum of horses.

Sample Population—Jejunal muscle strips from 8 horses.

Procedure—Muscle strips were suspended in isolated muscle baths. Isometric stress responses to 5-HT and cisapride, with and without specific antagonists, were determined.

Results—Muscle strips incubated with atropine and tetrodotoxin responded to 5-HT and cisapride with an increase in contractile force. The 5-HT caused a concentration-dependent increase in contractile amplitude, with a maximum response (Emax) of 1,151 ± 214 g/cm2 and a molar concentration that induces contractile force equal to 50% of maximum response (EC50) of 0.028 ± 0.002 µM. Prior incubation with the 5-HT2 antagonist ketanserin decreased the Emax (626 ± 147 g/cm2) and potency (EC50, 0.307 ± 0.105 µM) of 5-HT. Prior incubation with the 5-HT3 antagonist tropisetron decreased the efficacy (Emax, 894 ± 184 g/cm2) to 5-HT. Cisapride also caused a concentrationdependent increase in contractile amplitude, with an Emax of 331 ± 82 g/cm2 and an EC50 of 0.302 ± 0.122 µM. Prior incubation with ketanserin decreased the Emax (55 ± 17 g/cm2) and potency (EC50, 0.520 ± 0.274 µM) of cisapride.

Conclusion and Clinical Relevance—Stimulatory effects of 5-HT and cisapride on circular smooth muscle of equine jejunum are mediated primarily through a noncholinergic effect. The effects of 5-HT are mediated, at least partially, by 5-HT2 and 5-HT3 receptors, whereas the effects of cisapride are mediated primarily by 5-HT2 receptors. This may impact treatment of horses with postoperative ileus. (Am J Vet Res 2000;61:1561–1565)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To characterize the pharmacokinetics of remifentanil in conscious cats and cats anesthetized with isoflurane.

Animals—6 cats.

Procedures—Remifentanil (1 μg/kg/min for 5 minutes) was administered IV in conscious cats or cats anesthetized with 1.63% isoflurane in oxygen in a randomized crossover design. Blood samples were obtained immediately prior to remifentanil administration and every minute for 10 minutes, every 2 minutes for 10 minutes, and every 5 minutes for 10 minutes after the beginning of the infusion. Blood was immediately transferred to tubes containing citric acid, flash frozen in liquid nitrogen, and stored at −80°C until analysis. Blood remifentanil concentration was determined by use of liquid chromatography–mass spectrometry. Remifentanil concentration-time data were fitted to compartment models.

Results—A 2-compartment model (with zero-order input because of study design) best described the disposition of remifentanil in awake and isoflurane-anesthetized cats. The apparent volume of distribution of the central compartment, the apparent volume of distribution at steady state, the clearance, and the terminal half-life (median [range]) were 1,596 (1,164 to 2,111) and 567 (278 to 641) mL/kg, 7,632 (2,284 to 76,039) and 1,651 (446 to 29,229) mL/kg, 766 (408 to 1,473) and 371 (197 to 472) mL/min/kg, and 17.4 (5.5 to 920.3) and 15.7 (3.8 to 410.3) minutes in conscious and anesthetized cats, respectively.

Conclusions and Clinical Relevance—The disposition of remifentanil in cats was characterized by a high clearance. Isoflurane anesthesia significantly decreased the volume of the central compartment, likely by decreasing blood flow to vessel-rich organs.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine the effects of domperidone on in vivo and in vitro measures of gastrointestinal tract motility and contractility in healthy horses.

Sample—18 adult horses and tissue samples from an additional 26 adult horses.

Procedures—Domperidone or placebo paste was administered to healthy horses in a 2-period crossover study. Gastric emptying was evaluated after oral administration of domperidone paste (1.1 or 5.0 mg/kg) or placebo paste by means of the acetaminophen absorption test in 12 horses. Frequency of defecation, weight of feces produced, fecal moisture, and stomach-to-anus transit time of microspheres were evaluated after administration of domperidone paste (1.1 mg/kg) or placebo paste in 6 horses. The effect of domperidone on smooth muscle contractile activity in samples of duodenum, jejunum, ileum, or colon obtained from 26 horses immediately after euthanasia (for nonsystemic medical problems) was investigated.

Results—Oral administration of 5.0 mg of domperidone/kg increased peak plasma acetaminophen concentration and area under the curve, indicating increased gastric emptying. Administration of 1.1 mg of domperidone/kg had no effect on gastric emptying, transit time, defecation frequency, or amount and moisture of excreted feces. Contractile activities of circular and longitudinal muscle strips from the duodenum, jejunum, ileum, or colon were not altered by domperidone. Dopamine increased contractile activity of longitudinal muscle strips but not that of circular muscle strips from the midjejunum. Domperidone decreased the dopamine-induced contractile activity of midjejunal longitudinal muscle strips.

Conclusions and Clinical Relevance—The potential beneficial effects of domperidone in horses with ileus need to be evaluated in horses with decreased gastric emptying or adynamic ileus.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To evaluate effects of various doses of remifentanil on measures of analgesia in anesthetized cats.

Animals—6 healthy adult cats.

Procedures—Minimum alveolar concentration (MAC) for isoflurane and thermal threshold responses were evaluated in anesthetized cats. Remifentanil infusions of 0 (baseline), 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, and 16 μg/kg/min were administered; after a 45-minute equilibration period, isoflurane MAC and responses were determined. Isoflurane MAC was determined in anesthetized cats once for each remifentanil infusion rate by use of a standard tail clamp technique. Thermal threshold was measured in awake cats by use of a commercially available analgesiometric probe placed on the lateral portion of the thorax; remifentanil infusions were administered in randomized order to anesthetized cats, and thermal threshold determinations were made by an investigator who was unaware of the infusion rate.

Results—Mean ± SEM median effective concentration (EC50) for remifentanil and its active metabolite, GR90291, for the thermal threshold test was 1.00 ± 0.35 ng/mL and 307 ± 28 ng/mL of blood, respectively. Dysphoria was detected in all awake cats at the 2 highest remifentanil infusion rates. However, isoflurane MAC during remifentanil infusions was unchanged from baseline values, even at blood opioid concentrations approximately 75 times the analgesic EC50.

Conclusions and Clinical Relevance—Immobility and analgesia as reflected by thermal threshold testing were independent anesthetic end points in the cats. Results of MAC-sparing evaluations should not be used to infer analgesic potency without prior validation of an MAC-analgesia relationship for specific drugs and species.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To investigate penciclovir pharmacokinetics following single and multiple oral administrations of famciclovir to cats.

Animals—8 adult cats.

Procedures—A balanced crossover design was used. Phase I consisted of a single administration (62.5 mg, PO) of famciclovir. Phase II consisted of multiple doses of famciclovir (62.5 mg, PO) given every 8 or 12 hours for 3 days. Plasma penciclovir concentrations were assayed via liquid chromatography—mass spectrometry at fixed time points after famciclovir administration.

Results—Following a single dose of famciclovir, the dose-normalized (15 mg/kg) maximum concentration (Cmax) of penciclovir (350 ± 180 ng/mL) occurred at 4.6 ± 1.8 hours and mean ± SD apparent elimination half-life was 3.1 ± 0.9 hours. However, the dose-normalized area under the plasma penciclovir concentration-time curve extrapolated to infinity (AUC0→∞) during phase I decreased with increasing dose, suggesting either nonlinear pharmacokinetics or interindividual variability among cats. Accumulation occurred following multiple doses of famciclovir administered every 8 hours as indicated by a significantly increased dose-normalized AUC, compared with AUC0→∞ from phase 1. Dose-normalized penciclovir Cmaxfollowing administration of famciclovir every 12 or 8 hours (290 ± 150 ng/mL or 780 ± 250 ng/mL, respectively) was notably less than the in vitro concentration (3,500 ng/mL) required for activity against feline herpesvirus-1.

Conclusions and Clinical Relevance—Penciclovir pharmacokinetics following oral famciclovir administration in cats appeared complex within the dosage range studied. Famciclovir dosages of 15 mg/kg administered every 8 hours to cats are unlikely to result in plasma penciclovir concentrations with activity against feline herpesvirus-1.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE To determine short- and long-term outcomes and complications of dogs undergoing surgical correction of grade IV medial patellar luxation (MPL).

DESIGN Retrospective case series.

ANIMALS 24 dogs (29 stifle joints) that underwent surgical correction of grade IV MPL between March 2008 and April 2014.

PROCEDURES Medical records of all dogs were reviewed. When available, long-term follow-up information was obtained for each dog via the orthopedic surgeon (results of orthopedic examination and radiographic interpretation) and the dog's owner (responses to a questionnaire regarding postsurgical outcomes). Types of postsurgical complications and intervals to follow-up data collection were recorded. Recurrence of MPL was recorded separately. Successful outcome was defined as one without catastrophic complication, with owner-reported full or acceptable return to function and a surgeon- and owner-assigned pain or lameness score < 3.

RESULTS 24% (7/29) of stifle joints had major complications, and 21% (6) of joints required surgical revision. Grade II to IV recurrence of MPL was identified in 21% (6) of stifle joints. One dog had a catastrophic complication requiring limb amputation. For all other dogs, owner-reported return to function was full or acceptable. Surgeon-assigned pain and lameness scores for all dogs at the final follow-up evaluation were < 2/5 (0 = pain or lameness free). Surgical correction of grade IV MPL had an overall success rate of 93% (27/29).

CONCLUSIONS AND CLINICAL RELEVANCE Surgical correction of grade IV MPL in dogs had a favorable overall success rate; however, owners should be counseled regarding the high rate of complications associated with surgery.

Full access
in Journal of the American Veterinary Medical Association