Pharmacokinetics of three formulations of vitacoxib in horses

The pharmacokinetic properties of three formulations of vitacoxib were investigated in horses. To describe plasma concentrations and characterize the pharmacokinetics, 6 healthy adult Chinese Mongolian horses were administered a single dose of 0.1 mg/kg bodyweight intravenous (i.v.), oral paste, or oral tablet vitacoxib in a 3-way, randomized, parallel design. Blood samples were collected prior to and at various times up to 72 hr postadministration. Plasma vitacoxib concentrations were quantified using UPLC-MS/MS, and pharmacokinetic parameters were calculated using noncompartmental analysis. No complications resulting from the vitacoxib administration were noted on subsequent administrations, and all procedures were tolerated well by the horses throughout the study. The elimination half-life (T_1/2λz) was 4.24 ± 1.98 hr (i.v.), 8.77 ± 0.91 hr (oral paste), and 8.12 ± 4.24 hr (oral tablet), respectively. Maximum plasma concentration (C_max) was 28.61 ± 9.29 ng/ml (oral paste) and 19.64 ± 9.26 ng/ml (oral tablet), respectively. Area under the concentration-versus-time curve (AUC_last) was 336 ± 229 ng hr/ml (i.v.), 221 ± 94 ng hr/ml (oral paste), and 203 ± 139 ng hr/ml, respectively. The results showed statistically significant differences between the 2 oral vitacoxib groups in T_max value. T_1/2λz (hr), AUC_last (ng hr/ml), and MRT (hr) were significantly different between i.v. and oral groups. The longer half-life observed following oral administration was consistent with the flip-flop phenomenon.     

Pharmacokinetics and pharmacodynamics of hydromorphone hydrochloride in healthy horses

ObjectivesTo determine the physiologic and behavioral effects and pharmacokinetic profile of hydromorphone administered intravenously (IV) to horses.Study designProspective, randomized, crossover study.AnimalsA group of six adult healthy horses weighing 585.2 ± 58.7 kg.MethodsEach horse was administered IV hydromorphone (0.025 mg kg^–1; treatment H0.025), hydromorphone (0.05 mg kg^–1; treatment H0.05) or 0.9% saline in random order with a 7 day washout period. For each treatment, physiologic, hematologic, abdominal borborygmi scores and behavioral data were recorded over 5 hours and fecal output was totaled over 24 hours. Data were analyzed using repeated measures anova with significance at p < 0.05. Blood samples were collected in treatment H0.05 for quantification of plasma hydromorphone and hydromorphone-3-glucuronide and subsequent pharmacokinetic parameter calculation.ResultsHydromorphone administration resulted in a dose-dependent increase in heart rate (HR) and systolic arterial pressure (SAP). HR and SAP were 59 ± 17 beats minute^–1 and 230 ± 27 mmHg, respectively, in treatment H0.05 at 5 minutes after administration. No clinically relevant changes in respiratory rate, arterial gases or temperature were observed. The borborygmi scores in both hydromorphone treatments were lower than baseline values for 2 hours. Fecal output did not differ among treatments and no evidence of abdominal discomfort was observed. Recorded behaviors did not differ among treatments. For hydromorphone, mean ± standard deviation for volume of distribution at steady state, total systemic clearance and area under the curve until the last measured concentration were 1.00 ± 0.29 L kg^–1, 106 ± 21 mL minute^–1 kg^–1 and 8.0 ± 1.5 ng hour mL^–1, respectively.Conclusions and clinical relevanceHydromorphone administered IV to healthy horses increased HR and SAP, decreased abdominal borborygmi and did not affect fecal output.     

Effects of low-dose G-CSF formulation on hematology in healthy horses after long-distance transportation

The present study evaluated the effects of single-dose filgrastim on hematology in 16 healthy horses after long-distance transportation. Horses were assigned to receive filgrastim (0.23 µg/kg, SC, once; G-CSF group; n=8) or saline (0.9% NaCl) solution (0.3 ml, SC, once; control group; n=8) ≤ 1 hr before transportation. Horses were transported 2,530 km using commercial vans over the course of approximately 44 hr. Clinical examinations and hematologic analyses were performed on all horses before and after transportation. Because the post-transportation white blood cell counts and bacillary neutrophil to segmented neutrophil ratio were significantly higher in the G-CSF group, filgrastim may have promoted the mobilization of neutrophils from marrow. Filgrastim deserves a further study for efficacy in preventing horse shipping fever.     

Pharmacokinetics of amikacin in plasma and selected body fluids of healthy horses after a single intravenous dose

Reasons for performing study: No studies have determined the pharmacokinetics of low‐dose amikacin in the mature horse. Objectives: To determine if a single i.v. dose of amikacin (10 mg/kg bwt) will reach therapeutic concentrations in plasma, synovial, peritoneal and interstitial fluid of mature horses (n = 6). Methods: Drug concentrations of amikacin were measured across time in mature horses (n = 6); plasma, synovial, peritoneal and interstitial fluid were collected after a single i.v. dose of amikacin (10 mg/kg bwt). Results: The mean ± s.d. of selected parameters were: extrapolated plasma concentration of amikacin at time zero 144 ± 21.8 µg/ml; extrapolated plasma concentration for the elimination phase 67.8 ± 7.44 µg/ml, area under the curve 139 ± 34.0 µg*h/ml, elimination half‐life 1.34 ± 0.408 h, total body clearance 1.25 ± 0.281 ml/min/kg bwt; and mean residence time (MRT) 1.81 ± 0.561 h. At 24 h, the plasma concentration of amikacin for all horses was below the minimum detectable concentration for the assay. Selected parameters in synovial and peritoneal fluid were maximum concentration (C_max) 19.7 ± 7.14 µg/ml and 21.4 ± 4.39 µg/ml and time to maximum concentration 65 ± 12.2 min and 115 ± 12.2 min, respectively. Amikacin in the interstitial fluid reached a mean peak concentration of 12.7 ± 5.34 µg/ml and after 24 h the mean concentration was 3.31 ± 1.69 µg/ml. Based on a minimal inhibitory concentration (MIC) of 4 µg/ml, the mean C_max : MIC ratio was 16.9 ± 1.80 in plasma, 4.95 ± 1.78 in synovial fluid, 5.36 ± 1.10 in peritoneal fluid and 3.18 ± 1.33 in interstitial fluid. Conclusions: Amikacin dosed at 10 mg/kg bwt i.v. once a day in mature horses is anticipated to be effective for treatment of infection caused by most Gram‐negative bacteria. Potential relevance: Low dose amikacin (10 mg/kg bwt) administered once a day in mature horses may be efficacious against susceptible microorganisms.     

Pharmacokinetics of detomidine administered to horses at rest and after maximal exercise

Reason for performing study: Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. Objectives: To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Methods: Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatographymass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Results: Median back‐extrapolated time zero plasma concentration was significantly lower and median plasma half‐life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Conclusions and potential relevance: Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect.     

Pharmacokinetics of detomidine and its metabolites following intravenous and intramuscular administration in horses

Reasons for performing study: Detomidine is commonly used i.v. for sedation and analgesia in horses, but the pharmacokinetics and metabolism of this drug have not been well described. Objectives: To describe the pharmacokinetics of detomidine and its metabolites, 3‐hydroxy‐detomidine (OH‐detomidine) and detomidine 3‐carboxylic acid (COOH‐detomidine), after i.v. and i.m. administration of a single dose to horses. Methods: Eight horses were used in a balanced crossover design study. In Phase 1, 4 horses received a single dose of i.v. detomidine, administered 30 μg/kg bwt and 4 a single dose i.m. 30 üg/kg bwt. In Phase 2, treatments were reversed. Plasma detomidine, OH‐detomidine and COOH‐detomidine were measured at predetermined time points using liquid chromatography‐mass spectrometry. Results: Following i.v. administration, detomidine was distributed rapidly and eliminated with a half‐life (t_1/2(el)) of approximately 30 min. Following i.m. administration, detomidine was distributed and eliminated with t_1/2(el) of approximately one hour. Following, i.v. administration, detomidine clearance had a mean, median and range of 12.41, 11.66 and 10.10–18.37 ml/min/kg bwt, respectively. Detomidine had a volume of distribution with the mean, median and range for i.v. administration of 470, 478 and 215–687 ml/kg bwt, respectively. OH‐detomidine was detected sooner than COOH‐detomidine; however, COOH‐detomidine had a much greater area under the curve. Conclusions and potential relevance: These pharmacokinetic parameters provide information necessary for determination of peak plasma concentrations and clearance of detomidine in mature horses. The results suggest that, when a longer duration of plasma concentration is warranted, the i.m. route should be considered.     

Pharmacokinetics of carbetocin,a long‐acting oxytocin analogue,following intravenous administration in horses

Reason for performing study: Current therapy protocols to treat persistent post mating endometritis and retained fetal membranes in mares typically include the administration of ecbolic drugs. Evaluation of the pharmacokinetics and tolerability of carbetocin, a long‐acting oxytocin analogue, after i.v. administration is required. Objectives: To determine the pharmacokinetic parameters (principally half‐life) of carbetocin in horses. Methods: Five mature mares and one gelding received 0.175 mg carbetocin i.v. All animals were monitored periodically throughout the study for elevation in rectal temperature, heart rate, respiratory rate and signs of pain or discomfort. Plasma samples were collected for determination of carbetocin concentrations by radioimmunoassay. Results: Administration of carbetocin was well tolerated by all horses and its half‐life was 17.2 min. Conclusions: The half‐life of carbetocin is greater than that previously reported for oxytocin (6.8 min). Potential relevance: Carbetocin is an attractive alternative to oxytocin therapy in broodmare management.     

Comparative Pharmacokinetics of Diphenhydramine in Camels and Horses after Intravenous Administration

The pharmacokinetics of diphenhydramine (DPHM) was compared in camels (n = 8) and horses (n = 6) following intravenous (i.v.) administration of a dose of 0.625 mg/kg body weight. In addition, the metabolism and urinary detection time of DPHM was evaluated in camels. The data obtained (median and range in brackets) in camels and horses, respectively, were as follows. The terminal elimination half lives (h) were 1.58 (1.13–2.58) and 6.11 (4.80–14.1), and the total body clearances (L/h per kg) were 1.42 (1.13–1.74) and 0.79 (0.66–0.90). The volumes of distribution at steady state (L/kg) were 2.38 (1.58–4.43) and 5.98 (4.60–8.31) and the volumes of the central compartment of the two compartment pharmacokinetic model were 1.58 (0.80–2.54) and 2.48 (1.79–3.17). All the pharmacokinetic parameters in camels were significantly different from those of horses. Five metabolites of DPHM were tentatively identified in the camel's urine. Two metabolites, diphenylmethoxyacetic acid and 1-(4-hydroxyphenyl)-phenylmethoxyacetic acid, were present in the acid fraction. Two metabolites, desamino-DPHM and diphenylmethanol, were identified in the basic fraction, in addition to DPHM itself, which was present mainly as a conjugate. Even after enzymatic hydrolysis, DPHM could be detected for up to 24 h in camels after an i.v. dose of 0.625 mg/kg body weight.     

Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses

The objective of the current study was to describe and characterize the pharmacokinetics and selected pharmacodynamic effects of morphine and its two major metabolites in horses following several doses of morphine. A total of ten horses were administered a single intravenous dose of morphine: 0.05, 0.1, 0.2, or 0.5 mg/kg, or saline control. Blood samples were collected up to 72 hr, analyzed for morphine, and metabolites by LC/MS/MS, and pharmacokinetic parameters were determined. Step count, heart rate and rhythm, gastrointestinal borborygmi, fecal output, packed cell volume, and total protein were also assessed. Morphine‐3 glucuronide (M3G) was the predominant metabolite detected, with concentrations exceeding those of morphine‐6 glucuronide (M6G) at all time points. Maximal concentrations of M3G and M6G ranged from 55.1 to 504 and 6.2 to 28.4 ng/ml, respectively, across dose groups. The initial assessment of morphine pharmacokinetics was done using noncompartmental analysis (NCA). The volume of distribution at steady‐state and systemic clearance ranged from 9.40 to 16.9 L/kg and 23.3 to 32.4 ml min^?1 kg^?1, respectively. Adverse effects included signs of decreased gastrointestinal motility and increased central nervous excitation. There was a correlation between increasing doses of morphine, increases in M3G concentrations, and adverse effects. Findings from this study support direct administration of purified M3G and M6G to horses to better characterize the pharmacokinetics of morphine and its metabolites and to assess pharmacodynamic activity of these metabolites.     

Subepiglottic cysts in 15 horses

Subepiglottic cysts (SECs) are an infrequent cause of upper respiratory tract noise and exercise intolerance in horses. They may also be associated with no clinical signs and be an incidental finding during routine upper airway endoscopy. The aim of this study was to assess the effect on performance of horses undergoing surgical removal of SECs. The case records of 15 horses (1995–2009) diagnosed with SECs were retrieved. Eleven (73%) of the 15 horses included in the study were Thoroughbred racehorses. Eleven (73%) of the 15 horses had no preoperative clinical signs related to the SECs, with the remaining 4 (27%) having a respiratory noise (n = 4), nasal discharge (n = 1), difficulty swallowing (n = 1) or a cough (n = 1). Endoscopic examination in the standing horse was diagnostic in 93% (n = 14) of horses. Nine (82%) of the 11 Thoroughbred horses were yearlings, of which only one horse (11%) presented with clinical signs consisting of a respiratory noise and nasal discharge. Four of the 11 (36%) Thoroughbred horses were found to have concurrent epiglottic entrapment. Surgical removal was successful in all cases. Eight of the 11 (73%) Thoroughbred horses in this study raced following SEC removal. The majority of SECs are identified during routine endoscopic examinations and are not associated with clinical signs. The prognosis following surgical removal of SECs is good and future performance does not appear to be affected.