Pharmacokinetics of intra‐articular betamethasone sodium phosphate and betamethasone acetate and endogenous hydrocortisone suppression in exercising horses

To the date, no reports exist of the pharmacokinetics (PK) of betamethasone (BTM) sodium phosphate and betamethasone acetate administered intra‐articular (IA) into multiple joints in exercising horses. The purpose of the study was to determine the PK of BTM and HYD concentrations in plasma and urine after IA administration of a total of 30 mg BTM. Eight 4 years old Thoroughbred mares were exercised on a treadmill and BTM was administered IA. Plasma and urine BTM and HYD were determined via high performance liquid chromatography spectrometry for 6 weeks. Concentration‐time profiles of BTM and HYD in plasma and urine were used to generate PK estimates for non‐compartmental analyses and comparisons among times and HYD concentrations. BTM in plasma had greater T_max (T_max 0.8 h) vs. urine (T_max 7.1 h). Urine BTM concentration (ng/mL) and amount (AUC_last; h × ng/mL) were greater than plasma. HYD was suppressed for at least 3 days (<1 ng/mL) for all horses. The time of last quantifiable concentration of BTM (T_last; hour) was not significantly different in plasma than urine. Use of highly sensitive HPLC‐MS/MS assays enabled early detection and prolonged and consistent determination of BTM in plasma and urine.     

A pharmacokinetic/clinical approach to postulate a local action of intra‐articular xylazine administration in the horse: a preliminary study

The study aims to evaluate whether the analgesic effect of intra‐articular (IA) route of xylazine administered to horses following arthroscopic surgery is due to a local or a systemic action. Two connected studies were performed. In the first, 1 mg/kg b.w. of xylazine was injected IA, and blood samples were taken to assess drug systemic absorption. In addition, systemic effects of the drug (sedation, ataxia or reduction of respiratory and cardiac rate) were registered. Control horses injected with saline IA were included in the study to exclude the influence of anaesthesia in the occurrence of these manifestations. In the second study, 1 mg/kg b.w. of xylazine was administered intravenously (i.v.) in healthy horses. Blood samples were collected to determine the concentrations of xylazine, and the same signs of systemic effects of the drug were recorded. By correlating these parameters, a systemic ‘no effect’ concentration was defined. Pharmacokinetic data after IA administration resulted in some xylazine absorption (bioavailability equal to 58.12%) with values above the systemic ‘no effect’ concentration. The occurrence of some signs related to systemic effects in horses receiving IA xylazine was significant compared with horses receiving saline. In conclusion, a systemic action of the drug after IA administration cannot be excluded.     

Pharmacokinetics of procaterol in thoroughbred horses

Procaterol (PCR) is a beta‐2‐adrenergic bronchodilator widely used in Japanese racehorses for treating lower respiratory disease. The pharmacokinetics of PCR following single intravenous (0.5 μg/kg) and oral (2.0 μg/kg) administrations were investigated in six thoroughbred horses. Plasma and urine concentrations of PCR were measured using liquid chromatography–mass spectrometry. Plasma PCR concentration following intravenous administration showed a biphasic elimination pattern. The systemic clearance was 0.47 ± 0.16 L/h/kg, the steady‐state volume of the distribution was 1.21 ± 0.23 L/kg, and the elimination half‐life was 2.85 ± 1.35 h. Heart rate rapidly increased after intravenous administration and gradually decreased thereafter. A strong correlation between heart rate and plasma concentration of PCR was observed. Plasma concentrations of PCR after oral administration were not quantifiable in all horses. Urine concentrations of PCR following intravenous and oral administrations were quantified in all horses until 32 h after administration. Urine PCR concentrations were not significantly different on and after 24 h between intravenous and oral administrations. These results suggest that the bioavailability of orally administrated PCR in horses is very poor, and the drug was eliminated from the body slowly based on urinary concentrations. This report is the first study to demonstrate the pharmacokinetic character of PCR in thoroughbred horses.     

Endogenous concentrations,pharmacokinetics, and selected pharmacodynamic effects of a single dose of exogenous GABA in horses

The anti‐anxiety and calming effects following activation of the GABA receptor have been exploited in performance horses by administering products containing GABA. The primary goal of the study reported here was to describe endogenous concentrations of GABA in horses and the pharmacokinetics, selected pharmacodynamic effects, and CSF concentrations following administration of a GABA‐containing product. The mean (±SD) endogenous GABA level was 36.4 ± 12.5 ng/mL (n = 147). Sixteen of these horses received a single intravenous and oral dose of GABA (1650 mg). Blood, urine, and cerebrospinal fluid (n = 2) samples were collected at time 0 and at various times for up to 48 h and analyzed using LC‐MS. Plasma clearance and volume of distribution was 155.6 and 147.6 L/h and 0.154 and 7.39 L for the central and peripheral compartments, respectively. Terminal elimination half‐life was 22.1 (intravenous) and 25.1 (oral) min. Oral bioavailability was 9.81%. Urine GABA concentrations peaked rapidly returning to baseline levels by 3 h. Horses appeared behaviorally unaffected following oral administration, while sedative‐like changes following intravenous administration were transient. Heart rate was increased for 1 h postintravenous administration, and gastrointestinal sounds decreased for approximately 30 min following both intravenous and oral administration. Based on a limited number of horses and time points, exogenously administered GABA does not appear to enter the CSF to an appreciable extent.     

Pharmacokinetics of tobramycin following intravenous,intramuscular, and intra‐articular administration in healthy horses

The objectives of this study were to examine the pharmacokinetics of tobramycin in the horse following intravenous (IV), intramuscular (IM), and intra‐articular (IA) administration. Six mares received 4 mg/kg tobramycin IV, IM, and IV with concurrent IA administration (IV+IA) in a randomized 3‐way crossover design. A washout period of at least 7 days was allotted between experiments. After IV administration, the volume of distribution, clearance, and half‐life were 0.18 ± 0.04 L/kg, 1.18 ± 0.32 mL·kg/min, and 4.61 ± 1.10 h, respectively. Concurrent IA administration could not be demonstrated to influence IV pharmacokinetics. The mean maximum plasma concentration (C_max) after IM administration was 18.24 ± 9.23 μg/mL at 1.0 h (range 1.0–2.0 h), with a mean bioavailability of 81.22 ± 44.05%. Intramuscular administration was well tolerated, despite the high volume of drug administered (50 mL per 500 kg horse). Trough concentrations at 24 h were below 2 μg/mL in all horses after all routes of administration. Specifically, trough concentrations at 24 h were 0.04 ± 0.01 μg/mL for the IV route, 0.04 ± 0.02 μg/mL for the IV/IA route, and 0.02 ± 0.02 for the IM route. An additional six mares received IA administration of 240 mg tobramycin. Synovial fluid concentrations were 3056.47 ± 1310.89 μg/mL at 30 min after administration, and they persisted for up to 48 h with concentrations of 14.80 ± 7.47 μg/mL. Tobramycin IA resulted in a mild chemical synovitis as evidenced by an increase in synovial fluid cell count and total protein, but appeared to be safe for administration. Monte Carlo simulations suggest that tobramycin would be effective against bacteria with a minimum inhibitory concentration (MIC) of 2 μg/mL for IV administration and 1 μg/mL for IM administration based on C_max:MIC of 10.     

Comparative pharmacokinetics of minocycline in foals and adult horses

The objective of this study was to compare the pharmacokinetics of minocycline in foals vs. adult horses. Minocycline was administered to six healthy 6‐ to 9‐week‐old foals and six adult horses at a dose of 4 mg/kg intragastrically (IG) and 2 mg/kg intravenously (i.v.) in a cross‐over design. Five additional oral doses were administered at 12‐h intervals in foals. A microbiologic assay was used to measure minocycline concentration in plasma, urine, synovial fluid, and cerebrospinal fluid (CSF). Liquid chromatography–tandem mass spectrometry was used to measure minocycline concentrations in pulmonary epithelial lining fluid (PELF) and bronchoalveolar (BAL) cells. After i.v. administration to foals, minocycline had a mean (±SD) elimination half‐life of 8.5 ± 2.1 h, a systemic clearance of 113.3 ± 26.1 mL/h/kg, and an apparent volume of distribution of 1.24 ± 0.19 L/kg. Pharmacokinetic variables determined after i.v. administration to adult horses were not significantly different from those determined in foals. Bioavailability was significantly higher in foals (57.8 ± 19.3%) than in adult horses (32.0 ± 18.0%). Minocycline concentrations in PELF were higher than in other body fluids. Oral minocycline dosed at 4 mg/kg every 12 h might be adequate for the treatment of susceptible bacterial infections in foals.     

Pharmacokinetics and pharmacodynamics of butorphanol following intravenous administration to the horse

Knych, H. K., Casbeer, H. C., McKemie, D. S., Arthur, R. M. Pharmacokinetics and pharmacodynamics of butorphanol following intravenous administration to the horse. J. vet. Pharmacol. Therap.  36 , 21–30. Butorphanol is a narcotic analgesic commonly used in horses. Currently, any detectable concentration of butorphanol in biological samples collected from performance horses is considered a violation. The primary goal of the study reported here was to update the pharmacokinetics of butorphanol following intravenous administration, utilizing a highly sensitive liquid chromatography‐mass spectrometry (LC‐MS) assay that is currently employed in many drug‐testing laboratories. An additional objective was to characterize behavioral and cardiac effects following administration of butorphanol. Ten exercised adult horses received a single intravenous dose of 0.1 mg/kg butorphanol. Blood and urine samples were collected at time 0 and at various times for up to 120 h and analyzed using LC‐MS. Mean ± SD systemic clearance, steady‐state volume of distribution, and terminal elimination half‐life were 11.5 ± 2.5 mL/min/kg, 1.4 ± 0.3 L/kg, and 5.9 ± 1.5 h, respectively. Butorphanol plasma concentrations were below the limit of detection (LOD) (0.01 ng/mL) by 48 h post administration. Urine butorphanol concentrations were below the LOD (0.05 ng/mL) of the assay in seven of 10 horses by 120 h post drug administration. Following administration, horses appeared excited as noted by an increase in heart rate and locomotion. Gastrointestinal sounds were markedly decreased for up to 24 h.     

Disposition of methylprednisolone acetate in plasma,urine, and synovial fluid following intra‐articular administration to exercised thoroughbred horses

Methylprednisolone acetate (MPA) is commonly administered to performance horses, and therefore, establishing appropriate withdrawal times prior to performance is critical. The objectives of this study were to describe the plasma pharmacokinetics of MPA and time‐related urine and synovial fluid concentrations following intra‐articular administration to sixteen racing fit adult Thoroughbred horses. Horses received a single intra‐articular administration of MPA (100 mg). Blood, urine, and synovial fluid samples were collected prior to and at various times up to 77 days postdrug administration and analyzed using tandem liquid chromatography‐mass spectrometry (LC‐MS/MS). Maximum measured plasma MPA concentrations were 6.06 ± 1.57 at 0.271 days (6.5 h; range: 5.0–7.92 h) and 6.27 ± 1.29 ng/mL at 0.276 days (6.6 h; range: 4.03–12.0 h) for horses that had synovial fluid collected (group 1) and those that did not (group 2), respectively. The plasma terminal half‐life was 1.33 ± 0.80 and 0.843 ± 0.414 days for groups 1 and 2, respectively. MPA was undetectable by day 6.25 ± 2.12 (group 1) and 4.81 ± 2.56 (group 2) in plasma and day 17 (group 1) and 14 (group 2) in urine. MPA concentrations in synovial fluid remained above the limit of detection (LOD) for up to 77 days following intra‐articular administration, suggesting that plasma and urine concentrations are not a good indicator of synovial fluid concentrations.     

Pharmacokinetics and pharmacodynamics of dermorphin in the horse

Dermorphin is a μ‐opioid receptor‐binding peptide that causes both central and peripheral effects following intravenous administration to rats, dogs, and humans and has been identified in postrace horse samples. Ten horses were intravenously and/or intramuscularly administered dermorphin (9.3 ± 1.0 μg/kg), and plasma concentration vs. time data were evaluated using compartmental and noncompartmental analyses. Data from intravenous administrations fit a 2‐compartment model best with distribution and elimination half‐lives (harmonic mean ± pseudo SD) of 0.09 ± 0.02 and 0.76 ± 0.22 h, respectively. Data from intramuscular administrations fit a noncompartmental model best with a terminal elimination half‐life of 0.68 ± 0.24 (h). Bioavailability following intramuscular administration was variable (47–100%, n = 3). The percentage of dermorphin excreted in urine was 5.0 (3.7–10.6) %. Excitation accompanied by an increased heart rate followed intravenous administration only and subsided after 5 min. A plot of the mean change in heart rate vs. the plasma concentration of dermorphin fit a hyperbolic equation (simple Emax model), and an EC₅₀ of 21.1 ± 8.8 ng/mL was calculated. Dermorphin was detected in plasma for 12 h and in urine for 48 or 72 h following intravenous or intramuscular administration, respectively.     

Fluticasone Propionate Aerosol is More Effective for Prevention than Treatment of Recurrent Airway Obstruction

Background: Efficacy of inhaled fluticasone propionate (FP) for management of recurrent airway obstruction (RAO) has only been evaluated after several weeks' treatment.
Objectives: To compare efficacy of (1) 3-day treatments with FP to dexamethasone (DEX) for management of RAO; and (2) FP and DEX to no treatment in prevention of acute RAO exacerbations.
Animals: Nine RAO affected horses.
Methods: Crossover studies in RAO-affected horses compared (a) 3-day treatment of RAO exacerbation with FP (3 and 6 mg q12h) and DEX (0.1 mg/kg q24h) and (b) FP (6 mg q12h) and DEX (0.1 mg/kg q24h) to no treatment for prevention of acute exacerbations of RAO. Treatment efficacy and unwanted effects were judged from maximal change in pleural pressure (ΔPpl_max), serum cortisol (COR), bronchoalveolar lavage (BAL) cytology, and subjective scores for respiratory distress and lameness.
Results: In treatment trial, DEX and FP (6 mg) significantly decreased ΔPpl_max by 48 and 72 hours, respectively; FP (3 mg) had no significant effect. DEX decreased COR more than did FP. In prevention trial, both DEX and FP (6 mg) prevented the increase in ΔPpl_max that occurred in untreated horses. Both treatments decreased COR to the same degree. FP and DEX had no effects on bronchoalveolar lavage fluid (BALF) cytology and there was no evidence of laminitis.
Conclusions and Clinical Importance: FP (6 mg q12h) is as effective as DEX for prevention of acute exacerbations of RAO and lower doses should be evaluated. High-dose FP is not as effective as DEX for treatment of RAO exacerbations.     

Pharmacokinetics of methylprednisolone acetate after intra-articular administration and subsequent suppression of endogenous hydrocortisone secretion in exercising horses

Objective-To determine the pharmacokinetics of methylprednisolone (MP) and the relationship between MP and hydrocortisone (HYD) concentrations in plasma and urine after intra-articular (IA) administration of 100 or 200 mg of MP acetate (MPA) to horses. Animals-Five 3-year-old Thoroughbred mares. Procedures-Horses exercised on a treadmill 3 times/wk during the study. Horses received 100 mg of MPA IA, then 8 weeks later received 200 mg of MPA IA. Plasma and urine samples were obtained at various times for 8 weeks after horses received each dose of MPA; concentrations of MP and HYD were determined. Pharmacokinetic-pharmacodynamic estimates for noncompartmental and compartmental parameters were determined. Results-Maximum concentration of MP in plasma was similar for each MPA dose; concentrations remained greater than the lower limit of quantitation for 18 and 7 days after IA administration of 200 and 100 mg of MPA, respectively. Maximum concentration and area under the observed concentration-time curve for MP in urine were significantly higher (approximately 10-and 17-fold, respectively) after administration of 200 versus 100 mg of MPA. Hydrocortisone concentration was below quantifiable limits for ≥ 48 hours in plasma and urine of all horses after administration of each MPA dose. Conclusions and Clinical Relevance-Pharmacokinetics of MP may differ among IA MPA dosing protocols, and MP may be detected in plasma and urine for a longer time than previously reported. This information may aid veterinarians treating sport horses. Further research is warranted to determine whether plasma HYD concentration can aid identification of horses that received exogenous glucocorticoids.     

Evaluation of the combined dexamethasone suppression/ thyrotropin-releasing hormone stimulation test for detection of pars intermedia pituitary adenomas in horses

BACKGROUND: A combined dexamethasone (DEX) suppression/thyrotropin-releasing hormone (TRH) test (DEX/TRH test) has been developed to evaluate horses for presence of a pars intermedia pituitary adenoma (PIPA), but to the authors' knowledge, the accuracy of this test has not been previously determined. HYPOTHESIS: The sensitivity and specificity of the DEX/TRH test can be determined by comparing test results with histopathologic examination findings. ANIMALS: Age of 42 horses of various breeds ranged from 2 to 33 years. METHODS: Plasma cortisol concentration was measured before and 24 hours after IV administration of 40 microg of DEX/kg of body weight, and before and 30 minutes after IV administration of 1 mg of TRH that had been given 3 hours after the injection of DEX. Results of the DEX/TRH test were considered positive if either the plasma cortisol concentration exceeded 10 ng/mL 24 hours after DEX administration, or if the change in plasma cortisol concentration 30 minutes after injection of TRH was > or = 66% above the 3-hour baseline. Diagnosis of PIPA was determined by histologic examination of the pituitary gland. RESULTS: PIPA was detected in 17 of 42 (40%) horses. The DEX/TRH test had sensitivity, specificity, positive predictive value, and negative (NPV) predictive value of 88, 76, 71, and 90%, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: The combined DEX/TRH test was more sensitive than either of its component tests and had a high NPV, but was not as specific as the TRH component alone (92%). The DEX/TRH test should be used to screen older horses for PIPA.     

Pharmacokinetics of furosemide administered 4 and 24 hours prior to high‐speed exercise in horses

Furosemide is a diuretic agent used commonly in racehorses to attenuate the bleeding associated with exercise‐induced pulmonary hemorrhage (EIPH). The current study describes serum and urine concentrations and the pharmacokinetics of furosemide following administration at 4 and 24 hrs prior to maximal exercise. Eight exercised adult Thoroughbred horses received a single IV administration of 250 mg of furosemide at 4 and 24 hrs prior to maximal exercise on a high‐speed treadmill. Blood and urine samples were collected at time 0 and at various times for up to 72 hrs and furosemide concentrations determined using liquid chromatography–tandem mass spectrometry. Serum furosemide concentrations remained above the LOQ (0.05 ng/ml) for 36 hrs in 3/8 and 1/8 horses in the 4‐ and 24‐hrs groups, respectively. Serum concentration data were best fit by a two‐compartment model. There was not a significant difference in the volume of distribution at steady‐state (0.594 ± 0.178 [4 hrs] and 0.648 ± 0.147 [24 hrs] L/kg) or systemic clearance (0.541 ± 0.094 [4 hrs] and 0.617 ± 0.114 [24 hrs] L/hrs/kg) between horses that were exercised at 4‐ and 24 hrs postdrug administration. The mean ± SD elimination half‐life was 3.12 ± 0.387 and 3.23 ± 0.407 hrs following administration at 4 and 24 hrs prior to exercise, respectively.     

Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses

The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of eight horses (two per dose group) received a single intravenous dose of 0.05, 0.1, 0.2, or 0.5 mg/kg morphine. Blood samples were collected up to 72 h postdrug administration, analyzed using LC‐MS/MS and pharmacokinetic parameters determined. Behavior, step counts, and gastrointestinal activity were also assessed. The beta and gamma half‐life for morphine ranged from 0.675 to 2.09 and 6.70 to 18.1 h, respectively, following administration of the four different IV doses. The volume of distribution at steady‐state and systemic clearance ranged from 6.95 to 15.8 L/kg and 28.3 to 35.7 mL·min/kg, respectively. The only metabolites identified in blood samples were the primary metabolites identified in other species, 3‐morphine‐glucuronide and 6‐morphine‐glucuronide. Muscle fasciculations were observed at 0.2 and 0.5 mg/kg and ataxia noted at 0.5 mg/kg. Gastrointestinal activity was decreased in all dose groups (for up to 8 h in 7/8 horses and 24 h in one horse). This study extends previous studies and is the first report describing the metabolites of morphine in the horse. Plasma concentrations of morphine‐3‐glucuronide, a metabolite with demonstrated neuro‐excitatory activity in mice, far exceeded that of morphine‐6‐glucuronide. Further study is warranted to assess whether the high levels of the morphine‐3‐glucuronide contribute to the dose‐dependent excitation observed at high morphine doses.     

Pharmacokinetic and pharmacodynamic properties of pergolide mesylate following long‐term administration to horses with pituitary pars intermedia dysfunction

The objective of this study was to gain an understanding of the pharmacokinetic and pharmacodynamic properties of pergolide in horses with PPID after of long‐term oral administration. Six horses with confirmed PPID were treated with pergolide (Prascend^®) at 1 mg/horse po q24 h for 2 months, followed by 2 mg/horse po q24 h for 4 months. Following the last dose, plasma samples were collected for measurement of pergolide using an LC/MS/MS method and ACTH measurement using a chemiluminescent immunoassay. Noncompartmental and compartmental pharmacokinetic analyses were performed, as well as pharmacodynamic assessment of the effect of plasma pergolide concentrations on plasma ACTH concentrations. Pergolide effectively decreased plasma ACTH concentration in aged horses with PPID, with similar pharmacokinetic properties as reported in young horses, including an approximate terminal half‐life of 24 h. Plasma ACTH concentration increased by 50% in 3/6 horses at 2 days and 6/6 horses 10 days after discontinuing drug administration. Pergolide was quantified in all horses at 2 days and in none at 10 days after last dose. In summary, after discontinuing pergolide treatment, plasma ACTH concentration increased while pergolide was still quantifiable in some horses. Once‐daily dosing of pergolide is likely appropriate in most horses with PPID for regulating the plasma ACTH concentration.     

Influence of riders’ skill on plasma cortisol levels of horses walking on forest and field trekking courses

The aim of this study was to evaluate the influence of rider's skill on the plasma cortisol levels of trekking horses on two courses, walking on field and forest courses (about 4.5 to 5.1 km each). Three riders of different skills did horse trekking (HT) in a tandem line under a fixed order: advanced‐leading, beginner‐second and intermediate‐last. A total of six horses were used and they experienced all positions in both courses; a total of 12 experiments were done. Blood samples were obtained before HT, immediately after and 2 h after HT. As a control, additional blood samples were obtained from the same horses on non‐riding days. Irrespective of the course and the rider's skill, the cortisol level before HT was higher than that of control (P < 0.05). In both courses, the cortisol levels immediately after HT ridden by the advanced rider were higher than that of control (P < 0.05). However, in every case, the cortisol level 2 h after HT was closely similar to the level of the control. Thus, we concluded the stress of trekking horse was not sufficient to disturb the circadian rhythm of the cortisol level, irrespective of the course and the rider's skill.     

Systemic,Renal, and Colonic Effects of Intravenous and Enteral Rehydration in Horses

Background

Intravenous (IV) and intragastric (IG) administration of fluid therapy are commonly used in equine practice, but there are limited data on the systemic, renal, and enteric effects.

Hypothesis

IV fluid administration will increase intestinal and fecal hydration in a rate‐dependent manner after hypertonic dehydration, but will be associated with significant urinary water and electrolyte loss. Equivalent volumes of IG plain water will result in comparatively greater intestinal hydration with less renal loss.

Animals

Six Thoroughbred geldings.

Methods

Experimental study. 6 by 6 Latin square design investigating constant rate IV administration at 50, 100, and 150 mL/kg/d over 24 hours in horses dehydrated by water deprivation. Equivalent volumes of IG plain water were administered by 4 bolus doses over 24 hours.

Results

Water deprivation resulted in a significant decrease in the percentage of fecal water, and increases in serum and urine osmolality. IV fluids administered at 100 and 150 mL/kg/d restored fecal hydration, but increasing the rate from 100 to 150 mL/kg/d did not confer any additional intestinal benefit, but did result in significantly greater urine production and sodium loss. Equivalent 24‐hour volumes of plain water resulted in greater intestinal water and less urine output.

Conclusions and Clinical Importance

IV polyionic isotonic fluids can be used to hydrate intestinal contents in situations where enteral fluids are impractical. IV fluids administered at three times maintenance are no more efficacious and might be associated with adverse physiological findings after withdrawal. Bolus dosing of IG water can be used to restore intestinal water with minimal adverse effects.     

Pharmacokinetics and effects on thromboxane B2 production following intravenous administration of flunixin meglumine to exercised thoroughbred horses

Flunixin meglumine is commonly used in horses for the treatment of musculoskeletal injuries. The current ARCI threshold recommendation is 20 ng/mL when administered at least 24 h prior to race time. In light of samples exceeding the regulatory threshold at 24 h postadministration, the primary goal of the study reported here was to update the pharmacokinetics of flunixin following intravenous administration, utilizing a highly sensitive liquid chromatography–mass spectrometry (LC‐MS). An additional objective was to characterize the effects of flunixin on COX‐1 and COX‐2 inhibition when drug concentrations reached the recommended regulatory threshold. Sixteen exercised adult horses received a single intravenous dose of 1.1 mg/kg. Blood samples were collected up to 72 h postadministration and analyzed using LC‐MS. Blood samples were collected from 8 horses for determination of TxB₂ and PGE₂ concentrations prior to and up to 96 h postflunixin administration. Mean systemic clearance, steady‐state volume of distribution and terminal elimination half‐life was 0.767 ± 0.098 mL/min/kg, 0.137 ± 0.12 L/kg, and 4.8 ± 1.59 h, respectively. Four of the 16 horses had serum concentrations in excess of the current ARCI recommended regulatory threshold at 24 h postadministration. TxB₂ suppression was significant for up to 24 h postadministration.     

Pharmacokinetics and local tolerance of cefovecin sodium after intra‐articular administration in horses

Searching for new therapeutic options against septic arthritis in horses, this research was focused on the study of the kinetics and local side effects after the intra‐articular treatment of horses with cefovecin sodium. A single dose (240 mg) of the drug (Convenia^®) was administered into the radiocarpal joint of adult healthy horses (n = 6), and drug concentrations in plasma and synovial fluid were determined by high‐performance liquid chromatography (HPLC). Local tolerance was also studied based on the modification of different joint physiopathological parameters (pH, cellular, and protein concentration in synovial fluid). Although no clinically relevant joint damage was noticed, significant increases in the protein concentrations at 5 min and in the cellular concentration at 30 min after cefovecin administration were observed in the treated radiocarpal joints. The duration of the cefovecin above the minimal inhibitory concentration (MIC) ≤1 μg/mL was 28.80 ± 2.58 h in the radiocarpal joint and 16.00 ± 2.86 h in plasma. The results of this study showed that intra‐articular administration of cefovecin sodium in horses could be considered in the future to manage septic arthritis in horses, as it offers a good pharmacokinetic behavior and good local tolerance.     

Hydrocortisone levels in the urine and blood of horses treated with ACTH.

An investigation was undertaken to demonstrate whether therapeutic treatment with ACTH raises hydrocortisone (cortisol) levels in horse urine above the limit (1000 ng/ml) established by the International Conference of Racing Authorities with the aim of controlling the abuse of cortisol and ACTH in equine sports. ACTH (200 iu) was administered i.m. to 3 Thoroughbred horses; urine and blood samples were collected at intervals afterwards and analysed by an immunoenzymatic system (ELISA) and HPLC-MS. To ascertain post exercise cortisol levels in untreated horses, 101 urine and 103 serum samples were taken from horses immediately after racing and analysed by ELISA. The peak urine level of cortisol, detected 8 h after ACTH administration, was around 600 ng/ml using either ELISA or HPLC-MS. The peak serum cortisol concentration was found to be around 250 ng/ml by ELISA, but consistently less by HPLC-MS. Mean cortisol levels in post race horses were 135.1+/-72.1 ng/ml in urine and 90.1+/-41.7 ng/ml in serum. High levels of the metabolite 20beta-dihydrocortisol in urine and the cortisol precursor 11beta-desoxycortisol in serum were found. The latter showed high cross-reactivity with cortisol on ELISA. In our experiment, treatment with ACTH 200 iu i.m. did not raise urinary cortisol levels above the 1000 ng/ml threshold proposed by the ICRA.