Pharmacokinetics and metabolic effects of triamcinolone acetonide and their possible relationships to glucocorticoid-induced laminitis in horses

Experiments were performed to establish the pharmacokinetics of triamcinolone acetonide and the effects of the glucocorticoid on glucose metabolism in horses. The pharmacokinetics after intravenous (i.v.) dosing was best described by a three-compartment open model. There was rapid distribution from the central compartment followed by two phases of elimination. The half-life of the rapid elimination phase was 83.5 min and of the slower phase was 12 h. The term (Vss/Vc)-1was 12.3 indicating extensive distribution into the tissues. Triamcinolone acetonide given i.v. or intramuscularly (i.m. ) induced a prolonged period of hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia. Significant changes in plasma glucagon and serum non-esterified fatty acids were not observed. These observations suggest that the hyperglycaemia was a result of decreased glucose utilization by tissues and increased gluconeogenesis. The effects on glucose metabolism persisted for 3-4 days after triamcinolone was given i.m. at 0.05 mg/kg, the upper limit of the recommended dose range, and for 8 days when given at 0. 2 mg/kg. These observations, together with recent evidence implicating inhibition of glucose metabolism in the pathogenesis of equine laminitis, indicated that triamcinolone-induced laminitis may be associated with the long duration of action of the glucocorticoid when higher than recommended doses or when repeated doses are given.     

Plasma Concentrations of 13, 14‐Dihydro‐15‐keto‐Prostaglandin F2α, Progesterone and Cortisol During Periparturient Period in Yaks (Poephagus grunniens L.)

An attempt was made to determine plasma concentrations of, 13, 14‐dihydro‐15‐keto‐prostaglandin F_2α (PGFM), cortisol and progesterone during periparturient period in yak. Plasma PGFM level showed an increasing trend beginning day 5 prior to parturition (0.48 ± 0.14 ng/ml) and increased steeply thereafter to reach a peak level (17.16 ± 1.31 ng/ml) on the day of parturition. The levels, then, declined sharply on day 1 postpartum to reach 1.20 ± 0.40 ng/ml and thereafter declined gradually over the days to reach 0.28 ± 0.09 ng/ml on day 20 postpartum and this level was maintained with fluctuation within narrow limits thereafter till conclusion of the blood sampling on day 90 post‐calving. The plasma progesterone concentration on days 7 and 6 before parturition was high (2.10 ± 0.10 and 2.12 ± 0.10 ng/ml, respectively). The level then decreased gradually and abrupt fall was observed 1–2 days before parturition and became basal on day of parturition (0.24 ± 0.04 ng/ml). This basal level was maintained till the end of the blood sampling on day 90 postpartum. Plasma cortisol level showed an increasing trend beginning day 2 prior to parturition (2.36 ± 0.65 ng/ml) and increased steeply thereafter to reach a peak level (26.65 ± 5.28 ng/ml) on the day of parturition. The levels, then, declined gradually over the days and touched 2.36 ± 0.25 ng/ml on day 3 postpartum and this level was maintained with fluctuation within narrow limits thereafter till day 7 post‐calving.     

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.     

Synovial fluid and plasma kinetics of methylprednisolone and methylprednisolone acetate in horses following intra-articular administration of methylprednisolone acetate

Synovial fluid and plasma kinetics of methylprednisolone acetate (MPA) and methylprednisolone (MP) after a single intra-articular administration of MPA at a therapeutic dose (111 mg in toto) was measured in five horses. MPA was detected in synovial fluid for two to six days post injection and MP, which results from synovial MPA hydrolysis, was present in pharmacologically significant concentrations for 4.8 to 39 days, depending on the horse. MPA synovial concentration was maximal (289 +/- 284 micrograms/ml) at the first sampling time (2 h after administration) and MP synovial concentration was maximal (from 58.9 to 379.5 micrograms/ml) at the first or second sampling time (2 to 10 h after administration). Thereafter, both MP and MPA declined rapidly. From time of administration to about five days later, MP synovial fluid concentration fell progressively with a half-time of 9.95 h. Subsequently, the MP synovial fluid concentration decreased more slowly with an apparent half-time of 115 h. During the first 24 h following MPA administration, trace amounts of MP (less than 5 ng/ml) were detected in plasma. Plasma hydrocortisone levels were depressed for three to four days after administration but adrenal responsiveness to adrenocorticotrophic hormone tests remained unaffected.     

The ocular effects of intravitreal triamcinolone acetonide in dogs

The aim of the study was to determine the ocular safety of a single intravitreal dose of triamcinolone acetonide (IVTA) in dogs. Eleven healthy dogs received a single IVTA injection (8 mg) through the mid-temporal pars-plana of the left eye (OS) using a 27G needle. The dogs were re-evaluated immediately post-IVTA, every 5 min until pre-IVTA values had returned, then daily for 3 days, weekly for 1 month and monthly for 3 months. Immediately post-IVTA, all the treated eyes showed a rise in intraocular pressure (IOP) with a mean value of 41.8+/-8.9 mm Hg. The IOP values then decreased progressively to 14.5+/-2.1 mm Hg at 12.2+/-3.8 min post-IVTA. From then on, normal IOP values were maintained throughout the 3-month monitoring period. The most frequently observed clinical sign post-IVTA was conjunctival hyperaemia. The presence of triamcinolone acetonide in the vitreous was observed in all subsequent examinations of 10/11 eyes and there were still triamcinolone crystals in 5/11 eyes after 90 days. It was concluded that intravitreal injection of triamcinolone acetonide in dogs is feasible under sedation. The immediate increase in IOP post-IVTA is short-lived and pressure quickly returns to pre-IVTA levels.     

Sodium retention and cortisol (hydrocortisone) suppression caused by dexamethasone and triamcinolone in equids

Three ponies and 1 horse were bilaterally adrenalectomized (BADX). The initial hypoadrenal episode after BADX was reversed with 20 mg of dexamethasone (DXM) IM (n = 2) or 20 mg of triamcinolone (TMC) IM (n = 2). Nine hypoadrenal crises were reversed with 20 mg of DXM given IM (n = 4) or 20 mg of TMC given IM (n = 5). Sodium and chloride retention and potassium excretion were documented based on changes in serum electrolytes and urinary excretion. Eight intact adult horses were randomly assigned to 2 groups to study the effects of a single IM injection of DXM (0.044 mg/kg of body weight) or TMC (0.044 mg/kg). Cortisol (hydrocortisone) suppression was found to be maximal (nondetectable amounts of cortisol) by 12 hours in both groups. Cortisol was again detectable in the DXM group at 24 hours after injection and was at pretreatment values at 168 hours. Cortisol was not detectable in the TMC group for 192 hours and did not reach pretreatment values until 336 hours. The duration of the gluconeogenic effect was compared with the duration of cortisol suppression exerted by DXM and TMC in these intact animals. Assuming that the decrease in plasma glucose coincides with the decrease in glucocorticoid activity of the respective steroid, a relative hypoadrenocortical state was found in the animals treated with DXM between the 2nd and 7th day after treatment, whereas this state occurred between the 6th and 14th day after treatment with TMC.     

Continuous infusion of gentamicin into the tarsocrural joint of horses

OBJECTIVE: To develop a method for continuous infusion of gentamicin into the tarsocrural joint of horses, to determine pharmacokinetics of gentamicin in synovial fluid of the tarsocrural joint during continuous infusion, and to evaluate effects of continuous infusion of gentamicin on characteristics of the synovial fluid. ANIMALS: 12 healthy adult horses. PROCEDURE: An infusion catheter consisting of flow control tubing connected to a balloon infuser was used. Gentamicin solution (100 mg/ml) was infused in the right tarsocrural joint and balanced electrolyte solution was infused in the left tarsocrural joint for 5 days. Synovial fluid and serum gentamicin concentrations were measured by use of a fluorescence polarization immunoassay. RESULTS: 17 of the 24 (71%) infusion catheters initially placed functioned without complications for the entire 5-day infusion period. Median gentamicin concentration in synovial fluid from treated joints during the 5-day infusion period ranged from 2875 to 982 microg/ml. Median serum gentamicin concentration during this period ranged from 2.31 to 2.59 microg/ml. Mean (+/- SD) elimination half-life and total clearance of gentamicin from the synovial fluid were 6.25+/-1.01 hours and 1.52+/-0.96 ml/min, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: An infusion catheter can be used for continuous infusion of gentamicin into the tarsocrural joints of horses for up to 5 days. At a gentamicin dosage of 0.17+/-0.02 mg/kg/h, continuous intra-articular infusion results in synovial fluid gentamicin concentrations greater than 100 times the minimal inhibitory concentration reported for common equine pathogens.     

Lontophoretic administration of dexamethasone into the tarsocrural joint in horses

OBJECTIVE: To determine whether iontophoretic administration of dexamethasone to horses results in detectable concentrations in synovial fluid, plasma, and urine. ANIMALS: 6 adult mares. PROCEDURE: Iontophoresis was used to administer dexamethasone. Treatments (4 mA for 20 minutes) were administered to a tarsocrural joint of each mare. The drug electrode contained 3 ml of dexamethasone sodium phosphate at a concentration of 4 or 10 mg/ml. Samples of synovial fluid, blood, and urine were obtained before and 0.5, 4, 8, and 24 hours after each treatment. All samples were tested for dexamethasone using an ELISA. Synovial fluid also was evaluated for dexamethasone, using high-performance liquid chromatography. RESULTS: The lower and upper limits of detection for dexamethasone in synovial fluid with the ELISA were 0.21 and 1.5 ng/ml, respectively. Dexamethasone administered at a concentration of 10 mg/ml was detected by the ELISA in synovial fluid of 5 mares from 0.5 to 24 hours and in urine of 4 mares from 0.5 to 8 hours after each treatment, but it was not detected in plasma. Mean synovial fluid concentration of dexamethasone was 1.01 ng/ml. Dexamethasone administered at a concentration of 4 mg/ml was detected by the ELISA in urine of 2 mares at 0.5 and 4 hours after treatment, but it was not detected in synovial fluid or plasma. CONCLUSIONS AND CLINICAL RELEVANCE: Iontophoresis cannot be considered an effective method for delivery of dexamethasone to synovial fluid of horses, because drug concentrations achieved in this study were less than therapeutic concentrations.     

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.     

Serum and synovial fluid steady-state concentrations of trimethoprim and sulfadiazine in horses with experimentally induced infectious arthritis

The tarsocrural joints of 11 horses were inoculated with 1.2 to 2.16 x 10(6) viable Staphylococcus aureus organisms susceptible to a trimethoprim-sulfadiazine (TMP-SDZ) combination with minimal inhibitory concentration (MIC) of 0.25 micrograms of TMP/ml and 4.75 micrograms of SDZ/ml. Antimicrobial treatment consisted of oral administration of a TMP-SDZ combination--30 mg/kg of body weight given once daily (group-1 horses) or 60 mg/kg given as 30 mg/kg every 12 hours (group-2 horses). Paired serum and synovial fluid samples were obtained before intra-articular inoculation with the S aureus, after inoculation with S aureus but before antimicrobial treatment, and after inoculation at various hourly intervals after oral administration of the TMP-SDZ combination. The TMP-SDZ combination was administered daily in the 2 dosages for 21 days. Samples were collected after day 3 of repetitive drug administration so that drug steady-state concentration would have been achieved. Serum and synovial fluid samples were analyzed for TMP and SDZ concentrations. Administration of the TMP-SDZ combination at a dosage of 30 mg/kg once daily was not effective in maintaining TMP or SDZ concentrations above the MIC of TMP-SDZ for the S aureus (0.25 and 4.75 micrograms/ml for TMP and SDZ, respectively) in the infected synovial fluid or in maintaining adequate TMP concentration in the serum. The alternative use of the TMP-SDZ combination at a dosage of 60 mg/kg given as 30 mg/kg every 12 hours was effective in maintaining serum and synovial fluid concentrations of TMP and SDZ that were greater than the MIC for the infective organism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of an n‐3 long‐chain polyunsaturated fatty acid‐enriched diet on experimentally induced synovitis in horses

Dietary n‐3 long‐chain polyunsaturated fatty acid (LCPUFA) supplementation has previously been shown to modify joint‐related inflammation in several species, although information in the horse is lacking. We investigated whether dietary supplementation with n‐3 LCPUFA would modify experimentally induced synovitis in horses. Twelve, skeletally mature, non‐pregnant mares were randomly assigned to either a control diet (CONT) or an n‐3 long‐chain fatty acid‐enriched treatment diet (N3FA) containing 40 g/day of n‐3 LCPUFA for 91 days. Blood samples taken on days 0, 30, 60 and 90, and synovial fluid collected on days 0 and 90 were processed for lipid composition. On day 91, joint inflammation was stimulated using an intra‐articular (IA) injection of 100 ng of recombinant equine IL‐1beta (reIL‐1β). Synovial fluid samples taken at post‐injection hours (PIH) 0, 4, 8 and 24 were analysed for prostaglandin E₂ (PGE₂), matrix metalloproteinase (MMP) activity and routine cytology. Synovium and articular cartilage samples collected at PIH 8 were analysed for gene expression of MMP 1 and MMP 13, interleukin‐1beta (IL‐1β), cyclooxygenase 2 (COX‐2), tumour necrosis factor‐alpha and the aggrecanases, a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)‐4 and ADAMTS‐5. A 90‐day feeding period of n‐3 LCPUFA increased serum phospholipid and synovial fluid lipid compositions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared to CONT horses. The reIL‐1β injection caused an inflammatory response; however, there was no effect of dietary treatment on synovial fluid PGE2 content and MMP activity. Synovial tissue collected from N3FA horses exhibited lower expression of ADAMTS‐4 compared to CONT horses. Despite the presence of EPA and DHA in the synovial fluid of N3FA horses, dietary n‐3 LCPUFA supplementation did not modify synovial fluid biomarkers compared to CONT horses; however, the lower ADAMTS‐4 mRNA expression in N3FA synovium warrants further investigation of n‐3 LCPUFA as a joint therapy.     

Clearance of corticosteroids following intra‐articular administration of clinical doses to racehorses

Over the last few years there has been a nationwide cooperative effort to establish threshold concentrations and withdrawal time guidelines for corticosteroid use in racehorses. As dosing regimens are specific to individual horses and highly variable, it is not possible to establish regulatory guidelines for every dosing scenario and therefore they are often based on single dose administration studies. The goal of the study described here was to assess the applicability of current regulatory recommendations for intra‐articular corticosteroids based on clinical protocols used by practitioners. A total of 58 Thoroughbred and 82 Quarter Horse racehorses received varying doses of triamcinolone acetonide, methylprednisolone acetate, isoflupredone or betamethasone intra‐articularly in various joints by the treating practitioner. Blood samples were collected at 0, 7, 10, 14, 21, 28 and 35 days post drug administration and serum samples analysed by liquid chromatography mass spectrometry for quantitation of drug concentrations. Serum elimination varied depending upon the dose and the number and specific joints treated. Serum concentrations fell below the ARCI threshold guidance by Day 7 (100 pg/ml) for both triamcinolone acetonide (2–40 mg dose) and isoflupredone acetate (4–30 mg dose) and Day 21 (100 pg/ml) for methylprednisolone acetate (20–600 mg dose). Betamethasone fell below the regulatory threshold (10 pg/ml) by 7 days for all Quarter Horses and for 7/10 Thoroughbreds studied. Drug concentrations were below the regulatory threshold by Day 10 in the remaining 3 horses receiving betamethasone.     

Stress Response of Three-year-old Horse Mares to Changes in Husbandry System During Initial Equestrian Training

For initial training, horses are often transferred from group housing to individual boxes, which is a potential stressor. In this study, salivary cortisol concentrations, locomotion activity, and heart rate (HR) were analyzed and the HR variability (HRV) variables standard deviation of beat-to-beat interval (SDRR) and root mean square of successive RR differences (RMSSD) were calculated in 3-year-old mares (n = 8). Mares were transferred abruptly from a group stable with access to a paddock to individual boxes without a paddock and were studied from 4 days before to 5 days after changing the stable. Mares underwent routine equestrian training for young horses. On the days before mares were moved to individual boxes, cortisol concentrations showed a diurnal rhythm with values approximately 0.6 ng/ml in the morning and a decrease throughout the day. When horses were moved to individual boxes, cortisol concentrations increased to 1.8 ± 0.2 ng/ml within 30 minutes and did not return to baseline values within 6 hours (0.7 ± 0.1 ng/ml, P < .05 over time). On the following days, a diurnal rhythm was re-established but at a higher level than before the change of stable. Locomotion activity was higher when mares had access to a paddock than when kept in individual boxes. Heart rate increased for approximately 60 minutes when mares were separated from their group. In conclusion, separating young horses from their group and individual stabling are perceived as stressful.     

Body fluid and endometrial concentrations of ketoconazole in mares after intravenous injection or repeated gavage

After single oral administration of ketoconazole (30 mg/kg bodyweight [bwt]) in 50 ml of corn syrup to a healthy mare, the drug was not detected in serum. Ketoconazole in 0.2 N HC1 was administered intragastrically to six healthy adult horses in five consecutive doses of 30 mg/kg bwt at 12 h intervals. Ketoconazole concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid (CSF), urine and endometrium. Mean peak serum ketoconazole concentration was 3.76 micrograms/ml at 1.5 to 2 h after intragastric administration. Mean peak synovial concentration was 0.87 micrograms/ml 3 h after the fifth dose. Similarly, mean peritoneal concentration peaked 3 h after the fifth dose at 1.62 micrograms/ml. Mean endometrial concentrations peaked at 2.73 micrograms/ml 2 h after the fifth dose. Ketoconazole was detected in the CSF of only one of the six mares at a concentration of 0.28 micrograms/ml 3 h after the fifth dose. The highest measured concentration of ketoconazole in urine was 6.15 micrograms/ml 2 h after the fifth dose. A single intravenous injection of ketoconazole (10 mg/kg bwt) was given to one of the six mares; the overall elimination rate constant was estimated at 0.22/h and bioavailability after oral administration was 23 per cent.     

Effect of gentamicin sulfate and sodium bicarbonate on the synovium of clinically normal equine antebrachiocarpal joints

The effect of gentamicin sulfate, unbuffered and buffered with sodium bicarbonate, on synovial fluid and membrane of clinically normal equine joints was evaluated. Thirty-six adult horses with clinically normal antebrachiocarpal joints were allotted to 6 treatment groups of 6 horses each. One antebrachiocarpal joint in each horse was chosen for treatment. Group-1 horses were given gentamicin (3 ml; 50 mg/ml); group-2 horses were given sodium bicarbonate (3 ml; 1 mEq/ml); group-3 horses were given gentamicin (3 ml; 50 mg/ml) and sodium bicarbonate (3 ml; 1 mEq/ml); group-4 horses were not treated; and horses of groups 5 and 6 were given polyionic physiologic solution (3 and 6 ml, respectively). Synovial fluid specimens were obtained from 5 horses of each group for cytologic analysis at postinjection hours (PIH) 0, 24, 72, and 192 and for pH determination at PIH 0, 0.25, 0.5, 1, 4, 8, 24, 72, and 192. The sixth horse of each group was euthanatized at PIH 24, and the synovial membrane of the treated and contralateral (nontreated) antebrachiocarpal joints was examined macroscopically and microscopically. After intra-articular gentamicin administration, the mean synovial fluid pH was lowest (5.98) at PIH 0.25, but by PIH 8, it was not significantly different from the control value (group-5 horses). When sodium bicarbonate was combined with gentamicin before intra-articular administration, the mean synovial fluid pH was lowest (7.07) at PIH 0.25, but by PIH 1, it was not significantly different from the control value (group-6 horses).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute vitamin D3 toxicosis in horses: case reports and experimental studies of the comparative toxicity of vitamins D2 and D3

Acute vitamin D toxicosis was diagnosed in 2 horses fed a grain ration containing 1,102,311 IU of cholecalciferol (vitamin D3)/kg (500,000 IU/lb) for about 30 days. Horse 1 died acutely with extensive mineralization of cardiovascular and other soft tissues. Horse 2, which had severe clinical signs and clinicopathologic changes of toxicosis, was treated with nonsteroidal antiinflammatory drugs and recovered in about 6 months. In an experimental study, the toxicity of ergocalciferol (vitamin D2) and cholecalciferol was compared in 2 horses (No. 3 and 4) given the respective vitamins at a daily dosage of 33,000 IU/kg of initial (day 0) body weight for 30 days. Except for slight loss in body weight (8%) during the 1st few days of treatment, horse 3 remained clinically normal. Horse 4 developed limb stiffness and tachycardia, became anorectic, weak, and recumbent, lost 29% of body weight, and had polydipsia and polyuria. Horses 2, 3, and 4 developed persistent hyperphosphatemia. Horse 2 remained normocalcemic whereas horses 3 and 4 became hypercalcemic by day 28. In horse 3, serum vitamin D2 metabolite concentrations on days 0, 1, 14, and 26 were: vitamin D2 (ng/ml) = less than 5.0, 5.7, 71.4, and 188.0; 25-hydroxy-vitamin D2 (ng/ml) = less than 5.0, less than 5.0, 43.1, and 117.5; and 1,25-dihydroxy-vitamin D (pg/ml) = 19.7, 23.2, 25.0, and 45.7, respectively. In horse 4, serum vitamin D3 metabolite concentrations on the same days were: vitamin D3 (ng/ml) = less than 5.0, 110.0, 1,049.0, and 887.0; 25-hydroxy-vitamin D3 (ng/ml) = less than 5.0, 18.9, 201.0 and 182.0; and 1,25-dihydroxy-vitamin D (pg/ml) = 21.5, 18.9, 25.2, and 21.6, respectively. Urine of horses 2 and 4 became acidic (pH 6). Horses 2, 3, and 4 became hyposthenuric, but the decrease in urine specific gravity (sp gr) in horse 3 occurred only after 3 weeks of treatment and was only moderate (sp gr, 1.018 to 1.021) and nonprogressive. Hyposthenuria was evident in horse 4 on day 4 (sp gr, 1.028), and was progressive and marked (sp gr, days 28 to 32: 1.006 to 1.009). Urine sp gr of horse 2 ranged from 1.002 to 1.007. Fractures were demonstrated radiographically and histologically in the costochondral junctions of horses 3 and 4. Mineralization of cardiovascular and other soft tissues developed in horses 3 and 4, with lesions being more severe and having a wider tissue distribution in horse 4.     

Comparison of various treatments for experimentally induced equine infectious arthritis

To evaluate the effects of 5 treatments on clinical responses, synovial fluid analysis, radiographic changes, bacteriologic culture results of the synovial fluid and synovial membrane, microscopic characteristics of the synovial membrane, and articular cartilage histochemistry, Staphylococcus aureus organisms (1.6 X 10(6) colony-forming units) were inoculated into the tarsocrural joints of 12 horses (n = 24 joints; 2 joints/horse). Each horse was given phenylbutazone (2 g) orally, every 24 hours, beginning 24 hours after inoculation. Two horses (ie, 4 joints) were not given other treatment (controls; group 1). All other horses (ie, 20 joints) were given a trimethoprim-sulfadiazine combination orally, once daily (30 mg/kg; 8 joints) or twice daily (30 mg/kg q 12 hr; 12 joints). Each of these 20 joints were assigned to 1 of 5 treatment groups (4 joints/group) in a balanced incomplete block design. Group 2 (4 joints) was given only the antibiotics once daily. Twelve joints were treated by through-and-through joint lavage on day 1 (group 3), days 1 and 3 (group 4), or days 1, 3, and 6 (group 5). Joints in group 6 had an arthrotomy performed on day 1, with subsequent lavage via an indwelling drain every 12 hours for 4 days. In groups 3 through 6, 1 joint in each group was treated with antibiotics once daily, and 3 joints were treated with antibiotics twice daily. All horses were clinically assessed each day. Complete blood count was performed on days 3, 6, 10, and 21. Before inoculation and on days 0, 1, 3, 6, 10, and 21, synovial fluid specimens were collected and analyzed for color, clarity, total protein concentration, WBC count, differential count, and mucin clot-forming ability. Synovial fluid specimens were cultured bacteriologically before inoculation and on days 0 and 21. Horses in group 1 (controls) were euthanatized before day 6. All other horses were euthanatized on day 21. Tarsocrural joints were opened and examined. Synovial membrane specimens were bacteriologically cultured. Synovial membrane specimens were examined histologically (hemotoxylin and eosin stain) and articular cartilage specimens were (safranin O fast green stain) evaluated histochemically. Synovial membrane specimens were histologically graded into 5 categories. Intensity of articular cartilage intercellular staining with safranin 0 was graded for superficial, outer intermediate, inner intermediate, and deep zones. Two-way analysis of variance was performed to evaluate differences among groups and across time for the determinants evaluated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Adrenocortical suppression in the dog given a single intramuscular dose of prednisone or triamcinolone acetonide

Adrenocortical function was assessed in dogs given a single intramuscular dose of either prednisone or triamcinolone acetonide (TCA; or saline solution to controls) to determine the duration of adrenocortical suppression caused by 2 commonly used glucocorticoids. The glucocorticoids were administered at recommended therapeutic doses; therefore, dogs given prednisone received a greater amount of glucocorticoid activity than did in dogs given TCA. Basal and ACTH-stimulated plasma cortisol concentrations, as determined by radioimmunoassay, were obtained once a week. Total intravascular eosinophil concentration and skin responses to intradermally injected histamine phosphate were quantitated. Dogs given TCA showed suppressed basal and ACTH-stimulated plasma cortisol concentrations 1 week after injection; the latter change persisted 2 weeks after injection. Adrenocortical function in 1 of 4 dogs given TCA remained suppressed for 4 weeks. In contrast, prednisone did not significantly alter adrenocortical function. Although intravascular eosinophil concentrations did not vary among groups, skin responses to intradermally injected histamine phosphate were reduced 6 days after prednisone and TCA were given.     

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.     

Population distributions of phenylbutazone and oxyphenbutazone after oral and i.v. dosing in horses

Experiments to determine the residual plasma concentrations of phenylbutazone and its metabolites found in horses racing on a 'no-race day medication' or 24-h rule were carried out. One dosing schedule (oral-i.v.) consisted of 8.8 mg/kg (4 g/1000 lbs) orally for 3 days, followed by 4.4 mg/kg (2 g/1000 lbs) intravenously on day 4. A second schedule consisted of 4.4 mg/kg i.v. for 4 days. The experiments were carried out in Thoroughbred and Standardbred horses at pasture, half-bred horses at pasture, and in Thoroughbred horses in training. After administering the i.v. schedule for 4 days to Thoroughbred and Standardbred horses at pasture, the mean plasma concentrations of phenylbutazone increased from 0.77 microgram/ml on day 2 to 2.5 micrograms/ml on day 5. The shape of the frequency distribution of these populations was log-normal. These data are consistent with one horse in 1,000 yielding a plasma level of 8.07 micrograms/ml on day 5. After administration of the oral-i.v. schedule to Thoroughbred and Standardbred horses at pasture, the mean plasma concentrations of phenylbutazone were 3.4 micrograms/ml on day 2 and 3.5 micrograms/ml on day 5. The range on day 5 was from 1.4 to 8.98 micrograms/ml and the frequency distribution was log-normal. These data are consistent with one horse in 1000 having a plasma level of 15.8 micrograms/ml on day 5. In a final experiment, the oral dosing schedule was administered to 62 Thoroughbred horses in training. Plasma concentrations on day 5 in these horses averaged 5.3 micrograms/ml. The range was from 1.3 to 13.6 micrograms/ml and the frequency distribution was log-normal. Statistical projection of these values suggests that following this oral dosing schedule in racing horses about one horse in 1000 will yield a plasma level of 23.5 micrograms/ml of phenylbutazone 24 h after the last dose.