Hyaluronan in horses: physiological production rate, plasma and synovial fluid concentrations in control conditions and following sodium hyaluronate administration

REASONS FOR PERFORMING STUDY: Hyaluronic acid (HA) is an endogenous glycosaminoglycan used in the treatment of joint diseases, but medication control is required by horseracing authorities. Therefore, a medication control policy needs to be established. OBJECTIVES: To establish physiological plasma HA concentrations in post race horses, determine the HA endogenous production rate and document the disposition of HA after i.v. and intra-articular hyaluronic acid administration at recommended therapeutic doses. METHODS: Hyaluronan concentrations in plasma were determined using an ELISA specific test; concentrations in synovial fluid were determined using a radiometric binding assay. RESULTS: The overall mean plasma HA concentration in 120 post competition horses was 89 ng/ml. In a group of 6 experimental horses, synovial fluid control concentration was 328+/-112 microg/ml. After i.v. sodium hyaluronate administration (37.8 mg in toto), the terminal half-life was very short (43+/-29 mins) and after a delay of 3 h, the plasma concentration returned to control values. The endogenous HA production rate was 33-164 mg in toto per day, i.e. 1-4 times the recommended i.v. daily dose. Twenty-four hours after intra-articular administration, HA concentration was not significantly different from control values (328+/-112 microg/ml). CONCLUSIONS AND POTENTIAL RELEVANCE: Due to the rapid disappearance of HA from plasma after i.v. administration and from the joint after intra-articular administration, long-term detection needs a more appropriate approach to be developed.     

Determination of concentration of hyaluronate in equine serum

Concentration of hyaluronate (HA) in equine serum was determined by a recently developed specific radioassay. The mean +/- SD HA concentration in equine serum was 288 +/- 145 micrograms/L, was age dependent, and varied widely between horses (range, 190 to 760 micrograms/L). Light or moderate exercise increased serum HA concentration from baseline values by 1.5- to 3-fold. In all horses, serum HA concentration returned to or below the original resting values 1 and 2 hours after exercise.     

Serum level of cartilage oligomeric matrix protein (COMP) in equine osteoarthritis

This study was designed to assay and compare cartilage oligomeric matrix protein (COMP) in horse sera, in samples from normal and joint diseased horses, and to investigate the relationships between COMP in sera and synovial fluids (SF) with keratan sulphate (KS) data. Sera from 38 horses free of any joint pathology (controls) and from horses with aseptic joint disease (AJD horses, n = 40) were assayed for COMP and KS concentrations. Of the 78 horses in the study, 53 were also assayed for COMP and KS concentrations in SF. COMP and KS were measured by inhibition ELISA, using monoclonal antibodies 12C4 and 5D4, respectively. The COMP concentration in sera from AJD horses (mean +/- s.d. 10.7 +/- 7.4 microg/ml) was significantly (P<0.02) lower than in control sera (14.8 +/- 7.8 microg/ml). The joint disease sera also had significantly lower (P<0.01) KS levels (180.5 +/- 61.8 ng/ml) than controls (237.1 +/- 116.1 ng/ml). A significant correlation (r = 0.52, n = 53, P<0.001) was seen between serum and SF in COMP levels; no such relationship was seen in KS levels. It is possible that serum COMP concentration could be a more specific marker of equine joint disease than any other described to date.     

Determination of total protein concentration and viscosity of synovial fluid from the tibiotarsal joints of horses.

Viscosity of synovial fluid (SF) from 29 clinically normal horses was determined by use of a rotational cone and plate microviscosimeter. Total protein concentration in the SF of the 29 horses, as measured with a refractometer, was less than 2.5 g/dl. When the Coomassie brilliant blue test was used to determine total protein concentration in SF for 15 horses, the mean value was 1,088 mg/dl. Viscosity values at 60, 30, 12, 6, 3, and 1.5 revolutions/min (rpm) spindle speed were 4.41 +/- 1.54 centipoise (cp), 5.29 +/- 1.94 cp, 6.76 +/- 2.76 cp, 8.52 +/- 4.27 cp. 10.41 +/- 6.30 cp, and 13.07 +/- 9.05 cp, respectively. Synovial fluid viscosity increased with decreasing rpm and shear rate, but the shape of the curve for each horse fitted the asymptotic curve. The rotational cone and plate microviscosimeter was an accurate instrument in measuring SF viscosity at multiple rpm or shear rates in horses. The values obtained on clinically normal horses in this study will serve as a baseline for comparison in the evaluation of horses with joint disease.     

Pharmacokinetics of imipramine in narcoleptic horses

OBJECTIVE: To validate use of high-performance liquid chromatography (HPLC) in determining imipramine concentrations in equine serum and to determine pharmacokinetics of imipramine in narcoleptic horses. ANIMALS: 5 horses with adult-onset narcolepsy. PROCEDURE: Blood samples were collected before (time 0) and 3, 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 3, 4, 6, 8, 12, and 24 hours after IV administration of imipramine hydrochloride (2 or 4 mg/kg of body weight). Serum was analyzed, using HPLC, to determine imipramine concentration. The serum concentration-versus-time curve for each horse was analyzed separately to estimate pharmacokinetic values. RESULTS: Adverse effects (muscle fasciculations, tachycardia, hyperresponsiveness to sound, and hemolysis) were detected in most horses when serum imipramine concentrations were high, and these effects were most severe in horses receiving 4 mg of imipramine/kg. Residual adverse effects were not apparent. Value (mean +/- SD) for area under the curve was 3.9 +/- 0.7 h X microg/ml, whereas volume of distribution was 584 +/- 161.7 ml/kg, total body clearance was 522 +/- 102 ml/kg/h, and mean residence time was 1.8 +/- 0.6 hours. One horse had signs of narcolepsy 6 and 12 hours after imipramine administration; corrresponding serum imipramine concentrations were less than the therapeutic range. CONCLUSIONS AND CLINICAL RELEVANCE: Potentially serious adverse effects may be seen in horses administered doses of imipramine that exceed a dosage of 2 mg/kg. Total body clearance of imipramine in horses is slower than that in humans; thus, the interval between subsequent doses should be longer in horses.     

Safe and efficacious dosage of flecainide acetate for treating equine atrial fibrillation

To determine a safe and efficacious dose of flecainide acetate for treating equine atrial fibrillation (Af), the safe dosage level was determined by injecting 1, 2, or 3 mg/kg i.v. of 1% flecainide acetate solution at a rate of 0.2 mg/kg/min to five clinically healthy horses. Clinical signs and the ECG were monitored (HR, PR, QRS, and QT intervals) and blood was taken to measure the plasma flecainide concentration pre- and post-administration. No abnormal signs were observed in the 1- or 2-mg/kg groups, while agitation was observed in three of five horses in the 3-mg/kg group. The QRS, and QT intervals for the 3-mg/kg group increased significantly. The peak plasma flecainide concentrations were 1.316 +/- 358 (SD) ng/ml, 1,904 +/- 314 ng/ml, and 2,251 +/- 387 ng/ml for the 1-, 2-, and 3-mg/kg groups, respectively. To evaluate the efficacy of flecainide, Af was induced by right atrial pacing in six clinically healthy horses, and 1% flecainide acetate solution was then administered until they converted to sinus rhythm. All horses with induced Af converted. For the conversion, a total dose of 1.40 +/- 0.63 mg/kg flecainide was required, the duration of administration was 7.00 +/- 3.15 min and plasma flecainide concentration at conversion was 1,303 +/- 566 ng/ml. In conclusion, flecainide acetate is a safe and effective antiarrhythmic agent for equine Af, and the clinically effective dosage is 1 to 2 mg/kg.     

Pharmacokinetic disposition of an immediate-release aminophylline and a sustained-release theophylline formulation in the horse

The pharmacokinetic disposition of theophylline was determined by high-performance liquid chromatographic analysis of plasma samples from six healthy, adult horses following the administration of intravenous aminophylline (dosed at 9.94 mg/kg as theophylline), immediate-release aminophylline tablets (dosed at 9.94 mg/kg as theophylline), and sustained-release theophylline tablets (dosed at 20 mg/kg). The elimination rate constant (lambda z), apparent volume of distribution (Vz), and clearance (Cl) determined by compartmental analysis of the intravenous data were 0.07 +/- 0.01 h-1, 0.80 +/- 0.06 l/kg, and 0.06 +/- 0.01 l/kg/h (mean +/- SD), respectively. Mean residence time determined by statistical moment theory of the oral data was different (P less than 0.05) for the immediate-release aminophylline (13.8 +/- 2.8 h) and sustained-release theophylline (18.2 +/- 2.3 h) formulation. Immediate-release aminophylline tablets quickly achieved peak theophylline plasma concentration of 11.51 +/- 1.4 micrograms/ml at 1.6 +/- 0.6 h while the sustained-release theophylline tablets were more slowly absorbed and achieved peak theophylline concentrations of 17.20 +/- 1.3 micrograms/ml at 7.3 +/- 1.0 h. Absolute bioavailability was 87% for the immediate-release and 97% for the sustained-release formulation. Using the principle of superposition, a loading dose of 20 mg/kg of the sustained-release formulation followed by maintenance doses of 15 mg/kg every 24 h was predicted to achieve trough-peak theophylline plasma concentrations between 6 and 17 micrograms/ml.     

Pharmacokinetics of acetazolimide after intravenous and oral administration in horses

OBJECTIVE: To determine the pharmacokinetics of acetazolamide administered IV and orally to horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Horses received 2 doses of acetazolamide (4 mg/kg of body weight, IV; 8 mg/kg, PO), and blood samples were collected at regular intervals before and after administration. Samples were assayed for acetazolamide concentration by high-performance liquid chromatography, and concentration-time data were analyzed. RESULTS: After IV administration of acetazolamide, data analysis revealed a median mean residence time of 1.71 +/- 0.90 hours and median total body clearance of 263 +/- 38 ml/kg/h. Median steady-state volume of distribution was 433 +/- 218 ml/kg. After oral administration, mean peak plasma concentration was 1.90 +/- 1.09 microg/ml. Mean time to peak plasma concentration was 1.61 +/- 1.24 hours. Median oral bioavailability was 25 +/- 6%. CONCLUSIONS AND CLINICAL RELEVANCE: Oral pharmacokinetic disposition of acetazolamide in horses was characterized by rapid absorption, low bioavailability, and slower elimination than observed initially after IV administration. Pharmacokinetic data generated by this study should facilitate estimation of appropriate dosages for acetazolamide use in horses with hyperkalemic periodic paralysis.     

Use of 13C-acetate breath test for assessment of gastric emptying in horses

This study aimed to establish and standardize a breath test that uses 13C-acetate in a liquid diet for evaluation of gastric emptying in horses. Seven adult healthy thoroughbreds were used in this study. They were given 13C-acetate (125 mg, 250 mg, or 500 mg) in a test meal (2000 ml liquid diet) via an intranasal catheter. 13C concentrations in the exhaled CO2 were measured in samples taken before and after test meal administration using an infrared absorption spectroscope. In the 500 mg 13C-acetate group, Delta13CO2 showed a steep gradient immediately after meal administration compared to the 125 mg and 250 mg groups. Therefore, t(max) in the 500 mg group was easier to determine than in the 125 mg and 250 mg groups. In the 500 mg group, GEC, half-empty time (t1/2), calculated t(max) (t(lag)), and t(max) were 1.95 +/- 0.28 (mean +/- SD), 229.2 +/- 57.0 (min), 139.2 +/- 22.2 (min), and 124.0 +/- 28.4, respectively. Differences in CV observed in the 500 mg group were lower than those in the 125 mg and 250 mg groups. This study demonstrates that the 13C-acetate breath test is useful for evaluating gastric emptying in horses since it is non-invasive and does not require set up of special facilities or equipment. Optimum evaluation of gastric emptying in horses can be achieved with 500 mg of 13C-acetate given in a liquid diet.     

Comparison of high-performance liquid chromatography with a radiometric assay for determination of the effect of intra-articular administration of corticosteroid and saline solution on synovial fluid hyaluronate concentration in horses.

Two recently developed direct methods, radioassay-125I-labeled hyaluronic acid binding protein (125I-HABP)- and high-performance liquid chromatography (HPLC), were used to assess and compare the concentration of hyaluronate (HA) in synovial fluid of horses. Also determined were changes in the HA concentration in an experimental treatment model involving physiologic saline solution (PSS)-irrigated or methylprednisolone acetate-injected tarsocrural joints of clinically normal horses. Serum HA concentration was determined simultaneously, using the 125I-HABP assay. Synovial fluid HA concentration values obtained by use of the HPLC method were approximately double the values obtained by use of 125I-HABP assay. Correlation (r = 0.819) between the 2 methods was highly significant (P less than 0.001; linear regression analysis) for all samples studied and for various experimental subgroups. When pure HA standards were used, correlation between the 2 methods was close to 1 (r = 0.965; P less than 0.001), with higher values obtained by use of the 125I-HABP assay. It is suggested that the HA binding protein derived from endogenous cartilage proteoglycan interferes with the 125I-HABP assay on synovial fluid, resulting in excessively low values, compared with those obtained using the HPLC procedure. Intra-articular injection of methylprednisolone acetate significantly (P less than 0.01) increased synovial fluid HA concentration at 24 hours after injection. Increase was also detected after PSS irrigation, but owing to wide intersubject variation, this increase was not significant. The HPLC procedure, which provides simultaneous information about the concentration and degree of polymerization of HA, is recommended for the study of synovial fluid, whereas the 125I-HABP assay is more suitable for serum HA analysis.     

Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations of fluconazole following repeated oral dosing in horses

OBJECTIVE: To determine the pharmacokinetics of fluconazole in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Fluconazole (10 mg/kg of body weight) was administered intravenously or orally with 2 weeks between treatments. Plasma fluconazole concentrations were determined prior to and 10, 20, 30, 40, and 60 minutes and 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after administration. A long-term oral dosing regimen was designed in which all horses received a loading dose of fluconazole (14 mg/kg) followed by 5 mg/kg every 24 hours for 10 days. Fluconazole concentrations were determined in aqueous humor, plasma, CSF, synovial fluid, and urine after administration of the final dose. RESULTS: Mean (+/- SD) apparent volume of distribution of fluconazole at steady state was 1.21+/-0.01 L/kg. Systemic availability and time to maximum plasma concentration following oral administration were 101.24+/-27.50% and 1.97+/-1.68 hours, respectively. Maximum plasma concentrations and terminal half-lives after IV and oral administration were similar. Plasma, CSF, synovial fluid, aqueous humor, and urine concentrations of fluconazole after long-term oral administration of fluconazole were 30.50+/-23.88, 14.99+/-1.86, 14.19+/-5.07, 11.39+/-2.83, and 56.99+/-32.87 microg/ml, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bioavailability of fluconazole was high after oral administration to horses. Long-term oral administration maintained plasma and body fluid concentrations of fluconazole above the mean inhibitory concentration (8.0 mg/ml) reported for fungal pathogens in horses. Fluconazole may be an appropriate agent for treatment of fungal infections in horses.     

Determination of oral dosage and pharmacokinetic analysis of flecainide in horses.

To determine oral dosage and to evaluate the pharmacokinetics in horses of orally administered flecainide, an antiarrhythmic drug, the correlations between its plasma concentration and PR, QRS and QT intervals in equine electrocardiograms (ECG) were investigated. Six healthy horses were administered a randomly ordered dose of 4 or 6 mg/kg of flecainide acetate. The ECG was monitored (heart rate (HR), PR, QRS, and QT intervals) and blood was taken at timed intervals to measure the plasma flecainide concentrations pre- and post-administration. The maximum plasma concentration reached 1014+/-285 (SD) ng/m/ in 45+/-13 min and 1301+/-400 ng/ m/l in 60+/-37 min for doses of 4 and 6 mg/kg flecainide, respectively. From the pharmacokinetic analysis, clearance rates were 14.6+/-6.4 and 11.7+/-5.2 ml/kg/min and terminal elimination half-lives were 228+/-53 and 304+/-87 min. The QRS and QT intervals increased significantly for both doses following administration, though HR and PR intervals did not change. Plasma flecainide concentrations were significantly correlated with QRS (r=0.935, P<0.001) and QT intervals (r=0.753, P<0.001). In conclusion, plasma concentrations of flecainide for treating equine atrial fibrillation were obtained by oral administration of 4 and 6 mg/kg, and the drug was rapidly eliminated from plasma in horses.     

Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally infected with influenza virus A2.

OBJECTIVE: To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg, p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus. RESULTS: Estimated mean peak plasma concentration of rimantadine after i.v. administration was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/- 7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half-life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection.     

Plasma ionized calcium and parathyroid hormone concentrations in horses after endurance rides

OBJECTIVE: To evaluate changes in plasma ionized calcium (Ca2+) and parathyroid hormone (PTH) concentrations in horses competing in endurance rides. DESIGN: Longitudinal clinical study. ANIMALS: 28 horses. PROCEDURE: Venous blood samples were obtained from horses before and after racing 80 km. Plasma pH and concentrations of Ca2+, PTH, inorganic phosphorus, albumin, lactate, and magnesium were measured. RESULTS: Overall, a significant decrease in mean (+/- SD) plasma Ca2+ concentration (from 6.44 +/- 0.42 to 5.64 +/- 0.42 mg/dl) and a significant increase in plasma PTH concentration (from 49.9 +/- 30.1 to 148.1 +/- 183.0 pg/ml) were found after exercise. Exercise also resulted in significant increases in plasma inorganic phosphorus, albumin, and lactate concentrations. No changes in plasma magnesium concentration or pH were detected after exercise. Plasma PTH concentration was not increased after exercise in 8 horses; in these horses, plasma PTH concentration decreased from 58.2 +/- 26.3 to 27.4 +/- 22.4 pg/ml, although plasma Ca2+ concentration was also decreased. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma Ca2+ concentration was decreased after racing for 80 km, compared with values obtained before racing. In most horses, an increase in plasma PTH concentration that was commensurate with the decrease in plasma Ca2+ was detected; however, some horses had decreased plasma PTH concentrations.     

Spinal fluid concentrations of mepivacaine in horses and procaine in cows after thoracolumbar subarachnoid analgesia

The CSF concentrations of mepivacaine in 10 Standardbred horses and of procaine in 10 Holstein cows given the drugs by thoracolumbar subarachnoid injection were determined. Mepivacaine hydrochloride was injected into the horses (502 +/- 60.5 kg) at an average dosage of 30 mg (1.5 ml of 20 mg/ml solution). Analgesia was produced 7.5 +/- 4.3 minutes after injection, extended between spinal cord segments T13 and L3 on both sides of the spinal column, and lasted 47 +/- 18.7 minutes at the T18 dermatome. Procaine hydrochloride was injected into cows (614 +/- 51.5 kg) at a dosage ranging between 75 mg and 100 mg (1.5 ml and 2 ml of 50 mg/ml solution). Analgesia was produced 8.2 +/- 2.0 minutes after injection, extended between spinal cord segments T11 and L4 on both sides of the spinal column, and lasted 47 +/- 17.5 minutes at the T13 dermatome. The critical CSF concentrations of local anesthetics required to eliminate response to pinprick stimulation were 204.4 +/- 90.3 micrograms of mepivacaine/ml in horses and 197.0 +/- 86.1 micrograms of procaine/ml in cows. Average CSF concentrations at 120 minutes after injections were made were 16.8 +/- 15.5 micrograms of mepivacaine/ml and 30.6 +/- 17.1 micrograms of procaine/ml. In in vitro experiments to determine the rates of hydrolysis of mepivacaine and procaine in CSF, significant changes (P greater than 0.05) were not seen in the CSF concentrations of mepivacaine in horses and procaine in cattle after a 120-minute incubation (37 C). The analgesic threshold concentrations of mepivacaine in CSF of horses and procaine in CSF of cows were similar.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma profiles of ivermectin in horses following oral or intramuscular administration

A study was undertaken in order to evaluate and compare ivermectin's (IVM) plasma disposition kinetic parameters after oral or intramuscular (IM) administration in horses. Ten clinically healthy adult horses, weighing 380-496 kg body weight (BW), were allocated to two experimental groups of five horses. Group I, was treated with an oral paste formulation of IVM at the manufacturer's recommended dose of 0.2 mg/kg BW. Group II, was treated IM with an injectable 1% formulation of IVM at a dose of 0.2 mg/kg BW. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post-treatment. After plasma extraction and derivatization, samples were analysed by high-performance liquid chromatography with fluorescence detection. A computerized kinetic analysis was performed, and data were compared using the Wilcoxon signed rank test. The parent molecule was detected in plasma between 30 min and either 20 (oral) or 40 (IM) days post-treatment. Significant differences were found for the time corresponding to peak plasma concentrations (tmax) and for absorption half-life. Peak plasma concentrations (Cmax) of 51.3 +/- 16.1 ng/ml (mean +/- SD) were obtained after oral administration and of 31.4 +/- 6.0 ng/ml for the IM route. The values for area under concentration-time curve were 137.1 +/- 35.9 ng day/ml for the group treated orally, and 303.2 +/- 4.3 ng day/ml for the IM treated group. The mean plasma residence times were 4.2 +/- 0.4 and 8.9 +/- 0.7 days for oral and IM-treated groups, respectively. The results of this study show that the route of administration considerably affects the disposition of IVM. A significant difference in bioavailabilty and half-life of elimination of IVM was observed after IM administration compared with oral administration. A close relationship between pharmacokinetic profiles and the clinical efficacy of IVM was established.     

Isolation, characterization, and quantitative analysis of ceruloplasmin from horses.

Ceruloplasmin (Cp) was isolated from fresh equine plasma by precipitation, cellulose chromatography, and improved ion-exchange chromatography. Purified equine Cp is a glycoprotein having a molecular weight of approximately 115,000. In electrophoresis, equine Cp migrated to the alpha 1-globulin region, its isoelectric point was about 4.15 and consisted of about 890 amino acid residues. Serum Cp concentration was measured by use of the single radial immunodiffusion method. In clinically normal horses, the mean (+/- SD) serum Cp concentration of newborn foals was 2.87 +/- 0.40 mg/ml and that of 3-month-old foals was 5.02 +/- 0.92 mg/ml, which was similar to the adult value. It reached a peak of 6.06 +/- 0.74 mg/ml in 2-year-old horses. The Cp concentration in mares was not statistically different for the perinatal period, but it decreased immediately before and after delivery. Concentration of Cp increased at 6 days after IM administration of turpentine oil, castration, or jejunojejunostomy in adult horses, and increased to peak values twice as high as baseline values at 7 to 14 days, returning to baseline values at 28 days after treatment. We concluded that equine serum Cp is an acute-phase reactive protein increased in the intermediary or later phase of acute inflammation.     

Pharmacokinetics of enrofloxacin administered intravenously and orally to foals

OBJECTIVE: To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals. ANIMALS: 5 clinically normal foals. PROCEDURE: A 2-dose cross-over trial with IV and oral administration was performed. Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period. Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography. RESULTS: For IV administration, mean +/- SD total area under the curve (AUC0-infinity) was 48.54 +/- 10.46 microg x h/ml, clearance was 103.72 +/- 0.06 ml/kg/h, half-life (t1/2beta) was 17.10 +/- 0.09 hours, and apparent volume of distribution was 2.49 +/- 0.43 L/kg. For oral administration, AUC0-infinity was 58.47 +/- 16.37 microg x h/ml, t1/2beta was 18.39 +/- 0.06 hours, maximum concentration (Cmax) was 2.12 +/- 00.51 microg/ml, time to Cmax was 2.20 +/- 2.17 hours, mean absorption time was 2.09 +/- 0.51 hours, and bioavailability was 42 +/- 0.42%. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-infinity, longer t1/2beta, and lower clearance. Concentration of ciprofloxacin was negligible. Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen.     

Assessment of copper and zinc status of farm horses and training thoroughbreds in south-east Queensland

The copper and zinc concentrations in the blood of stabled thoroughbred horses and in Australian Stock Horses mares at pasture, either late pregnant or lactating were determined by an atomic absorption spectroscopic method. The plasma concentration of the trace elements in these apparently normal horses were generally below the "normal" range. The plasma copper, caeruloplasmin copper, whole blood copper and plasma zinc concentrations in the stabled thoroughbreds were 0.76 +/- 0.19 micrograms/ml (n = 82), 0.56 +/- 0.14 micrograms/ml (n = 83), 0.75 +/- 0.18 micrograms/ml (n = 82) and 0.47 +/- 0.09 micrograms/ml (n = 83) respectively. The plasma copper and zinc concentrations of all the brood mares at pasture (pregnant and lactating) were 0.56 +/- 0.20 micrograms/ml and 0.47 +/- 0.11 micrograms/ml (n = 30). The plasma copper concentration of the pregnant group of mares (0.64 +/- 0.18 micrograms/ml; (n = 14) was greater than that of the lactating mares (0.49 +/- 0.21; (n = 16). Variation in the plasma copper concentration was also identified between stabled and farm horses, between horses of different stables and between horses of different ages. The proportion of plasma copper bound to caeruloplasmin was 73 +/- 11.8%. These low concentrations of copper and zinc in the plasma of apparently normal horses are of clinical significance since recent evidence has indicated that copper deficiency appears to promote the development of skeletal abnormalities in foals. An alternative to the use of a single plasma sample to identify the copper or zinc deficient horse was discussed.     

Effect of probenecid on disposition kinetics of ampicillin in horses.

The effect of an oral dose of probenecid on the disposition kinetics of ampicillin was determined in four horses. An intravenous bolus dose (10 mg/kg) of ampicillin sodium was administered to the horses on two occasions. On the first occasion the antibiotic was administered on its own, and on the second occasion it was administered one hour after an oral dose of 75 mg/kg probenecid. The plasma concentration of probenecid reached a mean (+/- se) maximum concentration (Cmax) of 188-6 +/- 19.3 micrograms/ml after 120.0 +/- 21.2 minutes and concentrations greater than 15 micrograms/ml were present 25 hours after it was administered. The disposition kinetics of ampicillin were altered by the presence of probenecid and as a result the antibiotic had a slower body clearance (ClB; 109.4 +/- 6.71 ml/kg hours compared with 208.9 +/- 26.2 ml/kg hours) a longer elimination half-life (t1/2 beta 1.198 hours compared with 0.701 hours) and consequently a larger area under the plasma concentration versus time curve (AUC 92.3 +/- 5.09 mg/ml hours compared with 35.95 +/- 3.45 mg/ml hours) when compared with animals to which ampicillin was administered alone. The ampicillin concentrations observed suggest that the dosing interval for horses may be increased from between six and eight hours to 12 hours when probenecid is administered in conjunction with the ampicillin.