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Six healthy adult horses (5 mares and 1 stallion) were given a single dose of acetylsalicylic acid (ASA), 20 mg/kg of body weight, by intravenous (IV), rectal, and intragastric (IG) routes. Serial blood samples were collected via jugular venipuncture over a 36-h period, and plasma ASA and salicylic acid (SA) concentrations were determined by high-performance liquid chromatography. After IV administration, the mean elimination rate constant of ASA (+/- the standard error of the mean) was 1.32 +/- 0.09 h(-1), the mean elimination half-life was 0.53 +/- 0.04 h, the area under the plasma concentration-versus-time curve (AUC) was 2555 +/- 98 microg x min/mL, the plasma clearance was 472 +/- 18.9 mL/h/kg, and the volume of distribution at steady state was 0.22 +/- 0.01 L/kg. After rectal administration, the plasma concentration of ASA peaked at 5.05 +/- 0.80 microg/mL at 0.33 h, then decreased to undetectable levels by 4 h; the plasma concentration of SA peaked at 17.39 +/- 5.46 microg/mL at 2 h, then decreased to 1.92 +/- 0.25 microg/mL by 36 h. After rectal administration, the AUC for ASA was 439.4 +/- 94.55 microg x min/mL and the bioavailability was 0.17 +/- 0.037. After IG administration, the plasma concentration of ASA peaked at 1.26 +/- 0.10 microg/mL at 0.67 h, then declined to 0.37 +/- 0.37 microg/mL by 36 h; the plasma concentration of SA peaked at 23.90 +/- 4.94 microg/mL at 4 h and decreased to 0.85 +/- 0.31 microg/mL by 36 h. After IG administration, the AUC for ASA was 146.70 +/- 24.90 microg x min/mL and the bioavailability was 0.059 +/- 0.013. Administration of a single rectal dose of ASA of 20 mg/kg to horses results in higher peak plasma ASA concentrations and greater bioavailability than the same dose given IG. Plasma ASA concentrations after rectal administration should be sufficient to inhibit platelet thromboxane production, and doses lower than those suggested for IG administration may be adequate.

Clarithromycin offers numerous advantages over erythromycin and thus, is an attractive alternative for the treatment of Rhodococcus equi infections in foals. The disposition of clarithromycin was investigated in 6 foals after intragastric administration at a dose of 10 mg/kg body weight. Detectable serum concentrations of clarithromycin were found in 3 of 6 foals at 10 minutes and in all foals by 20 minutes post-administration. Time to peak serum concentration (Tmax) was 1.5 hours and peak serum concentration (Cmax) was 0.92+/-0.17 microg/ml. Mean serum concentrations decreased to 0.03 microg/ml at 24 h. No adverse reactions were noted during or after IG administration in any of the foals. Based on the pharmacokinetic parameters, the MIC90 of R. equi isolates, and predicted steady state concentrations, an oral dose of 7.5 mg/kg given every 12 hours would appear appropriate for the treatment of R. equi infections in foals.

Concentrations of caffeine (CA) and two metabolites were measured simultaneously in venous blood and splenius muscle of adult horses using a semi-automated in vivo microdialysis sampling technique. Dialysates from muscle and jugular vein were collected continuously for 48 h and drug levels were determined by high performance liquid chromatography (HPLC). Following i.v. injection, CA (3 mg/kg) attained a peak blood level of nearly 5400 +/- 600 ng/mL and decreased with a half-life of 15.3 +/- 0.7 h. Pharmacokinetic and statistical comparisons between CA concentrations in jugular dialysates and plasma samples revealed no significant differences between these sampling techniques. However, measurements in muscle and blood revealed unexpected pharmacokinetic differences, including significantly elevated concentrations of CA in muscle for 4 h following drug administration. In contrast, the CA metabolites theophylline (TP) and theobromine (TB) exhibited delayed appearances in muscle and blood with peak concentrations of 300 +/- 60 ng/mL (TP) and 150 +/- 50 ng/mL (TB) detected in both tissues 1 day following CA administration. This study demonstrates that our novel semi-automated microdialysis procedure for continuous monitoring of drug and metabolite levels may be useful for related studies in other domesticated large animal species.

Pharmacokinetics and distribution of orbifloxacin into body fluids and endometrium was studied in 6 mares after intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. Orbifloxacin concentrations were serially measured in serum, synovial fluid, peritoneal fluid, urine, cerebrospinal fluid, and endometrial tissues over 24 hours. Minimum inhibitory concentrations of orbifloxacin were determined for 120 equine pathogens over an 11-month period. The mean peak serum concentration (Cmax) was 2.41+/-0.30 microg/mL at 1.5 hours after administration and decreased to 0.17+/-0.01 microg/mL (Cmin) at 24 hours. The mean elimination half-life (t1/2) was 9.06+/-1.33 hours and area under the serum concentration vs time curve (AUC) was 20.54+/-1.70 mg h/L. Highest mean peritoneal fluid concentration was 2.15+/-0.49 microg/mL at 2 hours. Highest mean synovial fluid concentration was 1.17+/-0.28 microg/mL at 4 hours. Highest mean urine concentration was 536.67+/-244.79 microg/mL at 2 hours. Highest mean endometrial concentration was 0.72+/-0.23 microg/g at 1.5 hours. Mean CSF concentration was 0.46+/-0.55 microg/mL at 3 hours. The minimum inhibitory concentration of orbifloxacin required to inhibit 90% of isolates (MIC90) ranged from < or = 0.12 to > 8.0 microg/mL, with gram-negative organisms being more sensitive than gram-positive organisms. Orbifloxacin was uniformly absorbed in the 6 mares and was well distributed into body fluids and endometrial tissue. At a dosage of 7.5 mg/kg once a day, many gram-negative pathogens, such as Actinobacillus equuli, Escherichia coli, Pasteurella spp., and Salmonella spp. would be expected to be susceptible to orbifloxacin.

Serum concentrations and pharmacokinetics of enrofloxacin were studied in 6 mares after intravenous (IV) and intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. In experiment 1, an injectable formulation of enrofloxacin (100 mg/mL) was given IV. At 5 min after injection, mean serum concentration was 9.04 microg/mL and decreased to 0.09 microg/mL by 24 h. Elimination half-life was 5.33 +/- 1.05 h and the area under the serum concentration vs time curve (AUC) was 21.03 +/- 5.19 mg x h/L. In experiment 2, the same injectable formulation was given IG. The mean peak serum concentration was 0.94 +/- 0.97 microg/mL at 4 h after administration and declined to 0.29 +/- 0.12 microg/mL by 24 h. Absorption of this enrofloxacin preparation after IG administration was highly variable, and for this reason, pharmacokinetic values for each mare could not be determined. In experiment 3, a poultry formulation (32.3 mg/mL) was given IG. The mean peak serum concentration was 1.85 +/- 1.47 microg/mL at 45 min after administration and declined to 0.19 +/- 0.06 microg/mL by 24 h. Elimination half-life was 10.62 +/- 5.33 h and AUC was 16.30 +/- 4.69 mg x h/L. Bioavailability was calculated at 78.29 +/- 16.55%. Minimum inhibitory concentrations of enrofloxacin were determined for equine bacterial culture specimens submitted to the microbiology laboratory over an 11-month period. The minimum inhibitory concentration of enrofloxacin required to inhibit 90% of isolates (MIC90) was 0.25 microg/mL for Staphylococcus aureus, Escherichia coli, Salmonella spp., Klebsiella spp., and Pasteurella spp. The poultry formulation was well tolerated and could be potentially useful in the treatment of susceptible bacterial infections in adult horses. The injectable enrofloxacin solution should not be used orally.

The objectives of this study were to determine the pharmacokinetics and tissue concentrations of doxycycline after repeated intragastric administration, and to determine the minimum inhibitory concentrations (MIC) for equine pathogenic bacteria. In experiment 1, 2 mares received a single intragastric dose of doxycycline hyclate (3 mg/kg bwt). Mean peak serum concentration was 0.22 microg/ml 1 h postadministration. In experiment 2, 5 doses of doxycycline hyclate (10 mg/kg bwt), dissolved in water, were administered to each of 6 mares via nasogastric tube at 12 h intervals. The mean +/- s.e. peak serum doxycycline concentration was 0.32+/-0.16 microg/ml 1 h after the first dose and 0.42+/-0.05 microg/ml 2 h after the fifth dose. The mean trough serum concentrations were > 0.16 microg/ml. Highest mean synovial concentration was 0.46+/-0.13 microg/ml and highest mean peritoneal concentration was 0.43+/-0.07 microg/ml, both 2 h after the fifth dose. Highest urine concentration was mean +/- s.e. 145+/-25.4 microg/ml 2 h after the last dose. Highest endometrial concentration was mean +/- s.e. 1.30+/-0.36 microg/ml 3 h after the fifth dose. Doxycycline was not detected in any of the CSF samples. Mean +/- s.e. Vd(area) was 25.3+/-5.0 l/kg and mean t1/2 was 8.7+/-1.6 h. In experiment 3, minimum inhibitory concentrations of doxycycline were determined for 168 equine bacterial culture specimens. The MIC90 was < or = 1.0 microg/ml for Streptococcus zooepidemicus and 0.25 microg/ml for Staphylococcus aureus. Based on drug concentrations achieved in the serum, synovial and peritoneal fluids and endometrial tissues and MIC values determined in the present study, doxycycline at a dose of 10 mg/kg bwt per os every 12 h may be appropriate for the treatment of infections caused by susceptible (MIC < 0.25 microg/ml) gram-positive organisms in horses.

A radioimmunoassay was developed for prednisolone using IgG purified from rabbit antiserum. The assay was employed to determine the pharmacokinetics of prednisolone following intravenous administration of 450 mg of prednisolone sodium succinate (Solu Delta Cortef) to five adult Thoroughbred horses. The RIA had a sensitivity of 2 ng/ml and was relatively specific. It had cross-reactivity with 21-deoxycortisol (83.3%) cortisol (27.8%), 11-beta-hydroxyprogesterone (39.2%) and 17-hydroxyprogesterone (50%). However, it did not cross-react with naturally occurring steroids (cholesterol, testosterone, estradiol or progesterone) or synthetic steroids (betamethasone, methylprednisolone, prednisone or triamcinolone). Radioimmunoassay of the horse serum samples detected the presence of prednisolone for 5 to 7 hours post administration. The pharmacokinetic parameters tested and their means were a half-life of 1.150 +/- 0.233 (+/- SEM) hours, an excretion constant of 0.686 +/- 0.018 Ke/hr, a volume of distribution of 607 +/- 109 ml/kg, and a clearance rate of 374 +/- 47 ml/hr/kg. RIA also detected the presence of prednisolone in the urine beginning one hour post administration. The prednisolone in the urine increased significantly at 2 hours and reached a peak at 4 hours post administration. The urinary levels decreased at 5, 6, and 7 hours and peaked again at 8 hours. The level then gradually decreased and reached the minimal detectable levels in 48 hours. These results showed that the RIA was sensitive and relatively specific for the determination of prednisolone.(ABSTRACT TRUNCATED AT 250 WORDS)

Five healthy adult mares and 1 gelding were given a single dose (15 mg/kg of body weight) of metronidazole per rectum. After manual evacuation of feces from the rectum, a suspension of crushed tablets and water (40 ml) was administered via a 28-F catheter advanced 30 cm into the rectum. Blood samples were obtained by jugular venipuncture, and metronidazole concentration was measured serially for the 14 hours after drug administration. Mean serum concentration of metronidazole peaked at 4.5 micrograms/ml, 0.83 hour after administration, and decreased to 0.38 microgram/ml, 14 hours after administration. Mean elimination rate constant was 0.23/h, and the harmonic mean elimination half-life was 3.04 hours. Further study is necessary to determine a therapeutic dose regimen for metronidazole administered per rectum.

Serum concentrations of metronidazole were determined in 6 healthy adult mares after a single IV injection of metronidazole (15 mg/kg of body weight). The mean elimination rate (K) was 0.23 h-1, and the mean elimination half-life (t1/2) was 3.1 hours. The apparent volume of distribution at steady state was 0.69 L/kg, and the clearance was 168 ml/h/kg. Each mare was then given a loading dose (15 mg/kg) of metronidazole at time 0, followed by 4 maintenance doses (7.5 mg/kg, q 6 h) by nasogastric tube. Metronidazole concentrations were measured in serial samples of serum, synovia, peritoneal fluid, and urine. Metronidazole concentrations in CSF and endometrial tissues were measured after the fourth maintenance dose. The highest mean concentration in serum was 13.9 +/- 2.18 micrograms/ml at 40 minutes after the loading dose (time 0). The highest mean synovial and peritoneal fluid concentrations were 8.9 +/- 1.31 micrograms/ml and 12.8 +/- 3.21 micrograms/ml, respectively, 2 hours after the loading dose. The lowest mean trough concentration in urine was 32 micrograms/ml. Mean concentration of metronidazole in CSF was 4.3 +/- 2.51 micrograms/ml and the mean concentration in endometrial tissues was 0.9 +/- 0.48 micrograms/g at 3 hours after the fourth maintenance dose. Two mares hospitalized for treatment of bacterial pleuropneumonia were given metronidazole (15.0 mg/kg, PO, initially then 7.5 mg/kg, PO, q 6 h), while concurrently receiving gentamicin, potassium penicillin, and flunixin meglumine IV. Metronidazole pharmacokinetics and serum concentrations in the sick mares were similar to those obtained in the healthy mares.

Three sets of paired circular and square full-thickness skin wounds were made on the dorsum of the metacarpus (n = 48) of 8 horses. Each wound was 6.25 cm2 in area. The wounds were treated topically with an ointment, nonadherent dressing, and bandaged with a snug elastic wrap. Wounds were photographed every other day until healing was complete. Wound areas were measured and exponential and linear wound healing models were applied to the wound healing data generated. Wound healing variables measured for each wound were: number of days to healing, maximal size attained, rate of wound contraction (calculated by use of first-order and linear models), final wound size, and percentage of wound that healed by contraction. The exponential model fit the data significantly better than the linear model. The maximal size attained by circular wounds was significantly smaller than the maximal size attained by square wounds. Wound shape did not influence the rate of wound healing. On the basis of our findings, conversion of circular defects to square defects would not speed wound healing.

Each of seven mares was given an intravenous (IV) injection of 40% dimethyl sulfoxide (DMSO) at a dosage of 1 g/kg, over 35 min, immediately followed by a single IV injection of a trimethoprim (TMP) and sulfamethoxazole (SMZ) combination (SMZ 83%, TMP 17%) at a combined dosage of 44 mg/kg (7.48 mg/kg TMP; 36.52 mg/kg SMZ). Each horse served as its own control and was alternately treated with an identical dose of TMP-SMZ treatment alone at least seven days following or preceding the DMSO and TMP-SMZ treatment. Serum and cerebrospinal fluid (CSF) concentrations of TMP and SMZ were measured over a six hour period. Dimethyl sulfoxide treatment caused no significant difference in the mean serum concentration of SMZ or in the mean CSF concentrations of TMP or SMZ. The mean serum concentration of TMP was significantly (p less than 0.05) increased at the two, four and six hour sampling time in the mares receiving pretreatment with DMSO. The clearance of TMP was also significantly (p less than 0.05) decreased from 675 mL/h/kg to 327 mL/h/kg by DMSO administration. Concentrations of TMP and SMZ in the CSF in both treatment groups exceeded the minimum inhibitory concentrations for many common bacterial pathogens of equine origin. In addition, CSF concentration of TMP exceeded the serum concentrations required for 50% inhibition of dihydrofolate reductases of protozoan origin. Serum TMP and SMZ concentration were similar to those reported to be effective against Toxoplasma gondii in in vitro studies on the killing or inhibition of the organism.

Six healthy adult mares were given a single IV dose (25 mg/kg of body weight) of chloramphenicol sodium succinate. Chloramphenicol concentrations in serum, synovial fluid, peritoneal fluid, and urine were measured serially over a 48-hour period. The highest measured serum chloramphenicol concentration was 6.21 micrograms/ml at 0.5 hour. Chloramphenicol was detected in synovial and peritoneal fluids, with mean peak concentrations of 3.89 micrograms/ml and 3.50 micrograms/ml, respectively, at 0.5 hour. Serum and synovial concentrations declined rapidly and were not measurable at 3 hours. Chloramphenicol could not be detected in peritoneal fluid at 6 hours. The serum half-life was 0.43 hour and the apparent volume of distribution was 2.83 L/kg. Urine concentrations of chloramphenicol peaked at 0.5 hour at 106.72 micrograms/ml and also declined rapidly. The drug could not be detected in the urine at 36 hours.

Six healthy adult horse mares were each given a single injection of sodium cephapirin (20 mg/kg of body weight, IV), and serum cephapirin concentrations were measured serially over a 6-hour period. The mean elimination rate constant was 0.78 hour-1 and the elimination half-life was 0.92 hours. The apparent volume of distribution (at steady state) and the clearance of the drug were estimated at 0.17 L/kg and 598 ml/hour/kg, respectively. Each mare was then given 4 consecutive IM injections of sodium cephapirin (400 mg/ml) at a dosage level of 20 mg/kg. Cephapirin concentrations in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium were measured serially. After IM administration, the highest mean serum concentration was 14.8 micrograms/ml 25 minutes after the 4th injection. The highest mean synovial and peritoneal concentrations were 4.6 micrograms/ml and 5.0 micrograms/ml, respectively, 2 hours after the 4th injection. The highest mean endometrial concentration was 2.2 micrograms/g 4 hours after the 4th injection. Mean urine concentrations reached 7,421 micrograms/ml. Cephapirin did not readily penetrate the CSF. When cephapirin was given IM at the same dose, but in a less concentrated solution (250 mg/ml), serum concentrations peaked at 25.0 micrograms/ml 20 minutes after injection, but the area under the serum concentration-time curve was not significantly different (P greater than 0.05). The bioavailability of the drug was greater than or equal to 95% after IM injection.

Six healthy pony foals, from 2 to 11 days of age, were given a single IM injection of amikacin sulfate (250 mg/ml) at a dosage rate of 7 mg/kg of body weight. Serum amikacin concentrations were measured serially over a 24-hour period. The mean peak serum concentration was 14.7 micrograms/ml at 0.5 hour. The elimination rate constant for amikacin was 0.24/hour, the elimination half-life was 3.0 hours, and the apparent volume of distribution was 0.58 L/kg.

Six mares were given 5 IM injections (at 12-hour intervals between doses) of amikacin sulfate at a dosage of 7 mg/kg of body weight. Serum amikacin concentrations were measured serially throughout the study; synovial, peritoneal, endometrial, and urine concentrations were determined after the last injection. Amikacin concentrations of the CSF were measured serially in 3 of the 6 mares; 1 of the 3 mares had septic meningitis. Mean serum amikacin concentrations peaked at 1 to 2 hours after IM injection. The highest mean serum concentration was 19.2 micrograms/ml (1.5 hours after the 5th injection). The highest mean synovial concentration was 10.8 micrograms/ml at 2 hours after the 5th injection; the highest mean peritoneal concentration was 16.2 micrograms/ml at 3 hours after the 5th injection. The mean endometrial amikacin concentration was 2.5 micrograms/g (1.5 hours after the 5th injection). Amikacin reached a CSF concentration of 0.97 micrograms/ml in the mare with meningitis, but amikacin was not detected in CSF of healthy mares. Urine concentrations reached 1,458 micrograms/ml. Pharmacokinetic values were estimated after the 1st injection (elimination rate constant = 0.31/hour; half-life = 2.3 hours; apparent volume of distribution = 0.26 L/kg), and after the 5th injection (elimination rate constant = 0.28/hour; half-life = 2.6 hours; apparent volume of distribution = 0.30 L/kg); significant differences were not observed.

Four healthy adult mares were each given a single injection of sodium cefoxitin (20 mg/kg of body weight, IV), and serum cefoxitin concentrations were measured serially during a 6-hour period. The mean elimination rate constant was 1.08/hour and the elimination half-life was 0.82 hour. The apparent volume of distribution (at steady state) and the clearance of the drug were estimated at 0.12 L/kg and 259 ml/hr/kg, respectively. Each mare and 2 additional mares were then given 4 consecutive IM injections of sodium cefoxitin (400 mg/ml) at a dosage of 20 mg/kg. Cefoxitin concentrations in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium were measured serially. After IM administration, the highest mean serum concentration was 23.1 micrograms/ml 30 minutes after the 2nd injection. The highest mean synovial concentration was 11.4 micrograms/ml 1 hour after the 4th injection. The highest mean peritoneal concentration was 10.4 micrograms/ml 2 hours after the 4th injection. The highest mean endometrial concentration was 4.5 micrograms/g 4 hours after the 4th injection. Mean urine concentrations reached 11,645 micrograms/ml. Cefoxitin did not readily penetrate the CSF. Bioavailability of cefoxitin given IM was 65% to 89% (mean +/- SEM = 77% +/- 5.9%). One of the 6 mares developed acute laminitis during the IM experiment.

Bile acid pool size and synthesis rate were determined by both isotope-dilution and washout methods in ponies with chronic external biliary fistulas. Bile acid pool size (10.9 mumol/kg) and synthesis rate (11.2 mumol/day per kg) estimated by the isotope-dilution method did not differ significantly from pool size (9.4 mumol/kg) and synthesis rate (9.5 mumol/day per kg) estimated by washout method. Bile acid-dependent and -independent fractions of bile flow, determined by a method that circumvents any inevitable correlation of flow to bile acid secretion due to common factors in both parameters, did not differ from those values obtained by linear regression of bile flow versus bile acid secretion. The choleretic effect of infused chenodeoxycholic acid was higher than that of both endogenous bile acid and infused taurocholic acid.

Six healthy adult mares were each given an oral loading dose of ormetoprim(OMP)-sulfadimethoxine (SDM) at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg, followed by four maintenance doses of 4.6 mg of OMP/kg and 22.9 mg of SDM/kg, at 24 h intervals. Ormetoprim and SDM concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid, urine and endometrium. The highest mean serum OMP concentration was 0.92 micrograms/mL 0.5 h after the first dose; the highest mean SDM concentration was 80.9 micrograms/mL 8 h after the first dose. The highest mean synovial fluid concentrations were 0.14 microgram of OMP/mL and 28.5 micrograms of SDM/mL 12 h after the first dose. The highest mean peritoneal fluid concentrations were 0.19 micrograms of OMP/mL 6 h after the first dose and 25.5 micrograms of SDM/mL 8 h after the fifth dose. The highest mean endometrial concentrations were 0.56 micrograms of OMP/g and 28.5 micrograms of SDM/g 4 h after the fifth dose. The mean cerebrospinal fluid concentrations were 0.08 micrograms of OMP/mL and 2.1 micrograms of SDM/mL 5 h after the fifth dose. Mean trough urine drug concentrations were greater than or equal to 0.4 micrograms of OMP/mL and greater than or equal to 172 micrograms of SDM/mL. Two of the mares were each given a single intravenous (IV) injection of OMP and SDM at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg. Excitation and muscle fasciculations were observed in both mares after IV administration and all scheduled blood samples could be collected from only one of the two mares.(ABSTRACT TRUNCATED AT 250 WORDS)