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.     

Pulmonary vascular pressures of strenuously exercising Thoroughbreds after administration of varying doses of frusemide

The frusemide dose-response for attenuation of exercise-induced pulmonary capillary hypertension was studied in 7 healthy, exercise-conditioned Thoroughbred horses using previously described haemodynamic procedures. Four different doses of frusemide were tested: 250 mg regardless of bodyweight (amounting to 0.56 +/- 0.03 mg/kg bwt), 1.0 mg/kg bwt, 1.5 mg/kg bwt and 2.0 mg/kg bwt. Frusemide was administered i.v., 4 h before exercise. Haemodynamic data were obtained at rest and during treadmill exercise performed at 14.2 m/s on a 3.5% uphill grade; this workload elicited maximal heart rate of horses. Airway endoscopy was performed post exercise to detect exercise-induced pulmonary haemorrhage (EIPH). In standing horses, frusemide administration resulted in a significant (P<0.05) decrease in mean pulmonary arterial, pulmonary capillary and pulmonary artery wedge pressures, but significant differences among the various frusemide doses were not observed. In the control experiments, exercise caused significant increments in the right atrial as well as pulmonary arterial, wedge, and capillary pressures, and all horses experienced EIPH. Following frusemide administration, the exercise-induced rise in right atrial and pulmonary vascular pressures was significantly attenuated, but significant differences between the frusemide doses of 250 mg, 1.0 mg/kg, and 1.5 mg/kg were not discerned and all horses remained positive for EIPH. Although a further significant (P<0.05) attenuation of the exercise-induced rise in pulmonary capillary blood pressure occurred when frusemide dose increased from 250 mg to 2.0 mg/kg bwt, all horses still experienced EIPH. It is concluded that a linear response to increasing frusemide dosage in terms of attenuation of the pulmonary capillary hypertension does not exist in strenuously exercising Thoroughbred horses.     

Responses of horses to a water deprivation test

An investigation was made to determine the effects of water deprivation induced dehydration on changes in urine specific gravity (Usg) and urine osmolality (Uosm) in 6 horses with normal renal function. In addition, the effects of dehydration on serum and urine urea nitrogen, creatinine and various electrolytes as well as the effects of dehydration on acid-base status were studied.Following water deprivation sufficient to produce 12–15% decrease in body weight, 95% of the normal horses should have a Usg of at least 1.042, a Uosm of 1310 mOsmg/kg and a urine osmolality/serum osmolality ratio of 4.14.After 72 hours of water deprivation, the mean weight loss was 13.5% of previous body weight. Serum and urine urea nitrogen concentrations increased by 68% and 130%, respectively, while plasma sodium and chloride concentrations increased by 10% and 14%, respectively. In contrast, urine chloride and calcium concentrations decreased by 90.8% and 52.5%, respectively. There was little change in plasma potassium, phosphorus or calcium concentrations. Urine sodium and potassium concentrations increased initially but were near normal after 72 hours of water deprivation. Azotemia developed and was considered to be of extrarenal origin on the basis of normal routine urinalysis and renal clearance ratio of sodium.     

Effects of alpha2-adrenergic receptor agonists on urine production in horses deprived of food and water

OBJECTIVE: To quantitate the dose- and time-related effects of IV administration of xylazine and detomidine on urine characteristics in horses deprived of feed and water. ANIMALS: 6 horses. PROCEDURE: Feed and water were withheld for 24 hours followed by i.v. administration of saline (0.9% NaCI) solution, xylazine (0.5 or 1.0 mg/kg), or detomidine (0.03 mg/kg). Horses were treated 4 times, each time with a different protocol. Following treatment, urine and blood samples were obtained at 15, 30, 60, 120, and 180 minutes. Blood samples were analyzed for PCV and serum concentrations of total plasma solids, sodium, and potassium. Urine samples were analyzed for pH and concentrations of glucose, proteins, sodium, and potassium. RESULTS: Baseline (before treatment) urine flow was 0.30 +/- 0.03 mL/kg/h and did not significantly change after treatment with saline solution and low-dose xylazine but transiently increased by 1 hour after treatment with high-dose xylazine or detomidine. Total urine output at 2 hours following treatment was 312 +/- 101 mL versus 4,845 +/- 272 mL for saline solution and detomidine, respectively. Absolute values of urine concentrations of sodium and potassium also variably increased following xylazine and detomidine administration. CONCLUSIONS AND CLINICAL RELEVANCE: Xylazine and detomidine administration in horses deprived of feed and water causes transient increases in urine volume and loss of sodium and potassium. Increase in urine flow is directly related to dose and type of alpha2-adrenergic receptor agonist. Dehydration in horses may be exacerbated by concurrent administration of alpha2-adrenergic receptor agonists.     

Blood precipitate associated with intra-abdominal carboxymethylcellulose administration

A precipitate was observed on the blood films of horses (15 of 16) and one cow given a peritoneal infusion of 1 % sodium carboxymethylcellulose (SCMC) solution to prevent abdominal adhesions. The intensity of the precipitate seen 2 to 3 days post-infusion strongly correlated with the administered dose of SCMC (range 0.96 to 11.7 ml/kg). The dose given was inversely correlated with bodyweight and the most prominent precipitates were seen in foals. The precipitate was observed as early as 24 hours and persisted for as long as 9 days after SCMC administration. Fibrinogen was the only hematological or biochemical parameter consistently abnormal in horses receiving SCMC, mild increases (500 to 700 mg/dl) were noted in 11/16 cases but did not correlate with SCMC administration.     

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.     

Effects of glycopyrrolate on cardiorespiratory function in horses anesthetized with halothane and xylazine

OBJECTIVE: To evaluate cardiopulmonary effects of glycopyrrolate in horses anesthetized with halothane and xylazine. ANIMALS: 6 horses. PROCEDURE: Horses were allocated to 2 treatment groups in a randomized complete block design. Anesthesia was maintained in mechanically ventilated horses by administration of halothane (1% end-tidal concentration) combined with a constant-rate infusion of xylazine hydrochloride (1 mg/kg/h, i.v.). Hemodynamic variables were monitored after induction of anesthesia and for 120 minutes after administration of glycopyrrolate or saline (0.9% NaCl) solution. Glycopyrrolate (2.5 microg/kg, i.v.) was administered at 10-minute intervals until heart rate (HR) increased at least 30% above baseline or a maximum cumulative dose of 7.5 microg/kg had been injected. Recovery characteristics and intestinal auscultation scores were evaluated for 24 hours after the end of anesthesia. RESULTS: Cumulative dose of glycopyrrolate administered to 5 horses was 5 microg/kg, whereas 1 horse received 7.5 microg/kg. The positive chronotropic effects of glycopyrrolate were accompanied by an increase in cardiac output, arterial blood pressure, and tissue oxygen delivery. Whereas HR increased by 53% above baseline values at 20 minutes after the last glycopyrrolate injection, cardiac output and mean arterial pressure increased by 38% and 31%, respectively. Glycopyrrolate administration was associated with impaction of the large colon in 1 horse and low intestinal auscultation scores lasting 24 hours in 3 horses. CONCLUSIONS AND CLINICAL RELEVANCE: The positive chronotropic effects of glycopyrrolate resulted in improvement of hemodynamic function in horses anesthetized with halothane and xylazine. However, prolonged intestinal stasis and colic may limit its use during anesthesia.     

Pharmacokinetics and clinical utility of sodium bromide (NaBr) as an estimator of extracellular fluid volume in horses

The purpose of this study was to describe the pharmacokinetics of bromide in horses and to evaluate the corrected bromide space as an indicator of extracellular fluid volume (ECFV) in horses after the administration of a single dose of bromide by intravenous infusion. Sodium bromide (30 mg/kg of body weight, IV) was administered to 6 clinically healthy mares over a period of 3 minutes. Blood samples were collected before infusion and at intervals between 0.5 hours and 53 days after infusion. Mean elimination half-life (harmonic mean) was 126 hours (5.2 days), clearance was 1.4 +/- 0.09 mL/(kg x h), area under the curve was 17,520 +/- 1,100 microg x h/mL. and volume of distribution (steady state) was 0.255 +/- 0.015 L/kg. The mean corrected bromide space was determined from the volume of distribution (steady state) and the serum concentrations of bromide at equilibration. Corrected bromide space, an estimate of ECFV, was 0.218 +/- 0.01 L/kg. The conclusion was made that ECFV of horses can be estimated by measuring bromide concentrations in a preinfusion serum sample and a sample obtained 5 hours after the administration of bromide.     

Effects of dietary yeast culture supplementation during the conditioning period on equine exercise physiology

Two groups of previously unconditioned young adult horses participated in 6 weeks of gradually increasing exercise on an inclined plane treadmill while receiving a cornoats-hay diet with or without a commercially available dietary yeast culture preparation. Forced treadmill exercise at a workload of 11.98 j/kg/m, equivalent to a workrate of 18.34 j/sec/kg and an estimated ground speed of 5.36 m/sec, began at 5 minutes per day (2.75 Mjoules/500 kg body-weight) and was increased by 5 minutes per week to a maximum of 35 minutes per day (19.25 Mjoules/500 kg) after 6 weeks. Treadmill exercise increased venous plasma lactate concentrations in direct proportion to the duration of an exercise bout, but the increases tended to be smaller after a given amount of work as the horses became conditioned. At the end of 35 minutes of exercise, plasma lactate concentrations averaged 30.08 mg/dl in the supplemented horses and 41.29 mg/dl in the unsupplemented horses (p<.01). Plasma glucose concentrations decreased significantly and triglyceride concentrations increased significantly in both groups as exercise duration exceed 10 minutes. Changes in plasma glucose concentrations were not significantly affected by yeast culture supplementation, while the supplemented horses exhibited somewhat slower rates of increased plasma triglyceride concentrations. During the 35-minute exercise bouts, significantly lower heart rates were recorded in the supplemented horses during the first 5 and the final 10 minutes of the workouts (p<.01), suggesting an enhanced state of athletic fitness. The digestible energy required for work (Mcal/500 kg bodyweight) was calculated to be 0.454 (Mcal/Mjoule) (Mjoules of work/500 kg bodyweight) + 0.024 Mcal/500 kg bodyweight (r²=0.95), with an efficiency of converting dietary DE to work of 53% for both groups of horses. Although the exercise challenges to these horses were not severe, these results suggest that dietary yeast culture supplementation of horses entering into conditioning programs may well enhance athletic training.     

Comparison of an orally administered gastrointestinal lavage solution with traditional enema administration as preparation for colonoscopy in dogs

Forty dogs were randomly assigned to be given either multiple enemas (group A) or orally administered lavage solution (group B) before colonoscopy. Dogs of group A (n = 20) were given 3 large-volume warm-water enemas 6 hours apart, with the last enema given 9 to 15 hours before colonoscopy. Dogs of group B (n = 20) were given a total dose of 50 ml of the lavage solution/kg of body weight through an orogastric tube. The lavage solution was administered in 2 doses of 25 ml/kg given 1 hour apart, 12 to 18 hours before colonoscopy. Dogs were monitored for changes in body weight and in serum sodium, potassium, chloride, calcium, phosphate, urea nitrogen, creatinine, and total CO2 concentrations. Colonoscopy was performed on dogs under general anesthesia by an investigator blinded as to the method of preparation, and the quality of preparation was subjectively evaluated. The quality of colon preparation was significantly (P less than 0.005) better after administration of oral lavage solution, compared with that after multiple enemas. There were minimal changes in laboratory values, side-effects were minimal, and biopsy specimen artifacts were not seen. Because proper patient preparation is necessary for complete colonoscopic examination, results suggested that an orally administered polyethylene glycol-containing electrolyte solution is preferable to administration of multiple enemas in preparing dogs for colonoscopy.     

Plasma disposition,faecal excretion and in vitro metabolism of oxibendazole following oral administration in horses

Oxibendazole (OBZ) was administered to eight horses at an oral dose of 10 mg kg(-1) bodyweight each. Parent OBZ could only be detected in plasma at the 0.5 and 1.0 hours post administration sampling times and the mean maximum plasma concentration was 0.008 microg ml(-1). Parent OBZ was detected in faeces between 12 and 72 hours after administration and the highest dry faecal concentration was detected at 24 hours. An unidentified metabolite was detected in plasma between 0.5 and 72 hours. The unidentified metabolite in the plasma of treated horses corresponded to the second eluted metabolite in the in vitro study. Metabolism of OBZ to its metabolite in vitro was significantly inhibited by co-incubation with the cytochrome P450 inhibitor piperonyl butoxide. These results indicated that first-pass metabolism decreases OBZ bioavailability in horses. The in vitro metabolism of OBZ was significantly inhibited by piperonyl butoxide and this could be utilised to extend the exposure of nematodes to the parent molecule.     

Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite after oral and intravenous administration of pentoxifylline to healthy adult horses

OBJECTIVE: To determine serum pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite in horses after administration of a single IV dose and after single and multiple oral doses. ANIMALS: 8 healthy adult horses. PROCEDURES: A crossover study design was used with a washout period of 6 days between treatments. Treatments were IV administration of a single dose of pentoxifylline (8.5 mg/kg) and oral administration of generic sustained-release pentoxifylline (10 mg/kg, q 12 h, for 8 days). Blood samples were collected 0, 1, 3, 6, 12, 20, 30, and 45 minutes and 1, 2, 4, 6, 8, and 12 hours after IV administration. For oral administration, blood samples were collected 0, 0.25, 0.5, 0.75, 1, 2, 4, 8, and 12 hours after the first dose and 0, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 hours after the last dose. RESULTS: Elimination of pentoxifylline was rapid after IV administration. After oral administration, pentoxifylline was rapidly absorbed and variably eliminated. Higher serum concentrations of pentoxifylline and apparent bioavailability were observed after oral administration of the first dose, compared with values after administration of the last dose on day 8 of treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, oral administration of 10 mg of pentoxifylline/kg results in serum concentrations equivalent to those observed for therapeutic doses of pentoxifylline in humans. Twice daily administration appears to be appropriate. However, serum concentrations of pentoxifylline appear to decrease with repeated dosing; thus, practitioners may consider increasing the dosage if clinical response diminishes with repeated administration.     

Theophylline and dyphylline pharmacokinetics in the horse

The pharmacokinetics of theophylline and dyphylline were determined after IV administration in horses. In a preliminary experiment, the usual human dosage (milligram per kilogram) of each drug was given to 1 horse. Results were used to calculate dosages for a cross-over study, using 6 horses for each drug. Theophylline plasma concentrations decreased triexponentially in 5 of 6 healthy horses after IV infusion of 10 mg of aminophylline/kg of body weight for 16 to 32 minutes. In the 6 horses, total body elimination rate constants were variable, and the half-life of theophylline was 9.7 to 19.3 hours. Clearance was 42.3 to 69.2 ml/hr/kg. The initial distribution phase was rapid (t1/2 approx 3.5 to 4 minutes); a 2nd distribution phase was slower (t1/2 approx 1.5 to 2 hours). Plasma concentrations of theophylline were in the assumed effective range (10 to 20 micrograms/ml) from 15 minutes until 40 minutes after time zero. The mean apparent volume of distribution was 1.02 L/kg. After bolus IV injection of dyphylline (20 mg/kg), pharmacokinetics were best described by a 2-compartment open model in 2 horses and by a 3-compartment open model in 4 horses. In the 6 horses, elimination half-life of dyphylline was 1.9 to 2.9 hours, and clearance was 200 to 320 ml/hr/kg. Plasma concentrations (approx 50 micrograms/ml) were observed at 10 minutes after injection without adverse effects. Concentrations greater than 10 micrograms/ml were observed from time zero to about 1.5 hours after injection. Theophylline induced significant increases in heart rate, but dyphylline did not affect heart rate significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of safety and pharmacokinetics of vancomycin after intraosseous regional limb perfusion and comparison of results with those obtained after intravenous regional limb perfusion in horses

OBJECTIVE: To evaluate the clinical effects and pharmacokinetics of vancomycin in plasma and synovial fluid after intraosseous regional limb perfusion (IORLP) in horses and to compare results with those obtained after IV regional limb perfusion (IVRLP). ANIMALS: 6 horses. PROCEDURES: 1 forelimb of each horse received vancomycin hydrochloride (300 mg in 60 mL of saline [0.9% NaCl] solution) via IORLP; the contralateral limb received 60 mL of saline solution (control). Solutions were injected into the medullary cavity of the distal portion of the third metacarpal bone. Synovial fluid from the metacarpophalangeal (MTCP) and distal interphalangeal (DIP) joints and blood were collected prior to perfusion and 15, 30, 45, 65, and 90 minutes after beginning IORLP, and synovial fluid from the MTCP joint only and blood were collected 4, 8, 12, and 24 hours after beginning IORLP. Plasma urea and creatinine concentrations and clinical appearance of the MTCP joint region and infusion sites were determined daily for 7 days. Results were compared with those of a separate IVRLP study. RESULTS: Clinical complications were not observed after IORLP. Mean vancomycin concentration in the MTCP joint was 4 microg/mL for 24 hours after IORLP. Compared with IORLP, higher vancomycin concentrations were detected in the DIP joint after IVRLP. Compared with IVRLP, higher vancomycin concentrations were detected in the MTCP joint for a longer duration after IORLP. CONCLUSIONS AND CLINICAL RELEVANCE: IORLP with 300 mg of vancomycin in a 0.5% solution was safe and may be clinically useful in horses. Intravenous and intraosseous routes may be better indicated for infectious processes in the DIP and MTCP joints, respectively.     

Concentrations of gentamicin in serum and bronchial lavage fluid after intravenous and aerosol administration of gentamicin to horses

OBJECTIVE: To compare concentrations of gentamicin in serum and bronchial lavage fluid after IV and aerosol administration of gentamicin to horses. ANIMALS: 9 healthy adult horses. PROCEDURE: Gentamicin was administered by aerosolization (20 ml of gentamicin solution [50 mg/ml]) and IV injection (6.6 mg of gentamicin/kg of body weight) to each horse, with a minimum of 2 weeks between treatments. Samples of pulmonary epithelial lining fluid were collected by small volume (30 ml) bronchial lavage 0.5, 4, 8, and 24 hours after gentamicin administration. Serum samples were obtained at the same times. All samples were analyzed for gentamicin concentration, and cytologic examinations were performed on aliquots of bronchial lavage fluid collected at 0.5, 8, and 24 hours. RESULTS: Gentamicin concentrations in bronchial lavage fluid were significantly greater 0.5, 4, and 8 hours after aerosol administration, whereas serum concentrations were significantly less at all times after aerosol administration, compared with IV administration. Neutrophil counts in bronchial lavage fluid increased from 0.5 to 24 hours, regardless of route of gentamicin administration. CONCLUSIONS AND CLINICAL RELEVANCE: Aerosol administration of gentamicin to healthy horses resulted in gentamicin concentrations in bronchial fluid that were significantly greater than those obtained after IV administration. A mild inflammatory cell response was associated with aerosol delivery of gentamicin and repeated bronchial lavage. Aerosol administration of gentamicin may have clinical use in the treatment of bacterial bronchopneumonia in horses.     

Plasma and urine nitric oxide concentrations in horses given below a low dose of endotoxin.

OBJECTIVE: To quantify plasma and urine nitric oxide (NO) concentrations before and after low-dose endotoxin infusion in horses. ANIMALS: 11 healthy adult female horses. Procedure-Eight horses were given endotoxin (35 ng/kg of body weight,i.v.) over 30 minutes. Three sentinel horses received an equivalent volume of saline (0.9% NaCl) solution over the same time. Clinical signs of disease and hemodynamic variables were recorded, and urine and plasma samples were obtained to measure NO concentrations prior to endotoxin infusion (t = 0) and every hour until postinfusion hour (PIH) 6, then every 2 hours until PIH 24. Blood for hematologic and metabolic analyses and for serum cytokine bioassays were collected at 0 hour, every hour until PIH 6, every 2 hours through PIH 12, and finally, every 6 hours until PIH 24. RESULTS: Differences in plasma NO concentrations across time were not apparent, but urine NO concentrations significantly decreased at 4 and 20 to 24 hours in endotoxin-treated horses. Also in endotoxin-treated horses, alterations in clinical signs of disease, and hemodynamic, metabolic, and hematologic variables were significant and characteristic of endotoxemia. Serum interleukin-6 (IL-6) activity and tumor necrosis factor (TNF) concentrations were increased above baseline values from 1 to 8 hours and 1 to 2 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma and urine NO concentrations did not increase in horses after administration of a low dose of endotoxin, despite induction of an inflammatory response, which was confirmed by increased TNF and IL-6 values characteristic alterations in clinical signs of disease, and hematologic, hemodynamic and metabolic variables.     

Effect of hypertonic and isotonic saline solutions on plasma constituents of conscious horses.

Blood constituents and vascular volume indices were determined in 5 standing horses by use of 2-period crossover experimental design. Horses were either administered hypertonic (2,400 mosm/kg of body weight, i.v.) or isotonic (300 mosm/kg, i.v.) saline solution. Each solution was administered at a dosage of 5 ml/kg (infusion rate, 80 ml/min). Samples for determination of PCV, plasma volume, blood volume, plasma osmolality, total amount of plasma protein and plasma concentrations of protein, Na, K, and Cl were collected at 0 hour (baseline, before fluid infusion) and 0.5 hour (at the end of fluid infusion), and subsequently, at 0.25- or 0.5-hour intervals for 4.5 hours. All horses were given the predetermined dose of fluids by 0.5 hour after beginning the saline infusion. Values of P < or = 0.05 were considered significant. Administration of hypertonic saline solution was associated with decreased mean body weight by 4.5 hours, but weight change after isotonic saline administration was not significant. Other than body weight and plasma protein concentration, between-trial difference (treatment effect) was not observed for any measured variable or index. The F values indicated that increasing the number of horses would have not changed these results. A time effect was evident across both trials, so that mean (+/- SD) plasma volume increased (12.3 +/- 1.07%) and mean plasma protein concentration (-12.1 +/- 1.03%) and PCV (-11.9 + 0.67%) decreased proportionately and transiently in association with administration of either fluid at that volume. Other time effects included increased plasma osmolality and Na and Cl concentrations. Blood volume estimates and total amount of plasma protein remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of montelukast in the treatment of chronic obstructive pulmonary disease in five horses

Five horses with moderate to severe chronic obstructive pulmonary disease (COPD) were treated with 0.11 (0.01) mg/kg bodyweight of montelukast, a cysteinyl leukotriene receptor antagonist, once a day for 26 days. The horses were evaluated clinically and endoscopically and subjected to arterial blood gas analysis and lung function tests before and after the period of treatment, and the plasma concentrations of montelukast were determined by high-performance liquid chromatography with fluorescence detection. The treatment did not result in statistically significant differences in the total scores of clinical and endoscopical signs, or in the difference in the arterioalveolar partial pressure of oxygen, maximal changes in pleural pressure, pulmonary resistance or dynamic compliance. The mean (sd) peak plasma concentration (C(max0) of montelukast was 12 (4) ng/ml and was reached 66 (13) minutes (t(max)) after its oral administration. The dose of montelukast per kg bodyweight was approximately the same as that for human beings, but the C(max) in the horses was 28 times lower and the t(max) was reached in one-fifth of the time, suggesting that its oral bioavailability may be lower.     

Evaluation of polymyxin B in an ex vivo model of endotoxemia in horses

OBJECTIVE: To evaluate effects of polymyxin B sulfate (PMB) on response of horses to endotoxin, using an ex vivo model. ANIMALS: 8 healthy horses. PROCEDURE: In a crossover design, 3 doses of PMB (100, 1,000, and 10,000 U/kg of body weight) and physiologic saline solution (control) were evaluated. Prior to and for 24 hours after administration of PMB, blood samples were collected into heparinized tubes for use in 2 assays. For the endotoxin-induced tumor necrosis factor (TNF) assay, blood samples were incubated (37 C for 4 h) with 1 ng of Escherichia coli or Salmonella Typhimurium endotoxin/ml of blood. Plasma was harvested and assayed. For the residual endotoxin activity assay, plasma was collected into sterile endotoxin-free borosilicate tubes, diluted 1:10 with pyrogen-free water, and incubated for 10 minutes at 70 C. Escherichia coli endotoxin (0.1 or 1 ng/ml of plasma) was added to the thawed samples prior to performing the limulus ameobocyte lysate assay. Serum creatinine concentrations were monitored for 1 week. RESULTS: Compared with baseline values, PMB caused a significant dose- and time-dependent decrease in endotoxin-induced TNF activity. Compared with baseline values, residual endotoxin activity was significantly reduced after administration of 10,000 U of PMB/kg. Compared with baseline values, 1,000 and 5,000 U of PMB/kg should inhibit 75% of endotoxin-induced TNF activity for 3 and 12 hours, respectively. Serum creatinine concentrations remained within the reference range. CONCLUSION AND CLINICAL RELEVANCE: Results of the study suggest that PMB is a safe, effective inhibitor of endotoxin-induced inflammation in healthy horses.     

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)