Pharmacokinetics, disposition, and plasma concentrations of dimethyl sulfoxide (DMSO) in the horse following topical, oral, and intravenous administration.

Compartmental models were used to investigate the pharmacokinetics of intravenous (i.v.), oral (p.o.), and topical (TOP) administration of dimethyl sulfoxide (DMSO). The plasma concentration-time curve following a 15-min i.v. infusion of DMSO was described by a two-compartment model. Median and range of alpha (t1/2α ) and beta (t1/2ß ) half-lives were 0.029 (0.026-0.093) and 14.1 (6.6-16.4) hr, respectively. Plasma concentration-time curves of DMSO following p.o. and TOP administration were best described by one-compartment absorption and elimination models. Following the p.o. administration, median absorption (t1/2ab ) and elimination (t1/2e ) half-lives were 0.15 (0.01-0.77) and 15.5 (8.5-25.2) hr, respectively. The plasma concentrations of DMSO were 47.4-129.9 µg/ml, occurring between 15 min and 4 hr. The fractional absorption (F) during a 24-hr period was 47.4 (22.7-98.1)%. Following TOP administrations, the median t1/2ab and t1/2e were 1.2 (0.49-2.3) and 4.5 (2.1-11.0) hr, respectively. Plasma concentrations were 1.2-8.2 µg/ml occurring at 2-4 hr. Fractional absorption following TOP administration was 0.48 (0.315-4.4)% of the dose administered. Clearance (Cl) of DMSO following the i.v. administration was 3.2 (2.2-6.7) ml hr-1  kg-1 . The corrected clearances (ClF ) for p.o. and TOP administrations were 2.9 (1.1-5.5) and 4.5 (0.52-18.2) ml hr-1  kg-1 .

Pharmacokinetics and pharmacodynamics of dermorphin in the horse.

Dermorphin is a µ-opioid receptor-binding peptide that causes both central and peripheral effects following intravenous administration to rats, dogs, and humans and has been identified in postrace horse samples. Ten horses were intravenously and/or intramuscularly administered dermorphin (9.3 ± 1.0 µg/kg), and plasma concentration vs. time data were evaluated using compartmental and noncompartmental analyses. Data from intravenous administrations fit a 2-compartment model best with distribution and elimination half-lives (harmonic mean ± pseudo SD) of 0.09 ± 0.02 and 0.76 ± 0.22 h, respectively. Data from intramuscular administrations fit a noncompartmental model best with a terminal elimination half-life of 0.68 ± 0.24 (h). Bioavailability following intramuscular administration was variable (47-100%, n = 3). The percentage of dermorphin excreted in urine was 5.0 (3.7-10.6) %. Excitation accompanied by an increased heart rate followed intravenous administration only and subsided after 5 min. A plot of the mean change in heart rate vs. the plasma concentration of dermorphin fit a hyperbolic equation (simple Emax model), and an EC(50) of 21.1 ± 8.8 ng/mL was calculated. Dermorphin was detected in plasma for 12 h and in urine for 48 or 72 h following intravenous or intramuscular administration, respectively.

Pharmacokinetics of dexamethasone following intra-articular, intravenous, intramuscular, and oral administration in horses and its effects on endogenous hydrocortisone.

This study investigated and compared the pharmacokinetics of intra-articular (IA) administration of dexamethasone sodium phosphate (DSP) into three equine joints, femoropatellar (IAS), radiocarpal (IAC), and metacarpophalangeal (IAF), and the intramuscular (IM), oral (PO) and intravenous (IV) administrations. No significant differences in the pharmacokinetic estimates between the three joints were observed with the exception of maximum concentration (Cmax ) and time to maximum concentration (Tmax ). Median (range) Cmax for the IAC, IAF, and IAS were 16.9 (14.6-35.4), 23.4 (13.5-73.0), and 46.9 (24.0-72.1) ng/mL, respectively. The Tmax for IAC, IAF, and IAS were 1.0 (0.75-4.0), 0.62 (0.5-1.0), and 0.25 (0.08-0.25) h, respectively. Median (range) elimination half-lives for IA and IM administrations were 3.6 (3.0-4.6) h and 3.4 (2.9-3.7) h, respectively. A 3-compartment model was fitted to the plasma dexamethasone concentration-time curve following the IV administration of DSP; alpha, beta, and gamma half-lives were 0.03 (0.01-0.05), 1.8 (0.34-2.3), and 5.1 (3.3-5.6) h, respectively. Following the PO administration, the median absorption and elimination half-lives were 0.34 (0.29-1.6) and 3.4 (3.1-4.7) h, respectively. Endogenous hydrocortisone plasma concentrations declined from a baseline of 103.8 ± 29.1-3.1 ± 1.3 ng/mL at 20.0 ± 2.7 h following the administration of DSP and recovered to baseline values between 96 and 120 h for IV, IA, and IM administrations and at 72 h for the PO.

The use of phenylbutazone in the horse.

This review presents a brief historical prospective of the genesis of regulated medication in the US racing industry of which the nonsteroidal anti-inflammatory drug (NSAID) phenylbutazone (PBZ) is the focus. It presents some historical guideposts in the development of the current rules on the use of PBZ by racing jurisdictions in the US. Based on its prevalent use, PBZ remains a focus of attention. The review examines the information presented in a number of different models used to determine the effects and duration of PBZ in the horse. They include naturally occurring lameness and reversible-induced lameness models that directly examine the effects and duration of the administration of various doses of PBZ. The review also examines indirect plasma and tissue models studying the suppression of the release of arachidonic acid-derived mediators of inflammation. The majority of studies suggest an effect of PBZ at 24 h at 4.4 mg/kg. This reflects and substantiates the opinion of many clinical veterinarians, many of whom will not perform a prepurchase lameness examination unless the horse is free of NSAID. This remains the opinion of many regulatory veterinarians responsible for the prerace examination of race horses that they wish to examine a horse without the possibility of an NSAID interfering with the examination and masking possible musculoskeletal conditions. Based on scientific studies, residual effects of PBZ remain at 24 h. The impact of sustained effect on the health and welfare of the horse and its contribution to injuries during competition remains problematic.

Plasma concentrations of testosterone and nandrolone in racing and nonracing intact male horses.

Pennsylvania (PA) State Racing Commissions regulate the endogenous androgenic steroid, testosterone (TES), in racing intact males (RIM) by quantification of TES in post-race samples. Post-race plasma samples (2209) collected between March 2008 and November 2010 were analyzed for TES, nandrolone (NAN), and other anabolic steroids (ABS). Of the 2209 plasma samples, 2098 had quantifiable TES ≥ 25 pg/mL. Plasma (mean ± SD) concentrations of TES and NAN in RIM were 329.2 ± 266.4 and 96.0 ± 67.8 pg/mL, respectively. Only 64.6% of RIM had quantifiable concentration of NAN, and there was no relationship between TES and NAN. Plasma TES concentrations were significantly (P < 0.0001) higher during the months of April, May, June, July, and August. A significantly higher (P < 0.006) plasma TES was observed in Thoroughbred (TB) (347.6 ± 288.5 pg/mL) vs. that in Standardbred (STB) (315.4 ± 247.7 pg/mL). Plasma concentrations of TES from breeding stallions (BS) were 601.6 ± 356.5 pg/mL. Statistically significant (P < 0.0001) lower plasma concentrations of the two steroids were observed in RIM horses. Based on quantile distribution of TES in the RIM and BS populations, 99.5% were at or below 1546.1 and 1778.0 pg/mL, respectively. Based on this population of RIM, the suggested upper threshold plasma concentration of endogenous TES in horses competing in PA should remain at 2000 pg/mL.

Pharmacokinetic profile and pharmacodynamic effects of romifidine hydrochloride in the horse.

Romifidine HCl (romifidine) is an α(2)-agonist commonly used in horses. This study was undertaken to investigate the pharmacokinetics (PK) of romifidine following intravenous (i.v.) administration and describe the relationship between PK parameters and simultaneously recorded pharmacodynamic (PD) parameters. Romifidine (80 µg/kg) was administered by i.v. infusion over 2 min to six adult Thoroughbred horses, and plasma samples were collected and analyzed using liquid chromatography-mass spectrometry. Limit of quantification was <0.1 ng/mL. PD parameters and arterial blood gases were measured for 300 min following romifidine administration. Statistical PD data analysis included mixed-effect modeling. After i.v. administration of romifidine, the plasma concentration-vs.-time curve was best described by a two-compartmental model. Terminal elimination half-life (t(1/2ß) ) was 138.2 (104.6-171.0) min and volumes for central (V(c)) and peripheral (V(2)) compartments were 1.89 (0.93-2.39) and 2.57 (1.71-4.19) L/kg, respectively. Maximum plasma concentration (C(max)) was 51.9 ± 13.1 ng/mL measured at 4 min following commencement of drug administration. Systemic clearance (Cl) was 32.4 (25.5-38.4) mL · min/kg. Romifidine caused a significant reduction in heart rate and cardiac index and an increase in mean arterial pressure (P < 0.05). Sedation score and head height values were significantly different from the baseline values for 120 min (P < 0.05). The decline in cardiovascular and sedative effects correlated with the decline in plasma romifidine concentration (P < 0.05). In conclusion, a highly sensitive analytical technique for the detection of romifidine in equine plasma allowed detailed description of its PK profile. The drug produces long-lasting sedation in horses that corresponds with the long terminal elimination half-life of the drug.

Pharmacokinetic profile and behavioral effects of gabapentin in the horse.

Gabapentin is being used in horses although its pharmacokinetic (PK) profile, pharmacodynamic (PD) effects and safety in the equine are not fully investigated. Therefore, we characterized PKs and cardiovascular and behavioral effects of gabapentin in horses. Gabapentin (20 mg/kg) was administered i.v. or p.o. to six horses using a randomized crossover design. Plasma gabapentin concentrations were measured in samples collected 0-48 h postadministration employing liquid chromatography-tandem mass spectrometry. Blood pressures, ECG, and sedation scores were recorded before and for 12 h after gabapentin dosage. Nineteen quantitative measures of behaviors were evaluated. After i.v. gabapentin, the decline in plasma drug concentration over time was best described by a 3-compartment mammillary model. Terminal elimination half-life (t(1/2γ) ) was 8.5 (7.1-13.3) h. After p.o. gabapentin terminal elimination half-life () was 7.7 (6.7-11.9) h. The mean oral bioavailability of gabapentin (± SD) was 16.2 ± 2.8% indicating relatively poor absorption of gabapentin following oral administration in horses. Gabapentin caused a significant increase in sedation scores for 1 h after i.v. dose only (P < 0.05). Among behaviors, drinking frequency was greater and standing rest duration was lower with i.v. gabapentin (P < 0.05). Horses tolerated both i.v. and p.o. gabapentin doses well. There were no significant differences in and . Oral administration yielded much lower plasma concentrations because of low bioavailability.

Inflammatory mediators are potential biomarkers for extracorporeal shockwave therapy in horses.

BACKGROUND: Extracorporeal shockwave therapy (ESWT) can potentially mask painful injuries in equine athletes. Tests to detect whether a horse has received ESWT prior to competition are needed. Extracorporeal shockwave therapy is known to affect inflammatory mediators in other species, and if these mediators are altered in the horse, these could serve as biomarkers of ESWT. OBJECTIVES: To test the hypothesis that a single application of ESWT will alter the circulating protein concentrations of 10 inflammatory mediators in horse plasma. STUDY DESIGN: Prospective repeated measures experimental study. METHODS: Eleven healthy horses were administered a single dose of ESWT on the dorsal surface of proximal MCIII. Blood samples were collected at -168, -144, -120, -96, -72, -70, -68, -66, -48, -24, -6, -4, -2, 0 h before and 2, 4, 6, 24, 48, 72, 96, 168, 336 and 504 h after ESWT. Plasma concentrations of interleukin 1 beta (IL-1ß), IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-10, IL-15, interferon gamma (IFN-γ), soluble toll-like receptor 2 (sTLR2) and tumour necrosis factor alpha (TNF-α) were measured to assess the effects of ESWT on these mediators. RESULTS: Baseline concentrations of inflammatory mediators did not change substantially during the week prior to ESWT. Plasma concentrations of five inflammatory factors changed following ESWT. IL-1ß and IL-6 were significantly down-regulated (P<0.01), while TNF-α, IL-1RA and TLR2 were significantly up-regulated (P<0.01). The remaining cytokines were not significantly affected by ESWT. MAIN LIMITATIONS: This study was performed in a small number of sedentary, healthy pasture-kept horses using a single dose of ESWT applied to a single location. Additional studies are necessary to determine the effect of ESWT on inflammatory mediators in athletic horses undergoing treatment for musculoskeletal injuries. CONCLUSIONS: Plasma concentrations of TNF-α, IL-1ß, IL-1RA, IL-6 and TLR2 were significantly affected by ESWT, and deserve further investigation as possible biomarkers of ESWT.

Occurrence of cardiac arrhythmias in Standardbred racehorses.

REASONS FOR PERFORMING STUDY: Cardiac arrhythmias are a recognised but poorly characterised problem in the Standardbred racehorse. Frequency data could aid the development of cardiac arrhythmia screening programmes. OBJECTIVES: To characterise the occurrence of cardiac arrhythmias in Standardbreds prior to racing and in the late post race period using a handheld, noncontinuous recording device. STUDY DESIGN: Prospective, observational study, convenience sampling. METHODS: Noncontinuous electrocardiographic recordings were obtained over a 12 week period from Standardbred horses competing at a single racetrack. Electrocardiograms were obtained before racing and between 6 and 29 min after the race using a handheld recording device. Prevalence of arrhythmias was calculated for all horses and overall frequency of arrhythmias was calculated for race starts and poor performers. Univariate logistic regression analysis was used to identify risk factors for cardiac arrhythmias. RESULTS: A total of 8657 electrocardiogram recordings were obtained from 1816 horses. Six horses had atrial fibrillation after racing (prevalence = 0.11%, frequency = 0.14%), one horse had supraventricular tachycardia before racing (prevalence = 0.06%, frequency = 0.02%), and 2 horses had ventricular tachyarrhythmias after racing (prevalence = 0.06%, frequency = 0.05%). The frequency of atrial fibrillation among race starts with poor performance was 1.3-2.0%. Increasing age was a significant risk factor for the presence of atrial premature contractions before racing and atrial fibrillation and ventricular ectopy after racing. CONCLUSIONS: Both physiological and pathological cardiac arrhythmias can be detected in apparently healthy Standardbred horses in the prerace and late post race period using noncontinuous recording methods. Future studies should examine cumulative training or racing hours as a risk factor for cardiac arrhythmia. The prevalence and frequency information may be useful for track veterinarians and regulatory personnel following trends in cardiac arrhythmias.

AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.

Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P <0.05) in blood glucose and an increase (P <0.05) in insulin concentration without a change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P <0.05) in skeletal muscle. While GLUT4 and GLUT1 protein expression remained unchanged, GLUT8 was increased (P <0.05) following AICAR treatment. Up-regulation of GLUT8 protein expression by AICAR suggests that this novel GLUT isoform plays an important role in equine muscle glucose transport. In addition, the data suggest that AMPK activation enhances pancreatic insulin secretion. Collectively, the findings suggest that AICAR acutely promotes muscle glucose uptake in healthy horses and thus its therapeutic potential for managing IR requires investigation.

Anesthetic and analgesic considerations in the experimental animal.

Many new compounds and combinations of many of the more traditional drugs have been used in a wide range of species. This, plus the rapid development in equipment for inhalational anesthesia, has simplified the restraint, anesthetic, post-surgical, and analgesic management of experimental animals.

Characterization of bromhexine and ambroxol in equine urine: effect of furosemide on identification and confirmation.

The purpose of this study was two-fold: (1) to develop a simple and sensitive screening procedure for identifying and confirming bromhexine and ambroxol and, (2) to determine the effect of furosemide on the detection of bromhexine, ambroxol, or their metabolites in urine. Female horses (450-550 kg) treated with bromhexine or ambroxol (1 g, p.o.) were used. Urine samples were collected up to 48 h post-drug administration and analysed. Blind samples were used in evaluating the sensitivity of these methods and reproducibility of the results. Bromhexine and ambroxol were extensively metabolized in the horse. These agents and their respective metabolites were identified and confirmed using thin-layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS), respectively. Hydroxy-bromhexine and desmethyl-bromhexine were major metabolites found to be unique to bromhexine-treated horses. These metabolites selectively absent from ambroxol-treated horse urine provide a chemical means to distinguish bromhexine from ambroxol administration in horses. These specific metabolites were similarly identified and confirmed in "blind" horse urine samples. The concomitant presence of furosemide (300 mg, i.v.) with bromhexine or ambroxol did not mask the presence of these agents or alter their metabolite profile. By application of the methods described in this study, bromhexine and ambroxol metabolites in horse urine can be easily identified and confirmed.

Prerace venous blood acid-base values in standardbred horses.

The administration of sodium bicarbonate (NaHCO3) or 'milk shakes' to Standardbred horses before racing is widespread. This study analysed nonrace day (CTL) and prerace venous acid-base values from Standardbred horses racing in Pennsylvania (PA) and New Jersey (NJ). Mean +/- s.d. CTL bicarbonate (HCO3) and base excess (BE) values, for a group of horses stabled during the 1993 racing season at Pocono Downs, Pennsylvania, were 28.6 +/- 1.9 and 2.6 +/- 1.7 mmol/l, respectively. In the same population of horses, mean +/- s.d. values for prerace HCO3- and BE values were 33.1 +/- 2.8 and 7.0 +/- 2.3 mmol/l, respectively, for horses administered frusemide (F) 4 h before race time and 31.5 +/- 2.4 and 5.5 +/- 2.0 mmol/l for the horses not administered frusemide (NF). There were differences (P < 0.05) in pHv, PvCO2, HCO3- and BE values between the CTL and prerace samples. The venous acid-base values of the CTL horses were normally distributed. The prerace acid-base values measured during 1993 were not normally distributed, indicating changes due either to the administration of alkalising substances or other manipulations of the horses on race day. Changes in all acid-base values were observed during the subsequent 1994 racing season with further changes observed when horses were placed in a secured stable 8 h before the race. The criteria used in some racing jurisdictions for disqualifying a horse were the elevations in HCO3-, Na+ and pH. The correlation coefficients (r2) for the least squares regression for HCO3- vs. pH and HCO3- vs. Na+ in prerace venous blood samples were 0.31 and 0.21, respectively, indicating a poor relationship between the 3 acid-base values. To discourage the administration of NaHCO3 to horses before a race, the use of a BE value of > or = 10 mmol/l for NF and > or = 12 mmol/l for F was adopted as a single index for the disqualification of horses from a race. The results of this study indicate that the use of a single index and, in this case BE, has curtailed the prerace administration of NaHCO3 to horses.

The effects of frusemide on racing times of Standardbred pacers.

Seven hundred and eighty-eight Standardbred pacers competing in 8378 races at one racetrack were analysed to determine the effects of the administration of prerace frusemide on racing times (RT). Frusemide was administered i.v. 4 h before the race to pacers diagnosed with exercise-induced pulmonary haemorrhage (EIPH). Of the pacers, starting in the 1997 racing season, 32.5% received prerace frusemide. This study demonstrated that administration of frusemide prior to racing significantly decreased RT. There was an overall significant decrease (P<0.00001) in RT of 0.67 s. The overall RT for horses, geldings, and females, were mean +/- s.e 117.91 +/- 0.06, 118.20 +/- 0.03 and 118.86 +/- 0.04, respectively. RT progressively decreased until age 6 and increased thereafter. Horses, geldings and females ran a mean of 0.46, 0.31 and 0.74 s faster, respectively, with prerace administration of frusemide. This decrease in RT following prerace administration was most pronounced in younger pacers. In this study, a greater percentage of older pacers received prerace frusemide; however, the effect of frusemide on RT was decreasing with age. Prerace venous acid-base screening was performed in 2729 of the pacers competing. Pennsylvania Harness Racing Commission Regulations disqualify Standardbreds from racing with a base excess of over 10 and 12 mmol/l for Standardbreds without and with prerace administration of frusemide. The prerace venous acid-base levels were not significantly related to RT and, for those Standardbreds also sampled following the race, there was no correlation between pre- and postrace acid-base status.

Exercise-induced pulmonary hemorrhage in Thoroughbreds after racing and breezing.

Thoroughbred horses (n = 191) were examined with a flexible fiberoptic endoscope within 2 hours of racing on a dirt track; 147 (75.4%) had evidence of exercise-induced pulmonary hemorrhage (EIPH), and 13 (9.0%) had blood at the nostrils. Of 107 Thoroughbreds examined within the same period after breezing, 41 (38.3%) had evidence of EIPH. One horse (2.4%) of this group had blood at the nostrils. Statistical analysis of frequency data showed that a relationship existed between EIPH and the horse's age or distance raced or breezed. Relationship did not exist between EIPH and sex or finishing position. Thoroughbreds were also examined endoscopically after steeplechase, flat turf, and timber races; 67.7% (21/31), 14.3% (2/14), and 66.6% (2/3) of the horses in such races were EIPH-positive, respectively; and 14.3% (3/21), 0% (0/2), and 100% (2/2) of these EIPH-positive horses had blood at the nostrils. Of 32 breezing Thoroughbreds in a 3rd survey, 21 (65.5%) were EIPH-positive. None bled from the nostrils. Endoscopic findings of EIPH are repeatable in the horses, indicating that bleeding is not a random event.

Cardiopulmonary effects of positive end-expiratory pressure in anesthetized, mechanically ventilated ponies.

To investigate the cardiopulmonary effects of positive end-expiratory pressure (PEEP), values of 10, 20, and 30 cm of H2O, were applied to anesthetized, dorsally recumbent, ventilated ponies. After IV induction of general anesthesia, PEEP was superimposed on controlled ventilation with 100% oxygen, and changes in gas exchange and cardiac function were measured. Increasing values of PEEP in these ponies caused a linear increase in the mean (+/- SEM) functional residual capacity, from a control value (zero end-expiratory pressure) of 1.7 +/- 0.24 L to 2.2 +/- 0.31, 2.9 +/- 0.32 and 3.4 +/- 0.3 L at PEEP of 10, 20, and 30 cm of H2O, respectively (P less than 0.05). Paralleling these changes, intrapulmonary shunt fraction decreased significantly (P less than 0.05) from a control value of 12.9 +/- 0.5%, to 7.5 +/- 1.1 and 2.1 +/- 0.6%, at PEEP of 20 and 30 cm of H2O, respectively. Cardiac output was decreased by increasing values of PEEP, from control value of 11.7 +/- 1.56 L/min to 9.9 +/- 1.51, 8.8 +/- 1.33 and 5.62 +/- 0.56 L/min at PEEP of 10, 20, and 30 cm of H2O, respectively. Related to decreasing cardiac output, tissue oxygen delivery also decreased as PEEP was increased, from control value of 2.0 +/- 0.09 L/min to 1.8 +/- 0.07, 1.6 +/- 0.06, and 1.03 +/- 0.04 L/min at PEEP of 10, 20, and 30 cm of H2O, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of frequency and airway pressure on gas exchange during interrupted high-frequency, positive-pressure ventilation in ponies.

Cardiovascular effects and pulmonary gas exchange were compared during conventional mechanical ventilation (CMV) and interrupted high-frequency, positive-pressure ventilation (IHFPPV) in 6 anesthetized ponies in dorsal recumbency. When the peak airway pressure (Paw) was held constant at control values attained during CMV (18 to 20 cm of H2O), and the ventilator frequency of IHFPPV was varied over the range, 2.5 to 12.5 Hz, significant (P less than 0.05) changes from control values were observed only in the ratio of dead-space volume to tidal volume (VD/VT) and in the respiratory minute volume (VE). The mean (+/- SEM) carbon dioxide excretion (VCO2) was 2.12 +/- 0.1 ml/kg/min during IHFPPV. Dead-space ventilation ranged from 40 to 73.7% of total ventilation and increased directly with increasing frequency. The VE also increased, from 89 ml/kg/min at a ventilatory frequency of 2.5 Hz to 145 ml/kg/min at a frequency of 12.5 Hz. Maintaining the frequency of IHFPPV constant at 12.5 Hz and increasing the Paw over the range of 5 to 30 cm of H2O caused significant (P less than 0.05) changes in arterial partial pressure of O2 (PaO2), VCO2, pulmonary shunt fraction (QS/QT), VE, arterial-alveolar differences in oxygen tension (AaDO2), VD/VT, and cardiac output, compared with CMV. The PaO2 and the VCO2 increased linearly with increasing Paw. With increasing Paw, VD/VT decreased directly with increasing Paw from 98 to 69.3%. Gas exchange at a Paw of 15 cm of H2O during IHFPPV was equivalent to conditions at Paw of 20 cm of H2O during CMV. At a higher Paw during IHFPPV, improvements over control values were observed in gas exchange.

Effects of sedation, anesthesia, and endotracheal intubation on respiratory mechanics in adult horses.

OBJECTIVE: To determine the effects of endotracheal intubation on respiratory mechanics during xylazine sedation and xylazine-diazepam-ketamine anesthesia in adult horses. ANIMALS: 5 healthy adult horses. PROCEDURE: Measurements were derived from recordings of respiratory gas flow, and transpulmonary and transtracheal pressures. Total pulmonary resistance (RT) was partitioned into upper airway resistance (extrathoracic portion of trachea, larynx, pharynx, nasal cavity, nares; RUA) and lower airway resistance (intrathoracic portion of trachea, bronchi, bronchioles). Baseline measurements were obtained in unsedated horses, after xylazine administration, and following nasotracheal intubation (ID, 18 mm). Measurements were obtained following induction of xylazine-diazepam-ketamine anesthesia and subsequent to endotracheal intubations (ID, 22, 20, and 16 mm). During recovery, horses were nasotracheally intubated (ID, 18 mm). Measurements were obtained upon standing, and repeated after extubation. Data were examined by use of ANOVA with repeated measures. RESULTS: Significant increases in mean work of breathing (W), RT, and RUA observed with xylazine sedation were variably attenuated by nasotracheal intubation. During xylazine-diazepam-ketamine anesthesia, the highest mean values for W, RT, RUA, transpulmonary and transtracheal pressures developed during non-intubation periods. The magnitudes of resistance and pressure values were inversely proportional to the internal diameter of the endotracheal tube. At recovery, values of the W and all measurements of resistances and pressures were significantly increased, compared with presedation values. Extubation resulted in further increases in these measurements. CONCLUSIONS: Work of breathing in horses is substantially increased when RUA is increased during xylazine sedation and xylazine-diazepam-ketamine anesthesia. Endotracheal intubation reduces W by reducing RUA.

Disposition and excretion of flunixin meglumine in horses.

The disposition of flunixin meglumine administered IV at a dosage of 1.1 mg/kg was described by a 2-compartment model; the alpha and beta half-lives (t1/2) were 0.61 and 1.5 hours, respectively. When administered IV at a rate of 2.2 mg/kg, the disposition was best described by a 3-compartment model, and the alpha, beta, and lambda t1/2 were 0.16, 1.52, and 6.00 hours, respectively. The zero-time plasma concentrations after flunixin meglumine was administered at 1.1 and 2.2 mg/kg were 9.3 +/- 0.76 and 21.5 +/- 7.4 mg/L, respectively. The bioavailability after oral administration of 1.1 mg/kg was 85.8%. The absorption t1/2 was 0.57 hours, with a peak concentration of 2.50 +/- 1.25 mg/L. The cumulative urinary recoveries for IV and oral administrations were 61.0% and 63.3%, respectively, of the dose for the 12-hour collection period. The final asymptotic points of urine excretion after IV and oral administrations were 406.4 +/- 65.5 and 357.7 +/- 53.5 mg, respectively, which represented 75.5 and 77.5% of the drug accounted for between 30 and 35 hours after administration. Flunixin meglumine was rapidly excreted in urine over a 2- to 4-hour period after drug administration and was highly bound to protein in plasma.

Effects of furosemide on the plasma and urinary concentrations and the excretion of fentanyl: model for the study of drug interaction in the horse.

The effects of furosemide (0.55 mg/kg IV) on the plasma and urinary fentanyl (PFE UFE) concentrations were studied during steady-state conditions. The PFE during the steady-state period was 0.31 +/- 0.027 ng/ml, with no significant changes occurring, even though the rate of excretion of fentanyl (EX) increased during the 1st hour from 112.0 +/- 21.6 to 534.5 +/- 82.9 ng/minute. The EX returned to control levels within 3 hours, as did the UFE. The injection of furosemide increased glomerular filtration rate from 1.97 +/- 0.21 to 3.81 +/- 0.75 ml/kg/min. The fractional reabsorption decreased from a control of 70.3 +/- 6.2% to 25.2 +/- 2.3% during the 1st hour, returning to control levels at 3 hours after furosemide was given. The total body clearance of fentanyl increased slightly during the peak period of diuresis. The return of EX, fractional reabsorption, UFE, and clearance of endogenous creatinine to control levels occurred before the return of urine specific gravity, indicating the ability of the kidney to concentrate fentanyl before its water concentrating capacity had returned.