OBJECTIVE To determine the pharmacokinetic and pharmacodynamic effects of midazolam following IV and IM administration in sheep. ANIMALS 8 healthy adult rams. PROCEDURES Sheep were administered midazolam (0.5 mg/kg) by the IV route and then by the IM route 7 days later in a crossover study. Physiologic and behavioral variables were assessed and blood samples collected for determination of plasma midazolam and 1-hydroxymidazolam (primary midazolam metabolite) concentrations immediately before (baseline) and at predetermined times for 1,440 minutes after midazolam administration. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Following IV administration, midazolam was rapidly and extensively distributed and rapidly eliminated; mean ± SD apparent volume of distribution, elimination half-life, clearance, and area under the concentration-time curve were 838 ± 330 mL/kg, 0.79 ± 0.44 hours, 1,272 ± 310 mL/h/kg, and 423 ± 143 h·ng/mL, respectively. Following IM administration, midazolam was rapidly absorbed and bioavailability was high; mean ± SD maximum plasma concentration, time to maximum plasma concentration, area under the concentration-time curve, and bioavailability were 820 ± 268 ng/mL, 0.46 ± 0.26 hours, 1,396 ± 463 h·ng/mL, and 352 ± 148%, respectively. Respiratory rate was transiently decreased from baseline for 15 minutes after IV administration. Times to peak sedation and ataxia after IV administration were less than those after IM administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated midazolam was a suitable short-duration sedative for sheep, and IM administration may be a viable alternative when IV administration is not possible.

OBJECTIVE To quantify nausea and sedation scores, gastric emptying time, and gastrointestinal transit time after IV administration of a lidocaine hydrochloride bolus followed by a constant rate infusion (CRI) in clinically normal dogs. ANIMALS 6 Beagles. PROCEDURES In a crossover study, dogs were fed thirty 1.5-mm barium-impregnated spheres (BIPS) and received a saline (0.9% NaCl) solution bolus (0.05 mL/kg) IV (time 0) followed by a CRI at 10 mL/h, a lidocaine bolus (1 mg/kg) IV followed by a CRI at 25 μg/kg/min, or a lidocaine bolus (1 mg/kg) IV followed by a CRI at 50 μg/kg/min; CRIs were for 12 hours. Nausea and sedation scores were assessed and abdominal radiographs obtained immediately after feeding of BIPS and every hour for 12 hours and again 16 hours after CRI start. Percentage of BIPSs in the small and large intestines, gastric emptying time, and gastrointestinal transit time were assessed. RESULTS Gastric emptying time did not differ significantly among treatments. Significantly more BIPS were in the large intestine 4 to 7 hours after treatment start for the 50-μg/kg/min treatment than for the other 2 treatments. Six hours after treatment start, significantly more BIPS were in the large intestine for the 25-μg/kg/min treatment than for the saline solution treatment. Higher sedation and nausea scores were associated with the 50-μg/kg/min CRI. CONCLUSIONS AND CLINICAL RELEVANCE In clinically normal dogs, lidocaine CRI did not significantly affect gastric emptying. However, gastrointestinal transit time was mildly decreased and sedation and nausea scores increased in dogs administered a lidocaine CRI at clinically used doses.

OBJECTIVE To investigate the pharmacokinetics of metformin hydrochloride in healthy dogs after IV and oral bolus administrations and determine the oral dose of metformin that yields serum concentrations equivalent to those thought to be effective in humans. ANIMALS 7 healthy adult mixed-breed dogs. PROCEDURES Each dog was given a single dose of metformin IV (mean ± SD dose, 24.77 ± 0.60 mg/kg) or PO (mean dose, 19.14 ± 2.78 mg/kg) with a 1-week washout period between treatments. For each treatment, blood samples were collected before and at intervals up to 72 hours after metformin administration. Seventy-two hours after the crossover study, each dog was administered metformin (mean dose, 13.57 ± 0.55 mg/kg), PO, twice daily for 7 days. Blood samples were taken before treatment initiation on day 0 and immediately before the morning drug administration on days 2, 4, 6, and 7. Serum metformin concentrations were determined by means of a validated flow injection analysis–tandem mass spectrometry method. RESULTS After IV or oral administration to the 7 dogs, there was high interindividual variability in mean serum metformin concentrations over time. Mean ± SD half-life of metformin following IV administration was 20.4 ± 4.1 hours. The mean time to maximum serum concentration was 2.5 ± 0.4 hours. Mean systemic clearance and volume of distribution were 24.1 ± 7.8 mL/min/kg and 44.8 ± 23.5 L/kg, respectively. The mean oral bioavailability was 31%. CONCLUSIONS AND CLINICAL RELEVANCE The study data indicated that the general disposition pattern and bioavailability of metformin in dogs are similar to those reported for cats and humans

OBJECTIVE To compare cardiac output (CO) measured by use of CT coronary angiography and thermodilution (criterion-referenced standard) at various CO values, record adverse effects, and determine the time needed to measure CO. ANIMALS 5 healthy purpose-bred Beagles (2 males and 3 females). PROCEDURES A prospective nonrandomized crossover study was conducted. Dogs were premedicated with butorphanol tartrate (0.2 mg•kg−1, IM). Anesthesia was induced by IV administration of etomidate (1 to 2 mg•kg−1) and midazolam (0.25 mg•kg−1). Orotracheal intubation was performed, and anesthesia was maintained by administration of isoflurane. The CO was determined by use of thermodilution and by use of CT at 3 CO values. Dobutamine was infused at various rates to obtain the 3 CO values. RESULTS 13 values were obtained and analyzed. The mean ± SD difference between methods was 0.09 ± 0.71 L•min−1 (95% confidence interval [CI], 0.52 to −0.34 L•min−1). Only 1 of 13 values was located on the 100% agreement line (ie, 0 line), 7 of 13 values were located within the 95% CI, and 5 of 13 values were outside the 95% CI. CONCLUSIONS AND CLINICAL RELEVANCE For this study, there was poor agreement between the 2 methods. The 95% CI interval was 0.52 to −0.34 L•min−1, and 5 of 13 values were outside the 95% CI. Therefore, results for the CT method appeared to be inappropriate for use in making clinical decisions.

OBJECTIVE To evaluate the effect of gadoxetic acid (contrast) dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs. ANIMALS 8 healthy dogs. PROCEDURES The study had 2 parts. In part 1, 4 dogs were anesthetized and underwent CT cholangiography twice. Gadoxetic acid was administered IV at a low dose (0.025 mmol/kg) for the first procedure and high dose (0.3 mmol/kg) for the second procedure. Serial CT scans were obtained at predetermined times after contrast injection. In part 2, 4 dogs were sedated and underwent CT angiography 85 minutes after IV administration of the high contrast dose. Contrast enhancement of the biliary tract on all scans was objectively assessed by measurement of CT attenuation and qualitatively assessed by use of a subjective 4-point scoring system by 3 independent reviewers. All measurements were compared over time and between contrast doses for the dogs of part 1. Subjective measurements were compared between the sedated dogs of part 2 and anesthetized dogs of part 1. RESULTS Enhancement of the biliary tract was positively associated with contrast dose and time after contrast injection. Optimal enhancement was achieved 65 minutes after contrast injection. Subjective visualization of most biliary structures did not differ significantly between sedated and anesthetized dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated CT cholangiography with gadoxetic acid was feasible in sedated dogs. The high contrast dose provided better visualization of biliary structures than the low dose; CT scans should be obtained 65 minutes after contrast injection.

OBJECTIVE To compare analgesic and gastrointestinal effects of lidocaine and buprenorphine administered to rabbits undergoing ovariohysterectomy. ANIMALS Fourteen 12-month-old female New Zealand White rabbits. PROCEDURES Rabbits were assigned to 2 treatment groups (7 rabbits/group). One group received buprenorphine (0.06 mg/kg, IV, q 8 h for 2 days), and the other received lidocaine (continuous rate infusion [CRI] at 100 μg/kg/min for 2 days). Variables, including food and water consumption, fecal output, glucose and cortisol concentrations, and behaviors while in exercise pens, were recorded. RESULTS Rabbits receiving a lidocaine CRI had significantly higher gastrointestinal motility, food intake, and fecal output and significantly lower glucose concentrations, compared with results for rabbits receiving buprenorphine. Rabbits receiving lidocaine also had a higher number of normal behaviors (eg, sprawling, traveling, and frolicking) after surgery, compared with behaviors such as crouching and sitting that were seen more commonly in rabbits receiving buprenorphine. Both groups had significant weight loss after surgery. Pain scores did not differ significantly between treatment groups. Significant decreases in heart rate and respiratory rate were observed on the day of surgery, compared with values before and after surgery. Rabbits in the lidocaine group had significantly overall lower heart rates than did rabbits in the buprenorphine group. CONCLUSIONS AND CLINICAL RELEVANCE A CRI of lidocaine to rabbits provided better postoperative outcomes with respect to fecal output, food intake, and glucose concentrations. Thus, lidocaine appeared to be a suitable alternative to buprenorphine for alleviating postoperative pain with minimal risk of anorexia and gastrointestinal ileus.

OBJECTIVE To evaluate pharmacokinetics of cefazolin after IV injection of cefazolin (22 mg/kg) and after simultaneous IV and IM injections of cefazolin (total dose, 44 mg/kg) to dogs. ANIMALS 12 adult Beagles. PROCEDURES Dogs (6/group) were assigned to receive a single injection of cefazolin (IV group; 22 mg/kg, IV) or simultaneous injections (IV + IM group; 22 mg/kg, IV, and 22 mg/kg, IM). Interstitial fluid was collected over a 5-hour period by use of ultrafiltration probes for pharmacokinetic analysis. RESULTS Mean cefazolin concentration in the interstitial fluid at 1, 1.5, 2, 3, 4, and 5 hours after injection was 39.6, 29.1, 21.2, 10.3, 6.4, and 2.7 μg/mL, respectively, for the IV group and 38.3, 53.3, 46.4, 31.7, 19.1, and 8.9 μg/mL, respectively, for the IV + IM group. Mean area under the concentration-time curve extrapolated to infinity, maximum concentration, half-life, and time to maximum concentration was 74.99 and 154.16 h·μg/mL, 37.3 and 51.5 μg/mL, 0.96 and 1.11 hours, and 1.28 and 1.65 hours, respectively, for the IV and IV + IM groups. CONCLUSIONS AND CLINICAL RELEVANCE Cefazolin concentrations in interstitial fluid of dogs were maintained at > 4 μg/mL for 4 hours after a single IV injection and for 5 hours after simultaneous IV and IM injections. Therefore, simultaneous IV and IM administration of cefazolin 30 to 60 minutes before surgery should provide interstitial fluid concentrations effective against the most common commensal organisms (Staphylococcus spp and Streptococcus spp) on the skin of dogs for surgical procedures lasting ≤ 4 hours.

OBJECTIVE To characterize pharmacokinetics of cyclophosphamide and 4-hydoxycyclophosphamide (4-OHCP) in the plasma of healthy cats after oral, IV, and IP administration of cyclophosphamide. ANIMALS 6 healthy adult cats. PROCEDURES Cats were randomly assigned to receive cyclophosphamide (200 mg/m2) via each of 3 routes of administration (oral, IV, and IP); there was a 30-day washout period between successive treatments. Plasma samples were obtained at various time points for up to 8 hours after administration. Samples were treated with semicarbazide hydrochloride to trap the 4-OHCP in stable form, which allowed for cyclophosphamide and trapped 4-OHCP to be simultaneously measured by use of tandem mass spectrometry. Pharmacokinetic parameters were determined from drug concentration-versus-time data for both cyclophosphamide and 4-OHCP. RESULTS Cyclophosphamide was tolerated well regardless of route of administration. Pharmacokinetic parameters for 4-OHCP were similar after oral, IV, and IP administration. Area under the concentration-time curve for cyclophosphamide was lower after oral administration than after IV or IP administration. CONCLUSIONS AND CLINICAL RELEVANCE Cyclophosphamide can be administered interchangeably to cats as oral, IV, and IP formulations, which should provide benefits with regard to cost and ease of administration to certain feline patients.

OBJECTIVE To determine the ability of an accelerometer within a commercially available portable media device (PMD) to measure changes in postural stability of standing horses during various stance conditions and to compare these results with data obtained by use of a stationary force platform. ANIMALS 7 clinically normal horses. PROCEDURES A PMD was mounted on a surcingle; the surcingle was placed immediately caudal to the highest point of the shoulders (withers). Each horse was examined while standing on a stationary force platform system in a normal square stance, forelimb base-narrow stance, and normal square stance at 5 and 10 minutes after sedation induced by IV administration of xylazine hydrochloride. A minimum of 5 trials were conducted for each stance condition. Ranges of craniocaudal and mediolateral motion as well as SDs were collected for the PMD and force platform system. Analyses were performed with mixed-model ANOVAs, and correlation coefficients were calculated. RESULTS Stance condition significantly altered craniocaudal accelerations measured by use of the PMD, all craniocaudal and mediolateral displacements of the center of pressure, and velocities measured by use of the stationary force platform. For both the PMD and force platform, SDs were significantly affected by stance condition in both craniocaudal and mediolateral directions. Correlation coefficients between the systems for all variables were low to moderate (r = 0.18 to 0.58). CONCLUSIONS AND CLINICAL RELEVANCE Body-mounted PMDs should be investigated for use in assessment of postural stability in horses with neuromuscular abnormalities.

OBJECTIVE To describe concentration-over-time data for ampicillin and sulbactam in the digital and systemic circulations and synovial fluid (SYN) of cattle following a single injection of ampicillin-sulbactam as a regional IV perfusion (RIVP). ANIMALS 6 healthy adult nonlactating Jersey-crossbred cows. PROCEDURES The right hind limb of each cow was aseptically prepared. A tourniquet was applied around the midmetatarsal region, and 1.0 g of ampicillin with 0.5 g of sulbactam in a combined formulation was administered as an RIVP into the dorsal common digital vein (DCDV). Blood samples from the DCDV and jugular vein and SYN samples from the metatarsophalangeal joint of the prepared limb were collected immediately before and at predetermined times for 24 hours after RIVP. One blood sample was obtained from the abaxial proper plantar vein of the lateral digit of the prepared limb 0.25 hours after RIVP. Serum and SYN ampicillin and sulbactam concentrations were determined by high-performance liquid chromatography. RESULTS Mean ± SD maximum concentration of ampicillin in SYN and serum obtained from the abaxial proper plantar and jugular veins was 1,995 ± 1,011 μg/mL, 5,422 ± 1,953 μg/mL, and 2.5 ± 1.6 μg/mL, respectively. Corresponding serum and SYN concentrations of sulbactam were lower but followed the same pattern over time as those for ampicillin. Synovial fluid ampicillin concentration remained above 8 μg/mL for a mean time of 18.9 hours. CONCLUSIONS AND CLINICAL RELEVANCE Potentially therapeutic concentrations of ampicillin were achieved in regional serum and SYN samples; SYN concentrations remained at potentially therapeutic values for > 12 hours following RIVP of 1.5 g of ampicillin-sulbactam in the hind limb of healthy cows.