The pharmacokinetics of cefadroxil over a range of oral doses and animal ages in the foal

To evaluate the effect of foal age on the pharmacokinetics of cefadroxil, five foals were administered cefadroxil in a single intravenous dose (5 mg/kg) and a single oral dose (10 or 20 mg/kg) at ages of 0.5, 1, 2, 3 and 5 months. Pharmacokinetic parameters of terminal elimination rate constant (β_po), oral mean residence time (MRT_po), mean absorption time (MAT), rate constant for oral absorption (K_a), bioavailability F, peak serum concentrations(C_max) and time of peak concentration (t_max), were evaluated in a repeated measures analysis over dose. Across animal ages, parameters for the intravenous dose did not change significantly over animal age (P 0.05). Mean values ± SEM were: β_IV = 0.633 ± 0.038 h^?1; Cl = 0.316 ± 0.010 L/kg/h; V_c = 0.196 ± 0.008 L/kg; V_area = 0.526 ± 0.024 L/kg; V_SS =0.374 ± 0.014 L/kg; MRT_iv = 1.22 ± 0.07 h; K_el = 1.67 ± 0.08 ^h?1. Following oral administration, drug absorption became faster with age (P < 0.05), as reflected by MRT_po, MAT, K_a and t_max. However, oral bioavailability (±SE) declined significantly (P < 0.05) from 99.6 ± 3.69% at 0.5 months to 14.5 ± 1.40% at 5 months of age. To evaluate a dose effect on the pharmacokinetic parameters, a series of oral doses (5, 10, 20 and 40 mg/kg) were administered to these foals at 1 month of age. β_po (0.548 ± 0.023 h^?1) and F (68.26 ± 2.43%) were not affected significantly by the size of the dose. C_max was approximately doubled with each two-fold increase in dose: 3.15 ± 0.15, 5.84 ± 0.48, 12.17 ± 0.93 and 19.71 ± 2.19 μg/mL. Dose-dependent kinetics were observed in MRT_po, MAT, K_a and t_max.     

Pharmacokinetics of allopurinol in Dalmatian dogs

The pharmacokinetics of allopurinol were studied in Dalmatian dogs. Eight dogs were given allopurinol orally at a dose of 10 mg/kg for seven doses prior to sample collection. After a period of at least two weeks, four of these dogs and four additional Dalmatians were later given a single intravenous (i.v.) dose of allopurinol (6 mg/kg) prior to sample collection.Allopurinol was found to follow first-order absorption and elimination kinetics. In the i.v. kinetic study, the elimination constant (K_el) = 0.31±0.03 per h, the half-life (t_½) = 2.22±0.20 h, the initial concentration (C₀) = 5.26±0.34 μg/mL and the specific volume (V_d) = 1.14±0.07 L/kg. Clearance of allopurinol was estimated to be 0.36±0.03 L/kg·h. In the oral kinetic study, the absorption rate constant (K_ab) = 1.06±0.13 per h, the elimination rate constant (K_el) = 0.26±0.01 per h, the absorption half-life (t_½ab) = 0.66±0.06 h, and the elimination half-life (t_½el) = 2.69±0.14 h. Peak plasma concentrations (C_max) = 6.43±0.18 μg/mL were obtained within 1 to 3 h (mean time of maximum concentration (T_max) = 1.9±0.1 h). The volume of distribution corrected by the fraction of dose absorbed (V_d/F) was estimated to be 1.17±0.07 L/kg.Good agreement was obtained between mean kinetic parameters in the oral and i.v. studies. There was little variation between individual dogs in the i.v. study, whereas the rate of absorption and elimination of orally administered allopurinol was more varied among individual dogs. Because of this, and the fact that the magnitude of hyperuricosuria varies among Dalmatians, it is not possible to specify an exact dose of allopurinol that will effectively lower the urinary uric acid concentration to acceptable values in all Dalmatians with hyperuricosuria; rather, the dose must be titrated to the needs of each dog.     

Pharmacokinetics and perioperative efficacy of intravenous ketorolac in dogs

Ketorolac (KET) is a nonsteroidal anti‐inflammatory drug approved for the use in humans that possesses a potent analgesic activity, comparable to morphine, and could represent a useful tool to control acute pain also in animals. The clinical efficacy and pharmacokinetic profile of intravenous (IV) ketorolac tromethamine (0.5 mg/kg) were studied in 15 dogs undergoing gonadectomy. Intra‐operative cardiorespiratory variables were monitored, and post‐operative pain was assessed using a subjective pain score (0–24) in all dogs, whereas the pharmacokinetic profile of the drug was determined in 10 animals. During surgery, mean minimal alveolar concentration of isoflurane was 1.69 ± 0.11%, and normocapnia and spontaneous ventilation were maintained in all animals. During pain assessment, no significant differences between males and females were found, and in no case rescue analgesia was necessary. No adverse effects were reported. Serum samples were purified by solid‐phase extraction and analysed by HPLC with UV‐Vis detection. A large variability was observed in serum concentrations. The kinetics of ketorolac was described by a noncompartmental analysis. The elimination half‐life (t_½λz) and Cl_B were 10.95 ± 7.06 h and 92.66 ± 84.49 mL/h/kg, respectively, and V_dss and V_z were 1030.09 ± 620.50 mL/kg and 1512.25 ± 799.13 mL/kg, respectively. AUC_(0→last) and MRT_(0→last) were 6.08 ± 3.28 h × μg/mL and 5.59 ± 2.12 h, respectively. The results indicate that ketorolac possess good post‐operative analgesic effects until about 6 h after administration in dogs undergoing moderately painful surgery.     

The pharmacokinetics of DPH after the administration of a single intravenous or intramuscular dose in healthy dogs

The objective of this study was to determine the pharmacokinetics of diphenhydramine (DPH) in healthy dogs following a single i.v. or i.m. dose. Dogs were randomly allocated in two treatment groups and received DPH at 1 mg/kg, i.v., or 2 mg/kg, i.m. Blood samples were collected serially over 24 h. Plasma concentrations of DPH were determined by high‐performance liquid chromatography, and noncompartmental pharmacokinetic analysis was performed with the commercially available software. Cardio‐respiratory parameters, rectal temperature and effects on behaviour, such as sedation or excitement, were recorded. Diphenhydramine Cl_area, Vd_area and T_1/2 were 20.7 ± 2.9 mL/kg/min, 7.6 ± 0.7 L/kg and 4.2 ± 0.5 h for the i.v. route, respectively, and Cl_area/F, Vd_area/F and T_1/2 20.8 ± 2.7 mL/kg/min, 12.3 ± 1.2 L/kg and 6.8 ± 0.7 h for the i.m. route, respectively. Bioavailability was 88% after i.m. administration. No significant differences were found in physiological parameters between groups or within dogs of the same group, and values remained within normal limits. No adverse effects or changes in mental status were observed after the administration of DPH. Both routes of administration resulted in DPH plasma concentrations which exceeded levels considered therapeutic in humans.     

Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs

Kumar, V., Madabushi, R., Lucchesi, M. B. B., Derendorf, H. Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs. J. vet. Pharmacol. Therap. 34 , 130–135. Pharmacokinetics of cefpodoxime in plasma (total concentration) and subcutaneous fluid (free concentration using microdialysis) was investigated in dogs following single oral administration of prodrug cefpodoxime proxetil (equivalent to 5 and 10 mg/kg of cefpodoxime). In a cross over study design, six dogs per dose were utilized after a 1 week washout period. Plasma, microdialysate, and urine samples were collected upto 24 h and analyzed using high performance liquid chromatography. The average maximum concentration (C_max) of cefpodoxime in plasma was 13.66 (±6.30) and 27.14 (±4.56) μg/mL with elimination half‐life (t_1/2) of 3.01 (±0.49) and 4.72 (±1.46) h following 5 and 10 mg/kg dose, respectively. The respective average area under the curve (AUC_0–∞) was 82.94 (±30.17) and 107.71 (±30.79) μg·h/mL. Cefpodoxime was readily distributed to skin and average free C_max in subcutaneous fluid was 1.70 (±0.55) and 3.06 (±0.93) μg/mL at the two doses. Urinary excretion (unchanged cefpodoxime) was the major elimination route. Comparison of subcutaneous fluid concentrations using pharmacokinetic/pharmacodynamic indices of fT_>MIC indicated that at 10 mg/kg dose; cefpodoxime would yield good therapeutic outcome in skin infections for bacteria with MIC₅₀ upto 0.5 μg/mL while higher doses (or more frequent dosing) may be needed for bacteria with higher MICs. High urine concentrations suggested cefpodoxime use for urinary infections in dogs.     

Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean ± SD): AUC_(0–∞) 4.20 ± 1.66 μg·h/mL; C_max 6.64 ± 1.38 μg/mL; V_z 4.80 ± 0.91 L/kg; Cl_t 2.64 ± 0.84 L/h·kg; t_½λ 1.35 ± 0.40 h and MRT 1.50 ± 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean ± SD): C_max, 0.30 ± 0.17 and 0.17 ± 0.09 μg/mL; t_max, 1.75 ± 0.76 and 0.69 ± 0.30 h; t_½λ, 2.92 ± 0.79 and 1.53 ± 1.28 h and MRT, 5.10 ± 1.12 and 2.56 ± 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC₉₀ = 0.5 μg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.     

Pharmacokinetics of morphine in combination with dexmedetomidine and maropitant following intramuscular injection in dogs anaesthetized with halothane

The purpose of this study was to evaluate the pharmacokinetics of morphine in combination with dexmedetomidine and maropitant injected intramuscularly in dogs under general anaesthesia. Eight healthy dogs weighing 25.76 ± 3.16 kg and 3.87 ± 1.64 years of age were used in a crossover study. Dogs were randomly allocated to four groups: (1) morphine 0.6 mg/kg; (2) morphine 0.3 mg/kg + dexmedetomidine 5 μg/kg; (3) morphine 0.3 mg/kg + maropitant 1 mg/kg; (4) morphine 0.2 mg/kg + dexmedetomidine 3 μg/kg + maropitant 0.7 mg/kg. Blood samples were collected before, 15 and 30 min, and 1, 2, 3 4, 6 and 8 hr after injection of the test drugs. Plasma concentration of the drugs was determined by liquid chromatography-mass spectrometry. The elimination half-life (T_1/2) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T_1/2 = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg⁻¹ min⁻¹) compared to maropitant (T_1/2 = 52.73 min ± 13.823 ml kg⁻¹ min⁻¹, CL = 178.57 ± 70.55) or morphine alone at higher doses (T_1/2 = 50.53 ± 12.55 min, CL = 187.24 ± 34.45 ml kg⁻¹ min⁻¹). Combining morphine with dexmedetomidine may increase the dosing interval of morphine and may have a clinical advantage.     

Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs

The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady‐state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross‐over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one‐way anova ; P ≤ 0.05). Differences among blood compartments occurred in all derived pharmacokinetic paramenters for each route of administration after single and multiple dosing. After single PO dosing, plasma C_max was 14.4 ± 2.3 mcg/mL and elimination half‐life was 17.2 ± 3.6 h. After IV dosing, volume of distribution was 1.1 ± 0.25 L/kg, clearance was 58 ± 11 mL/h/kg and elimination t_1/2 was 12.9 ± 3.6 h. Oral bioavailability was 68 ± 12%; fraction of unbound drug approximated 60%. At steady‐state (4 days), differences occurred for for all parameters except C_max and C_min. Plasma C_max at steady‐state was 56 ± 12 mcg/mL, with 10% fluctuation between C_max and C_min. Plasma t_1/2 (h) was 23.52 ± 5.76 h. Clinical laboratory tests remained normal, with the exception of total T4, which was below normal limits at study end. In conclusion, 10 mg/kg twice daily results in peak plasma zonisamide which exceeds the recommended human therapeutic range (10 to 40 μg/mL) and is associated with suppression of thyroid hormone synthesis. A reasonable b.i.d starting dose for canine epileptics would be 3 mg/kg. Zonisamide monitored in either serum or plasma should be implemented at approximately 7 days.     

A comparison of two different methods for dead space measurements in ventilated dogs

The aim of the study was to compare two methods of measuring physiological dead space/tidal volume ratio (Vd /Vt ) and alveolar dead space (Vd _ALV). Measurements were obtained by automated single breath CO₂ analysis (Ventrak 1550/Capnoguard 1265 (V&C)) and classical calculations were carried out using the Enghoff–Bohr equation in anaesthetized dogs. The V&C consists of a mainstream capnometer, a pneumotachometer, a signal processor, and computer software to determine continuous single‐breath CO₂ analysis (SBT‐CO₂). Eleven dogs of mixed breed (five female, six male) mean body mass 35 ± 10 kg, aged 9 months to 8 years were studied. Pre‐anaesthetic medication was acepromazine (0.03 mg kg^?1) and methadone (0.1 mg kg^?1). Anaesthesia was induced with propofol given to effect and maintained with propofol (10 mg kg^?1 hour^?1) and fentanyl (0.02 mg kg^?1 hour^?1) by infusion. The dog's trachea were intubated and the carbon dioxide and flow sensor were placed between the tube and the Y‐piece of a circle system (Fi O₂ = 1.0). Controlled ventilation was started (tidal volume 10–15 mL kg^?1) and settings were not changed throughout the measurement period. Mixed expired PCO₂ (P e ?CO₂) was measured by analyzing expired gas collected in a mixing box in the expiratory limb of the circle system. The dorsal pedal artery was cannulated for arterial blood sampling and analysis. Measurements were done every 15 minutes for 1 hour. The Vd /Vt was automatically calculated and displayed from the SBT‐CO₂ analysis and also obtained using the Enghoff modification of the Bohr equation (Vd /Vt = (PaCO₂ ? P e ?CO₂)/PaCO₂). Alveolar dead space was determined by calculating the physiological dead space (Vd phys = expired volume × (Vd /Vt )) and subtracting the anatomical dead space measured by SBT‐CO₂. Values for Vd /Vt and Vd _ALV obtained with both methods were compared using Students t‐test. The mean values from the automatic dead space calculation (Vd /Vt : 0.62–0.63; Vd _ALV: 56.1–64.3 mL) did not differ significantly from those calculated arithmetically (Vd /Vt : 0.62–0.63; Vd _ALV: 54.09–66.31 mL). The mean differences and standard deviation in Vd /Vt was 0.63 ± 0.00 and in Vd _ALV 58.98 ± 4.28 mL for the two measurement techniques. Our data indicate that V&C can be used for accurate noninvasive online Vd /Vt and Vd _ALV measurements in anaesthetized ventilated dogs.     

Haemodynamic, electrocardiographic, electrophysiologic and pharmacokinetic activity of 4'-hydroxypropranolol in dogs

We determined the haemodynamic, electrocardiographic and electrophysiologic effects, and the pharmacokinetic properties of 4′-hydroxypropranolol (4′-OHP) by conducting three different experiments in dogs. In experiment 1 the plasma concentrations of 4′-OHP (mg/kg, i.v.) in pentobarbital anaesthetized dogs were determined by HPLC and pharmacokinetic parameter values were estimated. The terminal elimination half-life (t1/2) for 4′-OHP was 69.4 min, the apparent volume of distribution (V_d) was 3.39 L/kg and the total clearance (Cl_t) was 53.6 mL/min·kg. These data were subsequently used to calculate the loading and maintenance doses of 4′-OHP required to produce targeted steady-state plasma concentrations for 4′-OHP of 30, 60, 120, 240 and 480 ng/mL. In experiment 2 the haemodynamic and electrocardiographic effects for target plasma concentrations of 4′-OHP were determined in two groups of pentobarbital anaesthetized dogs, and beta-blocking activity was assessed by infusion or bolus doses of isoproterenol. The haemodynamic and electrocardiographic effects of the target plasma concentrations (30, 60, 120 ng/mL) of 4′-OHP were first determined in seven pentobarbital anaesthetized dogs (Group 1). Beta blocking activity was assessed by the infusion of 0.1 μg/kg/min isoproterenol. The infusion of 4′-OHP produced dose dependent decreases in heart rate, cardiac output, dP/dt_max, mean arterial pressure and left ventricular diastolic pressure. The PR interval of the lead II electrocardiogram increased and the QT_c interval decreased. These haemodynamic and electrocardiographic changes became apparent at plasma 4′-OHP concentrations equal to or greater than 30 ng/mL. Plasma concentrations of 4′-OHP equal to or greater than 30 ng/mL prevented the haemodynamic and electrocardiographic effects of isoproterenol infusion. In group 2 dogs, (seven dogs) the haemodynamic and electrocardiographic effects of target plasma concentrations (30, 60, 120, 240, 480 ng/mL) of 4′-OHP were evaluated and beta-blocking activity was assessed by the i.v. bolus administration of 1 and 4 μg/kg of isoproterenol. The infusion of 4′-OHP produced haemodynamic and electrocardiographic changes similar to those in group 1 dogs. In addition, the QRS duration of the electrocardiogram increased at plasma concentrations of 4′-OHP equal to or greater than 240 ng/mL. The haemodynamic and electrocardiographic effects of i.v. bolus dose administrations of 1 and 4 μg/kg isoproterenol were abolished by plasma concentrations of 4′-OHP equal to or greater than 240 ng/mL. In experiment 3 we determined the electrophysiologic effects of 10^?9 to 10^?5 mmol/L 4′-OHP on Tyrodes superfused bundles of canine Purkinje fibres. Action potential duration and the effective refractory period decreased at superfusate concentrations of 4′-OHP equal to or greater than 10^?7 mmol/L. Action potential overshoot, action potential total amplitude, the rate of rise of phase O (dV/dt) and spontaneous rate decreased at superfusage concentrations of 4′-OHP equal to or greater than 800 ng/mL. These studies demonstrate that: 1) 4′-OHP produces haemodynamic, electrocardiographic and electrophysiologic effects similar to those of other beta-blocking drugs in pentobarbital anaesthetized dogs; 2) the haemodynamic and electrocardiographic effects produced by 4′-OHP are     

Subarachnoid pressures and cardiorespiratory parameters during cisternal myelography in isoflurane anaesthetized dogs

ObjectiveTo measure subarachnoid pressures, systemic circulatory and respiratory effects, and to calculate cerebral perfusion pressure during cisternal myelography.Study designProspective clinical study.AnimalsForty‐three client owned dogs with clinical signs of spinal disease, weighing 6–56 kg.MethodsDogs were premedicated with butorphanol and diazepam intravenously (IV) and anaesthesia was induced with propofol and maintained with isoflurane vaporized in oxygen. Ventilation was spontaneous. Heart and respiratory rates, invasive mean arterial blood pressure (MAP), end tidal carbon dioxide and isoflurane concentration were measured continuously. Initial subarachnoid pressure (SaP₀) was measured in the cisterna magna with a needle pressure gauge. Iohexol 0.3 mL kg^?1 was injected at a rate of 4.1 mL minute^?1 into the cerebellomedullary cistern. The SaP was recorded during and at 120 seconds after contrast administration. The maximum SaP (SaP_max) and minimum calculated cerebral perfusion pressure (CPP_min) were recorded for each case.ResultsPrior to contrast injection, mean ± SD, MAP was 73 ± 20 mmHg and SaP₀ was 10 ± 3 mmHg. The cerebral perfusion pressure (CPP) was 64 ± 20 mmHg. The contrast injection increased the SaP₀ to 73 ± 33 mmHg (SaP_max). After injection, MAP increased to 97 ± 25 mmHg and the CPP decreased to 14 ± 34 mmHg. A negative correlation was found between the lowest CPP and body weight (ρ = ?0.77, p < 0.0001). Nine dogs had bradycardia, apnoea and hypertension, 21 dogs had at least one of these signs. The number of clinical signs showed significant correlation with body weight (ρ = ?0.68, p < 0.0001), SaP_max (ρ = ?0.66, p < 0.0001) and CPP_min (ρ = ?0.73, p < 0.0001).Conclusions and clinical relevanceCerebral perfusion can severely decrease during cisternal myelography using the standard dose of iohexol. Bradycardia, apnoea and systemic hypertension were associated with decreased CPP.     

Estimated plasma bupivacaine concentration after single dose and eight-hour continuous intra-articular infusion of bupivacaine in normal dogs

Objective— To estimate maximum plasma concentration (C_max) and time to maximum plasma (t_max) bupivacaine concentration after intra‐articular administration of bupivacaine for single injection (SI) and injection followed by continuous infusion (CI) in normal dogs. Study Design— Cross‐over design with a 2‐week washout period. Animals— Healthy Coon Hound dogs (n=8). Methods— Using gas chromatography/mass spectrometry, canine plasma bupivacaine concentration was measured before and after SI (1.5 mg/kg) and CI (1.5 mg/kg and 0.3 mg/kg/h). Software was used to establish plasma concentration–time curves and estimate C_max, T_max and other pharmacokinetic variables for comparison of SI and CI. Results— Bupivacaine plasma concentration after SI and CI best fit a 3 exponential model. For SI, mean maximum concentration (C_max, 1.33±0.954 μg/mL) occurred at 11.37±4.546 minutes. For CI, mean C_max (1.13±0.509 μg/mL) occurred at 10.37±4.109 minutes. The area under the concentration–time curve was smaller for SI (143.59±118.390 μg/mL × min) than for CI (626.502±423.653 μg/mL × min, P=.02) and half‐life was shorter for SI (61.33±77.706 minutes) than for CI (245.363±104.415 minutes, P=.01). The highest plasma bupivacaine concentration for any dog was 3.2 μg/mL for SI and 2.3 μg/mL for CI. Conclusion— Intra‐articular bupivacaine administration results in delayed absorption from the stifle into the systemic circulation with mean C_max below that considered toxic and no systemic drug accumulation. Clinical Relevance— Intra‐articular bupivacaine can be administered with small risk of reaching toxic plasma concentrations in dogs, though toxic concentrations may be approached. Caution should be exercised with multimodal bupivacaine administration because plasma drug concentration may rise higher than with single intra‐articular injection.     

Inotropic and lusitropic effects of incremental doses of dobutamine in dogs with right ventricular apical pacing‐induced cardiac dysfunction

This study aimed to assess the effects of incremental doses of dobutamine on diastolic function in healthy and rapid ventricular apical pacing (RVAP)‐induced cardiac dysfunction anesthetized dogs. Inotropic and lusitropic effects of dobutamine (2, 4, 8, and 12 μg kg^?1 min^?1) were assessed through left ventricle (LV) pressure–volume relation and Doppler echocardiography in six female dogs before and after 8 weeks of RVAP. Peak rate of LV pressure fall (?dP/dt_min) improved with doses >4 μg kg^?1 min^?1 in healthy (4,490 ± 970 vs. 3,265 ± 471 mmHg/s, p < 0.05) and >8 μg kg^?1 min^?1 in RVAP dogs (3,385 ± 1,122 vs. 1,864 ± 849 mmHg/s, p < 0.05) while the time constant of relaxation (tau) reduced with doses >4 μg kg^?1 min^?1 in both groups (healthy: 24.0 ± 3.7 vs. 28.2 ± 4.9 ms; RVAP: 32.6 ± 8.5 vs. 37.5 ± 11.4 ms, p < 0.05) comparing with baseline. Indices of relaxation (?dP/dt_min and tau) suggested preserved lusitropic response in contrast with markedly reduced indices of contractility in the RVAP group compared with healthy group at same infusion rates. Doppler echocardiography showed significant reduction of elastic recoil in failing hearts. The results of this study demonstrated maximal positive lusitropic effects of dobutamine at a dose of 8 μg kg^?1 min^?1 in ventricular pacing‐induced cardiac dysfunction without further impairment of ventricular filling.     

Pharmacokinetics and pharmacodynamics of alfaxalone after a single intramuscular or intravascular injection in mallard ducks (Anas platyrhynchos)

Pharmacokinetics and pharmacodynamics of alfaxalone was performed in mallard ducks (Anas platyrhynchos) after single bolus injections of 10 mg/kg administered intramuscularly (IM; n = 10) or intravenously (IV; n = 10), in a randomized cross‐over design with a washout period between doses. Mean (±SD) C_max following IM injection was 1.6 (±0.8) µg/ml with T_max at 15.0 (±10.5) min. Area under the curve (AUC) was 84.66 and 104.58 min*mg/ml following IV and IM administration, respectively. Volume of distribution (V_D) after IV dose was 3.0 L/kg. The mean plasma clearance after 10 mg/kg IV was 139.5 (±67.9) ml min^?1 kg^?1. Elimination half‐lives (mean [±SD]) were 15.0 and 16.1 (±3.0) min following IV and IM administration, respectively. Mean bioavailability at 10 mg/kg IM was 108.6%. None of the ducks achieved a sufficient anesthetic depth for invasive procedures, such as surgery, to be performed. Heart and respiratory rates measured after administration remained stable, but many ducks were hyperexcitable during recovery. Based on sedation levels and duration, alfaxalone administered at dosages of 10 mg/kg IV or IM in mallard ducks does not induce clinically acceptable anesthesia.     

The effect of low dose rocuronium bromide on eyeball position, muscle relaxation, and ventilation in dogs

A central eyeball position is often required during sedation or anaesthesia to facilitate examination of the eye. However, use of neuromuscular blockade to produce a central eye position may result in depressed ventilation. This study evaluated the eyeball position, muscle relaxation and changes in ventilation during general anaesthesia after the IV administration of 0.1 mg kg^?1 rocuronium. With client consent, 12 dogs of different breeds, body mass 27.2 ± 11.8 kg, aged 5.6 ± 2.8 years (mean ± SD) were anaesthetized for ocular examination. Pre‐anaesthetic medication was 0.01 mg kg^?1 medetomidine and 0.2 mg kg^?1 butorphanol IV. Anaesthesia was induced with propofol to effect and maintained with 10 mg kg^?1 hour^?1 propofol by infusion. The dogs were placed in left lateral recumbency, their trachea intubated and connected to a circle breathing system (Fi O₂ = 1.0). All dogs breathed spontaneously. The superficial peroneal nerve of the right hind leg was stimulated every 15 seconds with a train‐of‐four (TOF) stimulation pattern and neuromuscular function was assessed with an acceleromyograph (TOF‐Guard). Adequacy of ventilation was measured with the Ventrak 1550. After 10 minutes of anaesthesia to allow stabilisation of baseline values, 0.1 mg kg^?1 rocuronium was administered IV. Minute volume (Vm ), tidal volume (Vt ), respiratory rate (RR), Pe ′CO₂ and maximal depression of T1 and TOF ratio were measured. Data were analysed using a paired t‐test. The changes in the eyeball position were recorded. A total of 100 ± 33 seconds after the injection of rocuronium, T1 was maximally depressed to 62 ± 21% and the TOF ratio to 42 ± 18% of baseline values. Both variables returned to baseline after 366 ± 132 seconds (T1) and 478 ± 111 seconds (TOF). There was no significant reduction in Vm (2.32 ± 1.1 L minute^?1), Vt (124.1 ± 69.3 mL) and RR (10 ± 3.8 breaths minute^?1) and no increase in Pe ′CO₂ (6.5 ± 2.1 kPa (48.8 ± 16.1 mm Hg)) throughout the procedure. The eyeball rotated to a central position 35 ± 7 seconds after rocuronium IV and remained there for a minimum of 20 ± 7 minutes in all dogs. We conclude that rocuronium at a dose of 0.1 mg kg^?1 can be administered to dogs IV with minimal changes in ventilatory variables. The eyeball is fixed in a central position for at least 20 minutes, which greatly facilitates clinical examination.     

The Komesaroff anaesthetic machine for delivering sevoflurane to dogs

Objective To quantify the vapour output of the Komesaroff machine when using sevoflurane and to determine its performance for inducing and maintaining sevoflurane anaesthesia in dogs. Study design Prospective experimental study. Animals Six clinically normal beagles, aged 3–6 years and weighing 20 ± 1.65 kg (mean ± SEM). Methods The first study was performed using five Komesaroff vaporizers to measure the sevoflurane concentration delivered at each tap setting (I to IV) at 5, 10, 15, 20, 25, 30 and 35 minutes. For this study a ventilator was connected to the Komesaroff machine and set to deliver a tidal volume of 250 mL at 10 cycles minute^?1; oxygen flow was 100 mL minute^?1. A three‐litre reservoir bag was attached to the Y‐piece connector to act as a lung model. In the second study anaesthesia was induced in dogs with sevoflurane delivered by face‐mask mask and carried in 2 L minute^?1 100% oxygen and with the vaporizer set at the fully open position. The quality and speed of induction were recorded. After orotracheal intubation, anaesthesia was maintained for 60 minutes with sevoflurane using an oxygen flow of 100 mL minute^?1. The dogs were allowed to breathe spontaneously. The respiratory rate (RR), heart rate (HR), oesophageal temperature, systolic (SAP) mean (MAP) and diastolic (DAP) arterial pressure, end‐tidal CO₂ concentration (Fe ′_CO2) end‐tidal (Fe ′_SEVO) and peak‐inspired (Fi _SEVO) percentages of sevoflurane, and vaporizer tap setting were recorded every 5 minutes during anaesthesia. Results The delivery of sevoflurane was constant for each vaporizer setting. The mean output of sevoflurane was 0.44 ± 0.01% for setting I, 2.59 ± 0.18% for setting II, 3.28 ± 0.22% for setting III and 3.1 ± 0.5% for setting IV. In the second study, the mean induction time was 7.72 ± 0.60 minutes and the quality of the induction was good in all dogs. The mean vaporizer tap setting for the maintenance of anaesthesia was 3.48 ± 0.12 and the mean values for Fe ′_SEVO and Fi _SEVO were 2.42 ± 0.04% and 2.87 ± 0.06%, respectively. The pedal withdrawal reflex persisted throughout anaesthesia. Conclusions It proved impossible to produce surgical anaesthesia with sevoflurane delivered by the Komesaroff machine despite the highest possible sevoflurane concentration being delivered. Clinical relevance Sevoflurane delivered from the Komesaroff machine cannot be relied upon to maintain surgical anaesthesia in spontaneously breathing dogs.     

Sedative effects of hydromorphone or oxymorphone with or without acepromazine in dogs

Hydromorphone is an agonist opioid with potency approximately five times that of morphine and half that of oxymorphone. The purpose of this study was to compare hydromorphone with oxymorphone, with or without acepromazine, for sedation in dogs, and to measure plasma histamine before and after drug administration. Ten dogs received IM hydromorphone (H; 0.2 mg kg^?1), oxymorphone (O; 0.1 mg kg^?1), hydromorphone with acepromazine (H; 0.2 mg kg^?1, A; 0.05 mg kg^?1) or oxymorphone with acepromazine (O; 0.1 mg kg^?1, A; 0.05 mg kg^?1) in a randomized Latin‐square design. Sedation score, heart rate, respiratory rate, blood pressure, and SpO₂ were recorded at baseline and every 5 minutes after drug administration up to 25 minutes. Plasma histamine was measured at baseline and at 25 minutes post‐drug administration. Data were analyzed with repeated measures anova . Mean ± SD body weight was 21.62 ± 1.54 kg. Mean ± SD age was 1.07 ± 0.19 years. Sedation score was significantly greater for OA after 5 minutes than O alone (4.1 ± 3.5 versus 1.9 ± 1.5) and for HA after 15 minutes than H alone (8.6 ± 2.9 versus 5.9 ± 2.5). There was no significant difference in sedation between H and O at any time point. There was no significant difference between groups at any time with respect to heart rate, respiratory rate, blood pressure or SpO₂. Mean ± SD plasma histamine (nM ml^?1) for all groups was 1.72 ± 2.69 at baseline and 1.13 ± 1.18 at 25 minutes. There was no significant change in plasma histamine concentration in any group. Hydromorphone is effective for sedation in dogs and does not cause measurable increase in histamine. Sedation with hydromorphone is enhanced by acepromazine.     

The effects on the pharmacokinetics of intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous acetyl salicylate (aspirin) or probenecid

Ceftiofur sodium is a third-generation cephalosporin antibiotic. It is possible that non-steroidal anti-inflammatory drugs such as acetyl salicylate (aspirin) may be used concomitantly with ceftiofur sodium in dairy cattle. Therefore this study evaluated potential pharmacokinetic interactions between ceftiofur sodium and aspirin. In addition, this study evaluated the potential for interaction between ceftiofur and its active metabolites and the organic anion transporter. The organic anion transporter substrate used in this evaluation was probenecid. Ten healthy, non-pregnant, non-lactating dairy cows were used in a randomized complete three-way crossover design. In repeated experiments all cows were administered: (1) 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (2) 10 mg of probenecid per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (3) 26 mg of aspirin per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus. For treatment with ceftiofur sodium alone, the mean volume of distribution at steady-state V_d(33) was 0.2 ± 0.06 L/kg, the mean volume of distribution by the area method V_d(area) was 0.38 ± 0.22 L/kg, mean residence time (MRT) was 6.5 ± 1.8 h, mean residence time in peripheral tissues (MRT_p) was 2.6 ± 1.0 h, total body clearance (Cf) was 0.032 ± 0.013 L/kg/h and elimination rate constant (P) was 0.097 ± 0.044 h^-1(mean ± standard deviation). No statistically significant changes were detected as a result of preceding treatment with aspirin. Preceding treatment with probenecid resulted in a decrease in both Cl (0.007 ± 0.005 L/kg/h) and MRT_p (0.89 ± 0.45 h). These results suggest that ceftiofur or its metabolites may interact with the organic anion transporter, but that consideration of alterations to dose and dose interval may not be necessary when ceftiofur sodium is administered to the cow concomitantly with a single dose of aspirin.     

Cardiovascular effects following epidural injection of romifidine in isoflurane‐anaesthetized dogs

ObjectiveTo investigate the cardiovascular effects of epidural romifidine in isoflurane-anaesthetized dogs.Study designProspective, randomized, blinded experiment.AnimalsA total of six healthy adult female Beagles aged 1.25 ± 0.08 years and weighing 12.46 ± 1.48 (10.25–14.50) kg.MethodsAnaesthesia was induced with propofol (6–9 mg kg^?1) and maintained with 1.8–1.9% end-tidal isoflurane in oxygen. End-tidal CO₂ was kept between 35 and 45 mmHg (4.7–6.0 kPa) using intermittent positive pressure ventilation. Heart rate (HR), arterial blood pressure and cardiac output (CO) were monitored. Cardiac output was determined using a LiDCO monitor and the derived parameters were calculated. After baseline measurements, either 10 μg kg^?1 romifidine or saline (total volume 1 mL 4.5 kg^?1) was injected into the lumbosacral epidural space. Data were recorded for 1 hour after epidural injection. A minimum of 1 week elapsed between treatments.ResultsAfter epidural injection, the overall means (± standard deviation, SD) of HR (95 ± 20 bpm), mean arterial blood pressure (MAP) (81 ± 19 mmHg), CO (1.63 ± 0.66 L minute^?1), cardiac index (CI) (2.97 ± 1.1 L minute^?1 m^?2) and stroke volume index (SI) (1.38 ± 0.21 mL beat^?1 kg^?1) were significantly lower in the romifidine treatment compared with the overall means in the saline treatment [HR (129 ± 24 bpm), MAP (89 ± 17 mmHg), CO (3.35 ± 0.86 L minute^?1), CI (6.17 ± 1.4 L minute^?1 m^?2) and SI (2.21 ± 0.21 mL beat^?1 kg^?1)]. The overall mean of systemic vascular resistance index (SVRI) (7202 ± 2656 dynes seconds cm^?5 m^?2) after epidural romifidine injection was significantly higher than the overall mean of SVRI (3315 ± 1167 dynes seconds cm^?5 m^?2) after epidural saline injection.ConclusionEpidural romifidine in isoflurane-anaesthetized dogs caused significant cardiovascular effects similar to those reportedly produced by systemic romifidine administration.Clinical relevanceSimilar cardiovascular monitoring is required after epidural and systemically administered romifidine. Further studies are required to evaluate the analgesic effects of epidural romifidine.     

Pharmacokinetics of lincomycin following single intravenous administration in buffalo calves

Lincomycin 10 mg kg^?1, IV in buffalo calves followed two-compartment open model with high distribution rate constant α (11.2?±?0.42 h^?1) and K ₁₂/K ₂₁ ratio (4.40?±?0.10). Distribution half-life was 0.06?±?0.01 h and AUC was 41.6?±?1.73 μg mL^?1 h. Large Vd_area (1.15?±?0.03 L kg^?1) indicated good distribution of lincomycin in various body fluids and tissues. Peak plasma level of lincomycin (71.8?±?1.83 μg mL^?1) was observed at 1 min as expected by IV route. The elimination half-life and MRT of lincomycin were short (3.30?±?0.08 and 4.32?±?0.11 h, respectively). Lincomycin 10 mg kg^?1 IV at 12-h interval would be sufficient to maintain T?>?MIC above 60 % for bacteria with minimum inhibitory concentrations (MIC) values ≤1.6 μg mL^?1. Favourable pharmacokinetic profile in buffalo calves and a convenient dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin.