The effects of ketamine‐midazolam anesthesia on intraocular pressure in clinically normal dogs

Objective To determine the effects of intravenous ketamine‐midazolam anesthesia on intraocular pressure (IOP) in ocular normotensive dogs. Animals Thirteen adult mixed‐breed dogs. Procedures Dogs were randomly assigned to treatment (n = 7) and control (n = 6) groups. Dogs in the treatment group received intravenous ketamine 15 mg/kg and midazolam 0.2 mg/kg and dogs in the control group received intravenous saline. The time of intravenous drug injection was recorded (T₀). Measurements of IOP were then repeated 5 min (T₅) and 20 min (T₂₀) following the intravenous administration of ketamine‐midazolam combination and saline in both groups. Results Measurements showed normal IOP values in both groups. The mean ± SD baseline IOP values for treatment and control groups were 13.00 ± 1.47 and 10.33 ± 2.20, respectively. For baseline IOP values, there was no significant difference between treatment and control groups (P = 0.162). In the treatment group, the subsequent post‐treatment mean ± SD values were 15.64 ± 2.17 (5 min), and 14.92 ± 1.98 (20 min). There was no evidence of statistical difference between baseline values and post‐treatment values after treatment with ketamine‐midazolam (P₅ = 0.139; P₂₀ = 0.442). In control eyes, the mean ± SD values at 5 and 20 min were 10.41 ± 2.01 and 10.16 ± 1.69, respectively. There was no significant difference between baseline values and post‐treatment values in control group (P₅ = 1.000; P₂₀ = 1.000). Conclusion Ketamine‐midazolam combination has no clinically significant effect on IOP in the dog.     

Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows

Sellers, G., Lin, H. C., G. Riddell, M. G., Ravis, W. R., Lin, Y. J., Duran, S. H., Givens, M.D. Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows. J. vet. Pharmacol. Therap. 33 , 480–484. The purpose of this study was to evaluate the pharmacokinetics of ketamine in mature Holstein cows following administration of a single intravenous (i.v.) dose. Plasma and milk concentrations were determined using a high‐performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following i.v. administration, plasma T_max was 0.083 h and plasma C_max was 18 135 ± 22 720 ng/mL. Plasma AUC was 4484 ± 1,398 ng·h/mL. Plasma t_½β was 1.80 ± 0.50 h and mean residence time was 0.794 ± 0.318 h with total body clearance of 1.29 ± 0.70 L/h/kg. The mean plasma steady‐state volume of distribution was calculated as 0.990 ± 0.530 L/kg and volume of distribution based on area was calculated as 3.23 ± 1.51 L/kg. The last measurable time for ketamine detection in plasma was 8.0 h with a mean concentration of 24.9 ± 11.8 ng/mL. Milk T_max was detected at 0.67 ± 0.26 h with C_max of 2495 ± 904 ng/mL. Milk AUC till the last time was 6593 ± 2617 ng·h/mL with mean AUC milk to AUC plasma ratio of 1.99 ± 2.15. The last measurable time that ketamine was detected in milk was 44 ± 10.0 h with a mean concentration of 16.0 ± 9.0 ng/mL.     

Comparative Pharmacokinetics of Gentamicin after Intravenous,Intramuscular, Subcutaneous and Oral Administration in Broiler Chickens

The pharmacokinetics and bioavailability of gentamicin sulphate (5 mg/kg body weight) were studied in 50 female broiler chickens after single intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.) and oral administration. Blood samples were collected at time 0 (pretreatment), and at 5, 15 and 30 min and 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Gentamicin concentrations were determined using a microbiological assay and Bacillus subtillis ATCC 6633 as a test organism. The limit of quantification was 0.2 μg/ml. The plasma concentration–time curves were analysed using non-compartmental methods based on statistical moment theory. Following i.v. administration, the elimination half-life (t _1/2β), the mean residence time (MRT), the volume of distribution at steady state (V _ss), the volume of distribution (V _d,area) and the total body clearance (Cl_B) were 2.93 ± 0.15 h, 2.08 ± 0.12 h, 0.77 ± 0.05 L/kg, 1.68 ± 0.39 L/kg and 5.06 ± 0.21 ml/min per kg, respectively. After i.m. and s.c. dosing, the mean peak plasma concentrations (C _max) were 11.37 ± 0.73 and 16.65 ± 1.36 μg/ml, achieved at a post-injection times (t _max) of 0.55 ± 0.05 and 0.75 ± 0.08 h, respectively. The t _1/2β was 2.87 ± 0.44 and 3.48 ± 0.37 h, respectively after i.m. and s.c. administration. The V _d,area and Cl_B were 1.49 ± 0.21 L/kg and 6.18 ± 0.31 ml/min per kg, respectively, after i.m. administration and were 1.43 ± 0.19 L/kg and 4.7 ± 0.33 ml/min per kg, respectively, after s.c. administration. The absolute bioavailability (F) of gentamicin after i.m. administration was lower (79%) than that after s.c. administration (100%). Substantial differences in the resultant kinetics data were obtained between i.m. and s.c. administration. The in vitro protein binding of gentamicin in chicken plasma was 6.46%.     

A commercial foot pump for emergency ventilation of horses,proof‐of‐principle during equine field anaesthesia

At present there is no alternative to the use of a demand valve and pressurised oxygen for emergency ventilation in large animal field anaesthesia, therefore we aimed at providing a proof‐of‐principle of a small (2.5 l) commercial foot pump to provide emergency intermittent positive pressure ventilation (IPPV) in large animals. The study was performed during elective field anaesthesia for castration of 5 Haflinger stallions. Horses were premedicated with acepromazine i.m. after catheterisation of the jugular vein, further sedation was obtained with detomidine and butorphanol i.v. Anaesthesia was induced with ketamine and midazolam i.v. and maintained with a constant rate infusion of midazolam, ketamine and xylazine. After endotracheal intubation the foot pump, modified with a manually operated expiratory valve, was connected to the endotracheal tube and oxygen (6 l/min) was supplied. Anaesthesia was monitored using spirometry, respiratory gas analysis, pulse oximetry and arterial blood gas analysis. When arterial partial pressure of carbon dioxide (PaCO₂) exceeded 6.65 kPa, IPPV was provided by 2–4 consecutive compressions of the pump aiming at a tidal volume of 10 ml/kg bwt. The PaCO₂ was maintained at 6.18 ± 3.06 kPa (mean ± s.d.) with a respiratory rate of 4–10 breaths/min. The tidal volume was 2678–8300 ml with a peak inspiratory pressure of 24 ± 6.6 cmH₂O and a mean minute volume of 68.5 ± 13 l/min. Inspired oxygen concentration ranged from 26–46% (36 ± 7%) and arterial partial pressure of oxygen from 8.38–11.03 kPa (10.1 ± 0.93 kPa). The modified foot pump enables the practitioner to provide IPPV to large animals in emergency situations.     

Bioavailability,pharmacokinetics and residues of chloramphenicol in the chicken*

Anadón, A., Bringas, P., Martinez-Larrañaga, M.R., Diaz, M.J. Bioavailability, pharmacokinetics and residues of chloramphenicol in the chicken. J. vet. Pharmacol Therap. 17 , 52–58. The pharmacokinetic properties of chloramphenicol were determined in broiler chickens after two sinSle oral doses (30 and 50 mg/kS body weight) and after a single intravenous (i.v.) dose (30 mg/kg body weight). After oral and i.v. administration, the plasma concentration-time graph was characteristic of a two-compartment open model. After oral administration (30 and 50 mg/kg). chloramphenicol was absorbed rapidly (time to maximal concentration of 0.72 or 0.60 h) and eliminated with a mean half-life (t_½β) of 6.8 7 or 7.41 h, respectively. The bioavailability was 29% at 30 mg/kg chloramphenicol and 38% at 50 mg/kg chloramphenicol. Concentrations greater than 5 (m̈g/ml were achieved at 15 min and persisted up to 2 or 4 h post-administration, respectively. Statistically significant differences between the two routes of administration were found for the pharmacokinetic variables, half-lives of both distribution and elimination phases (t_½αt_½β) and apparent volume of distribution [V_d(area)]. The mean t_½β of chloramphenicol and i.v. administration was 5.23 h. Chloramphenicol was extensively metabolized into dehydrochloramphenicol (DH-CAP), nitrophenylaminopropanedione (NPAP) and nitroso-chlorampheni-col (NO-CAP) derivatives. Residues of chloramphenicol (CAP) and the three metabolites DH-CAP, NPAP and NO-CAP in kidney, liver and muscle were measured in chickens that received an oral dose of 50 mg/kg once daily for 4 days. The results indicate that CAP and DH-CAP residues were cleared slowly and were at or below the detection limit of 0.005 m̈g/ml within 12 days after dosing. However, at the time of slaughter (12 days), the NPAP and NO-CAP residues were detected in the tissue.     

Disposition Kinetics of Difloxacin After Intravenous,Intramuscular and Subcutaneous Administration in Calves

The pharmacokinetics of difloxacin (Dicural) was studied in a crossover study using three groups (n = 4) of male and female Friesian calves after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administrations of 5 mg/kg body weight. Drug concentration in plasma was determined by high-performance liquid chromatography using fluorescence detection. The plasma concentration–time data following i.v. administration were best fitted to a two-compartment open model and those following i.m. and s.c. routes were best fitted using one-compartment open model. The collected data were subjected to a computerized kinetic analysis. The mean i.v., i.m. and s.c. elimination half-lives (t _1/2β) were 5.56 ± 0.33 h, 6.12 ± 0.42 h and 7.26 ± 0.6 h, respectively. The steady-state volume of distribution (V _dss) was 1.12 ± 0.09 L/kg and total body clearance (Cl_B) was 2.19 ± 0.1 ml/(min. kg). The absorption half lives (t _1/2ab) were 0.38 ± 0.027 h and 2.1 ± 0.09 h, with systemic bioavailabilities (F) of 96.5% ± 6.4% and 84% ± 5.5% after i.m. and s.c. administration, respectively. After i.m. and s.c. dosing, peak plasma concentrations (C _max) of 3.38 ± 0.13 μg/ml and 2.18 ± 0.12 μg/ml were attained after (t _max) 1.22 ± 0.20 h and 3.7 ± 0.52 h. The MIC₉₀ of difloxacin for Mannheimia haemolytica was 0.29 ± 0.04 μg/ml. The AUC/MIC₉₀ and C _max/MIC₉₀ ratios for difloxacin following i.m. administration were 120 and 11.65, respectively and following s.c. administration were 97.58 and 7.51, respectively. Difloxacin was 31.7–36.8% bound to calf plasma protein. Since fluoroquinolones display concentration-dependent activities, the doses of difloxacin used in this study are likely to involve better pharmacodynamic characteristics that are associated with greater clinical efficacy following i.m. administration than following s.c. administration.     

Pharmacokinetics of ketamine and propofol combination administered as ketofol via continuous infusion in cats

Zonca, A., Ravasio, G., Gallo, M., Montesissa, C., Carli, S., Villa, R., Cagnardi, P. Pharmacokinetics of ketamine and propofol combination administered as ketofol via continuous infusion in cats. J. vet. Pharmacol. Therap.  35 , 580–587. The pharmacokinetics of the extemporaneous combination of low doses of ketamine and propofol, known as ‘ketofol’, frequently used for emergency procedures in humans to achieve safe sedation and analgesia was studied in cats. The study was performed to assess propofol, ketamine and norketamine kinetics in six female cats that received ketamine and propofol (1:1 ratio) as a loading dose (2 mg/kg each, IV) followed by a continuous infusion (10 mg/kg/h each, IV, 25 min of length). Blood samples were collected during the infusion period and up to 24 h afterwards. Drug quantification was achieved by HPLC analysis using UV‐visible detection for ketamine and fluorimetric detection for propofol. The pharmacokinetic parameters were deduced by a two‐compartment bolus plus infusion model for propofol and ketamine and a monocompartmental model for norketamine. Additional data were derived by a noncompartmental analysis. Propofol and ketamine were quantifiable in most animals until 24 and 8 h after the end of infusion, respectively. Propofol showed a long elimination half‐life (t_1/2λ2 7.55 ± 9.86 h), whereas ketamine was characterized by shorter half‐life (t_1/2λ2 4 ± 3.4 h) owing to its rapid biotransformation into norketamine. The clinical significance of propofol’s long elimination half‐life and low clearance is negligible when the drug is administered as short‐term and low‐dosage infusion. The concurrent administration of ketamine and propofol in cats did not produce adverse effects although it was not possible to exclude interference in the metabolism.     

Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim following intravenous, intramuscular and oral administration in ostriches (Struthio camelus)

A pharmacokinetic and bioavailability study of sulfadiazine combined with trimethoprim (sulfadiazine/trimethoprim) was carried out in fifteen healthy young ostriches after intravenous (i.v.), intramuscular (i.m.) and oral administration at a total dose of 30 mg/kg body weight (bw) (25 and 5 mg/kg bw of sulfadiazine and trimethoprim, respectively). The study followed a single dose, three periods, cross‐over randomized design. The sulfadiazine/trimethoprim combination was administered to ostriches after an overnight fasting on three treatment days, each separated by a 2‐week washout period. Blood samples were collected at 0 (pretreatment), 0.08, 0.25, 0.50, 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Following i.v. administration, the elimination half‐life (t_1/2β), the mean residence time (MRT), volume of distribution at steady‐state (V_d(ss)), volume of distribution based on terminal phase (V_d(z)), and the total body clearance (Cl_B) were (13.23 ± 2.24 and 1.95 ± 0.19 h), (10.06 ± 0.33 and 2.17 ± 0.20 h), (0.60 ± 0.08, and 2.35 ± 0.14 L/kg), (0.79 ± 0.12 and 2.49 ± 0.14 L/kg) and (0.69 ± 0.03 and 16.12 ± 1.38 mL/min/kg), for sulfadiazine and trimethoprim, respectively. No significant difference in C_max (35.47 ± 2.52 and 37.50 ± 3.39 μg/mL), t_max (2.47 ± 0.31 and 2.47 ± 0.36 h), t_½β (11.79 ± 0.79 and 10.96 ± 0.56 h), V_d(z)/F (0.77 ± 0.06 and 0.89 ± 0.07 L/kg), Cl_B/F (0.76 ± 0.04 and 0.89 ± 0.07) and MRT (12.39 ± 0.40 and 12.08 ± 0.36 h) were found in sulfadiazine after i.m. and oral dosing, respectively. There were also no differences in C_max (0.71 ± 0.06 and 0.78 ± 0.10 μg/mL), t_max (2.07 ± 0.28 and 3.27 ± 0.28 h), t_½β (3.30 ± 0.25 and 3.83 ± 0.33 h), V_d(z)/F (6.2 ± 0.56 and 6.27 ± 0.77 L/kg), Cl_B/F (21.9 ± 1.46 and 18.83 ± 1.72) and MRT (3.68 ± 0.19 and 4.34 ± 0.14 h) for trimethoprim after i.m. and oral dosing, respectively. The absolute bioavailability (F) was 95.41% and 86.20% for sulfadiazine and 70.02% and 79.58% for trimethoprim after i.m. and oral administration, respectively.     

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 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.     

Intravenous infusion of electrolyte solution changes pharmacokinetics of drugs: pharmacokinetics of ampicillin

The pharmacokinetics of ampicillin in dogs was determined after intravenous (i.v.) bolus and constant rate infusion. Ampicillin was administered to six beagle dogs as an i.v. bolus at 20 mg/kg and as a constant rate i.v. infusion (CRI) at 20 mg/kg during 8 h (0.042 mL/min/kg) in Ringer's lactate (Hartmann's) solution. The concentrations were determined by an LC/MS/MS method. After i.v. bolus, ampicillin total body clearance, apparent volume of distribution at steady‐state, mean residence time (MRT), and half‐life were 4.53 ± 0.70 mL/min/kg, 0.275 ± 0.044 L/kg, 61 ± 13 min, and 111 (85–169) min, respectively. The corresponding parameters calculated after CRI were 13.5 ± 1.06 mL/min/kg, 0.993 ± 0.415 L/kg, 73 ± 27 min, and 49 (31–69) min. Ampicillin concentration decreased by 30% in the Ringer's lactate infusion solution mostly during the first hour after preparation of the solution. Constant rate infusion of Ringer's lactate solution during 8 h caused significant changes in ampicillin pharmacokinetics. The results suggested that special attention should be given to drug pharmacokinetics when co‐administered intravenously with electrolyte solutions.     

Pharmacokinetics of ivermectin after maternal or fetal intravenous administration in sheep

In pregnant sheep at 120–130 days of gestational age, a study was undertaken in order to characterize the pharmacokinetics and transplacental exchange of Ivermectin after maternal or fetal intravenous administration. Eight pregnant Suffolk Down sheep of 73.2 ± 3.7 kg body weight (bw) were surgically prepared in order to insert polyvinyl catheters in the fetal femoral artery and vein and amniotic sac. Following 48 h of recovery, the ewes were randomly assigned to two experimental groups. In group 1, (maternal injection) five ewes were treated with an intravenous bolus of 0.2 mg ivermectin/kg bw. In group 2, (fetal injection) three ewes were injected with an intravenous bolus of 1 mg of ivermectin to the fetus through a fetal femoral vein catheter. Maternal and fetal blood and amniotic fluid samples were taken before and after ivermectin administration for a period of 144 h post‐treatment. Samples were analyzed by liquid chromatography (HPLC). A computerized non‐compartmental pharmacokinetic analysis was performed and the results were compared by means of the Student t‐test. The main pharmacokinetic changes observed in the maternal compartment were increases in the volume of distribution and in the half‐life of elimination (t_½β). A limited maternal‐fetal transfer of ivermectin was evidenced by a low fetal Cmax (1.72 ± 0.6 ng/mL) and AUC (89.1 ± 11.4 ng·h/mL). While the fetal administration of ivermectin resulted in higher values of clearance (554.1 ± 177.9 mL/kg) and lower values of t_½β (8.0 ± 1.4 h) and mean residence time (8.0 ± 2.9 h) indicating that fetal‐placental unit is highly efficient in eliminating the drug as well as limiting the transfer of ivermectin from the maternal to fetal compartment.     

Pharmacokinetics of vitacoxib in rabbits after intravenous and oral administration

This study describes the pharmacokinetics of vitacoxib in healthy rabbits following administration of 10 mg/kg intravenous (i.v.) and 10 mg/kg oral. Twelve New Zealand white rabbits were randomly allocated to two equally sized treatment groups. Blood samples were collected at predetermined times from 0 to 36 hr after treatment. Plasma drug concentrations were determined using UPLC‐MS/MS. Pharmacokinetic analysis was completed using noncompartmental methods via WinNonlin^? 6.4 software. The mean concentration area under curve (AUC_last) for vitacoxib was determined to be 11.0 ± 4.37 μg hr/ml for i.v. administration and 2.82 ± 0.98 μg hr/ml for oral administration. The elimination half‐life (T_1/2λz) was 6.30 ± 2.44 and 6.30 ± 1.19 hr for the i.v. and oral route, respectively. The C_max (maximum plasma concentration) and T_max (time to reach the observed maximum (peak) concentration at steady‐state) following oral application were 189 ± 83.1 ng/ml and 6.58 ± 3.41 hr, respectively. Mean residence time (MRT_last) following i.v. injection was 6.91 ± 3.22 and 11.7 ± 2.12 hr after oral administration. The mean bioavailability of oral administration was calculated to be 25.6%. No adverse effects were observed in any rabbit. Further studies characterizing the pharmacodynamics of vitacoxib are required to develop a formulation of vitacoxib for rabbits.     

Pharmacokinetics of oxytetracycline and therapeutic implications in veal calves

Pharmacokinetic parameters of oxytetracycline were analysed in healthy preruminant veal calves after intravenous, intramuscular and oral administration. The serum half-lives in the β-elimination phase of both 10% and 20% solutions after i.v. injection of 10 mg/kg were similar (7.07 ± 1.36 h and 7.16 ± 1.17 h, mean ± SD), whereas the total body clearance and the apparent volume of distribution were higher for the 20% solution. Serum concentrations above 0.5 μg/ml were maintained with both formulations during 12–24 h but were only above 4 μg/ml to 5 h. Intramuscular administration of the 20% solution gave a complete absorption with two rate constants of absorption, a faster (t_1/2a1= 0.27 h) and a slower one (t_1/2a2= 10.90 h) responsible for the delayed elimination half-life after this route of application (t_1/2β= 9.83 ± 1.35 h). Mean serum concentrations reached a maximum level of 3.01 ± 0.72 μg/ml at 4.01 ± 2.84 h and decreased to 0.5 μg/ml between 12 and 24 h. 50 mg/kg given orally with a milk replacer were found to have a mean bioavailability of 46.35%. A mean serum peak level of 4.99 ± 1.37 μg/ml was achieved at 9.16 ± 1.99 h and the mean concentration was still above 0.5 μg/ml after 48 h. The elimination half-life (t_1/2β= 10.66 ± 3.15 h) reflected the slow absorption step (t_1/2a2= 10.15 h) following that responsible for the initial faster absorption (t_1/2a2= 1.99 h). Comparison of the area under the serum curves gave mean values of 117% for tetracycline and of 53% for chlortetracycline relative to oxytetracycline (arbitrarily fixed at 100%) after identical oral dosage of the three tetracyclines. We also propose and discuss a dosage schedule based on minimal inhibitory concentrations of different susceptible pathogens     

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     

Midazolam and ketamine induction before halothane anaesthesia in ponies: cardiorespiratory, endocrine and metabolic changes

Six Welsh gelding ponies were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) prior to induction of anaesthesia with midazolam at 0.2 mg/kg and ketamine at 2 mg/kg i.v.. Anaesthesia was maintained for 2 h using 1.2 % halothane concentration in oxygen. Heart rate, electrocardiograph (ECG), arterial blood pressure, respiratory rate, blood gases, temperature, haematocrit, plasma arginine vasopressin (AVP), dynorphin, ß-endorphin, adrenocorticotropic hormone (ACTH), cortisol, dopamine, noradrenaline, adrenaline, glucose and lactate concentrations were measured before and after premedication, immediately after induction, every 20 min during anaesthesia, and at 20 and 120 min after disconnection. Induction was rapid, excitement-free and good muscle relaxation was observed. There were no changes in heart and respiratory rates. Decrease in temperature, hyperoxia and respiratory acidosis developed during anaes-thesia and slight hypotension was observed (minimum value 76 ± 10 mm Hg at 40 mins). No changes were observed in dynorphin, ß-endorphin, ACTH, catecholamines and glucose. Plasma cortisol concentration increased from 220 ± 17 basal to 354 ± 22 nmol/L at 120 min during anaesthesia; plasma AVP concentration increased from 3 ± 1 basal to 346 ± 64 pmol/L at 100 min during anaesthesia and plasma lactate concentration increased from 1.22 ± 0.08 basal to 1.76 ± 0.13 mmol/L at 80 min during anaesthesia. Recovery was rapid and uneventful with ponies taking 46 ± 6 min to stand. When midazolam/ketamine was compared with thiopentone or detomidine/ketamine for induction before halothane anaesthesia using an otherwise similar protocol in the same ponies, it caused slightly more respiratory depression, but less hypotension. Additionally, midazolam reduced the hormonal stress response commonly observed during halothane anaesthesia and appears to have a good potential for use in horses.     

Characterization of the pharmacokinetic disposition of levofloxacin in stallions after intravenous and intramuscular administration

The target of the present study was to investigate the plasma disposition kinetics of levofloxacin in stallions (n = 6) following a single intravenous (i.v.) bolus or intramuscular (i.m.) injection at a dose rate of 4 mg/kg bwt, using a two‐phase crossover design with 15 days as an interval period. Plasma samples were collected at appropriate times during a 48‐h administration interval, and were analyzed using a microbiological assay method. The plasma levofloxacin disposition was best fitted to a two‐compartment open model after i.v. dosing. The half‐lives of distribution and elimination were 0.21 ± 0.13 and 2.58 ± 0.51 h, respectively. The volume of distribution at steady‐state was 0.81 ± 0.26 L/kg, the total body clearance (Cl_tot) was 0.21 ± 0.18 L/h/kg, and the areas under the concentration–time curves (AUCs) were 18.79 ± 4.57 μg.h/mL. Following i.m. administration, the mean t_1/2el and AUC values were 2.94 ± 0.78 h and 17.21 ± 4.36 μg.h/mL. The bioavailability was high (91.76% ± 12.68%), with a peak plasma mean concentration (C_max) of 2.85 ± 0.89 μg/mL attained at 1.56 ± 0.71 h (T_max). The in vitro protein binding percentage was 27.84%. Calculation of efficacy predictors showed that levofloxacin might have a good therapeutic profile against Gram‐negative and Gram‐positive bacteria, with an MIC ≤ 0.1 μg/mL.     

Pharmacokinetics,oral bioavailability and tissue distribution of azithromycin in cats

Azithromycin is the first of a class of antibiotics classified as azalides. In an initial experiment four cats were given a single dose of azithromycin 5 mg/kg orally (p.o.), followed 2 weeks later by a single intravenous bolus (i.v.) dose of 5 mg/kg. Subsequently, six cats were given [¹⁴C]azithromycin p.o. in a single dose of 5.4 mg/kg for the study of tissue distribution and metabolism. In both experiments, serial blood samples were collected and the plasma assayed for unchanged azithromycin to determine various pharmacokinetic parameters. After p.o. administration, bioavailability was 58% and absorption rapid with a t_max of 0.85±0.72 h and a C_max of 0.97 ± 0.65 μg/mL The harmonic mean terminal t_1/2 after i.v. administration was 35 h. Tissue half-lives varied from 13 h in fat to 72 h in cardiac muscle. Three metabolites were identified in bile. Unchanged azithromycin accounted for 100% of the total radioactivity in lung and skin tissues when assayed. In comparison with other species, the bioavailability in cats is higher than in humans but lower than in dogs. As in the dog, > 50% of the azithromycin-related material in feline bile was unchanged azithromycin.     

The effects of glibenclamide,a blocker of K+ ATP-sensitive potassium channels,on diaphragmatic fatigue during endotoxaemia in pigs

An in vivo porcine model of endotoxaemia was used to study the effects of glibenclamide, a K⁺ ATP-sensitive potassium channel blocker. Escherichia coli lipopolysaccharides (LPS, 70 g/kg, i.v., as a bolus) were infused into anaesthetized, mechanically ventilated, indomethacin-treated pigs. After 120 min of endotoxaemia, glibenclamide was administered (10 mg/kg, i.v., over 5 min) to half the pigs. The steength at different frequencies of stimulation (10, 20, 30, 50 Hz, 20 V, 1 s) and the endurance capacity (10 Hz, 20 V, 30 s) of the diaphragm were evaluated after 120 min of endotoxaemia and 5, 10, 20 and 30 min after drug infusion. Glibenclamide transiently increased the blood pressure without changing the decreased cardiac output and at the same time further impaired the diaphragmatic activity. The reduced ability of the diaphragm to generate force in response to different electrical stimulations was shown by a significant reduction in strength. The endurance index decreased 5 min after glibenclamide infusion, returning to the pre-glibenclamide values by 150 min. These results indicate that glibenclamide modifies the activity of vascular smooth muscle and of the diaphragm.Abbreviations BP blood pressure - CO cardiac output - LPS lipopolysaccharides - Glib glibenclamide - i.m. intramuscular - i.v. intravenous - SEM standard error of the mean - v/v volume/volume P _ab, abdominal pressure - P _di transdiaphragmatic pressure - P _oes oesophageal pressure