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Increasing use of pigs as models in translational research, and growing focus on animal welfare are leading to better use of effective analgesics and anaesthetics when painful procedures are performed. However, there is a gap in basic knowledge such as pharmacokinetics of different anaesthetics in these species. The main objective of our study was to determine the pharmacokinetics of levobupivacaine in domestic pigs. Twelve female grower pigs weighing 31.17 ± 4.6 kg were subjected to general anaesthesia and experimental surgery, at the end of which they received 1 mg/kg levobupivacaine via peri-incisional subcutaneous infiltration. Plasma samples were collected before administration of levobupivacaine and at 0.5, 1, 2, 4, 8, 12, 24 and 48 h thereafter. Concentrations of levobupivacaine were determined by liquid chromatography coupled with tandem mass spectrometry. Following single dose of levobupivacaine, all animals had measurable plasma concentrations 0.5 h after drug administration, with most peak concentrations observed at the 1-h time point. In all 12 animals, levobupivacaine was below the limit of quantification 48 h after drug administration. The mean maximum plasma concentration, area under the curve and half-life were determined to be 809.98 μg/l, 6552.46 μg/l h and 6.25 h, respectively. Plasma clearance, volume of distribution and weight-normalized volume of distribution were 4.41 l/h, 35.57 l and 1.23 l/kg, respectively. Peak plasma concentrations in our study were well below concentrations that were found to produce toxicity in pigs., Competing Interests: Declaration of conflicting interestsThe authors have no conflicts of interest to declare.

Pain is a phenomenon present in the majority of the population, affecting, among others, the elderly, overweight people, and especially recently operated patients, analgesia being necessary. In the specific case of relief of postoperative pain, different kinds of anesthetics are being used, among them bupivacaine, a widely used drug which promotes long-lasting analgesic effects. However, cardiotoxicity and neurotoxicity are related to its repetitive use. To overcome these shortcomings, Novabupi® (a racemic mixture) was developed and is marketed as an injectable solution. This formulation contains an enantiomeric excess of the levogyre isomer, which has reduced toxicity effects. Seeking to rationalize its use by extending the duration of effect and reducing the number of applications, the objectives of this work were to develop and evaluate liposomes containing Novabupi (LBPV), followed by incorporation into thermogel. Liposomes were prepared using the lipid hydration method, followed by size reduction using sonication, and the developed formulations were characterized by hydrodynamic diameter, polydispersity index (PDI), surface zeta potential, and encapsulation efficiency. The selected optimal liposomal formulation was successfully incorporated into a thermogel without loss of thermoresponsive properties, being suitable for administration as a subcutaneous injection. In the ex vivo permeation studies with fresh rodent skin, the thermogel with liposomes loaded with 0.5% LBPV (T-gel formulation 3) showed higher permeation rates compared to the starting formulation, thermogel with 0.5% LBPV (T-Gel 1), which will probably translate into better therapeutic benefits for treatment of postoperative analgesia, especially with regard to the number of doses applied.

Levobupivacaine is a long-acting amide local anaesthetic used in analgesia and anaesthesia. Like other local anaesthetic drugs, levobupivacaine exhibits effects on motor and sensory nerves by inhibiting the opening of voltage-gated sodium channels, and hence propagation of neuronal action potentials. Levobupivacaine is the S(-) stereoisomer of dextrobupivacaine, although both are used commercially in the racemic form bupivacaine. A favourable safety and drug effect profile for levobupivacaine has led to widespread use. Levobupivacaine is generally well tolerated but dose adjustment is important in populations such as paediatrics and the elderly. The pharmacokinetic properties of levobupivacaine are similar to that of bupivacaine; both extensively metabolised in the liver, and excreted in the urine and faeces. In vitro, animal model and human studies confirm a lower risk of cardiac and central nervous system toxicity with levobupivacaine compared with bupivacaine. Clinical trials of relative potency are impaired by the variability in chosen endpoints for sensory and motor function blockade, but clinically significant differences in potency are minor, with most clinical trials showing similar duration and quality of anaesthesia between levo- and racemic bupivacaine. In practice, levobupivacaine is most commonly used in regional anaesthesia, neuraxial anaesthesia and local infiltration analgesia. This review includes an appraisal of evidence from clinical trials of the pharmacokinetic and pharmacodynamic properties of levobupivacaine.

Background: Levobupivacaine is commonly used during transversus abdominis plane (TAP) block in pediatric patients. However, the dosing regimen is still empirical, and the pharmacokinetic properties of levobupivacaine are not considered. Here, the pharmacokinetics of levobupivacaine during an ultrasound-guided TAP block were evaluated to optimize dosing regimen, regarding the between-subject variability (BSV) and the volume of levobupivacaine injected., Method: The clinical trial (prospective, randomized, double-blind study protocol) was conducted in 40 children aged 1-5 years, who were scheduled for inguinal surgery. Each patient received 0.4 mg/kg of levobupivacaine with a volume of local anesthesia solution adjusted to 0.2 mL/kg of 0.2% or 0.4 mL/kg of 0.1% levobupivacaine. Blood samples were collected at 5, 15, 20, 25, 30, 45, 60, and 75 minutes after the block injection. The population pharmacokinetic analysis was performed using the NONMEM software., Results: From the pharmacokinetic parameters obtained, median Cmax, tmax,, and area under the concentration versus time curve were 0.315 mg/L, 17 minutes, and 41 mg/L·min, respectively. BSV of clearance was explained by weight. At the dose regimen of 0.4 mg/kg, none of the infants showed signs of toxicity, but in 13 patients, TAP block failed. After analysis, BSV for absorption rate constant, distribution volume, and clearance were 81%, 47%, and 41%, respectively. Residual unexplained variability was estimated to be 14%., Conclusions: For improved efficiency in the pediatric population, the dose of levobupivacaine should be greater than 0.4 mg/kg. Children's weight should be considered to anticipate any risk of toxicity.

Objective: To compare the perioperative effects and pharmacoeconomics of peripheral nerve blocks (PNBs) versus fentanyl target-controlled infusion (fTCI) in dogs undergoing tibial plateau levelling osteotomy (TPLO)., Study Design: Randomized clinical study., Animals: A total of 39 dogs undergoing unilateral TPLO., Methods: After acepromazine and methadone, anaesthesia was induced with propofol and maintained with isoflurane. Dogs were allocated to group fTCI [target plasma concentration (TPC) 1 ng mL -1 ] or group PNB (nerve stimulator-guided femoral-sciatic block using 0.2 and 0.1 mL kg -1 of levobupivacaine 0.5%, respectively). If nociceptive response occurred, isoflurane was increased by 0.1%, and TPC was increased by 0.5 ng mL -1 in group fTCI; a fentanyl bolus (1 μg kg -1 ) was administered in group PNB. During the first 24 postoperative hours, methadone (0.2 mg kg -1 ) was administered intramuscularly according to the Short Form Glasgow Composite Pain Scale, or if pain was equal to 5/24 or 4/20 for two consecutive assessments, or if the dog was non-weight bearing. The area under the curve (AUC) of pain scores, cumulative postoperative methadone requirement, food intake and pharmacoeconomic implications were calculated., Results: Incidence of bradycardia (p = 0.025), nociceptive response to surgery (p = 0.041) and AUC of pain scores (p < 0.0001) were greater in group fTCI. Postoperatively, 16/19 (84.2%) and eight/20 (40%) dogs in groups fTCI and PNB, respectively, were given at least one dose of methadone (p = 0.0079). Food intake was greater in group PNB (p = 0.049). Although total cost was not different (p = 0.083), PNB was more cost-effective in dogs weighing >15 kg., Conclusions and Clinical Relevance: Compared with group fTCI, incidence of bradycardia, nociceptive response to surgery, postoperative pain scores, cumulative methadone requirement were lower, and food intake was greater in group PNB, with an economic advantage in dogs weighing >15 kg., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: The transversus abdominis plane (TAP) block has become a common regional anesthesia technique for pain management in a wide variety of abdominal procedures. Evidence to support any particular local anesthetic regimen as well as pharmacokinetic and systemic toxicity risks of TAP block remain insufficiently studied in children. The aim of this study was to compare the analgesic effects and investigate pharmacokinetic profile of levobupivacaine after ultrasound-guided TAP block using a low volume/high concentration (LVHC) or a high volume/low concentration (HVLC) solution in children., Methods: This prospective randomized study included children scheduled for day-case inguinal surgery. Children were randomized to receive TAP block using 0.4 mg·kg levobupivacaine as either HVLC (0.2 mL·kg of 0.2% levobupivacaine) or LVHC (0.1 mL·kg of 0.4% levobupivacaine). The primary outcome was the number of children who required opioid rescue analgesia postoperatively. Pharmacokinetic profile study of levobupivacaine was also performed., Results: Seventy patients were equally randomized, and 65 were included in the final analysis. Seventy-one percent of patients did not require any postoperative opioid analgesia. The number of patients who received rescue analgesia was 12 (35%) in the LVHC group and 7 (23%) in the HVLC group (relative risk, 0.64; 95% confidence interval [CI], 0.29-1.42; P = .26). Mean pain scores (FLACC [faces, legs, activity, cry, and consolability]) at postanesthesia care unit discharge did not differ between LVHC and HVLC groups, respectively, 0.39 ± 0.86 and 1 ± 1.71 with mean group difference -0.60 (95% CI, -1.27 to 0.06; P = .08). The pharmacokinetic profile of levobupivacaine was comparable in the 2 groups: the mean total and free levobupivacaine peak concentrations were 379 ± 248 and 3.95 ± 3.16 ng·mL, respectively, occurring 22.5 ± 11 minutes after injection. The highest total and free levobupivacaine concentrations collected, respectively, 1360 and 15.1 ng·mL, remained far below theoretical toxic thresholds., Conclusions: In children, quality of postoperative pain control provided by TAP block using levobupivacaine 0.4 mg·kg administered as either HVLC or LVHC did not differ and was associated with a very low risk of local anesthetic systemic toxicity.

Background: The local anesthetic, levobupivacaine, is the safer enantiomer of racemic bupivacaine. Present protocols for levobupivacaine are based on studies and pharmacokinetic modeling with racemic bupivacaine., Aims: The aim is to investigate total serum levobupivacaine concentrations after a caudalepidural loading dose followed by a maintenance infusion over 48 hours in infants aged 3-6 months., Methods: The clinical trial was conducted in eight infants aged 3-6 months, undergoing bladder exstrophy repair. Pharmacokinetic modeling allowed optimization of clinical sampling to measure total levobupivacaine and α 1 -acid glycoprotein and prediction of the effect of α 1 -acid glycoprotein on levobupivacaine plasma protein binding., Results: The observed median total levobupivacaine serum concentration was 0.30 mg/L (range: 0.20-0.70 mg/L) at 1 hour after the loading dose of 2 mg/kg. The median total levobupivacaine concentration after 47 hours of infusion, at 0.2 mg/kg/h, was 1.21 mg/L (0.07-1.85 mg/L). Concentrations of α 1 -acid glycoprotein were found to rise throughout the study period. Pharmacokinetic modeling suggested that unbound levobupivacaine quickly reached steady state at a concentration of approximately 0.03 mg/L., Conclusion: The study allows the development of a pharmacokinetic model, combining levobupivacaine and α 1 -acid glycoprotein data. Modeling indicates that unbound levobupivacaine quickly reaches steady state once the infusion is started. Simulations suggest that it may be possible to continue the infusion beyond 48 hours., (© 2018 John Wiley & Sons Ltd.)

Background: Transversus abdominis plane block is increasingly used for post-Caesarean section analgesia. Cases of toxicity and the limited pharmacokinetic information during pregnancy motivated this study. The objective of the study was to characterise and compare the pharmacokinetics of levobupivacaine with epinephrine in tranversus abdominis plane block, in post-Caesarean section patients and healthy volunteers., Methods: After approval by the Ethics Committee, we collected data from 12 healthy parturients after elective Caesarean section (Study 1) and data from 11 healthy male volunteers from a previous study (Study 2). Transversus abdominus plane block was performed under ultrasound guidance. The following injectates were used: levobupivacaine 0.25%, 20 ml with epinephrine 5 μg ml -1 (Study 1) per side; 20 ml of the same solution (unilateral block) (study 2). The plasma venous concentration of levobupivacaine was measured serially for 90 min. Pharmacokinetic parameters (volume of distribution, clearance, and absorption half-life) were estimated using a non-linear mixed effects model (NONMEM). Simulation in 1000 patients estimated the maximum concentration and the time to reach it after bilateral transversus abdominis plane block., Results: Venous concentrations were below toxic levels (2.62 mg L -1 ). Levobupivacaine volume of distribution after Caesarean section was higher than in healthy volunteers [172 L (70 kg) -1 (95% confidence interval: 137-207) vs 94.3 L (70 kg) -1 (95% CI: 62-128); P<0.01]. Clearance and absorption half-life were similar. The simulation showed that maximum levobupivacaine concentration is lower and occurs later in postpartum patients (P<0.01). Postoperative analgesia was effective., Conclusions: Postpartum women reached relatively low plasma concentrations of levobupivacaine after transversus abdominal plane block given a volume of distribution 80% higher than volunteers, which could confer a greater margin of safety., Clinical Trial Registration: NCT02852720., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)