Plasma Lidocaine Concentrations Research Articles

Propofol does not alter the protein binding and unbound concentration of lidocaine at clinically targeted plasma concentrations in vitro – A short communication

BackgroundIntravenous lidocaine is increasingly used as an analgesic adjunct during general anaesthesia. Lidocaine is highly protein-bound and changes to binding can alter drug efficacy or toxicity. We aimed to measure the effect of various propofol and lidocaine plasma concentration combinations on the protein binding and concentration of lidocaine in vitro. MethodsKnown targeted concentrations of propofol and lidocaine were added to drug-free human plasma in vitro. Samples were prepared and analysed in various clinically relevant concentration combinations; propofol at 0, 2, 4 and 6 µg/mL, and lidocaine at 1, 3 and 5 µg/mL. The total and unbound concentrations of lidocaine were measured by ultra-high performance liquid chromatography-mass spectrometry and percentage protein binding was determined. Data were presented as mean and standard deviation (SD) and differences between groups analysed. ResultsThe overall mean protein binding of lidocaine was 68.8% (SD 5.5, range 57.5–80.9%). Beta regression analysis revealed no statistically significant difference in lidocaine percentage binding across a range of propofol and lidocaine concentration combinations. ConclusionPropofol did not alter the unbound and free pharmacologically active proportion of lidocaine at different clinically targeted concentrations of propofol and lidocaine in plasma in vitro. The percentage of plasma protein binding of lidocaine in this study was consistent with previously published results.

Is Dosage Adjustment Based on Age Necessary for Intravenous Lidocaine in Patients Undergoing General Anesthesia: A Prospective Multi-Arm Comparative Study

It remains unclear whether dosage adjustment of intravenous lidocaine is necessary during general anesthesia for elderly patients over 75 years old. This study aimed to investigate the effects of age on the pharmacokinetics (PK) and safety of intravenous lidocaine in patients undergoing general anesthesia. A total of 599 plasma samples were collected from 76 general anesthesia patients across three age groups: 18–64, 65–74, and ≥ 75 years. Lidocaine was administered intravenously at a dose of 1.5 mg/kg for the 18–64 and 65–74 years groups, while the dose was adjusted to 1.0 mg/kg for the ≥ 75 years group. The plasma concentrations of lidocaine and its active metabolites were measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were analyzed using a noncompartmental analysis. The results revealed no significant age-related differences in the PK of lidocaine and its metabolites. Among the three age groups, over 90 % of patient achieved a lidocaine concentration within a safe and effective range when the dosage was normalized to 1.5 mg/kg. In conclusion, age-based dosage adjustment was unnecessary for intravenous lidocaine in patients below 86 years undergoing general anesthesia.

Safety of perioperative intravenous lidocaine in liver surgery - A pilot study.

Perioperative lidocaine infusion has many interesting properties such as analgesic effects in the context of enhanced recovery after surgery. However, its use is limited in liver surgery due to its hepatic metabolism. This prospective, monocentric study was conducted from 2020 to 2021. Patients undergoing liver surgery were included. They received a lidocaine infusion protocol until the beginning of hepatic transection (bolus dose of 1.5 mg kg-1, then a continuous infusion of 2 mg kg-1 h-1). Plasma concentrations of lidocaine were measured four times during and after lidocaine infusion. Twenty subjects who underwent liver resection were analyzed. There was 35% of preexisting liver disease before tumor diagnosis, and 75% of liver resection was defined as "major hepatectomy." Plasmatic levels of lidocaine were in the therapeutic range. No blood sample showed a concentration above the toxicity threshold: 1.6 (1.3-2.1) μg ml-1 one hour after the start of infusion, 2.5 (1.7-2.8) μg ml-1 at the end of hepatic transection, 1.7 (1.3-2.0) μg ml-1 one hour after the end of infusion, and 1.2 (0.8-1.4) μg ml-1 at the end of surgery. Comparative analysis between the presence of a preexisting liver disease or not and the association of intraoperative vascular clamping or not did not show significant difference concerning lidocaine blood levels. Perioperative lidocaine infusion seems safe in the field of liver surgery. Nevertheless, additional prospective studies need to assess the clinical usefulness in terms of analgesia and antitumoral effects.

Pharmacokinetics of intravenous and topical lidocaine in patients undergoing thoracoscopic pulmonary resection: a comparative study.

Lidocaine was the commonly used local anesthetic. The present study aimed to compare the pharmacokinetics of intravenous and topical lidocaine in patients undergoing thoracoscopic pulmonary resection. Sixty patients who were scheduled for thoracoscopic pulmonary resection were screened and randomly assigned to the intravenous lidocaine group and topical lidocaine group. After induction, the patient in the intravenous group was given an intravenous bolus of 1.5 mg/kg lidocaine, while the patient in the topical group was given 3.0 mg/kg lidocaine via the "spray-as-you-go" method. Arterial blood was sampled at preset intervals, and plasma concentrations of lidocaine and its metabolites [monoethylglycinexylidide (MEGX) and glycinexylidide (GX)] were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Following intravenous administration, plasma lidocaine concentration reached its peak with a time to reach Cmax (Tmax) of 0.05 h and then decreased in a biphasic manner with a very short half-life time (T1/2) of 1.85 h. After topical administration, lidocaine was well absorbed, with Tmax of 0.21 h and bioavailability of 71.02%. The mean Tmax, Cmax, and area under the curve from the time (AUC0-t) of MEGX and GX were higher in the topical group than in the intravenous group. There were no obvious differences in the Cmax, T1/2, clearance, or apparent volume of distribution of lidocaine between the two groups. No obvious adverse events were observed. Topical administration of 3 mg/kg lidocaine via the "spray-as-you-go" method is an effective and safe technology for patients undergoing thoracoscopic pulmonary resection.

Comparative evaluation of the perioperative anesthesia methods for cancer patients undergoing pancreaticoduodenectomy

BACKGROUND: Pancreatoduodenal resections are one of the most traumatic and technically complex interventions in abdominal surgery. The correct anesthetic management and pain relief allow to substantially reduce the risk of perioperative complications, which remains high even in high-volume oncology centers with extensive experience. Finding new components and methods of anesthesia combined with evaluation of their effectiveness and safety remains a pressing issue.
 AIM: To evaluate the efficacy and safety of using intravenous lidocaine infusion as a component of anesthesia and postoperative analgesia in cancer patients during pancreatoduodenal resection.
 MATERIALS AND METHODS: We analyzed the course of anesthesia, operation and postoperative period of 43 patients (mean age 63.2±7.1 years) undergoing pancreaticoduodenectomy. For the purposes of the study, patients were randomly divided into 2 groups, based on anesthesia method: for the first group (n=19) we used epidural analgesia as a component of perioperative anesthesia, for the second group (n=24) we used prolonged intravenous infusion of lidocaine at an average dose of 1 mg/(kg×h). We analyzed the severity of pain syndrome according to Numeric rating scale for pain in postoperative period, as well as opioid requirement, the time of gastrointestinal function recovery, and post-operative complications frequency. In order to prevent systemic toxicity, drug monitoring was carried out — the determination of the plasma concentration of lidocaine.
 RESULTS: Perioperative opioid requirement was comparable between groups, with no statistically significant differences observed. The degree of pain syndrome according to the Numeric rating scale for pain did not differ statistically, except for the number of points during activation on day 3: 4.00 (95% confidence interval 3.49–4.51) for epidural analgesia group, compared to 3.12 (95% confidence interval 2.64–3.61) for lidocaine infusion group, p=0.014. There was also a statistically significant increase in infusion volume for epidural analgesia group compared to lidocaine infusion group [8.83 ml/(kg×h) (Q1=7.90; Q3=10.06) and 7.33 ml/(kg×h) (Q1=6.28–Q3=8.49) respectively, p=0.034], as well as a greater need for intraoperative vasopressor support among the patients [15 (78.9%) and 10 (43.5%) respectively, p=0.029]. In the lidocaine group, the time to onset of peristalsis was significantly shorter than in the epidural analgesia group [median 48.0 h (Q1=48.00; Q3=72.00) compared to median 60.0 h (Q1=36.00; Q3=64.50) respectively, p=0.042]. The frequency of postoperative complications did not differ between the groups.
 CONCLUSION: Based on a comparative analysis of the study results, it can be concluded that prolonged intravenous infusion of lidocaine, as a component of perioperative anesthetic protection during pancreatoduodenal resections, is safe and comparable in terms of analgesic efficacy to epidural blockade.

Efficacy of prolonged intravenous lidocaine infusion for postoperative movement-evoked pain following hepatectomy: a double-blinded, randomised, placebo-controlled trial

BackgroundThe analgesic effect of intravenous lidocaine varies with the duration of lidocaine infusion and surgery type. We tested the hypothesis that prolonged lidocaine infusion alleviates postoperative pain in patients recovering from hepatectomy over the first 3 postoperative days. MethodsPatients undergoing elective hepatectomy were randomly assigned to receive prolonged i.v. lidocaine treatment or placebo. The primary outcome was incidence of moderate-to-severe movement-evoked pain at 24 h postoperatively. The secondary outcomes included incidence of moderate-to-severe pain during movement and at rest throughout the first 3 postoperative days, postoperative opioid consumption, and pulmonary complications. Plasma lidocaine concentration was also monitored. ResultsWe enrolled 260 subjects. Intravenous lidocaine lowered the incidence of moderate-to-severe movement-evoked pain at 24 h and 48 h postoperatively (47.7% vs 67.7%, P=0.001; 38.5% vs 58.5%, P=0.001) and reduced movement-evoked pain scores (3.7 [1.7] vs 4.2 [1.6]; mean difference 0.5 [95% confidence interval {CI}: 0.1–0.9]; P=0.018) and morphine equivalent consumption (47.2 [16.7] mg vs 52.6 [19.2] mg; mean difference 5.4 mg [95% CI: 1.0–9.8]; P=0.016) at 24 h postoperatively. Lidocaine also lowered the incidence of postoperative pulmonary complications (23.1% vs 38.5%; P=0.007). Median plasma lidocaine concentrations were 1.5, 1.9, and 1.1 μg ml−1 (inter-quartile ranges: 1.1–2.1, 1.4–2.6, and 0.8–1.6, respectively) after bolus injection, at the end of the surgery, and 24 h postoperatively. ConclusionsProlonged intravenous lidocaine infusion reduced the incidence of moderate-to-severe movement-evoked pain for 48 h after hepatectomy. However, the reduction in pain scores and opioid consumption by lidocaine was below the minimal clinically important difference. Clinical trial registrationNCT04295330.

Influence of Constant Rate Infusions of Fentanyl Alone or in Combination With Lidocaine and Ketamine on the Response to Surgery and Postoperative Pain in Isoflurane Anesthetized Dogs Undergoing Unilateral Mastectomy: A Randomized Clinical Trial

The aim of this study was to compare the effects of constant rate infusions (CRI) of fentanyl alone or combined with lidocaine and ketamine (FLK), on physiological parameters, isoflurane requirements and the number of postoperative analgesic rescues in dogs undergoing unilateral mastectomy. Twenty-two dogs were premedicated with acepromazine 0.02 mg/kg and morphine 0.5 mg/kg and anesthetized with propofol and isoflurane. Dogs were randomly assigned to 1 of 2 groups: Fentanyl group (fentanyl 5 µg/kg loading dose [LD] and 9 µg/kg/h CRI; n = 11); FLK group (fentanyl [same doses]; lidocaine 2 mg/kg LD and 3 mg/kg/h CRI; ketamine 1.0 mg/kg LD and 0.6 mg/kg/h CRI; = 11). Intraoperative evaluations were performed before the start of surgery and administration of the treatments (T0); three minutes after the LD (T1); during incision and tissue divulsion (T2); during closure of the surgical wound (T3). Meloxicam (0.1 mg/kg) was administered at T3. Blood samples were collected for determination of plasma concentrations of fentanyl, lidocaine and ketamine. Pain scores and the number of postoperative analgesic rescues with morphine (0.5 mg/kg) were evaluated for 24 hours postoperatively using the short form of the Glasgow Composite Measure Pain Scale. Compared to T0, significant decreases in heart rate (from 84 ± 28 to 53 ± 16 bpm in the Fentanyl group and from 93 ± 16 to 63 ± 15 bpm in FLK) and mean arterial pressure (from 61 ± 5 to 49 ± 10 mmHg in Fentanyl and from 59 ± 3 to 38 ± 6 mmHg in FLK) were observed at T1. Arterial hypotension was transient, with normalization of values at T2 and T3. The expired fraction of isoflurane did not differ significantly between the groups. Plasma concentrations of fentanyl, lidocaine and ketamine remained within the therapeutic range. Postoperatively, the number of dogs requiring analgesic rescue was significantly lower in the FLK (0/11, 0%) than in the Fentanyl group (5/11, 45%). In dogs administered morphine and meloxicam as part of the anesthesia protocol, an intraoperative CRI of FLK abolished the requirement for postoperative analgesic rescue for 24 hours in dogs undergoing mastectomy.

Effects of two continuous infusion doses of lidocaine on isoflurane minimum anesthetic concentration in chickens

ObjectiveTo assess the effect of two intravenous (IV) doses of lidocaine on the minimum anesthetic concentration (MAC) of isoflurane in chickens. Study designBlinded, prospective, randomized, experimental crossover study. AnimalsA total of six adult female chickens weighing 1.90 ± 0.15 kg. MethodsChickens were anesthetized with isoflurane and mechanically ventilated. Isoflurane MAC values were determined (T0) in duplicate using an electrical noxious stimulus and the bracketing method. After MAC determination, a low dose (LD; 3 mg kg–1 followed by 3 mg kg–1 hour–1) or high dose (HD; 6 mg kg−1 followed by 6 mg kg−1 hour–1) of lidocaine was administered IV. MAC determination was repeated at 1.5 (T1.5) and 3 (T3) hours of lidocaine administration and blood was collected for analysis of plasma lidocaine and monoethylglycinexylidide (MEGX) concentrations. Pulse rate, peripheral hemoglobin oxygen saturation, noninvasive systolic arterial pressure and cloacal temperature were recorded at T0, T1.5 and T3. Treatments were separated by 1 week. Data were analyzed using mixed-effects model for repeated measures. ResultsMAC of isoflurane (mean ± standard deviation) at T0 was 1.47 ± 0.18%. MAC at T1.5 and T3 was 1.32 ± 0.27% and 1.26 ± 0.09% (treatment LD); and 1.28 ± 0.06% and 1.30 ± 0.06% (treatment HD). There were no significant differences between treatments or times. Maximum plasma lidocaine concentrations at T3 were 496 ± 98 and 1200 ± 286 ng mL–1 for treatments LD and HD, respectively, and were not significantly different from T1.5. With treatment HD, plasma concentration of MEGX was significantly higher at T3 than at T1.5. Physiological variables were not significantly different among times with either treatment. Conclusions and clinical relevanceAdministration of lidocaine did not significantly change isoflurane MAC in chickens. Within treatments, plasma lidocaine concentrations were not significantly different at 1.5 and 3 hours.

Lidocaine Intraoperative Infusion Pharmacokinetics during Partial Hepatectomy for Living Liver Donation.

Postoperative pain associated with open partial hepatectomy can be intense and persistent. The multimodal approach used to lessen this problem includes an intraoperative intravenous infusion of lidocaine hydrochloride. Decreased hepatic metabolism after resection raises concerns about safe lidocaine dosing in this patient population. The hypothesis was that the elimination clearance of lidocaine and its metabolites, monoethylglycinexylidide and glycinexylidide, is reduced after a partial hepatectomy, as reflected by observed plasma concentrations that are higher and have a longer half-life than expected based on pharmacokinetic modeling (estimated for normal liver function). Secondarily, this study postulated that plasma concentrations of lidocaine, monoethylglycinexylidide, and glycinexylidide do not reach toxic concentrations with institutional protocol up to 24 h after surgery. Blood samples were collected from 15 patients undergoing a partial hepatectomy for living liver donation, at the following specific time points: before and immediately after induction of anesthesia, during hepatectomy, 30 min after hepatectomy completion, at case end, and 24 h after the end of surgery. Plasma concentrations of lidocaine and metabolites were measured by liquid chromatography-mass spectrometry. The population lidocaine pharmacokinetics were estimated, and total body weight and the fraction of remaining liver mass as potential model covariates were evaluated. The detection of any lidocaine, monoethylglycinexylidide, or glycinexylidide toxic plasma concentrations at any time point during and after hepatectomy were also evaluated. The typical value for lidocaine elimination clearance was 0.55 ± 0.12 l/min (± standard error of the estimate) which, on average, was reduced to about one third of the baseline clearance, 0.17 ± 0.02 l/min, once the donor graft was surgically isolated, and remained so for 24 h according to the current data and model. The fraction of remaining liver was a significant covariate for the posthepatectomy lidocaine clearance' such that if 50% of the liver is removed the clearance is reduced by approximately 60%. Plasma concentrations of lidocaine and its metabolites remained below their theoretical combined toxic threshold concentrations throughout the surgical and postoperative course in all patients, with one exception obtained near induction of anesthesia. Plasma lidocaine concentrations decreased at case end and postoperatively, while metabolite concentrations continued to rise at the end of surgery with reduction postoperatively. Pharmacokinetic modeling revealed that the only significant covariate in the model was the fraction of liver remaining after isolation of the donor graft. Intravenous lidocaine infusions are an acceptable option for multimodal pain management in patients undergoing a hepatectomy for living donation if the lidocaine infusion is stopped when the liver resection is complete. Clearance of lidocaine is decreased proportionally to the remaining liver mass, which should guide lidocaine infusion administration or dosing adjustments for patients undergoing liver resection surgery.

Intravesical sustained release system of lidocaine and oxybutynin results from in vitro and animal study.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic debilitating condition of unknown etiology. Intravesical lidocaine demonstrated pain relief in patients with IC/BPS. Intravesical oxybutynin has shown therapeutic efficacy in patients with urinary bladder disorders. However, loss of drug with urination requiring multiple administrations and immediate dilution of drug concentration by residual urine in the bladder mitigated intravesical use of both drugs in clinical practice. The aim of this study was to evaluate the efficacy and safety of fixed-dose combination of lidocaine and oxybutynin, forming in the urine a sustained delivery system named TRG-042. In-vitro, we have quantitatively tested the concentration of lidocaine and oxybutynin released from TRG-042 in artificial urine. Following the successful in-vitro study weekly formulation of TRG-042 was instilled intravesically to six pigs. All pigs were followed with cystoscopy to assess the gradual degradation of the delivery system and to evaluate bladder response over 7 days. Daily blood samples were tested for drug quantization. In-vitro studies have demonstrated oxybutynin and lidocaine sustained release over 1-week period coupled with full degradation of the matrix. None of the animals demonstrated any side effects following instillation. Cystoscopy examination observed gradual disintegration of TRG-042 over 1-week with no adverse reaction to the mucosa. Plasma concentrations of oxybutynin and lidocaine were uniformly stable over the 1-week period [1.46 ± 0.176ng/ml and 4.29 ± 2.48ng/ml respectively(mean ± SEM)] with almost undetectable concentration of N-desethyloxybutynin (NDO)[0.032 ± 0.068ng/ml]. The in-vitro and animal data demonstrated that TRG-042 can safely be used for intravesical sustained release of lidocaine and oxybutynin in the treatment of BPS/IC.

Designer self-assembling peptide nanofibers induce biomineralization of lidocaine for slow-release and prolonged analgesia

The burst release of small molecular water-soluble drugs is a major problem when pursuing their long-acting formulations. Although various types of carrier materials have been developed for tackling this problem, it is still a big challenge to prevent water-soluble small molecules from fast release and diffusion. In this study, a biomineralization strategy based upon a self-assembling peptide is proposed for the slow release of lidocaine, a classic anesthetic with high solubility and a very small molecular weight. A bolaamphiphilic peptide was designed to self-assemble and produce negatively charged nanofibers, which were used as the template to absorb positively charged lidocaine molecules through an electrostatic interaction. The biomineralization of lidocaine was then induced by adjusting the pH, which lead to the formation of lidocaine microcrystals with a homogenous size. The microcrystals were incorporated into a hyaluronic acid hydrogel to form an injectable formulation. This formulation slowly released lidocaine and generate a prolonged anesthetic and analgesic effect in rodent models. Due to the constrained local and plasma lidocaine concentration, as well as the biocompatibility and biodegradability of the peptide materials, this formulation also showed considerable safety. These results suggest that nanofiber assisted biomineralization can provide a potential strategy for the fabrication of long-acting formulations for small molecular water-soluble drugs. Statement of significanceLong-acting formulations are highly pursued to achieve stronger therapeutic effect, or to avoid repeated administration of drugs, especially through painful injection. Using carrier materials to slow down the release of bioactive molecules is a common strategy to reach this goal. However, for many water-soluble small molecular drugs currently used in clinic, it is notoriously difficult to slow down their release and diffusion. This study proposes a novel strategy based on a controllable mineralization process using self-assembling peptide nanofibers as the template. Taking lidocaine as an example, we showed how peptide-drug microcrystals with well-controlled size and shape could be obtained, which exhibit significantly prolonged anesthetic and analgesic effect. As a proof-of-concept study, this work proposes a promising strategy to control the release of water-soluble small molecular drugs.

LID study: Plasma lidocaine levels following airway topicalisation for paediatric microlaryngobronchoscopy (MLB).

A dose of 5 mg/kg lidocaine is considered appropriate for paediatric airway topicalisation. Existing literature suggests that younger children are susceptible to toxic lidocaine plasma levels and achieve this at a faster rate. The primary outcome of this study was to ascertain peak plasma lidocaine levels after topicalisation for airway endoscopy. Secondary endpoints included: time to peak lidocaine plasma levels, signs of lidocaine toxicity (restricted to ECG changes or seizures when under anaesthesia) and clinical adverse events of laryngospasm, coughing or desaturation during the procedure. Data were collected prospectively over 18months at Royal Manchester Children's Hospital. Children aged 0-8years undergoing elective diagnostic or therapeutic airway endoscopy were included within the study. Standardised 2% lidocaine was used for airway topicalisation. Dose varied depending upon the practitioner's usual practice. Venous bloodsampling occurred at 5, 10, 15 and 20 min post-administration and plasma lidocaine levels (ng/ml) were analysed. A significant relationship exists between higher peak plasma levels and ages <18 months (p=.00973). Strong linear correlation exists between body weight and age for our cohort (r=.88). Higher peak plasma lidocaine levels occur with total dose volumes between 2 and 3 mls of 2% lidocaine local anaesthetic (p=.03) compared with <2 ml total dose volumes. Data suggest a potential relationship of lower body weights achieving higher peak plasma levels (p=.0516). Reduced interquartile variation of peak plasma lidocaine levels exists when lidocaine dosing is <5 mg/kg. Age and total dose volume of topicalised lidocaine have a significant relationship with plasma lidocaine levels. A dose of 5mg/kg topicalised lidocaine for paediatric airway endoscopy is safe and provides good operating conditions. Lower patient body weights trend towards higher peak lidocaine plasma concentrations and require further investigation.

PD27-11 PRELIMINARY PHARMACOKINETIC DATA OF AN IN VITRO AND ANIMAL STUDY OF A NOVEL INTRAVESICAL SUSTAINED DELIVERY SYSTEM OF LIDOCAINE AND OXYBUTYNIN (TRG-042)

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology (PD27)1 Sep 2021PD27-11 PRELIMINARY PHARMACOKINETIC DATA OF AN IN VITRO AND ANIMAL STUDY OF A NOVEL INTRAVESICAL SUSTAINED DELIVERY SYSTEM OF LIDOCAINE AND OXYBUTYNIN (TRG-042) Boris Chertin, David Dothan, Nadav Malchi, Avi Gordon, and Dan Touitou Boris ChertinBoris Chertin More articles by this author , David DothanDavid Dothan More articles by this author , Nadav MalchiNadav Malchi More articles by this author , Avi GordonAvi Gordon More articles by this author , and Dan TouitouDan Touitou More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002020.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Interstitial Cystitis / Bladder pain syndrome (IC/BPS) is a chronic debilitating condition of unknown etiology. Intravesical lidocaine administration has demonstrated pain relief in patients with IC/BPS. Intravesical administration of Oxybutynin has a well-documented therapeutic effect in patients with urinary bladder disorders due to a direct local anesthetic, antimuscarinic and spasmolytic effect within the bladder wall. However, intravesical use of the both drugs in the clinical practice did not stand the test of time due to rapid dilution and loss of drug with urination requiring multiple administrations. The ability to prolong drug retention in the urinary bladder enhances the bladder wall tissue exposure to adequate therapeutic level of drugs. The aim of this study was to evaluate the efficacy and safety of fixed-dose combination of Lidocaine and Oxybutynin novel polymeric composition forming instantly in the urine a sustained delivery system named TRG-042. METHODS: We have In-Vitro tested release of Lidocaine and Oxybutynin from TRG-042 in artificial urine (AUF) and have quantitatively determined Oxybutynin and Lidocaine concertation utilizing high-pressure liquid chromatography(HPLC). Following the successful In-Vitro study weekly formulation of TRG-042 was instilled into urinary bladder of 6 pigs. All pigs were followed with cystoscopy and US in order to assess the gradual degradation of the intravesical delivery system and to evaluate the response of the bladder over the seven days. Daily blood samples were tested for drug quantitation. Three pigs, who received TRG-042 without Oxybutynin and Lidocaine served as a control. RESULTS: In-Vitro studies have demonstrated Oxybutynin and Lidocaine sustained release over the one-week period coupled with the full degradation of the matrix. None of the animals demonstrated any side effects following instillation. Cystoscopy examination observed gradual disintegration of the TRG-042 over one-week period with no adverse reaction of the bladder mucosa. Plasma concentrations of Oxybutynin and Lidocaine were uniformly high and stable over the one-week study period 1.46+/-0.176 ng/ml and 4.29+/-2.48 ng/ml respectively (mean+/-SEM) with almost undetectable concentration of active metabolite N-desethyloxybutynin (NDO) 0.032+/-0.068 ng/ml. CONCLUSIONS: The In-Vitro and animal data suggest that TRG-042 can safely be used for possible intravesical sustain release of Lidocaine and Oxybutynin in the treatment of BPS/IC. Our preliminary results should be further confirmed in clinical studies. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e448-e448 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Boris Chertin More articles by this author David Dothan More articles by this author Nadav Malchi More articles by this author Avi Gordon More articles by this author Dan Touitou More articles by this author Expand All Advertisement Loading ...

Pharmacokinetics of Single Dose Lidocaine and Epinephrine Following Iontophoresis of the Tympanic Membrane in a Double-Blinded Randomized Trial.

Objective:To evaluate local and systemic safety of bilateral iontophoretic administration of lidocaine with epinephrine or lidocaine alone to the tympanic membrane (TM).Study Design:A randomized, double-blind, two-arm study was conducted at a single center. Healthy adults were randomized to bilateral iontophoretic treatment with 2% lidocaine, 1:100,000 epinephrine, or 2% lidocaine (control). Otoscopy, cranial nerve examination, tympanometry, and audiometry safety evaluations were conducted before and 3-days post-procedure. Systemic safety was evaluated via analysis of vital signs taken before and up to 120 minutes post-iontophoresis, and blood samples collected before and up to 230 minutes post-iontophoresis.Results:Twenty-five subjects were treated with bilateral iontophoresis of either lidocaine and epinephrine (n = 15 subjects) or lidocaine alone (n = 10). Mean plasma epinephrine concentrations for both groups remained within the normal range for endogenous epinephrine. Mean plasma concentrations of lidocaine were not statistically different between groups, ranging from 0.245 to 2.28 ng/ml after administration of lidocaine with epinephrine (immediate post-iontophoresis to 230 min post-iontophoresis), compared with 1.35 to 2.14 ng/ml after administration of lidocaine alone. The presence of epinephrine slowed the systemic absorption of lidocaine. Lidocaine levels (Cmax 2.24 ng/ml) were approximately 2000-fold lower than the threshold for minor lidocaine toxicity. No device-, procedure- or drug-related adverse events were reported.Conclusion:The local and systemic safety of bilateral iontophoretic delivery of 2% lidocaine, 1:100,000 epinephrine to the TM was demonstrated by low plasma levels of drug and absence of both serious and non-serious device-, procedure-, or drug-related adverse events.

Evaluation of Lidocaine and Metabolite Pharmacokinetics in Hyaluronic Acid Injection.

Lidocaine-incorporated hyaluronic acid injection (LHA) is considered a promising way to increase patient compliance. Various reviews and analyses have been conducted to verify that the addition of lidocaine had no effect on the product quality of hyaluronic acid injections. However, possible pharmacokinetic (PK) alterations of lidocaine and its active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX), in hyaluronic acid injection have not been studied so far. Thus, the objective of this study was to evaluate lidocaine and its metabolite PK after 0.3% lidocaine solution or LHA injection and to investigate any changes in PK profiles of lidocaine and its active metabolites. To do this, a novel bio-analytical method for simultaneous determination of lidocaine, MEGX, and GX in rat plasma was developed and validated. Then, plasma concentrations of lidocaine and its active metabolites MEGX and GX following subcutaneous (SC) injection of 0.3% lidocaine solution or LHA with 0.3–1% lidocaine in male Sprague-Dawley rats were successfully determined. The obtained data were used to develop a parent-metabolite pharmacokinetic (PK) model for LHA injection. The half-life, dose-normalized Cmax, and AUCinf of lidocaine after SC injection of lidocaine solution and LHA did not show statistically significant difference. The PK characteristics of lidocaine after LHA administration were best captured using a two-compartment model with combined first-order and transit absorption and its clearance described with Michaelis–Menten and first-order elimination kinetics. Two one-compartment models were consecutively added to the parent model for the metabolites. In conclusion, the incorporation of lidocaine in hyaluronic acid filler injection did not alter the chemical’s pharmacokinetic characteristics.

Evaluation of serum lidocaine/monoethylglycylxylidide concentration to assess shunt closure in dogs with extrahepatic portosystemic shunts.

BackgroundLiver function tests do not always normalize despite successful attenuation of extrahepatic portosystemic shunts (EHPSS).ObjectivesAssess the lidocaine/monoethylglycylxylidide (MEGX) test to determine liver perfusion after EHPSS closure.AnimalsTwenty dogs with EHPSS.MethodsA prospective cohort study was performed and all dogs were tested at diagnosis, 1, 3, and 6 months postoperatively. After collecting a baseline blood sample (T0), 1 mg/kg body weight of lidocaine was injected intravenously. Fifteen (T15) and 30 minutes (T30) later, blood was collected. Plasma concentrations of lidocaine and its metabolites MEGX and glycylxylidide (GX) were determined, using a high‐performance liquid chromatography with electrospray ionization tandem mass spectrometry method. Three months postoperatively, transsplenic portal scintigraphy was performed to determine EHPSS closure.ResultsAt T15, median MEGX concentrations were higher in dogs with closed EHPSS compared to diagnosis (33.73 ng/mL [21.11‐66.44 ng/mL] vs 13.74 ng/mL [7.25‐21.93 ng/mL]; P < .001), but were not different (12.28 ng/mL [10.62‐23.17 ng/mL] vs 13.74 ng/mL [7.25‐21.93 ng/mL]) in dogs with persistent shunting. Sensitivity to determine shunt closure for MEGX at T15 was 96.2% (95% confidence interval [CI]: 78.4‐99.8) and specificity 82.8% (95% CI: 63.5‐93.5).Conclusions and Clinical ImportanceThe lidocaine/MEGX test is a promising, rapid, and noninvasive blood test that seems helpful to differentiate dogs with closed EHPSS and dogs with persistent shunting after gradual attenuation.

Evaluation of tumescent local anesthesia in cats undergoing unilateral mastectomy

ObjectiveTo evaluate the analgesic efficacy and safety of tumescent local anesthesia (TLA) in cats undergoing unilateral mastectomy. Study designProspective clinical trial. AnimalsA total of 12 ovariohysterectomized female cats. MethodsAll animals were premedicated with pethidine (4 mg kg–1) intramuscularly (IM), followed by induction of anesthesia with propofol (5 mg kg–1) intravenously and maintenance with isoflurane in oxygen. A refrigerated TLA solution (15 mL kg–1, 8 °C) was injected using a Klein cannula. The solution was composed of 0.5 mL of epinephrine (1 mg mL–1) and 40 mL of 2% lidocaine added to 210 mL lactated Ringer’s solution (final lidocaine concentration 0.32%). Heart and respiratory rates, systolic arterial blood pressure, temperature and oxygen saturation were measured during anesthesia. Blood samples were collected from the jugular vein for measurement of plasma lidocaine concentration using high performance liquid chromatography. Postoperative pain scores were evaluated hourly for 6 hours. Analgesic rescue was performed with tramadol (2 mg kg–1) IM and meloxicam (0.15 mg kg–1) subcutaneously. ResultsPlasma lidocaine concentration peaked at 90 minutes after injection of TLA, but no concentration considered toxic for the species was measured. The median postoperative analgesia time was 6 hours after injection of TLA. ConclusionsThis study found that TLA prevented sympathetic response to noxious stimuli during anesthesia and provided satisfactory postoperative analgesia in cats submitted to total unilateral mastectomy, with no apparent signs of toxicity. Clinical relevanceTLA can prevent sympathetic stimulation resulting from noxious stimuli during anesthesia, promoting good intraoperative conditions, proving to be a viable addition to analgesia in cats submitted to a total unilateral mastectomy.

Is intravenous lidocaine protective against myocardial ischaemia and reperfusion injury after cardiac surgery?

A best evidence topic was constructed using a described protocol. The three-part question addressed was: In patients undergoing cardiac surgery, does intravenous lidocaine exert a cardioprotective effect against postoperative myocardial ischaemia and reperfusion injury? Using the reported search, 461 papers were found, of which 5 studies represented the best evidence to answer the question. In 3 studies, lidocaine was associated with a postoperative fall in biomarkers of myocardial injury. An additional study lacked power, but the difference in biomarkers was marginally non-significant with a trend in favour of lidocaine. A final study evaluating ischaemic changes on continuous and 12 lead ECG found no benefit with lidocaine. The limited evidence suggests that lidocaine may be cardioprotective, although no study has demonstrated improvement in clinical outcomes. Furthermore, all trials were small studies with a multitude of dosing regimens in heterogenous patient populations. There is insufficient data to correlate dose with effect and not all studies measured plasma lidocaine concentration. The narrow therapeutic index and our current evidence base does not support lidocaine prophylaxis.

Effect of intra-operative intravenous lidocaine on opioid consumption after bariatric surgery: a prospective, randomised, blinded, placebo-controlled study.

Peri-operative lidocaine infusion warrants investigation in bariatric surgery because obese patients present different physiological and pharmacological risks. This single-centre, prospective, randomised double-blind placebo-controlled study enrolled obese patients scheduled for laparoscopic bariatric surgery using an enhanced recovery protocol. Patients received either lidocaine (bolus of 1.5mg.kg-1 , then a continuous infusion of 2mg.kg-1 .h-1 until the end of the surgery, then 1mg.kg-1 .h-1 for 1h in the recovery area) or identical volumes and rates of 0.9% saline. The primary outcome was the consumption of the equivalent of oxycodone consumption over the first 3 postoperative days. Secondary outcomes were: postoperative pain; incidence of nausea and vomiting; bowel function recovery; and lengths of stay in the recovery area and in hospital. Plasma concentrations of lidocaine were measured. On the 178 patients recruited, data were analysed from 176. The median (IQR [range]) equivalent intravenous oxycodone consumption was 3.3mg (0.0-6.0 [0.0-14.5]) and 5.0mg (3.3-7.0 [3.3-20.0]) in the lidocaine and saline groups, respectively (difference between medians (95%CI): 1.7 (0.6-3.4) mg; p=0.004). Length of stay in the recovery area, postoperative pain, nausea and vomiting, day of recovery of bowel function, and length of stay in hospital were not different between groups. Mean (SD) lidocaine plasma concentrations were 2.44 (0.70) µg.ml-1 and 1.77 (0.51) µg.ml-1 at the end of surgery and 1 hour after the end of infusion, respectively. Lidocaine infusion during bariatric surgery resulted in a clinically non-relevant difference in postoperative oxycodone consumption.

A Randomized, Open-Label, Bioequivalence Study of Lidocaine Topical System 1.8% and Lidocaine Patch 5% in Healthy Subjects.

PurposeThis study was designed to characterize drug delivery with lidocaine topical system 1.8% vs lidocaine patch 5% through 2 PK studies.Patients and MethodsTwo Phase 1, single-center, open-label, randomized PK studies were performed in healthy adults. In Study 1, 56 subjects received a single intravenous bolus of 0.7 mg/kg of lidocaine as a lead-in to allow for the accurate determination of apparent dose of both products. After a 7-day washout period, subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours followed by another 7-day washout period, after which subjects crossed over to receive the other treatment for 12 hours. In Study 2, 54 subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours. After a 7-day washout period, subjects crossed over to receive the other treatment. Adhesion and skin irritation assessments were performed after application of the products in Study 2. In both studies, serial blood samples were collected to measure the plasma concentration of lidocaine after product application. Safety assessments and adverse events were monitored in both studies.ResultsThe comparative PK analysis demonstrated that the two products, despite their difference in drug load and strength, are bioequivalent. Both products were well tolerated. In Study 2, dermal response scores (skin tolerability after removal) were similar between lidocaine topical system 1.8% and lidocaine patch 5%, with a mean irritation score per patch <1 (barely perceptible erythema), which is not considered to be clinically significant.ConclusionBioequivalence was demonstrated between lidocaine topical system 1.8% and lidocaine patch 5%. A comparison of the single-time adhesion scores at 12 hours in Study 2 favored lidocaine topical system 1.8% over lidocaine patch 5%. Both products were well tolerated as a single application in healthy adult human subjects.ClinicalTrials.govNCT04144192, NCT04149938.