Lidocaine Exposure Research Articles

Adverse Outcomes in Topical Lidocaine Exposure: A Pediatric Case Series From the United States National Poison Data System.

To examine the clinical outcomes of topical lidocaine exposures in pediatric patients reported to the National Poison Data System (NPDS). We performed a retrospective review of the NPDS in pediatric patients with topical lidocaine toxicity from 2000 to 2020. Specific data analyzed were age, exposure chronicity, medical outcome, clinical effects, treatments, and disposition. Narrative case records were requested from poison centers. Of 37 cases identified, mean age was 5 years with age distribution of 1- to 0 days (n = 8), 1 to 24 months (n = 11), and 2-18 years (n = 18). Exposure chronicity was acute in 33 (89.2%) or chronic in 4 (10.8%). Moderate effects were seen in 25 (67.6%), major effects in 10 (27%), and 2 deaths (5.4%). The most common clinical effects included cyanosis (29.7%), seizures (18.9%), central nervous systems (CNS) depression (13.5%), drowsiness/lethargy (13.5%), and tachycardia (10.8%). The most common treatments were dilution/irrigation (35.1%), intravenous (IV) fluids (29.7%), oxygen (29.7%), methylene blue (27%), benzodiazepines (13.5%), and intubation (10.8%). Non-intensive care unit (ICU) disposition occurred for 23 patients (62.2%) and ICU admission for 14 (37.8%). Case details were requested for 37 cases, 16 cases (43.2%) were provided. Of the 2 deaths, 1 had significant cardiac history. The most common use of topical lidocaine was at home prior to a dermatologic procedure (37.5%). Topical lidocaine can induce serious outcomes resulting in ICU level care or death; however, moderate/major effects were well tolerated without comorbidities. Most patients discharged home. Given frequent use of topical, especially in outpatient settings, greater vigilance should be taken with prescriptions, instructions for use, and anticipatory guidance.

Lidocaine induces neurotoxicity in spinal cord neurons in Goto-Kakizaki rats via AMPK-mediated mitophagy

Lidocaine has been reported to induce neurotoxicity, which is further enhanced by high glucose levels. This study is aimed to explore the underlying mechanisms of lidocaine neurotoxicity in spinal cord neurons of diabetes. Take thirty specific pathogen-free (SPF) healthy Sprague-Dawley (SD) rats and thirty Goto-Kakizaki (GK) rats, aged 12 weeks, weighing 180-200 g. The spinal cord neurons of rats were isolated and cultured in vitro. Cell Counting Kit-8 was used to detect cell proliferation to determine the appropriate concentration and duration of lidocaine. Mitochondrial function was assessed using ATP content, cellular oxygen consumption rate, mitochondrial membrane potential, ROS production, and mitochondrial ultrastructure. Western blot was applied to detect the expression of autophagy- and mitophagy-related molecules PINK1, p-AMPK, LC-3II/LC3-I ratio and mTORC1. Immunofluorescent staining was used to detect the expression of PINK1 and LC3. Lidocaine decreased cell viability of spinal cord neurons in concentration- and time-dependent manners. And lidocaine treatment aggravated mitochondrial dysfunction in GK rats. Furthermore, mitophagy was activated in diabetes, and lidocaine exposure up-regulated mitophagy. AMPK activator MK8722 aggravated mitochondrial damage, increased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and decreased the expression of mTORC1, while AMPK inhibitor Compound C and autophagy inhibitor Bafilomycin A1 reduced mitochondrial damage and decreased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and increased the expression of mTORC1. Lidocaine induced neurotoxicity of spinal cord neurons in GK rats via AMPK-mediated mitophagy.

Propofol Immersion As a Euthanasia Method for Adult Zebrafish (Danio Rerio).

The exponential rise of the zebrafish (Danio rerio) as a model organism in biomedical research has far outstripped our un- derstanding of basic husbandry and welfare for this species. As a case in point, here we investigate the efficacy and welfare impact of different euthanasia methods for zebrafish. Not only is a humane death central to welfare and the 3Rs, but stress during euthanasia can change scientific outcomes. However, the most frequently used methods of euthanasia have multiple shortcomings with regard to animal welfare and human safety. In this study, we propose the use of propofol for immersion euthanasia of adult zebrafish. Propofol has been known to rapidly induce anesthesia in many species, including zebrafish, but its efficacy as a euthanasia agent for zebrafish has not fully been explored. In this study, adult zebrafish were euthanized by immersion on one of 5 different preparations: ice bath, 250 ppm MS222, 600 ppm lidocaine hydrochloride, 100 ppm propofol, or 150 ppm propofol for 20 or 30 min. Display of aversive behaviors, time to loss of righting reflex, time to cessation of opercular movement, and time to recovery after transfer to clean tank water were assessed and recorded. Propofol at both concentrations induced loss of righting reflex and loss of opercular movement more quickly than did MS222 or lidocaine hydrochloride and caused no display of aversive behaviors as seen with ice bath or lidocaine exposure. However, fish exposed to propofol at either concentration for 20 min sometimes recovered, whereas a 30-min exposure was sufficient for euthanasia of all fish tested. These findings suggest that exposure to propofol for a duration of at least 30 min quickly and effectively euthanizes adult zebrafish without compromising end-of-life welfare.

Perturbation of Ca2+ stores and store-operated Ca2+ influx by lidocaine in neuronal N2A and NG108-15 cells

In this report we examined the effects of lidocaine on Ca2+ homeostasis of neuronal cells using microfluorimetric measurement of cytosolic Ca2+ with fura 2 as probe. In mouse neuroblastoma N2A cells, 10 mM lidocaine caused Ca2+ release from the cyclopiazonic acid (CPA)-dischargeable pool and abolished ATP-triggered Ca2+ release. Lidocaine-triggered Ca2+ release was not affected by xestospongin C (XeC), an inositol 1,4,5-trisphosphate receptor (IP3R) inhibitor. N2A cells did not have functional ryanodine receptors (RYR) (absence of caffeine response) and we used differentiated NG108-15 cells (presence of caffeine response) for further experiments. Caffeine-triggered Ca2+ release was unaffected by a brief lidocaine exposure, but was eliminated after a prolonged treatment of lidocaine, suggesting lidocaine abolished caffeine action possibly not by interfering caffeine binding but via Ca2+ store depletion. Lidocaine-elicited Ca2+ release was unaffected by XeC or a high concentration of ryanodine, suggesting Ca2+ release was not via IP3R or RYR. Lidocaine did not affect nigericin-dischargeable lysosomal Ca2+ stores. Lastly, we observed that lidocaine suppressed CPA-induced store-operated Ca2+ influx in both N2A cells and differentiated NG108-15 cells. Our results suggest two novel actions of lidocaine in neuronal cells, namely, depletion of Ca2+ store (via an IP3R- and RYR-independent manner) and suppression of store-operated Ca2+ influx.

A weight of evidence assessment of the genotoxicity of 2,6-xylidine based on existing and new data, with relevance to safety of lidocaine exposure

Lidocaine has not been associated with cancer in humans despite 8 decades of therapeutic use. Its metabolite, 2,6-xylidine, is a rat carcinogen, believed to induce genotoxicity via N-hydroxylation and DNA adduct formation, a non-threshold mechanism of action. To better understand this dichotomy, we review literature pertaining to metabolic activation and genotoxicity of 2,6-xylidine, identifying that it appears resistant to N-hydroxylation and instead metabolises almost exclusively to DMAP (an aminophenol). At high exposures (sufficient to saturate phase 2 metabolism), this may undergo metabolic threshold-dependent activation to a quinone-imine with potential to redox cycle producing ROS, inducing cytotoxicity and genotoxicity. A new rat study found no evidence of genotoxicity in vivo based on micronuclei in bone marrow, comets in nasal tissue or female liver, despite high level exposure to 2,6-xylidine (including metabolites). In male liver, weak dose-related comet increases, within the historical control range, were associated with metabolic overload and acute systemic toxicity. Benchmark dose analysis confirmed a non-linear dose response. The weight of evidence indicates 2,6-xylidine is a non-direct acting (metabolic threshold-dependent) genotoxin, and is not genotoxic in vivo in rats in the absence of acute systemic toxic effects, which occur at levels 35 × beyond lidocaine-related exposure in humans.

A Randomized, Crossover, Pharmacokinetic and Adhesion Performance Study of a Lidocaine Topical System 1.8% During Physical Activity and Heat Treatment in Healthy Subjects.

PurposeThis study compares the pharmacokinetic (PK) profile, adhesion, and safety of lidocaine topical system 1.8%, a novel lidocaine topical system approved to treat postherpetic neuralgia, under conditions of heat and exercise vs normal conditions.Materials and MethodsThis open-label, 3-period, 3-treatment crossover study randomized 12 healthy adults to receive three lidocaine topical systems 1.8% during each of three treatment periods, with 7-day washouts between treatments. The product was applied to the mid-lower back and was removed after 12 hours. During Treatment A, subjects exercised on a bicycle for 30 minutes at 0, 2.5, 5.5, and 8.5 hours. During Treatment B, heat (temperature set at 36.7–40.3°C) was applied at 0 and 8.5 hours. Treatment C was normal conditions. The PK profile of each subject under exercise and heat conditions was compared to normal conditions. Skin irritation, adhesion, and adverse events were assessed.ResultsTwelve subjects completed the study. Exposure to external heat resulted in increased peak plasma concentration of lidocaine with a mean Cmax of 160.3±100.1 ng/mL vs 97.6±36.9 ng/mL under normal conditions, with no effect on the extent of exposure (AUC). Concentrations returned to normal within 4 hours after the heat was removed. No clinically relevant differences in absorption were observed under exercise conditions with a mean Cmax of 90.5±25.4 ng/mL and no effect on the extent (AUC) of lidocaine exposure was observed relative to normal conditions. No systems detached during the study. Adverse events were mild, with none leading to discontinuation.ConclusionTransient heat exposure resulted in increased lidocaine plasma concentrations compared to normal conditions, whereas exercise had no effect. The effects of heat appear to be immediate, reversible, and below systemic therapeutic threshold in antiarrhythmic treatment (1000–1500 ng/mL), and well below the safe systemic threshold of 5000 ng/mL. Lidocaine topical system 1.8% remained adhered to the skin and was well tolerated under all conditions. ClinicalTrials.gov: NCT04150536.

Does Lidocaine Cause False Positive Results on Cocaine Urine Drug Screen?

Individuals who have tested positive for cocaine have claimed that lidocaine, or its primary metabolite, norlidocaine (monoethylglycinexylidide (MEGX)), have caused false positive results for the cocaine metabolite benzoylecgonine (BE) on urinary immunoassay testing. The goal of the study was to determine if lidocaine exposure from routine medical procedures can result in false positives on a commercially available cocaine immunoassay urine drug screen (UDS). We performed a cross-sectional observational study of patients receiving lidocaine as part of their regular care. Standard immunoassay drug screens and confirmatory liquid chromatography-mass spectrometry (LC-MS) were performed on all urine samples to assess for MEGX and BE. In total, 168 subjects were enrolled; 121 samples positive for lidocaine were ultimately included for analysis. One hundred fourteen of the 121 were also positive for MEGX. None of the 121 were positive for cocaine/BE on the UDS (95% CI), 0-3.7% for the full sample and 0-3.9% for the 114 who tested positive for MEGX. The present study found no evidence that lidocaine or norlidocaine are capable of producing false positive results on standard cocaine urine immunoassays.

Oxidative stress, metabolomics profiling, and mechanism of local anesthetic induced cell death in yeast

The World Health Organization designates lidocaine as an essential medicine in healthcare, greatly increasing the probability of human exposure. Its use has been associated with ROS generation and neurotoxicity. Physiological and metabolomic alterations, and genetics leading to the clinically observed adverse effects have not been temporally characterized. To study alterations that may lead to these undesirable effects, Saccharomyces cerevisiae grown on aerobic carbon sources to stationary phase was assessed over 6h. Exposure of an LC50 dose of lidocaine, increased mitochondrial depolarization and ROS/RNS generation assessed using JC-1, ROS/RNS specific probes, and FACS. Intracellular calcium also increased, assessed by ICP-MS. Measurement of the relative ATP and ADP concentrations indicates an initial 3-fold depletion of ATP suggesting an alteration in the ATP:ADP ratio. At the 6h time point the lidocaine exposed population contained ATP concentrations roughly 85% that of the negative control suggesting the surviving population adapted its metabolic pathways to, at least partially restore cellular bioenergetics. Metabolite analysis indicates an increase of intermediates in the pentose phosphate pathway, the preparatory phase of glycolysis, and NADPH. Oxidative stress produced by lidocaine exposure targets aconitase decreasing its activity with an observed decrease in isocitrate and an increase citrate. Similarly, increases in α-ketoglutarate, malate, and oxaloacetate imply activation of anaplerotic reactions. Antioxidant molecule glutathione and its precursor amino acids, cysteine and glutamate were greatly increased at later time points. Phosphatidylserine externalization suggestive of early phase apoptosis was also observed. Genetic studies using metacaspase null strains showed resistance to lidocaine induced cell death. These data suggest lidocaine induces perpetual mitochondrial depolarization, ROS/RNS generation along with increased glutathione to combat the oxidative cellular environment, glycolytic to PPP cycling of carbon generating NADPH, obstruction of carbon flow through the TCA cycle, decreased ATP generation, and metacaspase dependent apoptotic cell death.

Lidocaine Impairs Proliferative and Biosynthetic Functions of Aged Human Dermal Fibroblasts.

The aged are at increased risk of postoperative wound healing complications. Because local anesthetics are infiltrated commonly into the dermis of surgical wounds, we sought to determine whether local anesthetics adversely affect proliferative and biosynthetic functions of dermal fibroblasts. We also evaluated the effect of local anesthetics on insulin-like growth factor-1 (IGF-1) and transforming growth factor-β1 (TGF-β1), growth factors that are important regulators of wound healing. Human dermal fibroblasts (HFB) from aged and young donors were exposed to local anesthetic agents at clinically relevant concentrations. We screened the effects of lidocaine, bupivacaine, mepivacaine, and ropivacaine on proliferation of HFB. Lidocaine was most detrimental to proliferation in HFB. We then evaluated the effect of lidocaine on expression and function of the growth factors, IGF-1 and TGF-β1. Lastly, concurrent exposure to lidocaine and IGF-1 or TGF-β1 was evaluated for their effects on proliferation and expression of dermal collagens, respectively. Lidocaine and mepivacaine inhibited proliferation in aged HFB (for lidocaine 88% of control, 95% confidence interval [CI], 80%-98%, P = .009 and for mepivacaine 90% of control, 95% CI, 81%-99%, P = .032) but not in young HFB. Ropivacaine and bupivacaine did not inhibit proliferation. Because of the clinical utility of lidocaine relative to mepivacaine, we focused on lidocaine. Lidocaine decreased proliferation in aged HFB, which was abrogated by IGF-1. Lidocaine inhibited transcripts for IGF-1 and insulin-like growth factor-1 receptor (IGF1R) in fibroblasts from aged donors (IGF-1, log2 fold-change -1.25 [42% of control, 95% CI, 19%-92%, P = .035] and IGF1R, log2 fold-change -1.00 [50% of control, 95% CI, 31%-81%, P = .014]). In contrast, lidocaine did not affect the expression of IGF-1 or IGF1R transcripts in the young HFB. Transcripts for collagen III were decreased after lidocaine exposure in aged and young HFB (log2 fold-change -1.28 [41% of control, 95% CI, 20%-83%, P = .022] in aged HFB and log2 fold-change -1.60 [33% of control, 95% CI, 15%-73%, P = .019] in young HFB). Transcripts for collagen I were decreased in aged HFB (log2 fold-change -1.82 [28% of control, 95% CI, 14%-58%, P = .006]) but not in the young HFB. Similar to the transcripts, lidocaine also inhibited the protein expression of collagen III in young and aged HFB (log2 fold-change -1.79 [29% of control, 95% CI, 18%-47%, P = .003] in young HFB and log2 fold-change -1.76 [30% of control, 95% CI, 9%-93%, P = .043] in aged HFB). The effect of lidocaine on the expression of collagen III protein was obviated by TGF-β1 in both young and aged HFB. Our results show that lidocaine inhibits processes relevant to dermal repair in aged HFB. The detrimental responses to lidocaine are due, in part, to interactions with IGF-1 and TGF-β1.

Revealing oxidative damage to enzymes of carbohydrate metabolism in yeast: An integration of 2D DIGE, quantitative proteomics, and bioinformatics.

Clinical usage of lidocaine, a pro-oxidant has been linked with severe, mostly neurological complications. The mechanism(s) causing these complications is independent of the blockade of voltage-gated sodium channels. The budding yeast Saccharomyces cerevisiae lacks voltage-gated sodium channels, thus provides an ideal system to investigate lidocaine-induced protein and pathway alterations. Whole-proteome alterations leading to these complications have not been identified. To address this, S. cerevisiae was grown to stationary phase and exposed to an LC50 dose of lidocaine. The differential proteomes of lidocaine treatment and control were resolved 6 h post exposure using 2D DIGE. Amine reactive dyes and carbonyl reactive dyes were used to assess protein abundance and protein oxidation, respectively. Quantitative analysis of these dyes (⩾ 1.5-fold alteration, p ⩽ 0.05) revealed a total of 33 proteoforms identified by MS differing in abundance and/or oxidation upon lidocaine exposure. Network analysis showed enrichment of apoptotic proteins and cell wall maintenance proteins, while the abundance of proteins central to carbohydrate metabolism, such as triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase, and redox proteins superoxide dismutase and peroxiredoxin were significantly decreased. Enzymes of carbohydrate metabolism, such as phosphoglycerate kinase and enolase, the TCA cycle enzyme aconitase, and multiple ATP synthase subunits were found to be oxidatively modified. Also, the activity of aconitase was found to be decreased. Overall, these data suggest that toxic doses of lidocaine induce significant disruption of glycolytic pathways, energy production, and redox balance, potentially leading to cell malfunction and death.

In Response

In Response Hoffman et al.1 provide an elegant alternative hypothesis for the presumed lidocaine-induced neurotoxicity described by us.2 They suggest that the neurotoxicity could better be explained by the inhibition of ATP-binding cassette transporters, especially P-glycoprotein by phenytoin, leading to an intracellular accumulation of lidocaine in the brain. The authors had clearly noticed that the patient’s deterioration in neurological status was temporally related to the dosing of phenytoin. It was our interpretation that altered pharmacokinetics resulted in neurotoxicity despite nontoxic lidocaine concentrations by conventional assays, probably due to immaturity of the brain. However, this alternative hypothesis might provide a better explanation for lidocaine neurotoxicity in the clinical setting reported. We had raised the possibility of an interaction between phenytoin and lidocaine but could not generate the unifying hypothesis that Hoffman et al. have. We would argue that the contribution of phenytoin to the generation of refractory ventricular arrhythmia, however, was minimal, because phenytoin therapy was commenced at the end of the medical treatment phase. The emphasis of our paper was to highlight the occurrence of a possible reversible neurotoxicity after lidocaine exposure in a neonate with life-threatening arrhythmias. Our intent was not to elucidate the cause of the malignant arrhythmia or describe the antiarrhythmic therapy. This issue has been dealt with by several reviews describing the anesthetic management of patients with long QT syndrome.3,4 Although there is evidence that amiodarone in the acute phase may provoke torsades de pointes (TdP), there is also evidence to the contrary, especially in patients with chronic heart failure. In a case series of 6 consecutive patients chronic amiodarone therapy admitted due to syncope and TdP, the potential for TdP was increased in those with female gender, hypokalemia, concomitant use of other drugs adversely affecting transmural dispersion of repolarization (e.g., trazadone, loratadine), and bradycardia.5 Rapid phase III repolarization6 and a reduction of transmural dispersion of repolarization7 by amiodarone have been suggested as mechanisms that might reduce the incidence of TdP with amiodarone therapy. However, we do advocate careful choice and dosing of antiarrhythmic agents that adversely affect ventricular repolarization in children with long QT syndrome undergoing general anesthesia for noncardiac surgery. Aruna T. Nathan, MBBS, FRCA Maryam Y. Naim, MD Department of Anesthesiology and Critical Care Medicine Children’s Hospital of Philadelphia Philadelphia, PA Victoria L. Vetter, MD, MPH Division of Cardiology Department of Cardiology Children’s Hospital of Philadelphia Philadelphia, PA

825 ASCENDING DOSE COHORT STUDY OF LIRIS® (LIDOCAINE-RELEASING INTRAVESICAL SYSTEM) IN WOMEN WITH MODERATE TO SEVERE INTERSTITIAL CYSTITIS

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Interstitial Cystitis1 Apr 2012825 ASCENDING DOSE COHORT STUDY OF LIRIS® (LIDOCAINE-RELEASING INTRAVESICAL SYSTEM) IN WOMEN WITH MODERATE TO SEVERE INTERSTITIAL CYSTITIS J. Curtis Nickel, Stephen S. Steele, Julie Lekstrom-Himes, Neal Shore, Robert M. Moldwin, Kenneth M. Peters, Robert D. Mayer, and Philip M. Hanno J. Curtis NickelJ. Curtis Nickel Kingston, Canada More articles by this author , Stephen S. SteeleStephen S. Steele Kingston, Canada More articles by this author , Julie Lekstrom-HimesJulie Lekstrom-Himes Lexington, MA More articles by this author , Neal ShoreNeal Shore Myrtle Beach, SC More articles by this author , Robert M. MoldwinRobert M. Moldwin New Hyde Park, NY More articles by this author , Kenneth M. PetersKenneth M. Peters Royal Oak, MI More articles by this author , Robert D. MayerRobert D. Mayer Rochester, NY More articles by this author , and Philip M. HannoPhilip M. Hanno Philadelphia, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.915AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES LiRIS is a novel intravesical drug-delivery system, deployed and retrieved using standard urological procedures, which releases lidocaine into the bladder lumen over two weeks. This phase 1b open-label, ascending dose cohort study studied the tolerability, safety, efficacy and limited pharmacokinetics of LiRIS in women with moderate to severe IC. METHODS Eighteen women with IC meeting the NIDDK criteria for glomerulations and/or Hunner's lesions having baseline bladder pain of 4 or greater on a 10 cm visual analogue scale were enrolled. Patients received either the LiRIS 200 mg (cohort 1) or LiRIS 650 mg (cohort 2) for two weeks. LiRIS safety, efficacy, cystoscopic appearance of the bladder pre-and post- LiRIS, and limited PK were collected. RESULTS Both LiRIS 200 mg and LiRIS 650 mg were well tolerated. Efficacy endpoints are summarized in the Table. Clinically meaningful reductions were seen in pain, urgency, voiding frequency and disease questionnaires. Cystoscopic exam showed improvement on Day 14 (day of LiRIS removal) compared with Day 1 (day of LiRIS insertion) including resolution of Hunner's lesions in 6 of 7 patients with baseline lesions. Global Response Assessment (7-item Likert scale) showed an overall responder rate of 69% at Day 14 (day of LiRIS removal) which was maintained with an overall responder rate of 69% two weeks later (Day 28). Extended follow-up suggests the pain response was maintained to Day 60. The adverse events were typical of those seen in patients with IC and consistent with a cystoscopic procedure. The majority of adverse events reported were mild to moderate in intensity with no LiRIS related serious adverse events. The systemic levels of lidocaine were very low; no adverse events were attributable to lidocaine exposure. CONCLUSIONS LiRIS 200 mg and LiRIS 650 mg were safe and well tolerated and showed preliminary efficacy including mucosal healing and extended duration of effect in patients with moderate to severe IC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byTeichman J (2012) New Treatments for Painful Urological ConditionsJournal of Urology, VOL. 189, NO. 2, (415-416), Online publication date: 1-Feb-2013. Volume 187Issue 4SApril 2012Page: e337 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information J. Curtis Nickel Kingston, Canada More articles by this author Stephen S. Steele Kingston, Canada More articles by this author Julie Lekstrom-Himes Lexington, MA More articles by this author Neal Shore Myrtle Beach, SC More articles by this author Robert M. Moldwin New Hyde Park, NY More articles by this author Kenneth M. Peters Royal Oak, MI More articles by this author Robert D. Mayer Rochester, NY More articles by this author Philip M. Hanno Philadelphia, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Lidocaine treatment during synapse reformation periods permanently inhibits NGF-induced excitation in an identified reconstructed synapse of Lymnaea stagnalis

Nerve growth factor (NGF) has been reported to affect synaptic transmission and cause neuropathic pain. In contrast, lidocaine has been used to reduce neuropathic pain; however, the effect of NGF and lidocaine on spontaneous transmitter release and synapse excitation has not been fully defined. Therefore, the effect of NGF and lidocaine on nerve regeneration, synapse reformation, and subsequent spontaneous transmitter release was investigated. We used Lymnaea stagnalis soma-soma-identified synaptic reconstruction to demonstrate that a transient increase in both frequency and amplitude of spontaneous events of miniature endplate potentials (MEPPs) occurs following NGF treatment and a short burst of action potentials in the presynaptic cell; in addition, the effect of lidocaine on NGF-induced synapse reformation was investigated. Using a cell culture and electrophysiological and FM-143 imaging techniques for exocytosis on unequivocally identified presynaptic visceral dorsal 4 (VD4) and postsynaptic somata left pedal (LPeE) neurons from the mollusc Lymnaea stagnalis, the effects of NGF and lidocaine on nerve regeneration, synapse reformation, and its electrophysiological spontaneous synaptic transmission between cultured neurons were described. NGF increased axonal growth, frequency, and amplitudes of MEPPs. Lidocaine exposure during synapse reformation periods was drastically and permanently reduced axonal growth and the incidence of synapse excitation by NGF. NGF increased amplitudes and frequencies of MEPPs and induced synaptic excitation by increasing axonal growth and exocytosis. Lidocaine exposure during synapse reformation periods permanently suppressed NGF-induced excitation by suppressing axonal growth and exocytosis of presynaptic neurons in the identified reconstructed synapse of L. stagnalis.

Clinical dose of lidocaine destroys the cell membrane and induces both necrosis and apoptosis in an identified Lymnaea neuron

Although lidocaine-induced cell toxicity has been reported, its mechanism is unclear. Cell size, morphological change, and membrane resistance are related to homeostasis and damage to the cell membrane; however, the effects of lidocaine on these factors are unclear. Using an identified LPeD1 neuron from Lymnaea stagnalis, we sought to determine how lidocaine affects these factors and how lidocaine is related to damage of the cell membrane. Cell size and morphological form were measured by a micrograph and imaging analysis system. Membrane potential and survival rate were obtained by intracellular recording. Membrane resistance and capacitance were measured by whole-cell patch clamp. Phosphatidyl serine and nucleic acid were double stained and simultaneously measured by annexin V and propidium iodide. Lidocaine at a clinical dose (5-20 mM) induced morphological change (bulla and bleb) in the neuron and increased cell size in a concentration-dependent manner. Membrane potential was depolarized in a concentration-dependent manner. At perfusion of more than 5 mM lidocaine, the depolarized membrane potential was irreversible. Lidocaine decreased membrane resistance and increased membrane capacitance in a concentration-dependent manner. Both phosphatidyl serine and nucleic acid were stained under lidocaine exposure in a concentration-dependent manner. A clinical dose of lidocaine greater than 5 mM destroys the cell membrane and induces both necrosis and apoptosis in an identified Lymnaea neuron.

Systemic absorption of topical lidocaine in a bone marrow transplant recipient with hepatic sinusoidal obstruction syndrome

A case of systemic lidocaine exposure in a bone marrow transplant recipient with severe hepatic sinusoidal obstruction syndrome (SOS) receiving treatment with lidocaine patch 5% is reported. A 35-year-old Caucasian man with a history of refractory acute lymphoblastic leukemia was admitted for a third allogeneic, mismatched, peripheral blood hematopoietic stem cell transplant from an unrelated donor, with a conditioning regimen that included busulfan and fludarabine. The patient was receiving treatment with lidocaine patch 5% (two patches daily, which was started five months before another hospital admission for the treatment of vincristine-related peripheral neuropathy. Baseline laboratory findings were within normal limits except for disease-related neutropenia and thrombocytopenia. Twenty days after hematopoietic stem cell transplantation (HSCT), the patient developed signs and symptoms of severe hepatic SOS. His serum alanine transaminase concentration rose from 65 IU/L at baseline to 370 IU/L, and his serum aspartate transaminase concentration rose from 32 IU/L at baseline to 871 IU/L. His total bilirubin increased to 2.8 mg/dL, and his body weight increased by 15%. An abdominal ultrasound noted ascites and hepatomegaly without reversal of blood flow. The lidocaine patch was discontinued, but the patient's condition continued to deteriorate. He died 38 days after HSCT from complications of severe hepatic SOS. A 35-year-old man developed hepatic SOS 20 days after his third HSCT. As a result of his hepatic impairment, the patient, who had been receiving lidocaine patch 5% for the treatment of neuropathic pain, experienced increased systemic exposure to lidocaine, which led to discontinuation of the patch.

Simultaneous Erythema Nodosum and Erythema Multiforme After Local Lidocaine Injection

To report a case of simultaneous erythema nodosum and erythema multiforme after local lidocaine injection. A 33-year-old female experienced coexisting erythema nodosum and erythema multiforme after lidocaine spray was used for upper gastrointestinal endoscopy. The reaction was exacerbated after localized injection of 2% lidocaine for a skin biopsy. An objective causality assessment revealed that an adverse drug reaction was highly probable. Lidocaine is the most frequently used local anesthetic agent. The coexistence of erythema nodosum and erythema multiforme has been reported in lepromatous leprosy, Yersinia enterocolítica and Yersinia pseudotuberculosis gastrointestinal infection (both with diarrhea), histoplasmosis, hepatitis C, and milkeŕs nodule, but not with lidocaine. If clinicians observe similar lesions after lidocaine exposure, they should suspect an adverse drug reaction and exercise caution in the administration of amide anesthetics to patients with a documented history of adverse reaction to lidocaine.

Neurotoxicity of Lidocaine Involves Specific Activation of the p38 Mitogen-activated Protein Kinase, but Not Extracellular Signal–regulated or c-jun N-Terminal Kinases, and Is Mediated by Arachidonic Acid Metabolites

Pharmacologic inhibition of the p38 mitogen-activated protein kinase (MAPK) leads to a reduction in lidocaine neurotoxicity in vitro and in vivo. The current study investigated in vitro the hypotheses that lidocaine neurotoxicity is specific for dorsal root ganglion cells of different size or phenotype, involves time-dependent and specific activation of the p38 MAPK, that p38 MAPK inhibitors are only effective if applied with local anesthetic, and that p38 MAPK activation triggers activation of lipoxygenase pathways. The authors used primary sensory neuron cultures and pheochromocytoma cell line cultures to detect time-dependent activation of the p38 MAPK or related pathways such as extracellular signal-regulated kinases and c-jun N-terminal kinases. Cells were divided by size or by immunoreactivity for calcitonin gene-related peptide or isolectin B4, indicative of nociceptive phenotype. The authors also investigated whether arachidonic acid pathways represent a downstream effector of the p38 MAPK in local anesthetic-induced neurotoxicity. All types of dorsal root ganglion cells were subject to neurotoxic effects of lidocaine, which were mediated by specific activation of the p38 MAPK but not extracellular signal-regulated kinases or c-jun N-terminal kinases. Neuroprotective efficacy of p38 MAPK inhibitors declined significantly when administered more than 1 h after lidocaine exposure. Activation of p38 MAPK preceded activation of arachidonic acid pathways. Neurotoxicity of lidocaine, specific activation of p38 MAPK, and neuroprotective effects of a p38 MAPK inhibitor were further confirmed in pheochromocytoma cell line cultures. Specific and time-dependent activation of the p38 MAPK is involved in lidocaine-induced neurotoxicity, most likely followed by activation of lipoxygenase pathways.

Comparative gene expression of PSP-toxin producing and non-toxic Anabaena circinalis strains

Blooms of the freshwater cyanobacterium Anabaena circinalis are recognised as an important health risk worldwide due to the production of a range of toxins such as saxitoxin (STX) and its derivatives, also known as paralytic shellfish poisoning (PSP) toxins. In this study the transcriptional profile of PSP toxin-producing and non-toxic strains of A. circinalis was investigated by means of a DNA microarray approach. Additionally, gene expression was studied after exposure of toxic A. circinalis cultures to lidocaine hydrochloride at 1 μM for 2 h. Under standard growth conditions, a limited number of putative toxic-strain distinctive DNA fragments, identified in previous studies, were preferentially expressed in toxic versus non-toxic strains. The same genes did not significantly change their expression after exposure to 1 μM lidocaine, conditions previously shown to induce STX production in the cyanobacterium Cylindrospermopsis raciborskii T3. Lidocaine supplementation, however, enhanced the transcription of genes involved in physiological adaptive responses and bloom formation in cyanobacteria, such as the gas vesicle structural protein A and phycocyanin. The heat shock protein HSP-70 and the chlorophyll- a binding protein isiA were significantly repressed by lidocaine exposure. Stress response proteins and genes implicated in secondary metabolism were repressed, including phosphopantetheinyl transferases. The BGGM 1 DNA microarray, used in this study, was shown to be suitable for gene expression studies in cultured toxic cyanobacteria and allowed the analysis of gene transcripts associated with surface scum formation by toxic A. circinalis.

Interactions between intracellular Na+ levels and saxitoxin production in Cylindrospermopsis raciborskii T3.

Saxitoxin (STX) is the most potent representative among the paralytic shellfish poisoning (PSP) toxins, which are highly selective Na(+) channel-blocking alkaloids. This study investigated, in cultures of the cyanobacterium Cylindrospermopsis raciborskii T3, the effects of pH, salt, amiloride and lidocaine hydrochloride on total cellular levels of Na(+) and K(+) ions and STX accumulation. Both Na(+) levels and intracellular STX concentrations increased exponentially in response to rising alkalinity. NaCl inhibited cyanobacterial growth at a concentration of 10 mM. In comparison with osmotically stressed controls, however, NaCl promoted STX accumulation in a dose-dependent manner. A correlation was seen in the time-course of both total cellular Na(+) levels and intracellular STX for NaCl, amiloride and lidocaine exposure. The increase in cellular Na(+) induced by NaCl at 10 mM was coupled with a proportional accumulation of STX. The two Na(+) channel-blocking agents amiloride and lidocaine had opposing effects on both cellular Na(+) levels and STX accumulation. Amiloride at 1 mM reduced ion and toxin concentrations, while lidocaine at 1 micro M increased the total cellular Na(+) and STX levels. The effects of the channel-blockers were antagonistic and dependent on an alkaline pH. The results presented suggest that, in C. raciborskii T3, STX is responsive to cellular Na(+) levels. This may indicate that either STX metabolism or the toxin itself could be linked to the maintenance of cyanobacterial homeostasis. The results also enhance the understanding of STX production and the ecology of PSP toxin-producing cyanobacteria.

Intracameral anesthesia: in vitro iris and corneal uptake and washout of 1% lidocaine hydrochloride.

To characterize the uptake, washout, and metabolism of lidocaine hydrochloride in the iris/ciliary body and cornea. Iris/ciliary body uptake of lidocaine hydrochloride was measured by incubating human and rabbit irides in radiolabeled carbon 14-1% lidocaine hydrochloride for 2 to 60 minutes. Washout was determined by incubating the iris in 14C-1% lidocaine hydrochloride for 5 minutes and transferring the iris to a series of wells. The wells contained a common intraocular irrigating solution of essential ions, glucose, and glutathione buffered with bicarbonate (an enriched balanced salt solution [BSS PLUS]), which is similar to aqueous humor. Corneal uptake was measured by exposing the endothelial surface to 14C-1% lidocaine hydrochloride for 5 or 15 minutes. Corneal washout was performed after 5-minute exposure to 14C-1% lidocaine hydrochloride using a 2-chambered diffusion apparatus. Samples of the iris, cornea, and BSS PLUS washout solution were analyzed by high-performance liquid chromatography and liquid scintillation spectrometry. In vitro iris/ciliary body uptake of 14C-1% lidocaine hydrochloride follows a logarithmic curve, with 50% to 60% of maximum lidocaine hydrochloride uptake present at 5 minutes. There was no difference in uptake between human, albino rabbit, and pigmented rabbit irides. Washout of lidocaine from the iris occurs with a halflife of 8 to 9 minutes. Corneal uptake of lidocaine was greater after incubation for 15 vs. 5 minutes. The washout of lidocaine from the cornea had a half-life of 5 minutes. Results of high-performance liquid chromatography confirmed that there were no metabolites or breakdown products in the iris, cornea, or washout solution. Lidocaine is taken up quickly by the iris/ ciliary body and cornea and rapidly removed from these tissues after BSS PLUS washout. Irrigation during phacoemulsification seems to limit lidocaine exposure to the ocular tissues, resulting in a short duration of anesthesia. Lidocaine is not metabolized or broken down by the iris or cornea during this short period.