Epidermal growth factor receptor phosphorylation contributes to levobupivacaine-induced contraction in isolated rat aorta.

Vasoconstriction induced by levobupivacaine, a local anesthetic, is mediated by increased levels of calcium, tyrosine kinase, c-Jun NH2-terminal kinase (JNK), and phospholipase D, which are associated with prolonged local anesthesia. Epidermal growth factor receptor (EGFR) phosphorylation is associated with vasoconstriction. However, its role in levobupivacaine-induced contractions remains unknown. We determined whether EGFR phosphorylation is associated with levobupivacaine-induced contractions in isolated rat thoracic aortas and identified the underlying cellular signaling pathways. The effects of various inhibitors and a calcium-free solution alone or in combination on levobupivacaine-induced contractions were then assessed. Furthermore, we examined the effects of various inhibitors on levobupivacaine-induced EGFR and JNK phosphorylation and calcium levels in vascular smooth muscle cells (VSMCs) of rat aortas. The EGFR tyrosine kinase inhibitor AG1478, matrix metalloproteinase (MMP) inhibitor GM6001, Src kinase inhibitors PP1 and PP2, and JNK inhibitor SP600125 attenuated levobupivacaine-induced contractions. Moreover, although the calcium-free solution abolished levobupivacaine-induced contractions, calcium reversed this inhibitory effect. The magnitude of the calcium-mediated reversal of abolished levobupivacaine-induced contractions was lower in the combination treatment with calcium-free solution and AG1478 than in the treatment with calcium-free solution alone. Levobupivacaine induced EGFR and JNK phosphorylation. However, AG1478, GM6001, and PP2 attenuated levobupivacaine-induced EGFR and JNK phosphorylation. Moreover, although levobupivacaine induced JNK phosphorylation in control siRNA-transfected VSMCs, EGFR siRNA inhibited levobupivacaine-induced JNK phosphorylation. Furthermore, AG1478 inhibited levobupivacaine-induced calcium increases in VSMCs. Collectively, these findings suggest that levobupivacaine-induced EGFR phosphorylation, which may occur via the Src kinase-MMP pathway, contributes to vasoconstriction via JNK phosphorylation and increased calcium levels.

Hemodynamic Safety and Effect of Dexmedetomidine on Superficial Cervical Block Quality for Carotid Endarterectomy: A Prospective Study.

OBJECTIVE: Dexmedetomidine as an adjuvant to local anesthetics (LAs) in regional anesthesia has demonstrated a positive effect on the quality of regional blocks, but there are no studies on usage in superficial cervical block (SCB) for carotid endarterectomy (CEA), in which the management of mean arterial pressure is essential. The authors designed a prospective, randomized, double-blinded study to investigate the effects of the addition of dexmedetomidine on the hemodynamic management and quality of SCB. DESIGN: A prospective, randomized, double-blinded study. SETTING: A single-center study at a university hospital center. PARTICIPANTS: Ultrasound-guided SCB was performed on 60 patients classified as American Society of Anesthesiologists Grades II and III undergoing elective CEA surgery who were assigned into 2 groups randomly. INTERVENTION(S): Both groups received 2 mg/kg of 0.5% levobupivacaine with 2 mg/kg of 2% lidocaine. The intervention group additionally received 50 µg of dexmedetomidine. MEASUREMENTS AND MAIN RESULTS: The onset and duration of sensory block and analgesia, hemodynamic parameters, and adverse effects were recorded. There were minimum effects on hemodynamic parameters and no differences in the incidence of adverse effects. The time to first analgesia was longer in the intervention group than in the control group (N = 30). There was no difference in the duration of the sensory block between groups. The log-rank test indicated a significant difference in the probability of the Numeric Pain Rating Scale <3. CONCLUSION: The addition of 50 µg of dexmedetomidine to 0.5% levobupivacaine and 2% lidocaine for SCB did not influence the hemodynamics and frequency of adverse effects. The median sensory block duration time showed no statistical difference between the groups, but the quality of analgesia postoperatively was much improved in the study group.

In vitro chondrotoxicity of bupivacaine, levobupivacaine and ropivacaine and their effects on caspase activity in cultured canine articular chondrocytes.

Bupivacaine, levobupivacaine and ropivacaine are potent, long acting, amide-type local anesthetics that have several clinical applications including intra-articular administration. The objectives of this study were to evaluate their in vitro effects on cell viability and caspase activity to elucidate whether they activate the extrinsic or intrinsic pathways of apoptosis in canine articular chondrocytes. Chondrocytes in monolayer culture were treated with culture medium as the control, or with 0.062% (0.62 mg/mL) bupivacaine, 0.062% levobupivacaine, and 0.062% ropivacaine for 24 hr. Cell viability was evaluated using the live/dead, 3-(4,5-dimehylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), and Cell Counting Kit-8 (CCK-8) assays. Evaluation of caspase-3, caspase-8, and caspase-9 activity was performed using colorimetric assays. The MTT and CCK-8 assays were used to evaluate the effect of caspase inhibitors on local anesthetic chondrotoxicity. All three local anesthetics decreased chondrocyte viability after 24 hr (P<0.001). Apoptosis was induced through both the extrinsic and intrinsic pathways. Bupivacaine increased caspase-3, caspase-8, and caspase-9 activity (P<0.001). Levobupivacaine increased caspase-3 (P=0.03) while ropivacaine did not significantly upregulate activity for all three caspases. Caspase inhibition did not suppress bupivacaine chondrotoxicity whereas inhibition of caspase-8 and caspase-9 decreased ropivacaine chondrotoxicity and mildly attenuated levobupivacaine chondrotoxicity. In summary, the level of chondrotoxicity, the type of caspase activated, the level of caspase activation, and the response to caspase inhibitors was dependent on the type of local anesthetic. Therefore, ropivacaine may be a safer choice for intra-articular administration compared to levobupivacaine and bupivacaine.

Local anesthetic levobupivacaine inhibits stemness of osteosarcoma cells by epigenetically repressing MAFB though reducing KAT5 expression.

Osteosarcoma is the most prevalent bone cancer and accounts for over half of sarcomas. In this study, we identified that the treatment of levobupivacaine suppressed proliferation of osteosarcoma cells in vitro. The tumor xenograft analysis showed that levobupivacaine significantly repressed the osteosarcoma cell growth in the nude mice. The treatment of levobupivacaine improved the apoptosis rate and attenuated invasion and migration abilities of osteosarcoma cells. The sphere formation capabilities of osteosarcoma cells were repressed by levobupivacaine. The protein levels of Sox-2, Oct3/4, and Nanog were inhibited by the treatment of levobupivacaine in osteosarcoma cells. Regarding mechanism, we identified that levobupivacaine inhibited MAFB and KAT5 expression in osteosarcoma cells. We observed that lysine acetyltransferase 5 could enriched in the promoter region of MAF BZIP transcription factor B, while levobupivacaine treatment could repressed the enrichment. The suppression of KAT5 by siRNA repressed the enrichment of histone H3 acetylation at lysine 27 and RNA polymerase II on promoter of MAFB. The expression of MAFB was decreased by KAT5 knockdown in osteosarcoma cells. The expression of MAFB was repressed by levobupivacaine, while the overexpression of KAT5 could reverse the repression of MAFB. KAT5 contributes to the cell proliferation and stemness of osteosarcoma cells. The overexpression of KAT5 or MAFB could reverse levobupivacaine-attenuated cell proliferation and stemness of osteosarcoma cells. Therefore, we concluded that local anesthetic levobupivacaine inhibited stemness of osteosarcoma cells by epigenetically repressing MAFB though reducing KAT5 expression. Levobupivacaine may act as a potential therapeutic candidate for osteosarcoma by targeting cancer stem cells.

The Potential Effect of Lidocaine, Ropivacaine, Levobupivacaine and Morphine on Breast Cancer Pre-Clinical Models: A Systematic Review.

Breast cancer (BC) is one of the most common types of cancer and the second leading cause of death in women. Local anaesthetics (LAs) and opioids have been shown to influence cancer progression and metastasis formation in several pre-clinical studies. However, their effects do not seem to promote consensus. A systematic review was conducted using the databases Medline (via PubMed), Scopus, and Web of Science (2010 to December 2021). Search terms included "lidocaine", "ropivacaine", "levobupivacaine", "morphine", "methadone", "breast cancer", "breast carcinoma" and "breast neoplasms" in diverse combinations. The search yielded a total of 784 abstracts for initial review, 23 of which met the inclusion criteria. Here we summarise recent studies on the effect of analgesics and LAs on BC cell lines and animal models and in combination with other treatment regimens. The results suggest that local anaesthetics have anti-tumorigenic properties, hence their clinical application holds therapeutic potential. Regarding morphine, the findings are conflicting, but this opioid appears to be a tumour-promoting agent. Methadone-related results are scarce. Additional research is clearly required to further study the mechanisms underlying the controversial effects of each analgesic or LA to establish the implications upon the outcome and prognosis of BC patients' treatment.

A Prospective Randomized Trial Comparing Topical Intranasal Lidocaine and Levobupivacaine in Patients Undergoing Endoscopic Binostril Transnasal Transsphenoidal Resection of Pituitary Tumors.

INTRODUCTION: Local anesthetic intranasal packing is used in transnasal surgery to reduce hemodynamic fluctuations. We hypothesized that the long acting local anesthetic levobupivacaine would provide superior hemodynamic stability and postoperative analgesia compared with lidocaine in endoscopic transnasal transsphenoidal (TNTS) surgery. MATERIALS AND METHODS: In this prospective, randomized, double-blind trial, 48 patients undergoing TNTS surgery were allocated to the 2 groups to receive preoperative intranasal packing with 15 mL of 1.5% lidocaine or 0.5% levobupivacaine each mixed with 60 mg ephedrine. Heart rate and mean arterial blood pressure were recorded immediately before induction of anesthesia, at various time points throughout surgery, and at tracheal extubation. Bleeding in the surgical field, time to extubation, and postoperative pain were also assessed. RESULTS: There was no significant difference in heart rate between the lidocaine and levobupivacaine groups at any point. Mean arterial pressure was also similar between the 2 groups during surgery, whereas at extubation blood pressure was lower in the lidocaine compared with levobupivacaine group (85±10 vs. 96±16 mm Hg; P=0.0010). There were no differences between the 2 groups in the other outcome variables. CONCLUSIONS: Preoperative intranasal packing with 1.5% lidocaine or 0.5% levobupivacaine provide similar hemodynamic stability throughout TNTS. Lidocaine packing may be more advantageous for hemodynamic stability during extubation.

Sustained Release of Levobupivacaine, Lidocaine, and Acemetacin from Electrosprayed Microparticles: In Vitro and In Vivo Studies.

In this study, we explored the release characteristics of analgesics, namely levobupivacaine, lidocaine, and acemetacin, from electrosprayed poly(D,L-lactide-co-glycolide) (PLGA) microparticles. The drug-loaded particles were prepared using electrospraying techniques and evaluated for their morphology, drug release kinetics, and pain relief activity. The morphology of the produced microparticles elucidated by scanning electron microscopy revealed that the optimal parameters for electrospraying were 9 kV, 1 mL/h, and 10 cm for voltage, flow rate, and travel distance, respectively. Fourier-transform infrared spectrometry indicated that the analgesics had been successfully incorporated into the PLGA microparticles. The analgesic-loaded microparticles possessed low toxicity against human fibroblasts and were able to sustainably elute levobupivacaine, lidocaine, and acemetacin in vitro. Furthermore, electrosprayed microparticles were found to release high levels of lidocaine and acemetacin (well over the minimum therapeutic concentrations) and levobupivacaine at the fracture site of rats for more than 28 days and 12 days, respectively. Analgesic-loaded microparticles demonstrated their effectiveness and sustained performance for pain relief in fracture injuries.

Local anesthetics counteract cell proliferation and migration of human triple-negative breast cancer and melanoma cells.

In different retrospective studies, a protective role of regional anesthetics in reducing cancer recurrence after surgery was indicated. Accordingly, it has been previously demonstrated a protective effect of anesthetics in breast cancer cells and in other types of cancer. On the other hand, how anesthetics influence cancer needs in-depth investigations. For this purpose, two different human cancer cell lines, MDA-MB-231, triple-negative breast cancer, and A375, melanoma, were used in this study. By means of Western blotting and immunofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labeling analyses, the signal transduction pathways activated by the anesthetics, such as ropivacaine and levobupivacaine, were analyzed. The data obtained demonstrated that both anesthetics are able to counteract cell proliferation by positively modulating cell death signaling and by decreasing cell proliferation and survival pathways.

The effects of ropivacaine 0.0625% and levobupivacaine 0.0625% on uterine and abdominal muscle electromyographic activity during the second stage of labor.

BACKGROUND: This study investigated the effect of ropivacaine on uterine and abdominal muscle electromyographic activity during the second stage of labor. METHODS: A total of 161 patients, including 48 patients receiving 0.0625% ropivacaine for patient-controlled epidural analgesia (PCEA), 64 patients receiving 0.0625% levobupivacaine for PCEA, and 49 patients with no PCEA completed the study. Uterine and abdominal muscle electromyographic activity was continuously recorded from the abdominal surface during the second stage of labor. Maternal demographic and clinical characteristics, maternal and neonatal outcomes, and various electromyographic parameters were recorded. RESULTS: Second stage of labor was significantly prolonged (P=0.007) for levobupivacaine compared to ropivacaine or no PCEA. The root-mean-square and duration of uterine muscle electromyographic activity was significantly lower for levobupivacaine or ropivacaine compared to no PCEA. The root-mean-square and power of abdominal muscle electromyographic activity was significantly lower for levobupivacaine compared to ropivacaine or no PCEA; the peak frequency of abdominal muscle electromyographic activity was significantly higher for ropivacaine. Visual analogue scale pain scores in patients in the levobupivacaine group or ropivacaine group decreased significantly over time compared to patients in the no PCEA group. CONCLUSIONS: In conclusion 0.0625% ropivacaine does not suppress abdominal muscle electromyographic activity during the second stage of labor. Maternal and neonatal outcomes were similar in patients receiving ropivacaine or no PCEA.

Photoplethysmographic evaluation of sympathectomy during lumbar epidural analgesia: A randomized comparison of 0.125% ropivacaine and 0.125% levobupivacaine.

BACKGROUND: There are no data on the difference between the impact of ropivacaine and levobupivacaine on sympathetic nerve fibers during central neuraxial blocks. We hypothesized that there is no difference in the degree of sympathectomy between the two drugs during lumbar epidural analgesia for labor pain. METHODS: Sixty healthy parturients were randomized to the type of local anesthetic-opiod solution administered in the epidural space: 10 mL of 0.125% ropivacaine + 100 mcg of fentanyl or 10 mL of 0.125% levobupivacaine + 100 mcg of fentanyl. After the baseline measurement, photoplethysmography signal from the first toe of the leg was recorded 5, 10 and 20 minutes after administration of epidural analgesia. RESULTS: Area under the curve and the pulse transit time of the toe photoplethysmography increased in both groups during the first 20 minutes after administration of epidural analgesia (P < 0.001 for both parameters in both groups). No difference in the degree of sympathectomy was found between the groups for the area under the curve. The difference in the change of the pulse transit time suggests that the two local anesthetics might differ in the degree of sympathectomy (P = 0.024). CONCLUSION: 0.125% ropivacaine and 0.125% levobupivacaine do not differ in the terms of sympathectomy-mediated side effects of the epidural block for labor analgesia. However, the photoplethysmography findings suggest a certain difference in the degree of sympathectomy between the two local anesthetics.

Sciatic nerve block in dogs: description and evaluation of a modified ultrasound-guided parasacral approach.

OBJECTIVE: To develop a modified ultrasound-guided parasacral approach to the sciatic nerve and compare the effects of a volume of 0.2 mL kg-1 of 0.5% levobupivacaine with an equivalent volume of 0.9% saline injected near the sciatic nerve. STUDY DESIGN: Cadaveric and experimental, blinded, randomized study. ANIMALS: Seven canine cadavers and seven experimental Beagle dogs. METHODS: Both sciatic nerves of seven cadavers were identified using a modified in-plane ultrasound-guided approach. Methylene blue solution (0.2 mL) was injected perineurally, and success was evaluated through dissection. The same approach was repeated in seven Beagle dogs sedated with dexmedetomidine (50 µg kg-1) injected intramuscularly (IM). After randomization, 0.2 mL kg-1 of 0.5% levobupivacaine (limb L) and 0.2 mL kg-1 of 0.9% saline (limb C) were injected perineurally on either right or left limb. Block success was determined by sensory deficits every hour for 8 hours after an atipamezole injection (0.2 mg kg-1) IM. Reaction to pinprick (binary score) over the course of the sciatic nerve (four locations) and locomotion were assessed. RESULTS: The overall sciatic nerve block success was 93% in cadavers and 86% in sedated dogs. It was impossible to localize the sciatic nerves in one obese sedated dog. Significant differences between limb L and limb C were observed for pinprick at great trochanter, caudal thigh and lateral tarsal joint (p < 0.0001). Reaction to pinprick was absent in all dogs at great trochanter and caudal thigh up to at least 3 hours on limb L. Locomotion was impaired in all but one dog for 60 (30-210) minutes (median; interquartile range). No complications were observed. CONCLUSIONS AND CLINICAL RELEVANCE: A volume of ≥0.2 mL kg-1 and a concentration of 0.5% levobupivacaine can be recommended when using a modified ultrasound-guided parasacral approach to the sciatic nerve in dogs.

Levobupivacaine-induced vasoconstriction involves caldesmon phosphorylation mediated by tyrosine kinase-induced ERK phosphorylation.

The goals of this study were to examine the cellular signaling pathways associated with the phosphorylation of caldesmon, the phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17), and the 20-kDa regulatory light chain of myosin (MLC20) induced by levobupivacaine in isolated rat aortas. The effects of genistein, tyrphostin 23, GF109203X, PD98059, Y-27632, 1-butanol, and ML-7 HCl on levobupivacaine-induced contraction were assessed. The effect of genistein on the simultaneous calcium-tension curves induced by levobupivacaine was examined. The effects of GF109203X, genistein, PD98059 and extracellular signal-regulated kinase (ERK) siRNA on levobupivacaine-induced caldesmon phosphorylation were investigated. The effect of genistein on the ERK and tyrosine phosphorylation induced by levobupivacaine was examined. The effect of GF109203X, PD98059, Y-27632, SP600125, and ML-7 HCl on the levobupivacaine-induced phosphorylation of CPI-17 and MLC20 were investigated. Genistein, tyrphostin 23, GF109203X, PD98059, Y-27632, ML-7 HCl, and 1-butanol attenuated levobupivacaine-induced contraction. Genistein caused a right downward shift of the calcium-tension curves induced by levobupivacaine. Genistein attenuated levobupivacaine-induced phosphorylation of protein tyrosine, ERK and caldesmon. PD98059, ERK siRNA and GF109203X attenuated levobupivacaine-induced caldesmon phosphorylation. GF109203X, Y-27632, SP600125, ML-7 HCl and PD98059 attenuated CPI-17 phosphorylation and MLC20 phosphorylation induced by levobupivacaine. These results suggest that levobupivacaine-induced caldesmon phosphorylation contributing to levobupivacaine-induced contraction is mediated by a pathway involving ERK, which is activated by tyrosine kinase or protein kinase C (PKC). The phosphorylation of CPI-17 and MLC20 induced by levobupivacaine is mediated by cellular signaling pathways involving PKC, Rho-kinase, and c-Jun NH2-terminal kinase or PKC, Rho-kinase, ERK, and myosin light chain kinase.

Both Bupivacaine and Levobupivacaine inhibit colon cancer cell growth but not melanoma cells in vitro.

BACKGROUND: Retrospective studies indicate that the use of regional anaesthesia causes a reduction in cancer recurrence after oncological surgery, which could be due to anaesthetic's negating effect on immunosuppression related to the surgical stress response. Local anaesthetics may also exert direct suppressive effects on malignant cells, an area where further investigation is urgently needed. METHODS: Human colon cancer cells and human melanoma cells were cultured and then treated with 1 mM bupivacaine or levobupivacaine for up to 24 or 48 h. Their migratory ability was measured by scratch assay, proliferation determined with Ki67 immunofluorescence staining, and apoptosis accessed with annexin V and PI staining on flow cytometry. The effects of bupivacaine and levobupivacaine on cellular signaling and molecular response, specifically, on endoplasmic reticulum stress (ERS), were studied with immunostaining and western blot. RESULTS: In colon cancer cells, treatment with bupivacaine and levobupivacaine significantly inhibited cell migration (**p < 0.01, ***p < 0.001; n = 4) and proliferation (**p < 0.01; n = 4), while increasing the expression of CHOP (***p < 0.001; n = 4) and decreased the expression of Grp78 (*p < 0.05; n = 4). These effects were not mirrored by melanoma cells, such that no significant increase in apoptosis was seen in either melanoma cell lines following treatment. CONCLUSION: These in vitro data suggested that both bupivacaine and levobupivacaine suppress colorectal adenocarcinoma cell proliferation and migration, which are concurrent with increased endoplasmic reticulum stress. Conversely, melanoma cells are more resilient to these two commonly used local anaesthetics. Further in vivo studies or clinical trials are needed.

Effects of Ropivacaine in Patient-Controlled Epidural Analgesia on Uterine Electromyographic Activities during Labor.

Epidural analgesia is effective in relieving pain during labor. However, concerns as to compromised labor progress and outcomes arise. This study aimed to assess the effect of patient-controlled epidural analgesia (PCEA) with ropivacaine on uterine electromyography (EMG) activities and outcomes in labor. A total of 213 pregnant women were divided into three groups: the PCEA with ropivacaine group (n = 78), the PCEA with levobupivacaine group (n = 66), and a control group that did not receive PCEA (n = 69). Uterine EMG activities were recorded during the first stage of labor. Maternal and fetal outcomes also were assessed. The primary outcomes of this study were EMG activities. No significant differences were observed in patient demographics or neonatal weight among the three groups. Compared to the PCEA with levobupivacaine group, the control and PCEA with ropivacaine groups had lower rates of oxytocin administration (P < 0.05) and shorter durations of the first stage of labor (P < 0.05). For the EMG activities, the PCEA with ropivacaine group showed a higher power (P < 0.01) and higher peak frequency (P < 0.05) than the PCEA with levobupivacaine group. With ropivacaine, the EMG activities remained stable 30-120 min. Compared with levobupivacaine, the use of ropivacaine in PCEA has no suppressive effect on uterine EMG activities during the first stage of labor. In addition, ropivacaine leads to labor progress and delivery outcomes similar to those in the control group, as well as similar and favorable analgesic satisfaction with the use of levobupivacaine.

Effects of Thoracic Epidural Anaesthesia on the Serosal Microcirculation of the Human Small Intestine.

BACKGROUND: The effect of thoracic epidural analgesia (TEA) on splanchnic blood flow during abdominal surgery remains unclear. The purpose of this study was to examine whether the hemodynamic effects of TEA resulted in microcirculatory alterations to the intestinal serosa, which was visualized using incident dark-field (IDF) videomicroscopy. METHODS: An observational cohort study was performed. In 18 patients, the microcirculation of the intestinal serosa was visualized with IDF. Microcirculatory and hemodynamic measurements were performed prior to (T1) and after administering a bolus of levobupivacaine (T2). If correction of blood pressure was indicated, a third measurement was performed (T3). The following microcirculatory parameters were calculated: microvascular flow index, proportion of perfused vessels, perfused vessel density and total vessel density. Data are presented as median [IQR]. RESULTS: Mean arterial pressure decreased from 73 mmHg (68-83) at T1 to 63 mmHg (±11) at T2 (p = 0.001) with a systolic blood pressure of 114 mmHg (98-128) and 87 (81-97), respectively (p = 0.001). The microcirculatory parameters of the bowel serosa, however, were unaltered. In seven patients, blood pressure was corrected to baseline values from a MAP of 56 mmHg (55-57), while microcirculatory parameters remained constant. CONCLUSION: We examined the effects of TEA on the intestinal serosal microcirculation during abdominal surgery using IDF imaging for the first time in patients. Regardless of a marked decrease in hemodynamics, microcirculatory parameters of the bowel serosa were not significantly affected. TRIAL REGISTRY NUMBER: ClinicalTrials.gov identifier NCT02688946.

Opioid analgesia and the somatosensory memory of neonatal surgical injury in the adult rat.

BACKGROUND: Nociceptive input during early development can produce somatosensory memory that influences future pain response. Hind-paw incision during the 1st postnatal week in the rat enhances re-incision hyperalgesia in adulthood. We now evaluate its modulation by neonatal analgesia. METHODS: Neonatal rats [Postnatal Day 3 (P3)] received saline, intrathecal morphine 0.1 mg kg-1 (IT), subcutaneous morphine 1 mg kg-1 (SC), or sciatic levobupivacaine block (LA) before and after plantar hind-paw incision (three×2 hourly injections). Six weeks later, behavioural thresholds and electromyography (EMG) measures of re-incision hyperalgesia were compared with an age-matched adult-only incision (IN) group. Morphine effects on spontaneous (conditioned place preference) and evoked (EMG sensitivity) pain after adult incision were compared with prior neonatal incision and saline or morphine groups. The acute neonatal effects of incision and analgesia on behavioural hyperalgesia at P3 were also evaluated. RESULTS: Adult re-incision hyperalgesia was not prevented by neonatal peri-incision morphine (saline, IT, and SC groups > IN; P<0.05-0.01). Neonatal sciatic block, but not morphine, prevented the enhanced re-incision reflex sensitivity in adulthood (LA < saline and morphine groups, P<0.01; LA vs IN, not significant). Morphine efficacy in adulthood was altered after morphine alone in the neonatal period, but not when administered with neonatal incision. Morphine prevented the acute incision-induced hyperalgesia in neonatal rats, but only sciatic block had a preventive analgesic effect at 24 h. CONCLUSIONS: Long-term effects after neonatal injury highlight the need for preventive strategies. Despite effective analgesia at the time of neonatal incision, morphine as a sole analgesic did not alter the somatosensory memory of early-life surgical injury.

Potent Inactivation-Dependent Inhibition of Adult and Neonatal NaV1.5 Channels by Lidocaine and Levobupivacaine.

BACKGROUND: Cardiotoxic effects of local anesthetics (LAs) involve inhibition of NaV1.5 voltage-gated Na channels. Metastatic breast and colon cancer cells also express NaV1.5, predominantly the neonatal splice variant (nNaV1.5) and their inhibition by LAs reduces invasion and migration. It may be advantageous to target cancer cells while sparing cardiac function through selective blockade of nNaV1.5 and/or by preferentially affecting inactivated NaV1.5, which predominate in cancer cells. We tested the hypotheses that lidocaine and levobupivacaine differentially affect (1) adult (aNaV1.5) and nNaV1.5 and (2) the resting and inactivated states of NaV1.5. METHODS: The whole-cell voltage-clamp technique was used to evaluate the actions of lidocaine and levobupivacaine on recombinant NaV1.5 channels expressed in HEK-293 cells. Cells were transiently transfected with cDNAs encoding either aNaV1.5 or nNaV1.5. Voltage protocols were applied to determine depolarizing potentials that either activated or inactivated 50% of maximum conductance (V½ activation and V½ inactivation, respectively). RESULTS: Lidocaine and levobupivacaine potently inhibited aNaV1.5 (IC50 mean [SD]: 20 [22] and 1 [0.6] µM, respectively) and nNaV1.5 (IC50 mean [SD]: 17 [10] and 3 [1.6] µM, respectively) at a holding potential of -80 mV. IC50s differed significantly between lidocaine and levobupivacaine with no influence of splice variant. Levobupivacaine induced a statistically significant depolarizing shift in the V½ activation for aNaV1.5 (mean [SD] from -32 [4.6] mV to -26 [8.1] mV) but had no effect on the voltage dependence of activation of nNaV1.5. Lidocaine had no effect on V½ activation of either variant but caused a significantly greater depression of maximum current mediated by nNaV1.5 compared to aNaV1.5. Similar statistically significant shifts in the V½ inactivation (approximately -10 mV) occurred for both LAs and NaV1.5 variants. Levobupivacaine (1 µM) caused a significantly greater slowing of recovery from inactivation of both variants than did lidocaine (10 µM). Both LAs caused approximately 50% tonic inhibition of aNaV1.5 or nNaV1.5 when holding at -80 mV. Neither LA caused tonic block at a holding potential of either -90 or -120 mV, voltages at which there was little steady-state inactivation. Higher concentrations of either lidocaine (300 µM) or levobupivacaine (100 µM) caused significantly more tonic block at -120 mV. CONCLUSIONS: These data demonstrate that low concentrations of the LAs exhibit inactivation-dependent block of NaV1.5, which may provide a rationale for their use to safely inhibit migration and invasion by metastatic cancer cells without cardiotoxicity.

Realocação vertical da cicatriz umbilical em abdominoplastias do grupo IV de bozola e psillakis - padronização tática / Vertical relocation of the umbilical scar in abdominoplasty of Bozola and Psillakis Group IV cases ­ standardization of procedures

Introdução: O umbigo é a única cicatriz natural visível do corpo. É parte essencial da estética abdominal, fato que torna a umbilicoplastia fundamental no sucesso da abdominoplastia. A posição e a naturalidade de contorno são os dois fatores mais relevantes na avaliação do resultado estético da cicatriz umbilical. Classificações e padronizações têm sido ferramentas importantes para aprimoramento do diagnóstico e refinamentos no tratamento dos distúrbios estéticos do abdome. Além disso, têm facilitado a reprodutibilidade dos procedimentos e servido de base para estudos comparativos. Objetivos: Apresentar a experiência do autor com uma padronização tática para o reposicionamento e reimplante da cicatriz umbilical em casos de abdominoplastias do grupo IV. Demonstrar a tática de realocação vertical do umbigo com detalhamento da nova posição, avaliar a qualidade do resultado obtido e o grau de satisfação das pacientes. Métodos: Vinte pacientes, todas do sexo feminino, foram submetidas ao procedimento entre maio de 2010 e maio de 2012. O período mínimo de acompanhamento foi de trinta dias e o máximo, de dois anos. Resultados: A maioria dos resultados foi considerada excelente, atingindo alto nível de satisfação das pacientes, sem apresentar grandes complicações. Não foram necessárias reintervenções. A técnica mostrou-se segura, simples e de fácil execução. Conclusão: A marcação e o planejamento cirúrgico, com a proposta de um limite caudal máximo para o reposicionamento da cicatriz umbilical, podem ser de grande valia tanto no auxílio aos diagnósticos mais complexos dos tipos de defeitos estéticos do abdome quanto nas indicações das técnicas de abdominoplastias mais adequadas ao tratamento.

Introduction: The navel is the only natural visible scar on the body. It is an essential part of abdominal aesthetics, making umbilicoplasty critical for the success of abdominoplasty. The position and natural contour are the two important factors that are most relevant in evaluating the aesthetic result of the umbilical scar. Classifications and standards are important tools to improve the diagnosis and refine the treatment of abdomen aesthetic disorders. Furthermore, it has facilitated appropriate reproduction of the procedure and served as a basis for comparative studies. Objectives: This study presents the author's experience with procedure standardization for repositioning and re-implantation of the umbilical scar in abdominoplasty group IV cases. The study demonstrates the navel vertical relocation technique, along with details of the new position, and assesses the quality of results obtained and the degree of patient satisfaction. Case studies and methods: Twenty female patients underwent the procedure between May 2010 and May 2012. The minimum follow-up period was thirty days and the maximum follow-up period was two years. Results: Most results were considered excellent, with a high level of patient satisfaction and no major complications. There was no need for re-intervention. The technique was shown to be safe, simple and easy to perform. Conclusion: The marking and surgical planning, with a proposed maximum end limit for repositioning of the umbilical scar, can be valuable both in aiding the most complex diagnoses of aesthetic abdomen defect types and evaluating the technical aspects of abdominoplasty that are most appropriate for treatment.