Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer.

BACKGROUND: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. METHODS: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. RESULTS: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. CONCLUSION: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

Efficacy of transversus abdominis plane block on postoperative nausea and vomiting: a meta-analysis of randomized controlled trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common postoperative complication, and Transversus abdominis plane (TAP) block can provide effective analgesia for surgical operation. However, but there is not enough evidence to prove its advantage for nausea and vomiting. The objective of this meta-analysis was to evaluate the efficacy of TAP block on PONV. METHODS: Two independent researchers conducted searches for randomized controlled trials (RCTs) in PubMed, Embase, and Cochrane Central Register of Controlled Trials. We used Review Manager software for meta-analysis. RESULTS: In this meta-analysis, twenty-six trials with 1981 patients were examined. The results showed that TAP block reduced postoperative nausea (Risk Difference (RD) = -0.10, 95% confidence interval (CI): -0.15 to -0.05) compared with no TAP block. TAP block reduced the dose of fentanyl (Standardized Mean Difference (SMD) = -1.17, 95% CI: -2.07 to -0.26) and morphine (SMD = -1.12, 95% CI: -2.10 to -0.13) compared with no TAP block, when the timing of administration was before surgery (RD = -0.13, 95% CI: -0.19 to -0.07). TAP block reduced postoperative nausea when the ropivacaine dosage is ≤ 100 mg (RD = -0.13, 95% CI: -0.21 to -0.06), bupivacaine dosage ≥ 100 mg ( RD = -0.08, 95% CI: -0.13 to -0.03), and when the ropivacaine concentration was ≤ 0.375% (RD = -0.11, 95% CI: -0.18 to -0.04). TAP block significantly reduced the incidence of nausea when the types of opioid drugs in PCA is tramadol (RD = -0.13, 95% CI: -0.24 to -0.03). TAP block could reduce the VAS (SMD= -0.99, 95% CI: -1.29 to -0.70) and reduce the time of extubation (SMD = -0.71, 95% CI: -1.34 to -0.08). CONCLUSION: The meta-analysis conducted in this study revealed that TAP block could reduce the incidence of PONV, and the efficacy of TAP block may be influenced by factors such as administration time, local anesthetic dosage and concentration, types of opioid drugs in PCA.

Effect of ultrasound-guided stellate ganglion block on inflammatory cytokines and postoperative recovery after partial hepatectomy: a randomised clinical trial.

BACKGROUND: Stellate ganglion block (SGB) has been shown to reduce perioperative complications in various surgeries. Because laparoscopic techniques and instruments have advanced during the past two decades, laparoscopic liver resection is being increasingly adopted worldwide. Lesser blood loss, fewer postoperative complications, and shorter postoperative hospital stays are the advantages of laparoscopic liver resection, as compared to conventional open surgery. There is an urgent need for an effective intervention to reduce perioperative complications and accelerate postoperative recovery. This study investigated the effect of ultrasound-guided SGB on enhanced recovery after laparoscopic partial hepatectomy. METHODS: We compared patients who received SGB with 0.5% ropivacaine (group S) with those who received SGB with 0.9% saline (group N). A total of 58 patients with partial hepatectomy were enrolled (30 S) and (28 N). Before induction of anesthesia, SGB was performed with 0.5% ropivacaine in group S and 0.9% saline in group N. MAIN OUTCOME: Comparison of serum inflammatory cytokines concentration at each time point. RESULTS: Main outcome: When comparing IL-6 and IL-10 concentrations among groups, group S showed less variation over time compared to group N. For comparison between groups, the serum IL-6 concentration in group S was lower than that in group N at 6 and 24 h after operation (P < 0.01), and there was a significant linear relationship between serum IL-6 concentration at 24 h after operation and hospitalization situation. CONCLUSIONS: Ultrasound-guided SGB can stabilize perioperative inflammatory cytokines plays a positive role in the enhanced recovery of patients after laparoscopic partial hepatectomy. The serum IL-6 level within 24 h after surgery may be used as a predictor of hospitalization. TRIAL REGISTRATION: The study was registered at the ClinicalTrials.gov (Registration date: 13/09/2021; Trial ID: NCT05042583).

Ropivacaine combined with sorafenib attenuates hepatocellular carcinoma cell proliferation and metastasis by inhibiting the miR-224/HOXD10 axis.

OBJECTIVE: The development of drug resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib (Sor). However, the regulatory mechanisms underlying the effects of the combination Sor and ropivacaine (Rop) on HCC cells remain unclear. METHODS: miR-224 and HOXD10 mRNA expression in HCC cells was analyzed using qRT-PCR. CCK-8, Transwell assays and tumor formation experiments in nude mice were used to assess HCC cell proliferation, migration, and invasion. Migration of HCC cells was also analyzed using a cell scratch assay. Hematoxylin and eosin staining was used to detect tumor area. RESULTS: miR-224 expression profoundly increased in HepG2 and Huh7 cells. Treatment with Rop and/or Sor blocked miR-244 expression, especially the combination treatment. Transfection of miR-224 mimic increased HCC cell proliferation and tumor size in nude mice, and migration and invasion in vitro in the presence of Rop and Sor compared to the negative control mimic. Dual-luciferase reporter assays showed that HOXD10 was targeted by miR-224. HOXD10 protein expression and was markedly reduced in HepG2 and Huh7 cells. Rop and/or Sor treatment increased HOXD10 protein expression, particularly the combination treatment. miR-224 negatively regulated HOXD10 expression in HCC cells treated with Rop and Sor. Transfection-mediated silencing of HOXD10 increased HCC cell proliferation, migration, and invasion in the presence of Rop and Sor compared with negative control transfection. CONCLUSION: The combination of Rop and Sor attenuates HCC cell proliferation and metastasis via the miR-224/HOXD10 axis.

The impact of biological sex in peripheral nerve blockade: A prospective pharmacodynamic, pharmacokinetic and morphometric study in volunteers.

STUDY OBJECTIVE: The impact of biological sex in peripheral regional anaesthesia is largely unknown. We therefore designed a prospective study in volunteers to investigate the impact of biological sex on pharmacodynamic, pharmacokinetic and morphometric characteristics for peripheral nerve blockade. METHODS: The initial study plan was powered to include 90 volunteers to find a difference of 35 min in duration of sensory block (primary outcome variable) with 80% power and alpha error at 5%. After discussions in ethical review, a pilot study of 2 x 12 volunteers from each sex were studied. Female and male volunteers received ultrasound guided nerve blockade with 3.0 mL ropivacaine 7.5 mg mL-1. Sensory duration of blockade, as the primary outcome, was evaluated by pinprick testing. Secondary outcomes were sensory onset time of blockade, pharmacokinetic characteristics and the visibility of ulnar nerves using ultrasound. Analyses included Mann-Whitney U-statistics with P<0.05 (two-sided) as significant. RESULTS: After 24 participants, the median (IQR) duration of sensory blockade was 450 (420; 503) min in women and 480 (450; 510) min in men (P = 0.49). Sensory onset time of blockade, and ultrasound visibility of nerves were also similar between the study groups. The total drug exposure across time (AUC0-infinity) was significantly higher in women (P = 0.017). After a the planned power re-analysis after these 24 study paticipants, which suggested that > 400 subjects would be required with 80% power and alpha error of 5% to find significance for the primary outcome parameter for marginal differences, we terminated the study at this point. CONCLUSIONS: We did not detect significant differences between female and male study participants in terms of pharmacodynamic and morphometric characteristics after ultrasound guided ulnar nerve blocks. Women did show significantly greater pharmacokinetic ropivacaine exposures. The results of this study indicate that peripheral regional block pharmacodynamic characteristics are independent of the biological sex, whereas pharmacokinetic parameters are sex-dependent.

Ropivacaine inhibits the proliferation and metastasis of gastric cancer cells via the SNX10/SRC/STAT3 pathway.

Gastric cancer currently has no effective treatment due to its high metastasis and heterogeneity. It has been reported that ropivacaine (Rop) can inhibit the growth, migration, and invasion of gastric cancer. However, the therapeutic mechanism of Rop still needs to be further explored to provide insights for its clinical application. This study aimed to explore the effects of Rop on the growth, migration, and invasion of gastric cancer cells and the underlying mechanisms. The expression levels of SNX10 were assessed in gastric cancer tissues and cell line AGS by qRT-PCR. Cell Counting Kit-8 (CCK8) assay, wound-healing assay, and transwell assay were then used to examine the effects of Rop on the AGS cell viability, migration, invasion, and proliferation, respectively. Additionally, colony formation assay was used to measure cell proliferation ability, and flow cytometry was used to detect apoptosis level. Protein levels of SNX10, SRC, and STAT3 were detected by western blot. According to the experimental results, the decreased SNX10 mRNA expression was observed in gastric cancer tissue and cell line AGS. Rop inhibited the proliferation, migration, and invasion of AGS cells, but promoted apoptosis and upregulated SNX10 expression. Moreover, Rop inhibited the expression of MMP-2 and MMP-9, phosphorylation of SRC and STAT3. SNX10 knockdown could reverse Rop-induced anticancer effects. Collectively, Rop showed a potential role in preventing proliferation and metastasis of gastric cancer. The action mechanism of Rop may be related to the upregulation of SNX10 expression and further inhibition of SRC/STAT3 signaling pathway. Our findings provide new insights into the anticancer properties of Rop.

Effect of transversus abdominis plane block with or without buprenorphine after inguinal hernia surgery on postoperative pain.

INTRODUCTION: Transversus abdominis plane (TAP) has been mentioned as having bene-ficial effects on chronic pain after hernioplasty. This study assessed the effects of TAP block on acute and persistent postoperative pain after inguinal hernia surgery, with or without buprenorphine. MATERIAL AND METHODS: 64 patients were allocated to group R ( n = 32) and received 20 mL of 0.25% ropivacaine for TAP block; group RB ( n = 32) received 20 mL of 0.25% ropivacaine containing 300 µg of buprenorphine for TAP block. The primary outcome was the analgesic and antihyperalgesic effect of buprenorphine. The duration of analgesia, analgesic consumption, postoperative pain scores at rest and sitting up to 48 hours, and the effect on wound hyperalgesia were evaluated. Secondary outcomes included the incidence of side effects and complications. RESULTS: The median (IQR) duration of analgesia in group R was 386.5 (37.25) minutes vs. 868 (41.3) minutes in the RB group. Median pain scores on sitting were found to be significantly better in group RB than in group R at 6, 12, and 24 hours ( P < 0.001). The wound hyperalgesia index showed a significant difference between groups ( P < 0.001). The incidence of persistent postoperative pain was 6.25% in the R group, as compared to 0% in the RB group. Otherwise, the patients did not have any further complications associated with the block. CONCLUSIONS: The results demonstrated that TAP block with buprenorphine reduced acute postoperative pain severity, but we did not find a difference between groups in persistent pain.

Ropivacaine inhibits the malignant behavior of lung cancer cells by regulating retinoblastoma-binding protein 4.

Background: Ropivacaine is a local anesthetic commonly used in regional nerve blocks to manage perioperative pain during lung cancer surgery. Recently, the antitumor potential of ropivacaine has received considerable attention. Our previous study showed that ropivacaine treatment inhibits the malignant behavior of lung cancer cells in vitro. However, the potential targets of ropivacaine in lung cancer cells have not yet been fully identified. This study aimed to explore the antitumor effects and mechanisms of action of ropivacaine in lung cancer. Methods: Lung cancer A549 cells were treated with or without 1 mM ropivacaine for 48 h. Quantitative proteomics was performed to identify the differentially expressed proteins (DEPs) triggered by ropivacaine treatment. STRING and Cytoscape were used to construct protein-protein interaction (PPI) networks and analyze the most significant hub genes. Overexpression plasmids and small interfering RNA were used to modulate the expression of key DEPs in A549 and H1299 cells. MTS, transwell assays, and flow cytometry were performed to determine whether the key DEPs were closely related to the anticancer effect of ropivacaine on the malignant behavior of A549 and H1299 cells. Results: Quantitative proteomic analysis identified 327 DEPs (185 upregulated and 142 downregulated proteins) following ropivacaine treatment. Retinoblastoma-binding protein 4 (RBBP4) was one of the downregulated DEPs and was selected as the hub protein. TCGA database showed that RBBP4 was significantly upregulated in lung cancer and was associated with poor patient prognosis. Inhibition of RBBP4 by siRNA resulted in a significant decrease in the proliferation and invasive capacity of lung cancer cells and the induction of cell cycle arrest. Additionally, the results indicated RBBP4 knockdown enhanced antitumor effect of ropivacaine on A549 and H1299 cells. Conversely, the overexpression of RBBP4 using plasmids reversed the inhibitory effects of ropivacaine. Conclusion: Our data suggest that ropivacaine suppresses lung cancer cell malignancy by downregulating RBBP4 protein expression, which may help clarify the mechanisms underlying the antitumor effects of ropivacaine.

The effect of warming ropivacaine on ultrasound-guided subgluteal sciatic nerve block: a randomized controlled trial.

BACKGROUND: There is a long latent period for the sciatic nerve block before a satisfactory block is attained. Changes in the temperature of local anesthetics may influence the characters of the peripheral nerve block. This study was designed to evaluate the effect of warming ropivacaine on the ultrasound-guided subgluteal sciatic nerve block. METHODS: Fifty-four patients for distal lower limbs surgery were randomly allocated into warming group (group W, n = 27) or room tempeture group (group R, n = 27) with the ultrasound-guided subgluteal sciatic nerve block. The group W received 30 ml of ropivacaine 0.5% at 30℃ and the group R received 30 ml of ropivacaine 0.5% at 23℃. The sensory and motor blockade were assessed every 2 min for 30 min after injection. The primary outcome was the onset time of limb sensory blockade. RESULTS: The onset time of sensory blockade was shorter in group W than in group R (16 (16,18) min vs 22 (20,23) min, p < 0.001), and the onset time of motor blockade was also shorter in group W than in group R (22 (20,24) min vs 26 (24,28) min, p < 0.001). The onset time of sensory blockade for each nerve was shorter in group W than in group R (p < 0.001). No obvious differences for the duration of sensory and motor blockade and the patient satisfaction were discovered between both groups. No complications associated with nerve block were observed 2 days after surgery. CONCLUSIONS: Warming ropivacaine 0.5% to 30℃ accelerates the onset time of sensory and motor blockade in the ultrasound-guided subgluteal sciatic nerve block and it has no influence on the duration of sensory and motor blockade. TRIAL REGISTRATION: The trial was registered on October 3, 2022 in the Chinese Clinical Trial Registry ( https://www.chictr.org.cn/bin/project/edit?pid=181104 ), registration number ChiCTR2200064350 (03/10/2022).

Nanocrystals Slow-Releasing Ropivacaine and Doxorubicin to Synergistically Suppress Tumor Recurrence and Relieve Postoperative Pain.

Although surgical resection provides a straightforward and effective treatment for most malignant solid tumors, tumor recurrence and acute postoperative pain continue to be two big problems associated with this treatment. To resolve these problems, a nanocrystal composite slow-releasing ropivacaine and doxorubicin was fabricated in this study. Briefly, a self-assembling peptide was used to form nanoparticle complexes with the two drugs, based on which homogeneous nanocrystals were obtained by adjusting the pH. In cultured human melanoma cells, the nanocrystals exhibited improved antitumor activity due to a synergistic effect and enhanced cellular uptake of the two drugs. On the other hand, the nanocrystals could slowly release ropivacaine in vitro and in vivo, generating long-acting analgesia on the rat sciatic nerve block model and incisional pain model. On a nude mouse tumor resection model, the nanocrystals simultaneously suppressed the recurrence of solid tumor and relieved postoperative pain, indicating a potential postoperative treatment for tumor resection patients. This nanocrystal system also suggested a promising and facile strategy for developing multifunctional formulations combining different drugs, which could achieve better therapeutic outcomes in a synergistic and sustained manner.

Topical ropivacaine hydrochloride 0.5% and lidocaine hydrochloride 2% significantly reduce corneal sensitivity without short-term negative side effects in horses.

OBJECTIVE: To evaluate corneal sensitivity and acute side effects following application of ropivacaine hydrochloride 0.5% and lidocaine hydrochloride 2% on the healthy equine cornea. ANIMALS STUDIED: Eight healthy adult horses. PROCEDURE: A randomized, masked, crossover study design was utilized. Baseline Semiquantitative Preclinical Ocular Toxicology (SPOT) scores and corneal touch thresholds (CTT) using a Cochet-Bonnet esthesiometer were recorded and measured, respectively, for eight healthy adult horses before medication application. Commercially available eyewash was used as a negative control. Ropivacaine hydrochloride 0.5% or lidocaine hydrochloride 2% solution was sprayed on a randomly selected eye, and the contralateral eye received eyewash. CTT was measured in both eyes at 1, 5, 15, 25, 35, 45, 55, 65, and 75 min post-application. Post-application SPOT scores were recorded immediately following the trial. Linear mixed model statistical analyses (mean ± standard error) were performed (p < .05). RESULTS: Mean eyewash CTT (3.41 cm ± 0.464) was significantly different from ropivacaine-treated (1.44 cm ± 0.562) (p = .008) and lidocaine-treated eyes (1.75 cm ± 0.562) (p = .024); CTT was not significantly different between drug groups (p = .88). Time to maximum anesthesia was not significantly different between ropivacaine (13.25 min ± 3.353) and lidocaine (16.25 min ± 3.353) (p = .40). No side effects were appreciated as confirmed by SPOT. CONCLUSIONS: Ropivacaine and lidocaine similarly decreased corneal sensitivity when applied topically without clinically evident short-term ocular side effects. Lidocaine may be preferable in clinical settings due to its large, multi-use vials and similar effects to ropivacaine.

Comprehensive Analysis of Local Anesthetics Affecting Adipose Stem Cells In Vitro.

BACKGROUND: Adipose stem cells (ASCs) hold a great regenerative capacity because of their differentiation capability and their secretory activity. Thus, ASC survival is of great significance during perioperative harvesting. Various local anesthetics are commonly applied during fat grafting procedures. These substances are known to impair cellular viability, which would affect graft survival and final outcomes, but the exact extent of their impact on ASC biology is unknown. METHODS: The authors analyzed the short- and long-term effects of lidocaine, mepivacaine, ropivacaine, and bupivacaine at increasing concentrations (0.1 to 10 mM) on primary human ASC proliferation and metabolic activity. Trilinear differentiation was assessed by oil red O stain (adipogenesis), safranin O (chondrogenesis), and cresolphthalein (osteogenesis) labeling. In supernatants, cytokine [interleukin (IL)-6/IL-8, vascular endothelial growth factor, hepatocyte growth factor] secretion was analyzed by enzyme-linked immunosorbent assay. RESULTS: Bupivacaine at greater than 100 µM demonstrated the strongest anti proliferative effects, whereas lidocaine and ropivacaine did not affect cell numbers. Mepivacaine evoked reciprocal results regarding cell count at greater than 1 mM. Each compound impaired trilinear differentiation. Secretion of hepatocyte growth factor and IL-8 was reduced significantly by local anesthetic exposure; levels were restored after substances were washed out. CONCLUSIONS: In vitro data show that lidocaine, mepivacaine, and ropivacaine could be applied at concentrations of 1 to 10 mM without affecting ASC survival. In contrast, bupivacaine at concentrations greater than 100 µM should be administered with great caution. The differentiation of ASCs and the ASC's secretome might already be decreased by each local anesthetic at 1 mM. CLINICAL RELEVANCE STATEMENT: The authors' experimental data can be of great significance to the clinical practice, as local anesthetics are routinely administered during liposuction as a tumescent anesthesia adjunct. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Analgesic Effects of Ropivacaine Combined With Dexmedetomidine in Transversus Abdominis Plane Block in Patients Undergoing Laparoscopic Cholecystectomy: A Systematic Review and Meta-Analysis.

PURPOSE: This review aimed to conduct a meta-analysis of published randomized controlled studies (RCTs) comparing the effectiveness of dexmedetomidine (DEX) combined with ropivacaine versus single ropivacaine in transversus abdominis plane block (TAPB) for postoperative analgesia after laparoscopic cholecystectomy (LC). The purpose was to investigate whether DEX combined with ropivacaine in TAPB for postoperative analgesia in LC is superior to single ropivacaine administration. DESIGN: A Systematic Review and Meta-analysis. METHODS: Five electronic database systems were searched for RCTs on the effects of DEX combined with ropivacaine (joint group) and single ropivacaine on postoperative analgesia in LC. The standardized mean difference (SMD) or odds ratio (OR) and their corresponding 95% confidence interval (CI) of the indicators were calculated for comparison. FINDINGS: As of December 23, 2021, 153 articles were retrieved, but only 16 articles were finally included in this meta-analysis. The results showed that compared with single ropivacaine, DEX combined with ropivacaine in TAPB had better analgesia and lighter sedative effect in patients after LC. After LC 2h(T1), 4h(T2), 8h(T3), 12h(T4) and 24h (T5), the joint group participants have lower VAS scores (T1: SMD = -0.32, 95%CI: -0.49, -0.14; T2: SMD = -1.11, 95%CI: -1.56, -0.65; T3: SMD = -2.88, 95%CI: -3.74, -2.02; T4: SMD = -2.56, 95%CI: -3.04, -2.08; T5: SMD = -1.44, 95%CI: -1.81, -1.06). Also, the Ramsay score of the joint group is higher than the single group (T1: SMD = 1.05, 95%CI: 0.39, 1.71; T2: SMD = 1.57, 95%CI: 0.57, 2.57; T3: SMD = 1.64, 95%CI: 0.65, 2.63; T4: SMD = 1.72, 95%CI: 0.54, 2.89; T5: SMD = 0.57, 95%CI: 0.21, 0.94). CONCLUSIONS: The results of this review and meta-analysis suggest that DEX combined with ropivacaine has less postoperative pain, more patients got the status of sober and cooperative, and longer postoperative analgesia lasted than ropivacaine alone in TAPB, especially in the group of combined treatment with 1.0 mcg/kg DEX. Furthermore, the flow dynamics of the two groups are stable, and there is no notable difference in the incidence of adverse reactions.

Sodium bicarbonate reverts electrophysiologic cardiotoxicity of ropivacaine faster than lipid emulsions in a porcine model.

Ropivacaine has been described as a safer local anaesthetic (LA); however, serious cardiotoxic accidents have been reported. Intravenous-lipid-emulsion (ILE) therapy during LA intoxication seems to act as an antidote. Sodium bicarbonate is the standard treatment for sodium channel blocker drug toxicity. We compared both antidotes on the reversion of electrophysiologic toxicity induced by ropivacaine. Ropivacaine 5 mg kg-1 was administered in 24 pigs, and 3 min later, the animals received ILE: 1.5 ml kg-1  + 0.25 ml kg-1  min-1 (ILE group); sodium bicarbonate: 2 mEq kg-1  + 1 mEq kg-1  h-1 (NaHCO3 group); saline solution (CTL group). Electrophysiological parameters were evaluated for 30 min. The area under the curve (AUC) for the first 5 or 30 min was compared between groups. Ropivacaine induced a lengthening of the PR interval by 17% (P = 0.0001), His-ventricle-interval by 58% (P = 0.001), sinus QRS complex by 56% (P = 0.0001), paced QRS at 150 bpm by 257% (P = 0.0001), and at 120 bpm by 143% (P = 0.0001) in all groups. At 5 min after treatment, sinus QRS in the NaHCO3 group was shorter than that in the CTL group (AUCQRS5 , P = 0.003) or ILE group (AUCQRS5 , P = 0.045). During the first minute, seven of the animals in the NaHCO3 group vs. two in the ILE or 0 in the CTL group recovered more than 30% of the sinus QRS previously lengthened by ropivacaine (P = 0.003). Sodium bicarbonate reversed the electrophysiological toxicity of ropivacaine faster than ILE and control groups.

Ropivacaine inhibits proliferation and invasion and promotes apoptosis and autophagy in bladder cancer cells via inhibiting PI3K/AKT pathway.

Application of a certain concentration of local anesthetics during tumor resection inhibits the progression of tumor. The effects of ropivacaine in bladder cancer (BC) have never been explored. We explored the effects of ropivacaine on the progression of BC in vitro and in vivo. CCK8 assay and EDU staining was conducted to examine cell proliferation. Flow cytometry and transwell assay were performed to evaluate apoptosis and invasion, respectively. Expression of light chain 3 (LC3) was observed through immunofluorescence. Furthermore, the xenograft tumor model of BC was built to detect the effects of ropivacaine in vivo. IHC and TUNEL assay were conducted to detect cell proliferation and apoptosis in vivo. Ropivacaine inhibited the proliferation of T24 and 5639 cells with the 50% inhibitory concentration (IC50) of 20.08 and 31.86 µM, respectively. Ropivacaine suppressed the invasion ability and induces the apoptosis of cells. Besides, ropivacaine triggers obvious autophagy in BC cells. Moreover, ropivacaine blocks the PI3K/AKT signal pathway in BC cells. The impact of ropivacaine on cell viability, motility, and autophagy was reversed by 740 Y-P, the activator of PI3K/AKT signal pathway. The in vivo experiments demonstrated that ropivacaine inhibited the proliferation and mobility of BC. Ropivacaine has anti-carcinoma effects in BC via inactivating PI3K/AKT pathway, providing a new theoretical reference for the use of local anesthetics in the treatment of BC.

Apoptosis, Proliferation, and Autophagy Are Involved in Local Anesthetic-Induced Cytotoxicity of Human Breast Cancer Cells.

Breast cancer accounts for almost one quarter of all female cancers worldwide, and more than 90% of those who are diagnosed with breast cancer undergo mastectomy or breast conservation surgery. Local anesthetics effectively inhibit the invasion of cancer cells at concentrations that are used in surgical procedures. The limited treatment options for triple-negative breast cancer (TNBC) demonstrate unmet clinical needs. In this study, four local anesthetics, lidocaine, levobupivacaine, bupivacaine, and ropivacaine, were applied to two breast tumor cell types, TNBC MDA-MB-231 cells and triple-positive breast cancer BT-474 cells. In addition to the induction of apoptosis and the suppression of the cellular proliferation rate, the four local anesthetics decreased the levels of reactive oxygen species and increased the autophagy elongation indicator in both cell types. Our combination index analysis with doxorubicin showed that ropivacaine had a synergistic effect on the two cell types, and lidocaine had a synergistic effect only in MDA-MB-231 cells; the others had no synergistic effects on doxorubicin. Lidocaine contributed significantly to the formation of autophagolysosomes in a dose-dependent manner in MDA-MB-231 cells but not in BT-474 cells. Our study demonstrated that the four local anesthetics can reduce tumor growth and proliferation and promote apoptosis and autophagy.

Application of methylene blue combined with ropivacaine intercostal nerve block in postoperative analgesia of autologous costal cartilage augmentation rhinoplasty.

OBJECTIVE: To observe the effect of methylene blue combined with ropivacaine intercostal nerve block on postoperative analgesia after autologous costal cartilage augmentation rhinoplasty. METHODS: In this study 100 female patients who underwent autologous costal cartilage comprehensive augmentation rhinoplasty in Chongqing Huamei Plastic Surgery Hospital from April to November 2021 were randomly divided into an experimental group and a control group, with 50 cases in each group. In the experimental group methylene blue was combined with ropivacaine intercostal nerve block as patient controlled intravenous analgesia (PCIA), and the control group was ropivacaine intercostal nerve block combined with PCIA. The visual analogue scale (VAS) scores of resting and coughing at 6 h (T1), 24 h (T2), 48 h (T3), 72 h (T4) after surgery were recorded and evaluated. At the same time, the number and times of oral analgesics were recorded as well as nausea, vomiting, burning pain and paresthesia. RESULTS: The VAS scores of the experimental group were lower than those of the control group at all time points. At 6 h, 24 h and 48 h after surgery, the VAS score of the experimental group was lower than that in the control group, but the difference was not statistically significant (P > 0.05). The VAS score of calm 72 h after surgery in the experimental group was significantly lower than that in the control group (P < 0.05). The analgesic effect of the two groups was better when they coughed after surgery. At 6 h after surgery, the VAS score of coughing in the experimental group was lower than that in the control group, but the difference was not statistically significant (P > 0.05); At 24 h, 48 h and 72 h after surgery, the VAS score of the coughing state in the experimental group was significantly lower than that in the control group (P < 0.05). CONCLUSION: Intercostal nerve block with methylene blue combined with ropivacaine can achieve good postoperative analgesic effects in augmentation rhinoplasty with autologous costal cartilage.

The effect of thoracic epidural nerve block with dezocine and ropivacaine on arterial oxygen saturation and IDO gene expression during pulmonary ventilation in lung resection surgery.

During lung resection surgery, the blood supply to the lungs increases the intrapulmonary shunt and reduces arterial oxygenation in patients. Ventilation anesthesia of a lung may affect oxygenation. The present study aimed to compare intravenous anesthesia with and without thoracic epidural block (dezocine and ropivacaine) on oxygen saturation during lung ventilation in patients undergoing lung resection surgery. For this purpose, this study was performed as a double-blind, randomized clinical trial. Sixty patients who were candidates for lung resection were divided into two intervention groups (thoracic epidural block with dezocine and ropivacaine and intravenous anesthesia) and a control group (placebo thoracic epidural block and intravenous anesthesia). Hemodynamic variables, Aldert score, and possible complications were compared between the two groups before surgery and after recovery. Also, the expression level of the IDO gene was evaluated using the real-time PCR technique. SPSS, t-test, Mann-Whitney U, Chi-square, and Fisher performed data analysis and comparison.  The results showed that the changes in hemodynamic variables and PaO2, SaO2, and ETCO2 were not statistically significant between the two groups. Aldrete's score at entry and exit of recovery was similar between the two groups. During the recovery period, the percentage of pain or chills in the group under complete intravenous anesthesia was significantly higher. There was no significant difference between the two groups regarding the frequency of nausea and hypotension. Also, the results of IDO gene expression showed that general anesthesia with the thoracic epidural block (dezocine and ropivacaine), which is involved in inducing immunological tolerance and suppressing immune responses, has no significant effect. The stress of performing surgery before surgery can play a role in suppressing the patient's immunity, and anesthesia of the thoracic epidural block (dezocine and ropivacaine) has no significant effect on IDO expression. In general, thoracic epidural block with complete intravenous anesthesia has no significant effect on oxygen saturation in ventilated lungs compared with intravenous anesthesia alone. Nevertheless, this combination significantly reduces postoperative pain and chills.

Ropivacaine-induced seizures evoked pain sensitization in rats: Participation of 5-HT/5-HT3R.

Due to the increasing use of local anesthetic techniques in various healthcare settings, local anesthetic toxicity still occurs. Seizures are the most common symptom of local anesthetic toxicity. The relationship between local anesthetic-induced seizures and the sensation of pain has not been established till now. Here, we assessed the development of pain hypersensitivity after ropivacaine-induced seizures (RIS) and the influence of RIS on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. In addition, the involvement of spinal 5-HT/5-HT3R in RIS-induced pain sensitization was investigated. According to a sequential exploratory experimental strategy, we first calculated the 50% seizure dosage of ropivacaine to be 42.66 mg/kg (95% confidence interval: 40.19-45.28 mg/kg). We showed that RIS induced significant bilateral mechanical pain hypersensitivity that lasted around 5 days, accompanied by an increase in spinal 5-HT. Moreover, RIS considerably protracted postsurgical pain and enhanced formalin-induced spontaneous flinching in the second phase. Depletion of spinal 5-HT with intrathecal injection of 5,7-dihydroxytryptamine (5,7-DHT) reduced RIS-induced pain hypersensitivity and prevented the prolonging of postsurgical pain following RIS. Likewise, blocking spinal 5-HT3R by intrathecal administration of ondansetron reversed RIS-induced pain hypersensitivity and attenuated the pronociception of RIS in the formalin test. Our findings revealed that acute RIS led to pain hypersensitivity and had pronociceptive effects on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. Moreover, our data implied that RIS-induced pain sensitization depends on spinal 5-HT/5-HT3R signaling. Thus, targeting the descending serotonergic facilitation system should be an important element of the precise treatment for local anesthetic toxicity.

Effect of species, concentration and volume of local anesthetics on intervertebral disk degeneration in rats with discoblock.

PURPOSE: Discoblock is effective in relieving discogenic low back pain, but it can also cause intervertebral disk degeneration (IDD). The effect of species, concentration and volume of local anesthetics on IDD with discoblock have not been reported. The purpose was to study the effect of species, concentration and volume of local anesthetics on IDD in rats undergoing discoblock. METHODS: The effects of local anesthetics on nucleus pulposus cell (NPC) viability in vitro were studied. NPCs were exposed to lidocaine, bupivacaine and ropivacaine at different concentrations. NPC viability was measured. The least cytotoxic local anesthetic was used in vivo. The concentration and volume of local anesthetics on IDD in rat with discoblocks were tested in vivo. Detection indicators included X-ray, MRI, water content of the disk and histological changes. RESULTS: The toxicity of local anesthetics to NPCs was dose and time dependent, and the cytotoxicity of different local anesthetics was different. Among the three local anesthetics, ropivacaine was the least toxic to NPCs. The effect of ropivacaine concentration on IDD was not significant, as detected by X-ray, MRI, disk water content and histology (P < 0.05). The volume of ropivacaine has a significant effect on IDD, as supported by X-ray, MRI, disk water content and histology (P < 0.05). Acupuncture itself significantly increased IDD, as detected by MRI, disk water content and histology (P < 0.05). CONCLUSION: Ropivacaine should be selected for its low cytotoxicity. A lower volume and slow injection speed should be used to reduce IDD during discoblock.