Onset and duration of action of escalating doses of atracurium in anesthetized healthy goats.

OBJECTIVE: The aim of this study was to describe the onset and duration of action of escalating doses of atracurium in healthy, anesthetized goats. STUDY DESIGN: Randomized, blinded, triple crossover study. Animals A total of eight (five males and three females) healthy goats weighing 42.7-123.5 kg and aged from 11 months to 8 years. METHODS: Goats were anesthetized three times with propofol and anesthesia was maintained with isoflurane. One of three doses of atracurium was administered intravenously 30 minutes after induction: 0.25 mg kg-1 (AT25), 0.5 mg kg-1 (AT50) or 0.75 mg kg-1 (AT75). Acceleromyographic train-of-four ratio (TOFR) followed by train-of-four counts (TOFC) were recorded at 30 second intervals after atracurium administration to determine blockade onset (TOFC = 0). The TOFR followed by TOFC were recorded at 5 minute intervals until return to pre-atracurium baseline (TOFR = 1.0). Normally distributed data were analyzed with repeated measures anova and a Tukey multiple comparison test. Data not normally distributed were analyzed with a Friedman test and a Dunn's multiple comparison test. RESULTS: For AT50 and AT75, 100% of goats achieved TOFC = 0 after atracurium administration. For AT25, however, 87.5% of goats achieved TOFC = 0 after atracurium administration. The onset time was shorter for AT75 [1.5 (0.5-1.5) minutes; median (range)] than for AT25 [2 (1-4) minutes] (p = 0.048). The duration of action [from onset time to complete reversal (TOFR = 1.0)] was significantly shorter for AT25 (52 ± 12 minutes, mean ± SD) than for AT50 (77 ± 18 minutes) (p < 0.001) and AT75 (85 ± 16 minutes) (p < 0.001). There was no significant difference in duration between AT50 and AT75 (p = 0.238). CONCLUSIONS AND CLINICAL RELEVANCE: Doses of 0.5 and 0.75 mg kg-1 atracurium may produce complete neuromuscular blockade in healthy, anesthetized goats.

Comparison of the Onset of Action, Maintenance, and Recovery of Three Weight-based Dosing of Cisatracurium in Patients with Morbid Obesity in Laparoscopic Bariatric Surgery: A Randomized Clinical Trial.

Background: For patients with morbid obesity, different cisatracurium dosage regimens are recommended. This study aimed to compare the onset of action, the sufficiency of neuromuscular blockade during infusion, and the recovery of the three distinct cisatracurium dosage scalars in patients with morbid obesity undergoing laparoscopic bariatric surgery. Methods: In this randomized clinical trial, 55 patients were scheduled for bariatric surgery at Firoozgar Hospital from March 2020 to August 2021. Using a block randomization method, they were randomly divided into three groups, based on total body weight (TBW group), fat-free mass (FFM group), or ideal body weight (IBW group), to receive a bolus of cisatracurium 0.2 mg/Kg, followed by an infusion of 2 µg/Kg, to maintain a train-of-four (TOF) count≤2. Data were analyzed using SPSS software. P<0.05 was considered statistically significant. Results: The mean time (seconds) to reach TOF0 in the TBW group was significantly shorter (201.89, 95%CI=192.99-210.79; P=0.004) than the IBW group (233.53, 95%CI=218.71-248.34; P=0.01). However, this difference was not statistically significant between TBW and FFM groups (220.83, 95%CI=199.73-241.94; P=0.81) or between FFM and the IBW groups (P=0.23). The rescue dose and increments of cisatracurium infusion were not required in the TBW group, whereas their probability was 4.81 times higher in the IBW group than the FFM group. Furthermore, the TBW and FFM groups had higher mean surgical condition scores than the IBW group (P<0.001, and P=0.006, respectively). Conclusion: Cisatracurium loading and infusion dosing based on FFM provide a comparable onset of action and surgical field condition to the TBW-based dosing with a shorter recovery time. However, IBW-based dosing of cisatracurium was insufficient for laparoscopic bariatric surgery.Trial Registration Number: IRCT20151107024909N9.A preprint of this study was published at . doi: .

Generalised neuromuscular blockade after intraurethral administration of atracurium besilate in a male cat with urethral obstruction.

A 4-year-old, entire, male, domestic long-haired cat was presented with an acute history of stranguria and dysuria and diagnosed with urolithiasis causing urethral obstruction. The patient was induced to general anaesthesia and several unsuccessful attempts to flush the uroliths retrogradely towards the bladder were made. An intraurethral administration of the neuromuscular blocking agent atracurium was performed as it has been reported to facilitate urethral catheterisation without any side effects. Respiratory arrest developed after 15 minutes from atracurium administration, which was promptly recognized and treated with mechanical ventilation. The absence of muscle contraction in response to a nerve stimulation confirmed a generalised muscle blockade. Approximately 35 minutes after, a muscle response to nerve stimulation appeared. Neostigmine combined with glycopyrrolate was administered resulting in complete recovery from neuromuscular blockade. In conclusion, the use of intraurethral atracurium can result in systemic absorption of the drug with subsequent generalised neuromuscular blockade.

Duration of neuromuscular block is more variable and recovery time is shorter with rocuronium than cisatracurium in anesthetized dogs.

OBJECTIVE: To compare the variability in the duration of action of a single dose of rocuronium or cisatracurium, and duration of subsequent top-up doses in anesthetized dogs. ANIMALS: Thirty dogs requiring ophthalmic surgery with neuromuscular block. PROCEDURES: Neuromuscular function was monitored with train-of-four (TOF) and acceleromyography. Dogs received an initial dose of rocuronium 0.6 mg/kg, or cisatracurium 0.15 mg/kg IV, which produced complete neuromuscular block. Upon return of the first response (T1) of TOF, a third of the initial dose was repeated. The duration of the initial dose and its variability were compared between agents. Duration of subsequent top-up doses was assessed with mixed effect models. Spontaneous (from last return of T1) or neostigmine-enhanced (from administration to complete recovery) recovery times were measured for each agent. RESULTS: Duration of action of the initial dose was [median (range)] 25 (10-60) min with rocuronium and 35 (15-45) min with cisatracurium (p = .231). The variability of rocuronium was 3.25 times larger than cisatracurium (p = .034). Duration of top-up doses did not vary for either agent. Spontaneous recovery was shorter for rocuronium [15 (10-20) min] than cisatracurium [25 (15-45) min] (p = .02). Neostigmine-enhanced recovery times were 5 (5-25) for rocuronium and 10 (5-10) for cisatracurium (p = .491). CONCLUSIONS: Duration of action for a single dose is significantly more variable with rocuronium than cisatracurium. Time to spontaneous recovery was longer for cisatracurium, and cases of unexpectedly long recovery times were observed with both agents. Objective monitoring is recommended.

Impact of intravenous dexamethasone on the initiation and recovery of atracurium in children: A double-blinded randomized controlled trial.

BACKGROUND: Chronic steroid intake has been associated with attenuation of neuromuscular block. Despite some promising animal and adult studies, the effect of a single dose of intravenous dexamethasone on neuromuscular blockers is not well established. Thus, the present study aimed to demonstrate the effect of dexamethasone given at the time of induction for the prevention of PONV on the action of neuromuscular blockers in children undergoing elective surgery. METHOD: After obtaining approval from the Institute Ethics Committee and written informed parental consent, 100 ASA I and II children aged 4-15 years undergoing elective surgery randomized to receive either: 0.15 mg/kg (maximum of 5 mg) of dexamethasone diluted to a total volume of 2 ml with 0.9% saline (n = 50) or 2 ml of 0.9% saline (n = 50) at the time of induction. The time interval between application of atracurium and maximum T1 depression, 25% twitch height recovery of T1, amid 25% and 75% twitch height recovery of T1, amid the 25% twitch height recovery of T1 and recovery of the neuromuscular block to a TOF ratio of 0.9, and in between the initiation of atracurium injection till the recovery of the neuromuscular block to a TOF ratio of 0.9 was defined as onset time, clinical duration, recovery index, recovery time, and total recovery period, respectively, and recorded. RESULTS: The onset time and recovery index time were lower (1.96 ± 0.39, 8.04 ± 2.14, respectively) with dexamethasone in comparison with saline (2.01 ± 0.51, 8.9 ± 3.4, respectively) but not statistically significant. The clinical duration, recovery time, and total recovery period were similar. CONCLUSION: Application of a single bolus dose (0.15 mg/kg) of dexamethasone during induction does not attenuate atracurium-induced neuromuscular blockade in children.

Efficacy of Atracurium-Vecuronium Combination in Patients Undergoing Laparoscopic Surgery: A Randomized Controlled Study.

INTRODUCTION: Deep neuromuscular blockade (d-NMB) is an essential requirement for carboperitoneum during laparoscopy surgery. However, sustaining d-NMB till the completion of surgery delays the reversal of the residual block. Therefore, there is a merit in exploring the effect of synergistic vecuronium-atracurium combination on the duration-of-action of d-NMB during "laparoscopic" surgery when we compare intubating bolus non-depolarizers (atracurium, vecuronium) administered alone. This study aims to evaluate whether the synergistic effect atracurium-vecuronium combination increases duration-of-action of d-NMB "laparoscopic" surgery settings. METHODS: Forty-eight patients (18-60 years, American Society of Anesthesiologists physical status- II/III, either sex) undergoing laparoscopic cholecystectomy were randomly allocated to receive vecuronium (vecuronium group, n = 16) or atracurium (atracurium group, n = 16) or vecuroniumatr-acurium combination (vecuronium-atracurium combination group, n = 16) and analyzed for the effects on the duration-of-action (primary objective); onset-of-action, reversibility, and quality of intubating conditions (secondary objectives) profile of neuromuscular blockade in patients undergoing laparoscopic cholecystectomy. RESULTS: Duration-of-action of neuromuscular blockade was significantly longer in patients who received atracurium-vecuronium combination (53.9 ± 9.7 minutes) versus atracurium-alone (41.1 ± 3.8 minutes) or vecuronium-alone (43.5 ± 9.2 minutes) (P = 0.000). No difference was found for the time to onset-of-action (vecuronium [198.1 ± 34.9 seconds], atracurium [188.5 ± 50.6 seconds], or atracurium-vecuronium combination [196.3 ± 46.3 seconds] [P = 0.829]); time for the reversal of muscle relaxation effect (vecuronium [559.9 ± 216.2 seconds], atracurium [584.7 ± 258.3 seconds], and atracurium-vecuronium combination [555.0 ± 205.4 seconds] [P = 0.925]); and quality-of-intubating conditions (vecuronium group [9.6 ± 1.3]; atracurium group [10.0 ± 0.0]; atracurium-vecuronium group [10.0 ± 0.0] [P = 0.182]). CONCLUSION: The synergistic effect of the atracurium-vecuronium combination leads to an increased duration-of-action of d-NMB during laparoscopic cholecystectomy without impacting onset-of-action, quality of intubating conditions, and reversal of muscle relaxant effect.

Comparison of onset time, duration of action, and intubating conditions after cisatracurium 0.15 mg/kg in young and elderly patients.

INTRODUCTION: Tracheal intubation during anesthesia can be facilitated by the neuromuscular blocking agent cisatracurium. However, limited data exists about onset time, duration of action and effect on intubating conditions in elderly patients above 80 years of age. We hypothesized that elderly patients would present a longer onset time and duration of action compared to younger adults. METHODS: This prospective observational study included 31 young (18-40 years) and 29 elderly (≥ 80 years) patients. Patients were given fentanyl 2 µg/kg and propofol 1.5-2.5 mg/kg for induction of anesthesia and maintained with remifentanil and propofol. Monitoring of neuromuscular function was performed with acceleromyography. Primary outcome was onset time defined as time from injection of cisatracurium 0.15 mg/kg (based on ideal body weight) to a train-of-four (TOF) count of 0. Other outcomes included duration of action (time to TOF ratio ≥ 0.9), intubation conditions using the Fuchs-Buder scale and the Intubating Difficulty Scale (IDS), and occurrence of hoarseness and sore throat postoperatively. RESULTS: Elderly patients had significantly longer onset time compared with younger patients; 297 seconds (SD 120) vs. 199 seconds (SD 59) (difference: 98 seconds (95% CI: 49-147), P < 0.001)). Duration of action was also significantly longer in elderly patients compared with younger patients; 89 minutes (SD 17) vs. 77 minutes (SD 14) (difference: 12 minutes (95% CI: 2.5-20.5) P = 0.01)). No difference was found in the proportion of excellent intubating conditions (Fuchs-Buder); 19/29 (66%) vs 21/31 (68%) (P = 0.86) or IDS score (P = 0.74). A larger proportion of elderly patients reported hoarseness 24 hours postoperatively; 62% vs 34% P = 0.04. CONCLUSION: In elderly patients cisatracurium 0.15 mg/kg had significantly longer onset time and duration of action compared with younger patients. No difference was found in intubating conditions at a TOF count of 0. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04921735, date of registration 10 June 2021).

Pharmacokinetics and pharmacodynamics studies of a loading dose of cisatracurium in critically ill patients with respiratory failure.

BACKGROUND: Previous studies reported a slow neuromuscular response with the currently recommended dose of cisatracurium in critically ill patients. Pharmacokinetic and pharmacodynamic studies of cisatracurium in critically ill patients are still limited. To our knowledge, this is the first study performed to better understand the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a loading dose of cisatracurium and to identify factors that affect PK and PD changes in critically ill patients. METHODS: A prospective PKs and PDs study was designed. Arterial blood samples of 10 critically ill patients with respiratory failure were collected after administering a loading dose of 0.2 mg/kg of cisatracurium. Plasma cisatracurium and laudanosine concentrations were determined using liquid chromatography-tandem mass spectrometry. The achievement of the desired pharmacodynamic response was evaluated by both 1) clinical assessment and 2) train-of-four monitoring. The PK/PD indices were analyzed for their correlation with patient'characteristics and other factors. RESULTS: The one-compartment model best described the plasma pharmacokinetic parameters of cisatracurium. The volume of distribution at steady state and total clearance were 0.11 ± 0.04 L/kg and 2.74 ± 0.87 ml/minute/kg, respectively. The mean time to train-of-four 0/4 was 6 ± 3.86 minutes. A time to the desired pharmacodynamic response of less than 5 minutes was found in 10% of the patients. A positive correlation was found between cisatracurium concentration and albumin levels and between pharmacokinetics data and patient factors [partial pressure of carbon dioxide and respiratory alkalosis]. CONCLUSION: The currently recommended loading dose of cisatracurium might not lead to the desired pharmacodynamic response in critically ill patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03337373. Registered on 9 November 2017.

Cisatracurium besilate enhances the TRAIL-induced apoptosis of gastric cancer cells via p53 signaling.

Cisatracurium besilate is the most commonly used non-depolarizing muscle relaxant in general anesthesia and in intensive care units. Studies have indicated that the proliferation of gastric cancer (GC) cells can be restrained by cisatracurium besilate. The present study aimed to investigate the mechanism underlying the role of cisatracurium besilate in TNF-related apoptosis-inducing ligand (TRAIL)-induced GC. The AGS cell line was exposed to cisatracurium besilate, and then cell viability, colony formation and apoptosis were assessed by performing Cell Counting Kit-8, colony formation, TUNEL and Western blot assays, respectively. Furthermore, the expression levels of p53 and p53 upregulated modulator of apoptosis (PUMA) were measured by Western blotting to determine the effect of cisatracurium besilate on p53/PUMA signaling. After co-treatment with p53 inhibitor, cisatracurium besilate and pifithrin-α/TRAIL, cell apoptosis was detected. Finally, cisatracurium besilate and pifithrin-α were used to co-treat TRAIL-induced AGS cells followed by apoptosis detection. Cisatracurium besilate treatment restrained the proliferation and promoted the apoptosis of AGS cells. Cisatracurium besilate also promoted the expression of p53 and PUMA in AGS cells. Furthermore, TRAIL induced the apoptosis of AGS cells, which was aggravated by cisatracurium besilate treatment. However, pifithrin-α reversed the synergistic effects of cisatracurium besilate and TRAIL on the activities of AGS cells. Therefore, the present study suggested that cisatracurium besilate enhanced the TRAIL-induced apoptosis of GC cells via p53 signaling, and the synergistic effects of cisatracurium besilate and TRAIL may achieve maximal therapeutic efficacy in GC management.

Facial Nerve Monitoring under Different Levels of Neuromuscular Blockade with Cisatracurium Besilate in Parotid Tumour Surgery.

BACKGROUND: Anaesthesia can alter neuronal excitability and vascular reactivity and ultimately lead to neurovascular coupling. Precise control of the skeletal muscle relaxant doses is the key in reducing anaesthetic damage. METHODS: A total of 102 patients with the normal functioning preoperative facial nerve who required parotid tumour resection were included in this study. Facial nerve monitoring was conducted intraoperatively. The surgeon stimulated the facial nerve at different myorelaxation intervals at TOF% (T4/T1) and T1% (T1/T0) and recorded the responses and the amplitude of electromyogram (EMG). Body movements (BM) or patient-ventilator asynchrony (PVA) was recorded intraoperatively. RESULTS: In parotid tumour resection, T1% should be maintained at a range of 30 to 60% while TOF% should be maintained at a range of 20 to 30%. Analysis of the decision tree model for facial nerve monitoring suggests a partial muscle relaxation level of 30% < T1% ≤ 50% and TOF ≤ 60%. A nomogram prediction model, while incorporating factors such as sex, age, BMI, TOF%, and T1%, was constructed to predict the risk of BM/PVA during surgery, showing good predictive performance. CONCLUSIONS: This study revealed an adequate level of neuromuscular blockade in intraoperative parotid tumour resection while conducting facial nerve monitoring. A visual nomogram prediction model was constructed to guide anaesthetists in improving the anaesthetic plan.

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.

Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc-38. We found unc-38 RNAi to improve healthspan, lifespan, and stimulate DAF-16 nuclear localization, similar to atracurium treatment. Finally, using RNA-seq transcriptomics, we identify atracurium activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.

Cisatracurium inhibits the growth and induces apoptosis of ovarian cancer cells by promoting lincRNA-p21.

As a common muscle relaxant, cisatracurium has shown good antitumor effect on some tumors. Recent studies reported that cisatracurium could inhibit the progression of colon cancer by upregulating tumor suppressor gene p53. However, its role in ovarian cancer and its regulatory effect on p53 and p53 downstream targeting gene long intergenic noncoding RNA p21 (lincRNA-p21) is still unknown. Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) was used to assess the expression of p53, lincRNA-p21 and miR-181b. Cell viability and proliferation were detected by CCK-8 assay and Edu staining, respectively. Wound-healing and Transwell assays were performed to determine the abilities of cell migration and invasion. Apoptosis was evaluated by TUNEL staining. Luciferase reporter assay was conducted to detect the relationship between lincRNA-p21 and miR-181b. As a result, cisatracurium could increase the expressions of p53 and lincRNA-p21 of ovarian cancer cell line (OVCAR-3) in a dose-dependent manner. In addition, cisatracurium significantly inhibited the proliferation, migration and invasion of OVACR-3 cells, and induced apoptosis. However, these above changes in biological function can be attenuated by lincRNA-p21 knockdown. Next, lincRNA-p21 could directly target miR-181b and negatively regulate its expression by luciferase reporter assay. In conclusion, cisatracurium inhibited the progression of OVCAR-3 cells through upregulation of lincRNA-p21 expression activated by p53 inhibiting miR-181b expression. The experimental results provide a new research idea for the application of cisatracurium in ovarian cancer.

Cisatracurium attenuates LPS-induced modulation of MMP3 and junctional protein expression in human microvascular endothelial cells.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI) associated with hypoxemic lung damage and inflammation. Matrix metalloproteinase protein-3 (MMP3 or Stromelysin-1) is known to promote vascular injury in ALI/ARDS. Cisatracurium, a nicotinic neuromuscular blocker, is used in ARDS patients to decrease mechanical ventilator dyssynchrony, increase oxygenation, and improve mortality. However, the magnitude and the underlying mechanisms of these potential benefits of cisatracurium remains unclear. We investigated the effect of cisatracurium on lipopolysaccharide-induced MMP3 expression in human microvascular endothelial cells. In our results, cisatracurium treatment significantly decreased LPS-induced MMP3 expression and increased expression of cell junction proteins such as vascular endothelial cadherin (VE-cadherin) and claudin-5.

Cisatracurium regulates the CXCR4/let-7a-5p axis to inhibit colorectal cancer progression by suppressing TGF-ß/SMAD2/3 signalling.

OBJECTIVE: To reveal the effects and related mechanism of cisatracurium on colorectal cancer (CRC) development. METHODS: HCT116 and SW480 cells were treated with various concentrations of cisatracurium or transforming growth factor-ß (TGF-ß). Chemokine C-X-C-Motif Receptor 4 (CXCR4) was overexpressed and let-7a-5p was silenced in cells by transfection with pcDNA3.1-CXCR4 or let-7a-5p inhibitor. Cell Counting Kit-8 (CCK-8) assay measured cell viability, and transwell and wound healing assays evaluated cell invasion and migration, respectively. The expression levels of let-7a-5p and CXCR4 were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Western blotting was conducted to test the levels of CXCR4, TGF-ß/SMAD2/3 signalling and metastasis-related proteins. A tumour xenograft assay was performed to assess tumour growth. RESULTS: Cisatracurium treatment suppressed the viability and metastasis of HCT116 and SW480 cells in a concentration-dependent manner, whereas activating TGF-ß/SMAD2/3 signalling significantly reversed these effects. Cisatracurium treatment markedly reduced CXCR4 expression by inhibiting TGF-ß/SMAD2/3 signalling. Besides, let-7a-5p was identified as a target of CXCR4 and could be upregulated by cisatracurium. Both CXCR4 overexpression and let-7a-5p knockdown alleviated the biological roles of cisatracurium in CRC cells. Moreover, a tumour xenograft assay further confirmed that cisatracurium inhibited tumour growth and metastasis by increasing let-7a-5p expression. CONCLUSION: Cisatracurium suppressed the viability, metastasis and tumour growth of CRC by regulating the CXCR4/let-7a-5p axis via inhibiting TGF-ß/SMAD2/3 signalling. These findings provide a theoretical basis for the role of cisatracurium in the prognosis of CRC patients.

Cisatracurium stimulates testosterone synthesis in rat and mouse Leydig cells via nicotinic acetylcholine receptor.

As a cis-acting non-depolarizing neuromuscular blocker through a nicotinic acetylcholine receptor (nAChR), cisatracurium (CAC) is widely used in anaesthesia and intensive care units. nAChR may be present on Leydig cells to mediate the action of CAC. Here, by Western blotting, immunohistochemistry and immunofluorescence, we identified that CHRNA4 (a subunit of nAChR) exists only on rat adult Leydig cells. We studied the effect of CAC on the synthesis of testosterone in rat adult Leydig cells and mouse MLTC-1 tumour cells. Rat Leydig cells and MLTC-1 cells were treated with CAC (5, 10 and 50 µmol/L) or nAChR agonists (50 µmol/L nicotine or 50 µmol/L lobeline) for 12 hours, respectively. We found that CAC significantly increased testosterone output in rat Leydig cells and mouse MLTC-1 cells at 5 µmol/L and higher concentrations. However, nicotine and lobeline inhibited testosterone synthesis. CAC increased intracellular cAMP levels, and nicotine and lobeline reversed this change in rat Leydig cells. CAC may increase testosterone synthesis in rat Leydig cells and mouse MLTC-1 cells by up-regulating the expression of Lhcgr and Star. Up-regulation of Scarb1 and Hsd3b1 expression by CAC was also observed in rat Leydig cells. In addition to cAMP signal transduction, CAC can induce ERK1/2 phosphorylation in rat Leydig cells. In conclusion, CAC binds to nAChR on Leydig cells, and activates cAMP and ERK1/2 phosphorylation, thereby up-regulating the expression of key genes and proteins in the steroidogenic cascade, resulting in increased testosterone synthesis in Leydig cells.

Cisatracurium inhibits the proliferation, migration and invasion of breast cancer cells by regulating the expression of miR-3174.

Breast cancer is a type of cancer that begins in the breast tissue. Being a woman is the most important factor in the risk of breast cancer. Although men also get the cancer, women are much more likely to get it. This experiment was founded to investigate the effect and mechanism of Cisatracurium on breast cancer cell proliferation, migration and invasion. Breast cancer cells MDA-MB-231 were cultured in vitro. MDA-MB-231 cells were treated with cisatracurium of different concentrations for 48 h. CCK-8method detected cell proliferation, Transwell detected cell migration and invasion, Western Blot method detected the expression levels of CyclinD1, p21, MMP-2andMMP-9protein in cells, RT-qPCR) detected the expression level of miR-3174in cells. After miR-3174 inhibitor was transfected into MDA-MB-231 in order to down-regulate the expression of miR-3174, the same methods as above were used to observe the effect of the down-regulating miR-3174 expression on MDA-MB-231 cell proliferation, migration and invasion as well as the expression levels of CyclinD1, p21, MMP -2 andMMP-9 protein. After different concentrations of Cisatracurium acted on MDA-MB-231 cells, the cell inhibition rate and p21 protein expression were significantly increased (p<0.05), the number of cell migration and invasion and the expression levels of CyclinD1, MMP-2 and MMP-9 were significantly reduced (p<0.05), and the expression of miR-3174 in cells was significantly reduced (p<0.05). After down-regulating the expression of miR-3174, the cell inhibition rate and p21 protein expression were significantly increased (p<0.05), the number of cell migration and invasion and the expression levels of CyclinD1, MMP-2 and MMP-9 were significantly reduced (p<0.05). Up-regulating miR-3174 expression could reverse the effect of Cisatracurium on the proliferation, migration and invasion of MDA-MB-231 cells. Cisatracurium can inhibit the proliferation, migration and invasion of breast cancer MDA-MB-231 cells, and its mechanism is related to the down-regulation of miR-3174 expression in cells.

[Influence of different local anesthetics on atracurium neuromuscular blockade on rats]. / Influência de diferentes anestésicos locais no bloqueio neuromuscular produzido pelo atracúrio em ratos.

INTRODUCTION: The association between Local Anesthetics (LAs) and Neuromuscular Blocking (NMB) drugs in clinical practice, and the possibility of interaction between these drugs has been investigated. LAs act on neuromuscular transmission in a dose-dependent manner and may potentiate the effects of NMB drugs. OBJECTIVE: The aim of this study was to evaluate, in an experimental model, the effect of lidocaine and racemic bupivacaine on neuromuscular transmission and the influence on neuromuscular blockade produced by atracurium. METHODS: Male Wistar rats, weighing from 250 g to 300g were used. The preparation was set up based on a technique proposed by Bülbring. Groups were formed (n = 5) according to the drug studied: lidocaine 20 µg.mL-1 (Group I); racemic bupivacaine 5 µg.mL-1 (Group II); atracurium 20 µg.mL-1 (Group III); atracurium 20 µg.mL-1 in a preparation previously exposed to lidocaine 20 µg.mL-1 and racemic bupivacaine 5 µg.mL-1, Groups IV and V, respectively. The following parameters were assessed: 1) Amplitude of hemi diaphragmatic response to indirect stimulation before and 60 minutes after addition of the drugs; 2) Membrane Potentials (MP) and Miniature Endplate Potentials (MEPPs). RESULTS: Lidocaine and racemic bupivacaine alone did not alter the amplitude of muscle response. With previous use of lidocaine and racemic bupivacaine, the neuromuscular blockade (%) induced by atracurium was 86.66 ± 12.48 and 100, respectively, with a significant difference (p = 0.003), in comparison to the blockade produced by atracurium alone (55.7 ± 11.22). These drugs did not alter membrane potential. Lidocaine initially increased the frequency of MEPPs, followed by blockade. With the use of bupivacaine, the blockade was progressive. CONCLUSIONS: Lidocaine and racemic bupivacaine had a presynaptic effect expressed by alterations in MEPPs, which may explain the interaction and potentiation of NMB produced by atracurium.

Influence of different local anesthetics on atracurium neuromuscular blockade on rats / Influência de diferentes anestésicos locais no bloqueio neuromuscular produzido pelo atracúrio em ratos

Abstract Introduction: The association between local anesthetics (LA) and neuromuscular blocking (NMB) drugs in clinical practice, and the possibility of interaction between these drugs has been investigated. LAs act on neuromuscular transmission in a dose-dependent manner and may potentiate the effects of NMB drugs. Objective: The aim of this study was to evaluate, in an experimental model, the effect of lidocaine and racemic bupivacaine on neuromuscular transmission and the influence on neuromuscular blockade produced by atracurium. Methods: Male Wistar rats, weighing from 250 to 300 g were used. The preparation was set up based on a technique proposed by Bülbring. Groups were formed (n = 5) according to the drug studied: lidocaine 20 µg.mL−1 (Group I); racemic bupivacaine 5 µg.mL−1 (Group II); atracurium 20 µg.mL−1 (Group III); atracurium 20 µg.mL−1 in a preparation previously exposed to lidocaine 20 µg.mL−1 and racemic bupivacaine 5 µg.mL−1, Groups IV and V, respectively. The following parameters were assessed: 1) Amplitude of hemi diaphragmatic response to indirect stimulation before and 60 minutes after addition of the drugs; 2) Membrane potentials (MP) and miniature endplate potentials (MEPPs). Results: Lidocaine and racemic bupivacaine alone did not alter the amplitude of muscle response. With previous use of lidocaine and racemic bupivacaine, the neuromuscular blockade (%) induced by atracurium was 86.66 ± 12.48 and 100, respectively, with a significant difference (p = 0.003), in comparison to the blockade produced by atracurium alone (55.7 ± 11.22). These drugs did not alter membrane potential. Lidocaine initially increased the frequency of MEPPs, followed by blockade. With the use of bupivacaine, the blockade was progressive. Conclusions: Lidocaine and racemic bupivacaine had a presynaptic effect expressed by alterations in MEPPs, which may explain the interaction and potentiation of NMB produced by atracurium.

Resumo Introdução: A associação de anestésicos locais (AL) com bloqueadores neuromusculares (BNM) na prática clínica e a possibilidade de interação entre esses fármacos têm sido investigadas. Objetivo: Avaliar, em modelo experimental, o efeito da lidocaína e da bupivacaína racêmica na transmissão neuromuscular e sua influência no bloqueio neuromuscular produzido pelo atracúrio. Método: Ratos machos da linhagem Wistar, peso entre 250 e 300 g. A preparação foi feita de acordo com a técnica proposta por Bulbring. Grupos (n = 5) de acordo com o fármaco em estudo: lidocaína 20 µg.mL-1 (Grupo I); bupivacaína racêmica 5 µg.mL-1 (Grupo II); atracúrio 20 µg.mL-1 (Grupo III); atracúrio 20 µg.mL-1 em preparação previamente exposta a lidocaína 20 µg.mL-1 e bupivacaína racêmica 5 µg.mL-1, Grupos IV e V, respectivamente. Foram avaliados: 1) A amplitude das respostas do hemidiafragma à estimulação indireta antes e 60 minutos após a adição dos fármacos; 2) Os potenciais de membrana (PM) e os potenciais de placa terminal em miniatura (PPTM). Resultados: Os AL, isoladamente, não alteraram a amplitude das respostas musculares. Com o uso prévio dos AL, o bloqueio neuromuscular (%) do atracúrio foi 86,66 ± 12,48 e 100, respectivamente, com diferença significante (p= 0,003) em relação ao produzido pelo atracúrio isoladamente (55,7 ± 11,22). Não alteraram o PM. A lidocaína inicialmente aumentou a frequência dos PPTM, seguido de bloqueio; com a bupivacaína, o bloqueio foi progressivo. Conclusão: A lidocaína e a bupivacaína racêmica apresentaram efeito pré-sináptico expresso por alterações nos PPTM, podem justificar a potencialização do bloqueio neuromuscular produzido pelo atracúrio.