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Antioxidants (Basel, Switzerland) Dec 2022Research reports using animal models of ischemic insults have demonstrated that oxcarbazepine (a carbamazepine analog: one of the anticonvulsant compounds) extends...
Therapeutic Administration of Oxcarbazepine Saves Cerebellar Purkinje Cells from Ischemia and Reperfusion Injury Induced by Cardiac Arrest through Attenuation of Oxidative Stress.
Research reports using animal models of ischemic insults have demonstrated that oxcarbazepine (a carbamazepine analog: one of the anticonvulsant compounds) extends neuroprotective effects against cerebral or forebrain injury induced by ischemia and reperfusion. However, research on protective effects against ischemia and reperfusion cerebellar injury induced by cardiac arrest (CA) and the return of spontaneous circulation has been poor. Rats were assigned to four groups as follows: (Groups 1 and 2) sham asphyxial CA and vehicle- or oxcarbazepine-treated, and (Groups 3 and 4) CA and vehicle- or oxcarbazepine-treated. Vehicle (0.3% dimethyl sulfoxide/saline) or oxcarbazepine (200 mg/kg) was administered intravenously ten minutes after the return of spontaneous circulation. In this study, CA was induced by asphyxia using vecuronium bromide (2 mg/kg). We conducted immunohistochemistry for calbindin D-28kDa and Fluoro-Jade B histofluorescence to examine Purkinje cell death induced by CA. In addition, immunohistochemistry for 4-hydroxy-2-nonenal (4HNE) was carried out to investigate CA-induced oxidative stress, and immunohistochemistry for Cu, Zn-superoxide dismutase (SOD1) and Mn-superoxide dismutase (SOD2) was performed to examine changes in endogenous antioxidant enzymes. Oxcarbazepine treatment after CA significantly increased the survival rate and improved neurological deficit when compared with vehicle-treated rats with CA (survival rates ≥ 63.6 versus 6.5%), showing that oxcarbazepine treatment dramatically protected cerebellar Purkinje cells from ischemia and reperfusion injury induced by CA. The salvation of the Purkinje cells from ischemic injury by oxcarbazepine treatment paralleled a dramatic reduction in 4HNE (an end-product of lipid peroxidation) and increased or maintained the endogenous antioxidant enzymes (SOD1 and SOD2). In brief, this study shows that therapeutic treatment with oxcarbazepine after CA apparently saved cerebellar neurons (Purkinje cells) from CA-induced neuronal death by attenuating oxidative stress and suggests that oxcarbazepine can be utilized as a therapeutic medicine for ischemia and reperfusion brain (cerebellar) injury induced by CA.
PubMed: 36552657
DOI: 10.3390/antiox11122450 -
Cells Jan 2023Cardiac arrest (CA) and return of spontaneous circulation (ROSC), a global ischemia and reperfusion event, lead to neuronal damage and/or death in the spinal cord as...
Therapeutic Hypothermia after Cardiac Arrest Attenuates Hindlimb Paralysis and Damage of Spinal Motor Neurons and Astrocytes through Modulating Nrf2/HO-1 Signaling Pathway in Rats.
Cardiac arrest (CA) and return of spontaneous circulation (ROSC), a global ischemia and reperfusion event, lead to neuronal damage and/or death in the spinal cord as well as the brain. Hypothermic therapy is reported to protect neurons from damage and improve hindlimb paralysis after resuscitation in a rat model of CA induced by asphyxia. In this study, we investigated roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the lumbar spinal cord protected by therapeutic hypothermia in a rat model of asphyxial CA. Male Sprague-Dawley rats were subjected to seven minutes of asphyxial CA (induced by injection of 2 mg/kg vecuronium bromide) and hypothermia (four hours of cooling, 33 ± 0.5 °C). Survival rate, hindlimb motor function, histopathology, western blotting, and immunohistochemistry were examined at 12, 24, and 48 h after CA/ROSC. The rats of the CA/ROSC and hypothermia-treated groups had an increased survival rate and showed an attenuated hindlimb paralysis and a mild damage/death of motor neurons located in the anterior horn of the lumbar spinal cord compared with those of the CA/ROSC and normothermia-treated groups. In the CA/ROSC and hypothermia-treated groups, expressions of cytoplasmic and nuclear Nrf2 and HO-1 were significantly higher in the anterior horn compared with those of the CA/ROSC and normothermia-treated groups, showing that cytoplasmic and nuclear Nrf2 was expressed in both motor neurons and astrocytes. Moreover, in the CA/ROSC and hypothermia-treated group, interleukin-1β (IL-1β, a pro-inflammatory cytokine) expressed in the motor neurons was significantly reduced, and astrocyte damage was apparently attenuated compared with those found in the CA/ROSC and normothermia group. Taken together, our results indicate that hypothermic therapy after CA/ROSC attenuates CA-induced hindlimb paralysis by protecting motor neurons in the lumbar spinal cord via activating the Nrf2/HO-1 signaling pathway and attenuating pro-inflammation and astrocyte damage (reactive astrogliosis).
Topics: Animals; Male; Rats; Astrocytes; Heart Arrest; Heme Oxygenase-1; Hindlimb; Hypothermia; Hypothermia, Induced; Motor Neurons; NF-E2-Related Factor 2; Paralysis; Rats, Sprague-Dawley; Signal Transduction
PubMed: 36766758
DOI: 10.3390/cells12030414 -
Paediatric Anaesthesia Mar 2022Few randomized studies have assessed recovery from rocuronium- or vecuronium-induced moderate or deep neuromuscular blockade with sugammadex in pediatric participants. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Few randomized studies have assessed recovery from rocuronium- or vecuronium-induced moderate or deep neuromuscular blockade with sugammadex in pediatric participants.
AIM
To assess sugammadex for reversal of neuromuscular blockade in pediatric participants.
METHODS
This was a randomized, phase IV, active comparator-controlled, double-blind study. Participants aged 2 to <17 years, under moderate or deep neuromuscular blockade, were administered sugammadex (2 or 4 mg/kg) or neostigmine (50 µg/kg; for moderate neuromuscular blockade only). Predefined adverse events of clinical interest, including clinically relevant bradycardia, hypersensitivity, and anaphylaxis, were monitored. The primary efficacy endpoint was time to recovery to a train-of-four ratio of ≥0.9 in participants receiving sugammadex 2 mg/kg versus neostigmine for reversal of moderate neuromuscular blockade, analyzed by analysis of variance adjusted for neuromuscular blocking agent and age.
RESULTS
Of 288 randomized participants, 272 completed the study and 276 were included in the analyses. Clinically relevant bradycardia was experienced by 2.0%, 1.6%, and 5.9% of participants in the sugammadex 2 mg/kg, sugammadex 4 mg/kg, and neostigmine groups, respectively. No hypersensitivity or anaphylaxis events were observed. Recovery to a train-of-four ratio of ≥0.9 with sugammadex 2 mg/kg was faster than neostigmine (1.6 min, 95% CI 1.3 to 2.0 vs. 7.5 min, 95% CI 5.6 to 10.0; p < .0001) and was comparable to sugammadex 4 mg/kg (2.0 min, 95% CI 1.8 to 2.3).
CONCLUSIONS
Pediatric participants recovered from rocuronium- or vecuronium-induced moderate neuromuscular blockade significantly faster with sugammadex 2 mg/kg than with neostigmine. Time to reversal of deep neuromuscular blockade with sugammadex 4 mg/kg was consistent with that of moderate neuromuscular blockade reversal. No meaningful differences in clinically relevant bradycardia, hypersensitivity, or anaphylaxis were seen with sugammadex vs neostigmine. These results support the use of sugammadex for reversal of moderate and deep rocuronium- and vecuronium-induced neuromuscular blockade in patients aged 2 to <17 years.
CLINICAL TRIAL REGISTRATION
NCT03351608/EudraCT 2017-000692-92.
Topics: Anaphylaxis; Anesthetics; Bradycardia; Child; Humans; Neostigmine; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Rocuronium; Sugammadex; Vecuronium Bromide
PubMed: 34878707
DOI: 10.1111/pan.14370 -
Chemical Communications (Cambridge,... Apr 2024The binding affinity of pillar[6]MaxQ toward a panel of neuromuscular blockers and neurotransmitters was measured in phosphate buffered saline by isothermal titration...
The binding affinity of pillar[6]MaxQ toward a panel of neuromuscular blockers and neurotransmitters was measured in phosphate buffered saline by isothermal titration calorimetry and H NMR spectroscopy. efficacy studies showed that P6MQ sequesters rocuronium and vecuronium and reverses their influence on the recovery of the train-of-four (TOF) ratio.
Topics: Vecuronium Bromide; Rocuronium; Androstanols; Neuromuscular Nondepolarizing Agents; Calorimetry
PubMed: 38546190
DOI: 10.1039/d4cc00772g -
Biochemical Pharmacology Oct 2021Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate...
Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 µM. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcuronium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane..
Topics: Allosteric Regulation; Androstanes; Androstenes; Animals; Benzimidazoles; Binding Sites; CHO Cells; Cholesterol; Cricetinae; Cricetulus; Gallamine Triethiodide; Humans; Neuromuscular Nondepolarizing Agents; Neurosteroids; Receptors, Muscarinic; Vecuronium Bromide
PubMed: 34324870
DOI: 10.1016/j.bcp.2021.114699 -
Clinical and Translational Science Jan 2022Residual shallow neuromuscular block (NMB) is potentially harmful and contributes to critical respiratory events. Evidence for the optimal dose of sugammadex required to...
Residual shallow neuromuscular block (NMB) is potentially harmful and contributes to critical respiratory events. Evidence for the optimal dose of sugammadex required to reverse vecuronium-induced shallow NMB is scarce. The aims of the present study were to find suitable doses of sugammadex and neostigmine to reverse a residual vecuronium-induced NMB from a time of flight (TOF) ratio of 0.3-0.9 and evaluate their safety and efficacy. In total, 121 patients aged 18-65 years were randomly assigned to 11 groups to receive placebo, sugammadex (doses of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg), or neostigmine (doses of 10, 25, 40, 55, or 70 μg/kg). The reversal time of sugammadex and neostigmine to antagonize a vecuronium-induced shallow residual NMB (i.e., TOF ratio of 0.3) and related adverse reactions were recorded. Several statistical models were tested to find an appropriate statistical model to explore the suitable doses of sugammadex and neostigmine required to reverse a residual vecuronium-induced NMB. Based on a monoexponential model with the response variable on a logarithmic scale, sugammadex 0.56 mg/kg may be sufficient to reverse vecuronium-induced shallow residual NMB at a TOF ratio of 0.3 under anesthesia maintained with propofol. Neostigmine may not provide prompt and satisfactory antagonism as sugammadex, even in shallow NMB.
Topics: Delayed Emergence from Anesthesia; Dose-Response Relationship, Drug; Humans; Neostigmine; Sugammadex; Vecuronium Bromide
PubMed: 34435439
DOI: 10.1111/cts.13143 -
BMC Anesthesiology Oct 2021The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest.
METHODS
Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias.
RESULTS
Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study.
CONCLUSIONS
Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03346057 .
Topics: Aged; Bradycardia; Cholinergic Agents; Double-Blind Method; Female; Glycopyrrolate; Humans; Male; Neostigmine; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Rocuronium; Sugammadex; Tachycardia; Vecuronium Bromide
PubMed: 34711192
DOI: 10.1186/s12871-021-01477-5 -
Indian Journal of Anaesthesia Oct 2017Previous studies suggest that administration of vecuronium based on total body weight rather than ideal body weight (IBW) in obesity results in overdosing with prolonged...
BACKGROUND AND AIMS
Previous studies suggest that administration of vecuronium based on total body weight rather than ideal body weight (IBW) in obesity results in overdosing with prolonged recovery times. We hypothesised that larger doses of neostigmine could result in faster recovery in obese patients administered vecuronium based on total body weight.
METHODS
Forty-five obese American Society of Anesthesiologists' II patients undergoing elective surgery under general anaesthesia were randomised into 3 groups to receive neostigmine 30, 40 and 50 μg/kg. Following induction, patients were paralysed with vecuronium 0.1 mg/kg based on total body weight. Reversal was achieved with neostigmine based on the patient's group, and time to train-of-four (TOF) ratios of 0.5, 0.7 and 0.9 measured. The primary outcome variable was time to achieve TOF ratio >0.9.
RESULTS
Neostigmine 50 μg/kg achieved faster recovery to TOF 0.7 than neostigmine 30 and 40 μg/kg. There was no significant difference in recovery times to TOF 0.7 in patients receiving either 30 or 40 μg/kg of neostigmine. However, neostigmine 40 μg/kg attained TOF ratio 0.9 faster than 30 μg/kg. We did not note a significant difference between the 40 and 50 μg/kg dose with regard to recovery of TOF to 0.9.
CONCLUSION
Facilitated recovery from neuromuscular blockade to TOF of 0.7 was faster with neostigmine 50 μg/kg compared to 40 or 30 μg/kg. Recovery to TOF ratio of 0.9 was not significantly different with 40 or 50 μg/kg doses although such time was faster as compared to 30 μg/kg dose.
PubMed: 29242649
DOI: 10.4103/ija.IJA_297_17 -
American Journal of Physiology.... Nov 2016The aim of this study was to clarify the effect of vagal afferent activation on salivation and swallowing-like events. Salivation is part of a reflex induced by...
The aim of this study was to clarify the effect of vagal afferent activation on salivation and swallowing-like events. Salivation is part of a reflex induced by stimulation of the oral area during feeding or chewing. Recently, we reported that nausea induced by gastroesophageal reflux (GER) activation produced salivation and swallowing in humans. Here, we investigated the ability of visceral sensation to enhance salivation and swallowing in rodents in order to inform the mechanism of GER-mediated stomatognathic activation. First, we administered LiCl to anesthetized male rats to induce nausea. LiCl significantly increased salivation and increased the activity of the vagal afferent nerve. Next, we simultaneously recorded salivation and swallowing using an electrode attached to the mylohyoid muscle during vagal afferent stimulation in a physiological range of frequencies. Vagal afferent stimulation significantly increased salivation and swallowing-like events in a frequency-dependent manner. A muscle relaxant, vecuronium bromide, diminished the swallowing-like response but did not affect salivation. These results indicate that visceral sensation induces salivation and swallowing-like events in anesthetized rodents through vagal afferent activation.
Topics: Afferent Pathways; Anesthesia; Animals; Deglutition; Electric Stimulation; Male; Rats; Rats, Wistar; Reflex; Salivation; Vagus Nerve
PubMed: 27707722
DOI: 10.1152/ajpregu.00292.2016 -
Clinical and Translational Science Mar 2021This analysis of a published study (NCT03346070) evaluated the pharmacokinetics (PKs) of sugammadex dosed by actual body weight (ABW) or ideal body weight (IBW) for... (Randomized Controlled Trial)
Randomized Controlled Trial
This analysis of a published study (NCT03346070) evaluated the pharmacokinetics (PKs) of sugammadex dosed by actual body weight (ABW) or ideal body weight (IBW) for reversal of moderate or deep neuromuscular block (M-NMB or D-NMB) in adults with morbid obesity. Adults with body mass index ≥ 40 kg/m , ABW ≥ 100 kg, and American Society of Anesthesiologists (ASA) Class 3 were stratified by NMB agent (rocuronium or vecuronium) and randomized 1:1:1:1:1 to (i) M-NMB, sugammadex 2 mg/kg ABW; (ii) M-NMB, sugammadex 2 mg/kg IBW; (iii) M-NMB, neostigmine 5 mg + glycopyrrolate 1 mg; (iv) D-NMB, sugammadex 4 mg/kg ABW; and (v) D-NMB, sugammadex 4 mg/kg IBW. Plasma samples for sugammadex quantification were collected predose, 2, 5, 15, 60, and 120 minutes, and 4, 6 hours postdose. Natural log PK parameters were analyzed using linear fixed effect model with treatment, mode (ABW and IBW), and mode by treatment interaction as fixed terms. The sugammadex PK profile showed rapid distribution followed by monophasic decline consistent with a two-compartment model examined by dose and mode. Absolute sugammadex exposures were ~ 50% higher in the ABW vs. IBW group; dose-independent parameters (clearance and volume of distribution) and terminal half-life remained constant. Sugammadex PK parameter values increased in dose-dependent, linear manner following dosing by ABW or IBW, such that PK continues to be predictive across the clinical dose range. In conjunction with previously published results showing faster recovery with ABW vs. IBW dosing across NMB agent and depth of NMB, these PK findings continue to support dosing by ABW in patients with morbid obesity irrespective of depth of NMB.
Topics: Adult; Body Mass Index; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; Humans; Ideal Body Weight; Male; Middle Aged; Models, Biological; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Obesity, Morbid; Rocuronium; Sugammadex; Vecuronium Bromide
PubMed: 33278332
DOI: 10.1111/cts.12941