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Background: Sugammadex binds progesterone with high affinity and may interfere with hormonal contraceptive effectiveness. The clinical, economical, and ethical implications of unintended pregnancy should prompt anesthesiologists to actively consider and manage this pharmacologic interaction. We surveyed anesthesiology providers at our institution about knowledge of this potential adverse drug interaction, how they manage it clinically, and the extent to which they involve patients in shared decision-making regarding choice of neuromuscular blocker antagonist., Methods: A survey instrument was distributed to anesthesiology providers at a large, tertiary-care medical center. The survey explored prior experience using neostigmine and sugammadex, knowledge about potential sugammadex interference with hormonal contraception, pre-/postoperative counseling practices, clinical management, and shared decision-making regarding potential use of neostigmine in lieu of sugammadex to avoid this drug-drug interaction., Results: Of 259 surveys distributed, 155 were fully completed, and 10 were partially completed. Overall response rate was 60% (residents 85%, student nurse anesthetists 53%, certified registered nurse anesthetists 58%, attendings 48%). All but 1 respondent recognized the potential for sugammadex interference with oral hormonal contraception. Far fewer accurately identified potential interference with hormonal intrauterine devices (44%) and hormonal contraceptive implants (55%). The manufacturer's recommended 7-day duration of alternative contraception was correctly identified by 72% of respondents; others (22%) reported longer durations (range 10-30 days). Most (78% overall) agreed/strongly agreed that potential interference with contraceptive effectiveness should be discussed with patients preoperatively. Despite the majority (86% overall) that endorsed shared decision-making and inviting patient input regarding choice between sugammadex and neostigmine, many respondents reported "rarely/never" having discussed this drug interaction with patients in actual clinical practice, either preoperatively (67%) or postoperatively (80%). Furthermore, most respondents (79%) reported "rarely/never" administering neostigmine to intentionally avoid this drug interaction., Conclusions: Two years after designating sugammadex as antagonist of choice, physician and nurse anesthesia providers reported seldom inquiring about contraceptive use among women of childbearing potential and rarely discussing potential risk of contraceptive failure from sugammadex exposure. Most lack accurate knowledge of sugammadex interference with hormonal intrauterine and subcutaneous contraceptive devices. Although most endorse preoperative counseling and support patient autonomy or shared decision-making regarding choice of reversal agent, the same respondents report rarely, if ever, actualizing these positions in clinical practice. These conflicting findings highlight the need for education regarding residual neuromuscular block versus adverse drug interactions, collaboration among providers involved in patient counseling, and intentional mindfulness of reproductive justice when caring for women of childbearing potential., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Background: Residual neuromuscular block at the end of surgery may compromise the patient's safety. The risk of airway complications can be minimized through monitoring of neuromuscular function and reversal of neuromuscular block if needed. Effective reversal can be achieved with selective relaxant binding agents, however, sugammadex is the only clinically approved drug in this group. We investigated the concentration-response properties of a novel selective relaxant binding agent, carboxymethyl-γ-cyclodextrin for the reversal of neuromuscular block. We evaluated the hypothesis that it is equally potent for reversing neuromuscular block as sugammadex., Methods: Phrenic nerve - hemidiaphragm tissue preparations were isolated from male Wistar rats and suspended in a tissue holder allowing electrical stimulation of the nerve and monitoring of muscle contraction force. Concentration-response relationships were constructed for the neuromuscular blocking agents rocuronium, pipecuronium, and vecuronium. The half-effective concentrations of sugammadex and carboxymethyl-γ-cyclodextrin for reversal of neuromuscular block were determined., Results: The half effective concentrations (95% confidence interval, CI) were 7.50 (6.93-8.12) μM for rocuronium, 1.38 (1.33-1.42) μM for pipecuronium, and 3.69 (3.59-3.80) μM for vecuronium. The half effective concentrations (95% CI) of carboxymethyl-γ-cyclodextrin and sugammadex were 35.89 (32.67-39.41) μM and 3.67 (3.43-3.92) μM, respectively, for the reversal of rocuronium-induced block; 10.14 (9.61-10.70) μM and 0.67 (0.62-0.74) μM, respectively, for the reversal of pipecuronium-induced block; and 376.1 (341.9-413.8) μM and 1.45 (1.35-1.56) μM, respectively, for the reversal of vecuronium-induced block., Conclusions: Carboxymethyl-γ-cyclodextrin is an effective, but less potent agent for reversal of neuromuscular block than sugammadex., (© 2021. The Author(s).)

Coastal taipan ( Oxyuranus scutellatus ) envenoming causes life-threatening neuromuscular paralysis in humans. We studied the time period during which antivenom remains effective in preventing and arresting in vitro neuromuscular block caused by taipan venom and taipoxin. Venom showed predominant pre-synaptic neurotoxicity at 3 µg/mL and post-synaptic neurotoxicity at 10 µg/mL. Pre-synaptic neurotoxicity was prevented by addition of Australian polyvalent antivenom before the venom and taipoxin and, reversed when antivenom was added 5 min after venom and taipoxin. Antivenom only partially reversed the neurotoxicity when added 15 min after venom and had no significant effect when added 30 min after venom. In contrast, post-synaptic activity was fully reversed when antivenom was added 30 min after venom. The effect of antivenom on pre-synaptic neuromuscular block was reproduced by washing the bath at similar time intervals for 3 µg/mL, but not for 10 µg/mL. We found an approximate 10-15 min time window in which antivenom can prevent pre-synaptic neuromuscular block. This time window is likely to be longer in envenomed patients due to the delay in venom absorption. Similar effectiveness of antivenom and washing with 3 µg/mL venom suggests that antivenom most likely acts by neutralizing pre-synaptic toxins before they interfere with neurotransmission inside the motor nerve terminals.

While some US populations of the Mohave rattlesnake (Crotalus scutulatus scutulatus) are infamous for being potently neurotoxic, the Mexican subspecies C. s. salvini (Huamantlan rattlesnake) has been largely unstudied beyond crude lethality testing upon mice. In this study we show that at least some populations of this snake are as potently neurotoxic as its northern cousin. Testing of the Mexican antivenom Antivipmyn showed a complete lack of neutralisation for the neurotoxic effects of C. s. salvini venom, while the neurotoxic effects of the US subspecies C. s. scutulatus were time-delayed but ultimately not eliminated. These results document unrecognised potent neurological effects of a Mexican snake and highlight the medical importance of this subspecies, a finding augmented by the ineffectiveness of the Antivipmyn antivenom. These results also influence our understanding of the venom evolution of Crotalus scutulatus, suggesting that neurotoxicity is the ancestral feature of this species, with the US populations which lack neurotoxicity being derived states., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Study Objective: The use of neuromuscular blockade agents (NMBA), had been associated with significant residual post-operative paralysis and morbidity. There is a lack of clinical evidence on incidence of postoperative complications within the post-anesthesia care unit (PACU) in patients exposed to intraoperative NMBA's. This study aims to estimate the incidence of post-operative complications associated with use of NMBAs and assessing its association with healthcare resource utilization., Design: Retrospective cohort., Setting: Post-anesthesia care unit in tertiary care center., Patients: Adults having non-cardiac surgery and receiving NMBAs between April-2005 and December-2013 MEASUREMENTS: We assessed: 1) incidences of major and minor PACU complications, 2) incidence of any postoperative complication in patients receiving a NMBA reversal (neostigmine) vs. without. 3) We secondarily assessed the relationship between PACU complications and use of healthcare resources., Main Results: The incidence of any major complications was 2.1% and that of any minor complication was 35.2%. ICU admission rate was 1.3% in patients without any complications, versus 5.2% in patients with any minor and 30.6% in patients with any major complication. ICU length of stay was prolonged in patients with any major (52.1±203h), compared to patients with any minor (6.2±64h) and with no complications (1.7±28h). Patients who received a NMBA and neostigmine, compared to without neostigmine, had a lower incidence of any major complication (1.7% vs. 6.05%), rate of re-intubation (0.8% vs. 4.6%) and unplanned ICU admission (0.8% vs. 3.2%)., Conclusions: This study documents that incidence of major PACU complications after non-cardiac surgery was 2.1%, with the most frequent complications being re-intubation and ICU admission. Patients receiving NMBA reversal were at a lower risk of re-intubation and unplanned ICU admission, justifying routine use of reversals. Complete NMBA reversals are crucial in reducing preventable patient harm and healthcare utilization., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Anticholinesterase drugs may produce paradoxical neuromuscular block when administered at shallow levels of neuromuscular block. The objective of this study was to evaluate the effects of neostigmine and edrophonium when administered at near-complete reversal from nondepolarizing block in anesthetized dogs., Study Design: Incomplete crossover, randomized, blinded experimental study., Animals: A total of 12 Beagle dogs., Methods: Each dog was anesthetized twice with propofol and maintained with isoflurane and dexmedetomidine. Intravenous (IV) vecuronium (0.1 mg kg -1 ) was administered. When the mechanographic train-of-four (TOF) ratio had spontaneously recovered to ≥0.9, either neostigmine (0.04 mg kg -1 ) or edrophonium (0.5 mg kg -1 ) was administered IV, preceeded by atropine. Changes in twitch height or TOF ratio were measured for the next 10 minutes. Recurarization was considered to be present if values decreased by ≥10%., Results: Data from four dogs in each treatment were excluded from analysis, resulting in data from five dogs administered both treatments, three dogs administered neostigmine and three dogs administered edrophonium. There was no difference between groups for age, weight, T1 and T4 twitch heights or TOF ratio values, before or after anticholinesterase administration. The TOF ratio decreased by 17% and 18% in two of the eight dogs administered neostigmine, resulting from a larger increase in T1 relative to T4. No reductions in individual twitch amplitudes were recorded in those dogs. When edrophonium was used, no cases of recurarization were observed., Conclusions and Clinical Relevance: The results support use of edrophonium for reversal of shallow neuromuscular block. The decreases in TOF ratio recorded after neostigmine does not necessarily indicate muscular weakness. Although the clinical implications are uncertain, the results suggest that, at these doses, edrophonium may be preferable to neostigmine for reversal of shallow neuromuscular block in dogs., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study is to assess the effect of sugammadex on postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy., Methods: Eighty patients who were scheduled for elective laparoscopic cholecystectomy surgery were enrolled in this prospective study. Patients were randomly assigned to neostigmine (group N) or sugammadex (group S) for neuromuscular antagonism at the end of anesthesia. The incidence of PONV and antiemetic consumption were recorded., Results: Nausea and vomiting were observed in 60% of the patients given sugammadex and 77.5% given neostigmine during the initial 24 hours postoperatively. The incidence of nausea and the need for rescue antiemetic were lower in group S than group N during all time intervals but there were no significant differences between the groups., Conclusions: Sugammadex seems to be effective in decreasing the incidence of PONV, severity of nausea, number of patients who suffered from nausea and vomiting, and need for rescue antiemetic, although there were no significant differences.

Even small degrees of residual neuromuscular blockade, i. e. a train-of-four (TOF) ratio >0.6, may lead to clinically relevant consequences for the patient. Especially upper airway integrity and the ability to swallow may still be markedly impaired. Moreover, increasing evidence suggests that residual neuromuscular blockade may affect postoperative outcome of patients. The incidence of these small degrees of residual blockade is relatively high and may persist for more than 90 min after a single intubating dose of an intermediately acting neuromuscular blocking agent, such as rocuronium and atracurium. Both neuromuscular monitoring and pharmacological reversal are key elements for the prevention of postoperative residual blockade.

Medication shortages have become an all-too-common inconvenience that has forced anesthesia providers to examine our administering practices. Because of these shortages, commonly used medications are at the greatest risk. Glycopyrrolate (Robinul), which has been in short supply in recent years, is one of the most widely used anticholinergic agents, especially in conjunction with the anticholinesterase neostigmine, for reversal of neuromuscular blockade (NMB) drugs. Here we review multiple studies from 1972 through 1986 that used varying methods of patient selection and dosage and drug combination criteria, and which noted that glycopyrrolate had a superior efficacy and adverse effect profile when compared with atropine in NMB reversal. Meta-analysis from these studies indicated that the dosage of 0.2 mg of glycopyrrolate for every 1 mg of neostigmine, given concomitantly (maximum 1 mg glycopyrrolate and 5 mg neostigmine), demonstrated the greatest efficacy with the lowest incidence of unwanted adverse effects. It has now become common practice to use a dosage ratio of 0.2 mg glycopyrrolate to 1.0 mg neostigmine for NMB reversal. Yet since 1986, there have been no studies on reversal with glycopyrrolate and neostigmine. Frequent medication shortages and good medical practice should be an impetus for clinicians to reevaluate dosing practices of critical medications and revisit these drugs, such as glycopyrrolate, with more current studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We examined the use of neostigmine for reversing shallow (defined as train-of-four ratio of 0.5), cisatracurium- and rocuronium-induced neuromuscular block in 112 patients, by use of 0 μg.kg(-1) , 10 μg.kg(-1) , 20 μg.kg(-1) or 40 μg.kg(-1) dose of neostigmine for reversal. The times from neostigmine administration to train-of-four ratios of 0.7, 0.9 and 1.0 were evaluated. Analysis of variance showed that the duration of action was significantly longer after cisatracurium compared with rocuronium. The time to reach a train-of-four ratio of 1.0 was significantly shorter with neostigmine 40 μg.kg(-1) compared with lower neostigmine doses, and at this dose the time did not differ between cisatracurium and rocuronium. The recovery time from a train-of-four ratio of 0.5-1.0 did not differ between cisatracurium and rocuronium, and was significantly shortened by the administration of neostigmine. We conclude that a neostigmine dose of 40 μg.kg(-1) was the most effective at reducing recovery time after neuromuscular blockade., (© 2016 The Association of Anaesthetists of Great Britain and Ireland.)

Background: Centronuclear myopathy (CNM) is a rare congenital condition associated with skeletal muscle weakness. Patients with CNM may have decreased acetylcholine receptor expression and a reduced number of releasable quanta. Such perturbations could affect the time-course of neuromuscular blocking agents (NMBAs) and their antagonism with cholinesterase inhibitors. As a result of the rarity of CNM, prospective data regarding NMBA use in this subpopulation is scarce. We evaluated the neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of CNM., Methods: Six dogs with congenital autosomal-recessive CNM and six controls received cisatracurium 0.15 mg kg(-1) i.v. under general anaesthesia and intermittent positive pressure ventilation. Neuromuscular function was monitored with acceleromyography.When the second response (T2) to train-of-four (TOF) stimulation returned, neostigmine 0.04 mg kg(-1) (with glycopyrrolate) were administered i.v. The onset time, time to spontaneous return of T2, and the time to reach a TOF ratio ≥0.9 after neostigmine administration were recorded., Results: Onset time was no different between groups. Median (interquartile range) time to return of T2 was 27 (24-31) min for control dogs and 26 (22-31) min for CNM dogs (P=0.93).After neostigmine administration, a TOF ratio ≥0.9 was reached in 12 (10-15) min and 17 (16-19) min in control and CNM, respectively (P=0.005)., Conclusions: The spontaneous return of T2 was not different between groups. However, neostigmine-facilitated recovery was significantly slower in dogs with CNM. Canine autosomal-recessive CNM does not preclude the use of cisatracurium or its antagonism with neostigmine., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Muscle relaxation facilitates tracheal intubation and improves surgical conditions during anaesthesia. However, unexpected prolonged muscle relaxation may occur. This article describes important causes of prolonged muscle relaxation and gives suggestions for its prevention. Drug interactions, incomplete reversal, co-morbidity, inaccurate neuromuscular monitoring and critical illness may prolong the effect of muscle relaxants. The anaesthetist must titrate the muscle relaxants using objective neuromuscular monitoring and proper reversal of the blockade when needed.

Purpose of Review: The use of neuromuscular blocking agents in ambulatory surgery has been described as a double-edged sword. Muscle relaxants may improve the outcome following endotracheal intubation and could be helpful for the surgeon to some extent. However, these agents might increase the risk of postoperative complications because of residual paralysis. This review should summarize recent developments in neuromuscular blockade, neuromuscular monitoring, and reversal with a special reference to day case surgery., Recent Findings: The use of neuromuscular blocking agents begs a risk of postoperative muscle weakness and has been associated with adverse respiratory events. From the surgical side, there could be an increased request for a more intense neuromuscular block during laparoscopic surgery. Therefore, the use of quantitative neuromuscular monitoring and selective reversal binding agents may gain more importance in the future. For the reversal of a shallow neuromuscular block, cholinesterase inhibitors are still appropriate., Summary: The management of neuromuscular blocks in day case surgery requests a comprehensive approach that should include an adequate dosing of the muscle relaxant, quantitative objective monitoring, and a sufficient and appropriate reversal.

Objective: To study an expediency and efficacy of application of different reverses drugs (naloxone, flumazenil, neostigmine, galantamine, sugammadex) either their separate or combined using., Methods: We studied 119 patients underwent endoluminal endoscopic procedures and surgeries on trachea-bronchial tree and intestines under sedation or general anaesthesia., Results: The article deals with conceptual approaches to the reversal of residual effects of opioids, benzodiazepine sedation and neuromuscular block (the so-called agonist-antagonist technique)., Conclusions: A reversion of neuromuscular block without using of antagonists' combination does not provide complete recovery of psychomotor and cognitive functions for rapid socialization of patients after anaesthesia.

Objective: Sugammadex rapidly reverses neuromuscular blockade (NMB) induced by rocuronium. NMB induced by rocuronium is prolonged in patients with liver dysfunction, because the drug is mainly excreted into the bile. However, the efficacy and safety of sugammadex in terms of reversing rocuronium-induced NMB in patients with liver dysfunction undergoing hepatic surgery have not been evaluated. This observational study investigated the efficacy and safety of sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery., Methods: Remifentanil/propofol anesthesia was administered to 31 patients: 15 patients in the control group, and 16 patients from a group with liver dysfunction. Rocuronium (0.6 mg/kg) was administered, followed by continuous infusion. The enrolled patients were then subdivided into two groups according to the dose of sugammadex. In the first group a single dose of sugammadex (2.0 mg/kg) was given at the reappearance of the second twitch (T2). In the second group a single dose of sugammadex (4.0 mg/kg) was given at the first twitch response if T2 did not reappear in 15 minutes after stopping rocuronium. The primary outcome was time from administration of sugammadex to recovery of a train-of-four ratio to 0.9., Results: The dose of rocuronium required in the liver dysfunction group was lower than that in the control group (6.2 vs. 8.2 μg/kg/min, p = 0.002). The mean time from the administration of sugammadex to recovery of the train-of-four ratio to 0.9 was not significantly different between the liver dysfunction group and the control group (2.2 minutes vs. 2.0 minutes in the 2 mg/kg administration group, p = 0.44 and 1.9 minutes vs. 1.7 minutes in the 4 mg/kg administration group, p = 0.70, respectively). No evidence of recurarization was observed in any of the patients. Most of the adverse events were found to be mild and such events were not related to the use of sugammadex. None of the patients was eliminated from the study because of an adverse event. One patient died due to cholestatic liver cirrhosis because of repeated hepatic surgery., Conclusion: Sugammadex can rapidly reverse NMB after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Sugammadex was found to be safe and well tolerated. However, further studies of sugammadex under similar conditions should be conducted involving a large number of patients with liver dysfunction undergoing hepatic surgery., (Copyright © 2014. Published by Elsevier B.V.)

Background: The routine use of neuromuscular blocking agents reduces the occurrence of unacceptable surgical conditions. In some surgeries, such as retroperitoneal laparoscopies, deep neuromuscular block (NMB) may further improve surgical conditions compared with moderate NMB. In this study, the effect of deep NMB on surgical conditions was assessed., Methods: Twenty-four patients undergoing elective laparoscopic surgery for prostatectomy or nephrectomy were randomized to receive moderate NMB (train-of-four 1-2) using the combination of atracurium/mivacurium, or deep NMB (post-tetanic count 1-2) using high-dose rocuronium. After surgery, NMB was antagonized with neostigmine (moderate NMB), or sugammadex (deep NMB). During all surgeries, one surgeon scored the quality of surgical conditions using a five-point surgical rating scale (SRS) ranging from 1 (extremely poor conditions) to 5 (optimal conditions). Video images were obtained and 12 anaesthetists rated a random selection of images., Results: Mean (standard deviation) SRS was 4.0 (0.4) during moderate and 4.7 (0.4) during deep NMB (P<0.001). Moderate block resulted in 18% of scores at the low end of the scale (Scores 1-3); deep block resulted in 99% of scores at the high end of the scale (Scores 4 and 5). Cardiorespiratory conditions were similar during and after surgery in both groups. Between anaesthetists and surgeon, there was poor agreement between scores of individual images (average κ statistic 0.05)., Conclusions: Application of the five-point SRS showed that deep NMB results in an improved quality of surgical conditions compared with moderate block in retroperitoneal laparoscopies, without compromise to the patients' peri- and postoperative cardiorespiratory conditions. Trial registration The study was registered at clinicaltrials.gov under number NCT01361149.

Objective: To determine current clinical neuromuscular use in Morocco anesthetic practice., Study Design: Clinical practice survey., Methods: Anesthesiologists were invited to answer anonymously to question about neuromuscular blocking agents (NMBA): pharmacology, monitoring and antagonism drug use. Corrected yates test was used to compare qualitative parameters and variance analysis for quantitative parameters. P<0.05 was considered as significant., Results: We had 171 answers, 54% were paramedics (n=93) and 46% (n=78) were physicians (20% global effective in Morocco). Fifty-five percent were seniors. Vecuronium was the most NMBA used in Morocco for 51% of the anesthesiologists. Mean action time of NMBA was underestimate in more than 60% of the staff questioned specially for seniors (24.6%) than juniors (19.2%). Residual neuromuscular blockade was evaluated only by clinical and spirometric parameters in 72%. TOF monitor was used in 18% more in military hospitals (36%) and insurance clinics (40%) than private hospitals (12.5%). Administration of reversal drugs was systematic in 5.8% of anesthesiologists, frequent for 36.3% and rare for 55%., Conclusions: This study show an underestimation of residual neuromuscular blockade, poor neuromuscular monitor use and lack of knowledge of NMBA specially for senior anesthesiologists and in private hospitals. We should elaborate Moroccan guideline for NMBA use and provide formal training programs for our anesthetic staff., (Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Introduction: Seven Neuromuscular Blocking Agents (NMBA) are commercialized in France. Four of them have an intermediate duration of action. Sugammadex required the use of NMBA slightly employed in clinical practice in France. Its introduction in routine practice could have an impact on NMBA use in clinical practice. This study was then conducted to assess and compare NMBA use before and after the commercialization of sugammadex., Materials and Methods: A longitudinal, retrospective, observational study was conducted between 2008 and 2011 in French university hospitals and military hospitals. The consumption data for sugammadex and NMBA were collected using a collection grid which was filled by pharmacists or anesthesiologists. Drug use was measured by the number of vials used divided by the annual number of hospitalizations in surgery and obstetrics (HSO). An overall analysis of the annual frequency of NMBA use was firstly performed, then individual data of each hospital were analyzed. Descriptive statistical analysis including mean, standard deviation, median, minimum and maximum was achieved., Results: Thirty-four out of 39 hospitals participated in the study (87%) and analysis was performed on 26 of them (7%). The data of eight institutions were excluded due to missing values or because of the non-admission of sugammadex in their formulary. The NMBA mostly used were non-steroidal NMBA (75% of market share) with an increased use between 2008 and 2011 concerning atracurium (from 41 to 51 vials of 50mg atracurium used per 100 HSO). The overall analysis revealed an increase of the occurrence of rocuronium (between 2008 and 2011: from 1 to 4.8 vials of 50mg rocuronium used per 100 HSO). Individual analyses on each hospital showed a possible effect of sugammadex introduction on NMBA use in nine hospitals., Discussion and Conclusions: The commercialization of sugammadex seems to have induced a discrete increase of steroidal NMBA but non-steroidal NMBA remain the leading agent in France. A long-term follow-up is deserved., (Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Introduction: To evaluate whether calabadion 1, an acyclic member of the Cucurbit[n]uril family of molecular containers, reverses benzylisoquinoline and steroidal neuromuscular-blocking agent effects., Methods: A total of 60 rats were anesthetized, tracheotomized, and instrumented with IV and arterial catheters. Rocuronium (3.5 mg/kg) or cisatracurium (0.6 mg/kg) was administered and neuromuscular transmission quantified by acceleromyography. Calabadion 1 at 30, 60, and 90 mg/kg (for rocuronium) or 90, 120, and 150 mg/kg (for cisatracurium), or neostigmine/glycopyrrolate at 0.06/0.012 mg/kg were administered at maximum twitch depression, and renal calabadion 1 elimination was determined by using a H NMR assay. The authors also measured heart rate, arterial blood gas parameters, and arterial blood pressure., Results: After the administration of rocuronium, resumption of spontaneous breathing and recovery of train-of-four ratio to 0.9 were accelerated from 12.3 ± 1.1 and 16.2 ± 3.3 min with placebo to 4.6 ± 1.8 min with neostigmine/glycopyrrolate to 15 ± 8 and 84 ± 33 s with calabadion 1 (90 mg/kg), respectively. After the administration of cisatracurium, recovery of breathing and train-of-four ratio of 0.9 were accelerated from 8.7 ± 2.8 and 9.9 ± 1.7 min with placebo to 2.8 ± 0.8 and 7.6 ± 2.1 min with neostigmine/glycopyrrolate to 47 ± 13 and 87 ± 16 s with calabadion 1 (150 mg/kg), respectively. Calabadion 1 did not affect heart rate, mean arterial blood pressure, pH, carbon dioxide pressure, and oxygen tension. More than 90% of the IV administered calabadion 1 appeared in the urine within 1 h., Conclusion: Calabadion 1 is a new drug for rapid and complete reversal of the effects of steroidal and benzylisoquinoline neuromuscular-blocking agents.

Purpose: Over the past three decades, many studies have shown a high proportion of patients in the recovery room with residual neuromuscular blockade after anesthesia. The purpose of this Continuing Professional Development module is to present the physiological consequences of residual paralysis, estimate the extent of the problem, and suggest solutions to prevent its occurrence., Principal Findings: Residual paralysis is defined as a train-of-four ratio (TOFR) < 0.9 at the adductor pollicis. While tidal volume and, to a lesser extent, vital capacity are well preserved as the intensity of blockade increases, the probability of airway obstruction, impaired swallowing, and pulmonary aspiration increases markedly as TOFR decreases. In recent studies, incidences of residual paralysis from 4-57% have been reported, but surveys indicate that anesthesiologists estimate the incidence of the problem at 1% or less. The decision to administer neostigmine or sugammadex should be based on the degree of spontaneous recovery at the adductor pollicis muscle (thumb), not on recovery at the corrugator supercilii (eyebrow). The most important drawback of neostigmine is its inability to reverse profound blockade, which is a consequence of its ceiling effect. When spontaneous recovery reaches the point where TOFR > 0.4 or four equal twitch responses are seen, reduced doses of neostigmine may be given. The dose of sugammadex required in a given situation depends on the intensity of blockade., Conclusion: Careful monitoring and delaying the administration of neostigmine until four twitches are observed at the adductor pollicis can decrease the incidence of residual paralysis. The clinical and pharmacoeconomic effects of unrestricted sugammadex use are unknown at this time.

Sugammadex, the first selective relaxant-binding agent indicated to reverse the neuromuscular blockade induced during general anesthesia, was recently introduced into clinical practice. In the present report, the following issues pertinent to the use of sugammadex in anesthesia practice are discussed: the intraoperative use of NMBAs and the incidence of postoperative residual curarization (PORC); the efficacy and safety of rocuronium plus sugammadex compared to succinylcholine for rapid sequence induction; the availability of sugammadex in hospitals; and, finally, some relevant legal medical aspects. Sugammadex is considerably more expensive than neostigmine, but its use can be advocated based on its safety and efficacy profile as a reversal agent of steroidal neuro muscular blocking agents (NMBAs), and as a mean to prevent PORC. The availability of sugammadex in Italian hospitals may have a beneficial impact on patient safety. This is due to the fact that PORC is a common and dangerous condition that may lead to postoperative inhalational events, hypoxemia, and pneumonia; and at the moment, it is not completely preventable even when advanced neuro-muscolar monitoring techniques are applied". In the case of rapid sequence intubation (RSI), rocuronium (1.2 mg/kg) administration followed by sugammadex represents a better choice in terms of efficacy and safety than succinylcholine. If a new drug is proven to be safer and more efficient than the one it is replacing, hospitals should consider the new drug and make it available, at least for selected patients or in situations at risk of severe complications. It is reasonable to hypothesize that, when discussing informed consent for elective procedures, patients and families may want to know if the admitting facilities have the superior agent available, and that the absence of such agent could create concerns and complains.

This survey of anaesthetists in Australia and New Zealand aimed to investigate their attitudes and practice relating to the management of neuromuscular blockade monitoring. All medical practitioner members (3188) of the Australian and New Zealand Societies of Anaesthetists were invited to complete an anonymous survey, which was available online for two months. A total of 678 survey questionnaires were completed (response rate 21%). Most respondents (71.4%) underestimated the incidence of residual neuromuscular blockade and 63.2% believed this to be a significant clinical problem. Objective monitoring of neuromuscular function was used routinely only by 17% of respondents, although 70% believed routine monitoring would reduce the incidence of residual neuromuscular blockade. Only 25% of respondents correctly indicated that quantitative train-of-four counts of greater than 90% were the accepted criteria for safe extubation, with 52% using clinical judgement only. Only 29% of respondents believed neuromuscular function monitors should be part of minimum monitoring standards; quantitative neuromuscular function monitors were not available in 42% of the hospitals in which the respondents practiced. Despite the low response rate, the large sample size and heterogeneity of respondents make the findings of this survey concerning. There is a need for more education, availability of appropriate monitoring equipment and evidence-based guidelines for management of neuromuscular blockade in Australia and New Zealand.

Background: Postoperative hypoxemia is a common complication in the anesthesia recovery room (ARR), which is predominantly based on the development of atelectasis, excessive intraoperative fluid shift and insufficient ventilation. The goal of this prospective observational study was to compare the effect of standard oxygen administration via a face mask with oxygen administration using the EzPAP® system, a device which additionally provides a positive end-expiratory pressure (PEEP)., Methods: This study included 210 patients with postoperative hypoxemia (S(p)O(2) < 93%) subdivided into the control group (105 patients) and the EzPAP group (105 patients). Postoperative residual paralysis was excluded using relaxometry and a train of four (TOF) ratio of 0.9 was assumed to ensure sufficient recovery of respiratory function from neuromuscular blockade. Patients who received a reversal of neuromuscular blockade were excluded. In cases of hypoxemia (S(p)O(2) < 93%) control patients were treated with oxygen (6 l/min) using a face mask, whereas the EzPAP group received oxygen using the EzPAP® system. In order to adjust the PEEP in the EzPAP group, the O(2) flow was verified and measured by a manometer. After 1 h of oxygen therapy, the oxygen supply was stopped. In cases of reoccurring hypoxemia (S(p)O(2) < 93%, persistence > 5 min), the oxygen therapy was restarted in both groups via a facemask. Both groups were compared using repeat measurement analysis of variance (ANOVA), the unpaired t-test, the Mann-Whitney U-test, Fisher's exact test and the χ(2)-test. The correlation of O(2) flow and PEEP was evaluated by regression analysis and p < 0.05 was considered to be statistically significant. Apart from this a subgroup analysis was performed depending on body-mass index (BMI), American Society of Anesthesiologists (ASA) classification, intraoperative airway management, the use of neuromuscular blocking agents and co-existing disorders, e.g. chronic obstructive lung disease (COLD), obesity and chronic heart failure., Results: All patients were equally distributed between both groups with respect to demographic data, ASA classification, BMI, co-existing disorders and surgical procedures. The S(p)O(2) values did not differ between the EzPAP patients and the control group, except for 0.5 min after initiation of oxygen therapy: EzPAP group 96 ± 3.7% (mean ± standard deviation) versus the control group 93.8 ± 4.4% (p < 0.001). However, restarting oxygen therapy was less common in the EzPAP group (EzPAP group 25 versus control group 41, p = 0.03), as well as the occurrence of postoperative complications (EzPAP group 13 versus control group 25, p = 0.02), e.g. nosocomial pneumonia (0 versus 4) and wound infections (2 versus 3). Furthermore, patients with obesity and pulmonary disorders, such as COLD had a benefit from oxygen administration using the EzPAP device and showed higher postoperative than preoperative S(p)O(2) values. In contrast, the subgroup analysis of patients with heart failure did not reveal any differences between both groups and both groups did not differ in terms of time spent in the recovery room (EzPAP group 113 min versus control group 174.8 min, p = 0.2)., Conclusions: In this observational study oxygen supply using the EzPAP® system appeared to be at least equally as effective in the therapy of postoperative hypoxemia compared to standard oxygen supply using a face mask. In patients with a high risk of postoperative hypoxemia, such as patients with obesity and/or pulmonary disorders, oxygen administration using the EzPAP® system possibly improves pulmonary oxygenation more effectively and is longer lasting compared to standard oxygen supply via a face mask. Hence, the EzPAP® system represents a well-tolerated, effective, cost-effective and easily operated tool to improve postoperative oxygenation. In order to investigate the possibilities of this promising tool more intensively, randomized clinical trials are warranted.

Philodryas olfersii is responsible for most colubrid snakebites in Brazil. In this work, we examined the ability of an ethanolic extract from Mikania laevigata (guaco) leaves to protect against the in vitro neuromuscular activity of P. olfersii venom in mouse phrenic nerve-diaphragm (PND) and chick biventer cervicis (BC) preparations. M. laevigata extract caused moderate twitch-tension facilitation at low concentrations (107.4 ± 6.2% with 20 μl/ml and 118.9 ± 9.3% with 40 μl/ml in PND, and 120.7 ± 7.7% with 40 μl/ml and 114.5 ± 4.4% with 50 μl/ml in BC after 120 min; n = 4-6, mean ± SEM). In PND, the ethanol alone (40 μl/ml, n = 4) did not change the twitch-tension when compared with control. However, in BC, the ethanol produced a higher facilitation when compared to control. At higher concentrations (>50 μl/ml) the extract caused total and reversible blockade in both preparations. Venom (50 μg/ml) caused partial blockade in PND (58.5 ± 12%, n = 4) and almost total blockade in BC (93.5 ± 2.2%, n = 4). Pretreatment of the preparations with extract (40 μl/ml) for 30 min before incubation with venom (50 μg/ml) completely protected PND from neuromuscular blockade and delayed the blockade in BC. The extract alone caused only mild morphological alterations (12.5 ± 0.5% and 10.9 ± 2.3% fiber damage in PND and BC, respectively, compared to 2.3 ± 0.3% and 3 ± 0 in controls; n = 3), with no increase in expression of the inflammatory cytokines TNFα and IFNγ. The ethanol alone also caused slight muscle damage: 4.3 ± 2.4% in PND and 6.7 ± 3.3% in BC (both n = 3) and little or no TNFα and IFNγ expression in both preparations as observed in control. Venom (50 μg/ml) caused 53.5 ± 8.5% and 55.8 ± 4.3% fiber damage in PND and BC, respectively; (n = 3, p < 0.05 vs. controls) and enhanced expression of TNFα and IFNγ. Pretreatment of the preparations with extract protected against venom-induced muscle damage by 80.3 and 60.4 in PND and BC, respectively, and prevented TNFα and IFNγ expression. These results indicate that the M. laevigata extract protected nerve-muscle preparations against the myotoxic, neurotoxic and inflammatory effects of P. olfersii venom., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: We performed a prevalidation of the compound muscle action potential (CMAP) assay to determine the potency of botulinum neurotoxin type A (BoNT/A) with the aim of substituting for the mouse lethality test (LD₅₀), which is used for quality control., Methods: Prevalidation experiments were performed to demonstrate the specificity, linearity, accuracy, precision, range, limit of quantitation (LOQ), and robustness of the assay. For specificity, toxin detection ability was determined in the presence of neutralizing antibodies (0.8 and 8 IU/mL). Linearity of this assay was determined by measuring CMAP amplitude using nine concentrations (n = 3) in the range of 1-100 U/mL (n = 3). Accuracy was assessed using five concentrations (n = 3) in the range of 4-40 U/mL. Intermediate precision was confirmed by analyzing individually prepared reagents on multiple days by one operator (n = 3). Different body weights (23-25 and 25-27 g) and measurement times (3-5 and 5-7 min) after anesthetic induction were tested to assess robustness., Results: This assay might have BoNT/A specificity, based on the CMAP amplitude recovery using a concentration of neutralizing antibodies. The calibration curves were linear over the range of 2-40 U/mL (R² = 0.982). The accuracy of 14 determinations was within the range of 89.8-118.6% compared to the theoretical values among 15 determinations, except one (131.3%). Assay variability was acceptable with coefficients of variation of 4.3-14.4%. The range of quantification and the LOQ were 4-40 U/mL and 4 U/mL, respectively. Different body weights and measurement times after inducing anesthesia had no effect on CMAP amplitude., Conclusions: These results suggest that the mouse CMAP assay is an alternative method to the standard LD₅₀ potency test and meets the requirement of the three Rs (particularly refinement and reduction)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Pharmacologic reversal of neuromuscular blockade is a topic not very well acknowledged and controversially discussed. Reasons for this are numerous and include missing perception of the potential complications of residual neuromuscular paralysis including an increased morbidity and mortality, as well as low efficacy and numerous unwanted side effects of the available antagonists. Duration of action of muscle relaxants cannot be pharmacologically predicted. Objective neuromuscular monitoring is the only way to detect residual paralysis. This review article would like to discuss in its first part some of the myths which revolve around the use of muscle relaxants, then highlight the problems regarding the use of acetylcholine esterase inhibitors and, in the third part, discuss the steroidal muscle relaxant encapsulator sugammadex.

Sugammadex is known to rapidly and completely reverse the effects of amino-steroidal neuromuscular blocking agents. However, the high costs of sugammadex have so far prevented its introduction as the standard reversal agent in most healthcare systems. At the Royal Perth Hospital, sugammadex was recently introduced as an unrestricted alternative to neostigmine for the reversal of amino-steroidal neuromuscular blocking agents. The aim of this retrospective observational audit was to investigate the impact of this change on clinical practice and associated healthcare costs. Data from all patients intubated during a one-month period in April to May 2010 and for a similar period in 2011 were retrospectively collected and the use of neuromuscular blocking agents and reversal agents were identified and the associated costs were calculated. More steroidal neuromuscular blocking agents and sugammadex (+743%), but less glycopyrrolate and neostigmine (-48%) were used in 2011. Using the manufacturer's list price, muscle relaxation and reversal costs increased from about A$42 per case to about A$127 per case. Between the investigated time periods no differences were found for anaesthesia time, operating time or time spent in the post anaesthesia care unit. However, there was a statistically significant decrease in the time between surgery and discharge (median 2.0 vs 2.2 days). While the design of the audit was such that no inferences can be made about the cause of this change, this is an interesting observation worthy of further investigation.

Myasthenia gravis (MG) is a disease affecting the nicotinic acetylcholine receptor of the post-synaptic membrane of the neuromuscular junction, causing muscle fatigue and weakness. The myasthenic patient can be a challenge to anesthesiologists, and the post-surgical risk of respiratory failure has always been a matter of concern. The incidence and prevalence of MG have been increasing for decades and the disease is underdiagnosed. This makes it important for the anesthesiologist to be aware of possible signs of the disease and to be properly updated on the optimal perioperative anesthesiological management of the myasthenic patient. The review is based on electronic searches on PubMed and a review of the references of the articles. The following keywords were used: myasthenia gravis AND neuromuscular blocking agents, myasthenia gravis AND sevoflurane, myasthenia gravis AND epidural, myasthenia gravis AND neuromuscular blockade reversal and myasthenia gravis AND pyridostigmine. The articles included were from reviews and clinical trials written in English. MG patients can easily be anesthetized without need for post-surgery mechanical ventilation whether it is general anesthesia or peripheral nerve block. Volatile anesthesia or the use of an epidural for the patient makes it possible to avoid the use of neuromuscular blocking agents, and when used, it should be in smaller doses and the patient should be carefully monitored. This review shows that with thorough pre-operative evaluation, continuing the daily pyridostigmine and careful monitoring the MG patient can be managed safely., (© 2011 The Authors Acta Anaesthesiologica Scandinavica © 2011 The Acta Anaesthesiologica Scandinavica Foundation.)

Electroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to induce generalised seizures for the treatment of selected psychiatric disorders. The clinical indications for ECT as an effective therapeutic modality have been considerably expanded since its introduction. Anaesthesia and neuromuscular blocking agents (NMBAs) are required to ensure patients' safety during ECT. The optimal dose of muscle relaxant for ECT reduces muscle contractions without inducing complete paralysis. Slight residual motor convulsive activity is helpful in ascertaining that a seizure has occurred, while total paralysis prolongs the procedure unnecessarily. Suxamethonium is commonly used, but nondepolarising NMBAs are indicated in patients with certain comorbidities. In this review, we summarise current concepts of NMBA management for ECT., (© 2011 The Authors. Acta Anaesthesiologica Scandinavica © 2011 The Acta Anaesthesiologica Scandinavica Foundation.)

Sugammadex, a thiolated γCD derivative used as an antagonist of steroidal blockers, was studied with regard to its tendency to self-associate in aqueous solution. Three independent methods - permeation through semi-permeable cellophane membranes, dynamic light scattering, and sedimentation equilibrium analytical ultracentrifugation - were used for this purpose. The results were in agreement with each other and showed no evidence of self-association in a wide sugammadex concentration range from 0.25 to 100mg/ml., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A case of prolonged muscle relaxation after vecuronium in an anesthetized dog is presented. After using peripheral nerve stimulation to confirm partial recovery of neuromuscular transmission, administration of 0.5 mg/kg IV of intravenous edrophonium failed to complete the reversal process. Subsequent administration of neostigmine resulted in complete recovery from blockade. Without monitoring neuromuscular function with a peripheral nerve stimulator until reversal was complete, it was very likely this patient would have been extubated with incomplete neuromuscular transmission. Several factors affecting the duration of neuromuscular blockade and its reversal are addressed.

Botulinum toxin is an agent that is typically encountered in two settings: as an agent that can cause disease (e.g. botulism), and as an agent that can be used to treat disease (i.e., a variety of neurologic disorders). In both cases it would be advantageous to develop a sound understanding of the mechanisms by which antibodies neutralize the toxin. In the present study, recombinant antigens were used to generate antibodies against the carboxyterminal half of the toxin heavy chain (HC50), the entire toxin light chain (LC), and the HA17, HA35 and HA70 components of the progenitor toxin complex. These antibodies were then evaluated for their respective abilities to alter botulinum toxin-induced changes in locomotor behavior in mice. The botulinum toxin type A complex was shown to produce dose-dependent depression of locomotor behavior within the dose range of 0.3-0.7 mouse LD50 units. At a dose of 0.5 LD50, the toxin typically reduced running behavior by 90% or more, and full recovery was not observed for approximately 4 weeks. Mice that were actively or passively vaccinated against the HC50 polypeptide were resistant to toxin action, presumably because the antibodies occluded the toxin binding domain. Interestingly, mice that were actively or passively vaccinated against LC were also resistant to toxin action. This effect may have been due to steric hindrance of the binding process. There was no scenario in which anti-HA antibodies altered the effects of toxin on locomotor behavior. This absence of effect was likely due to the fact that HAs and neurotoxin in the progenitor toxin complex spontaneously dissociate in physiologic media., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: The ultra-short-acting neuromuscular blocker gantacurium is chemically degraded in vitro by rapid adduction of L-cysteine to its central olefinic double bond. Preliminary data have suggested that exogenous (intravenous) L-cysteine abolishes gantacurium blockade. Two new analogues of gantacurium (CW 002 and CW 011) have been synthesized to undergo slower L-cysteine adduction, yielding intermediate duration. L-cysteine adduction to and antagonism of these novel agents is further defined herein., Methods: Comparative reaction half-time for L-cysteine adduction in vitro of the three compounds was determined by high-performance liquid chromatography. ED95 for twitch inhibition in monkeys under isoflurane was calculated, and duration at approximately 4-5x ED95 was correlated with reaction half-time for adduction. Speed of L-cysteine antagonism was contrasted with anticholinesterase reversal. Potencies of CW 002 and its adduction product were compared to provide a basis for L-cysteine antagonism., Results: Rate of L-cysteine adduction in vitro (reaction half-time) was 11.4 and 13.7 min for CW 002 and CW 011 versus 0.2 min for gantacurium, and was inversely related to duration of block (P < 0.0001). CW 002 and CW 011 were 3x longer acting than gantacurium (28.1 and 33.3 min vs. 10.4 min), but only half the duration of cisatracurium. The adduct of CW 002 was approximately 70x less potent than CW 002. L-cysteine (10-50 mg/kg intravenously) given 1 min after approximately 4-5x ED95 doses of all the three compounds abolished block within 2-3 min., Conclusions: L-cysteine adduction occurs at different rates by design in olefinic isoquinolinium diester neuromuscular blockers, yielding corresponding durations of action. Antagonism by exogenous L-cysteine is superior to anticholinesterases, inducing inactivation of the active molecules to restore function rapidly at any time.

Background: CW002 is a neuromuscular blocking drug that is inactivated by endogenous L-cysteine. This study determined the exogenous L-cysteine dose-response relationship for CW002 reversal along with acute cardiovascular effects and organ toxicity in dogs., Methods: Six dogs were each studied four times during isoflurane-nitrous oxide anesthesia and recording of muscle twitch, arterial pressure, and heart rate. CW002 (0.08 mg/kg or 9 x ED95) was injected, and the time to spontaneous muscle recovery was determined. CW002 was then administered again followed 1 min later by 10, 20, 50, or 100 mg/kg L-cysteine (1 dose/experiment). After twitch recovery, CW002 was given a third time to determine whether residual L-cysteine influenced duration. Preliminary toxicology was performed in an additional group of dogs that received CW002 followed by vehicle (n = 8) or 200 mg/kg L-cysteine (n = 8). Animals were awakened and observed for 2 or 14 days before sacrificing and anatomic, biochemical, and histopathologic analyses., Results: L-cysteine at all doses accelerated recovery from CW002, with both 50 and 100 mg/kg decreasing median duration from more than 70 min to less than 5 min. After reversal, duration of a subsequent CW002 dose was also decreased in a dose-dependent manner. Over the studied dose range, L-cysteine had less than 10% effect on blood pressure and heart rate. Animals receiving a single 200-mg/kg dose of L-cysteine showed no clinical, anatomic, biochemical, or histologic evidence of organ toxicity., Conclusion: The optimal L-cysteine dose for rapidly reversing the neuromuscular blockade produced by a large dose of CW002 in dogs is approximately 50 mg/kg, which has no concomitant hemodynamic effect. A dose of 200 mg/kg had no evident organ toxicity.

Background: CW002 is a novel neuromuscular blocking drug with a duration dependent on the rate of cysteine adduction to the molecule. The current study characterized the pharmacodynamics and cardiopulmonary side effects of CW002 in dogs., Methods: In eight beagles, the dose required to produce 95% neuromuscular blockade (ED95) for CW002 was first determined and cysteine reversibility was confirmed. Five to 7 days later, incrementally larger doses were injected starting with 6.25 x ED95 and doubling the dose every 15 min. Before and after injection, blood was obtained for histamine analysis. Systemic and pulmonary arterial pressures, cardiac output, and left ventricular pressure and volume were recorded along with inspiratory pressure and pulmonary compliance. Ventricular contractility and lusitropy were indexed from pressure and volume data., Results: The ED95 for CW002 from pooled data was 0.009 mg/kg. At 3 x ED95, onset time was 2.6 +/- 0.9 min and duration was 47 +/- 9 min. The duration was shortened to 3.7 +/- 0.6 min by 50 mg/kg L-cysteine injected 1 min after CW002. At 25 x ED95, CW002 reduced mean arterial pressure with concomitant decreases in systemic vascular resistance, mean pulmonary artery pressure, cardiac output, contractility, and lusitropy, beginning at 50 x ED95. However, even at a dose of 100 x ED95, the average change in any variable was less than 20%. There were no changes in pulmonary vascular resistance or ventilation mechanics at any dose, and histamine release occurred in only two of eight animals., Conclusions: CW002 is a potent neuromuscular blocking drug that at doses up to 100 x ED95 produces modest hemodynamic effects that are not associated with bronchoconstriction or consistent histamine release.

Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimer's disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimer's disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)