Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Structure-activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by L-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program. METHODS: Adduction of CW 1759-50 with L-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee-approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by L-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared. RESULTS: The half-time of adduction of L-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of L-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium. CONCLUSIONS: CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by L-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.

Incidence of Anaphylaxis Associated With Sugammadex.

We retrospectively investigated the incidence of potential sugammadex-induced anaphylaxis at a single center in Japan over a period of 3 years. The overall incidence of intraoperative hypersensitivity reaction was 0.22% (95% confidence interval [CI], 0.17%-0.29%), and the incidence of anaphylaxis was 0.059% (95% CI, 0.032%-0.10%). The total number of patients who received sugammadex during the study period was 15,479, and the incidence of anaphylaxis associated with sugammadex was 0.039% (n = 6; 95% CI, 0.014%-0.084%). This result implies that the incidence of sugammadex-associated anaphylaxis could be as high as that for succinylcholine or rocuronium. A prospective study, including testing for identification of cause, is necessary to confirm the exact incidence of sugammadex-induced anaphylaxis; however, the present finding calls attention to this potential.

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating the expression of genes involved in xenobiotic response. Recent studies have suggested that AhR plays essential roles not only in xenobiotic detoxification but also energy metabolism. Thus, in this study, we studied the roles of AhR in lipid metabolism. Under high fat diet (HFD) challenge, liver-specific AhR knock-out (AhR LKO) mice exhibited severe steatosis, inflammation, and injury in the liver. Gene expression analysis and biochemical study revealed thatde novolipogenesis activity was significantly increased in AhR LKO mice. In contrast, induction of suppressor of cytokine signal 3 (Socs3) expression by HFD was attenuated in the livers of AhR LKO mice. Rescue of theSocs3gene in the liver of AhR LKO mice cancelled the HFD-induced hepatic lipotoxicities. Promoter analysis established Socs3 as novel transcriptional target of AhR. These results indicated that AhR plays a protective role against HFD-induced hepatic steatosis and the subsequent lipotoxicity effects, such as inflammation, and that the mechanism of protection involves the direct transcriptional regulation ofSocs3expression by AhR.

Anesthesia for nonintubated video-assisted thoracic surgery.

PURPOSE OF REVIEW: This review focuses primarily on nonintubated video-assisted thoracic surgery (NIVATS), and discusses advantages, indications, anesthetic techniques, and approaches to intraoperative crisis management. RECENT FINDINGS: Advancements in endoscopic, endovascular, and robotic techniques have expanded the range of surgical procedures that can be performed in a minimally invasive fashion. For thoracic operations in particular, video-assisted thoracic surgery (VATS) has largely replaced traditional thoracotomy, and continued technical development has made surgical access into the pleural space even less disruptive. As a consequence, the need for general anesthesia and endotracheal intubation has been re-examined, such that regional or epidural analgesia may be sufficient for cases where lung collapse can be accomplished with spontaneous ventilation and an open hemithorax. This concept of NIVATS has gained popularity, and in some centers has now expanded to include procedures involving placement of multiple ports. Although still relatively uncommon at present, a small number of randomized trials and meta-analyses have indicated some advantages, suggesting that NIVATS may be a desirable alternative to general anesthesia with endotracheal intubation for specific indications. SUMMARY: Although anesthesia for NIVATS is associated with some of the same risks as general anesthesia with endotracheal intubation, NIVATS can be successfully performed in carefully selected patients.

Dose-response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man.

BACKGROUND: CW002 is a benzylisoquinolinium nondepolarizing neuromuscular-blocking drug found to be inactivated by cysteine in preclinical studies. The current study represents a dose escalation clinical trial designed to describe CW002 potency, duration, cardiopulmonary side effects, and histamine release. METHODS: Healthy subjects anesthetized with sevoflurane/nitrous oxide were divided into five groups (n = 6), each receiving a fixed CW002 dose (0.02, 0.04, 0.06, 0.08, or 0.10 mg/kg), and one group (n = 4) receiving 0.14 mg/kg. Blood pressure and heart rate were continuously recorded along with airway dynamic compliance. Neuromuscular blockade was assessed with mechanomyography at the adductor pollicis. Arterial blood was obtained before and after CW002 injection for analysis of plasma histamine concentration. Potency was estimated from a baseline sigmoid Emax model. RESULTS: ED50 was found to be 0.036 mg/kg (95% CI, 0.020 to 0.053 mg/kg) and ED95 0.077 mg/kg (95% CI, 0.044 to 0.114 mg/kg). At 0.14 mg/kg (1.8 × ED95), 80% twitch depression occurred in 94 ± 18 s with complete block in 200 ± 87 s. Clinical recovery (25% of maximum twitch) occurred in 34 ± 3.4 min, with a 5 to 95% recovery interval of 35.0 ± 2.7 min. The time to a train-of-four ratio greater than 0.9 ranged from 59 to 86 min. CW002 did not elicit histamine release or significant (greater than 10%) changes in blood pressure, heart rate, or dynamic airway compliance. CONCLUSIONS: In healthy subjects receiving sevoflurane/nitrous oxide, CW002 at 1.8 × estimated ED95 produces a clinical duration less than 40 min, elicits no histamine release, and has minimal cardiopulmonary side effects.

Preclinical Pharmacology of CW002: A Nondepolarizing Neuromuscular Blocking Drug of Intermediate Duration, Degraded and Antagonized by l-cysteine-Additional Studies of Safety and Efficacy in the Anesthetized Rhesus Monkey and Cat.

BACKGROUND: CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by L-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous L-cysteine. Further, Institutional Animal Care and Use Committee-approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. METHODS: Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by L-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated. RESULTS: ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; L-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95. CONCLUSIONS: The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by L-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.

Pancuronium enhances isoflurane anesthesia in rats via inhibition of cerebral nicotinic acetylcholine receptors.

PURPOSE: This study was conducted to elucidate the mechanism of enhancement of volatile anesthetics by neuromuscular blocking agents in rats and to consider the relevance of this enhancement to clinical anesthesia. METHODS: Male Sprague-Dawley rats were used. After confirming a movement in response to tail clamping under 1.1 % isoflurane anesthesia, response was determined when the tail clamp was applied at several points after microinjection of pancuronium into the lateral ventricle. Arousal responses to microinjection of nicotine into the lateral ventricle were assessed with or without pretreatment with intraventricular pancuronium. The intravenous 50 % effective dose (ED50) and 95 % effective dose (ED95) for neuromuscular blockade with pancuronium administered in a cumulative fashion at 1.1 % isoflurane were calculated. RESULTS: Intraventricular pancuronium dose-dependently reduced the response to tail clamping, and the dose required to show immobilization of 50 % of rats (intraventricular ED50) was 1.62 µg/kg. Pretreatment with pancuronium at 6 µg/kg significantly reduced the effect of awakening by nicotine under isoflurane anesthesia (P = 0.044). The intravenous ED50 and ED95 for neuromuscular blockade were 63 µg/kg (90 % confidence interval [CI] 52-75 µg/kg) and 133 µg/kg (90 % CI 109-158 µg/kg), respectively. The ratio of intraventricular ED50 to intravenous ED50 was 0.026. CONCLUSION: Pancuronium microinjection into the lateral ventricle dose-dependently enhances the depth of isoflurane anesthesia, which might be caused by inhibition of neuronal nicotinic acetylcholine receptor transmission in the cerebrum. Intravenous injection of pancuronium at high doses might increase the cerebrospinal concentration to a level at which an effect can be observed.

Novel neuromuscular blocking drugs and antagonists.

PURPOSE OF REVIEW: This review summarizes recent progress in the development of new muscle relaxants that are inactivated by cysteine, and considers the evolving paradigm of selective relaxant binding or degrading agents that can reverse neuromuscular blockade at any time. RECENT FINDINGS: The benzylisoquinoline compound gantacurium is a nondepolarizing muscle relaxant with an ultrashort duration largely determined by the rapid rate at which endogenous L-cysteine binds to, and permanently inactivates, the molecule. Although the clinical development of gantacurium has been hampered by modest histamine release, preclinical studies demonstrating that the drug can be rapidly reversed by injecting L-cysteine led to the development of CW002, an intermediate duration molecule that can also be reversed at any time by L-cysteine injection. Clinical trials with CW002 are now underway. The ability to reverse complete paralysis with cysteine dovetails with the established selective aminosteroid binding agent sugammadex, and the recently described universal relaxant binding agent calabadion. Taken together, the concept of rapid reversal at any time raises the question of whether an ultrashort nondepolarizing drug is needed if safe and cost-effective relaxant binding agents are available. SUMMARY: The gantacurium derivative CW002 is an intermediate duration, nondepolarizing, cysteine-inactivated, neuromuscular blocking drug currently in clinical trials. Like sugammadex reversal of rocuronium, CW002 can be reversed at any time by cysteine injection.

Aryl hydrocarbon receptor modulates NADPH oxidase activity via direct transcriptional regulation of p40phox expression.

A member of the NADPH oxidase subunits, p40(phox) plays an important role in the regulation of NADPH oxidase activity and the subsequent production of reactive oxygen species (ROS). In this study, we show that mouse p40(phox) is a novel transcriptional target of the aryl hydrocarbon receptor (AhR), known as a dioxin receptor or xenobiotic receptor, in the liver. Treatment of mice with 3-methylcholanthrene (3MC) increased p40(phox) gene expression in the liver, but this induction of p40(phox) gene expression was diminished by the deletion of the AhR gene in the liver. Consistent with the in vivo results, the expression of the p40(phox) gene was increased in 3MC-treated Hepa1c1c7 cells in an AhR-dependent manner. In addition, promoter analysis established p40(phox) as a transcriptional target of AhR. Studies using the RNA-interference technique revealed that p40(phox) is involved in the increase of NADPH oxidase activity and the subsequent ROS production in AhR-activated Hepa1c1c7 cells. Consequently, the results obtained here may provide a novel molecular mechanism for ROS production after exposure to dioxins.

Long-term compliance with nasal continuous positive airway pressure therapy for sleep apnea syndrome in an otorhinolaryngological office.

Continuous positive airway pressure (CPAP) is effective for patients with SAS. CPAP therapy requires long-term usage to prevent recurrence of symptoms. It is, thus, important to examine the level of long-term CPAP use and the factors influencing compliance with CPAP therapy for SAS. Compliance with CPAP therapy was examined in 204 patients in whom such therapy was started between 2003 and 2009. The median follow-up duration was 19 months (IQR = 6.8-37.5). Although the subjective and objective curative effects were significant, 18 patients (8.9%) refused CPAP therapy. Survival analysis showed that the patients' adherence to CPAP after 5 years was 89.8%. Multivariate analysis, including gender, age, BMI, AHI, arousal index, minSpO2, ESS, sleep stage, and LMI, indicated that the degree of improvement of AHI, percentage of deep sleep stage, and LMI were clinical variables independently associated with long-term adherence to CPAP. Furthermore, use of appropriate drugs for the patients with nasal congestion resulted in better satisfaction and adherence to CPAP therapy. We have shown that the rate of compliance and the subjective and objective curative effects of CPAP therapy were high, and detected the independent clinical factors associated with continued CPAP therapy.

Propofol anesthesia decreases the incidence of new-onset postoperative atrial fibrillation compared to desflurane in patients undergoing video-assisted thoracoscopic surgery: A retrospective single-center study.

BACKGROUND: Postoperative atrial fibrillation (POAF) increases postoperative morbidity, mortality, and length of hospital stay. Propofol is reported to modulate atrial electrophysiology and the cardiac autonomic nervous system. Therefore, we retrospectively examined whether propofol suppresses POAF in patients undergoing video-assisted thoracoscopic surgery (VATS) compared to desflurane. METHODS: We retrospectively recruited adult patients who underwent VATS during the period from January 2011 to May 2018 in an academic university hospital. Between continuous propofol and desflurane administration during anesthetic maintenance, we investigated the incidence of new-onset POAF (within 48 hours after surgery) before and after propensity score matching. RESULTS: Of the 482 patients, 344 received propofol, and 138 received desflurane during anesthetic maintenance. The incidence of POAF in the propofol group was less than that in the desflurane group (4 [1.2%] vs. 8 patients [5.8%], odds ratio [OR]; 0.161, 95% confidence interval (CI), 0.040-0.653, p = 0.011) in the present study population. After adjustment for propensity score matching (n = 254, n = 127 each group), the incidence of POAF was still less in propofol group than desflurane group (1 [0.8%] vs. 8 patients [6.3%], OR; 0.068, 95% CI: 0.007-0.626, p = 0.018). CONCLUSIONS: These retrospective data suggest propofol anesthesia significantly inhibits POAF compared to desflurane anesthesia in patients undergoing VATS. Further prospective studies are needed to elucidate the mechanism of propofol on the inhibition of POAF.

B type CpG-DNA suppresses poly(I:C)-induced BLyS expression and production in human tonsillar fibroblasts.

Although B lymphocyte stimulator (BLyS) has potent costimulatory effects on B cells, the details of BLyS-expression in tonsillar fibroblasts remain unexplored. We examined the effect of the Toll-like receptor (TLR) ligands on BLyS-expression in human tonsillar fibroblasts as well as the crosstalk that occurs among different TLR ligands. The expression of BLyS mRNA by tonsillar fibroblasts was strongly induced in the presence of polyinosinic-polycytidylic acid (poly(I:C)) that is a ligand, of TLR3. We also revealed that DNA containing CpG motifs (CpG-DNA), coding for a TLR9 ligand, markedly suppressed the poly(I:C)-induced mRNA expression and protein production of BLyS. B type CpG-DNA decreased the poly(I:C)-induced phosphorylation of inhibitor kappa B alpha (IκBα) and its degradation. Pre-incubation with nuclear factor kappa B (NF-κB) signaling inhibitors reduced the poly(I:C)-induced BLyS-expression. These results indicate that human tonsillar fibroblasts strongly induce BLyS-expression and production that can be inhibited by CpG-DNA and regulated through NF-κB signaling.

Platelet derived endothelial cell growth factor/thymidine phosphorylase enhanced human IgE production.

BACKGROUND: Angiogenesis is one pathogenesis of allergic airway disease. METHODS: A potent angiogenic factor is platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase (TP) in the field of cancer-associated research. Vascular endothelial growth factor (VEGF) is another representative angiogenic factor. Both factors were added to the culture system of human peripheral blood mononuclear cells (PBMC) with IL-4 and anti-CD40 monoclonal antibody (mAb). Total IgE levels in the supernatants and signal transduction of stimulated PBMC were evaluated. RESULTS: Addition of PD-ECGF enhances in vitro IgE production by PBMC in the presence of IL-4 and anti-CD40 mAb, but VEGF does not enhance IgE production. Although PD-ECGF catalyzes the reversible phosphorolysis of thymidine to 2-deoxy-D-ribose-1-phosphate (2DDR), treatment of 2DDR has no effect on IgE production by human PBMC. Both IL-4 and anti-CD40 mAb induce PD-ECGF by human PBMC. Thymidine phosphorylase inhibitor (TPI), 5-chloro-6-[1- (2-iminopyrrolidinyl) methyl] uracil hydrochloride reduce IgE production via blocking of STAT6- phosphorylation. CONCLUSIONS: Taken together, these results suggest TP involvement in the enhancement of IgE production and suggest that TPI is a novel strategy against IgE-related allergic disease.

Evaluation of the effect of apixaban using a viscoelastic coagulation assay with Russell's viper venom reagent.

BACKGROUND: Conventional coagulation tests, such as prothrombin time and activated partial thromboplastin time, are not sensitive to anticoagulation by apixaban. We evaluated the antithrombotic effect of apixaban using a Russell viper venom (RVV) test for a patient who underwent posterior spine fusion surgery. CASE PRESENTATION: An 84-year-old man was scheduled for percutaneous posterior spine fusion. He continued apixaban until the night before surgery and resumed it on the first day after surgery. We performed an RVV test as point-of-care coagulation monitoring in combination with chromogenic anti-activated factor X (anti-Xa) activity, prothrombin time, and activated partial thromboplastin time. Clotting time with the RVV test was prolonged according to the anti-Xa activity of apixaban, which was in the therapeutic range during surgery. CONCLUSIONS: An RVV test might be useful as a point-of-care assay for estimation of the anti-Xa level induced by apixaban during the perioperative period.

Intravenous infusion of rocuronium bromide prolongs emergence from propofol anesthesia in rats.

BACKGROUND: Neuromuscular blocking agents induce muscle paralysis via the prevention of synaptic transmission at the neuromuscular junction and may have additional effects at other sites of action. With regard to potential effects of neuromuscular blocking agents on the central nervous system, a definitive view has not been established. We investigated whether intravenous infusion of rocuronium bromide affects the emergence from propofol anesthesia. METHODS: Using an in vivo rat model, we performed propofol infusion for 60 minutes, along with rocuronium bromide at various infusion rates or normal saline. Sugammadex or normal saline was injected at the end of the infusion period, and we evaluated the time to emergence from propofol anesthesia. We also examined the neuromuscular blocking, circulatory, and respiratory properties of propofol infusion along with rocuronium bromide infusion to ascertain possible factors affecting emergence. RESULTS: Intravenous infusion of rocuronium bromide dose-dependently increased the time to emergence from propofol anesthesia. Sugammadex administered after propofol infusion not containing rocuronium bromide did not affect the time to emergence. Mean arterial pressure, heart rate, partial pressures of oxygen and carbon dioxide, and pH were not affected by rocuronium bromide infusion. Neuromuscular blockade induced by rocuronium bromide, even at the greatest infusion rate in the emergence experiment, was rapidly antagonized by sugammadex. CONCLUSIONS: These results suggest that intravenous infusion of rocuronium bromide dose-dependently delays the emergence from propofol anesthesia in rats. Future studies, such as detection of rocuronium in the cerebrospinal fluid or central nervous system, electrophysiologic studies, microinjection of sugammadex into the brain, etc., are necessary to determine the mechanism of this effect.

Gantacurium and CW002 do not potentiate muscarinic receptor-mediated airway smooth muscle constriction in guinea pigs.

BACKGROUND: Neuromuscular blocking agents are an integral component of general anesthesia. In addition to their intended pharmacologic target on skeletal muscle nicotinic receptors, undesirable airway effects (i.e., bronchoconstriction) can result from neuromuscular blocking agents' affinity for airway muscarinic receptors. We questioned whether two new members of a bisquaternary nondepolarizing muscle relaxant family, gantacurium and CW002, demonstrated detrimental effects of airway muscarinic receptors using an in vivo model in guinea pig airways. METHODS: Urethane-anesthetized male guinea pigs were ventilated through a tracheostomy with continuous digital recordings of pulmonary inflation pressure and heart rate. The dose for 95% twitch suppression for gantacurium, CW002, cisatracurium, and rapacuronium was defined in the guinea pig. Transient and reproducible changes in pulmonary inflation pressure and heart rate were recorded after vagal nerve stimulation or intravenous injection of acetylcholine before and after pretreatment with cumulatively increasing concentrations of gantacurium, CW002, cisatracurium or a single concentration of rapacuronium. RESULTS: The doses for 95% twitch suppression for gantacurium, CW002, cisatracurium, and rapacuronium were 0.064 +/- 0.006, 0.012 +/- 0.0006, 0.10 +/- 0.003, and 0.31 +/- 0.05 mg/kg, respectively. Gantacurium, CW002, and cisatracurium were without effects on baseline pulmonary inflation pressures and were devoid of significant interactions with M2 and M3 muscarinic receptors in vivo. CONCLUSION: These findings suggest that gantacurium and CW002 are devoid of significant effects at airway muscarinic receptors particularly M3 receptors on bronchial smooth musculature at doses several fold higher than those required for functional muscle paralysis.

Cysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: pharmacodynamics, acute cardiovascular effects, and preliminary toxicology.

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.