Hiroshi Sunaga

Rapid Chemical Antagonism of Neuromuscular Blockade by L-Cysteine Adduction to and Inactivation of the Olefinic (Double-bonded) Isoquinolinium Diester Compounds Gantacurium (AV430A), CW 002, and CW 011

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 ∼4–5× 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 3× 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 ∼70× less potent than CW 002. l-Cysteine (10–50 mg/kg intravenously) given 1 min after approximately 4–5× 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.

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 × 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.

Pharmacodynamics and cardiopulmonary side effects of CW002, a cysteine-reversible neuromuscular blocking drug in dogs.

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 blokade (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 × 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 × 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 × 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 × ED95. However, even at a dose of 100 × 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 × ED95 produces modest hemodynamic effects that are not associated with bronchoconstriction or consistent histamine release.

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.

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.

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.1 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.

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.

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.

The efficacy of intratracheal administration of vecuronium in rats, compared with intravenous and intramuscular administration.

To investigate the suitability of the intratracheal (IT) route as an alternative route for the administration of vecuronium, we compared the pharmacodynamic parameters for neuromuscular block in three groups of rats given vecuronium via the IT, IM, and IV routes. We also examined the pharmacokinetics of vecuronium in the three groups. The doses for the IT, IV, and IM groups were set at 1.50, 0.300, and 2.25 mg/kg, respectively. The onset of action in the IT group (127 ± 17 s) was significantly earlier than that in the IM group (267 ± 62 s), and significantly later than that in the IV group (18 ± 7 s) (P < 0.05 by analysis of variance and the Tukey-Kramer analysis). The duration of action in the IT group (794 ± 162 s) was significantly longer than that in the IV group (93 ± 30 s) but not significantly different from that in the IM group (743 ± 131 s). The recovery index in the IT group (134 ± 30 s) was significantly shorter than that in the IM group (222 ± 47 s) and significantly longer than that in the IV group (32 ± 12 s). Although IT administration of vecuronium is still slower than IV administration, it appears to be more advantageous as compared with IM administration, given the more rapid absorption and faster onset of action.

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 Gantacurium is an ultra-short acting nondepolarizing neuromuscular blocking agent in the monkey and in man that is degraded nonenzymatically by adduction of L-cysteine under physiologic conditions Administration of gantacurium results in decreased mean arterial pressure and increased heart rate What This Article Tells Us That Is New CW 1759-50 is a new nondepolarizing neuromuscular blocking agent that may have a clinical profile that is superior to that of gantacurium Studies in rhesus monkeys comparing CW 1759-50 with gantacurium found both of them to be ultra-short acting because of their rapid degradation by L-cysteine adduction The effects of CW 1759-50 on mean arterial pressure and heart rate were substantially less than those of gantacurium 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% &Dgr; [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.