REVIEW URRENT C OPINION
Novel neuromuscular blocking drugs and antagonists Paul M. Heerdt a, Hiroshi Sunaga b, and John J. Savarese c
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. Keywords calabadion, CW002, gantacurium, isoquinolines, L-cysteine, sugammadex
INTRODUCTION Despite a propensity for adverse side-effects, the depolarizing drug succinylcholine remains the only rapid onset, ultrashort duration (25 ED95) of what would be considered an intubating dose in humans [14,15]. Further evaluation of autonomic side-effects in a cat model confirmed gantacurium to have a high safety ratio, that is, very low potency for vagolysis or ganglionic blockade relative to neuromuscular blockade [14]. Other studies in a guinea pig preparation confirmed little potential for gantacurium to induce bronchoconstriction mediated by effects on airway muscarinic subtype 2 and 3 receptors [16].
Clinical pharmacology Clinical trials with gantacurium began in the late 1990s, and were first summarized in 2004 [17]. In volunteers anesthetized with propofol/fentanyl/ nitrous oxide, gantacurium was found to have an ED95 of 0.19 mg/kg, and at this dose, an onset of 2 min and duration (train-of-four ratio 0.9) of 12– 14 min (Table 1). Ascending dose studies revealed that at nearly 4xED95 duration was increased by only 5 min, and recovery intervals (5 95%, 25 75%, and 25% to T4:T10.9) were unchanged. These studies also demonstrated that in contrast to preclinical studies, in which potency was enhanced by volatile anesthetics, thus the total bolus dose as a multiple of ED95 was low, human volunteers
Development status
receiving 4 ED95 exhibited increases in plasma histamine concentrations. On average, volunteers receiving this dose had a 17% reduction in blood pressure. Attempts to alter histamine release in subsequent clinical trials by reformulating gantacurium with excipients thought to stabilize membranes were largely unsuccessful [8].
The concept of cysteine reversal Appreciation of the prominent role that endogenous L-cysteine plays in terminating the effect of gantacurium led to two early observations. First, mixing L-cysteine with gantacurium shortly before injection prevented both neuromuscular blockade and the histamine release produced by 50 ED95 in dogs (Fig. 2). In addition, even at very high doses, when gantacurium was mixed with L-cysteine, there was no evidence of a delayed onset of neuromuscular blockade, indicating the cysteine gantacugantacurium interaction was not transient. Second, in both dogs and monkeys, injecting Lcysteine at the onset of complete paralysis rapidly produced recovery of neuromuscular function (Fig. 3). Taken together, these observations indicated that exogenous L-cysteine rapidly and irreversibly alters the gantacurium molecule such that it no longer has significant affinity for nicotinic receptors at the motor end plate. Once additional observations confirmed the consistency and permanence of gantacurium reversal by L-cysteine and showed the reaction half-time for the gantacurium–cysteine interaction to be less than 20 s, a new question arose:
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60 min 50xED95
(b)
120
120
60
60
0
0
30
35
20
20
10
5
50xED95 + L-cysteine
Twitch (TOF)
LVV
LVP
(a)
90 seconds
90 seconds
FIGURE 2. The effect of high-dose gantacurium (50 ED95) alone or in combination with L-cysteine on left ventricular pressure (LVP, in mmHg), left ventricular volume (LVV, in ml) and muscle twitch response to train-of-four (TOF, arbitrary units) stimulation in a beagle. Panel A shows that gantacurium alone reduces LVP and LVV consistent with marked histamine-mediated vasodilation and venodilation, and produces rapid neuromuscular blockade. In contrast, mixing gantacurium with cysteine prior to injection (panel B) prevents both hemodynamic change and neuromuscular blockade.
what if we designed a molecule that interacts more slowly with endogenous cysteine to produce an intermediate duration, but can be reversed at any time by exogenous L-cysteine?
CW002 Initial discovery In 2007–2008, chemists at Cedarburg Laboratories in collaboration with investigators at Weill Cornell Medical College synthesized CW002, a nonhalogenated, symmetrical, benzylisoquinolinium fumaratediester (Fig. 4) that was specifically designed to interact more slowly with endogenous L-cysteine than gantacurium. Subsequent in-vivo studies revealed neuromuscular blockade of intermediate duration, paralleling in-vitro analysis that demonstrated a slower cysteine-CW002 reaction half-time [13,18] (Table 1). 406
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Molecular pharmacology: what makes it intermediate As shown in Fig. 4, CW002 is structurally similar to gantacurium with the exception of two fewer 1-benzyl methoxy groups, and no chloride to facilitate the cysteine sulfhydryl group interaction with the central olefinic double bond. Consequently, in-vitro measurements indicate an 11-min reaction half-time for cysteine adduction to CW002 [13].
Preclinical in-vivo pharmacology As with gantacurium, the preclinical evaluation of CW002 has included studies in multiple animal models [14,16,18,19 ]. In contrast to gantacurium, these investigations have demonstrated more variation in potency across species, with the ED95 for dogs, and rabbits (0.01 mg/kg) substantially lower than that for cats and monkeys (0.03 &
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Novel neuromuscular blocking drugs and antagonists Heerdt et al.
10 min
40 sec
Gantacurium 0.2 mg/kg
Gantacurium 0.2 mg/kg Followed 1 minute later by 10 mg/kg L-cysteine
FIGURE 3. Demonstration of cysteine reversal of gantacurium in a monkey. Injection of L-cysteine produced recovery from complete paralysis in less than a minute.
and 0.04 mg/kg, respectively). Nonetheless, despite potency differences, the same multiples of ED95 produce an intermediate duration across species. A systematic study of beagles receiving a range of CW002 doses over several weeks indicated that 3x ED95 had an onset time of 2.6 0.09 min and duration of 47 9 min [18]. Although relatively devoid of hemodynamic effects at low multiples of ED95, at doses of 25 ED95 and higher, CW002 modestly decreased arterial blood pressure, cardiac output, and left ventricular contractility [18]. This response was not directly attributable to histamine release (measured plasma concentrations), and there was no in-vivo evidence of bronchoconstriction. This study also clearly established cysteine reversal of CW002 at any time.
OMe MeO
CW002
OMe
+
N
O
CH3
H
OMe
O (Z) O
OMe H O
CH3
+
N OMe
OMe OMe
FIGURE 4. The structure of CW002, highlighting the lack of a chloride on the fumarate component.
Subsequent studies in guinea pigs and cats confirmed that CW002, like gantacurium, has little potential to induce bronchoconstriction mediated by effects on muscarinic subtype 2 and 3 receptors [16], and relative to potency for neuromuscular blockade, minimal potency for vagolysis, or ganglionic blockade [8].
Clinical pharmacology Clinical trials with CW002 began in 2012 (ClinicalTrials.govNCT01338935) with the first phase 1, dose escalation (range 0.02 0.14 mg/kg), pharmacodynamic/pharmacokinetic study in volunteers now completed. For this study, anesthesia was induced with propofol and tracheal intubation performed without muscle relaxant. Anesthesia was then maintained with nitrous oxide (70%) and sevoflurane (0.8–1.2% end-tidal) because of concerns that the high plasma propofol concentrations achieved with continuous infusion could potentially interfere with measurement of plasma CW002. A radial arterial catheter was placed for BP monitoring and blood sampling (for both histamine and CW002 levels), and neuromuscular blockade assessed using mechanomyography at the adductor pollicis. Preliminary analyses of pharmacodynamic/pharmacokinetic data from this trial have been reported [20,21], and indicate an ED95 of 0.07 mg/kg, a duration at 1.5–2.0 ED95 of 55 min with an onset time of 2.9 min, and a mean terminal half-life of about 26 min. There were no hemodynamic changes observed, nor evidence of histamine release or bronchoconstriction.
Next directions in muscle relaxant development Development of CW002 as a drug with a duration that can be tailored to clinical need continues, and more human trials are planned. Interestingly, there
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is an emerging interest in CW002 for veterinary anesthesia in large part because of the significant side-effects associated with neostigmine/antimuscarinic reversal of currently available drugs in some animals, and the cost of newer reversal agents [19 ]. In addition, other work directed toward modifying gantacurium to maintain potency, speed of onset, and short duration while reducing histamine release has been conducted. Recent preliminary structure-activity studies suggest that relative to gantacurium, one candidate molecule (CW1759– 50) has a similar duration but no histamine related side-effects at high doses, all in conjunction with high autonomic safety and very low potency for airway M2 and M3 receptors [22–25]. &
New paradigms for reversal of neuromuscular blockage: sugammadex, calabadion, and cysteine As with other nondepolarizing NMBDs, neostigmine accelerates recovery from CW002 neuromuscular blockade when spontaneous recovery has begun, but has no effect when given in the setting of complete paralysis [8]. The concept of using exogenous L-cysteine to facilitate molecular inactivation of novel NMBD molecules evolved in the early 2000s, the same time that reports describing sugammadex reversal of rocuronium were first published [26]. A large cyclodextrin molecule that conceptually works by enveloping rocuronium, and to a somewhat lesser extent vecuronium, in a lipophilic cavity, sugammadex can reverse complete paralysis by essentially hiding steroidal NMBAs from the motor end plate (Table 2) [27 ]. Reflecting a high binding affinity for rocuronium, sugammadex reversal of neuromuscular blockade occurs rapidly and without the potential for ‘recurarization.’ Although not yet approved for use in the USA because of apparent Food and Drug Administration (FDA) concerns over the potential for hypersensitivity reactions, sugammadex is available for clinical use elsewhere in the world, and despite potential side-effects the concept of selective relaxant binding &
agents or ‘SRBAs’ for rapid reversal of NMBDs has become widely accepted and desirable [27 ,28, 29,30 ]. Nonetheless, routine use of sugammadex has been limited by high cost, a feature accentuated by the fact that higher doses are required to reverse complete paralysis when rocuronium plasma concentrations are high. More recently, Hoffman et al. [31] reported preliminary studies with calabadions [30 ,32], acyclic tetrameric derivatives of Cucurbit[n]uril, a class of complex molecules that have been characterized as ‘molecular containers’ (Table 2) [32–34]. Previously used as components of drug delivery vehicles [35], molecules in the Cucurbit[n]uril family such as calabadion have now been shown to cover the quaternary amine sites for both benzylisoquinolinium and steroidal NMBDs to prevent binding to neuromuscular nicotinic receptors [32,31]. Although similar to sugammadex in terms of rapid reversal at any time without the need for antimuscarinics, the mechanism of action for calabadion appears to be somewhat more specific: changing affinity of the NMBA for neuromuscular nicotinic receptors as opposed to enveloping and removing free NMBA from the motor end plate. In contrast to calabadion, L-cysteine adduction to gantacurium and CW002 occurs in an area of the molecule away from the quaternary amines (Figs 1 and 3). For CW002, the resulting adduction product retains some, but very low, affinity for neuromuscular nicotinic receptors, with potency for neuromuscular blockade decreased 70 100-fold [13]. The adduct then is hydrolyzed to fragments that are 500 1000-fold less potent than the parent compound. Unlike sugammadex, the same dose of Lcysteine produces the same rate of recovery regardless of how soon after CW002 injection the cysteine is given. A nonessential amino acid in adults, Lcysteine is a key component in the synthesis of glutathione (a tripeptide of L-cysteine, L-glutamic acid and lysine). In preterm infants with enzymatic immaturity of the transsulfuration pathways that form cysteine from methionine, L-cysteine has been &
&&
&&
Table 2. Comparison of reversal agents that act directly on neuromuscular blocking drug molecules Structure
Target
Mechanism
Dose response relative to NMBA injection
Developmental stage
Sugammadex
Cyclodextrin
Steroidal compounds
Envelops NMBD with high affinity binding
Increasing dose for early reversal
Approved in EU and Japan; awaiting FDA approval in USA
Calabadion
Acyclic cucurbit[n]uril
All NMBDs
Binds to quaternary amines
?
Not yet approved
Cysteine
Amino acid with thiol side chain
Novel isoquinoliniums
Adducts to fumarate moiety
Reversal at any time with same dose
Not yet approved
NMBD, neuromuscular blocking drug.
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Novel neuromuscular blocking drugs and antagonists Heerdt et al.
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CW002 0.08 mg/kg
0
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10
CW002 0.08 mg/kg
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FIGURE 5. An example of the twitch response to 0.08 mg/kg CW002 alone or when followed after 1 min by 50 mg/kg L-cysteine. Duration is reduced from 65 to 4 min. The example also shows that a repeat dose of 0.08 mg/kg after L-cysteine is effective but of much shorter duration, presumably due to residual L-cysteine (from [42]).
infused intravenously over extended periods as a supplement to parenteral nutrition [36]. The acetylated derivative N-acetyl L-cysteine has been widely administered as a treatment to increase glutathione production and enhance antioxidant capacity [37– 42]. Currently, FDA-approved oral and intravenous preparations of N-acetyl cysteine are available for use in the treatment of acetaminophen toxicity. However, it has been speculated that sustained excess of L-cysteine within the central nervous system may be neuroexcitatory and contribute to neurodegeneration [43–45]. Currently, it remains unclear how studies in rodents using L-cysteine injected directly into the brain or administered in systemic doses close to the LD50 relate to the effects of smaller intravenous doses in large animals or humans. In a study conducted in beagles using 9 ED95 CW002 (a dose in mg/kg close to 2 ED95 for monkeys and >1 ED95 in humans), the optimal L-cysteine dose for reversal of complete paralysis was estimated to be 30–50 mg/kg [42], or 30–50-fold lower than the intraperitoneal L-cysteine found to be neurotoxic in rodents. Nonetheless, although studies in beagles found that 20–50 mg/kg L-cysteine produced rapid reversal of CW002 (Fig. 5) [42] with minimal side-effects, and that reversal with 200 mg/kg L-cysteine was not associated with clinical, anatomic, or biochemical evidence of toxicity [42], safety and efficacy in humans remains to be determined.
hydrolysis, subsequent work showed the brief duration was largely determined by rapid binding of endogenous L-cysteine to the molecule. Clinical development of gantacurium was ultimately hampered by histamine release. However, preclinical studies demonstrating the drug can be rapidly reversed at any time by injecting L-cysteine led to development of CW002, a gantacurium-related molecule specifically designed to produce an intermediate duration that can be reversed at any time by L-cysteine injection. Clinical trials now underway with CW002 have been favorable. The ability to reverse CW002 at any time with cysteine dovetails with the established sugammadex reversal of rocuronium, and the recently described reversal of both rocuronium and cisatracurium by the 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. Acknowledgements The authors would like to thank several individuals involved with the development and synthesis of novel compounds: Jeff McGilvra, Scott Van Ornum, Eric Boros, Vicente Samano, and Robert Mook.
CONCLUSION
Financial support and sponsorship The Department of Anesthesiology, Weill Cornell Medical College, The CB Starr Foundation, and Nancy Paduano IRA.
The search continues for a safe and effective, nondepolarizing, alternative to succinylcholine. Gantacurium is a benzylisoquinoline nondepolarizing muscle relaxant with a 12-min at 3 ED95 duration. Initially thought to reflect rapid
Conflicts of interest J.J.S. is the inventor of the cysteine-inactivated neuromuscular blocking drugs described in the text. The patents for these molecules are held by Cornell University.
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P.M.H. and J.J.S. are inventors of cysteine formulations for reversal of the novel drugs. The patents for these molecules are held by Cornell University. Hiroshi Sunaga has no conflicts to disclose.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Marshall RJ, Muir AW, Sleigh T, Savage DS. Research and development of aminosteroid neuromuscular blocking agents: past and future. Eur J Anesthesiol 1995; 11:5–10. 2. Savarese JJ, Lien CA, Belmont MR, Rubin L. The clinical and basic pharmacology of mivacurium: a short-acting nondepolarizing benzylisoquinoliniumdiester neuromuscular blocking drug. Acta Anaesth Scand 1995; 39:18–22. 3. White PF. Rapacuronium: why did it fail as a replacement for succinylcholine? Br J Anaesth 2002; 88:163–165. 4. Gyermek L. Development of ultra short-acting muscle relaxant agents: history, research strategies, and challenges. Med Res Rev 2005; 25:610–654. 5. Gyermek L, Lee C. The development of ultrashort acting neuromuscular relaxant tropane derivatives. J Crit Care 2009; 24:58–65. 6. Lien CA, Savard P, Belmont M, et al. Fumarates: unique nondepolarizing neuromuscular blocking agents that are antagonized by cysteine. J Crit Care 2009; 24:50–57. 7. Naguib M, Brull SJ. Update on neuromuscular pharmacology. Curr Opin Anaesthesiol 2009; 22:483–490. 8. Lien CA. Development and potential clinical impact of ultra-short-acting neuromuscular blocking agents. Br J Anaesth 2011; 107 (Suppl 1):i60–i71. 9. Samano V, Ray JA, Thompson JB, et al. Synthesis of ultra-short-acting neuromuscular blocker GW 0430: a remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinoliniumchlorofumarates. Org Lett 1999; 1:1993–1996. 10. Boros EE, Bigham EC, Boswell GE, et al. Bis- and mixed-tetrahydroisoquinoliniumchlorofumarates: new ultra-short-acting nondepolarizing neuromuscular blockers. J Med Chem 1999; 42:1114. 11. Kaldor I, Feldman PL, Mook RA Jr, et al. Stereocontrolled synthesis of cisdibenzoquinolizinechlorofumarates: curare-like agents of ultrashort duration. J Org Chem 2001; 66:3495–3501. 12. Boros EE, Samano V, Ray JA, et al. Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinoliniumhalofumarates and halosuccinates in rhesus monkeys. J Med Chem 2003; 46:2502–2515. 13. Savarese JJ, McGilvra JD, Sunaga H, et al. Rapid chemical antagonism of neuromuscular blockade by l-cysteine adduction to and inactivation of the olefinic (double-bonded) isoquinoliniumdiester compounds gantacurium(AV430A), CW002, and CW 011. Anesthesiology 2010; 113:58–73. 14. Savarese JJ, Belmont MR, Hashim MA, et al. Preclinical pharmacology of GW280430A(AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium. Anesthesiology 2004; 100:835–845. 15. Heerdt PM, Kang R, The A, et al. Cardiopulmonary effects of the novel neuromuscular blocking drug GW280430A (AV430) in dogs. Anesthesiology 2004; 100:846–851. 16. Sunaga H, Zhang Y, Savarese JJ, et al. Gantacurium and CW002 do not potentiate muscarinic receptor-mediated airway smooth muscle constriction in guinea pigs. Anesthesiology 2010; 112:892–899. 17. Belmont MR, Lien CA, Tjan J, et al. Clinical pharmacology of GW280430A in humans. Anesthesiology 2004; 100:768–773. 18. Heerdt PM, Malhotra JK, Pan BY, et al. Pharmacodynamics and cardiopulmonary side effects of CW002, a cysteine-reversible neuromuscular blocking drug in dogs. Anesthesiology 2010; 112:910–916. 19. Diaz LL, Zhang J, Heerdt PM. Comparative pharmacodynamics of pancur& onium, cisatracurium, and CW002 in rabbits. J Am Assoc Lab Anim Sci 2014; 53:283–289. This report describes the potency, duration, and cysteine reversal of CW002 in a common laboratory animal model. 20. Murrell MT, Malhotra JK, Sunaga H, et al. Potency and preliminary pharmacodynamics of the novel neuromuscular blocking drug CW002 in humans during sevoflurane/nitrous oxide anesthesia (ASA Abstracts 2013, LBB03).
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21. Owens JS, Heerdt PM, Malhotra JK, et al. Pharmacokinetics of CW002, a novel neuromuscular blocking agent in the initial cohorts of a phase 1 clinical trial (AAPS Annual Meeting, 2014). 22. Savarese JJ, Belmont MR, Sunaga H, et al. Crossover studies in monkeys show that a new ultra-short acting nondepolarizer, CW 1759-50, in contrast with gantacurium, elicits no histaminoid phenomena (ASA Abstracts 2013, A2201. 23. Sunaga H, McGilvra J, Belmont MR, et al. CW1759-50: A new ultra-short acting nondepolarizer: Spontaneous recovery versus antagonism by L-cysteine (ASA Abstracts 2013, A4034). 24. Savarese JJ, Yi Zhang Y, Heerdt PM, Emala CW. The ultra-short acting neuromuscular blocker CW 1759-50 has approximately 5 times the safety of rapacurium at M2 and M3 receptor (ASA Abstracts 2014, A4003). 25. Savarese JJ, Sunaga H, Belmont MR, et al. The ultra-short acting neuromuscular blocker CW 1759-50 has very high autonomic safety in the isofluraneanesthetized cat (ASA Abstracts 2014, A4000). 26. Adam JM, Bennett DJ, Bom A, et al. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships. J Med Chem 2002; 45:1806–1816. 27. Ledowski T. Sugammadex. What do we know and what do we still need to & know? A review of the recent (2013 to 2014) literature. Anaesth Intensive Care 2015; 43:14–22. This describes current thought regarding the benefits and potential pitfalls of sugammadex. 28. Abrishami A, Ho J, Wong J, et al. Cochrane corner: sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. AnesthAnalg 2010; 110:1239. 29. Schepens T, Cammu G. Neuromuscular blockade: what was, is and will be. Acta Anaesthesiol 2014; 65:151–159. 30. Farhan H, Moreno-Duarte I, McLean D, Eikermann M. Residual paralysis: does && it influence outcome after ambulatory surgery? Curr Anesthesiol Rep 2014; 4:290–302. This article reviews the use of neuromuscular blocking drugs in the ambulatory surgical population. The potential for complications related to residual postoperative weakness is described, and used as a platform to underscore the need for new reversal agents such as sugammadex and calabadion. 31. Hoffmann U, Grosse-Sundrup M, Eikermann-Haerter K, et al. Calabadion: a new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents. Anesthesiology 2013; 119:317–325. 32. Ma D, Zhang B, Hoffmann U, et al. Acyclic cucurbit[n]uril-type molecular containers bind neuromuscular blocking agents in vitro and reverse neuromuscular block in vivo. Angew Chem Int Ed Engl 2012; 51:11358–11362. 33. Macartney DH. Cucurbit[n]uril type hosts for the reversal of steroidal neuromuscular blocking agents. Future Med Chem 2013; 5:2075–2089. 34. Isaacs L. Stimuli responsive systems constructed using cucurbit[n]uril-type molecular containers. Acc Chem Res 2014; 47:2052–2062. 35. Wang Y, Li D, Wang H, et al. pH responsive supramolecular prodrug micelles based on cucurbit[8]uril for intracellular drug delivery. Chem Commun (Camb) 2014; 50:9390–9392. 36. Zlotkin SH, Bryan MH, Anderson GH. Cysteine supplementation to cysteinefree intravenous feeding regimens in newborn infants. Am J ClinNutr 1981; 34:914–923. 37. Zuin R, Palamidese A, Negrin R, et al. High-dose n-acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease. Clin Drug Investig 2005; 25:401–408. 38. Schaller G, Pleiner J, Mittermayer F, et al. Effects of N-acetylcysteine against systemic and renal hemodynamic effects of endotoxin in healthy humans. Crit Care Med 2007; 35:1869–1875. 39. Kortsalioudaki C, Taylor RM, Cheeseman P, et al. Safety and efficacy of Nacetylcysteine in children with nonacetaminophen-induced acute liver failure. Liver Transpl 2008; 14:25–30. 40. Karila L, Gorelick D, Weinstein A, et al. New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 2008; 11:425–438. 41. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 2008; 11:851–876. 42. Sunaga H, Malhotra JK, Yoon E, et al. Cysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: pharmacodynamics, acute cardiovascular effects, and preliminary toxicology. Anesthesiology 2010; 112:900–909. 43. Sharpe LG, Olney JW, Ohlendorf C, et al. Brain damage and associated behavioral deficits following the administration of l-cysteine to infant rats. Pharmacol Biochem Behav 1975; 3:291–298. 44. Sawamoto O, Hagiwara R, Kurisu K. L-cysteine-induced brain damage in adult rats. Exp Toxicol Pathol 2004; 56:45–52. 45. Janaky R, Varga V, Hermann A, et al. Mechanisms of l-cysteine neurotoxicity. Neurochem Res 2000; 25:1397–1405.
Volume 28 Number 4 August 2015
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Novel neuromuscular blocking drugs and antagonists Paul M. Heerdt a, Hiroshi Sunaga b, and John J. Savarese c
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. Keywords calabadion, CW002, gantacurium, isoquinolines, L-cysteine, sugammadex
INTRODUCTION Despite a propensity for adverse side-effects, the depolarizing drug succinylcholine remains the only rapid onset, ultrashort duration (25 ED95) of what would be considered an intubating dose in humans [14,15]. Further evaluation of autonomic side-effects in a cat model confirmed gantacurium to have a high safety ratio, that is, very low potency for vagolysis or ganglionic blockade relative to neuromuscular blockade [14]. Other studies in a guinea pig preparation confirmed little potential for gantacurium to induce bronchoconstriction mediated by effects on airway muscarinic subtype 2 and 3 receptors [16].
Clinical pharmacology Clinical trials with gantacurium began in the late 1990s, and were first summarized in 2004 [17]. In volunteers anesthetized with propofol/fentanyl/ nitrous oxide, gantacurium was found to have an ED95 of 0.19 mg/kg, and at this dose, an onset of 2 min and duration (train-of-four ratio 0.9) of 12– 14 min (Table 1). Ascending dose studies revealed that at nearly 4xED95 duration was increased by only 5 min, and recovery intervals (5 95%, 25 75%, and 25% to T4:T10.9) were unchanged. These studies also demonstrated that in contrast to preclinical studies, in which potency was enhanced by volatile anesthetics, thus the total bolus dose as a multiple of ED95 was low, human volunteers
Development status
receiving 4 ED95 exhibited increases in plasma histamine concentrations. On average, volunteers receiving this dose had a 17% reduction in blood pressure. Attempts to alter histamine release in subsequent clinical trials by reformulating gantacurium with excipients thought to stabilize membranes were largely unsuccessful [8].
The concept of cysteine reversal Appreciation of the prominent role that endogenous L-cysteine plays in terminating the effect of gantacurium led to two early observations. First, mixing L-cysteine with gantacurium shortly before injection prevented both neuromuscular blockade and the histamine release produced by 50 ED95 in dogs (Fig. 2). In addition, even at very high doses, when gantacurium was mixed with L-cysteine, there was no evidence of a delayed onset of neuromuscular blockade, indicating the cysteine gantacugantacurium interaction was not transient. Second, in both dogs and monkeys, injecting Lcysteine at the onset of complete paralysis rapidly produced recovery of neuromuscular function (Fig. 3). Taken together, these observations indicated that exogenous L-cysteine rapidly and irreversibly alters the gantacurium molecule such that it no longer has significant affinity for nicotinic receptors at the motor end plate. Once additional observations confirmed the consistency and permanence of gantacurium reversal by L-cysteine and showed the reaction half-time for the gantacurium–cysteine interaction to be less than 20 s, a new question arose:
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60 min 50xED95
(b)
120
120
60
60
0
0
30
35
20
20
10
5
50xED95 + L-cysteine
Twitch (TOF)
LVV
LVP
(a)
90 seconds
90 seconds
FIGURE 2. The effect of high-dose gantacurium (50 ED95) alone or in combination with L-cysteine on left ventricular pressure (LVP, in mmHg), left ventricular volume (LVV, in ml) and muscle twitch response to train-of-four (TOF, arbitrary units) stimulation in a beagle. Panel A shows that gantacurium alone reduces LVP and LVV consistent with marked histamine-mediated vasodilation and venodilation, and produces rapid neuromuscular blockade. In contrast, mixing gantacurium with cysteine prior to injection (panel B) prevents both hemodynamic change and neuromuscular blockade.
what if we designed a molecule that interacts more slowly with endogenous cysteine to produce an intermediate duration, but can be reversed at any time by exogenous L-cysteine?
CW002 Initial discovery In 2007–2008, chemists at Cedarburg Laboratories in collaboration with investigators at Weill Cornell Medical College synthesized CW002, a nonhalogenated, symmetrical, benzylisoquinolinium fumaratediester (Fig. 4) that was specifically designed to interact more slowly with endogenous L-cysteine than gantacurium. Subsequent in-vivo studies revealed neuromuscular blockade of intermediate duration, paralleling in-vitro analysis that demonstrated a slower cysteine-CW002 reaction half-time [13,18] (Table 1). 406
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Molecular pharmacology: what makes it intermediate As shown in Fig. 4, CW002 is structurally similar to gantacurium with the exception of two fewer 1-benzyl methoxy groups, and no chloride to facilitate the cysteine sulfhydryl group interaction with the central olefinic double bond. Consequently, in-vitro measurements indicate an 11-min reaction half-time for cysteine adduction to CW002 [13].
Preclinical in-vivo pharmacology As with gantacurium, the preclinical evaluation of CW002 has included studies in multiple animal models [14,16,18,19 ]. In contrast to gantacurium, these investigations have demonstrated more variation in potency across species, with the ED95 for dogs, and rabbits (0.01 mg/kg) substantially lower than that for cats and monkeys (0.03 &
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Novel neuromuscular blocking drugs and antagonists Heerdt et al.
10 min
40 sec
Gantacurium 0.2 mg/kg
Gantacurium 0.2 mg/kg Followed 1 minute later by 10 mg/kg L-cysteine
FIGURE 3. Demonstration of cysteine reversal of gantacurium in a monkey. Injection of L-cysteine produced recovery from complete paralysis in less than a minute.
and 0.04 mg/kg, respectively). Nonetheless, despite potency differences, the same multiples of ED95 produce an intermediate duration across species. A systematic study of beagles receiving a range of CW002 doses over several weeks indicated that 3x ED95 had an onset time of 2.6 0.09 min and duration of 47 9 min [18]. Although relatively devoid of hemodynamic effects at low multiples of ED95, at doses of 25 ED95 and higher, CW002 modestly decreased arterial blood pressure, cardiac output, and left ventricular contractility [18]. This response was not directly attributable to histamine release (measured plasma concentrations), and there was no in-vivo evidence of bronchoconstriction. This study also clearly established cysteine reversal of CW002 at any time.
OMe MeO
CW002
OMe
+
N
O
CH3
H
OMe
O (Z) O
OMe H O
CH3
+
N OMe
OMe OMe
FIGURE 4. The structure of CW002, highlighting the lack of a chloride on the fumarate component.
Subsequent studies in guinea pigs and cats confirmed that CW002, like gantacurium, has little potential to induce bronchoconstriction mediated by effects on muscarinic subtype 2 and 3 receptors [16], and relative to potency for neuromuscular blockade, minimal potency for vagolysis, or ganglionic blockade [8].
Clinical pharmacology Clinical trials with CW002 began in 2012 (ClinicalTrials.govNCT01338935) with the first phase 1, dose escalation (range 0.02 0.14 mg/kg), pharmacodynamic/pharmacokinetic study in volunteers now completed. For this study, anesthesia was induced with propofol and tracheal intubation performed without muscle relaxant. Anesthesia was then maintained with nitrous oxide (70%) and sevoflurane (0.8–1.2% end-tidal) because of concerns that the high plasma propofol concentrations achieved with continuous infusion could potentially interfere with measurement of plasma CW002. A radial arterial catheter was placed for BP monitoring and blood sampling (for both histamine and CW002 levels), and neuromuscular blockade assessed using mechanomyography at the adductor pollicis. Preliminary analyses of pharmacodynamic/pharmacokinetic data from this trial have been reported [20,21], and indicate an ED95 of 0.07 mg/kg, a duration at 1.5–2.0 ED95 of 55 min with an onset time of 2.9 min, and a mean terminal half-life of about 26 min. There were no hemodynamic changes observed, nor evidence of histamine release or bronchoconstriction.
Next directions in muscle relaxant development Development of CW002 as a drug with a duration that can be tailored to clinical need continues, and more human trials are planned. Interestingly, there
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is an emerging interest in CW002 for veterinary anesthesia in large part because of the significant side-effects associated with neostigmine/antimuscarinic reversal of currently available drugs in some animals, and the cost of newer reversal agents [19 ]. In addition, other work directed toward modifying gantacurium to maintain potency, speed of onset, and short duration while reducing histamine release has been conducted. Recent preliminary structure-activity studies suggest that relative to gantacurium, one candidate molecule (CW1759– 50) has a similar duration but no histamine related side-effects at high doses, all in conjunction with high autonomic safety and very low potency for airway M2 and M3 receptors [22–25]. &
New paradigms for reversal of neuromuscular blockage: sugammadex, calabadion, and cysteine As with other nondepolarizing NMBDs, neostigmine accelerates recovery from CW002 neuromuscular blockade when spontaneous recovery has begun, but has no effect when given in the setting of complete paralysis [8]. The concept of using exogenous L-cysteine to facilitate molecular inactivation of novel NMBD molecules evolved in the early 2000s, the same time that reports describing sugammadex reversal of rocuronium were first published [26]. A large cyclodextrin molecule that conceptually works by enveloping rocuronium, and to a somewhat lesser extent vecuronium, in a lipophilic cavity, sugammadex can reverse complete paralysis by essentially hiding steroidal NMBAs from the motor end plate (Table 2) [27 ]. Reflecting a high binding affinity for rocuronium, sugammadex reversal of neuromuscular blockade occurs rapidly and without the potential for ‘recurarization.’ Although not yet approved for use in the USA because of apparent Food and Drug Administration (FDA) concerns over the potential for hypersensitivity reactions, sugammadex is available for clinical use elsewhere in the world, and despite potential side-effects the concept of selective relaxant binding &
agents or ‘SRBAs’ for rapid reversal of NMBDs has become widely accepted and desirable [27 ,28, 29,30 ]. Nonetheless, routine use of sugammadex has been limited by high cost, a feature accentuated by the fact that higher doses are required to reverse complete paralysis when rocuronium plasma concentrations are high. More recently, Hoffman et al. [31] reported preliminary studies with calabadions [30 ,32], acyclic tetrameric derivatives of Cucurbit[n]uril, a class of complex molecules that have been characterized as ‘molecular containers’ (Table 2) [32–34]. Previously used as components of drug delivery vehicles [35], molecules in the Cucurbit[n]uril family such as calabadion have now been shown to cover the quaternary amine sites for both benzylisoquinolinium and steroidal NMBDs to prevent binding to neuromuscular nicotinic receptors [32,31]. Although similar to sugammadex in terms of rapid reversal at any time without the need for antimuscarinics, the mechanism of action for calabadion appears to be somewhat more specific: changing affinity of the NMBA for neuromuscular nicotinic receptors as opposed to enveloping and removing free NMBA from the motor end plate. In contrast to calabadion, L-cysteine adduction to gantacurium and CW002 occurs in an area of the molecule away from the quaternary amines (Figs 1 and 3). For CW002, the resulting adduction product retains some, but very low, affinity for neuromuscular nicotinic receptors, with potency for neuromuscular blockade decreased 70 100-fold [13]. The adduct then is hydrolyzed to fragments that are 500 1000-fold less potent than the parent compound. Unlike sugammadex, the same dose of Lcysteine produces the same rate of recovery regardless of how soon after CW002 injection the cysteine is given. A nonessential amino acid in adults, Lcysteine is a key component in the synthesis of glutathione (a tripeptide of L-cysteine, L-glutamic acid and lysine). In preterm infants with enzymatic immaturity of the transsulfuration pathways that form cysteine from methionine, L-cysteine has been &
&&
&&
Table 2. Comparison of reversal agents that act directly on neuromuscular blocking drug molecules Structure
Target
Mechanism
Dose response relative to NMBA injection
Developmental stage
Sugammadex
Cyclodextrin
Steroidal compounds
Envelops NMBD with high affinity binding
Increasing dose for early reversal
Approved in EU and Japan; awaiting FDA approval in USA
Calabadion
Acyclic cucurbit[n]uril
All NMBDs
Binds to quaternary amines
?
Not yet approved
Cysteine
Amino acid with thiol side chain
Novel isoquinoliniums
Adducts to fumarate moiety
Reversal at any time with same dose
Not yet approved
NMBD, neuromuscular blocking drug.
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Twitch amplitude
CW002 0.08 mg/kg
0
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40
50
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10
CW002 0.08 mg/kg
0
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minutes
FIGURE 5. An example of the twitch response to 0.08 mg/kg CW002 alone or when followed after 1 min by 50 mg/kg L-cysteine. Duration is reduced from 65 to 4 min. The example also shows that a repeat dose of 0.08 mg/kg after L-cysteine is effective but of much shorter duration, presumably due to residual L-cysteine (from [42]).
infused intravenously over extended periods as a supplement to parenteral nutrition [36]. The acetylated derivative N-acetyl L-cysteine has been widely administered as a treatment to increase glutathione production and enhance antioxidant capacity [37– 42]. Currently, FDA-approved oral and intravenous preparations of N-acetyl cysteine are available for use in the treatment of acetaminophen toxicity. However, it has been speculated that sustained excess of L-cysteine within the central nervous system may be neuroexcitatory and contribute to neurodegeneration [43–45]. Currently, it remains unclear how studies in rodents using L-cysteine injected directly into the brain or administered in systemic doses close to the LD50 relate to the effects of smaller intravenous doses in large animals or humans. In a study conducted in beagles using 9 ED95 CW002 (a dose in mg/kg close to 2 ED95 for monkeys and >1 ED95 in humans), the optimal L-cysteine dose for reversal of complete paralysis was estimated to be 30–50 mg/kg [42], or 30–50-fold lower than the intraperitoneal L-cysteine found to be neurotoxic in rodents. Nonetheless, although studies in beagles found that 20–50 mg/kg L-cysteine produced rapid reversal of CW002 (Fig. 5) [42] with minimal side-effects, and that reversal with 200 mg/kg L-cysteine was not associated with clinical, anatomic, or biochemical evidence of toxicity [42], safety and efficacy in humans remains to be determined.
hydrolysis, subsequent work showed the brief duration was largely determined by rapid binding of endogenous L-cysteine to the molecule. Clinical development of gantacurium was ultimately hampered by histamine release. However, preclinical studies demonstrating the drug can be rapidly reversed at any time by injecting L-cysteine led to development of CW002, a gantacurium-related molecule specifically designed to produce an intermediate duration that can be reversed at any time by L-cysteine injection. Clinical trials now underway with CW002 have been favorable. The ability to reverse CW002 at any time with cysteine dovetails with the established sugammadex reversal of rocuronium, and the recently described reversal of both rocuronium and cisatracurium by the 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. Acknowledgements The authors would like to thank several individuals involved with the development and synthesis of novel compounds: Jeff McGilvra, Scott Van Ornum, Eric Boros, Vicente Samano, and Robert Mook.
CONCLUSION
Financial support and sponsorship The Department of Anesthesiology, Weill Cornell Medical College, The CB Starr Foundation, and Nancy Paduano IRA.
The search continues for a safe and effective, nondepolarizing, alternative to succinylcholine. Gantacurium is a benzylisoquinoline nondepolarizing muscle relaxant with a 12-min at 3 ED95 duration. Initially thought to reflect rapid
Conflicts of interest J.J.S. is the inventor of the cysteine-inactivated neuromuscular blocking drugs described in the text. The patents for these molecules are held by Cornell University.
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P.M.H. and J.J.S. are inventors of cysteine formulations for reversal of the novel drugs. The patents for these molecules are held by Cornell University. Hiroshi Sunaga has no conflicts to disclose.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Marshall RJ, Muir AW, Sleigh T, Savage DS. Research and development of aminosteroid neuromuscular blocking agents: past and future. Eur J Anesthesiol 1995; 11:5–10. 2. Savarese JJ, Lien CA, Belmont MR, Rubin L. The clinical and basic pharmacology of mivacurium: a short-acting nondepolarizing benzylisoquinoliniumdiester neuromuscular blocking drug. Acta Anaesth Scand 1995; 39:18–22. 3. White PF. Rapacuronium: why did it fail as a replacement for succinylcholine? Br J Anaesth 2002; 88:163–165. 4. Gyermek L. Development of ultra short-acting muscle relaxant agents: history, research strategies, and challenges. Med Res Rev 2005; 25:610–654. 5. Gyermek L, Lee C. The development of ultrashort acting neuromuscular relaxant tropane derivatives. J Crit Care 2009; 24:58–65. 6. Lien CA, Savard P, Belmont M, et al. Fumarates: unique nondepolarizing neuromuscular blocking agents that are antagonized by cysteine. J Crit Care 2009; 24:50–57. 7. Naguib M, Brull SJ. Update on neuromuscular pharmacology. Curr Opin Anaesthesiol 2009; 22:483–490. 8. Lien CA. Development and potential clinical impact of ultra-short-acting neuromuscular blocking agents. Br J Anaesth 2011; 107 (Suppl 1):i60–i71. 9. Samano V, Ray JA, Thompson JB, et al. Synthesis of ultra-short-acting neuromuscular blocker GW 0430: a remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinoliniumchlorofumarates. Org Lett 1999; 1:1993–1996. 10. Boros EE, Bigham EC, Boswell GE, et al. Bis- and mixed-tetrahydroisoquinoliniumchlorofumarates: new ultra-short-acting nondepolarizing neuromuscular blockers. J Med Chem 1999; 42:1114. 11. Kaldor I, Feldman PL, Mook RA Jr, et al. Stereocontrolled synthesis of cisdibenzoquinolizinechlorofumarates: curare-like agents of ultrashort duration. J Org Chem 2001; 66:3495–3501. 12. Boros EE, Samano V, Ray JA, et al. Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinoliniumhalofumarates and halosuccinates in rhesus monkeys. J Med Chem 2003; 46:2502–2515. 13. Savarese JJ, McGilvra JD, Sunaga H, et al. Rapid chemical antagonism of neuromuscular blockade by l-cysteine adduction to and inactivation of the olefinic (double-bonded) isoquinoliniumdiester compounds gantacurium(AV430A), CW002, and CW 011. Anesthesiology 2010; 113:58–73. 14. Savarese JJ, Belmont MR, Hashim MA, et al. Preclinical pharmacology of GW280430A(AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium. Anesthesiology 2004; 100:835–845. 15. Heerdt PM, Kang R, The A, et al. Cardiopulmonary effects of the novel neuromuscular blocking drug GW280430A (AV430) in dogs. Anesthesiology 2004; 100:846–851. 16. Sunaga H, Zhang Y, Savarese JJ, et al. Gantacurium and CW002 do not potentiate muscarinic receptor-mediated airway smooth muscle constriction in guinea pigs. Anesthesiology 2010; 112:892–899. 17. Belmont MR, Lien CA, Tjan J, et al. Clinical pharmacology of GW280430A in humans. Anesthesiology 2004; 100:768–773. 18. Heerdt PM, Malhotra JK, Pan BY, et al. Pharmacodynamics and cardiopulmonary side effects of CW002, a cysteine-reversible neuromuscular blocking drug in dogs. Anesthesiology 2010; 112:910–916. 19. Diaz LL, Zhang J, Heerdt PM. Comparative pharmacodynamics of pancur& onium, cisatracurium, and CW002 in rabbits. J Am Assoc Lab Anim Sci 2014; 53:283–289. This report describes the potency, duration, and cysteine reversal of CW002 in a common laboratory animal model. 20. Murrell MT, Malhotra JK, Sunaga H, et al. Potency and preliminary pharmacodynamics of the novel neuromuscular blocking drug CW002 in humans during sevoflurane/nitrous oxide anesthesia (ASA Abstracts 2013, LBB03).
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21. Owens JS, Heerdt PM, Malhotra JK, et al. Pharmacokinetics of CW002, a novel neuromuscular blocking agent in the initial cohorts of a phase 1 clinical trial (AAPS Annual Meeting, 2014). 22. Savarese JJ, Belmont MR, Sunaga H, et al. Crossover studies in monkeys show that a new ultra-short acting nondepolarizer, CW 1759-50, in contrast with gantacurium, elicits no histaminoid phenomena (ASA Abstracts 2013, A2201. 23. Sunaga H, McGilvra J, Belmont MR, et al. CW1759-50: A new ultra-short acting nondepolarizer: Spontaneous recovery versus antagonism by L-cysteine (ASA Abstracts 2013, A4034). 24. Savarese JJ, Yi Zhang Y, Heerdt PM, Emala CW. The ultra-short acting neuromuscular blocker CW 1759-50 has approximately 5 times the safety of rapacurium at M2 and M3 receptor (ASA Abstracts 2014, A4003). 25. Savarese JJ, Sunaga H, Belmont MR, et al. The ultra-short acting neuromuscular blocker CW 1759-50 has very high autonomic safety in the isofluraneanesthetized cat (ASA Abstracts 2014, A4000). 26. Adam JM, Bennett DJ, Bom A, et al. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships. J Med Chem 2002; 45:1806–1816. 27. Ledowski T. Sugammadex. What do we know and what do we still need to & know? A review of the recent (2013 to 2014) literature. Anaesth Intensive Care 2015; 43:14–22. This describes current thought regarding the benefits and potential pitfalls of sugammadex. 28. Abrishami A, Ho J, Wong J, et al. Cochrane corner: sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. AnesthAnalg 2010; 110:1239. 29. Schepens T, Cammu G. Neuromuscular blockade: what was, is and will be. Acta Anaesthesiol 2014; 65:151–159. 30. Farhan H, Moreno-Duarte I, McLean D, Eikermann M. Residual paralysis: does && it influence outcome after ambulatory surgery? Curr Anesthesiol Rep 2014; 4:290–302. This article reviews the use of neuromuscular blocking drugs in the ambulatory surgical population. The potential for complications related to residual postoperative weakness is described, and used as a platform to underscore the need for new reversal agents such as sugammadex and calabadion. 31. Hoffmann U, Grosse-Sundrup M, Eikermann-Haerter K, et al. Calabadion: a new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents. Anesthesiology 2013; 119:317–325. 32. Ma D, Zhang B, Hoffmann U, et al. Acyclic cucurbit[n]uril-type molecular containers bind neuromuscular blocking agents in vitro and reverse neuromuscular block in vivo. Angew Chem Int Ed Engl 2012; 51:11358–11362. 33. Macartney DH. Cucurbit[n]uril type hosts for the reversal of steroidal neuromuscular blocking agents. Future Med Chem 2013; 5:2075–2089. 34. Isaacs L. Stimuli responsive systems constructed using cucurbit[n]uril-type molecular containers. Acc Chem Res 2014; 47:2052–2062. 35. Wang Y, Li D, Wang H, et al. pH responsive supramolecular prodrug micelles based on cucurbit[8]uril for intracellular drug delivery. Chem Commun (Camb) 2014; 50:9390–9392. 36. Zlotkin SH, Bryan MH, Anderson GH. Cysteine supplementation to cysteinefree intravenous feeding regimens in newborn infants. Am J ClinNutr 1981; 34:914–923. 37. Zuin R, Palamidese A, Negrin R, et al. High-dose n-acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease. Clin Drug Investig 2005; 25:401–408. 38. Schaller G, Pleiner J, Mittermayer F, et al. Effects of N-acetylcysteine against systemic and renal hemodynamic effects of endotoxin in healthy humans. Crit Care Med 2007; 35:1869–1875. 39. Kortsalioudaki C, Taylor RM, Cheeseman P, et al. Safety and efficacy of Nacetylcysteine in children with nonacetaminophen-induced acute liver failure. Liver Transpl 2008; 14:25–30. 40. Karila L, Gorelick D, Weinstein A, et al. New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 2008; 11:425–438. 41. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 2008; 11:851–876. 42. Sunaga H, Malhotra JK, Yoon E, et al. Cysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: pharmacodynamics, acute cardiovascular effects, and preliminary toxicology. Anesthesiology 2010; 112:900–909. 43. Sharpe LG, Olney JW, Ohlendorf C, et al. Brain damage and associated behavioral deficits following the administration of l-cysteine to infant rats. Pharmacol Biochem Behav 1975; 3:291–298. 44. Sawamoto O, Hagiwara R, Kurisu K. L-cysteine-induced brain damage in adult rats. Exp Toxicol Pathol 2004; 56:45–52. 45. Janaky R, Varga V, Hermann A, et al. Mechanisms of l-cysteine neurotoxicity. Neurochem Res 2000; 25:1397–1405.
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