Purpose of Review The purpose of this chapter is to provide a brief review of the literature on the recent developments in neuromuscular blockade and reversal agents. Recent Findings Novel drug development resulted in pharmacological advancements in neuromuscular management and led to a new series of compounds, chlorofumarates, such as gantacurium, CW002, and CW011. These drugs have a fast onset and rapid to intermediate duration of action and can be rapidly reversed by L-cysteine adduction without side effects that are commonly observed with anticholinesterase reversal drugs. Another new advancement is the development of a new class of reversal drugs, the calabadions. These drugs are able to reverse both steroidal and non-steroidal non-depolarizing neuromuscular blocking drugs rapidly. Summary Recent advancements in neuromuscular blocking agents and reversal drugs have shown promise in improving safety of management of neuromuscular blockade. Preclinical and clinical studies are discussed. However, to date these new drugs are not yet available for clinical use. . . . Keywords Gantacurium CW002 CW011 Calabadion Introduction a continuing search for a replacement for succinylcholine. For this reason, an ideal neuromuscular blocking drug was de- Over 75 years ago, Harold Griffith and Enid Johnson pub- fined: the profile of an ideal neuromuscular blocking drug lished their famous paper on the use of curare in general an- should meet the criteria developed by Savarese and Kitz and esthesia . The introduction of curare allowed adequate mus- should distinguish among others three types of drugs: short, cle relaxation at a lighter, and therefore better-tolerated, depth intermediate, and long-acting . However, to date, a of general anesthesia. During these last 75 years, several new short-acting non-depolarizing neuromuscular blocking drug compounds were developed to maintain neuromuscular block. with a fast onset, comparable pharmacodynamically to succi- One important area of research was the development of a nylcholine, but without the well-known undesirable side ef- short-acting non-depolarizing neuromuscular blocking drug fects, is still not available for clinical use. Furthermore, in with a fast onset of effect, short duration of action, which 1954, Beecher and Todd reported a study of the mortality was independent of end-organ metabolism and allowed for associated with anesthesia and surgery, in which they found rapid and complete reversal. Actually, this research reflected that mortality rates were six times higher when neuromuscular blocking drugs were used and that 63% of the deaths were caused by respiratory failure . Since then, many publica- This article is part of the Topical Collection on Neuromuscular Blockade tions have reported the risks of using neuromuscular blocking drug and the concomitant high incidence of residual neuro- * Hans Donald de Boer muscular block [4, 5�� ]. Therefore, reversal of neuromuscular firstname.lastname@example.org block is essential when using these drugs. Novel drug development resulted in pharmacological ad- Department of Anesthesiology and Pain Medicine, Martini General vancements in neuromuscular management and led to a new Hospital Groningen, PO Box 30033, 9700 RM Groningen, the series of compounds, chlorofumarates as new neuromuscular Netherlands blocking drugs and calabadion and L-cysteine adduction for Department of Anesthesiology, Child Institute, Hospital das Clinicas, reversal of neuromuscular block [6, 7]. Sao Paulo University Medical School, Sao Paulo, Brazil 120 Curr Anesthesiol Rep (2018) 8:119–124 This review will highlight the recent advancements in the Interestingly, while gantacurium is shorter acting than suc- field of neuromuscular blocking drugs and reversal of neuro- cinylcholine in dogs, the results of studies in other animal muscular blockade. species (Rhesus monkeys and cats) with gantacurium showed comparable neuromuscular properties. This raises the ques- tion whether gantacurium might replace succinylcholine in Recent Advancements of Neuromuscular the future [8, 12]. Blocking Drugs In preclinical studies, gantacurium in a dose of 25–50× ED showed a 10–25% decrease in arterial pressure and minimal Gantacurium histamine release [8, 10, 11]. This was confirmed in beagles. No pulmonary vasoconstriction or bronchoconstriction was ob- Gantacurium was the first compound of this new class of neu- served in these animals. Based on the promising preclinical romuscular blocking drugs, the asymmetric mixed-onium studies, gantacurium was investigated in humans. chlorofumarates. Gantacurium is an asymmetric enantiomeric isoquinolinium diester of chlorofumaric acid [6, 7]. Human Studies Gantacurium, like cisatracurium, is a single isomer as atracurium and mivacurium are consisting of a mixture of iso- In human volunteers, the ED of gantacurium was 0.19 mg/kg mers . Gantacurium is an ultra-short acting non-depolarizing . The onset of 1× ED gantacurium was less than 3 min neuromuscular blocking drug with a rapid onset and a wide and could be shortened to approximately 1.5 min by increas- safety margin [8–10]. As cisatracurium and atracurium are ing the dose to 4× ED . At these doses, the duration of action inactivated by Hofmann elimination, gantacurium is metabo- of gantacurium (recovery to train-of-four of ≥ 0.90) was ap- lized by chemical degradation which involves cysteine adduc- proximately 15 min. In this study, transient cardiovascular tion (fast process) and pH-sensitive hydrolysis (slow process) side effects were observed at doses of 3× ED or higher. [8, 9]. Cysteine adduction results in replacement of chlorine by Furthermore, humans showed significant histamine release cysteine whereafter a heterocyclic ring is formed which cannot when gantacurium was administered in doses of 4× ED [9, longer interact with the postjunctional acetylcholine receptor. 13, 14]. However, at lower doses (2.5× ED ), there was no Therefore, the metabolites of gantacurium showed no neuro- evidence of histamine release [9, 13, 14]. The margin of safety muscular properties [8, 9]. Moreover, there is no renal and for histamine release, therefore, appears improved over that of hepatic involvement in the elimination of gantacurium [7–9]. mivacurium. However, there have been attempts to change the Reversal of a gantacurium-induced neuromuscular block is pos- chemical structure of gantacurium in order to stabilize mem- sible with administration of cysteine . This first drug in class branes of the molecule to alter histamine release, but to date, showed promising results in animal and human studies which these attempts were not successful . will be discussed. These results confirmed the promising characteristics of gantacurium in humans. The neuromuscular properties of Preclinical Studies gantacurium were comparable with the depolarizing neuromus- cular blocking drug succinylcholine. Gantacurium in doses of Preclinical studies in Rhesus monkeys, in which gantacurium 2–3× ED resulted in a 100% neuromuscular block at the was compared with mivacurium, showed that the potencies laryngeal adductors and larynx in 1 min, whereas succinylcho- between gantacurium and mivacurium were identical . line reached its maximal effect in 0.8 min [9, 13]. The sponta- The 3× ED of gantacurium and mivacurium was in both neous recovery of a neuromuscular block induced by drugs 0.16 mg/kg. The onset was significantly faster com- gantacurium 2× ED was almost identical compared with the pared with mivacurium. Administration of 0.18 mg/kg spontaneous recovery of a succinylcholine-induced neuromus- gantacurium resulted in a spontaneous recovery of a cular block . Therefore, based on these results, gantacurium train-of-four ration ≥ 0.9 within 10 min. The duration at doses seems to have nearly identical neuromuscular properties of suc- of 3× ED of either gantacurium or mivacurium to 95% cinylcholine without the unwanted side effects of this twitch recovery was 8.5 ± 0.5 vs 22 ± 2.6 min respectively. depolarizing neuromuscular blocking drug [9, 15]. Further Further increasing of the dose of gantacurium (up to research is needed to confirm this preliminary conclusion. 3.2 mg/kg) showed no changes in recovery intervals . However, despite the results in preclinical and clinical studies, Doses higher than 6.4 mg/kg resulted in a longer duration gantacurium is not available in clinical practice. (1.5–3.0 min), but no cumulative effects were observed. The spontaneous recovery from a neuromuscular block induced by Reversal of Gantacurium-Induced Neuromuscular Blockade gantacurium was shorter than that for a mivacurium-induced neuromuscular block. These results were confirmed in cats [8, Spontaneous recovery of a gantacurium-induced neuromuscu- 10, 12]. lar block is rapid. However, as gantacurium is a �� Curr Anesthesiol Rep (2018) 8:119–124 121 non-depolarizing neuromuscular blocking drug, gantacurium be rapidly reversed by L-cysteine which has been shown in can be reversed with cholinesterase inhibitors . As the different animal models. Preclinical and human studies showed spontaneous recovery of gantacurium is rapid, the most suit- that a single bolus of CW002 resulted in minimal cardiopul- able drug for reversal is edrophonium as the peak effect of this monary side effects and no histamine release [16, 17]. reversal drug is less than 2 min. In humans, edrophonium was CW002 has been studied in a variety of animal models and able to decrease the reversal time of a gantacurium-induced in human volunteers and has shown initial promising results. neuromuscular block at 10% recovery of T1 to a train-of-four ratio ≥ 0.90 to 3.8 min. Spontaneous reversal of the same Preclinical Studies neuromuscular block occurred in 5.7 min. Neostigmine as result of its peak effect at 7–11 min is not suitable for reversal Preclinical studies with CW002 demonstrated 100% neuromus- of a gantacurium-induced neuromuscular block . cular blockade within 1 min and a duration of action of 27 ± Gantacurium is, due to its unique metabolism, rapidly 7 min in Rhesus monkeys (3.75× ED )and47 ±9minindogs. inactivated by cysteine adduction and alkaline hydrolysis. This results in a ratio of 2:3 duration of action compared with One of these routes of inactivation is adduction of the amino cisatracurium [16, 17]. The onset times of CW002 were found acid cysteine to the molecule of gantacurium. Cysteine exists to be shorter than that of cisatracurium, but longer than that of as L-and D-enantiomers and the L-enantiomer is suitable as a rocuronium. CW002 is inactivated by cysteine adduction and reversal drug for the new class of neuromuscular blocking hydrolysis. The metabolite of CW002 (NB 1043-10) was 70 drugs: the asymmetric mixed-onium chlorofumarates times less potent than CW002. In animal studies, it was shown [12–14, 15�� ]. Administration of intravenous L-cysteine re- that the ED was 0.01–0.04 mg/kg. Spontaneous recovery to a sults in replacement of chlorine by cysteine whereafter a het- train-of-four ratio ≥ 95% occurred in about 30 min, and there- erocyclic ring is formed which cannot longer interact with the foreCW002showedanintermediatedurationofaction. The postjunctional acetylcholine receptor and the neuromuscular potency of CW002 in Rhesus monkeys differs from block can be reversed. L-Cysteine (-hydrochloric) is acidic and rocuronium as the latter showed 40% of the potency of commonly administered in humans as an essential component CW002 [16, 17]. The safety of CW002 was investigated in of parental nutrition. L-Cysteine given in as a bolus dose of animal models in large doses up to 10× ED and showed no 10–50 mg/kg for reversal of neuromuscular block is not significant hemodynamic changes. Only very high doses of known to have any toxicity [12–14, 15��]. Therefore, CW002 (27 and 54× ED )resultedina 20%decreaseinmean gantacurium can also be reversed by administration of arterial pressure and a 20% increase in heart rate. Furthermore, L-cysteine. In preclinical studies, L-cysteine administration af- CW002 showed low potential for bronchoconstrictive activity ter 8× ED of gantacurium resulted in a decrease in recovery or histamine release [16, 17]. In Rhesus monkeys, flushing and times (to a train-of-four ratio ≥ 0.90) by 2 min. When histamine release were observed at doses up to 40 to 60× ED . L-cysteine was administered just 1 min after 8× ED95 of In contrast, animal studies with gantacurium showed gantacurium, the recovery to a train-of-four ratio ≥ 0.90 was histaminoid responses after doses up to 12.5 to 25× ED ,and shortened by 6 min . No signs of residual neuromuscular histaminoid responses in humans for mivacurium and blockade or recurarization were observed . To date, no gantacurium were seen after doses of 2.5× ED and 3 to 4× clinical studies were conducted in which L-cysteine reversal ED respectively [16, 17]. Basedonthese preclinicalresults, was investigated. CW002 was further investigated in humans. CW002 Human Studies CW002 is a new benzoquinolinium fumarate diester The first human study investigated the dose-response and car- non-depolarizing neuromuscular blocking drug of an interme- diopulmonary side effects of C002 . The results of this diate duration of action which belongs to the family of study showed that CW002 is less potent in humans compared tetrahydroisoquinolinium drugs [16, 17]. The molecular struc- with the results seen in animal studies. The ED in humans is ture of CW002 is similar to that of gantacurium; the only dif- 0.077 mg/kg. In a dose of 1.8× ED (0.14 mg/kg) of CW002, ference is that CW002 is lacking a chlorine at the fumarate the onset time for neuromuscular block was approximately double bond and being symmetrical [16, 17]. CW002 was de- 90 s. The clinical duration was almost 33.8 min (range 28.8– signed to interact more slowly with endogenous L-cysteine than 36.1 min), time from 25 to 75% recovery of T1 (interval 25– gantacurium and is degraded by L-cysteine adduction and alka- 75%) 14 min. The spontaneous recovery to a train-of-four ≥ line hydrolysis (t1/2 = 11.4 min). This degradation results in 0.90 was 73 min . molecular fragments (NB 1043-10) which have 0.01–0.001 This study confirmed the findings shown in preclinical times the neuromuscular potency of CW002. L-Cysteine ad- studies: CW002 in doses up to 0.14 mg/kg did not result in duction is pH dependent [16, 17]. Furthermore, CW002 can significant cardiopulmonary side effects [16–18]. 122 Curr Anesthesiol Rep (2018) 8:119–124 Furthermore, there were no signs of histamine release . As Reversal of CW011-Induced Neuromuscular Blockade this is the first and only study in which CW002 was investi- gated in humans, more clinical investigations must be con- As CW011 is inactivated by cysteine adduction, ducted to determine the role of CW002 in modern neuromus- CW011-induced neuromuscular block can be reversed by ad- cular management. To date, CW002 is not available for the ministration of exogenous L-cysteine. L-Cysteine (50 mg/kg) use in clinical practice. administration resulted in a significant acceleration of the re- covery of a neuromuscular block induced by 4–64× ED Reversal of CW002-Induced Neuromuscular Blockade CW011 and showed a reduction of the total duration and the 5–95% recovery interval . L-Cysteine reversal showed full CW002 is a non-depolarizing neuromuscular blocking drug, reversal from a neuromuscular block induced by CW011 5× and therefore neuromuscular block induced by CW002 can be ED within 2–3min. L-Cysteine reversal was superior reversed with cholinesterase inhibitors [16–18]. Doses of neo- compared with cholinesterase inhibitors in terms of speed and stigmine 50 μg/kg given at spontaneous recovery of T1 of 2% effectiveness of reversal of a CW011-induced neuromuscular shortened the duration of a CW002-induced neuromuscular block . block minimally (from 25 to 22.5 min). Furthermore, CW002 reversal with neostigmine was significant faster than cisatracurium reversal by neostigmine (P <0.05) [16–18]. Recent Advancements in Reversal CW002, like gantacurium, is inactivated rapidly by adduc- of Neuromuscular Block tion of cysteine and by hydrolysis. It is to be expected that in contrast with neostigmine (in which only moderate-to-light level Calabadion as of blockade can be antagonized), reversal from every level of CW002-induced neuromuscular block can be facilitated. Nowadays, pharmacological reversal of neuromuscular block However, this process is slower than that observed with can be achieved by either administering cholinesterase inhibitors gantacurium as duration of action of CW002 is intermediate. or administering sugammadex. The latter encapsulates the In vitro studies showed that the rate of L-cysteine adduction rocuronium or vecuronium molecule and results in a rapid and was inversely related to the duration of neuromuscular block effective reversal of a rocuronium- or vecuronium-induced neu- in monkeys. Administration of L-cysteine 50 mg/kg resulted in romuscular block by lowering the concentration of the neuro- a reversal of a CW002-induced neuromuscular block within 2– muscular drug molecule at the neuromuscular junction. 3 min when administered 60 s after 4–5× ED [16–18]. However, sugammadex is not able to reverse neuromuscular Comparative reversal of a CW002-induced neuromuscular block induced by benzylisoquinolinium neuromuscular block with cholinesterase inhibitors was significant slower. blocking drugs. In vitro and in vivo studies with calabadion 1 However, no study on the reversal with L-cysteine in humans caused a fast and dose-dependent reversal of a cisatracurium- is available, and therefore the clinical benefits of L-cysteine re- and rocuronium-induced neuromuscular block . Calabadion versal of a CW002-induced neuromuscular block in humans 1, used in rats, in a dose of 90 mg/kg was able to reverse a have yet to be confirmed. rocuronium- and cisatracurium-induced neuromuscular block to recovery to a train-of-four ratio > 0.90 within 1–2min[19, CW011 20, 21� , 22]. There were no signs of recurarization and there were no effects on heart rate, blood pressure, or pH. CW011 (an asymmetrical maleate) is, as CW002 (a symmetri- Furthermore, calabadion 1 was fast eliminated by the kidney cal fumarate), a non-halogenated olefinic diester analogue of [19, 20, 21� , 22]. Calabadion 1 is also able to form an inclusion gantacurium . An in vitro study showed that this new drug complex with local anesthetics in aqueous solution in vitro, had predictable slower L-cysteine adduction, and therefore a which may play a role in the treatment of local anesthetic toxic- longer lasting neuromuscular blocking effect than gantacurium ity. However, further research is necessary to confirm this is to be expected . In an animal study, the duration of neu- in vivo. romuscular block at 4–5× ED was approximately 20.8 min, half of cisatracurium duration and three times longer than that Calabadion 2 of gantacurium. CW011 showed a high potency and the calcu- lated ED was 0.025 mg/kg. Based on this study, it was con- Calabadion 2 is the second-generation acyclic member of the cluded that the rate of L-cysteine adduction was inversely relat- calabadion family and chemically slightly different from ed to the duration of action of a CW011-induced neuromuscular calabadion 1 [20, 21� , 22]. In vitro and in vivo studies with block in monkeys . To date, no studies in humans are avail- calabadion 2 showed a higher binding affinity to rocuronium 9 −1 able and therefore the abovementioned results have to be inves- (Ka 3.4 × 10 M ) compared with blocking drugs [15�� ]. tigated and confirmed in humans. Calabadion is a recent developed drug which is able to Curr Anesthesiol Rep (2018) 8:119–124 123 Human and Animal Rights and Informed Consent This article does not encapsulate both steroidal and benzylisoquinolinium neuro- contain any studies with human or animal subjects performed by any of muscular blocking drugs [15 , 19, 20, 21� , 22]. Calabadion the authors. complexes are enhancing solubility, binding affinity toward Open Access This article is distributed under the terms of the Creative cations as a result of electrostatic interactions, and lowering Commons Attribution 4.0 International License (http://creativecommons. the concentration of neuromuscular blocking drugs that are org/licenses/by/4.0/), which permits unrestricted use, distribution, and molecular containers and acyclic members of the cucurbituril reproduction in any medium, provided you give appropriate credit to family [19, 20, 21� , 22]. These molecules are flexible and can the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. expand their cavity thereby able to encapsulate larger mole- cules like benzylisoquinolinium molecules [15 , 19, 20, 21� , 22]. Calabadions can form host-guest including rocuronium, vecuronium, and cisatracurium [15�� , 19, 20, 21� , 22]. References Calabadion 1 Papers of particular interest, published recently, have been highlighted as: Calabadion 1 is the first-generation calabadion and is able to � Of importance reverse neuromuscular block with the binding affinity of �� Of major importance 7 −1 sugammadex to rocuronium (Ka 3.8 × 10 M ). Therefore, 1. Griffith HR, Johnson GE. The use of curare in general anesthesia. calabadion 2 showed a 89-fold stronger affinity toward Anesthesiology. 1942;3:418–20. rocuronium than sugammadex [20, 21� , 22]. In vivo experi- 2. Savarese JJ, Kitz RJ. Does clinical anesthesia need new neuromus- ments with calabadion 2 showed a faster recovery of neuro- cular blocking agents? Anesthesiology. 1975;42(3):236–9. muscular blockade than reversal with calabadion 1 and more 3. Beecher HK, Todd DP. A study of the deaths associated with anes- important with lower doses. 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Sunaga H, Zhang Y, Savarese JJ, Emala CW. Gantacurium and CW002 do not potentiate muscarinic receptor-mediated airway smooth muscle constriction in guinea pigs. Anesthesiology. Compliance with Ethical Standards 2010;112(4):892–9. 12. Savarese JJ, McGilvra JD, Sunaga H, Belmont MR, Van Ornum Conflict of Interest Hans Donald de Boer and Ricardo Vieira Carlos SG, Savard PM, et al. Rapid chemical antagonism of neuromuscu- declare that they have no conflict of interest. lar blockade by L-cysteine adduction to and inactivation of the �� �� 124 Curr Anesthesiol Rep (2018) 8:119–124 olefinic (double-bonded) isoquinolinium diester compounds 18. Sunaga H, Malhotra JK, Yoon E, Savarese JJ, Heerdt PM. Cysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: gantacurium (AV430A), CW 002, and CW 011. Anesthesiology. 2010;113(1):58–73. pharmacodynamics, acute cardiovascular effects, and preliminary 13. Lien CA, Savard P, Belmont M, Sunaga H, Savarese JJ. Fumarates: toxicology. 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Current Anesthesiology Reports – Springer Journals
Published: Mar 22, 2018
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