Developing a non-depolarizing neuromuscular blocking agent that, like succinylcholine, has a rapid onset and a short duration of effect remains a goal of ongoing research. While rocuronium fills a portion of this need, the large doses required for rapid intubation render it a much longer-acting neuromuscular blocking agent. Postoperative residual neuromuscular block NMB is an increasingly recognized complication of non-depolarizing neuromuscular blocking agents. This occurs because of dosing choices for neuromuscular blocking agents and anticholinesterases as well as insensitivity of typically used monitors of depth of NMB.
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The purpose of this chapter is to provide a brief review of the literature on the recent developments in neuromuscular blockade and reversal agents.
Novel drug development resulted in pharmacological advancements in neuromuscular management and led to a new series of compounds, chlorofumarates, such as gantacurium, CW, and CW 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.
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. The introduction of curare allowed adequate muscle relaxation at a lighter, and therefore better-tolerated, depth of general anesthesia.
One important area of research was the development of a short-acting non-depolarizing neuromuscular blocking drug with a fast onset of effect, short duration of action, which was independent of end-organ metabolism and allowed for rapid and complete reversal.
Actually, this research reflected a continuing search for a replacement for succinylcholine. For this reason, an ideal neuromuscular blocking drug was defined: the profile of an ideal neuromuscular blocking drug should meet the criteria developed by Savarese and Kitz and should distinguish among others three types of drugs: short, intermediate, and long-acting [ 2 ].
However, to date, a short-acting non-depolarizing neuromuscular blocking drug with a fast onset, comparable pharmacodynamically to succinylcholine, but without the well-known undesirable side effects, is still not available for clinical use. Therefore, reversal of neuromuscular block is essential when using these drugs. Novel drug development resulted in pharmacological advancements in neuromuscular management and led to a new series of compounds, chlorofumarates as new neuromuscular blocking drugs and calabadion and l -cysteine adduction for reversal of neuromuscular block [ 6 , 7 ].
This review will highlight the recent advancements in the field of neuromuscular blocking drugs and reversal of neuromuscular blockade. Gantacurium was the first compound of this new class of neuromuscular blocking drugs, the asymmetric mixed-onium chlorofumarates. Gantacurium is an asymmetric enantiomeric isoquinolinium diester of chlorofumaric acid [ 6 , 7 ].
Gantacurium, like cisatracurium, is a single isomer as atracurium and mivacurium are consisting of a mixture of isomers [ 8 ]. Gantacurium is an ultra-short acting non-depolarizing neuromuscular blocking drug with a rapid onset and a wide safety margin [ 8 — 10 ].
As cisatracurium and atracurium are inactivated by Hofmann elimination, gantacurium is metabolized by chemical degradation which involves cysteine adduction fast process and pH-sensitive hydrolysis slow process [ 8 , 9 ]. Cysteine adduction results in replacement of chlorine by cysteine whereafter a heterocyclic ring is formed which cannot longer interact with the postjunctional acetylcholine receptor.
Therefore, the metabolites of gantacurium showed no neuromuscular properties [ 8 , 9 ]. Moreover, there is no renal and hepatic involvement in the elimination of gantacurium [ 7 — 9 ]. Reversal of a gantacurium-induced neuromuscular block is possible with administration of cysteine [ 11 ].
This first drug in class showed promising results in animal and human studies which will be discussed. Preclinical studies in Rhesus monkeys, in which gantacurium was compared with mivacurium, showed that the potencies between gantacurium and mivacurium were identical [ 8 ]. The onset was significantly faster compared with mivacurium. Administration of 0. Further increasing of the dose of gantacurium up to 3. Doses higher than 6.
The spontaneous recovery from a neuromuscular block induced by gantacurium was shorter than that for a mivacurium-induced neuromuscular block. These results were confirmed in cats [ 8 , 10 , 12 ]. Interestingly, while gantacurium is shorter acting than succinylcholine in dogs, the results of studies in other animal species Rhesus monkeys and cats with gantacurium showed comparable neuromuscular properties.
This raises the question whether gantacurium might replace succinylcholine in the future [ 8 , 12 ]. This was confirmed in beagles. No pulmonary vasoconstriction or bronchoconstriction was observed in these animals. Based on the promising preclinical studies, gantacurium was investigated in humans. In human volunteers, the ED 95 of gantacurium was 0. However, at lower doses 2. The margin of safety for histamine release, therefore, appears improved over that of mivacurium.
However, there have been attempts to change the chemical structure of gantacurium in order to stabilize membranes of the molecule to alter histamine release, but to date, these attempts were not successful [ 14 ].
These results confirmed the promising characteristics of gantacurium in humans. The neuromuscular properties of gantacurium were comparable with the depolarizing neuromuscular blocking drug succinylcholine. Further research is needed to confirm this preliminary conclusion. However, despite the results in preclinical and clinical studies, gantacurium is not available in clinical practice.
Spontaneous recovery of a gantacurium-induced neuromuscular block is rapid. However, as gantacurium is a non-depolarizing neuromuscular blocking drug, gantacurium can be reversed with cholinesterase inhibitors [ 12 ]. Spontaneous reversal of the same neuromuscular block occurred in 5.
Gantacurium is, due to its unique metabolism, rapidly inactivated by cysteine adduction and alkaline hydrolysis. One of these routes of inactivation is adduction of the amino acid cysteine to the molecule of gantacurium. Administration of intravenous l -cysteine results in replacement of chlorine by cysteine whereafter a heterocyclic ring is formed which cannot longer interact with the postjunctional acetylcholine receptor and the neuromuscular block can be reversed.
Therefore, gantacurium can also be reversed by administration of l -cysteine. No signs of residual neuromuscular blockade or recurarization were observed [ 12 ]. To date, no clinical studies were conducted in which l -cysteine reversal was investigated.
CW is a new benzoquinolinium fumarate diester non-depolarizing neuromuscular blocking drug of an intermediate duration of action which belongs to the family of tetrahydroisoquinolinium drugs [ 16 , 17 ]. The molecular structure of CW is similar to that of gantacurium; the only difference is that CW is lacking a chlorine at the fumarate double bond and being symmetrical [ 16 , 17 ].
This degradation results in molecular fragments NB which have 0. Furthermore, CW can be rapidly reversed by l -cysteine which has been shown in different animal models. Preclinical and human studies showed that a single bolus of CW resulted in minimal cardiopulmonary side effects and no histamine release [ 16 , 17 ].
CW has been studied in a variety of animal models and in human volunteers and has shown initial promising results. This results in a ratio of duration of action compared with cisatracurium [ 16 , 17 ]. The onset times of CW were found to be shorter than that of cisatracurium, but longer than that of rocuronium.
CW is inactivated by cysteine adduction and hydrolysis. In animal studies, it was shown that the ED 95 was 0. Furthermore, CW showed low potential for bronchoconstrictive activity or histamine release [ 16 , 17 ]. In contrast, animal studies with gantacurium showed histaminoid responses after doses up to Based on these preclinical results, CW was further investigated in humans. The first human study investigated the dose-response and cardiopulmonary side effects of C [ 17 ].
The results of this study showed that CW is less potent in humans compared with the results seen in animal studies. The ED 95 in humans is 0. In a dose of 1. The clinical duration was almost This study confirmed the findings shown in preclinical studies: CW in doses up to 0.
Furthermore, there were no signs of histamine release [ 18 ]. As this is the first and only study in which CW was investigated in humans, more clinical investigations must be conducted to determine the role of CW in modern neuromuscular management.
To date, CW is not available for the use in clinical practice. CW is a non-depolarizing neuromuscular blocking drug, and therefore neuromuscular block induced by CW can be reversed with cholinesterase inhibitors [ 16 — 18 ]. CW, like gantacurium, is inactivated rapidly by adduction of cysteine and by hydrolysis. It is to be expected that in contrast with neostigmine in which only moderate-to-light level as of blockade can be antagonized , reversal from every level of CWinduced neuromuscular block can be facilitated.
However, this process is slower than that observed with gantacurium as duration of action of CW is intermediate. In vitro studies showed that the rate of l -cysteine adduction was inversely related to the duration of neuromuscular block in monkeys.
Comparative reversal of a CWinduced neuromuscular block with cholinesterase inhibitors was significant slower. However, no study on the reversal with l -cysteine in humans is available, and therefore the clinical benefits of l -cysteine reversal of a CWinduced neuromuscular block in humans have yet to be confirmed.
CW an asymmetrical maleate is, as CW a symmetrical fumarate , a non-halogenated olefinic diester analogue of gantacurium [ 12 ]. An in vitro study showed that this new drug had predictable slower l -cysteine adduction, and therefore a longer lasting neuromuscular blocking effect than gantacurium is to be expected [ 12 ].
CW showed a high potency and the calculated ED 95 was 0. Based on this study, it was concluded that the rate of l -cysteine adduction was inversely related to the duration of action of a CWinduced neuromuscular block in monkeys [ 12 ]. To date, no studies in humans are available and therefore the abovementioned results have to be investigated and confirmed in humans. As CW is inactivated by cysteine adduction, CWinduced neuromuscular block can be reversed by administration of exogenous l -cysteine.
Nowadays, pharmacological reversal of neuromuscular block can be achieved by either administering cholinesterase inhibitors or administering sugammadex. The latter encapsulates the rocuronium or vecuronium molecule and results in a rapid and effective reversal of a rocuronium- or vecuronium-induced neuromuscular block by lowering the concentration of the neuromuscular drug molecule at the neuromuscular junction. However, sugammadex is not able to reverse neuromuscular block induced by benzylisoquinolinium neuromuscular blocking drugs.
In vitro and in vivo studies with calabadion 1 caused a fast and dose-dependent reversal of a cisatracurium- and rocuronium-induced neuromuscular block [ 20 ]. There were no signs of recurarization and there were no effects on heart rate, blood pressure, or pH. Calabadion 1 is also able to form an inclusion complex with local anesthetics in aqueous solution in vitro, which may play a role in the treatment of local anesthetic toxicity.
However, further research is necessary to confirm this in vivo. In vitro and in vivo studies with calabadion 2 showed a higher binding affinity to rocuronium Ka 3. Calabadion 1 is the first-generation calabadion and is able to reverse neuromuscular block with the binding affinity of sugammadex to rocuronium Ka 3.
Study record managers: refer to the Data Element Definitions if submitting registration or results information. This is a multicenter, randomized, controlled, observer-blinded, dose-response study to evaluate the efficacy in tracheal intubation and safety of gantacurium chloride for injection in healthy adult patients undergoing surgery with general anesthesia. Gantacurium chloride for injection previously referred to as AVA is a new, investigational non-depolarizing ultra-short acting neuromuscular blocking agent NMB. Preliminary results in animals and healthy human subjects Phase 1 studies in adult volunteers suggest that gantacurium chloride for injection may provide a useful adjunct to general anesthesia by permitting rapid intubation. This Phase 2 study will provide more definitive information on the ultra-short acting profile of the compound by determining the quality of intubation in patients, at 60 seconds, as assessed by a blinded intubator. In addition, the safety of the compound will be assessed. In this study, the efficacy and safety of gantacurium chloride for injection will also be compared to a reference drug, succinylcholine, and to placebo.
The purpose of this chapter is to provide a brief review of the literature on the recent developments in neuromuscular blockade and reversal agents. Novel drug development resulted in pharmacological advancements in neuromuscular management and led to a new series of compounds, chlorofumarates, such as gantacurium, CW, and CW 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. 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.