Cysteine Reversal of the Novel Neuromuscular Blocking Drug CW002 in Dogs

Sunaga, Hiroshi; Malhotra, Jaideep; Yoon, Edward; Savarese, John J.; Heerdt, Paul M.

doi:10.1097/aln.0b013e3181d31f8c

Cited by 22 publications

(11 citation statements)

References 21 publications

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“…This study confirmed the findings shown in preclinical studies: CW002 in doses up to 0.14 mg/kg did not result in significant cardiopulmonary side effects [ 16 – 18 ]. Furthermore, there were no signs of histamine release [ 18 ].…”

Section: Recent Advancements Of Neuromuscular Blocking Drugssupporting

confidence: 91%

New Drug Developments for Neuromuscular Blockade and Reversal: Gantacurium, CW002, CW011, and Calabadion

Boer

Carlos

2018

Curr Anesthesiol Rep

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Purpose of ReviewThe purpose of this chapter is to provide a brief review of the literature on the recent developments in neuromuscular blockade and reversal agents.Recent FindingsNovel 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.SummaryRecent 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.

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Section: Recent Advancements Of Neuromuscular Blocking Drugssupporting

confidence: 91%

New Drug Developments for Neuromuscular Blockade and Reversal: Gantacurium, CW002, CW011, and Calabadion

Boer

Carlos

2018

Curr Anesthesiol Rep

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“…3) [61]. Cysteine 100 mg/kg given to four dogs anesthetized with isoflurane/nitrous oxide produced an acute decline in mean arterial blood pressure, followed by a more sustained increase [62]. This pattern was accompanied by minimal changes in heart rate and multiphasic shifts in systemic vascular resistance, stroke volume, left ventricular ejection fraction, and left ventricular inotropy (assessed as delta pressure/delta time normalized to left ventricular end-diastolic volume) [62].…”

Section: Animal Datamentioning

confidence: 99%

Update on neuromuscular pharmacology

Naguib

Brull²

2009

Current Opinion in Anaesthesiology

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In a multicenter phase-2 randomized controlled study in the European Union, the efficacy and safety of gantacurium were evaluated, but results have not yet been published. Sugammadex is currently available in the European Union, but the United States Food and Drug Administration has had concerns about its safety (hypersensitivity and allergic reactions) and has asked for additional safety data. It is hoped that the widespread use of sugammadex in the European Union will provide additional information.

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“…13 The prototype of this kind of amino acid is cysteine, which can be used to very rapidly terminate the neuromuscular blocking action of a new class of relaxants, the asymmetric mixed-onium chlorofumarates gantacurium (GW280430A, also known as AV430A) 14 and AV002 (CW002). 15 These compounds have undergone initial animal testing (gantacurium), or are scheduled to start testing in 2009 (AV002).…”

Section: Dovepressmentioning

confidence: 99%

“…51 Cysteine 100 mg/kg given to four dogs anesthetized with isoflurane/nitrous oxide produced a brief (2-3 min) decline in mean arterial blood pressure, followed by a sustained increase. 52 This pattern was accompanied by minimal changes in heart rate and systemic vascular resistance, stroke volume, left ventricular ejection fraction, and left ventricular inotropy (assessed as change in pressure/change in time normalized to left ventricular end-diastolic volume). The authors noted that the hemodynamic effects reported were consistent with both direct and reflex responses in combination with a centrally-mediated vasopressin release.…”

mentioning

confidence: 99%

“…The authors noted that the hemodynamic effects reported were consistent with both direct and reflex responses in combination with a centrally-mediated vasopressin release. 52 Doses ranging from 20 to 50 mg/kg of cysteine resulted in minimal changes in mean arterial blood pressure and heart rate. Only a 100 mg/kg dose of cysteine resulted in a 14.6% increase in mean arterial pressure and a 5.2% decrease in heart rate.…”

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confidence: 99%

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Selective reversal of muscle relaxation in general anesthesia: focus on sugammadex

Naguib¹

2009

DDDT

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Despite the significant improvements in the pharmacology of muscle relaxants in the past six decades, the search for the ideal muscle relaxant continues, mainly because of the incomplete efficacy and persistent side effects associated with their antagonism. Clinical concerns remain about the residual paralysis and hemodynamic side effects associated with the classic pharmacologic reversal agents, the acetylcholinesterase inhibitors. Although the development of the "ideal muscle relaxant" remains illusory, pharmacologic advancements hold promise for improved clinical care and patient safety. Recent clinical advances include the development of short-acting nondepolarizing muscle relaxant agents that have fast onset and a very rapid metabolism that allows reliable and complete recovery; and the development of selective, "designer" reversal agents that are specific for a single drug or class of drugs. This article reviews recent developments in the pharmacology of these selective reversal agents: plasma cholinesterases, cysteine, and sugammadex. Although each of the selective reversal agents is specific in its substrate, the clinical use of the combination of muscle relaxant with its specific reversal agent will allow much greater intraoperative titrating ability, decreased side effect profile, and may result in a decreased incidence of postoperative residual paralysis and improved patient safety.

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Cysteine Reversal of the Novel Neuromuscular Blocking Drug CW002 in Dogs

Abstract: The optimal L-cysteine dose for rapidly reversing the neuromuscular blockade produced by a large dose of CW002 in dogs is approximately 50 mg/kg, which has no concomitant hemodynamic effect. A dose of 200 mg/kg had no evident organ toxicity.

Cited by 22 publications

References 21 publications

New Drug Developments for Neuromuscular Blockade and Reversal: Gantacurium, CW002, CW011, and Calabadion

New Drug Developments for Neuromuscular Blockade and Reversal: Gantacurium, CW002, CW011, and Calabadion

Update on neuromuscular pharmacology

Selective reversal of muscle relaxation in general anesthesia: focus on sugammadex

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