Pharmacodynamics and Cardiopulmonary Side Effects of CW002, a Cysteine-reversible Neuromuscular Blocking Drug in Dogs

Heerdt, Paul M.; Malhotra, Jaideep; Pan, Brian Y.; Sunaga, Hiroshi; Savarese, John J.

doi:10.1097/aln.0b013e3181d31f71

Cited by 18 publications

(19 citation statements)

References 9 publications

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“…The unique pharmacology of gantacurium has led to the development of related compounds with an intermediate duration of action that can be rapidly reversed by intravenous injection of L-cysteine, even in the absence of any spontaneous muscle recovery. 4 # One of these compounds is CW002, a nonhalogenated, symmetrical benzylisoquinolinium fumarate diester, which exhibits an intermediate duration and reversal by L-cysteine in rhesus monkeys and dogs. 5,6 To date, the optimal intravenous L-cysteine dose for reversal of CW002 as well as any acute cardiovascular effects and systemic organ toxicity associated with the relevant dose range remain unclear.…”

mentioning

confidence: 99%

Cysteine Reversal of the Novel Neuromuscular Blocking Drug CW002 in Dogs

Sunaga¹,

Malhotra²,

Yoon

et al. 2010

Anesthesiology

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confidence: 99%

Cysteine Reversal of the Novel Neuromuscular Blocking Drug CW002 in Dogs

Sunaga¹,

Malhotra²,

Yoon

et al. 2010

Anesthesiology

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“…In dogs, sequential increasing dosing of CW002 to supratherapeutic levels produced a small but significant reduction of mean arterial pressure (MAP) [67]. In this model, dose-related reductions were also evident in heart rate and cardiac output starting at 509 ED 95 and mean pulmonary arterial pressure at 1009 ED 95 .…”

Section: Adverse Effectsmentioning

confidence: 78%

Development of New Neuromuscular Blocking Agents

Sunaga

Lien

2013

Curr Anesthesiol Rep

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Increased understanding of structure-activity relationships has allowed the development of neuromuscular blocking compounds and reversal agents that are unique and offer pharmacokinetic and dynamic improvements over their predecessors. Compounds have been developed that have a short duration of effect, a rapid clearance and a decrease in adverse effects. The fumarates comprise one of the series of compounds that have resulted from this research. These compounds are inactivated through a mechanism that is completely new for neuromuscular blocking agents-that of cysteine adduction. The work has also led to the development of alternative ways to enhance recovery of neuromuscular function. Sugammadex encapsulates steroidal neuromuscular blocking compounds making them unable to interact with the acetylcholine receptor and reversing their effect within minutes. Recovery from gantacurium-or CW002-induced neuromuscular block can be shortened by administration of L-cysteine. These new neuromuscular blocking and reversal agents allow for maintenance of an adequate depth of neuromuscular block intraoperatively and almost immediate recovery of neuromuscular function, a sensible goal as the risks of residual neuromuscular block are increasingly appreciated.

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“…Based on this, CW 002 should have no cardiovascular effects in humans. In dogs, administration of 25 times the ED 95 of CW 002 causes a significant decrease in mean arterial pressure, 79 and administration of larger doses causes greater decreases. Heart rate, systemic vascular resistance, and cardiac output begin to decrease at doses of 50 times the ED 95 and pulmonary arterial pressure at doses of 100 times the ED 95 .…”

Section: Cw 002mentioning

confidence: 96%

Development and potential clinical impact of ultra-short acting neuromuscular blocking agents

Lien

2011

British Journal of Anaesthesia

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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. While antagonism of NMB is necessary with partial recovery, it is unnecessary with more complete recovery. Even when monitoring with an accelerograph, reversal of NMB is complicated. In addition to the pharmacodynamics of the individual neuromuscular blocking agents, factors such as timing of anticholinesterase administration, dose of anticholinesterase, concomitant medications, electrolyte abnormalities, and hepatic or renal disease can influence the degree of reversal. Sugammadex works differently than anticholinesterases and, when administered in appropriate doses, can reverse even profound block induced with vecuronium or rocuronium. Two new fumarate neuromuscular blocking agents have a rapid onset of effect and can be reversed at any time by administration of cysteine, which could significantly reduce the risk of postoperative residual NMB.

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Pharmacodynamics and Cardiopulmonary Side Effects of CW002, a Cysteine-reversible Neuromuscular Blocking Drug in Dogs

Abstract: CW002 is a potent neuromuscular blocking drug that at doses up to 100 x ED95 produces modest hemodynamic effects that are not associated with bronchoconstriction or consistent histamine release.

Cited by 18 publications

References 9 publications

Cysteine Reversal of the Novel Neuromuscular Blocking Drug CW002 in Dogs

Cysteine Reversal of the Novel Neuromuscular Blocking Drug CW002 in Dogs

Development of New Neuromuscular Blocking Agents

Development and potential clinical impact of ultra-short acting neuromuscular blocking agents

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