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Paul M Heerdt, Hiroshi Sunaga, Joel S Owen, Matthew T Murrell, Jaideep K Malhotra, Deena Godfrey, Michelle Steinkamp, Peter Savard, John J Savarese, Cynthia A Lien
BACKGROUND: CW002 is a benzylisoquinolinium nondepolarizing neuromuscular-blocking drug found to be inactivated by cysteine in preclinical studies. The current study represents a dose escalation clinical trial designed to describe CW002 potency, duration, cardiopulmonary side effects, and histamine release. METHODS: Healthy subjects anesthetized with sevoflurane/nitrous oxide were divided into five groups (n = 6), each receiving a fixed CW002 dose (0.02, 0.04, 0...
October 6, 2016: Anesthesiology
Amit Prabhakar, Alan D Kaye, Melville Q Wyche, Orlando J Salinas, Kenneth Mancuso, Richard D Urman
Pharmacological advances in anesthesia in recent decades have resulted in safer practice and better outcomes. These advances include improvement in anesthesia drugs with regard to efficacy and safety profiles. Although neuromuscular blockers were first introduced over a half century ago, few new neuromuscular blockers and reversal agents have come to market and even fewer have remained as common clinically employed medications. In recent years, newer agents have been studied and are presented in this review...
July 2016: Journal of Anaesthesiology, Clinical Pharmacology
Hiroshi Sunaga, John J Savarese, Jeff D McGilvra, Paul M Heerdt, Matthew R Belmont, Scott G Van Ornum, Matthew T Murrell, Jaideep K Malhotra, Peter M Savard, Erin Jeannotte, Bryce J Petty, Erica Allen, Gilbert W Carnathan
BACKGROUND: CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by L-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous L-cysteine. Further, Institutional Animal Care and Use Committee-approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. METHODS: Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived...
July 26, 2016: Anesthesiology
Paul M Heerdt, Hiroshi Sunaga, John J Savarese
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...
August 2015: Current Opinion in Anaesthesiology
Leslie L Diaz, Jingwei Zhang, Paul M Heerdt
Pancuronium is a long-duration neuromuscular blocking drug (NMBD) that has been used in anesthetized rabbits at 0.1 mg/kg. However, there are limited data regarding the time course for recovery from this dose either spontaneously or with pharmacologic reversal. Here we defined the potency, onset, and recovery characteristics for the intermediate-duration NMBD cisatracurium and CW002 (a novel cysteine-inactivated molecule) in the rabbit, and test the hypothesis that these drugs may be alternatives to 0.1 mg/kg pancuronium for survival procedures...
May 2014: Journal of the American Association for Laboratory Animal Science: JAALAS
Paul M Heerdt, Jaideep K Malhotra, Brian Y Pan, Hiroshi Sunaga, John J Savarese
BACKGROUND: CW002 is a novel neuromuscular blocking drug with a duration dependent on the rate of cysteine adduction to the molecule. The current study characterized the pharmacodynamics and cardiopulmonary side effects of CW002 in dogs. METHODS: In eight beagles, the dose required to produce 95% neuromuscular blockade (ED95) for CW002 was first determined and cysteine reversibility was confirmed. Five to 7 days later, incrementally larger doses were injected starting with 6...
April 2010: Anesthesiology
Hiroshi Sunaga, Jaideep K Malhotra, Edward Yoon, John J Savarese, Paul M Heerdt
BACKGROUND: CW002 is a neuromuscular blocking drug that is inactivated by endogenous L-cysteine. This study determined the exogenous L-cysteine dose-response relationship for CW002 reversal along with acute cardiovascular effects and organ toxicity in dogs. METHODS: Six dogs were each studied four times during isoflurane-nitrous oxide anesthesia and recording of muscle twitch, arterial pressure, and heart rate. CW002 (0.08 mg/kg or 9 x ED95) was injected, and the time to spontaneous muscle recovery was determined...
April 2010: Anesthesiology
Hiroshi Sunaga, Yi Zhang, John J Savarese, Charles W Emala
BACKGROUND: Neuromuscular blocking agents are an integral component of general anesthesia. In addition to their intended pharmacologic target on skeletal muscle nicotinic receptors, undesirable airway effects (i.e., bronchoconstriction) can result from neuromuscular blocking agents' affinity for airway muscarinic receptors. We questioned whether two new members of a bisquaternary nondepolarizing muscle relaxant family, gantacurium and CW002, demonstrated detrimental effects of airway muscarinic receptors using an in vivo model in guinea pig airways...
April 2010: Anesthesiology
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