Dose–response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man

Abstract

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, 0.06, 0.08, or 0.10 mg/kg), and one group (n = 4) receiving 0.14 mg/kg. Blood pressure and heart rate were continuously recorded along with airway dynamic compliance. Neuromuscular blockade was assessed with mechanomyography at the adductor pollicis. Arterial blood was obtained before and after CW002 injection for analysis of plasma histamine concentration. Potency was estimated from a baseline sigmoid Emax model. Results ED50 was found to be 0.036 mg/kg (95% CI, 0.020 to 0.053 mg/kg) and ED95 0.077 mg/kg (95% CI, 0.044 to 0.114 mg/kg). At 0.14 mg/kg (1.8 × ED95), 80% twitch depression occurred in 94 ± 18 s with complete block in 200 ± 87 s. Clinical recovery (25% of maximum twitch) occurred in 34 ± 3.4 min, with a 5 to 95% recovery interval of 35.0 ± 2.7 min. The time to a train-of-four ratio greater than 0.9 ranged from 59 to 86 min. CW002 did not elicit histamine release or significant (greater than 10%) changes in blood pressure, heart rate, or dynamic airway compliance. Conclusions In healthy subjects receiving sevoflurane/nitrous oxide, CW002 at 1.8 × estimated ED95 produces a clinical duration less than 40 min, elicits no histamine release, and has minimal cardiopulmonary side effects.

Reversal of residual neuromuscular block: complications associated with perioperative management of muscle relaxation

“…11 In doses of 1.8 Â ED 95 , it has a mean onset of action of 200 s in humans. 73 Clinical duration of action is about 34 min, which is similar to atracurium and vecuronium. This early report of its use in healthy patients suggests that CW002 does not release histamine and has few autonomic effects in the normal dose range.…”

“…In an attempt to develop a NDNMBD with a rapid onset and a short duration of action that does not cause histamine release or other autonomic effects, Savarese and colleagues have reported the clinical pharmacology of CW002, a fumarate belonging to a family of tetrahydroisoquinolinium compounds. 73 This drug is degraded in the plasma by endogenous Lcysteine. 11 In doses of 1.8 Â ED 95 , it has a mean onset of action of 200 s in humans.…”

“…This early report of its use in healthy patients suggests that CW002 does not release histamine and has few autonomic effects in the normal dose range. 73 Profound block from CW002 can be reversed with exogenous cysteine (Table 1). CW002 is not yet available for clinical use.…”

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

“…CW002 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 CW002 is similar to that of gantacurium; the only difference is that CW002 is lacking a chlorine at the fumarate double bond and being symmetrical [ 16 , 17 ]. CW002 was designed to interact more slowly with endogenous l -cysteine than gantacurium and is degraded by l -cysteine adduction and alkaline hydrolysis (t1/2 = 11.4 min).…”

“…This degradation results in molecular fragments (NB 1043-10) which have 0.01–0.001 times the neuromuscular potency of CW002. l -Cysteine adduction is pH dependent [ 16 , 17 ]. Furthermore, CW002 can be rapidly reversed by l -cysteine which has been shown in different animal models.…”