Studies on a new rapid onset and short-acting neuromuscular blocking agent, TAAC3, in anaesthetized cats

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Structure–activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by l-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program. Methods Adduction of CW 1759-50 with l-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee–approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by l-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared. Results The half-time of adduction of l-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of l-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium. Conclusions CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by l-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.

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CLINICAL NEUROMUSCULAR PHARMACOLOGY OF BW785U, AN ULTRA-SHORT–ACTING NONDEPOLARIZING ESTER NEUROMUSCULAR BLOCKING AGENT

Anesthesiology ◽

10.1097/00000542-198009001-00274 ◽

1980 ◽

Vol 53 (3 Suppl) ◽

pp. S274-S274 ◽

Cited By ~ 2

Author(s):

J. J. Savarese ◽

H. H. Ali ◽

S. J. Basta ◽

F. M. Ramsey ◽

C. E. Rosow ◽

...

Keyword(s):

Blocking Agent ◽

Neuromuscular Blocking ◽

Neuromuscular Blocking Agent ◽

Short Acting

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Metabolic fate of the short-acting peripheral neuromuscular blocking agent stercuronium in the rat, as related to its action

Biochemical Pharmacology ◽

10.1016/0006-2952(71)90351-0 ◽

1971 ◽

Vol 20 (6) ◽

pp. 1213-1224 ◽

Cited By ~ 11

Author(s):

W. Hespe ◽

J. Wieriks

Keyword(s):

Blocking Agent ◽

Neuromuscular Blocking ◽

Neuromuscular Blocking Agent ◽

Metabolic Fate ◽

Short Acting

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Clinical pharmacology of ORG 7617, a short-acting non-depolarizing neuromuscular blocking agent

European Journal of Clinical Pharmacology ◽

10.1007/bf00192553 ◽

1994 ◽

Vol 46 (3) ◽

pp. 225-229 ◽

Cited By ~ 3

Author(s):

L. van den Broek ◽

J. M. K. H. Wierda ◽

J. H. Proost ◽

F. D. M. Hommes ◽

S. Agoston

Keyword(s):

Clinical Pharmacology ◽

Blocking Agent ◽

Neuromuscular Blocking ◽

Neuromuscular Blocking Agent ◽

Short Acting ◽

Org 7617

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Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers

Anesthesiology ◽

10.1097/aln.0000000000002157 ◽

2018 ◽

Vol 128 (6) ◽

pp. 1107-1116

Author(s):

Josh D. Kaullen ◽

Joel S. Owen ◽

Kim L. R. Brouwer ◽

Paul M. Heerdt ◽

Cynthia A. Lien ◽

...

Keyword(s):

Plasma Concentrations ◽

Blocking Agent ◽

Rapid Onset ◽

Neuromuscular Blocking ◽

Neuromuscular Blocking Agent ◽

Population Pharmacokinetic ◽

Time Data ◽

Muscle Twitch ◽

Concentration Data ◽

Duration Of Action

Abstract Background CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. Methods Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose–response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. Results A four-compartment model was fit to the concentration–time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. Conclusions CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.

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