BACKGROUND: Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development. METHODS: Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium. RESULTS: Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95NMB values varied approximately tenfold (43 +/- 2 microgram/kg -488 +/- 56 microgram/kg. The "R-series" isomers were more potent than the corresponding "S-series" isomers. With the exception of the S,Trans-S', Trans isomers, the NMB effects, i.e., onset times (range 2.6 +/- 0.2 min to 4.7 +/- 0.3 min) and total durations (range 9.9 +/- 1.4 min to 14 +/- 0.9 min), of the other five isomers were very similar to that atracurium. The former isomers had relatively short duration of action. The 25-75% recovery times after cisatracurium at 1 x ED95 (4.4 +/- 0.4 min), 4 x ED95 (4.5 +/- 0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8% +/- 0.4 min) indicated a noncumulative effect. The vagal ID50:NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25:NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micrograms/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60X the NMB ED95 (62 +/- 8 micrograms/kg). CONCLUSIONS: Cisatracurium has neuromuscular blocking effects identical to those of atracurium, is more potent, and does not produce cardiovascular effects or increase plasma histamine concentrations.
BACKGROUND:Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development. METHODS: Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium. RESULTS: Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95NMB values varied approximately tenfold (43 +/- 2 microgram/kg -488 +/- 56 microgram/kg. The "R-series" isomers were more potent than the corresponding "S-series" isomers. With the exception of the S,Trans-S', Trans isomers, the NMB effects, i.e., onset times (range 2.6 +/- 0.2 min to 4.7 +/- 0.3 min) and total durations (range 9.9 +/- 1.4 min to 14 +/- 0.9 min), of the other five isomers were very similar to that atracurium. The former isomers had relatively short duration of action. The 25-75% recovery times after cisatracurium at 1 x ED95 (4.4 +/- 0.4 min), 4 x ED95 (4.5 +/- 0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8% +/- 0.4 min) indicated a noncumulative effect. The vagal ID50:NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25:NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micrograms/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60X the NMB ED95 (62 +/- 8 micrograms/kg). CONCLUSIONS:Cisatracurium has neuromuscular blocking effects identical to those of atracurium, is more potent, and does not produce cardiovascular effects or increase plasma histamine concentrations.