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A4003
October 14, 2014
8:00 AM - 9:30 AM
Room Room 245
The Ultra-Short Acting Neuromuscular Blocker CW 1759-50 Has Approximately 5 Times the Safety of Rapacurium at M2 and M3 Receptors in the Guinea Pig Airway
John J. Savarese, M.D., Yi Zhang, M.D., Paul M. Heerdt, M.D., Ph.D., Charles W. Emala, M.D.
Weill Cornell Medical College, New York, New York, United States
Introduction

CW 1759-50 is a rapid-onset short-acting, cysteine-inactivated, nondepolarizing neuromuscular blocker (NMBA) under consideration for Phase I study. Its clinical application might ultimately involve tracheal intubation. Accordingly, safety at M2 muscarinic receptors on vagal nerve endings in distal airways and M3 muscarinic receptors on tracheo-bronchial smooth muscle should be evaluated.

The steroidal NMBA rapacuronium most likely caused bronchospasm in humans as a result of: a) high-degree blockade of M2 muscarinic receptors, which act as auto-inhibitory receptors which block further acetylcholine (ACh) release at vagal endings in the distal airways; and b) an allosteric mechanism at M3 muscarinic receptors on airway smooth muscle (Ref 1) which promotes smooth muscle contraction. To rule out these mechanisms as potential causes of increased airway resistance by CW 1759-50, we compared its activity at M2 and M3 receptors with the activity of rapacuronium at these receptors in the anesthetized guinea pig, a model used for more than 25 years, to investigate these interactions of NMBAs with airway reactivity.

Methods

Male Hartley guinea pigs (wt ~ 400 gm) were studied. They were maintained according to NIH guidelines, and the protocol was approved by the IACUC of Columbia University. Animals were anesthetized with urethane 1.7 g/kg, the trachea was cannulated, and animals were ventilated at 8 ml/kg x 60 BPM. Breath-by-breath peak pulmonary inflation pressure (PIP) was continuously recorded along with heart rate and arterial pressure via carotid catheter. Both vagus nerves were placed on shielded platinum electrodes, and stimulated at 10 min intervals with trains of square waves (10-20V x 0.2 msec, 20 Hz x 10 sec) to assay M2 receptor function. Vagal stimulation was alternated with i.v. boluses (jugular vein) of ACh (4-24 µg/kg) to assay M3 receptor function. ED for M2 receptor block was defined as 100% increase in PIP above baseline. ED for M3 receptor allosteric sensitization was defined as ~ 300% increase in PIP. NMB was studied by measurement of the twitch of the Achilles Tendon elicited at 0.15 Hz via the popliteal nerve. Statistical comparison was done by unpaired t-test. Data were analyzed using an Excel program.



Results

Results are summarized in Table 1.

The dose-ratios M2/NMB and M3/NMB represent safety in the airway of the guinea pig, in multiples of the ED95 NMB required to cause the two undesirable side effects: M2 muscarinic blockade and M3 muscarinic potentiation/sensitization. A higher dose ratio indicates greater safety.

Discussion

The data suggest that CW 1759-50 has 5 x greater safety than rapacuronium in eliciting detrimental increase in airway tone. This greater safety is present at both M2 and M3 muscarinic receptors. This allows continued M2 function. The protective effect of M2 receptors in limiting excessive ACh release may be maintained. M3 receptor-mediated allosteric potentiation of airway smooth muscle contraction may be prevented. NMBAs which may be given to facilitate tracheal intubation, such as 1759-50, need a wide safety ratio for M2 blockade, importantly because the protective effect of prevention of excessive ACh release should remain after high doses.

Reference:

1. Jooste, E, Zhang, Y, Emala, CW: Anesthesiology 2007; 106: 763-772



Figure 1

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