A Novel Concept of Reversing Neuromuscular Block

Dr Ronnie Palin
Organon, Newhouse, Scotland

Cyclodextrins (CDs) are well-known host molecules capable of forming inclusion complexes with guest molecules. Compared with other synthetic host molecules, CDs are usually more water soluble and biologically well tolerated. The increasing commercial availability of CDs plus their favourable supramolecular chemistry properties makes them interesting targets for development as medicinal agents.

We hypothesized that chemical encapsulation of neuromuscular blocking agents (NMBAs) by a host molecule would promote dissociation of the latter from nicotinic acetylcholine receptors (nAChR) on the muscle, leading to the reversal of neuromuscular blockade. Since this mechanism of action does not involve direct interaction with the cholinergic system, it may circumvent the undesired side-effects attendant with acetylcholinesterase (AChE) inhibitors such as neostigmine. Therefore, there should be no need for the concomitant use of a muscarinic acetylcholine receptor (mAChR) antagonist such as atropine or glycopyrrolate. The use of chemical chelators as reversal agents for NMBAs has also the potential advantage that they could be used to reverse the action of both depolarizing and non-depolarizing NMBAs, because of this lack of involvement of nAChRs in the mechanism of action. In addition, they may further be safely employed for the reversal of 'profound (or complete) block'.

In this presentation we shall describe the discovery of Org 25969, a synthetic cyclodextrin-based host molecule that forms tight host-guest complex with rocuronium (association constant Ka: >107 M-1) and as a result reverses rocuronium-induced neuromuscular block. The reversal produced by Org 25969 in animal models including anesthetized monkeys was fast and highly efficient. More importantly, no significant changes in haemodynamic parameters were observed during the application of Org 25969.

Biography

Dr Ronald Palin completed his PhD in Organic Synthesis at the University of Strathclyde. He is currently Team Leader at Organon Laboratories, Scotland, working in the field of Analgesia.