2004 Annual Scientific Meeting - CLICK FOR PROGRAMME

NOVEL APPROACH TO REVERSAL

Jennifer M Hunter, Department of Anaesthesia, University of Liverpool, Duncan Building, Daulby Street, Liverpool L69 3GA England

Tel: 00 44 151 706 4008, Fax: 00 151 706 5884, email: jennie@liv.ac.uk

Although the vast majority of anaesthetists use anticholinesterases in their daily practice, they recognise the limitations of these drugs.  The most important is that recovery from block needs to be established before these drugs are given; reappearance of the second twitch of the train-of-four (TOF) response is often recommended¹.  Other (lesser) disadvantages, some of which are related to the muscarinic effect of these drugs, include: nausea and vomiting; bronchoconstriction; abdominal cramps; bradycardia; and a prolonged effect in the presence of renal dysfunction.

An ideal antagonist to a neuromuscular blocking drug would work at any time after any dose of muscle relaxant is administered to any patient (even one who is acidotic or has sub-clinical myopathy). No side-effects, including allergy, would be encountered.  Will such a perfect reversal agent ever exist?  Probably not, but it would be ideal if any new one was so predictable that it removed the need for neuromuscular monitoring.  Such versatility is probably, in pharmacological terms, unrealistic.

The novel concept of using a ring-shaped cyclodextrin to engulf a neuromuscular blocking drug is fascinating.²  Cyclodextrins are cyclic oligosaccharides which are recognised to encapsulate lipophilic molecules such as steroids.  They are water soluble and well tolerated biologically.  Org 25969 consists of eight such sugar molecules in a ring, the outside of which is hydrophilic, and the inside, hydrophobic.  The size and shape of the ring is designed to produce a cavity into which a neuromuscular blocking drug such as rocuronium will tightly fit.  Org 25969 is capable of forming a binary host – guest complex of high affinity with rocuronium, for two of its externally charged side-chains react with the quaternary nitrogen groups of the muscle relaxant.  It is able to encapsulate all four steroidal rings of rocuronium within its lipophilic cavity. This encapsulation or chelation reverses the effect of rocuronium, by preventing its access to the nicotinic receptor and promoting its dissociation from it.  Reversal of rocuronium is more efficacious with Org 25969 than with neostigmine;  Org 25969 reverses profound block at three times the rate of the anticholinesterase.  The complex is filtered by the glomerulus and excreted in the urine.  As Org 25969 has no direct cholinergic effect, there is no need to administer an antimuscarinic drug with it.

Bom and colleagues (2001) demonstrated 90% recovery from profound (90%) block within three minutes after Org 25969 1 mg kg^-1 had been given to three animal species (guinea pig, cat, monkey), albeit with a marked variability of effect (SEM = 1.3 min).³  Similar findings were reported by Gijsenberg et al in 29 human volunteers, with doses of Org 25696 up to 8 mg kg^-1, and no signs of recurarisation after 90 min.⁴  There were no serious adverse events in the human studies except for paraesthesiae in the conscious subjects, which is also described when small doses of neuromuscular blocking drugs are given to awake volunteers.  No marked cardiovascular changes were noted.  In animal studies, antagonism by Org 25969 has not been found to be dependent on renal perfusion and not modified by acid-base changes.

Thus, at this early stage in its development, Org 25969 would seem to produce rapid reversal of profound neuromuscular block produced by rocuronium without significant side-effects.  It is unfortunate, but predictable, that this specific cyclodextrin does not appear to antagonise other neuromuscular blocking drugs. Most clinical anaesthetists would undoubtedly prefer to use the same antagonist throughout their practice.  It is also too early to be certain about lack of side-effects; these are often not confirmed with a new drug until several thousand exposures have occurred.  Nevertheless, Org 25969 is a most exciting approach to antagonism of neuromuscular block, which heralds a new development in anaesthetic pharmacology.  Initial results of its use in several animal species, including man, to reverse rocuronium are encouraging.

REFERENCES

1.  Ali HH, Utting JE, Gray TC.   Quantitative assessment of residual antidepolarising block (Part I).  Br J Anaesth 1971; 43: 473-7

2.  Zhang M-Q.  Drug-specific cyclodextrins: the future of rapid neuromuscular block reversal? Drugs of the Future 2003: 28: 347-54

3.  Bom A, Mason R, Hope F, van Egmond J, Muir A.  The cyclodextrin derivative ORG 25969, which forms complexes with steroidal neuromuscular blocking agents, causes selective reversal of normal and profound neuromuscular block.  Anesthesiology 2001; 94: A1020

4. Gijsenberg F, Ramael S, De Bruyn S, Rietbergen H, van Iersel T.  Preliminary assessment of Org 25969 as a reversal agent for rocuronium in healthy male volunteers. Anesthesiology 2002; 96: A1008