Anesthesiology 2005; 103:695–703 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. First Human Exposure of Org 25969, a Novel Agent to Reverse the Action of Rocuronium Bromide Francois Gijsenbergh, M.D.,* Steven Ramael, M.D.,† Natalie Houwing, M.Sc.,‡ Thijs van Iersel, M.D.§ Background: Acetylcholinesterase inhibitors are widely used for the reversal of neuromuscular blocking agents. However, acetylcholinesterase inhibitors have several side effects and are not effective during profound block. Org 25969 is a modified -cyclodextrin that encapsulates the neuromuscular blocking agent, rocuronium bromide (Esmeron ® /Zemuron ® , NV Or- ganon, Oss, The Netherlands), forming a tightly bound complex with an association constant of approximately 10 7 M 1 . Chem- ical encapsulation of rocuronium promotes dissociation of rocuronium from the acetylcholine receptor, thereby reversing the neuromuscular block without the side effects associated with acetylcholinesterase inhibitors. Methods: Twenty-nine healthy male volunteers were enrolled to investigate the safety, pharmacokinetics, and efficacy of Org 25969. In part 1, Org 25969 or placebo was administered to 19 subjects during one to three treatment periods each. In part 2, a further 10 subjects received general anesthesia on two sepa- rate occasions, using an intubating dose of 0.6 mg/kg rocuro- nium. Three minutes after rocuronium administration, Org 25969 or placebo was given in random order. Six doses of 0.1– 8.0 mg/kg Org 25969 were evaluated. Neuromuscular block was measured using an acceleromyograph, the TOF-Watch-SX ® (NV Organon, Oss, The Netherlands). Results: All adverse events related to Org 25969 treatment were of limited duration and mild intensity, except for a period of paresthesia, seen in one patient receiving 8 mg/kg Org 25969, which was of moderate intensity. No adverse events required any treatment, and all subjects recovered from them. When 8 mg/kg Org 25969 was given, the train-of-four ratio returned to 0.9 within 2 min after its administration. No signs of recurari- zation were observed. Conclusions: Org 25969 was both well tolerated and effective in reversing neuromuscular block induced by rocuronium in 29 human volunteers. NEUROMUSCULAR blocking agents (NMBAs), which produce muscle relaxation during surgery, are an essen- tial adjunct to anesthesia. However, rapid reversal of their effects, particularly in cases of profound block, has proved difficult. Recently, a novel fast-acting agent, Org 25969, a modified -cyclodextrin, has been developed to routinely reverse rocuronium bromide (Esmeron ® /Ze- muron ® ; NV Organon, Oss, The Netherlands)–induced neuromuscular block (NMB). 1 Cyclodextrins are cyclic oligosaccharides, well known for their capability to en- capsulate lipophilic guest molecules. 2 The advantage of using cyclodextrins as NMB reversal agents is that they are generally very water soluble, have no endogenous targets, and are therefore unlikely to cause major side effects. 3 Org 25969 was designed to have an optimal affinity for rocuronium, and its hydrophobic interior was tailored to fully encapsulate the hydrophobic steroid skeleton of rocuronium (fig. 1). 4 Once the Org 25969 – rocuronium interaction has been established, it prevents the binding of rocuronium to nicotinic receptors in the neuromuscular junction and hence results in cessation of NMB in vivo. 5 In addition, in the guinea pig in vivo, Org 25969 was found to increase plasma and urine concen- trations of rocuronium, 6 indicating that Org 25969 in- creases the clearance of rocuronium by the kidney. Thus, Org 25969 –rocuronium interaction leads to a shift of rocuronium into the plasma, reducing the level of free rocuronium availability at the neuromuscular junctions. Eriksson et al. 7 and Kopman et al. 8 clearly showed that recovery from NMB to a train-of-four (TOF) ratio of 0.9 or greater was predictive of the recovery of pharyngeal muscles, striated muscles of the upper esophagus, the masseter muscle, and the extraocular muscles. This find- ing suggests that there may be a substantial risk of aspiration at TOF ratios below 0.9. Furthermore, after the use of NMBAs of intermediate duration, such as rocuronium, and using a TOF ratio of 0.9 as the criterion for adequate recovery, Debaene et al. 9 showed a 45% incidence of postoperative residual curarization in pa- tients arriving in the recovery room. Anticholinesterases, such as neostigmine, are routinely used as reversal agents for NMBAs. However, the use of anticholinesterases as reversal agents has major draw- backs regarding safety and efficacy. They nonspecifically activate both nicotinic and muscarinic synapses by com- petitively inhibiting the breakdown of acetylcholine, rather than acting as true reversal agents. Their use leads to bradycardia, hypersalivation, and bronchoconstric- tion, which are reduced by using anticholinergics such as atropine and glycopyrrolate. In addition, anticholines- terases have little effect against profound block and show considerable interindividual variation in efficacy. This article is featured in “This Month in Anesthesiology.” Please see this issue of Anesthesiology, page 5A.  * Staff Anesthesiologist, Department of Anesthesia, Stuivenberg Hospital. † Research Physician, Socie ´te ´ Ge ´ne ´rale de Surveillance (SGS) Biopharma, Re- search Unit Stuivenberg, Antwerp, Belgium. ‡ Development Scientist, § Re- search Physician, NV Organon, Oss, The Netherlands. Received from the Department of Anesthesia, Stuivenberg Hospital, Antwerp, Belgium. Submitted for publication December 30, 2003. Accepted for publica- tion March 25, 2005. Supported by NV Organon, Oss, The Netherlands. Dr. van Iersel was employed by NV Organon, the manufacturer of Org 25969, at the time of this study. Dr. Ramael is employed by SGS Biopharma, Antwerp, Belgium, the company contracted by NV Organon to execute the study. For the study, Dr. Gijsenbergh was contracted by SGS Biopharma. Ms. Houwing is an employee of NV Organon. A preliminary version of this study was presented at the Annual Meeting of the American Society of Anesthesiologists, Orlando, Florida, October 15, 2002. Address reprint requests to Dr. van Iersel: Boomgaard 79, 9603 HL Hoogezand, The Netherlands. Address electronic mail to: thijsvaniersel@home.nl. Individ- ual article reprints may be purchased through the Journal Web site, www. anesthesiology.org. 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