First Human Exposure of Org 25969, a Novel Agent to Reverse the Action of Rocuronium Bromide

Department of Anesthesia, Stuivenberg Hospital, Antwerp, Belgium.
Anesthesiology (Impact Factor: 5.88). 11/2005; 103(4):695-703. DOI: 10.1097/00000542-200510000-00007
Source: PubMed

ABSTRACT 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 gamma-cyclodextrin that encapsulates the neuromuscular blocking agent, rocuronium bromide (Esmeron/Zemuron, NV Organon, Oss, The Netherlands), forming a tightly bound complex with an association constant of approximately 10 m. Chemical encapsulation of rocuronium promotes dissociation of rocuronium from the acetylcholine receptor, thereby reversing the neuromuscular block without the side effects associated with acetylcholinesterase inhibitors.
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 separate occasions, using an intubating dose of 0.6 mg/kg rocuronium. 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).
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 recurarization were observed.
Org 25969 was both well tolerated and effective in reversing neuromuscular block induced by rocuronium in 29 human volunteers.

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    • "It is excreted by the kidneys intact and has been found to increase the excretion of rocuronium molecules that it encapsulates (Sorgenfrei et al 2006). The renal excretion of sugammadex mirrors glomerular fi ltration rate (Gijsenbergh et al 2005) and it can be removed by dialysis (Hartman et al 2007). "
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    • "As for postoperatively, proper awakening of these patients is extremely important for minimizing the postoperative respiratory complications as laryngo-spasm, stridor, and difficulty in breathing, so that adequate reversal of the residual of non-depolarizing neuromuscular blocking drugs at the end of the surgery is of critical importance for avoiding these complications in the early postoperative period [5], as it involves the muscles that maintain the patency of the airway or attenuate the ventilatory response to hypoxia especially with the patients who had postoperative nasal obstructions [6]. Sugammadex is a new selective relaxant binding drug that is designed to encapsulate steroidal non-depolarizing neuromuscular blocking agents (NDBAs) and that will allow an effective reverse of any degree of block of both rocuronium and vecuronium [7], as it provides a rapid decrease in free rocuronium in the plasma and subsequently at nicotinic receptor at motor end plate; this promotes the liberation of acetylcholine in which its deficiency may prolong the action of neuromuscular blocking agent [8]. It is a modified –c– cyclodextrin compound (Organon USA Inc., Roseland NJ). "
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    ABSTRACT: Sinonasal surgery is one of the shared airway surgeries that are not uncommonly complicated intra or postoperatively. The proper anesthetic management of these cases plays a crucial role creating a bloodless field. Sugammadex is a new selective relaxant binding drug as it provides a rapid decrease in free rocuronium in the plasma and at nicotinic receptor that help proper awakening of these patients which is extremely important for minimizing the postoperative respiratory complications. The aim of this study is to compare recovery profile in sinonasal surgery in patients reversed by conventional anticholine esterase (Neostigmine) versus those reversed by Sugammadex.
    Egyptian Journal of Anaesthesia 07/2012; 28(3):175–178. DOI:10.1016/j.egja.2011.12.007
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    • "Since all drugs behave in a dose-response manner,64 rare instances of re-paralysis (“recurarization”) have been reported in human and animal studies after administration of inadequate doses (<2 mg/kg) of sugammadex.58–60,62,65–67 A temporary decrease in TOF response was thus observed after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 minutes after 0.9 mg/kg of rocuronium, indicating there were insufficient numbers of sugammadex molecules available to encapsulate all existing rocuronium molecules.68 "
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    ABSTRACT: Despite the significant improvements in the pharmacology of muscle relaxants in the past six decades, the search for the ideal muscle relaxant continues, mainly because of the incomplete efficacy and persistent side effects associated with their antagonism. Clinical concerns remain about the residual paralysis and hemodynamic side effects associated with the classic pharmacologic reversal agents, the acetylcholinesterase inhibitors. Although the development of the "ideal muscle relaxant" remains illusory, pharmacologic advancements hold promise for improved clinical care and patient safety. Recent clinical advances include the development of short-acting nondepolarizing muscle relaxant agents that have fast onset and a very rapid metabolism that allows reliable and complete recovery; and the development of selective, "designer" reversal agents that are specific for a single drug or class of drugs. This article reviews recent developments in the pharmacology of these selective reversal agents: plasma cholinesterases, cysteine, and sugammadex. Although each of the selective reversal agents is specific in its substrate, the clinical use of the combination of muscle relaxant with its specific reversal agent will allow much greater intraoperative titrating ability, decreased side effect profile, and may result in a decreased incidence of postoperative residual paralysis and improved patient safety.
    Drug Design, Development and Therapy 09/2009; 3(3):119-29. DOI:10.2147/DDDT.S3868 · 3.03 Impact Factor
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