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


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). "

    Full-text · Dataset · Dec 2012
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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.
    Preview · Article · Jul 2012 · Egyptian Journal of Anaesthesia
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    • "The complex structure is excreted unchanged (40–50%) in bile and (65–97%) in urine within 2–24 h (Gijsenbergh et al. 2005; Jones et al. 2008). However, sugammadex– rocuronium complexes are not eliminated via the biliary route. "
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    ABSTRACT: Reversal of neuromuscular blockage induced by steroidal neuromuscular blocking agents such as rocuronium can be achieved using normal dose of sugammadex, which has been shown to be very effective for such reversal. In this study, we determined the effects of sugammadex on calcineurin immunoreactivity by examining the histopathological and histochemical structure of rat testis cells after neuromuscular blockage. Moreover, the regional distribution levels of calcineurin immunopositive testes cells were investigated. Eighteen adult male, Sprague-Dawley rats were divided into one control and two study groups. Study groups 1 and 2 rats received sugammadex at doses of 16 and 96 mg kg(-1) i.v., respectively, after rocuronium treatment (mg kg(-1) i.v.). The control group received intravenous 0.9% NaCl 1 ml. i.v without any drug. Our study demonstrates that sugammadex is safe and effective for reversal of rocuronium effects in rats, as well as in other animals and humans. Furthermore, histopathological examination indicates that high levels of sugammadex-rocuronium complexes accumulate a little in testis tissue. We found that rocuronium-sugammadex complexes were remained in circulation for a long time resulting in a decrease in interstitial space, testis size, germ cell numbers and Leydig cell numbers. Calcineurin immunoreactivity was higher in the experimental groups than the control group due to increase of calcium level. The results suggest that sugammadex-rocuronium complexes are cause histopathological and immunohistochemical changes in testis interstitial tissues, as well as changes in sperm density and germ cell number.
    Full-text · Article · Dec 2011 · Journal of molecular histology
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