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History of the development of antagonists for neuromuscular blocking agents

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Abstract

Muscle relaxation induced by neuromuscular blocking agents (NMBAs) is necessary for tracheal intubation and immobilization during surgery. Although acetylcholinesterase inhibitors have been successfully used as antagonists for NMBAs, they have their limitations; their effects are transient and ineffective against profound neuromuscular blockade. In the past, alternative antagonists were developed, such as germine and 4-aminopyridine, which are effective for the treatment of diseases causing muscle weakness and could potentially be used as antagonists for NMBAs. Unfortunately, these drugs did not come into practical use due to unwanted side-effects. Sugammadex is an almost ideal antagonist because it rapidly forms a rigid complex with rocuronium and produces less adverse effects. The development of novel NMBAs and antagonists, especially sugammadex, has revolutionized anesthesia practice. Recently, novel short-acting NMBAs, such as gantacurium and CW002 have been developed. Their effects can be reversed by the amino-acid l-cysteine. More recently, calabadions have been developed, which can form complexes with both steroidal and bisbenzyl-isoquinolinium NMBAs, in a similar fashion as sugammadex. Understanding the history of the NMBA antagonist’s development is interesting and useful for modern anesthesiologists since it enhances their knowledge about the mechanisms involved in neuromuscular transmission and might lead to the development of ideal NMBA antagonists.

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References

  1. Bovet D, Bovet-Nitti F. Succinyl choline and short acting muscle relaxants. Schweiz Med Wochenschr. 1952;82(40):1009–122.

    CAS  Google Scholar 

  2. Tran DT, Newton EK, Mount VA, Lee JS, Wells GA, Perry JJ. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev. 2015;10:Cd002788.

    Google Scholar 

  3. Holland R. Anaesthetic mortality in New South Wales. Br J Anaesth. 1987;59(7):834–41.

    CAS  Google Scholar 

  4. Lunn JN, Mushin WW. Mortality associated with anaesthesia. Anaesthesia. 1982;37(8):856.

    CAS  Google Scholar 

  5. Orihara M, Takazawa T, Horiuchi T, Sakamoto S, Nagumo K, Tomita Y, Tomioka A, Yoshida N, Yokohama A, Saito S. Comparison of incidence of anaphylaxis between sugammadex and neostigmine: a retrospective multicentre observational study. Br J Anaesth. 2020;124(2):154–63.

    Google Scholar 

  6. Luo J, Chen S, Min S, Peng L. Reevaluation and update on efficacy and safety of neostigmine for reversal of neuromuscular blockade. Ther Clin Risk Manag. 2018;14:2397–406.

    CAS  Google Scholar 

  7. Taylor P. Anticholinesterase Agents. In: Brunton L, editor. Goodman and Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 2017. p. 239–254.

    Google Scholar 

  8. Zhao B, Moochhala SM, Tham SY. Biologically active components of Physostigma venenosum. J Chromatogr B. 2004;812(1):183–92.

    CAS  Google Scholar 

  9. Doyle D. Notable Fellows: Sir Thomas Richard Fraser. J R Coll Physicians Edinb. 2009;39:283.

    Google Scholar 

  10. Proudfoot A. The early toxicology of physostigmine: a tale of beans, great men and egos. Toxicol Rev. 2006;25(2):99–138.

    CAS  Google Scholar 

  11. Nickalls RW, Nickalls D, Elisabeth A. The first reversal of curare. Anaesthesia. 1985;40(6):572–3.

    CAS  Google Scholar 

  12. Aschlimann JA, Reinert M. The pharmacological action of some analogues of physostigmine. J Pharmacol Exp Ther. 1931;43(3):413–44.

    Google Scholar 

  13. Katz RL. Pyridostigmin (mestinon) as an antagonist of d-tubocurarine. Anesthesiology. 1967;28(3):528–34.

    CAS  Google Scholar 

  14. Randall LO, Conroy CE, Ferruggia TM, Kappell BH, Knoeppel CR. Pharmacology of the anticholinesterase drugs; mestinon, prostigmin, tensilon and TEPP. Am J Med. 1955;19(5):673–8.

    CAS  Google Scholar 

  15. Randall LO. Anticurare action of phenolic quaternary ammonium salts. J Pharmacol Exp Ther. 1950;100(1):83–93.

    CAS  Google Scholar 

  16. Randall LO, Lehmann G. Pharmacological properties of some neostigmine analogs. J Pharmacol Exp Ther. 1950;99(1):16–32.

    CAS  Google Scholar 

  17. Hunter AR. Tensilon; a new anti-curare agent. Br J Anaesth. 1952;24(3):175–86.

    CAS  Google Scholar 

  18. Barrow ME, Johnson JK. A study of the anticholinesterase and anticurare effects of some cholinesterase inhibitors. Br J Anaesth. 1966;38(6):420–31.

    CAS  Google Scholar 

  19. Stojanov E, Dobrev H, Paskov D. The effect of nivalin on respiration in steroid narcosis (Experimental study). Nauchni Tr Vissh Med Inst Sofiia. 1965;44(5):1–12.

    CAS  Google Scholar 

  20. Viby-Mogensen J, Jorgensen BC, Ording H. Residual curarization in the recovery room. Anesthesiology. 1979;50(6):539–41.

    CAS  Google Scholar 

  21. Donati F, McCarroll SM, Antzaka C, McCready D, Bevan DR. Dose-response curves for edrophonium, neostigmine, and pyridostigmine after pancuronium and d-tubocurarine. Anesthesiology. 1987;66(4):471–6.

    CAS  Google Scholar 

  22. Saarnivaara L, Simola M. Effects of four anticholinesterase-anticholinergic combinations and tracheal extubation on QTc interval of the ECG, heart rate and arterial pressure. Acta Anaesthesiol Scand. 1998;42(4):460–3.

    CAS  Google Scholar 

  23. Sasaki N, Meyer MJ, Malviya SA, Stanislaus AB, MacDonald T, Doran ME, Igumenshcheva A, Hoang AH, Eikermann M. Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study. Anesthesiology. 2014;121(5):959–68.

    CAS  Google Scholar 

  24. Yost CS, Maestrone E. Clinical concentrations of edrophonium enhance desensitization of the nicotinic acetylcholine receptor. Anesth Analg. 1994;78(3):520–6.

    CAS  Google Scholar 

  25. Payne JP, Hughes R, Al AS. Neuromuscular blockade by neostigmine in anaesthetized man. Br J Anaesth. 1980;52(1):69–766.

    CAS  Google Scholar 

  26. Kupchan SM, Narayanan CR. Veratrum Alkaloids. XXVIII.1 The structure and configuration of germine2–4. J Am Chem Soc. 1959;81(8):1913–21.

    CAS  Google Scholar 

  27. Paskov DS, Stoianov NA, Mitsov VZ. New anti-curare and analeptic drug, Pimadin, and its use in anesthesia. Eksp Khir Anesteziol. 1973;18(4):48–52.

    CAS  Google Scholar 

  28. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology. 2005;103(4):695–703.

    CAS  Google Scholar 

  29. Murphy G. The development and regulatory history of sugammadex in the United States. APSF Newslett. 2016;30(3):53–4.

    Google Scholar 

  30. Adam JM, Bennett DJ, Bom A, Clark JK, Feilden H, Hutchinson EJ, Palin R, Prosser A, Rees DC, Rosair GM, Stevenson D, Tarver GJ, Zhang MQ. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships. J Med Chem. 2002;45(9):1806–16.

    CAS  Google Scholar 

  31. Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J, Feilden H, MacLean EJ, Muir AW, Palin R, Rees DC, Zhang MQ. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem Int Ed Engl. 2002;41(2):266–70.

    Google Scholar 

  32. Bom A, Hope F, Rutherford S, Thomson K. Preclinical pharmacology of sugammadex. J Crit Care. 2009;24(1):29–35.

    CAS  Google Scholar 

  33. Epemolu O, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969. Anesthesiology. 2003;99(3):632–7 (discussion 6A).

    CAS  Google Scholar 

  34. Carron M, Zarantonello F, Tellaroli P, Ori C. Efficacy and safety of sugammadex compared to neostigmine for reversal of neuromuscular blockade: a meta-analysis of randomized controlled trials. J Clin Anesth. 2016;35:1–12.

    CAS  Google Scholar 

  35. Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine. Anesthesiology. 2008;109(5):816–24.

    CAS  Google Scholar 

  36. Godai K, Hasegawa-Moriyama M, Kuniyoshi T, Kakoi T, Ikoma K, Isowaki S, et al. Three cases of suspected sugammadex-induced hypersensitivity reactions. Br J Anaesth. 2012;109(2):216–8.

    CAS  Google Scholar 

  37. Takazawa T, Mitsuhata H, Mertes PM. Sugammadex and rocuronium-induced anaphylaxis. J Anesth. 2016;30(2):290–7.

    Google Scholar 

  38. Takazawa T, Tomita Y, Yoshida N, Tomioka A, Horiuchi T, Nagata C, Orihara M, Yamada MH, Saito S. Three suspected cases of sugammadex-induced anaphylactic shock. BMC Anesthesiol. 2014;14:92.

    Google Scholar 

  39. Tsur A, Kalansky A. Hypersensitivity associated with sugammadex administration: a systematic review. Anaesthesia. 2014;69(11):1251–7.

    CAS  Google Scholar 

  40. Petitpain N, Argoullon L, Masmoudi K, Fedrizzi S, Cottin J, Latarche C, Mertes PM, Gillet P. Neuromuscular blocking agents induced anaphylaxis: results and trends of a French pharmacovigilance survey from 2000 to 2012. Allergy. 2018;73(11):2224–33.

    CAS  Google Scholar 

  41. Savic L, Savic S, Hopkins PM. Anaphylaxis to sugammadex: should we be concerned by the Japanese experience? Br J Anaesth. 2020;124(4):370–2.

    Google Scholar 

  42. Le Corre F, Nejmeddine S, Fatahine C, Tayar C, Marty J, Plaud B. Recurarization after sugammadex reversal in an obese patient. Can J Anaesth. 2011;58(10):944–7.

    Google Scholar 

  43. Murata T, Kubodera T, Ohbayashi M, Murase K, Adachi YU, Matsuda N. Recurarization after sugammadex following a prolonged rocuronium infusion for induced hypothermia. Can J Anaesth. 2013;60(5):508–9.

    Google Scholar 

  44. Muramatsu T, Isono S, Ishikawa T, Nozaki-Taguchi N, Okazaki J, Kitamura Y, Murakami N, Sato Y. Differences of recovery from rocuronium-induced deep paralysis in response to small doses of sugammadex between elderly and nonelderly patients. Anesthesiology. 2018;129(5):901–11.

    CAS  Google Scholar 

  45. Boros EE, Bigham EC, Boswell GE, Mook RA Jr, Patel SS, Savarese JJ, Ray JA, Thompson JB, Hashim MA, Wisowaty JC, Feldman PL, Samano V. Bis- and mixed-tetrahydroisoquinolinium chlorofumarates: new ultra-short-acting nondepolarizing neuromuscular blockers. J Med Chem. 1999;42(2):206–9.

    CAS  Google Scholar 

  46. Samano V, Ray JA, Thompson JB, Mook RA Jr, Jung DK, Koble CS, Martin MT, Bigham EC, Regitz CS, Feldman PL, Boros EE. Synthesis of ultra-short-acting neuromuscular blocker GW 0430: a remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinolinium chlorofumarates. Org Lett. 1999;1(12):1993–6.

    CAS  Google Scholar 

  47. Belmont MR, Lien CA, Tjan J, Bradley E, Stein B, Patel SS, Savarese JJ. Clinical pharmacology of GW280430A in humans. Anesthesiology. 2004;100(4):768–73.

    CAS  Google Scholar 

  48. Heerdt PM, Malhotra JK, Pan BY, Sunaga H, Savarese JJ. Pharmacodynamics and cardiopulmonary side effects of CW002, a cysteine-reversible neuromuscular blocking drug in dogs. Anesthesiology. 2010;112(4):910–6.

    Google Scholar 

  49. Heerdt PM, Sunaga H, Owen JS, Murrell MT, Malhotra JK, Godfrey D, Steinkamp M, Savard P, Savarese JJ, Lien CA. Dose-response and cardiopulmonary side effects of the novel neuromuscular-blocking drug CW002 in man. Anesthesiology. 2016;125(6):1136–43.

    CAS  Google Scholar 

  50. Hoffmann U, Grosse-Sundrup M, Eikermann-Haerter K, Zaremba S, Ayata C, Zhang B, Ma D, Isaacs L, Eikermann M. Calabadion: a new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents. Anesthesiology. 2013;119(2):317–25.

    CAS  Google Scholar 

  51. Haerter F, Simons JCP, Foerster U, Moreno Duarte I, Diaz-Gil D, Ganapati S, Eikermann-Haerter K, Ayata C, Zhang B, Blobner M, Isaacs L, Eikermann M. Comparative effectiveness of calabadion and sugammadex to reverse non-depolarizing neuromuscular-blocking agents. Anesthesiology. 2015;123(6):1337–499.

    CAS  Google Scholar 

  52. de Boer HD, Carlos RV. New drug developments for neuromuscular blockade and reversal: gantacurium, CW002, CW011, and calabadion. Curr Anesthesiol Rep. 2018;8(2):119–24.

    Google Scholar 

  53. Stenlake JB, Waigh RD, Urwin J, Dewar GH, Coker GG. Atracurium: conception and inception. Br J Anaesth. 1983;55(Suppl 1):3S–10S.

    Google Scholar 

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Acknowledgements

We would like to thank Dr. Anton Bom for the information provided regarding the preclinical development of sugammadex.

Funding

This manuscript was supported by JSPS KAKENHI Grant Number 18K08809.

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Authors and Affiliations

  1. Intensive Care Unit, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Keiko Suzuki, Tomonori Takazawa & Shigeru Saito

  2. Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Shigeru Saito

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  1. Keiko Suzuki
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  2. Tomonori Takazawa
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Correspondence to Tomonori Takazawa.

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Suzuki, K., Takazawa, T. & Saito, S. History of the development of antagonists for neuromuscular blocking agents. J Anesth 34, 723–728 (2020). https://doi.org/10.1007/s00540-020-02836-1

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