title: Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents.
abstract: BACKGROUND
  The authors evaluated the comparative effectiveness of calabadion 2 to reverse non-depolarizing neuromuscular-blocking agents (NMBAs) by binding and inactivation.
  
  
  METHODS
  The dose-response relationship of drugs to reverse vecuronium-, rocuronium-, and cisatracurium-induced neuromuscular block (NMB) was evaluated in vitro (competition binding assays and urine analysis), ex vivo (n = 34; phrenic nerve hemidiaphragm preparation), and in vivo (n = 108; quadriceps femoris muscle of the rat). Cumulative dose-response curves of calabadions, neostigmine, or sugammadex were created ex vivo at a steady-state deep NMB. In living rats, the authors studied the dose-response relationship of the test drugs to reverse deep block under physiologic conditions, and they measured the amount of calabadion 2 excreted in the urine.
  
  
  RESULTS
  In vitro experiments showed that calabadion 2 binds rocuronium with 89 times the affinity of sugammadex (Ka = 3.4 × 10 M and Ka = 3.8 × 10 M-). The results of urine analysis (proton nuclear magnetic resonance), competition binding assays, and ex vivo study obtained in the absence of metabolic deactivation are in accordance with an 1:1 binding ratio of sugammadex and calabadion 2 toward rocuronium. In living rats, calabadion 2 dose-dependently and rapidly reversed all NMBAs tested. The molar potency of calabadion 2 to reverse vecuronium and rocuronium was higher compared with that of sugammadex. Calabadion 2 was eliminated renally and did not affect blood pressure or heart rate.
  
  
  CONCLUSIONS
  Calabadion 2 reverses NMB induced by benzylisoquinolines and steroidal NMBAs in rats more effectively, i.e., faster than sugammadex. Calabadion 2 is eliminated in the urine and well tolerated in rats.
authors.affiliation: From the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (F.H., J.C.P.S., I.M.D., D.D.-G., M.E.); Clinic of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (U.F., M.B.); Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland (S.G., B.Z., L.I.); Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (K.E.-H., C.A.); and Department of Anesthesia and Critical Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany (M.E.).
authors.forename: Friederike
authors.initials: F
authors.lastname: Haerter
authors.forename: Jeroen Cedric Peter
authors.initials: JC
authors.lastname: Simons
authors.forename: Urs
authors.initials: U
authors.lastname: Foerster
authors.forename: Ingrid
authors.initials: I
authors.lastname: Moreno Duarte
authors.forename: Daniel
authors.initials: D
authors.lastname: Diaz-Gil
authors.forename: Shweta
authors.initials: S
authors.lastname: Ganapati
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.forename: Ben
authors.initials: B
authors.lastname: Zhang
authors.forename: Manfred
authors.initials: M
authors.lastname: Blobner
authors.forename: Lyle
authors.initials: L
authors.lastname: Isaacs
authors.forename: Matthias
authors.initials: M
authors.lastname: Eikermann
mesh_terms: D000732:Androstanols / Q000037:antagonists & inhibitors; D000818:Animals; D001279:Atracurium / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D008297:Male; D009388:Neostigmine / Q000494:pharmacology; D003473:Neuromuscular Nondepolarizing Agents / Q000037:antagonists & inhibitors*; D051381:Rats; D000077123:Rocuronium; D000077122:Sugammadex; D013451:Sulfonic Acids / Q000494:pharmacology*; D014673:Vecuronium Bromide / Q000037:antagonists & inhibitors; D047408:gamma-Cyclodextrins / Q000494:pharmacology*
chemical_list: D000732:Androstanols; D006576:Heterocyclic Compounds, 4 or More Rings; D003473:Neuromuscular Nondepolarizing Agents; D013451:Sulfonic Acids; C583725:calabadion 1; D047408:gamma-Cyclodextrins; D001279:Atracurium; D000077122:Sugammadex; D009388:Neostigmine; D014673:Vecuronium Bromide; C101584:cisatracurium; D000077123:Rocuronium