Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents

TY - JOUR

T1 - Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents

AU - Haerter, Friederike

AU - Simons, Jeroen Cedric Peter

AU - Foerster, Urs

AU - Moreno Duarte, Ingrid

AU - Diaz-Gil, Daniel

AU - Ganapati, Shweta

AU - Eikermann-Haerter, Katharina

AU - Ayata, Cenk

AU - Zhang, Ben

AU - Blobner, Manfred

AU - Isaacs, Lyle

AU - Eikermann, Matthias

PY - 2015/12

Y1 - 2015/12

N2 - 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.

AB - 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.

KW - Androstanols/antagonists & inhibitors

KW - Animals

KW - Atracurium/analogs & derivatives

KW - Dose-Response Relationship, Drug

KW - Heterocyclic Compounds, 4 or More Rings/pharmacology

KW - Male

KW - Neostigmine/pharmacology

KW - Neuromuscular Nondepolarizing Agents/antagonists & inhibitors

KW - Rats

KW - Rocuronium

KW - Sugammadex

KW - Sulfonic Acids/pharmacology

KW - Vecuronium Bromide/antagonists & inhibitors

KW - gamma-Cyclodextrins/pharmacology

U2 - 10.1097/ALN.0000000000000868

DO - 10.1097/ALN.0000000000000868

M3 - SCORING: Journal article

C2 - 26418697

VL - 123

SP - 1337

EP - 1349

JO - ANESTHESIOLOGY

JF - ANESTHESIOLOGY

SN - 0003-3022

IS - 6

ER -