Anton Bom

Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969

Background The purpose of this study was to determine the changes in the plasma concentration of rocuronium and the reversal of its neuromuscular blockade after the intravenous infusion of Org 25969, the novel neuromuscular block–reversal agent, in anesthetized guinea pigs. Methods Rocuronium was infused for 1 h at a rate of 12–19 nmol·kg−1·min−1 to produce a steady-state 90% neuromuscular block. After 30 min, a concomitant infusion of either the reversal agent Org 25969 at a rate of 50 nmol·kg−1·min−1 or an infusion of an equivalent volume of saline was started. The time course of plasma concentrations of rocuronium was determined by use of liquid chromatography–mass spectrometry/mass spectrometry. Results In both treatment groups, a steady-state plasma concentration of rocuronium was obtained after 30 min. In the saline-treated group, the plasma concentration of rocuronium and depth of block remained constant. In the Org 25969 group, neuromuscular block was reversed while the rocuronium infusion was ongoing. Simultaneously, an increase in the total plasma concentration of rocuronium (free and complexed) was observed, even though the infusion rate of rocuronium was not changed. Compared with the saline-treated group, a small increase in the postmortem bladder concentration of rocuronium was detected. Conclusions The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).

2-O-substituted cyclodextrins as reversal agents for the neuromuscular blocker rocuronium bromide.

A series of secondary face modified cyclodextrins (CDs) were synthesised with the aim of constructing host molecules capable of forming host-guest complexes with neuromuscular blockers, especially with rocuronium bromide. Perfacial 2-O-substitution of gamma-CD with 4-carboxybenzyl resulted in a CD host molecule 1 that forms a 1:1 binary complex with rocuronium bromide (K(a) 6.2 x 10(5) M(-1)). The biological activities of this compound and other derivatives as reversal agents of rocuronium bromide were examined in vitro (mouse hemi-diaphragm) and in vivo (anaesthetized guinea pigs). The host molecule 1 was found to exert potent reversal activity (ED(50) 0.21 micromol/kg, iv) against rocuronium-induced neuromuscular block, and thus proved the viability of using host molecules as antidotes of a biologically active compound.

Reversal of profound rocuronium neuromuscular blockade by sugammadex in anesthetized rhesus monkeys

Background: Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic γ-cyclodextrin derivative. The current study determined the feasibility of reversal of rocuronium-induced profound neuromuscular blockade with sugammadex in the anesthetized rhesus monkey using train-of-four stimulation. Methods: Four female rhesus monkeys each underwent three experiments. In each experiment, first, a 100-&mgr;g/kg dose of rocuronium was injected and spontaneous recovery was monitored. After full recovery, a 500-&mgr;g/kg dose of rocuronium was injected. Up to this point, all three experiments in a single monkey were identical. One minute after this rocuronium injection, either one of the two tested dosages of sugammadex (1.0 or 2.5 mg/kg) was injected or saline was injected. Results: Injection of 100 &mgr;g/kg rocuronium resulted in a mean neuromuscular blockade of 93.0% (SD = 4%), and profound blockade was achieved by injection of 500 &mgr;g/kg. In all experiments, a 100% neuromuscular blockade was achieved at this dose. After injection of the high rocuronium dose, the 90% recovery of the train-of-four ratio took 28 min (SD = 7 min) after saline, 26 min (SD = 9.5 min) after 1 mg/kg sugammadex, and 8 min (SD = 3.6 min) after 2.5 mg/kg sugammadex. Signs of residual blockade or recurarization were not observed. Injection of sugammadex had no significant effects on blood pressure or heart rate. Conclusions: Chemical encapsulation of rocuronium by sugammadex is a new therapeutic mechanism allowing effective and rapid reversal of profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys.

Synthesis of novel analogues of the delta opioid ligand SNC-80 using AlCl3-promoted aminolysis

Two focused libraries of delta opioid ligands were synthesised using AlCl3 facilitated aminolysis. Several compounds were identified with DOR binding affinities higher or similar to SNC-80. A novel acyclic derivative of SNC-80 produced antinociception in the acetic acid abdominal constriction test, which is at least partially mediated via the delta-opioid receptor.

Parallel solid-Phase synthesis of zatebradine analogues as potential If channel blockers

The first solid-phase synthesis of zatebradine 1 and its analogues is reported. This has resulted in the preparation of compounds with increased ability to reduce the spontaneous beating of isolated guinea-pig atria in a concentration-dependent manner. One example, 8g, showed a maximum reduction of beating of 80% at 3 microM compared to a reduction of 40% at 3 microM with zatebradine 1.

Sugammadex reverses neuromuscular block induced by 3-desacetyl-vecuronium, an active metabolite of vecuronium, in the anaesthetised rhesus monkey.

Background and objective 3-Desacetyl-vecuronium is an active metabolite of the neuromuscular blocking agent (NMBA) vecuronium, which might lead to residual paralysis after prolonged administration of vecuronium in critically ill patients with renal failure. This study investigated the ability of sugammadex to reverse 3-desacetyl-vecuronium-induced neuromuscular block (NMB) in the anaesthetised rhesus monkey. Methods Experiments were performed in anaesthetised female rhesus monkeys. After bolus intravenous injection of vecuronium (n = 8) or 3-desacetyl-vecuronium (n = 8) 10 μg kg−1 (ED90), a continuous infusion of the same NMBA was started to maintain the first twitch of the train-of-four (TOF) at 10% of baseline value. The infusion was stopped and NMB recovered spontaneously. The procedure was repeated, but immediately after stopping the infusion, an intravenous bolus dose of sugammadex 0.5 or 1.0 mg kg−1 was given. For each NMBA, four placebo experiments were performed, in which the second recovery from NMB was also spontaneous. For all experiments, time to recovery of the TOF ratio to 90% was retrieved. Results After administration of sugammadex for reversal of 3-desacetyl-vecuronium-induced NMB, recovery was significantly faster than spontaneous recovery. Mean time to recovery of TOF to 90% was 3.2 min (sugammadex 0.5 mg kg−1) and 2.6 min (1.0 mg kg−1), compared to spontaneous recovery (17.6 min). For vecuronium-induced NMB, mean time to recovery of TOF to 90% was 17.1 min (0.5 mg kg−1) and 4.6 min (1.0 mg kg−1), compared to spontaneous recovery (23.4 min). Conclusion Sugammadex rapidly and effectively reversed 3-desacetyl-vecuronium-induced NMB in the rhesus monkey, at a lower dose than that needed to reverse vecuronium-induced NMB.