Supramolecular therapeutics to treat the side effects induced by a depolarizing neuromuscular blocking agent

Abstract

Succinylcholine (Sch) is the only depolarizing neuromuscular blocking agent widely used for rapid sequence induction in emergency rooms. Unfortunately, a variety of (sometimes lethal) adverse effects, such as hyperkalemia and cardiac arrest, are associated with its use, and currently there are no specific antidotes to reverse Sch or to treat these side-effects. Methods: The binding behaviors of Sch and several synthetic receptors, including cucurbit[7]uril, sulfo-calix[4]arene and water-soluble carboxylatopillar[6]arene (WP[6]), were first investigated. With a mouse model, a leathal dose of Sch was selected for evaluation of the antidotal effects of these synthetic receptors on Sch induced mortality. The antidotal effects of a selected synthetic receptor, WP[6], on Sch induced cardiac arrhythmias, hyperkalemia, rhabdomyolysis and paralysis were subsequently evaluated with rat and mouse models. The reversal mechanism was also investigated at a cellular level. Results: All of these macrocyclic molecules exhibited relatively high binding affinities with Sch in vitro . In a Sch-overdosed mouse model, immediate injection of these synthetic receptors right after Sch administration increased the overall survival rate, with WP[6] standing out with the most effective antidotal effects. In addition, administration of WP[6] also reversed the paralysis induced by Sch in a mouse model. Moreover, infusion of WP[6] to Sch-overdosed rats reduced the incidence of cardiac arrhythmia, inhibited the otherwise abnormally high serum potassium levels, and relieved the muscular damage. At the cellular level, WP[6] reversed the Sch induced depolarization and reduced the efflux of intracellular potassium. Conclusion: Synthetic receptors, particularly WP[6], exhibited high binding affinities towards Sch, and presented a significant potential as supramolecular therapeutics to treat the various side effects of Sch by specifically sequestering Sch in vivo .

Recent advances in supramolecular antidotes

“…Succinylcholine (Sch, Figure 1 ) is the only depolarizing NMBA that is widely used for rapid sequence induction in emergency rooms 90 . However, its use can be accompanied by severe side-effects, such as hyperkalemia and cardiac arrest.…”

“…Among these hosts, WPA 6 exhibited excellent antidotal effects. In vivo studies showed that the encapsulation of Sch by WPA 6 reduced the guest side-effects', such as the incidence of cardiac arrhythmia, high serum potassium levels, and muscular damage 90 . Inspired by the success of sugammadex, Stoikov and co-workers synthesized a water soluble PA 5 , namely WPA 5 (Figure 2 B), containing similar side-chains as those of sugammadex, and aimed at achieving a better reversal effect for the use of rocuronium bromide.…”

Biomedizinische Anwendungen von Calixarenen: Stand der Wissenschaft und Perspektiven

“…Hamilton et al berichteten über eine Reihe potenter C4A-basierter Wachstumsfaktor (Platelet-Derived Growth Factor,PDGF)-Antagonisten (163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177), die in der Lage sind die Ty rosinphosphorylierung des PDGF-stimulierten PDGF-Rezeptors (PDGFR) zu inhibieren. [158] CAs wurden entwickelt, um an die Drei-Schleifen-Region von PDGF zu binden und dessen Interaktion mit PDGFR zu stçren.…”

“…Diese Verbindung weist jedoch zahlreiche Nebenwirkungen wie Myalgie und prolongierte Apnoe auf. [166] Wang et al verwendeten supramolekulare Therapeutika zur Behandlung dieser Nebenwirkungen und setzten 31 ein, das starke Affinitäten zu Sch zeigte.In einem Sch-überdosierten Mausmodell, wurde 31 unmittelbar nach Sch-Administration injiziert. Die Gesamtüberlebensraten stiegen signifikant an, was auf eine erfolgreiche Detoxifikation hinweist.…”

Supramolecular Nanotheranostics

“…The most prominent examples include amphiphilic cyclodextrins, calixarenes and pillararenes as non-viral vectors for gene condensation, membrane permeation and targeted delivery. Zhang et al 15 studied the use of synthetic supramolecular receptors such as cucurbit[7]uril, sulfo-calix[4]arene and water-soluble carboxylatopillar[6]arene (WP6) to evaluate the antidotal effect of neuromuscular blocking agent succinylcholine (Sch). Among these, WP6 with high binding affinity towards Sch was able to reverse Sch induced depolarization and reduce the efflux of intracellular potassium.…”