W. Clarke Wescoe

The pharmacology of Flaxedil, with observations on certain analogs.

Until as recently as 1946, the classical pharmacologic action of the natural curare alkaloids had had no counterpart in the many synthetic compounds examined in laboratories of pharmacology and physiology. True, Crum Hrown and Fraserl had described a paralytic action resulting from the yuaternization of the nitrogen atom of certain alkaloids, but this effect was soon proved to he characteristic for most quaternary amines and was recognized by physiologists as different in mechanism from the neuromuscular blockade produced by the natural curare alkaloids. In 1946, Bovet and his collaborators attempted to reproduce synthetically a simplified version of the d-tubocurarine molecule. They achieved the synthesis of a series of bis quinoline derivatives wherein the aromatic structures were connected through a methylene chain by ether linkages.‘ These compounds were actively curariform. Shortly thereafter, they examined simple mono and poly phenolic ethers of certain amino alcohols and found that these substances also possessed a striking curariform action.a In the latter series was the compound, triiodoethylate of Iris (triethylamino ethoxy) 1,2,3 benzene. This compound, named Flaxedil, exerted a potent curariform action in the rabbit. The following year! Barlow and In

THE INFLUENCE OF ATROPINE AND SCOPOLAMINE ON THE CENTRAL EFFECTS OF DFP

and I’aton and Zaimis5 reported that the paralytic action of quaternary amines could be intensified by the twinning of the aniine groups through polymethylene chains of varying lengths. This represented, in principle, the distant quaternary ammonium groups found in the molecule of d-tubocurarine. Most recently, Kimura et d6 described the potent neuromuscular blocking action that results from the twinning of two atropine molecules through an amyl chain. Thus, the principle was established by which compounds with strong neuromuscular blocking action could be synthesized by establishing at least two quaternary ammonium groupings a t an optimal intramolecular,distance. Of these compounds, two have had a considerable preliminary clinical trial in the practice of anesthesiology, namely, Flaxedil and decamethonium bromide, the bis trimethylammonium decamethylene compound. The present report is concerned with the pharmacologic properties of Flaxedil, particularly as they compare with those of d-tubocurarine. The onset and development of paralysis that follows the intravenous injection of Flaxedil into the intact cat is entirely like that occurring in this animal after an equipotent dose of d-tubocurarine. The order of events is such that the respiratory musculature is usually the last to succumb. As with other compounds of this nature, resulting paralysis of the muscles of respiration is not only the direct cause of death but the