The pharmacological actions of polymethylene bistrimethylammonium salts / by W.D.M. Paton and Eleanor J. Zaimis.

  • Paton, William D. M.
Date:
[1949?]
Catalogue details

Licence: In copyright

Credit: The pharmacological actions of polymethylene bistrimethylammonium salts / by W.D.M. Paton and Eleanor J. Zaimis. Source: Wellcome Collection.

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    Fig. 5.—Cat, chloralose, 2.6 kg. Tibialis; nerve shocks every 10 sec. At arrow, 26 /xg. CIO injected intraven¬ ously. The same dose was given 5 min. previously without any effect. increases the block for the succeeding twitches (Bacq and Brown, 1937). We have used this phenomenon as a test of the nature of the block caused by CIO. Figs, la and 4 show that there is no such depressant action by a tetanus or by injection of acetylcholine respectively on the twitch of a muscle partially paralysed with CIO ; and it has been our constant experience that it would be hard to judge from the subsequent twitches that a tetanus had been applied or an injection made. (An apparent slight deepening of the block by acetylcholine in Fig. 9 was due to traces of CIO from the previous injection.) We have, moreover, never observed any relation between the rate of stimulation and the development of the block. Indeed, with a large dose of CIO almost complete paralysis may occur after a single twitch. It is unlikely, therefore, that block due to CIO is the result of the accumulation of acetylcholine at the end-plate. We do not wish, however, to under¬ estimate the resemblance of some of our tracings to those resulting from injections of potent anti¬ esterases (cf. Brown, Burns, and Feldberg, 1948), but it is possible that some of the latter produce a block otherwise than by their antiesterase action. Our experiments in this connexion also showed that a muscle could still maintain a tetanic con¬ traction at a height comparable with the twitch tension when partially paralysed with CIO. It is well known that the curarized muscle cannot do this ; our experiments on this important difference will be reported separately. Duration of action In the anaesthetized cat, the complete or nearly complete paralysis of tibialis that follows an intra¬ venous dose of 30 /ig./'kg. of CIO usually begins to recover in 5-10 min., and recovery is complete in about 15 min. Sometimes a twitch tension greater than the initial may be observed for a few minutes of the recovery (recapitulating the initial potentiation) before it returns to the original level. The presence of the drug, however, is still detectable for some time after the twitch tension has returned to normal, since the same dose given again less than 30 min. after the first injection produces a greater effect. But with suitable spacing of doses, reproducible cycles of paralysis and com¬ plete recovery can be obtained for many hours, the only important change commonly observed being a diminution of the initial potentiation with the lapse of time. Our experience also suggests that CIO has a rather steep dose-response curve ; thus, a dose of 20 fig. I kg. was sometimes without visible effect on twitch tension in an animal in which 30 fig. I kg. produced temporarily a complete block. Corresponding to this, recovery from a CIO block, once it starts, is often rather rapid. d-Tubocurarine chloride differs significantly both in having a longer duration of action for a given peak action and in the slower waning of its effects. Similar time relations are observed in unanaes¬ thetized cats and in rabbits ; both animals, after a dose of CIO sufficient to paralyse them fully, recover in about 10 min., whereas d-tubocurarine chloride has a somewhat more prolonged action. In the monkey, however, the reverse is the case, and with equally effective doses CIO has a dura¬ tion of action about two to three times longer than that of d-tubocurarine chloride. We have given CIO by other routes in a few experiments. Administered by stomach tube, CIO is ineffective in cat and rabbit in doses less than fifty times the effective intravenous dose, but a dose of a hundred times may be lethal in an animal starved for 24 hours. The paralysis takes an hour or more to appear. By the subcutaneous route in the rabbit, about three times the intravenous dose is required for equal maximum effects, and the paralysis does not appear for about 10 min. nor disappear entirely for about 2 hours. With intra¬ muscular injections, slightly smaller doses are required, and the onset of paralysis is quicker. We have not, however, studied the relative doses required for equal peak effects by the various routes in any detail, and the values quoted are only approximate.