Ergotoxine and some other constituents of ergot / by George Barger and H.H. Dale.

  • Barger, George, 1878-1939.
Date:
[1907]
    view that ergotinine is inactive. These arguments are based on the activity of commercial (impure) ergotinine specimens, and prove nothing as to the activity of the chemically pure base—a point with which we shall deal in a later section of this paper. The substance described as 4 cornutin ’ by Keller was examined physiologically in 1902 by Santesson (39), who used a specimen obtained from Keller himself, and others prepared according to the latter’s directions. In frogs, rabbits, and fowls he obtained with this preparation, in considerable doses, only a partial and feeble reproduc- tion of some of the effects attributed by Kobert to sphacelinic acid and cornutine. A significant rise of blood-pressure was obtained only in the fowl, and the effect on pregnant rodents was not of a constant or definite nature. He concludes that this substance is not the important active principle. Up till 1906 two further attempts to isolate the active principle were made by Jacobj (37) and by Meulenhoff (38). Both these investigators adopted as their chief criterion of activity the reaction of the cock’s comb, which Kobert only obtained with sphacelinic acid. According to Jacobj the active principle is a non-nitrogenous resin, with feebly acid properties, for which he adopted the name 4 sphacelotoxin,’ and which he described as combined in ergot with two inert substances—(a) with 4 ergochrysin,’ to form the compound 4 chrysotoxin ’ ; (b) with the crystalline alkaloid 4 secaline ’ to form the compound 4 secalintoxin.’ Sphacelotoxin Jacobj regarded as sphacelinic acid in a pure form. Both chrysotoxin and secalintoxin caused uterine contractions and gangrene of the cock’s comb. Meulenhoff likewise concluded that the activity of ergot is due to an acid resin (Kobert’s sphacelinic acid). With regard to cornutine, Meulenhoff confirmed Tanret’s view that it is a decomposition product of ergotinine formed by the acid used in its extraction, and does not occur in ergot as such. It is evident from the above account that when, a few years ago, we began to work on ergot the more recent invetigators had held that the activity of ergot, or, at any rate, the production of gangrene, was determined by an acidic principle. Our own
    experiments have, however, led us to believe that all these acidic preparations owed their activity to a powerfully active amorphous alkaloid, of which crystalline salts were isolated by F. H. Carr and one of us, and to which the name ergotoxine was given (45). Soon afterwards Kraft (46) described the same alkaloid under the name hydroergotinine, regarding it as the hydrate of Tanret’s ergotinine. Recently ergotoxine and some of its salts have been described in detail by Barger and Carr (51), who, from their analyses, assign to ergotoxine the formula C35H4i06N5, and to ergotinine the formula C35H39O5N5, thus establishing Kraft’s view as to the relationship of the two alkaloids. Meanwhile a substance of an entirely different kind, neither acidic nor alkaloidal, was described by Vahlen (44) as the essential therapeutic principle of ergot. With the nature of this substance, to which he gave the name 4 clavin,’ we shall deal in a later section of the paper. Ergotoxine Chemical The chemical description of the alkaloid ergotoxine, which has already been given elsewhere by Barger and Carr (51), may be sum- marised as follows :—Ergotoxine is a white amorphous powder having the composition C35H4106N5, and melting, with decomposition, at 162° to 164°. It is freely soluble in most organic solvents, but only slightly so in ether, and is insoluble in light petroleum. It is soluble in dilute caustic soda, and is a feeble monacid base. Ergotoxine forms crystalline salts, one of the most characteristic of which is the phosphate C35H4i06N5, H3P04, H20, forming minute needles, melting at 1860 to 187°. Barger and Carr have amended Tanret’s original formula for crystalline ergotinine to CssE^OgNs. (Compare with this Tanret’s recent formula, C35H4o05N5 (49).) Hence it will be seen that the crystalline alkaloid is the anhydride of the amorphous, as first suggested by Kraft. Either alkaloid can be readily converted into the other. Both give the colour reaction described by Tanret and by Keller as
    characteristic of ergotinine. The chief differences between the two alkaloids are that ergotinine crystallises very readily, whereas ergo- toxine has so far resisted all attempts at crystallisation, and that ergotoxine is very soluble in cold alcohol while ergotinine is but slightly soluble. So far only amorphous ergotinine salts have been prepared, whereas nearly all the ergotoxine salts hitherto examined have been obtained crystalline. The salts of both alkaloids form colloidal solutions in water, and are precipitated by electrolytes, so that they are little soluble in the presence of the stronger mineral acids. Physiological One of us recently (43) described certain physiological effects— best observed in a cat with the brain destroyed and artificial respira- tion—which were characteristically produced by a large number of ergot preparations. An analysis of these effects showed that they could be divided into— (1) A primary stimulation of plain muscular tissues, especially the arteries, the uterus, and the sphincter of the pupil. (2) A secondary specific paralysis of the motor elements in the so-called ‘ myoneural junctions ’ associated with innervation by the true sympathetic system and stimulated by the suprarenal active principle ; the inhibitor elements of the same retaining their normal function, as do also the autonomic nerves of cranial and sacral root origin. The vaso-motor effects may be taken as a typical and easily observed example of this double action. When a powerful dose of one of these ergot preparations (chrysotoxin, commercial ergotinine, etc.) is injected intravenously into a pithed cat the first result is a marked and very prolonged rise of blood-pressure. If, while this rise persists, the sympathetic nerve supply to the arteries is excited at any level, as by faradising the spinal cord or the splanchnic nerves, or injecting intravenously nicotine or a suprarenal preparation, the effect is a very marked fall of blood-pressure in place of the customary rise. This particular instance of the action is easy to observe, and is capable
    of quantitative application, and we shall frequently refer to the dose of a given preparation causing 6 vaso-motor reversal,’ meaning thereby the quantity just sufficing to replace the normal pressor effect of a given dose (o*i mgm.) of the suprarenal active principle by a depressor effect. The accuracy of the measurement is admittedly not great, but it has, at least, a fairly definite end-point, and we have found it preferable to observation of such uncertain effects as those on the cock’s comb. At the outset it was necessary to recognise the possibility that more than one active principle might be concerned in the various actions, and for a long time we were engaged in the search for a principle of which we could only postulate that it caused the vaso-motor reversal. Only later were we able to transfer conclusions based on this reaction to the other physiological effects, which the principle, when isolated, was found to produce. In the former communication it was suggested as probable that the primary stimulant action on plain muscle was due to a different principle from that responsible for the secondary sympathetic motor paralysis, although the two were found in close association. This suggestion has recently been supported by Cushny (50), who observed, as we did, that certain pharmacopoeial preparations, such as the liquid extract, produced stimulant effects on plain muscle, resembling, superficially at least, those which we had described, but followed by a disproportionately weak sympathetic motor paralysis. Like ourselves, he regarded this as indicating that the principle responsible for the paralytic effects probably had none of the stimulant properties, and that, where the two sets of effects were observed, two principles were at work. The isolation of ergotoxine, in the form of pure crystalline salts, at once showed, however, that this conclusion was wrong. What, if any, is the relation to ergotoxine of the substance which gives to the liquid extract what specific activity it possesses is at present quite uncertain, and will probably remain so until the substance can be obtained free from other physiologically active principles, such as choline. Possibly the further experiments on ergotoxine, with which we are now engaged, will throw light on the question. However that may be, it is certain that pure salts of ergotoxine produce, in very small dose,
    all the effects described in the former paper (43) as characteristic of chrysotoxin, etc. Fig. 1 Pithed Cat, z kilos. Artificial respiration. Carotid blood-pressure. At A—Intravenous injection of o‘5 mgm. of the suprarenal principle. At B—Intravenous injection of i mgm. of ergotoxine phosphate. At C—Intravenous injection of o'o$ mgm. of the suprarenal principle. Time marker in this and all the other tracings showed ten seconds intervals. Reference to that paper will show that, at the time of its publica- tion, we had already found that certain alkaloidal preparations pro- duced the effects in smaller dosage than those of an acidic, resinous nature. The only step needed was the isolation of the alkaloid, in chemically pure form, which was made possible by the discovery that it gave well-crystalline salts. Without repeating the details of the various manifestations of the physiological action already described, it will be sufficient to indicate the relative activity of the pure alkaloid as compared with the impure preparations previously used. As with these impure preparations it was found that, owing probably to the depressant action of the alkaloid on the medullary centres, the stimulant effects were observed in most characteristic form in an