Chapter 6

The alkaloid _atropine_ has been quite thoroughly studied with results of great interest. When heated with baryta-water or hydrochloric acid, it takes up a molecule of water and is split into tropine, C_{8}H_{15}NO, and tropic acid, C_{9}H_{10}O_{3}. This latter is phenyl-oxypropionic acid. Tropine, when heated to 180°C. with concentrated hydrochloric acid, splits off a molecule of water, and yields tropidine, C_{8}H_{13}N, a liquid base, with an odor resembling conine. When this tropidine is heated with an excess of bromine, it yields dibrompyridine.

_Piperine_, the alkaloid of pepper, has also been well studied. When boiled with alcoholic potash solution, it takes up a molecule of water and splits apart into piperic acid, C_{12}H_{10}O_{4}, and piperidine, C_{5}H_{11}N. This latter base has been shown to be a hydrogen addition product of pyridine, C_{5}H_{5}N. When heated with concentrated sulphuric acid, it is oxidized to pyridine. Piperidine hydrochlorate, also, when heated with excess of bromine to 180° C., yields dibrompyridine.

_Sinapine_, the alkaloid which exists as sulphocyanate in white mustard seed, yields, under the same reaction as that applied to atropine and piperine, quite different results. When boiled with baryta water, sinapine decomposes into sinapic acid, C_{11}H_{12}O_{5}, and choline, C_{5}H_{15}NO_{2}, the latter a well-known constituent of the bile, and produced also in the decomposition of the lecithin of the brain and yolk of egg.

_Cocaine_, the alkaloid of coca leaves, is decomposed by heating with hydrochloric acid into methyl alcohol, benzoic acid, and a crystalline base, ecgonine, C_{9}H_{15}NO_{3}.

_Caffeine_ and _theobromine_ have also quite different relations. Caffeine, it will be remembered, is the methyl ester of theobromine, and can be prepared from it. When caffeine is carefully oxidized with chlorine, it yields dimethyl-alloxan and methyl-urea. Both theobromine and caffeine are decomposed by heating to 240° C. in sealed tubes with hydrochloric acid, identical products being obtained. These products are carbon dioxide, formic acid, ammonia, methyl-amine, and sarcosine, the last three being of course in combination with the excess of hydrochloric acid. The artificial preparation of theobromine and caffeine from xanthine, and guanine also show clearly their relations.

If, having completed our survey of what has been done in the way of decomposing the alkaloids by the different classes of reagents, we review the field, it will be seen that with all the alkaloids mentioned, except the last four, a more or less immediate connection with the pyridine and quinoline bases has been indicated. The conviction accordingly forces itself upon us that, if we want to attack the problem of building up any of these important alkaloids artificially, we must turn to these bases as our starting point.

As already stated, both series occur in coal-tar and the pyridine series also more abundantly in bone-oil. Pyridine, picoline, lutidine, and collidine, the first four members of the pyridine series, have, moreover, all been formed synthetically, although the processes are not such as would yield the products as cheaply as they can be gotten from Dippel's oil. Quinoline, the first member of the higher series, had been made synthetically by several chemists, but by expensive and involved methods, when Skraup, in 1881, effected its synthesis from nitrobenzol and glycerin, or still better, a mixture of nitrobenzol and aniline with glycerin. This process allows of its being made on a commercial scale if desirable. Shortly after, by an application of the same principle, Dobner and Miller effected the synthesis of lepidine, the second member of the quinoline series.

At the same time that this general agreement to consider these bases as the starting point in the endeavor to effect the synthesis of the natural alkaloids had been arrived at by chemists, it was thought well to look into the question whether these bases and their immediate derivatives had any therapeutic value of their own.

Piperidine, the decomposition product of piperine, which we have shown may be considered to be hexahydropyridine, was examined by Dr. Kronecker, of Berlin, at the request of Prof. Hofmann, and was found to have an action upon animals in many respects resembling that of conine. Prof. Filehne, of Erlangen, who has studied a large number of these pyridine and quinoline derivatives, found, moreover, that the hydrochlorate of ethyl-piperidine had a physiological action quite analogous to that of conine.

The physiological action of quinoline itself has been studied quite extensively by Donath and others, and it was found that several of its salts were quite valuable febrifuges, acting very like quinine, and capable in cases of being used as a substitute for it. In general, the hydrogen addition products were found to be more active than the simple base, an observation entirely in accord with the theory formed by Wischnegradsky, and by Konigs, as the result of the study of the decomposition products of the alkaloids, viz., the alkaloids are in general hydrogen addition products of pyridine and quinoline, or of the two bases combined. Thus Prof. Filehne found that hydrochlorate of tetrahydroquinoline was much more energetic in its action than quinoline, but could not be used on account of a too powerful local effect. The hydrochlorate of dimethyl-tetrahydroquinoline, which was distinguished by its strong bitter taste, much resembling that of quinine, had an effect like that of curare poison. The most decided febrifuge action, however was found by Prof. Filehne to reside in the hydrochlorate of oxyhydro-methyl-quinoline, introduced to public notice by Prof. O. Fischer under the name of "Kairin," and in the acid sulphate of tetrahydro-methylquinoline, introduced under the name of "Kairolin." These compounds had a very surprising febrifuge action, without any unpleasant after effects or local disturbances.

The most active workers in the field of synthetic formation of the alkaloids have been Wischnegradsky, of St. Petersburg--who, unfortunately for science, died at an untimely age in 1880--Königs and Fischer, of Munich, and Ladenburg, of Kiel. The study of the decomposition products of the cinchona alkaloids especially points quite distinctly to the probable existence in quinine of a hydrogen addition product of pyridine, in combination with a methyl-quinoline group. The many experiments that are now being made to test this and other questions that suggest themselves, will not long leave us in the dark. Whether a practical commercial synthesis of quinine will follow is another matter, but it is within the bounds of possibility, or perhaps even of probability.

It must not be supposed that no syntheses of alkaloids have been effected as yet. By heating butyl-aldehyde with alcoholic ammonia is formed _paraconine_, an alkaloid isomeric with the natural conine, but differing in physiological action. By the action of sodium upon pyridine is produced a compound C_{10}H_{8}N_{2}, known as dipyridyl, and this, under the influence of nascent hydrogen, takes up six atoms and becomes _isonicotine_ C_{10}H_{14}N_{2}, a physiologically active alkaloid, isomeric with the true nicotine. The formation of a series of alkaloids under the name of _codeines_, by the substitution of other organic radicals instead of methyl in the codeine reaction, has already been alluded to. _Atropine_ can be formed by uniting tropine and tropic acid, the two decomposition products already noted. The latter of these products is already shown to be capable of synthetical formation, and the other will no doubt be formed in the same way. The artificial atropine is identical with the natural alkaloid. Ladenburg has also formed a series of artificial alkaloids, called _tropeines_, by uniting the base tropine with different organic acids, as in the case of the compound of mandelic acid and tropine, known as _homatropine_, an alkaloid of action similar to atropine, but possessing some decided advantages in its use. _Piperine_ has also been made by the uniting of piperidine and piperic acid, and, as piperidine has already been formed from pyridine, we have here a true synthesis also. Both _theobromine_ and _caffeine_, its methyl derivative, have been made from xanthine, which itself can be formed from guanine, a constituent of guano.

We may conclude from this reference to what has been done in the last few years, that the reproach mentioned in first speaking of the alkaloids as a class, that almost nothing was known of their constitution, will not long remain, and that as their molecular structure is laid bare in these studies now being made, keen-sighted chemists will effect their artificial formation. When these most valuable compounds can be made by exact methods, in a state of entire purity, and at a cost much below that paid for the present extraction of them from relatively rare plants, organic chemistry will have placed all of us under obligations as great as those owing any branch of science, no matter how practical we call it.--_Amer. Jour. of Pharmacy_.

* * * * *

ON THE TREATMENT OF CONGESTIVE HEADACHE.

By J. LEONARD CORNING, M.D., New York.

If we examine the literature of our theme, we are astounded by the apparently hopeless confusion in which the whole is involved. Everywhere attempts at ill-founded generalization are encountered. We are compelled to admit, after perusing long debates in regard to the relative merits of various therapeutic measures, that those who were foremost to disparage the treatment pursued by others were totally ignorant of the fact that those same symptomatic manifestations which they were considering might be owing to entirely different causes from similar conditions described by others. Hence a commensurate modification in therapy might not only be admissible, but eminently desirable. It is more especially of recent years that a laudable attempt to differentiate the various etiological factors involved in different forms of headache has been made. In 1832 Dr. James Mease, of Philadelphia published a monograph on "The Cause, Cure, and Prevention of the Sick Headache," which is substantially a treatise on the dietetics of this particular form of headache. The work, however, is conspicuously lacking in those philosophical qualities which are so necessary to a true understanding of the questions involved. Dr. E.H. Sieveking published in 1854[1] a most interesting paper on "Chronic and Periodical Headache." The views therein expressed are remarkable for their succinct and thoroughly scientific elucidation of the two great physiological principles involved in the consideration of by far the greater majority of instances of cephalalgia. I refer namely to the importance ascribed by this eminent physician to the fluctuations of the blood-stream within the cranial vault. In speaking of this subject Dr. Sieveking says: "Nothing is of more importance in reference to the pathology and therapeutics of the head than clear and well-defined notions on the physiological subject of the circulation within the cranium; for, among the various sources of medical skepticism, no one is more puzzling or more destructive of logical practice than a contradiction between the doctrine of physiology and the daily practice of medicine."

[Footnote 1: On Chronic and Periodical Headache, by E.H. Sieveking, M.D., _Medical Times and Gazette_ London, August 12, 1854.]

What Dr. Sieveking said in 1854 holds equally good to-day; and, indeed, the position then taken has received substantial indorsement through the positive results of more recent experimental physiology. Conspicuous in this connection are the inductive researches of Durham, Fleming, and Hammond, touching the modifications in the cerebral circulation during sleep and wakefulness. By these experiments it has been conclusively proved that the amount of blood in the brain is decreased during sleep and increased during wakefulness. More, recently I have had occasion to confirm the experiments of Fleming in this direction, and have published the results of those researches in various papers and articles.[1] "What Hippocrates said of spasm," says Dr. Sieveking, "that it results either from fullness or emptiness, or, to use more modern terms, from hyperæmia or anæmia, applies equally to headache; but, to embrace all the causes of this affection we must add a third element, which, though most commonly complicating one of the above circumstances, is not necessarily included in them, namely a change in the constitution of the blood." While I agree with Dr. Sieveking as regards the importance to be ascribed to the first two factors--cerebral hyperæmia and anæmia, in the production of the group of symptoms known as "headache,"--I fail to perceive why especial prominence should be given to the third condition mentioned by Dr. Sieveking. Indeed, I am quite unable to imagine how the periodical, and more especially the intermittent form, of headache is to be explained by what Dr. Sieveking describes rather ambiguously as a "change in the constitution of the blood." It is quite evident, admitting that such a change is capable of producing an amount of cerebral irritation sufficient to develop well-marked cephalalgia, that the latter must of necessity be within certain limits continuous. This is not the case, as the causative factor is constant and not fluctuating. I am, therefore, not prepared to accept this third causative factor without question. Nevertheless I am perfectly willing to admit that other factors besides cerebral hyperæmia and anæmia may produce the functional variety of headache. There would seem to be ample ground for ascribing great causative importance to excessive irritation of the brain plasma itself. Hence those forms of headache which while, being unaccompanied by any especial circulatory derangements, succeed, oftentimes, with relentless regularity upon any considerable degree of mental work. It is not my purpose to discuss the treatment of the multifarious forms of cephalalgia on this occasion, did time permit. As regards the so-called "neuralgic" variety I content myself by referring to the admirable work on "Neuralgia and Kindred Diseases of the Nervous System," by Dr. John Chapman of London, in which will be found many interesting facts bearing on the question. Accepting the propositions, then, that the more adjacent causes of headache are (1) cerebral hyperæmia, (2) cerebral anæmia, and (3) irritation of the cerebral plasma itself, let us now consider how these morbid factors are most scientifically and speedily met at the bedside; and how, more particularly, those distressing conditions of engorgement, which are so baneful an item in the causation of a certain form of cephalalgia, are best overcome.

[Footnote 1: _Vide_ Carotid Compression and Brain Rest, by J.L. Corning, M.D. New York: Anson D.F. Randolph & Co.]

Two years ago I began a series of experiments on epileptics and maniacs, which involved the application of protracted pressure to the common carotid artery on both sides. In the course of these experiments the thought suggested itself that suppression of the carotids might prove a salutary means of reducing that form of cerebral congestion which is so prolific a source of headache and vertigo. Accordingly I made a protracted series of experiments with carotid compression upon those suffering from congestive headache, and I can only say that I have been so far pleased with the uniformly good results obtained, that I have felt it a duty to call the attention of the profession to a procedure which, for obvious reasons, possesses all the advantages of local depletion by leeching or cupping, without the manifest disadvantages of either of these methods. The instruments which I have devised as substitutes for the primitive procedure of digital compression of the carotids have already been described in former communications. It is only necessary to say that the implements in question are of two kinds; one, the "carotid fork," is an adjustable instrument, which being held in the hand of the operator permits him to exert any degree of pressure upon both carotids for any desired length of time. The other instrument, which I have designated as the "carotid truss," for lack of a better name, is a circular spring provided with adjustable pads at each extremity. The spring is placed about the neck of the patient, and by suitable appliances the pads at the extremities can be placed directly above the trunks of the two common carotid arteries. By turning the screws to which the pads are attached the desired amount of pressure can be applied to the arteries, and the apparatus can be worn for any length of time by the patient.

With these instruments I have frequently succeeded in arresting the most obstinate form of congestive headache in an incredibly short time (on one occasion in about five minutes). Where, however, the headache is of manifestly nervous origin and uncomplicated by any especial circulatory derangements, I have never been able to achieve notable results with this method. Indeed, pressure upon the carotids is an excellent method of differentiating the congestive form of headache from the nervous varieties of head pains.

Of galvanism this much may be said, that it is one of the most valuable methods which we possess for treating the form of headache under consideration, for not only does it cause contraction of the smaller arteries, but it also exerts a soothing influence upon the plasma of the brain itself.

A powerful therapeutic agent, and one which has been more or less extensively employed in the treatment of various forms of head and spinal symptoms, is cold.

A very excellent method of applying both cold and galvanism to the head, at the same time, is afforded by a species of refrigerating electrode, designed by myself for this purpose. The apparatus in question consists of a concave sponge electrode, the concavity of which corresponds to the convexity of the external aspect of the cranium. Above the electrode is a chamber of metal or India-rubber, designed to contain ice. The whole is secured to the head of the patient by a single chin-strap, and connection established with an ordinary galvanic battery by means of an appropriate clamp and insulated cord. The indifferent pole is applied over the sternum or other convenient point. Care should be taken not to employ too strong currents, as otherwise vertigo and other unpleasant symptoms may be produced. An application of from five to ten minutes is usually sufficient to arrest the head-pain. As an additional security it is well to recommend the patient to take a hot foot-bath, and to remain as quiet as possible for twelve hours succeeding the treatment. In hyperæmic headache cupping and blood-letting have been recommended; but as a rule both procedures are not only unnecessary but positively inadmissible, as exclusion of the superfluous amount of blood by compression upon the carotids, followed by a corresponding dilatation of the peripheral circulation by means of the foot-bath, will almost always be sufficient to cause a permanent cessation of the symptoms. Among the internal remedies which may be employed with good effect in certain cases are aconite, bromide of potassium, and Indian hemp. The inhalation of from five to ten drops of chloroform is an excellent expedient in some instances. Chlorodyne, which is nothing more than a mixture of sedatives, often works well, and indeed frequently excels other remedies. The regulation of the heart's action is also of very great importance in these cases, and the physician should have no hesitancy in resorting to such remedies as digitalis and belladonna for the purpose of reducing the tension in the domain of the cerebral circulation. As a matter of course the digestive functions should be carefully looked to; the bowels should be kept open; and in all cases where there are indications of a congestive origin, alcohol in all forms should be absolutely forbidden.--_Med. Record_.

* * * * *

THE USE OF THE MULLEIN PLANT IN THE TREATMENT OF PULMONARY CONSUMPTION.

[Footnote: From a paper published in the _British Medical Journal_.]

By F.J.B. QUINLAN, M.D., M.R.I.A., F.K.Q.C P., Physician to St. Vincent's Hospital, Dublin.

From time immemorial, the _Verbascum thapsus_, or great mullein, has been a trusted popular remedy, in Ireland, for the treatment of the above formidable malady. It is a wild plant--most persons would call it a weed--found in many parts of the United Kingdom; and, according to Sowerby's _British Botany_, vol. vi., page 110, is "rather sparingly distributed over England and the south of Scotland." In most parts of Ireland, however, in addition to growing wild it is carefully cultivated in gardens, and occasionally on a rather extensive scale; and this is done wholly and solely in obedience to a steady popular call for the herb by phthisical sufferers. Constantly, in Irish newspapers, there are advertisements offering it for sale; and there are, in this city, pharmaceutical establishments of the first rank in which it can be bought. Still it does not appear in the Pharmacopoeia; nor, as far as I know, has its use received the official sanction of the medical profession. Some friends with whom I talked over the matter at the Pharmaceutical Conference at Southampton last August, suggested that it would be desirable to make a therapeutical research into the powers of this drug, and ascertain by actual experiment its efficacy or otherwise. Having partially accomplished this, I am anxious to very briefly set forth what has been done, in order that others may be induced to co-operate in the work.

"There are five mulleins, all belonging to the parent order of the Scrophulariaceæ; but the old Irish remedy is the great mullein, or _Verbascum thapsus_, a faithful delineation of which will be found in Plate 1, 437, vol. vi., of Sowerby. It is a hardy biennial, with a thick stalk, from eighteen inches to four feet high, and with very peculiar large woolly and mucilaginous leaves, and a long flower spike with ugly yellow and nearly sessile flowers. The leaves are best gathered in late summer or autumn, shortly before the plant flowers. In former times it appears to have been rather highly thought of, particularly as a remedy for diarrhoea; and Dioscorides, Culpepper, and Gerarde favorably allude to it.

"Having been furnished with a good supply of fresh mullein from a garden near this city, where it is extensively grown, I commenced operations. As it proved useful, subsequent supplies were procured from our drug-contractor.

"The old Irish method of administering the mullein is to place an ounce of dried leaves, or a corresponding quantity of the fresh ones, in a pint of milk; to boil for ten minutes, and then to strain. This strained fluid is given warm to the patient, with or without a little sugar. It is administered twice a day; and the taste of the mixture is bland, mucilaginous, comforting to the praecordia, and not disagreeable. I resolved to try this method, and also the watery infusion; and, moreover, the natural expressed juice fortified with glycerin. This latter preparation was carefully made for me, from fresh mullein leaves, by Dr. John Evans, chemist to the Queen and the Prince of Wales.