Chapter III: Part 3

RECENT STUDIES ON THE CONSTITUTION OF THE ALKALOIDS.

By SAMUEL P. SADTLER, Ph.D.

[Footnote: Introductory lecture, Course of 1883-84, Philadelphia College of Pharmacy.]

The sciences of to-day present, as might be expected, a very different aspect from the same branches of knowledge as they appeared fifty or sixty years ago. It is not merely that the mass of observations in most of these lines of study has enormously increased during this interval. Were that all, the change could hardly be considered as an unmixed benefit, because of the increased difficulty of assimilation of this additional matter. Many would be the contradictions in the observations and hopeless would be the task of bringing order out of such a chaos. The advance in the several branches of knowledge has been largely one resulting from improved methods of study, rather than one following simply from diligence in the application of the old ways.

Let us turn to chemistry for our illustration of this. The chemistry of the last century and the early decades of this was largely a descriptive science, such as the natural history branches, zoology, and botany are still in great part. Reasonably exact mineral analyses were made, it is true, but the laws of chemical combination and the fundamental conceptions of atoms and molecules had not been as yet generally established. Now, this want of comprehensive views of chemical reactions, their why and wherefore, was bad enough as it affected the study of inorganic and metallic compounds, but what must have been the conditions for studying the complex compounds of carbon, so widely spread in the vegetable and animal kingdoms. Their number is so enormous that, in the absence of any established relationships, not much more than a mere enumeration was possible for the student of this branch of chemistry. It is only within the last twenty years that chemists have attained to any comprehensive views at all in the domain of organic chemistry. It has been found possible to gradually range most carbon compounds under two categories, either as marsh-gas or as benzol derivatives, as fatty compounds or as aromatic compounds. To do this, methods of analysis very different from those used in mineral chemistry had to be applied. The mere finding out of percentage composition tells us little or nothing about an organic compound. What the elements are that compose the compound is not to be found out. That can be told beforehand with almost absolute certainty. What is wanted is to know how the atoms of carbon, hydrogen, oxygen, and nitrogen are linked together, for, strange to say, these differences of groupings, which may be found to exist between these three or four elements, endow the compounds with radically different properties and serve us as a basis of classification.

The development of this part of chemistry, therefore, required very different methods of research. Instead of at once destroying a compound in order to learn of what elements it was composed, we submit it to a course of treatment with reagents, which take it apart very gradually, or modify it in the production of some related substance. In this way, we are enabled to establish its relations with well defined classes and to put it in its proper place. Of equal importance with the analytical method of study, however, is the synthetical. This method of research, as applied to organic compounds, embodies in it the highest triumphs of modern chemistry. It has been most fruitful of results, both theoretical and practical. Within recent years, hundreds of the products of vegetable and animal life have been built up from simpler compounds. Thousands of valuable dye-colors and other compounds used in the arts attest its practical value. It may, therefore, seem anomalous when I say that one of the most important of all the classes of organic compounds has not shared in this advance. The alkaloids, that most important class from a medical and pharmaceutical point of view, have until quite recently been defined in the books simply as "vegetable bases, containing nitrogen." Whether they were marsh-gas or benzol derivatives was not made out; how the four elements, carbon, hydrogen, oxygen, and nitrogen, were grouped together in them was absolutely a thing unknown. Chemists all admitted two things--first, that their constitution was very complex, and, second, that the synthesis of any of the more important medicinal alkaloids would be an eminently desirable thing to effect from every point of view. Within the last five years, however, quite considerable progress has been made in arriving at a clearer understanding of these most important compounds, and I shall offer to your attention this evening a brief statement of what has been done and what seems likely to be accomplished in the near future.

It was early recognized that the alkaloids were complex amines or ammonia derivatives. The more or less strongly marked basic character of these bodies, the presence of nitrogen as an essential element, and, above all, the analogy shown to ammonia in the way these bases united with acids to form salts, not by replacement of the hydrogen of the acid, but by direct addition of acid and base, pointed unmistakably to this constitution. But with this granted, the simplest alkaloid formulas, those of conine, C_{8}H_{17}N, and nicotine, C_{10}H_{14}N_{2}, still showed that the amine molecule contained quite complex groups of carbon and hydrogen atoms, and the great majority of the alkaloids--the non-volatile ones--contained groups in which the three elements, carbon, hydrogen, and oxygen, all entered. Hence the difficulty in acquiring a knowledge of the molecular structure of those alkaloids at all comparable with that attained in the case of other organic compounds. Of course synthesis could not be applied until analysis had revealed something of the molecular grouping of these compounds, so the action of different classes of reagents was tried upon the alkaloids. Before summarizing the results of this study of the decomposition and alteration products of the alkaloids, a brief reference to a related class of organic compounds will be of assistance to those unfamiliar with recent researches in this field.

It is well known that in coal-tar is found a series of ammonia-like bases, aniline or amido-benzol, toluidine or amido-toluol, and xylidine or amido-xylol, which are utilized practically in the manufacture of the so-called aniline dye-colors. It is perhaps not so well known that there are other series of bases found there too. The first of these is the pyridine series, including _pyridine_, C_{5}H_{5}N, _picoline_ (methyl-pyridine), C_{5}H_{4}N(CH_{3}), _lutidine_ (dimethyl-pyridine), C_{5}H_{5}N(CH_{3})_{2}, and _collidine_ (trimethyl-pyridine), C_{5}H_{2}N(CH_{3})_{3}. This series is also found in relatively larger proportion in what is known as Dippel's oil, the product of the dry distillation of bones.

The second series is the quinoline series, including _quinoline_, C_{9}H_{7}N, _lepidine_ (methyl-quinoline), C_{10}H_{9}N, and _cryptidine_ (dimethyl-quinoline), C_{11}H_{11}N. The two compounds which give name to these series, pyridine, C_{5}H_{5}N, and quinoline, C_{9}H_{7}N, respectively, bear to each other a relation analogous to that existing between benzol, C_{6}H_{6}, and naphthalene, C_{10}H_{8}; and the theory generally accepted by those chemists who have been occupying themselves with these bases and their derivatives is that pyridine is simply benzol, in which an atom of nitrogen replaces the triad group, CH, and quinoline, the naphthalene molecule with a similar change. Indeed, Ladenberg has recently succeeded in obtaining benzol as an alteration product from pyridine, in certain reactions. Moreover, from methyl-pyridine, C_{5}H_{4}N(CH_{3}), would be derived an acid know as pyridine-carboxylic acid, C_{5}H_{4}N(COOH), just as benzoic acid, C_{6}H_{5}COOH, is derived from methyl-benzol, C_{6}H_{5}CH_{3}, and from dimethyl-pyridine, C_{5}H_{3}N(CH_{3})_{2}, an acid known as pyridine-dicarboxylic acid, C_{5}H_{3}N(COOH)_{2}, just as phthalic acid, C_{6}H_{4}(COOH)_{2}, is derived from dimethyl-benzol, C_{6}H_{4}(CH_{3})_{2}. The same thing applies to quinoline as compared to naphthalene.

We may now look at the question of the decomposing effect of reagents upon the alkaloids. The means which have proved most efficacious in decomposing these bases are the action of oxidizing and reducing agents, of bromine, of organic iodides, of concentrated acids and alkalies, and of heat.

Taking up the volatile alkaloids, we find with regard to _conine_, first, that the action of methyl iodide shows it to be a secondary amine, that is, it restrains only one replaceable hydrogen atom of the original ammonia molecule. Its formula is therefore C_{8}H_{16}NH. From conine can be prepared methyl-conine, which also occurs in nature, and dimethyl-conine. From this latter has been gotten a hydrocarbon, C_{8}H_{14}, conylene, homologous with acetylene, C_{2}H_{2}. Conine, on oxidation, yields chiefly butyric acid, but among the products of oxidation has been found the pyridine carboxylic acid before referred to. The formula of conine, C_{8}H_{17}N, shows it to be homologous with piperidine, C_{5}H_{11}N, a derivative of piperine, the alkaloid of pepper, to be spoken of later; and, just as piperidine is derived from pyridine by the action of reducing agents, so conine is probably derived from a propyl-pyridine. The artificial alkaloid paraconine, isomeric with the natural conine, will be referred to later.

_Nicotine_, C_{10}H_{14}N_{2}, the next simplest in formula of the alkaloids, is a tertiary base, that is, contains no replaceable hydrogen atoms in its molecule. It shows very close relations to pyridine. When nicotine vapor is passed through a red-hot tube, it yields essentially collidine, and, with this, some pyridine, picoline, lutidine, and gases such as hydrogen, marsh-gas, and ethylene. Heated with bromine water to 120°C. it decomposes into bromoform, carbon dioxide, nitrogen, and pyridine. When its alcoholic solution is treated with ferricyanide of potassium it is oxidized to dipyridine, C_{10}H_{10}N_{2}. Potassium permanganate, chromic or nitric acid oxidises it to nicotinic acid, C_{6}H_{5}NO_{2}, which is simply pyridine-carboxylic acid, C_{5}H_{4}N(COOH), and which, distilled over quick-lime, yields pyridine, C_{5}H_{5}N.

Turning now to the non-volatile and oxygenized bases, we take up first the opium alkaloids. _Morphine_, C_{17}H_{19}NO_{3}, is a tertiary amine, and appears to contain a hydroxyl group like phenols, to which class of bodies it has some analogies, as is shown in its reaction with ferric chloride. Its meythl ester, which can be formed from it, is _codeine_, one of the accompanying alkaloids of opium. Besides the methyl derivative, however, others are possible, and several have been recently prepared, giving rise to a class of artificial alkaloids known as _codeines_. Morphine, rapidly distilled over zinc dust, yields phenanthren, trimethyl-amine, pyrrol, pyridine, quinoline, and other bases. The action of strong hydrocholoric acid upon morphine changes it into apomorphine, C_{17}H_{17}NO_{2}, by the withdrawal of a molecule of water. Ferricyanide of potassium and caustic soda solution change morphine into oxidimorphine, C_{34}H_{36}N_{2}O_{6}. When heated with strong potassium hydrate, it yields methylamine.

_Narcotine_, another of the opium alkaloids, when heated with manganese dioxide and sulphuric acid, is oxidized and splits apart into opianic acid, C_{10}H_{10}O_{5}, and cotarnine, C_{12}H_{13}NO_{3}. This latter, by careful oxidation, yields apophyllenic acid, C_{8}H_{7}NO_{4}, and this, on heating with hydrochloric acid to 240° C., yields pyridine-dicarboxylic acid, C_{5}H_{9}N(COOH)_{2}. The base cotarnine also results from the prolonged heating of narcotine with water alone. In this case, instead of opianic acid, its reduction product meconine, C_{10}H_{10}O_{4}, is produced.

_Meconic acid_, C_{7}H_{4}O_{7}, which is found in opium in combination with the different bases, has also been investigated. By acting upon meconic acid with ammonia, comenamic acid is formed, and this latter, when heated with zinc dust, yields pyridine.

If we go now to the cinchona alkaloids, we meet with exceedingly interesting results. _Quinine_, C_{20}H_{24}N_{2}O_{2}, when carefully oxidized with chromic acid or potassium permanganate, yields a series of products. First is formed quitenine, C_{19}H_{22}N_{2}O_{4}, a weak base, then quininic acid, C_{11}H_{9}NO_{3}, then the so-called oxycinchomeronic acid, C_{8}H_{5}N0_{6}, and finally cinchomeronic acid, C_{7}H_{6}NO_{4}. Now the two acids last mentioned are simple substitution products of pyridine, oxycinchomeronic acid being a pyridine-dicarboxylic acid, C_{5}H_{2}N(COOH)_{3}, and cinchomeronic acid, a pyridine-dicarboxylic acid, C_{5}H_{3}N(COOH)_{2}. When distilled with potassium hydrate, quinine yields quinoline and its homologues. The alkaloid has been shown to be a tertiary base.

_Quinidine_ yields with chromic acid the same decomposition products as quinine.

_Cinchonine_, C_{19}H_{22}N_{2}O, the second most important alkaloid of these barks, when oxidized with potassium permanganate, yields cinchonic acid, which is a quinoline-carboxylic acid, C_{9}H_{6}N(COOH), cinchomeronic acid, which has just been stated to be a pyridine dicarboxylic acid, and a pyridine tricarboxylic acid. When cinchonine is treated with potassium hydrate, it is decomposed into quinoline and a solid body, which on further treatment yields a liquid base, C_{7}H_{9}N, which is probably lutidine. It has been found, moreover, that both tetrahydroquinoline and dihydroquinoline, hydrogen addition products of quinoline, are present. When cinchonine is distilled with solid potassium hydrate, it yields pyrrol and bases of both the pyridine and quinoline series.

_Cinchonidine_, when heated with potassium hydrate, yields quinoline also, and with nitric acid the same products as cinchonine.

_Strychnine_ has been found to be a tertiary amine. When distilled with potassium hydrate, quinoline is formed.

_Brucine_ is a tertiary diamine, that is, formed by substitution in a double ammonia molecule. When distilled with potassium hydrate it yields quinoline, lutidine, and two isomeric collidines.

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.

"Some phthisical sufferers, of whom there are here, alas! too many, were now admitted from time to time into St. Vincent's Hospital. They were admitted in all stages, from an early one to the most advanced. On each admission the case was carefully examined; the history, symptoms, and physical signs were exactly noted; and the patient was weighed on a stage balance with great accuracy. The patient was put as much as possible on the mullein treatment only. For obvious reasons, no cod-liver oil, koumiss, or other weight producer was given; the patients got the diet suitable to such sufferers; and, if the special symptoms became troublesome, received appropriate treatment. As much as possible, however, they were left to the mullein--a proceeding which was entirely satisfactory to themselves. In addition to the admission weighing, they were carefully weighed every week, and care was taken that this should be done as nearly as possible on the same day and hour, with the same clothes, and, in fact, as much as could be under the same conditions. In securing this the patients anxiously co-operated; and it was frequently amusing, but sometimes painful, to watch the satisfaction or chagrin with which the weekly result was received. I must here tender my acknowledgments to our zealous, attentive, and accurate house surgeon, Mr. Denis P. Kenna, by whom this important, but tedious, duty was discharged."

Dr. Quinlan then refers to several cases, in which the mullein plant has been tried as a remedy for consumption, and remarks that these cases, although too few to justify any general conclusion, appear to establish some useful facts. The mullein plant boiled in milk is liked by the patients; in watery infusion it is disagreeable, and the succus is still more so. The hot milk decoction causes a comfortable (what our Gallic neighbors call _pectorale_) sensation, and when once patients take it they experience a physiological want, and when the supply was once or twice interrupted, complained much in consequence. That it eases phthisical cough there can be no doubt; in fact, some of the patients scarcely took their cough mixtures at all--an unmixed boon to phthisical sufferers with delicate stomachs. Its power of checking phthisical looseness of the bowels was very marked, and experiment proved that this was not merely due to the well known astringent properties of boiled milk. It also gave great relief to the dyspnoea. For phthisical night sweats it is utterly useless; but these can be completely checked by the hypodermic use of from one-eighteenth to one-fiftieth of a grain of the atropia sulphate; the smaller dose, if it will answer, being preferable, as the larger causes dryness of the pharynx, and interferes with ocular accommodation. In advanced cases, it does not prevent loss of weight, nor am I aware of anything that will, except koumiss. Dr. Carrick, in his interesting work on the koumiss treatment of Southern Russia (page 213), says: "I have seen a consumption invalid gain largely in weight, while the disease was making rapid progress in her lungs, and the evening temperature rarely fell below 101° Fahr. Until then I considered that an increase of weight in phthisis pulmonalis was a proof of the arrest of the malady." If koumiss possesses this power, mullein does not; but unfortunately, as real koumiss can be made from the milk of the mare only, and as it does not bear traveling, the consumptive invalid must go at least to Samara or Southern Russia. In pretubercular and early cases of pulmonary consumption, mullein appears to have a distinct weight-increasing power; and I have observed this in several private cases also. Having no weighings of these latter, however, makes this statement merely an expression of opinion. In early cases, mullein milk appears to act very much in the same manner as cod-liver oil; and when we consider that it is at once cheap and palatable it is certainly worth a trial. I will continue the research by careful weighings of early cases; and will further endeavor to ascertain whether the addition of mullein to the cultivating solution prevents the propagation of the phthisical bacillus.

* * * * *

ACTION OF MINERAL WATERS AND OF HOT WATER UPON THE BILE.

Lewaschew and Klikowitch, from experiments upon dogs, conclude that the use of ordinary alkaline mineral waters was to increase the quantity of bile and to make it more fluid and watery. This increased flow is beneficial in clearing out any bile stagnating in the gall-bladder. A subsequent increase in the quantity of bile indicates a greater flow of bile into the gall-bladder, and this also is of service in emptying out any stagnant bile, and restoring the normal condition when this is disturbed. Artificial solutions of alkaline salts were found to have a similar action to the natural mineral waters, and, as with them, the action varies according to the concentration of the solution. Bicarbonate of sodium has a quicker, more powerful, and more lasting effect on the composition of the bile than the sulphate of sodium, and weak solutions than strong ones. Vichy was more efficacious than Carlsbad water. Hot water was found to have an effect on the bile much like that of the mineral waters.

* * * * *

VIVISECTION.

Although Magendie is rightly considered the true initiator of experimentation upon living beings, the practice of vivisection is as old as science itself.

Galien, the physician of Marcus Aurelius (in the second century of the Christian era), dissected living animals, and yet he is regarded as having merited his name (_Galenus_, "gentle") from the mildness of his character. Five centuries before him, under the Ptolemies, Egyptian experimenters had operated upon condemned persons. So, then, vivisection is not, as usually thought, a diabolical invention of modern science.

In all ages the necessity has been recognized of operating upon animals that are nearest allied to man, such as the monkey, the hog, and the dog, and who share with the king of creation the privilege of eating a little of everything. Claude Bernard, however, had another way of looking at things. It is true that he especially made researches into the general laws of physiology, the secret of the vital functions, and the operation of the various organic systems that constitute living matter, but his immediate object was not to furnish weapons for the art of curing. He left to physicians and surgeons the care of drawing conclusions from his great work in biology, and of acting experimentally upon animals allied to man in order to found a rational system of therapeutics. So he preferred to operate upon beings placed low in the animal scale--the frog especially, an animal that has rendered him greater service than even man himself could have done. Cold-blooded animals offer, moreover, the advantage of being less impressionable than others, and the experiments to which they are submitted present more accurate conclusions, since it is not necessary to take so much account of the victim's restlessness. And then it is necessary in many cases to choose subjects that possess endurance. The unfortunate frog, so aptly named "the Job of physiology," becomes resigned to living under most dreadful conditions, and when, through sheer exhaustion, he has succumbed, his twitching limbs may still he used as an object of experimentation for twenty-four hours. Thanks are due to nature for giving so extraordinary a vitality to the tissues of a modest batrachian! We owe to it the famous experiment of Galvani that led Volta to the discovery of the pile and what followed it, the astonishing conquests of electricity and those more marvelous ones still that are now in their dawn. Science is much indebted to the frog, and may the homage that we pay him help to alleviate the sufferings that have been imposed upon this brave animal!

The simple fact that we have just enunciated pleads loudly enough for the cause of vivisection to make it useless to defend it. No one, however, has risen to ask for an absolute proscription of it, but it is only desired that the abuse of an abominable practice shall be curbed. Does the abuse exist? That is the question, and it may be answered in the affirmative. Yes, we do sometimes impose useless sufferings upon animals. It is a culpable folly, a beastly cruelty, to constantly repeat barbarous experiments with the object of exhibiting a well known physical fact, a hundred times verified and always the same, when it would only be necessary to enunciate it. But this is not the place to expatiate upon the subject. After proclaiming the utility of vivisection, we give it as our opinion that the practice of it should be confined within narrow limits. It is not too much to ask that it be confined to the privacy of laboratories, with the exclusion of visitors, and to require from students a diploma guaranteeing their knowledge and giving a programme of researches to be made. It is useless to seek in the living what a study of the corpse reveals in all its details.

And now, after these preliminary remarks, we present herewith a series of cuts representing the various apparatus used in the practice of vivisection, which are taken from a recent work by Claude Bernard. Fig. 1 shows the mode of muzzling a dog with a strong cord placed behind an iron bit. Fig. 2 shows a method of tying a dog. Fig. 3 is a vessel in which hares or cats are placed in order to anæsthetize them. Fig. 4 shows the mode of fixing an animal on its side, and Fig. 5 the mode of fixing him on his back. Fig. 6 shows a dog fixed upon the vivisecting table, and Fig. 7 a hare secured to the same. Fig. 8 exhibits the general arrangement of a vivisecting table, properly so called. Fig. 9 shows (1) an anæsthetizing muzzle applied to a dog, and (2) the extremity of the apparatus in section. Fig. 10 shows how the muzzle is applied for anæsthetizing, and gives the details of construction of the chloroform box. Fig. 11 exhibits the arrangement of the apparatus used for holding the animal's jaws open upon the vivisecting table.--_L'Illustration_.

* * * * *

INSANITY FROM ALCOHOL.

[Footnote: Read at the late meeting of the National Association for the Protection of the Insane and translated for the American Psychological Journal by Carl Sieler, M.D., of Philadelphia.]

By A. BAER, M.D., of Berlin, Germany.

The benevolent efforts of your society diverge in two different directions, which have totally different aims and purposes, and which require different means in order to attain lasting success. Since the number of insane has increased alarmingly within the last few years, in all civilized countries, so that the responsibility of the proper charge of them occupies continually not only the community, but also the State; and since the public as well as the private asylums are filled almost before they are finished, it becomes necessary to rid the institutions, as soon as possible, of those patients which have been cured, as well as of those which are improved. Patients of this kind are, as early as possible, returned to the unrestrained enjoyment of liberty with the expectation that the new scenes and surroundings may have a beneficial influence, besides having the advantage of relieving the overcrowded institutions. Unfortunately, however, it has been frequently found that the hut suddenly restored mental and emotional equilibrium is not of sufficient stability to withstand the storm of conflicting interests. Frequently it happens that the but recently discharged patient returns to the institution, after a short lapse of time, because the "rudder" (steuer) of his intelligence was soon shattered in the turmoil of life. How can, for instance, the indigent and poor patient, after his discharge from the institution in which he has found a shelter and the proper care, stand up in the struggle for existence and the support of his family? Is it not to be expected that a large proportion of those who have been discharged as improved, or even cured, cannot withstand the ever-moving sea of the outside life and bear up under the turmoil which constantly stirs mind and soul?

Starting with the recognition of this fact, societies of benevolent people have been formed in all countries in which true civilization and humanity are at work, to diminish or abolish social evils, whose object is to assist the restored patient who has been discharged from the institution, at a time when he is most in need of help and assistance. Switzerland has taken the lead of all countries by her brilliant example, and there these societies found the greatest encouragement. It should be looked upon as a good sign of the spirit of modern times, that the seed of true humanity, with astonishing rapidity, found its way, far and wide, for the benefit of suffering mankind. Everywhere, in all European countries, and also on the American continent, has this branch of a truly noble thought become acclimated, and many societies have been organized for the purpose of assisting cured insane patients, by aiding them in obtaining suitable occupations, or by direct donations of money, etc., with a view of preventing, if possible, a relapse of the disease. May this portion of the work of your society be an ever-flowing fountain of joy and satisfaction to your members!

Of much greater importance is the best portion of your work, namely, _the prevention of insanity_. It is nevertheless true, and cannot be doubted, that in all civilized countries insanity increases in a manner which is out of proportion to the increase of the population. Much thought has been given to the cause of this phenomenon, and physicians as well as moralists, national economists as well as philosophers and philanthropists, have endeavored to fathom the connection between this fact and the conditions of modern social life. According to all observations, it is certain that the cause of this phenomenon is not a single etiological condition, but that it is the sum of a number of influences which act upon the human race and produce their travages in the mental and moral life of our patients. The conditions which give rise to this increase of insanity may be looked for in the manner in which modern civilization influences mankind, in its development and culture, in the family and in the school-room, in its views of life and habits; also in the manner in which civilization forces a man to fight a heavier and harder battle for pleasure and possessions, power and knowledge, and causes him to go even beyond his powers of endurance.

More than even civilization itself, are at fault those pernicious abnormities, rare monstrosities, which are transmitted from generation to generation, or are also often newly developed and appear to belong to our civilization. If we want to prevent the increase of insanity, we must endeavor to do away with these monstrosities and eccentricities from our social life which remove mankind more and more, in a pernicious manner, from its natural development and from the normal conditions of moral and physical life; we must endeavor to kill these poisonous offshoots of pseudo civilization, which are the enemies of the normal existence of man. It is necessary to liberate the individual, as well as the entire society of modern times, from the potentiated egotism which spurs man on in overhaste, and in all departments of mental and physical life, to a feverish activity, and then leads to an early senile decay of both body and mind; from that terrible materialism which causes the modern individual in every class of society to find satisfaction in over excited taste and ingenious luxury. It is necessary to strengthen more than has been done heretofore the young, by means of their education, in their physical development, and at the same time to diminish, in proper proportion, the amount of mental over-exertion; and finally it is necessary to fight against, to do away with, those habits of modern society-life which have a pernicious influence upon the physical as well as the mental and moral organization of man. And of these latter, there is none so lasting in its effects, none so harmful to the physical as well as moral life, as the abuse of intoxicating liquors.

Intemperance is an inexhaustible source of the development and increase of insanity. It demands our undivided attention, not only on account of its existing relation, but particularly because intemperance, among all the factors which aid in the increase of insanity, can best be diminished, and its influence weakened, through the will of the single individual, as well as of society as a whole. The relation between intemperance and insanity is so definite and clear, that it is not necessary to adduce proofs of this fact. I will not refer to the writings of the older authors, such as Rush, in America; Hutchison, Macnish, Carpenter, and others, in England; Huss and Dahl, in Sweden; Ramaer, in Holland; Esquirol, Pinel Brierre de Boismont, Morel, and others, in France; Flemming, Jameson, Roller, Griesinger, and others, in Germany. I could name a much larger number of the greatest modern authorities on insanity, who are all unanimous in their opinion that the increase of intemperance (alcoholism) produces a corresponding increase of insanity. Of especial interest is this fact in those countries in which the consumption of concentrated alcohol, and particularly in the form of whiskies distilled from potatoes and corn, has only in later years become general. Thus Lunier has shown the number of alcoholic insane increased by ten per cent. in those departments in which more whisky and less wine is consumed.

In Italy a similar result has been reached by investigation; and in that country (according to Kanti, Sormani, Vesay, Rareri, Castiglione, Ferri, and others) the frequency of insanity caused by the abuse of alcohol stands in an unmistakable relation to the consumption of alcohol in certain provinces of Italy.