^Ma^j#«»w>|>w*» ^ W^ ^ LIBRARY OF CONGRESS. %p (8oppT$t ftt.- Shelf _B&.\S\ L-L!o_ UNITED STATES OF AMERICA. THE INCIDENTAL EFFECTS OF DRUGS PHARMACOLOGICAL /ND CLINICAL HAND-BOOK DR. L. LE WIN ASSISTANT AT THE PHARMACOLOGICAL INSTITUTE OF THE UNIVERSITY OF BERLIN TRANSLATED BY V W. T. ALEXANDER, M.D. tp NEW YORK WILLIAM WOOD & CO M P A N Y v Copyright by WILLIAM WOOD & COMPANY. 1882. STEAM PRESS OF H. O. A. Industrial School, 189 E. 76TH Street. TRANSLATOR'S PREFACE. A recognition of the importance of a knowledge of the incidental, accidental, or unexpected effects (Nebenwirkun- gen) of drugs upon the various organs and systems of the body, has led the translator of this manual to believe that it will prove of interest and advantage to a larger number of readers than it can obtain in its original form alone. The literature of the subject of which it treats, as far, at least, as he is familiar with it, is comparatively meagre, the only systematic work upon it being one confined to the study of a single organ, viz., a portion of the interesting book of Dr. H. G. Piffard, upon the " Materia Medica and Therapeutics of the Skin." In view of the active interest which is at present taken in the study of materia medica and therapeutics, especially in this country, it is to be hoped that others may be stimu- lated to study and record with more care than in the past the peculiar actions of drugs upon individual organs. W. T. A. PREFACE. The science of materia medica, as an essential connect- ing link between purely experimental investigation and empiricism, receives contributions both from the labora- tory and from observation at the bedside. The facts ob- tained from these sources present in their totality the picture of the typical mode of action of individual drugs. But in the therapeutic employment of certain drugs, de- viations sometimes occur from this typical and, as one may say, normal action, whose recognition and correct in- terpretation are not always easy. A knowledge of them is, however, of great importance to the physician, since they may, in a given case, shed light upon the cause of the unexpected phenomena which show themselves, and also furnish indications to guide him in his practical interfe- rence. The individual facts bearing upon this subject, the phe- nomena of abnormal drug-action, are widely scattered through medical literature, and are either not at all men- tioned, or are only superficially treated of in text-books on materia medica and therapeutics. For this reason I have for a long time occupied myself in collecting and anno- tating them, and in making additions to their number from my own experience. The result is contained in this w T ork, which will, I hope, not only satisfy practical require- ments, but also stimulate to further observations in this direction. L. Lewin. Berlin, January, 1881. CONTENTS. PAGE Introduction I Tonics 29 Astringents 51 Acids * 70 Alteratives *77 Excitants 131 Narcotics 134 Evacuants 196 Purgatives 196 Emetics '. 200 Diuretics 206 Expectorants 207 Antiparasitics 208 Sudorifics , 215 Emollients 221 Rubefacients and Vesicants , .222 A The Incidental Effects of Drugs. INTRODUCTION. Drugs act locally in the animal economy , i. c, they influence exclusively, or in a particular manner, according to their chemical or physical properties, certain classes of cells or cellular structures. " Certain substances have affinities for certain parts of the body " is an axiom first enunciated by Virchow, 1 upon which it follows as a natu- ral consequence, that certain drugs, in addition to their curative effects, may, by either a direct or reflex action, produce symptoms affecting homologous or heterologous cell-groups which, for therapeutic purposes, should not be acted upon. After the administration of opiates, for instance, not only is an influence exerted upon the central nervous system, but also upon peripheral nerve-centres and nerves, so that, in addition to a more or less pro- nounced hypnotic effect, there occurs a temporary paraly- sis of the nerves which regulate the movements of the intestines, and in consequence of this, a stagnation of the intestinal contents. When tartar emetic is taken, vomit- ing occurs in consequence of irritation of the gastric mucous membrane, and at the same time, the activity of Virchow: Specificer und Specifisches, Archiv f. path. Anatomie, Bd. vi., p. 24. I 2 INCIDENTAL EFFECTS OF DRUGS. the heart is lessened by the direct action of the drug upon its substance. The inhalation of chloroform produces an effect upon the nerve-centres, particularly the cerebrum, and, by a reflex action from the respiratory mucous membrane, the action of the heart is also interfered with. While, therefore, homogeneous elements of a nervous nature, in different regions of the body, are affected by opium and chloroform, the antimony in tartar emetic exerts its influence upon heterogeneous tissues, viz., mucous membranes and muscles. In an analogous man- ner, substances which possess the inherent power of influencing a still greater number of cell-forms, may pro- duce a whole chain of pathological symptoms. Such effects as these are, however, regarded as physiological, because while inseparable from one another, they belong in their totality to the action of the drug. The individ- ual symptoms are only separated from each other when, in accordance with the therapeutic indication for the drug, it becomes desirable to distinguish between pri- mary and incidental action. § 2 - Although, in this manner, nearly all active drugs exert the influences peculiar to themselves upon certain groups of cells, e. g., a diseased organ, and thus bring about cura- tive results, it not infrequently happens that in the cases of certain persons, the desired local effect is not produced, the drug proving itself " inactive." Thus, chloroform may fail to produce anaesthesia, quinine to reduce a swol- len spleen, and cathartics, even those belonging to the class of drastics, to cause an evacuation. If the drugs used be of good quality (which in this case is taken for granted), the cause of this anomalous result can lie only in the person taking the remedy. His organ- ization, or the structure of the healthy or diseased parts upon which it is desired to act, must be different from that INTRODUCTION. 3 of the same parts in other persons. The same postulate must be advanced for such individuals as possess an organization exceptional as regards its capacity for resisting disease, in consequence of which they are never attacked by certain contagious maladies, e. g., exanthematic typhus. In the latter, as in the former cases, the immunity may be due, not to gross anomalies of structure, which will be dis- cussed later at greater length, but to physiological differ- ences in tissues or organs. It will be readily understood that, if certain organs of an individual fail to respond to the action of certain drugs which ordinarily produce well-known functional effects, therapeutical experiments with these drugs may lead to erroneous conclusions, when made upon such persons. This fact may perhaps explain the often diametrically opposed results which follow the use of a given drug in different persons. §3- Of far greater importance to the physician than the non-occurrence of a normal drug effect, are the not infre- quently observed incidental effects of remedies, which either take the place of the normal action, or appear simul- taneously with it. The administration of quinine, for instance, is not uncommonly followed by the appearance of a polymorphous exanthema, or, in very rare cases, intense effects upon the organ of vision, manifested by permanent amaurosis. The usually somewhat inert cod- liver oil may cause vesicular eruptions, iodide of potassium induce hypersecretion from the ocular and nasal mucous membranes, and salicylic acid excite, among other effects, sweating and phenomena of irritation of the nervous sys- tem. Many different designations for the anomalous symp- toms produced by drugs are found in literature. In Ger- many, they were and are still called " Nebenwirkungen," 4 , INCIDENTAL EFFECTS OF DRUGS. " physiologische Nebenwirkungen," " Arzneisymptome," also accidental, or special, or peculiar effects. French authors designate them " inconvenients," or "inconve- nients therapeutiques," also, " accidents," or " cas d'acci- dents." In England, they are sometimes called " acciden- tal poisoning." Writers have always hesitated to regard these incidental effects as toxicological, and with justice, for we are not warranted in pronouncing one or more symptoms, which do not appear in a thousand cases after taking a drug, to be the result of poisoning when they show themselves in the next case. It is further to be remembered that the majority of these incidental effects in no wise correspond to the symptoms produced by a poisonous dose of the same drug, and that we cannot produce them at will, especially those affecting the skin. These appear only under definite individual conditions, and are, therefore, almost beyond the reach of experimental provocation. Up to the present time, there has been no lack of physi- cians thoroughly imbued with humoral-pathological ideas, who, in given cases, attribute a certain teleological significance to the appearance of incidental drug effects, such as was formerly claimed, e. g., for hemorrhage from the hemorrhoidal vessels. In the same manner as it was then regarded as a fortunate circumstance that the " anima " which presided over the vascular system should have chosen the hemorrhoidal vessels for the elimination of "impurities" from the body, were the "drug symp- toms," particularly those affecting the skin, considered as the expression of a struggle between the drug and the morbid humors of the blood, by which the latter, either through functional changes or material anatomical lesions, gave evidence of their subjection or their elimination from the body. In opposition to this vitalistic humoral-pathological aspect of the subject, another hypothesis has been ad- INTRODUCTION. 5 vanced to explain the occurrence of incidental drug- effects, as well of those which are the almost constant attendants upon every drug-action, as of those which dnly occasionally appear. Their causes may be either pe- culiar to the individual, or dependent upon temporal or local influences, or the quality of the drug. The former shall be first considered. §4. The peculiarity of each individual, as compared with others, may be permanent or of limited duration. It is most strikingly manifested when the person is exposed to the manifold occasional causes of disease. The same external noxious influence acting upon the organism is capable of producing such different effects upon different individuals, that while some are affected to a scarcely appreciable extent, others are only temporarily injured, and others again experience permanent functional de- rangements. Individual susceptibility to external influ- ences varies, therefore, within wide limits. It may be so great that causes belonging to the domain of physiol- ogy may be capable of producing pathological manifesta- tions. The smelling of a rose, the tasting of a strawberry, etc., may cause in certain persons nervous disturbances or changes in the skin (thus proving the existence of a condi- tion called heightened individual irritability or idiosyn- crasy), while the immense majority of persons are in no wise affected by such agencies. Analogous appearances sometimes show themselves after the external or internal use of certain drugs. The extract of Calabar bean, instilled into the eye, causes in certain persons only a burning sensation in the conjuncti- val sac and increased lachrymation ; morphia, taken inter- nally, causes spasm of the accommodation in excitable subjects only, and pilocarpine, in certain cases and in cer- tain doses, induces profuse sweating, while others, after 6 INCIDENTAL EFFECTS OF DRUGS. the same doses, experience a scarcely perceptible increase of this function. Here we see, under conditions otherwise similar, variations in the influence of external agencies upon homologous tissues, which can only be explained upon the ground of the existence of individual peculiarities. To the question, what is the nature of these peculiarities ? it is impossible to give an entirely satisfactory answer. Only recently have comparative investigations been under taken into the physical behavior of certain organs, the heart, blood-vessels, intestines, etc., in individuals of differ- ent sexes and ages, in the hope of arriving at a compre- hension of so-called constitutional peculiarities. There are furthermore, as we shall see later, a number of physiological processes going on in the body, which render it under certain circumstances peculiarly predis- posed to disease, and we are familiar with pathological conditions of so trivial a nature that they pass unrecog- nized during life, but which render the individual in whom they occur highly susceptible to irritation. But do all these factors suffice to explain " the mystery of individuality," as Virchow calls it ? Certain] v not ! When we recall only a few of the minutiae which must be taken into account, e. g., the infinitely great differences in the distribution of blood-vessels in organs, the multiform arrangement of glandular tissues in glands, the deviations in innervation of organs, the differences in size of indi- vidual nerves and in the distribution of nerve-plexuses, the variations in the gross and histological construction of the same muscles in different individuals, we must confess, that not only is our present ignorance great, but that it will always continue. It is nevertheless wrong to entirely ignore the existence of individuality, or to deny its im- portance. " The possibility of explanation," as Virchow says, "is no test of knowledge, for we know many things empirically whose causes we cannot comprehend. No exact investigation, either anatomical or physiological, patho- INTRODUCTION. 7 logical or therapeutical, has ever succeeded in lifting the veil which conceals the conditions governing individual peculiarities. In all times it has been regarded as the pecu- liar prerogative of exceptionally gifted spirits or of great experience to possess that subtle insight which enables one to recognize, even approximately, the specific charac- ter of the individual." It is so well known as to hardly need mention, that since the existence of medicine as a practical and descriptive art, constitutional peculiarities have been ap- preciated and made the object of investigation. The doc- trine of temperaments, the recognition of the sanguine, phlegmatic, and melancholic constitutions, under the hypothesis, that in accordance with the preponderance in the body of the blood, bile, mucus, and black bile, individual peculiarities are established, was for centuries the firm foundation which remained standing after the disappear- ance of all other medical theories, and although, as the quintessence of humoral pathology, the doctrine is highly one-sided and rests upon a false basis, it is still in complete harmony with the effort to properly appreciate subtle individual peculiarities. The factors to be considered in the study of the latter cannot be of a gross nature. This is especially true of the specific peculiarities of particular organs. If anything is essentially calculated to support the dictum of Virchow 1 that " the reaction of the tissues does not depend primarily upon external influences, but upon their intimate struc- ture," it is the individual peculiarities which the tissues of certain persons manifest under the influence of drugs. The application of the tincture of iodine to the skin pro- duces usually only an erythema, and yet there are persons upon whom the same preparation causes vesiculation and 1 Virchow: Krankheitswesen und Krankheitsursachen. Archiv f. path. Anat., • Ed. 79, Heft i., p. 10. 8 INCIDENTAL EFFECTS OF DRUGS. extensive oedema. Even an absolutely inert ointment, made out of any fresh fat, may cause inflammation when rubbed upon the skin of some persons. In such cases, the cause of the unusual effect can only be the existence of subtle alterations in the component parts of the skin, which are physically and chemically unrecognizable. The difficulty of regarding such great functional differences as the consequence of slight variations in the structure of the organ in question, is easily overcome when we consider the differences in the chemical and physical behavior of isomeric bodies, i. e., those which contain the same ele- ments united in the same proportions. In these, a change in the relative position of certain molecules produces so great a difference in their character that they seem essen- tially distinct from each other. Nevertheless, in them the number of atoms of carbon, hydrogen, and oxygen is always the same, as in pyrogallic acid and phloroglucin, hydroquinone, resorcin, and pyrocatechin. The behavior of allotropic bodies may here also be recalled. These, probably on account of differences in molecular arrange- ment, although of identical chemical composition, manifest widely differing physical characteristics, as in the well- known case of carbon in the form of the diamond, gra- phite, and coal. It is easy to imagine that certain organs in certain per- sons are so constituted that, although of the same chemical composition, and even the same histological structure, they are nevertheless so different from others that they respond to a trivial irritation, or show an abnormally intense reac- tion under ordinary stimulation. §5- We have hitherto considered only individuals or organs in their varying relations to others of the same kind. Although the differences which we have thus far found to exist are extraordinarily great, they are nevertheless ex- INTRODUCTION. g ceeded by those manifested by similar and dissimilar organs in the same individual tinder the influence of external agencies, especially those of a medicinal nature, without regard to whether the action is primary, or secondary and reflected. Even the physiological working power of certain simitar organs may be different. The lifting power of a gastroc- nemius muscle of one side is seldom, under the same external conditions, identical with that of the muscle of the other side, or the irritability of a nerve equal to that of the corresponding nerve. The explanation of this fact is to be sought in the natural differences in size of the functional elements of the parts, one muscle containing more primi- tive fibres than its fellow, and one nerve more nerve-fibres than the other, or it may depend upon their relative de- gree of development. This latter condition may be readily recognized in the greater size of the muscles of the more used right extremities in comparison with those on the left side of the bod} 7 . The fact is further to be recognized that similar, but not corresponding portions of the body, as for example, differ- ent groups of muscles, may, from the same causes, present differences of action, without being the subject of disease. Thus, a given volume of a deltoid muscle will surpass in working power a similar volume of the intercostal muscles. We know that while the cardiac branches of the pneu- mogastric nerve can be excited only by very powerful electric currents, the pulmonary branches of the same nerve show an unusual excitability. Still more striking are the differences between structures into whose forma- tion tissues of different kinds enter, e. g., the joints. One is readily inclined to believe that in this case complete identity exists as regards the arrangement of the individual constituents, and a similarity as regards reaction against external influences. This is, however, not the case. Such complex structures as these, made up, in the instance cited, of muscle, connective tissue, cartilage and bone in widely 10 INCIDENTAL EFFECTS OF DRUGS. varying proportions, and presenting the greatest diversity as regards richness of vascular and nervous supply, are not to be placed in the same category, and are certainly not to be regarded as of equal functional importance. This is most distinctly manifest, when in diseased condi- tions of such parts it is desired to produce therapeutic effects upon them by a particular drug. Even when direct applications are made, unexpected differences show them- selves. In this connection, an observation of Senator 1 is very instructive. He found that, after the injection of car- bolic acid into the joints in acute rheumatism, the benefi- cial effects appeared first in the shoulder, later in the knee, hand and elbow, and last in the hip. In discussing the sub- ject, Senator mentions as factors probably instrumental in producing these singular results: anatomical differences, the number and arrangement of the vessels, or simply unknown peculiarities of structure of the joints, without, however, being willing to pronounce definitely for the one or the other. The possibilities to be here taken into consideration are so numerous, and we are so far from being able to com- prehend even the smallest part of them, that we must con- tent ourselves for the present with studying them with the utmost possible care. But even if, in a given case, we had demonstrated, e.g., an abnormal arrangement of the vessels of the right shoulder- joint as compared with the left, or a more abundant inner- vation of the knee than of the elbow-joint, we would still only be able to form a conjecture to explain why the same agent should produce different results when applied to these parts, why it should cure one person and do harm to another. If this inquiry be still further pursued, it will be found, that in specially predisposed, luckily rarely encountered persons, the simultaneously appearing favorable and unfa- vorable effects of a drug upon different organs are so 1 Senator, Berl. Klin. Wochenschrift, 1876, p. 70 INTRODUCTION. II closely connected that the more desirable cannot be ob- tained without the undesirable. We know of cases in which the employment of iodide of potassium for the pur- pose of producing- a diminution in volume of hyperplastic glands, as the cervical lymphatic or the thyroid, etc., pro- duced the desired effect, and at the same time, a serious atrophy of glands previously healthy, as the mammae or testes. Such a change can, however, only be due to the fact that those organs, which to our appreciation seemed normal, had already widely departed from the standard of health. Only an abnormality in their intimate structure can allow them to be influenced by an agent which does usually not produce such effects. §6. The differences thus far considered in the reaction mani- fested by certain individuals, or single tissues of the same organism, towards certain medicinal influences, were found to depend upon a constitutional predisposition in the econ- omy, either congenital, or acquired and become unalterable. There is also a predisposition limited as regards time. This may be due either to the presence in the body in excess, of cliemical substances which render more soluble than usual the medicinal agents introduced, or which enter into combination with them, thus forming new and directly deleterious agents, or it may depend upon pre-existing pathological changes in organs, or diseases of the regulatory apparatus. With regard to the first explanation, it is well to con- sider the apposite observations of Mialhe. 1 This author designates the abnormal reaction to medicinal agents due to " differences in composition of the animal fluids," as " chemical idiosyncrasy," as distinguished from " the idio- pathic idiosyncrasy," which is to be regarded as the ex- pression of differences in the structure of tissues. It is, 1 Mialhe: Die Receptirkunst, ubers. von Biefel, Breslau, 1852, p. 239. 12 INCIDENTAL EFFECTS OF DRUGS. for instance, well known that, under some circumstances, insoluble substances, as the oxides of iron, zinc, kermes min- eral, etc., may produce in the body effects differing widely from those which usually follow the administration of these drugs, i. e., they may produce injurious effects. The ex- planation of this is found in the excessive quantity of acid present in the stomach, in consequence of which a larger amount than usual of the metals is dissolved. This differ- ence in the fluids, which may be regarded as the expres- sion of a local disturbance, is entirely distinct from a true humoral-pathological dyscrasia, owing to the fact that it is of a transitory nature, and is often amenable to correc- tion by chemical or dietetic means. The recognition of the possibility of such a condition of the stomach renders easy, in a given case, the comprehension of certain drug effects. Opinions have differed until now, for instance, as to the reason why the much-used subnitrate of bismuth, even in quite small doses, sometimes causes violent local irritative phenomena in the stomach and intes- tines, such as vomiting, diarrhoea, etc., as well as general manifestations, while in other cases large doses, 4 to 6 grams, ( 3 i- 3 iss.) produce no abnormal effects. It has been definitely established that the presence of lead or arsenic in the bismuth, which was generally be lieved to be the cause of these untoward results, cannot be so regarded, since they are present in too small quantities. It is much more probable that these effects are due to the quantity of acid present in the stomach. If this be more than normal, the intrinsically harmless basic salt may be converted into the corrosive neutral body, or in consequence of the action of water upon the latter, into the poisonous acid salt, and the absorption of the metal, with its local as well as its general toxic action, be thus rendered possible. That the stomach at different times, according to the indi- viduality of the person, the food consumed, the condition of digestion, etc., may contain different quantities of acid, INTRODUCTION. 1 3 is a fact which can be so easily determined clinically and experimentally that it hardly requires further proof. This is also true of the intestinal juices. The greater or lesser degree of alkalinity which they present is of im- portance in the solution of a great many mineral and veg- etable substances, and when their reaction is only slightly alkaline, a drug-effect may fail entirely or occur in only a slight degree, or, when an opposite condition prevails, so large a quantity of the drug may be dissolved that a modification of the usual curative effect occurs. This latter result is now and then observed to follow the use of the golden sulphuret of antimony. While, as a rule, it produces only a slight expectorant effect, in some cases the full action of the antimony is manifested by the occur- rence of vomiting, diarrhoea, and weakness of the heart's action. This can be due only to the fact that an excess of alkali in the intestinesjdissolves the drug. Just as great as that of the gastric acid and the intes- tinal alkali is the influence exerted by the chloride of sodium, which may be present in the body in much more variable quantities than the above-mentioned substances. If calomel be administered, for example, widely-varying effects are produced upon the functions of individual organs, according to the quantity of common salt in the body. In the cases of patients who have been long kept upon a low diet, calomel has almost no effect, because, in consequence of the excessive use of food in a liquid form, the greater part of the chloride of sodium has been already washed out of the body. On the other hand, as Mialhe asserts, persons who have long lived upon a salty diet, as sailors, are peculiarly sensitive to the action of calomel, and may pre- sent exceedingly intense local irritative effects in the intestines, as well as a number of other unpleasant effects of mercury. From these few briefly-described etiological considera- tions, there result numerous possibilities for the occurrence 14 INCIDENTAL EFFECTS OF DRUGS. of perverse drug-effects. In the majority of them, no spe- cial constitutional predisposition is requisite. Pathologi- cal alterations in the stomach and intestines, as well as febrile conditions, which exert an influence upon the com- position of the secretions of these organs, or even the in- judicious consumption of an article of food capable of forming hurtful combinations with certain medicinal agents, may predispose to the occurrence of undesirable incidental effects. While in this manner alterations may be produced in different parts of the body, wherever the conditions requisite to the formation of products of decomposition are present, certain organs which, at the time of the in- troduction of certain drugs, are in a pathological state, however trivial, may, for this reason, cause temporarily such a condition of the body that either the already existing alterations are made worse by the medicine, or new pathological symptoms are developed in the same organs, which, in all probability, would not otherwise have appeared. A few illustrations will make this plain. It is well known that iodide of potassium is partially elimi- nated by the mucous membrane of the air-passages, and that it occasionally causes a slight catarrh of these parts, which usually disappears when the use of the drug is discon- tinued. If, however, these or other lesions be present before the administration of the remedy, there may be developed, as has been frequently observed, particularly in syphilitic patients with ulcers in the larynx, well- marked oedema of the glottis, which may speedily result fatally. In like manner, very small quantities of drastic cathartics, such as elaterium, gamboge, etc., which, in medicinal doses, occasionally cause transitory, almost- physiological, irritative effects in the intestines, may, when the intestinal mucous membrane is in an abnormal condition, produce intense inflammation with its con- sequences, such as tenesmus, bloody stools, etc. If the INTRODUCTION. 15 causal relation between such drug-effects and the pre- existing- slight organic changes be not understood, it would be easy to erroneously regard the former as a spontaneous disease of the affected organ. It is scarcely necessary to mention the fact that such conditions as menstruation, pregnancy, mental excite- ment, intense intellectual effort, and sleeplessness — even the physiological conditions of fasting or digestion — are also capable of modifying the actions of medicines in dif- ferent ways. § 7- The third cause of a transitory predisposition to the occurrence of unusual drug-effects is found in a dis- turbance of regulation. When any cause of disease acts upon a part of the body, a disturbance is produced, as Schiitz has explained upon the ground of Virchow's teach- ing. " This disturbance is, however, not pathological, if the regulatory apparatus be in a normal condition. Dan- ger appears only when regulation is difficult or impossi- ble." The good or bad effects of medicines may also depend upon the condition of regulation. The latter is here to be regarded as identical with elimination. Thus, calomel, in a suitable dose, by means of some action upon the intes- tinal canal, causes an evacuation of the bowels. As soon as this occurs, the greater part of the drug leaves the body with the faeces, under the form of sulphate of mercury. But if, for any reason, the cathartic effect does not take place, the calomel may remain in the intestines, especially the cascum, and, by prolonged contact with the chloride of sodium there present, be transformed into corrosive sub- limate, and thus produce injurious corrosion with ulcera- tion of the mucous membrane. If a normal regulation, or, better, a proper performance of function on the part of the usual emunctories takes place, even directly poisonous substances may be taken into the l6 INCIDENTAL EFFECTS OF DRUGS. body without deleterious effects, while evidences of poison- ing manifest themselves as soon as one or the other avenue of escape is closed to the drug. Hermann * has utilized this fact to explain the intermittent appearance of the symp- toms produced by lead. He advanced the hypothesis, " that while lead-cachexia is to be regarded as the effect of the distribution of certain quantities of lead throughout the body, the other symptoms must have a special cause which may disappear in spite of the persistence of lead- poisoning." This cause he finds in a temporary increase in the quantity of lead in the body, either by means of the in- troduction of a fresh supply, or a diminution in elimination. He designates the condition of saturnism, in which quan- tities of lead constantly pass through the body, because elimination equals introduction, as " a condition of com- pensation." It will be readily understood from this " that any diminution of the amount excreted, in consequence of any functional disturbance of the eliminating organs, must temporarily increase the quantity of lead in the body, and so produce new symptoms of an acute character, for the causation of which the usual amount of lead is insuffi- cient." This is also the reason why many persons seem to possess an immunity against the poisonous effects of lead, while others become seriously ill after the intro- duction of small quantities into the body. It is not even necessary that the channels of elimination should be pathologically altered ; for there are conditions comprised within physiological limits which cause interference with the functions of organs ; e. g, the kidneys. According to the temperature of the atmosphere, changes occur in the quantity of urine excreted, vicariously with increase or diminution of the perspiration. This is, perhaps, the reason why the great majority of cases of lead colic occur during the hot summer months, when the excretion of 1 Hermann, Archiv f. Anat. u. Phys., 1867, p. 64, und Lehrbuch der Toxi- kologie. Berlin, 1874, p. 205. INTRODUCTION. l y urine is so much diminished in consequence of the free perspiration. §8. In order to thoroughly understand certain abnormal effects of drugs, it is necessary, in addition to what has already been advanced, to take into consideration that condition known under the name of habituation. It is well known that, if psychical impressions in their widest range, from the most ardent desire to the most in- tense aversion, from the greatest joy to the deepest grief operate continuously upon the mind, they gradually lose their influence. The person becomes habituated to them, and the test of their operation, the subjective manifesta- tions which they generally produce, finally cease to show themselves. We are justified in believing that in such cases, the centres of sensibility gradually lose their energy, in consequence of the irritations exercised in such rapid suc- cession upon them, and fail to present the usual evidences of reaction. A readily comprehended analogy for this condition is found in the behavior of muscular tissue to- wards the electric current. If a muscle be thrown into functional activity by frequent irritation of its nerve, the action continually increases until the maximum capacity of the muscle is reached, and is then succeeded by a stage of exhaustion. This continues as long as the muscle is not allowed to rest, or until time is given to cast off into the blood the products of decomposition resulting from the labor. Exactly similar conditions obtain in habituation of the system to a number of medicinal agents. Antiquity fur- nishes us with instances of habituation to poisons. We are told that Mithridates could at last find no poison with which to destroy his life, because he had gradually so ac- customed himself to the use of all that were then known, that he could take them in large doses without injurious 1 8 INCIDENTAL EFFECTS OF DRUGS. effects. Aside from this somewhat doubtful tradition, it is well to call attention to the use of very active agents, such as alcohol, arsenic, opium, and morphine, as practised in our own time bv so many persons. The quantity of these substances sometimes taken without ap- parent injury, by increasing the dose gradually, often amounts to ten or twentv times as much as would certainlv prove fatal to a healthy man. Other less active drugs, e. g., many belonging to the class of laxatives and diuretics, entirely lose their characteristic pharmacological effects when too frequently administered. At first the effect may be still produced by increasing the dose, but this be- comes impossible finally, even though the quantity of the drug be still gradually augmented. Such results are known, e.g., to be produced by rhubarb, castor oil, the neu- tral salts such as the acetate of potash, squill, etc. How are we to explain these peculiar facts ? If we sup- pose any one of these substances to exert its influence upon certain cell-groups in the bodv, a normal effect will be produced, e. g., sleep will follow the use of morphia, an evacuation from the bowels that of rhubarb. A nerve or a muscle becomes incapable of performing its function under the continued influence of the electric current, on account of the material changes which occur in its sub- stance. A similar result is produced by the action upon the tissues of the bodv of the above-mentioned drugs. The difference between the two influences is only this, that while on the one hand restitution to the normal condition speedily ensues after the cessation of the electric current, either by elimination of the products of decomposition, or the furnishing of a sufficient supply of new material, on the other hand, after the action of drugs upon organs, a restitu- tio ad integrum can only occur when the foreign substance is in some manner removed from the affected spot. But as the complete elimination of such matters from the body usually requires considerable time, each newly introduced INTRODUCTION. 19 quantity finds some of the old still present, and there- fore the affected groups of cells are exposed to a con- tinuous stimulating or depressing influence. As they are thus deprived of the opportunity for recovery, their func- tional capacity is lessened, and a physiological or artificial stimulus is therefore no longer able to call forth the usual reaction. It is true that after every further increase in the quantity of the drug administered, an effect is pro- duced, but this condition lasts only until exhaustion of the tissues occurs. If the drug be discontinued, complete re- covery may take place, and the same parts eventually re- act normally to medicines. The processes above described furnish some insight into the possibility of toleration of certain poisonous substances. In consequence of the gradually increased consumption of such agents, whole cell-groups, particularly those specially affected by the poison, are rendered inactive, still adapted, it is true, to passive vegetative processes, but no longer capable of a definite independent functional activity. The poison acts upon inert tissues, which respond to an exces- sive dose in the same manner as do normal tissues to one small dose. Poisonous effects may also be produced even in one habituated to the drug, when it is administered in such large quantities that the vegetative sphere of the tissues is affected and their integrity endangered. This is, however, not the only way in which abnormal effects may be produced during the persistent habitual use of drugs. It is conceivable, in view of the intimate con- nection existing between different tissues or organs in the production of the functional manifestations of the body, that the suppression or limitation of the activity of certain parts will be followed by disturbances in the working of such organs as stand in functional connection with them. In this manner a permanent affection of the brain and spinal cord may be followed by alterations in the periphe- 2o INCIDENTAL EFFECTS OF DRUGS. ral nerves, the function of the heart, etc. For this reason, not only a number of more or less intense cerebral symp- toms occur in those accustomed to the use of opium, but also disturbances in the functions of digestion, respiration, etc. If the drug be withheld from the bod) 7 , there appear symptoms which manifest themselves as a disturbance of the previously existing artificial balance in the functions of the individual organs. The most characteristic of these is the persistent craving for the forbidden drug, reminding one of the hunger which is felt for common salt after long abstinence from it. Just as this, an essential constituent of the body, must be supplied, so has the drug, from its habit- ual use, become an integral element for certain organs, and its omission is resented in the same way as would be that of any other elementary constituent of the body. Many facts essential to the comprehension of abnormal drug effects result from the considerations just detailed bearing upon habituation. It is plain, e. g., that when the central nervous system performs its functions in an abnor- mal manner, in consequence of the habitual use of a drug which specially affects it, the action of another agent, which also possesses a special action upon these organs, will be an abnormal one. Either no reaction will occur or it will be manifested in a perverse direction. As instances the action of opium and chloroform on drunkards, partic- ularly in delirium tremens, may be cited. As an additional and certainly not an unimportant factor in the production of many abnormal effects of drugs, it is necessary to consider the time of the day or year, and the parts of the earth in which they are administered. Tempo- ral and localinfluences, although in generalbut little attention is now paid to them, even if they do not alone constitute a specific idiosyncrasy in man, contribute largely to its pro- INTRODUCTION. 21 duction. For this reason, as Virchow x says, physicians in ancient times considered man in relation to the time in which he lived, and devoted special attention to " the epidemic constitution." Do we not see that certain mor- bid influences exert their action only in certain parts of the world, and that at different times the same noxious agency acts with different degrees of intensity upon the body ? If individuals are affected by such external agencies* it is easy to understand that certain drugs in a given case may produce manifestations abnormal in kind or degree. Careful clinical observation has led to the discovery of differences in the action of certain drugs in consequence of such influences. Thus Charvet 2 found that the effects of opium differed in accordance with the time of day, the climate, and the race of the subject. Similar observations were often made by physicians in the English colonies. According to the experience of Lisfranc, the medicinal action of the chloride of barium varies greatly in different places, much larger doses being borne in southern than in northern climates. These facts, whose number might be somewhat in- creased, are all the more worthy of consideration on the part of physicians because, in this very direction, there prevails a wide-spread, although unfounded, scepticism. We are convinced that careful observation of certain effects of drugs, with regard to these points, would result in the discovery of a large number of similar deviations from the normal. §10. In view of the importance which, under given circum- stances, may attach to the abnormal or injurious effects of drugs, another fact is to be considered, viz., that they may 1 Virchow, 1. c, Bd. vi., p. 29. 2 Charvet: Die Wirkungen des Opiums auf die th'erische Oekonomie. Leip- zig, 1827. 22 INCIDENTAL EFFECTS OF DRUGS. be due to the quality of the drug used. It certainly hap- pens much more frequently than is known, or even sup- posed, that the non-occurrence of a desired result, or the appearance of an undesirable one, is due to an abnormal condition of the drugs or pharmaceutical preparations which have been administered. This abnormality may be due to various causes ; cither the drugs (and this is specially true of vegetable agents) while in the crude con- dition were pure but of poor quality, or they were good and became bad because kept too long, or they were sold mixed with foreign substances, or finally, they may obtain unusual qualities in consequence of different methods of preparation. It must be remembered that in special cases it is extremely difficult, or even impossible, to distinguish physically and chemically between good and bad drugs, and that very thorough study is necessary in order to enable one to form a judgment in this regard, particularly in the case of ani" mal and vegetable substances. The variation in the quality of drugs may also be due to the place of their growth. The different kinds of opium, aloes, colocynth, etc., are estimated in trade according to their origin, which is generally the best criterion of the value of a drug. The differences in the modes of action of drugs grown in different places are often very great. While, e.g., abundant stools are produced by 0.06 to 0.12 grams (grs. i.-ij.) of Socotrine aloes, a similar result is rarely obtained by a dose five times as large of Muscat or Ara- bian aloes. Similar differences are seen in the cases of many of our domestic officinal plants. Thus the digitalis which grows in mountainous regions far surpasses in activity both that which grows in the plains and the cultivated variety* From the hemp cultivated by us no such haschish can be produced as from that grown in hot countries ; and hemlock, which with us contains coniine, is in Scotland destitute of this alkaloid. The most diverse factors, character of soil, temperature of atmosphere, season of the year, etc., are INTRODUCTION. * 23 instrumental in causing these differences. The influence of this last factor, in particular, is shown in many of our most active drugs, and has here been definitely determined by accurate observation. We know that even the digitalis which grows in mountainous regions, the Hartz and Black Forest, manifests differences in its pharmacological be- havior according to the season in which the leaves are gathered, it being most active when in full bloom. This is also the case with colchicum. It has here also been de- monstrated 1 that the roots and seeds gathered while the plants are in blossom are the most active, i. e., contain the greatest proportion of colchicin. Long preservation causes, in the cases of many drugs, even when they were originally active, changes in consti- tution, or the formation of new and not uncommonly noxious products. This is the result of desiccation and the oxidizing influence of the air. If, e. g., in the prepa- ration of the extract of hyoscyamus, dry, instead of fresh leaves are used, it will contain almost no hyoscyamin, while the same quantity of leaves from the fresh plant would fur- nish it in appreciable quantity. Secale cornutum loses its power if not sufficiently dried and kept closely sealed. Such a change is most strikingly manifested in the activity of the bark of pomegranate root. While the fresh root possesses most reliable anthelmintic powers, the dried no longer manifests this action, but only produces vomiting or dis- turbs digestion. There can be no doubt but that a more careful method of treating and preserving drugs than has ever been, or is even now, practised, according to the opinion of those specially skilled in such matters, would have saved many medicinal agents, particularly of the class of vegetables, from the fate of being rejected as inert by physicians. The influence of the atmosphere causes alterations in 1 Schroff, Zeitschrift der Wiener Aerzte, Jahrg. 7, Bd. i., 185 1. 2 4 INCIDENTAL EFFECTS OF DRUGS. many purely vegetable as well as other organic and inor- ganic combinations. It is well known that, under certain conditions, a number of toxic chlorine products may be formed in chloroform. In the opinion of French authors, morphia acquires its emetic powers by its partial transfor- mation into apomorphia, and it has been proven 1 that Fowler's solution loses arsenious acid in the course of time, probablv under the influence of organic substances which have gained access to it. The acid is reduced, and escapes as arseniuretted hydrogen gas. Great loss may be occa- sioned in this way. A further occasion for the occurrence of abnormal effects of drugs is furnished by the fact that they are often sold mixed with foreign substances, which may find their way into the mixture during the process of dispensing. Attention has been called to this fact by an expert 2 who has shown that very active substances, such as belladonna root, hellebore root, etc., may sometimes be found mixed with comparatively inert drugs, although in a small pro- portion, and that special attention to this fact and accurate knowledge of the subject are necessary to avoid the possi- bility of harm. Finally, as regards the purity of drugs, in so far as this is dependent upon the method of preparation, we know that a number of vegetable alkaloids, aconitine, digitaline, etc., as well as other chemical bodies, produce therapeutical effects, sometimes undesirable ones, varying with the methods employed in their preparations. In contrast with the variations in the action of drugs above-cited, due to the quality of the remedies employed, we must consider certain effects which may be produced by unsuitable methods of administration, Thus loss of appetite, a feeling of oppression in the stomach, diarrhoea, etc., in short the symptoms of a catarrhal condition of the 1 Bretet, Journ. de Pharm. et Chimie, October, 1879, p. 355. 2 Mayer, Pharmaceutische Centralhalle, 29th July, 1880. INTRODUCTION. 25 intestines, sometimes manifest themselves after the exhibi- tion in the form of powder of substances which cause irri- tation of mucous membranes, in consequence of the adhe- sion of small particles to the lining membrane of the stom- ach and intestines. Such symptoms, e. g., may not rarely be traced to the use of tannin in the form of a powder. In a similar manner the administration of irritating drugs in capsules may give rise to functional disturbances in the stomach and intestines. §n. If a general view be taken of all the influences thus far considered, which may be the causes of injurious inci- dental effects of drugs, it will be seen from their variety how often they may come into play, and how essential a knowledge of them is. It is true that, as a rule, no per- manent functional ill-effects occur in this manner. There are, however, many conditions in which permanent disturb- ances, even death, may result. It is evident, with this in view, that no slight importance is to be attached to these considerations from a forensic standpoint. Foreign and domestic literature bearing upon this point furnishes abun- dant proof of the truth of this statement. Cases have been published in which the unfavorable result of a therapeutic measure, undertaken with due consideration of the laws of the art, has brought the attending physician into a court of justice, although the same procedure may have often been resorted to by others. For instance, when, after the injec- tion into the rectum of an ordinary dose of a solution of carbolic acid, death follows, owing to some individual pe- culiarity of the patient, or the patient dies in the beginning of the administration of chloroform, although a pure drug was used, these events are to be regarded as accidents, for which no one can be held responsible. The same remark applies to other drugs which, under certain circumstances, may produce hurtful effects. Well established cases are on 2 6 INCIDENTAL EFFECTS OF DRUGS. record of death occurring in children after the administra- tion of 0.006, even 0.0007 gram (gr. -^ — T ^) of opium. If the physician were forced to bear the blame in such cases, the administration of such drugs would be attended with grave personal danger. The most complete safeguard against the occurrence of such accidents seems to consist in giving the widest possible publicity to them, in order that a greater amount of information regarding them may be at our disposal than is at present the case. § 12. It remains now to give a general view of the mode of occurrence of the most important incidental effects hither- to recorded in literature of individual drugs. They may be the consequence of a direct or reflex action. In only the smallest number of cases is it possible to determine with absolute certainty in which of these two ways they have been produced, owing partly to the method of application of the remedy, and partly to the manner in which it is eliminated from the body. Thus, it is possible that irritating substances introduced into the stomach may exert an ab- normal influence in it or in the intestines, and cause gastro- intestinal catarrh, with its results. But, in addition, through the local changes in the stomach, there may be exerted a reflex action upon the functions of the heart, as is the case, e. g., with the preparations of antimony. This does not preclude the possibility of the heart's action being directly affected by the drug after its absorption. This, in fact, sometimes occurs. It is also conceivable that reflex pathological condi- tions of the skin may follow an irritation set up by a drug in the intestines or larger bile-ducts, 1 since it is well known that other irritating foreign substances, such as the pro- glottides of taeniae or gall-stones may by reflex action cause 1 Litten: Dermatologische Beobachtungen. Charite Annalen, iv., 1S78, p. 194. INTRODUCTION. 27 changes resembling those of urticaria. In an analogous manner, material changes may be produced upon other points of application of a drug, such as the subcutaneous cellular tissue, the mucous membrane of the eye, the bladder or the rectum, and by an action reflected from these, func- tional disturbances be set up in other organs, and, finally, during the circulation of the substance in the blood, phe- nomena may occur which differ widely from the primary local and reflex symptoms. The instillation of atropia, for instance, may cause conjunctivitis, and this, by a re- flex action, produce photophobia. But, if the drug be absorbed from the lachrymal ducts, symptoms of general poisoning may also appear. However, such a subtle dis- crimination between these different kinds of effects is, as a rule, impossible. With regard to the influence of the manner of elimina- tion of remedies in bringing about incidental effects, it should be stated that in this way effects may be pro- duced on different organs, according to the individuality of the patients. We know a number of drugs which are never eliminated from the body by any other channels than the intestines or kidneys, the former when they are taken internally, the latter when administered externally or subcutaneously. But there are drugs, e. g, antimony, which, when applied externally, are first carried into the stomach and intestines, and manifest their action in these organs. Finally, those remedies must be mentioned which usually leave the body with the urine, but, under the in- fluence of any of the abnormal individual conditions de- tailed in the preceding paragraphs, may, after their inter- nal exhibition, choose the skin as their place of exit, their presence in this organ being chemically demonstrable. As such, among others, may be mentioned iodide of potas- sium, bromide of potassium, and arsenic. Others, e. g., iodine, may, after injection, be carried into serous cavities and thence into the stomach. 28 INCIDENTAL EFFECTS OF DRUGS. If, as is generally the case, active drugs are used, they may produce irritant or depressing effects upon the organs by which they are eliminated. Attempts to explain such phenomena have been made most frequently in the case of pathological changes in the skin, following the internal use of certain drugs. To attribute such effects to one cause only, as is now and then done, is apt to lead to errors. It is certain that they may be produced in different ways, and are not exclusively due either to direct irritation of the glands of the skin or the strata of connective tissue, or, through a reflected action, to an alteration in the vessels, or to an influence upon the cutaneous nerves. It is in all cases the drug, as such, which furnishes the efficient cause for the changes in the skin, whether it be administered in small or large doses. For it is pecu- liarly characteristic of individuality and the specific dis- position which it causes that influences of whatever kind which ordinarily produce no effect, may manifest them- selves by causing in different organs changes varying in importance. For this reason, the unfounded hypothe- sis, 1 that in certain cases, not the drug itself, but certain entirely hypothetical substances formed by it in the blood were the cause of the pathological phenomena, must be absolutely rejected. The form of a given drug-exanthema may be differ- ent in different persons, and may also be multiform in one individual. The differences here manifested must be re- garded as tlje expression of individual peculiarities, or as dependent upon the varying structure of the skin in differ- ent parts of the body. The symptoms produced in the organs of special sense, as well as in other parts of the body, after the use of dif- 1 Behrend, Berliner klin. Wochenschrift, 1879, No. 43. TONICS 2 Q ferent drugs are discussed at length, as regards their gene- sis, in the special part of this work. TONICS. Ferrum. A number of incidental effects may be produced by the long-continued use of iron, principally upon the digestive tract. One observes, not infrequently, in persons with normal digestive powers, after the administration of re- duced iron, sulphate of iron and other preparations, and even iron waters, a disturbance of digestion, a feeling of weight in the epigastrium, and vomiting, especially when the remedy is taken upon an empty stomach. Defecation is delayed, and the fasces are colored black by sulphate of iron. In very rare cases, hemorrhages are said to occur from mucous membranes. More commonly there appears after the use of iron, as Trousseau 1 states, in healthy individuals, particularly women, an acne, occupying the face, breast, and back, and running its course without the occurrence of fever. After the prolonged use of this remedy, the teeth are blackened by a deposit of sulphate of iron. But for the production of this result the development of sulphur- etted hydrogen, from carious teeth or decomposing secre- tions, is essential. The iron dissolved in the alkaline fluids of the mouth is at once precipitated by the gas. Even when the teeth are healthy, if articles of food or drink containing tannin are taken, the formation of tannate of iron (ink) may take place. Regarding the external application of the sesquichloride of iron as a styptic, it is well to call attention to the fact that the pain in the wound which is often caused by it is 1 Trousseau, Gaz. medic, de Paris, 1843, No. 12. 30 INCIDENTAL EFFECTS OF DRUGS. due to the fact that the preparation used was of a bad quality, since no pain is produced if the iron salt contain no free hydrochloric acid. If it does, the pain is intense, although it soon ceases. What is true of the drug in sub- stance applies also to the styptic cotton found in trade. In order to make the sesquichloride of iron more easy to take, and to disguise the sour, sharp taste, which does not disappear even after dilution with water, Hager 1 recom- mends that the drug be mixed with glycerin or simple syrup, and the mixture diluted with cow's milk shortly before taking. He claims that in this way the teeth are not affected, and that the taste of the iron is concealed. Quinine. In explanation of the appearance of injurious incidental effects after the use of quinine, the opinion has been advanced that they are due to a saturation of the or- ganism with the drug. From the very great frequency of these accidents, however, it has been established that some- times even one small dose is sufficient to produce these effects, and that, therefore, a certain susceptibility to the production of these particular results of the action of qui- nine must exist in those cases in which they appear. It has indeed been demonstrated by King 2 upon the basis of an observation of this kind, that this individual predisposition to the production of injurious effects by a certain drug, as in this case by quinine, may be hereditary. The most different organs may be influenced in this manner by quinine, and give evidence of pathological alterations. On the part of the central nervous system, there are ob- served headache, deafness, general muscular excitability, sometimes also chilliness and vertigo, disappearing in the 1 Hager, Pharmac. Ce.itralhalle, 18S0, No. 46, p. 408. 2 King, Vierte'.jahrschr. f. Dermat. und Syphilis, 1879, P- 37°- TONICS. 31 horizontal position. Occasionally there appear precor- dial anxiety, fainting, or symptoms of collapse. Condi- tions of excitation, delirium, etc., on the other hand, are very seldom observed. On the part of the circulatory apparatus, the action of quinine is manifested by a diminution of the heart's ac- tion, pallor of the face, and coldness of the lips and skin. These phenomena may appear alone, or be attended by one of the affections to be later considered, and may last from hours to days. The skin of many persons is affected in a peculiar man- ner by the internal use of even small doses of quinine. The eruptions thus produced are characterized by their multiformity. Of importance for the explanation of the occurrence of these affections is an observation first made by Chevallier, 1 and later by other authors, that workmen in quinine factories are exposed, by contact with the drug-, to an affection of the skin characterized by the appearance of vesicles, pustules, or papules on different parts of the body, particularly the hands, arms, and legs. This fact goes to prove that when diseases of the skin are caused by the medicinal administration of quinine, they are due solely to the circumstance that the drug is carried into the skin, and by irritating this organ produces lesions varying in extent, probably in accordance with the vascular distri- bution. Of still greater value for the proof of the correct- ness of this view than the observation of Chevallier, is a fact experimentally discovered by Munk. 2 When he allow- ed a current produced by ten Grove's elements to pass through a part of the body, after the electrodes had been moistened with a solution of the sulphate of quinine, the portions of skin acted upon appeared anaemic, dry and depressed, immediately after the interruption of the cur- 1 Chevallier, Annal. d'Hygiene et de Medec. leg., 1851, T. 68, p. 5. 2 Munk, Archiv f. Anat. und Physiol., 1873, Heft 5. 32 INCIDENTAL EFFECTS OF DRUGS. rent. Within the next hour, the same parts became much swollen, so that they projected considerably above the surrounding skin, without, however, undergoing any change in color. The swelling disappeared during the course of several hours, and gave place to a hyperasmia in which there appeared a large number of extravasations of blood no larger than the head of a pin, which remained after the hyperaemia had subsided. Quinine could still be found in the urine twelve hours after the passage of the current. In this case, therefore, in consequence of the passage of quinine through the tissues, an erythema, and later a purpura-like eruption was produced. Further proof of the local origin of a quinine eruption is furnished by Delioux de Savignac, 1 who saw " a prurigi- nous eruption" follow the application to the skin of a salve containing the sulphate of quinine. Similar eruptions have also been observed after the in- ternal use of quinine. These, according to Grissac, 2 appear as : i.. Purpura. 2. Roseola. 3. Scarlatinous exanthema. 4. Eczema. 1. Vepan 3 first observed the petechial form. He reports that in the case of a lady suffering from neuralgia, who took first 0.1, later 0.15 gram (gr. ij.-iij.) of quinine, spots of purpura developed all over the body after two days. They disappeared nine days after the suspension of the remedy, but again showed themselves when its use was re- commenced. In this case, the eruption increased in vio- lence and extent with the increase of the dose, and hemor- 1 Deiioux de Savignac, Article quinine, Diet, encyclop. de Scien. med., 1874, P- 188. 2 Grissac: Des eruptions quiniques. Paris, 1876, p. 8. 3 Vepan, Gazette med. de Strassbourg, 1865. INTRODUCTION. 33 rhage took place from the gums while it lasted. Gauchet 1 observed a similar petechial eruption on the person of a lady who had previously suffered from haemoptysis after taking quinine. The petechias were abundantly scattered all over the body, and disappeared on the discontinuance of the remedy. 2. A simple roseola, which, however, differs but slightly from the eruption next to be described, has been repeatedly observed by DaubceuP in males and females. It made its appearance attended with intense itching, usually after a number of doses had been taken, in one case even eight days after the last dose was taken. It was sometimes con- fined to the extremities or trunk, and sometimes spread over the whole body, and usually appeared only in the form of disseminated patches. 3. The scarlatiniform erythema was first described by English authors. Garraway 3 saw it appear simultaneously with oedema of the face. In Hemming's case, 4 it appeared after the patient took 0.06 gram (gr. i.) of quinine, was at- tended with intense itching, a feeling of oppression in the prascordial region, and a coated tongue, and disappeared with slow desquamation. Skinner 5 saw it appear on a lady after 0.06, even 0.03 gram (gr. i., i^),.with shivering and a violent chill. It spread over the whole body, and was fol- lowed by desquamation which lasted three months. The mixed forms of quinine eruptions, a combination of the scarlatiniform erythema and acute eczema in its earliest stage, are next to be considered. Such an eruption was described by Kobner. 6 An eruption which was mistaken for scarlatina, preceded by chills, a feeling of prascordial 1 Gauchet, Bullet, de Therap., lxxxx., p. 373. 2 Daubceuf, by Grissac, 1. c, p. 22. 3 Garraway, Brit. Med. Jour., 1869, ii., p. 388. 4 Hemming, Eod. loco, p. 533. 5 Skinner, Eod. loco, 1870, i., p. 103. 6 Kobner, Berl. klin. Wochenschr., 1877, p. 305. 34 INCIDENTAL EFFECTS OF DRUGS. anxiety, nausea, vomiting, and burning on the skin, ap- peared in the case of a lady after taking 0.22 gram (gr. iv.) of the sulphate of quinine. When the medicine was again administered, the face became slightly bloated, and was covered with a uniform dark redness which spread also over the scalp, ears, neck, and extremities. A few spots of nor- mal skin remained on the arms. The flexor surfaces of the lower third of both thighs were normal, while the extensor surfaces were the seat of isolated papules, of the size of a pea, dark-red in color, becoming pale on pressure. The intervening tissue was healthy, and the epidermis showed fine wrinkling. Heusinger 1 has communicated a somewhat similar observation. A nodular eruption, some- what similar to erythema exudativum multiforme, ap- peared in the case of a lady after she took only 0.025 gram (gr. y 2 ) of quinine, on the eyelids, cheeks, and a portion of the forehead, with headache, fever, nausea, a sensation of intense burning and marked cedematous swelling. On another occasion, there appeared in the same case, after 0.1 gram (gr. ii.) of quinine, only herpetic vesicles on the cheeks. The affection disappeared with branny desquam- ation immediately after the use of the drug was aban- doned. The papules upon an erythematous base may also be transformed into vesicles, and the eruption thus present more of the appearance of an eczema. In this case, the itching may be wanting and the general disturbance be but slight. Thus Denk 2 reports the case of a boy, in which, after the use of 0.8 gram (gr. xiii.) of quinine in four days, an eruption appeared without itching, which extended over the whole body, became pale on pressure, was of a scar- latinous redness, and presented numerous yellow vesicles of pin-head size, most thickly collected on the neck, in the 1 Heusinger, Berl. klin. Wochenschr., 1877, p. 361. 2 Denk, Wiener med. Wochenschr., 1880, p. 946. TONICS. 35 axillae, and over the sternum. The general condition, with the exception of a slight elevation of temperature in the morning and evening, was not affected. After the drug was discontinued, the vesicles began to break and dry up. Desquamation occurred in small scales and large lamellae. 4. According to Grissac, the appearance of an acute eczema may be still more closely simulated than in the cases just cited, if the numerous vesicles burst and form thick crusts. Such cases are not found in German litera- ture. In order to distinguish the ordinary quinine exanthema from scarlatina, it is necessary, according to Kobner, to observe the course of the temperature and to find quin- ine in the urine. Denk adds, as diagnostic points, the absence of the tongue of scarlatina and the inflammation of the palate and tonsils, the fact that the pulse is too slow for the initial stage of scarlet fever, and the sudden appear- ance of the scarlet redness upon the skin without premon- itory symptoms. The presence of quinine in the urine may be demonstrated either by discovering fluorescence in this fluid after it has been freed from chloride of sodium (by precipitating it with nitrate of silver), or by separating the quinine in the form of an iodide by means of a solution of iodine (two parts of iodine, one of iodide of potassium, and forty of water). The iodide of quinine is dissolved on the application of heat. More unpleasant than the symptoms already mentioned, are the disturbances in the organs of special sense observed after the use of quinine. We shall first consider the disturbances of vision so care- fully described by A. von Graefe. 1 After small doses, pho- tophobia, as well as temporary amblyopia, is frequently ob- served. Under the continued use of larger doses, however, 1 Von G^raefe, Arch. f. Ophthalmol., Bd. iii., 2, p. 396. 36 INCIDENTAL EFFECTS OF DRUGS. graver disturbances of function occasionally show them- selves, which may persist for a long- time and obstinately resist treatment. Thus Graefe studied the case of a man who, to cure an intermittent fever, took quinine in increas- ing doses to 0.9 gram (gr. xiv.) each, or in all about 30 grams (3 viiss.). While the dose was being increased one-third daily, weakness of vision appeared in the right eye, followed in a few days by complete blindness. The left eye remained healthy. Nothing abnormal was revealed by an ophthalmo- scopic examination made three months later, but the quan- titative appreciation of light had disappeared on the right side. As von Graefe regarded a disturbance of the intra- cranial circulation as the cause of the affection, blood was drawn from the temple by means of Heurteloup's leech. Quantitative appreciation of light gradually returned first, the motion of the hand could next be appreciated, and after some time the eye returned to its normal condition. In another case, in which 1.8 gram (gr. xxviii.) of the sulphate of quinine was taken daily, also for the cure of intermittent fever, and in which bilateral amblyopia of a high degree appeared, the full power of vision returned spontaneously in the left eye, but the right regained only the power to read large print. The ear may be functionally affected in the same way as the eye, and its disturbances may appear with varying intensity either simultaneously with the affection of the eye or independently of it. Very frequently, as the mildest form of the affection, appearing at the same time as other nervous disturbances, only a buzzing or ringing in one or both ears is observed ; but later difficulty of hearing, and even deafness may also appear. According to Briquet, 1 these symptoms, in most cases, last only a short time. On the other hand, Bailly 2 states that incurable deafness may follow the use of quinine. 1 Briquet : Traite Therapeut. de Quinquina et de ses preparats. Paris, 1853. 2 Bailly, Gazette med. de Paris, 1850, 9. TONICS. 37 It must also be mentioned that stomach and intestinal catarrhs of different grades of intensity are produced with tolerable frequency by the use of quinine. For this rea- son, Binz 1 warns against the introduction into the stomachs of patients with fever, of quinia salts which are not easily dissolved. Quinine in a slightly acid solution is readily absorbed, and may be taken for weeks without injury ; but qininine in powder or pill form, especially the almost in- soluble sulphate, may, on account of the lack of gastric acid which probably exists in persons with fever, easily produce irritation in the stomach and intestines. It has been further observed by Guyochin 2 that, after the use of quinine, slight irritation of the kidneys and the mucous membranes of the bladder and urethra may occur, probably owing to the direct contact of the drug with these parts. Faginoli 3 treated a child, who suffered from painful micturition, and passed a few drops of blood every time it took quinine. Monneret saw a genuine hema- turia arise in this manner. Piorry and Briquet also claim, in very rare cases, to have observed symptoms of cystitis following the use of quinine. In the case of Gauchet reported above, we have men- tioned a symptom which is very rarely alluded to in the literature of quinine, viz., haemoptysis. Simon de Ronchard 4 was the first to observe several cases of spit- ting of blood after daily doses of quinine of 0.5 gram (gr. viij.). The affected persons had healthy lungs and hearts. As soon as the drug was discontinued the haemoptysis ceased, but blood again made its appearance in the sputa when it was again used. How this effect of quinine 1 Binz, Deutsche Klinik, 46, p. 409. 2 Guyochin : Absorption, Action physiol. et therapeut. de la Quinine, Paris, 1872. 3 F?.ginoli, by Grissac, 1. c, p. 43. 4 Simon de Ronchard, Gazette des hopitaux, Janvier, 1861. 38 INCIDENTAL EFFECTS OF DRUGS. occurs has not yet been explained. It has, however, been established by the investigations of Merat that, after the internal use of quinine, the drug may be found in the bronchial mucus. Therapeutic measures are but rarely necessary against such symptoms as have been detailed, since they disappear spontaneously after the discontinuance of the drug. For the relief of the conditions of weakness which have been described, symptomatic tonics are to be employed if they become excessive. To prevent the headaches which so frequently appear, Wade 1 recommends hydrobromic acid. Fothergill exper- imented with this drug, and was able to confirm its reputed efficacy. He prescribed two to twelve grams (fl. 3 ss. to fl. 3 iij.) diluted with water, of the acid obtained by pre- cipitating a solution of forty-seven parts of bromide of potassium in three hundred and fifty parts of water with fifty-eight parts of tartaric acid. Rapid disappearance of the quinine eruption was noticed by Lightfoot 2 to follow the administration of twenty-five drops of the tincture of hy oscyamus and sponging the body with alkalies. Heusinger (1. c.) had the affected portions of skin powdered with wheat-flour. Salicylic Acid — Salicylate of Sodium. Salicylic acid is to be classed with the drugs which most frequently and extensively produce undesired effects. Some of this class of symptoms seem to be typical attend- ants upon the anti-febrile action of the drug, and therefore very frequently follow its use. In this category belong certain phenomena, yet to be considered, manifested by the central nervous system. Other symptoms, such as changes on the skin and dis- 1 Wade, Ref. Virchow-Hirsch Jahresber., 1876, i., p. 400. 2 Lightfoot, Brit. Med. Jour., 1870, i., p. 30. TONICS. 39 turbances of the functions of internal organs, appear but seldom, and are probably dependent upon an individual predisposition on the part of the affected patient. They all have this in common, that they disappear rapidly with- out leaving injurious results behind. On taking salicylic acid, there is experienced a repulsive taste, with burning and itching in the mouth and throat. After absorption, as Strieker * first stated, there may oc- cur buzzing in the ears, difficulty of hearing, and profuse sweating — symptoms which do not contra-indicate the con- tinued use of the drug. Still more important nervous symptoms have been observed by other authors. Thus, Riegel, 2 after doses of four to six grams ( 3 i. to 3 iss.), noticed, in addition to the above-mentioned symptoms, headache, giddiness, and very temporary delirium, and Schuhmacher, 3 in addition to these, observed hallucina- tions of visions which caused great anxiety. According to Riess, 4 besides this condition of psychical excitation, there may appear weakness of vision, as well as specks before the eyes. Mtiller 5 observed, on the other hand, after the daily use for nine days of fifteen grams ( \ ss.) of salicylate of so- dium, in a case of diabetes, a condition of psychical depres- sion, with violent headache and mental weakness, and, at the same time, peculiar motor disturbances. The patient complained of weakness in the legs, uncertainty of motion, a paretic inclination of the body to the right side, and also that, although his sight was good, he ran against objects while walking. The symptoms disappeared within five days after the use of the drug was discontinued, and reappeared when it was again taken in smaller doses. 1 Strieker, Berl. klin. Wochenschr, 1876, No. 8. 2 Riegel, Berl. klin. Wochenschr., 1876, 182. 3 Schuhmacher, Deutsche med. Wochenschr., 1876, No. 18. 4 Riess, Berl. klin. Wochenschr., 1875, p. 675. 5 Muller, Berl. klin. Wochenschr., 1877, p. 29. 40 INCIDENTAL EFFECTS OF DRUGS. Goltdammer 1 observed conditions of collapse of differ- ent degrees several times after small doses, five grams (gr. lxxv.), of salicylate of sodium. No investigations have as yet been made as to the man- ner of occurrence of these symptoms, which bear a certain resemblance to those produced by quinine, They are probably the expression of the direct action of the drug upon certain parts of the brain. Among functional disturbances of internal organs, those which affect the stomach and intestines are first to be con- sidered. There exists an isolated observation of Goltdam- mer, who, after the administration of twelve grams ( 3 iij.) of salicylic acid to a patient with acute miliary tuberculo- sis, found after death a number of deep ulcerations of the size of a pea, on the mucous membranes of these organs. These he attributed to hemorrhagic erosions, probably due to the irritating quality of the drug. In opposition to this view, Riegel (1. c.) states that, after four to six grams ( 3 i. to 3 iss.) doses of the drug, he could never find changes in the mucous membrane of the oeso- phagus, stomach or intestines. Nevertheless, cases have been reported by different observers, in which, after the use of salicylic acid and salicylate of sodium, pain was felt in the stomach, with vomiting and diarrhoea. It would seem that the drug, under certain circum- stances, although rarely, is capable of causing irritation of the kidneys. Liirmann 2 reports the occurrence, after taking four grams ( 3 i.) of salicylate of sodium, of albumin- uria, with oedema of both forearms and legs, which ceased when the drug was stopped, and reappeared when it was again administered. After larger doses, Miiller (1. c.) also witnessed the occurrence of diminution in the amount of urine, and albuminuria. 1 Goltdammer, Berl. klin. Wochenschr., 1876, p. 47, 2 Liirmann, Berl. klin. Wochenschr., 1876, p. 477. TONICS. 4 I It still remains to consider the changes in the skin oc- casionally observed after the use of salicylate of sodium. These generally appear as erythema or urticaria, or in a petechial form, and are usually attended with intense itching. After four grams ( 3 i.) of the drug, Heinlein 1 witnessed, in a case of articular rheumatism, the appearance, accom- panied by unbearable itching, of a diffuse redness of the left half of the face, the lower extremities, and the right side of the chest, with slight oedema of both eyelids, the upper lip, and the legs as far as the middle of the thighs. All these symptoms disappeared within twenty-four hours after the discontinuance of the drug. When four grams (3 i.) of the salt were again administered, there appeared a diffuse erythematous redness, with itching, while the whole ab- domen, as well as the lower extremities, became covered with wheals seated upon a reddened base. The latter disappeared spontaneously after an hour, the other mani- festations on the following day. Leube also saw an urti- caria appear after four grams (3 i.) of salicylate of sodium. Freudenberg 2 saw a petechial eruption in an individual suf- fering from marasmus, after five grams (gr. lxxv.) of sali'cy late of sodium were taken daily for five days. The pete- chias, which were the seat of intense itching, and some of which were as large as a half-dollar, were originally seated upon the back, but spread on the following day over the breast, shoulders, upper arms, hips, and thighs. In the course of eight days, the spots became paler, and the epi- dermis was cast off in great scales from the affected parts After complete recovery, five grams (gr. lxxv.) of salicylic acid were administered in capsules, with a similar result. Resorcin. This drug, but recently introduced into the materia 1 Heinlein, Aerztl. Intelligenzblatt, April, 1878. ' 2 Freudenberg, Berl. klin. Wochenschr., 1878, p. 630. 42 INCIDENTAL EFFECTS OF DRUGS. medica, produces, like other antifebrile remedies, when administered in active doses, incidental effects, especially upon the central nervous system. Lichtheim 1 and Brie- fer 2 have reported observations bearing upon this point. If two or three grams (gr. xxx. to xlv.) of resorcin are administered in solution or in substance, an effect is mani- fested in a very few minutes. There appear giddiness, buzzing in the ears, and an increase in the frequency of pulse and respiration. The face is reddened and the eyes become brilliant, the patients being in a condition resembling in- toxication. They are sometimes delirious, and manifest hallucinations. Speech is stammering, and slight convul- sive tremors appear in the hands. Soon after taking the drug, the skin becomes moist, and in 15 to 20 minutes profuse sweating occurs. At the same time, the temperature of the body falls, and the above- described symptoms of excitation diminish in intensity. Brieger saw collapse occur in this stage, which so increased with the diminution of temperature, that powerful stimu- lants had to be frequently employed. The fall in tempera- ture lasted only a short time. After two or three hours, fever abruptly appeared, with a feeling of coolness or even a chill. Strychnia. Strychnia, even in permissible doses, may produce a chain of threatening symptoms, differing only in degree from true strychnine poisoning. After 0.005, 0.01 gram (gr. yV-^) of strychnine, there may appear nausea, red- ness of the eyes, formication, exalted sensibility to external impressions, a feeling of weight in the feet, and stiff- ness in the limbs. With these symptoms are occasionally associated disagreeable tension of certain groups of mus- 1 Lichtheim, Correspondenzblatt f. schweizer Aerzte, 1880, 14, 15 Juli. 2 Brieger, Centralbl. f . med. Wissenschaft, 1880, 37. TONICS. 43 cles, and painful erections. Girl 1 several times observed, after the repeated internal administration of strychnia, the occurrence of periodic spasmodic attacks, reappearing during- the course of several weeks, of a tertian type, re- sembling an intermittent fever, and ending with sweating. After they had ceased, they could be reproduced by strychnia. Children are specially susceptible to the injurious ef- fects of strychnia, and for them it must be prescribed with extreme caution. A number of cases have been observed of severe, even fatal, poisoning by medicinal doses of the drug administered subcutaneously for the relief of diph- theritic paralysis. A skin affection produced by the internal adminis- tration of strychnia has also been described. In the case of a woman who took 0.0004 gram (gr. y-^-) of the drug, Skinner 2 saw a scarlatinous exanthema, which disappeared after it was discontinued. Colombo Root. The Colombo root, so much prescribed as a bitter and astringent, probably contains as its active principle berbe- rine and the crystalline bitter substance colombine. As shown by an experiment of Kohler 3 upon himself, with an infusion of twenty grams to one hundred and twenty grams of water, a certain amount of care should be taken in the use of this drug. It produced nausea, repeated vomit- ing, pain in the epigastrium, and finally unconsciousness after the subsidence of which a condition resembling that following a debauch remained. All these symptoms had disappeared after twenty-four hours. For this reason, it seems advisable, until more accurate pharmacological in- 1 Girl, Buchner's Repertorium, xxi., 2. 2 Skinner, British Med. Jour., 1870, p. 303. 3 Kohler: Handbuch d. physiol. Therapeutik, 1876, p. 159. 4 4 INCIDENTAL EFFECTS OF DRUGS. vestigations of this substance are at hand, to prescribe it only in small doses, rather than as is now the custom. Probably in this way only the bitter principle exerts the main action, and in larger doses the alkaloid berberine. Lignum Quassde. Quassia wood, which is an intense poison to the lower insects, produces no functional disturbances when occa- sionally taken in -small doses as a stomachic. But when taken for a long time or in large doses, it produces digestive disturbances in some persons, which may be accompanied by oppression in the stomach, nausea, and inclination to vomit. Furthermore, according to Wibmer, 1 in children and delicate adults, dizziness, headache, and deafness ma)^ be produced by large doses. Barbier saw in sensitive wo- men involuntary muscular movements follow the use of a watery solution of quassia wood. Herba Chelidonii. Celandine, which was formerly regarded as a specific for affections of the liver, exerts an action only when freshly gathered. The herb then contains a yellow juice which may cause an irritation of the skin with the forma- tion of vesicles. Taken internally in small doses, it may cause nausea and an inclination to vomit, vomiting or diarrhoea, and headache. It is said that, after its external use, there sometimes appear papular or vesicular eruptions on different parts of the body, especially the face. Creasotum. After the long-continued internal use of creosote in the treatment of diarrhoea, there appear, as Richardson found, dryness in the mouth, a burning sensation extending from the pharynx to the stomach, a white membraniform coating 1 Wibmer: Die Wirkungen der Arzneimittel und Gifte. Munich, 1842, Bd. iv., p. 380. TONICS. 45 of the tongue, and increased frequency of the pulse. In rare cases, vomiting and increased frequency of micturi- tion also occur, attended with persistent headache. An affection of the skin has also been observed after taking creosote. M. Bernard 1 saw in the case of a lady, no matter in what form he prescribed the drug, an eruption attended with violent itching, which proved to be urticaria. It disappeared after stopping the medicine, and reappeared when its use was a^ain beg^un. After the external application of this drug for caries of the teeth, there may appear a stomatitis and swelling of the tongue, if it comes in contact with this organ and the gums. When incidental effects make their appearance during the internal use of creosote, it must be at once discontin- ued, and if gastric disturbance be present, demulcent drinks should be prescribed symptomatically. The local affections of the mouth soon disappear spontaneously, or yield to an antiphlogistic or astringent treatment. Oleum Terebinthin^e. The oil of turpentine, obtained by distillation with water from turpentine, the resinous juice of several varie- ties of fir, used either internally or externally in varying doses, produces in some persons a number of undesirable incidental effects which, in some cases, may render its further use unadvisable. After the application of the drug to the uninjured skin, erythematous changes, sometimes even vesicular eruptions, appear, with a feeling of warmth and itching. They soon pass off when the drug is discontinued. Upon the sur- faces of wounds the action is very intense and may cause extensive inflammation. The vapor of turpentine, also, may produce a burning and itching erythema, as proved 1 M. Bernard, Gazette des hopitaux, 1879, p. 170. 46 INCIDENTAL EFFECTS OF DRUGS. by the employment of turpentine vapor-baths in the treat- ment of rheumatism, as recommended by Chevandier. 1 In animals, the effect upon the skin is manifested by falling of the hair. Schlothauer 2 also observed the appearance of intense salivation and stomatitis after one application of turpen- tine for the cure of scabies. This result of the absorption of the drug is in all probability due to a reflex excitation of the salivary secretion in consequence of an irritation of the buccal mucous membrane by the turpentine elimi- nated with the expired air, since the introduction of the drug into the mouth also may cause an increase in the flow of saliva and redness of the mucous membrane. The internal use of the oil of turpentine resorted to, as is well known, in a large number of affections, such as neural- gias, phosphorus poisoning, and colic from gall-stones, fre- quently causes many accidental effects, which may be intensified to a dangerous degree. Thus, after small doses, one occasionally observes burning in the primas viae, the formation of vesicles in the mouth, pains in the epigastric region, diarrhoea with colicky pains, and vesical tenesmus, leading to the discharge of an increased quan- tity of urine usually with an odor of violets, and sometimes bloody. With the irritation of the kidneys there may be associated redness of the urethral mucous membrane and painful erections. After the repeated use of medicinal doses of the oil of turpentine, an effect upon the central nervous system is not unfrequently produced, manifested by headache, gid- diness, and a feeling of fulness. Purkinje, 3 who took each morning for 3 days 4 grams ( 3 i.) of the oil, became sleepy after it, and could keep awake only with difficulty ; capa- 1 Chevandier, Revue Medico-chirurg., 185 1. 2 Schlothauer, Medic. Zeitung des Vereins fur Heilkunde, 25 Tuni, 1851. 2 Purkinje, Ref. in 'Mitscherlich's Lehrb. der Arzneimittellehre, Bd. ii., p. 251. TONICS. 47 city for thought and power of motion remained intact. The occurrence of these symptoms may be partially ex- plained, since Rossbach and Fleischmann 1 have shown that turpentine possesses the power to diminish the excit- ability of the central nervous system. Similar effects, due to a general action of the drug, may be produced by the extensive external application of the oil of turpentine. It is finally to be mentioned that, as after its external application, changes in the skin sometimes occur after its internal use also. According to Berenguier, 2 after com- paratively large doses, there appears a simple scarlatina- like erythema, spreading by preference over the face and the upper part of the body in irregular patches. Some- times there appears upon the reddened surfaces, with itching, a large number of small papules, which give to the skin an eczematous appearance. In rare cases, a vesic- ular eruption is noticed. A number of such cases have been reported by Brochin, 3 in which erythema or an urticaria-like eruption always showed itself in certain per- sons after the administration of turpentine, either in solu- tion or in capsules or in a pure state. Balsamum Copaiba. After the use of balsam of copaiba, generally after the first day, seldom after the eighth, certain affections of the skin appear in certain persons, usually suddenly. They were first described by Montegre (1817). In the majority of such cases, only a roseola is observed in the beginning. The rose-red irregular spots may, however, be transformed into true papules, projecting above the skin. Now and then the eruption is papular from the start, but, according 1 Rossbach and Fleischmann : Pharmak. Untersuchungen aus dem Wurzburg Instit., Bd. iii. 3 Berenguier : Des eruptions provoquees par l'ingestion des medicaments. Paris, 1874. 3 Brochin, Gaz. des hopitaux, 1879, Fev., p. 99. 48 INCIDENTAL EFFECTS OF DRUGS. to Bazin, 1 it differs somewhat from an ordinary febrile urticaria. Gubler and Rayer have described miliary and scarlatina-like eruptions, and also an eczema, as sometimes following the use of copaiba, although very rarely. These appear by preference upon the upper and lower extremi- ties, especially the backs of the hands, the knees, and around the malleoli and upon the breast, and sometimes spread over the whole body, and are occasionally attended with tolerably high fever. According to Berenguier, 2 the rose- ola produced by balsam of copaiba sometimes bears a strik- ing resemblance to a papular syphilide, but is distinguished from it by its sudden appearance, the presence of itching, by its affecting by preference the above-mentioned parts of the body, and by a peculiar disagreeable odor of the skin, and especially by the fact that it disappears when the use of the drug is discontinued. The eruption is attended with intense itching. The spots or papules are either isolated or collected in groups, and in the latter case they may form patches of consider- able size. They disappear upon pressure, and return when it is removed. If the use of the drug be discontinued after the appearance of the eruption, the latter may either disappear in i or 2 days, without desquamation, or, in ac- cordance with the individuality of the patient, or the length of time during which the drug was taken, this may require from 1 to 3 weeks. Under continued use of the drug, the eruption may be transformed into a more severe form, and even involve the subcutaneous tissue. With reference to a statement of Hardy 3 who saw a pemphigus-like eruption after the use of copaiba, Hebra 4 calls attention to the fact that the eruption was probably not a pemphigus, but only an urticaria, and that the ser- 1 Bazin : Lecons sur les affections cutanees artif. Paris, 1862, p. 184. 2 Berenguier, 1. c., p. 22. 3 Hardy, Gazette des hopitaux, 1869. 4 Hebra: Hautkrankheiten, i., p. 673. tonics. 49 ous infiltration of the layers of the epidermis, which causes the wheals of the latter, need only be present in a more intense degree in order to produce a bulla. Balsam of copaiba also acts injuriously upon various mucous membranes, even in not excessive doses, when long used. There is not unfrequently observed loss of appe- tite, a feeling of weight in the stomach, nausea and vomit- ing, and also, according to Bazin (1. a), hyperasmia of the conjunctiva and the pharynx, as well as irritation of the kidneys and bladder, sometimes resulting in the produc- tion of nephritis and cystitis. The manner in which these effects are produced is clear. Like other resinous substances, balsam of copaiba pro- duces a tolerably intense irritation of mucous membranes, probably through the oil of copaiba or the copaibic acid which it contains. Elimination takes place through the lungs, as well as the kidneys, and therefore the urinary passages may be irritated in proportion to the quantity of the balsam passing through them. The skin may also serve as a point of exit for the drug, and, therefore, this, organ or its glands may be the starting-point of inflam- matory processes. In how far, in different persons, an abnormality in vascular distribution, or a peculiar con- dition of the glandular elements of the skin may contri- bute to the production of such effects, has not yet been determined. The fact is, however, established that> after the use of balsam of copaiba, the skin frequently emits a peculiar odor, probably due to volatile products of decomposition of the drug, and that in such cases the curative powers of the drug in gonorrhoea are very slight. It should be stated that the urine passed during the use of balsam of copaiba furnishes a deposit with nitric acid, which consists of copaibic acid, and may easily be con- founded with albumen. 4 EjO INCIDENTAL EFFECTS OF DRUGS. Maestri and Pidoux 1 report that large doses of balsam of copaiba sometimes cause symptoms of poisoning, such as paralyses with convulsions and tetanic symptoms. In milder cases, there may appear weakness of the arms and the muscles of the face, with diminution of the general sensibility. CUBEB^E. As a rule, incidental effects do not follow the use of cubebs. In some persons it produces colicky pains and diarrhoea. An eruption is usually produced only by large doses, and in the cases of young persons. It is characterized either as an erythema or more frequently a papular eruption, which, as in a case reported by Berenguier (1. a), spreads over the face, the trunk, arms, and legs. The papules are miliary, but unite in many places to form large elevations above the skin. The eruption appears without attending symptoms, such as fever, etc., and disappears in a few days, after the discontinuance of the drug, with slight branny desquamation. Aqua Calcis. The continued use of lime-water, in consequence of the persistent neutralization of the gastric acid, not unfre- quently causes disturbances of digestion and loss of appe- tite ; vomiting has also been observed to follow its use. The excretion of urine is increased by this remedy, defecation is usually retarded, and in rare cases diarrhoea is produced. In order to avoid these evils, it has been proposed to use saccharate of lime, in doses of 0.5-1 gram (gr. viij.-xv.), in watery solution, instead of lime-water. The above remarks are also applicable to the carbonate of lime. 1 Maestri and Pidoux, Ref. Schnvdt's Jahrbucher, Bd. 97, p. 301. ASTRINGENTS. 5! SODII NlTRAS. x\fter the use for some time of large, but still medicinal, doses of the nitrate of sodium, Loffler 1 observed certain changes in the persons who had taken the drug as an experiment. Twice there appeared pain and rumbling in the abdomen. Digestion was, as a rule, not at all affected by the drug. But, increasing with the quantity of the drug consumed, there appeared a feeling of general lassi- tude, increased on motion, and lasting several days after the discontinuance of the drug, disinclination to bodily and mental activity, depression of spirits, a tired feeling after the slightest exertion, pains in the muscles and joints, particularly in the knees, and a continuous inclination to sleep. The quantity of urea is increased during the first few days of the administration of the drug, but afterwards returns to, or even falls below, the normal standard. ADSTRINGENTIA. Alumen. After the frequent use of alum, there are observed in some persons gastric symptoms, such as loss of appetite, nausea, a tendency to vomit, and diarrhoea. These effects are due to a direct irritation of the gastro-intestinal mucous membrane by the drug, and are dependent upon the degree of fulness of the stomach. For if the alum introduced into this organ does not meet with enough al- bumen or albuminoid substances to precipitate it, the mucous membrane is affected by the drug in a greater or lesser degree. In the experience of Begin and also of Barbier, the long- continued use of small doses of alum sometimes produces cough in persons with sensitive bronchial tubes. 1 Lofflei- in Barth, Toxikologische Untersuchungen des Chilisalpeters. Bonn, 1879, p. 5. 52 INCIDENTAL EFFECTS OF DRUGS. BlSMUTHI SUBNITRAS. Perhaps in the case of no other drug do opinions as to its eventual hurtfulness or innocuousness differ so widely as in that of subnitrate of bismuth. While Monneret, 1 among others, assures us that the irritating or even poison- ous qualities which have been attributed to this substance are only imaginary, that it may be taken by patients to the extent of three to six teaspoonfuls daily without any inconvenience, and that it can act curatively only in such large doses, there is a large number of reliable obser- vations which go to prove that subnitrate of bismuth in medicinal doses [2 to 4 grams (gr. xxx. to 3 j.) daily], may sometimes produce hurtful effects. The attempt has been made to explain these contradictory statements, by regard- ing the impurity of the preparation used, particularly its admixture with lead or arsenic, as the cause of the unde- sirable incidental effects. In fact, Carnot, 2 among others, in all the specimens of subnitrate of bismuth which he ex- amined, found lead in quantities varying from from 1 to 10 per cent. Riche, 3 on the other hand, found it in a much smaller proportion, and states that the quantities of this metal discovered by him were too small to cause dis- turbances in the organism. In fact, Bouchut 4 regards the presence of lead as beneficial, claiming that it is this sub- stance which enables the bismuth to exert its curative action in diarrhoea. The proportion of arsenic found in bismuth is also too small to produce the symptoms soon to be detailed. The anomalous effects of the agent must, therefore, be ascribed to the temporary condition of the individual who reacts 1 Monneret, Centralzeitung, 1849, 43. 2 Carnot, Comptes rend, des Seances de l'Academie des sciences, T. lxxxvi., p. 118, 1878. 3 Riche, Jour, de Pharm. et Chimie, 1878, 28, p. 147. 4 Bouchut : Jahresb. iiber Pharmakog. u. Toxikol. von Dragendorff, 1879, p. 268. ASTRINGENTS. 5. abnormally under its use, or to its employment in an im- proper manner. The condition of the individual may be influential in so far as the presence in the stomach of greater quantities of acid may cause the formation in large quantities, from the subnitrate of bismuth, of the corrosive neutral salt, or, if this be decomposed by water, of the acid salt. These are, however, as Orfila 1 proved by experiments on animals, intense poisons, producing gastro-enteritis. The same changes would take place if the basic salt were adminis- tered at the same time with acid remedies, or if the patient should take acid substances after the salt. In this manner, the readily soluble nitrate of bismuth, which would be formed in the stomach, would be absorbed. The incidental effects observed after the use of subni- trate of bismuth are almost identical with the pathological phenomena which are characteristic of the action of the acid salt, and affect principally the stomach and intes- tines. Odier 2 saw nausea after its use, Werneck 3 vom- iting, colicky pains, and, in some cases, diarrhoea, in others, obstinate constipation. With these local symptoms were associated a feeling of heat, headache, dizziness, and general lassitude. It is especially worthy of remark that the stools, after the use of subnitrate of bismuth, are gen- erally of a grayish-black color, and almost odorless. This is due to the fact that the bismuth salt is transformed in the intestine, under the influence of sulphuretted hydro- gen gas, into the sulphate of bismuth, and the gas is thus held fast. The therapeutical indications against the above-men- tioned incidental effects are the discontinuance of the drug, and the occasional employment of calcined mag- nesia in small doses, or of milk, emulsions, etc. 1 Orfila : Toxikologie, ubers. v. Krupp, 1854, ii., p. 9. 2 Odier, Jour, de Medecine, 1768, T. 68, p. 49. 3 Werneck by Wibmer: Wirkungen d. Arzneimittel, T. 1, p. 418. 54 INCIDENTAL EFFECTS OF DRUGS. ACIDUM BORACICUM. According to the investigations of Binswanger, 1 boracic acid in medicinal doses exerts no action in the human organism. If the dose be increased to two or four grams (grs. xxx.-lx.), there may occur frequent desire to mictu- rate, and an increase in the quantity of urine. In one case, after six grams ( 3 iss.) daily, forty-five minutes after taking the second dose, nausea and vomiting occurred. No incidental effects have as yet been observed after the external application of boracic acid. Argenti Nitras. The changes which silver produces by its long-contin- ued external or internal use, consist in a discoloration of the tissues in consequence of a deposition of the metal in them. Secondarily, as an effect of the presence of this foreign substance, functional disturbances may be devel- oped in different organs. The alterations in the tissues have been frequently made the subject of microscopical investigations. Virchow a examined a portion of the conjunctiva of a man for whom a solution of nitrate of silver had been prescribed as an application to the eye, Avhich he had, by mistake, used continuously for four months. The conjunctiva presented an intense bluish, almost black appearance. A deposition of the silver in its substance had taken place, " in such a manner, that on the surface the connective tissue was of a light brownish-yellow color, and in the deeper portions, the deposit had occurred only in the fine elastic fibres or corpuscles of the connective tissue." The basis-, or inter- cellular substance itself, was normal. That the healthy skin may also be the point of entrance 1 Binswanger : Pharmakolog. Wirkungen der Borsaure und des Borax,. Miinchen, 1847. 2 Virchow: Cellularpathologie, 1871, p. 250. ASTRINGENTS. 55 of the silver is proved by the case ol a woman reported by Gamberini. 1 This person, in order to dye her hair black, rubbed it every two weeks, for a period of two and a half years, with a pomade containing nitrate of silver. She afterwards suffered from dyspnoea, palpitation of the heart, ascites, and oedema of the legs, after the disappearance of which last symptom, the skin became of a slaty-gray or light-brown color. The recommendation of nitrate of silver for the treat- ment of epilepsy, tabes dorsalis, and similar diseases, has, in consequence of the chronicity of these affections, led to the long-continued use of the drug, and this has frequently produced that condition of deposition of silver in the tissues known as arguria, with its consequences. It is stated that thirty grams ( 3 viiss.) is the smallest quantity of silver which has been known to produce this condition. The discoloration may affect the whole cutaneous surface equally, or be most intense in certain parts, as the face. Scars, nails, and hair may also experience changes in color. Functional disturbances are frequently manifested only in the form of gastritis, but in many cases they are entirely lacking. From the irritation which the drug excites upon the mucous membrane of the cheeks, when long used, there may result, as Guipon 1 once observed, a stomatitis with- out salivation. In this case, the gums were of a dark-red color and swollen, and showed a violet border along their edges. The incisor teeth were of a slate color, and the buccal mucous membrane exceedingly sensitive, particu- larly to heat. More recently this affection has also been observed by Magitot, 3 and described as "gingivite argen- 1 Gamberini, Jour, de Medecine, Decembre, i860. 2 Guipon, Bullet, de Therapeutique, 1866, vo 1 . 71, p 86. 3 Magitot, Gazette des Hopitaux, 1879, p. 165. 56 INCIDENTAL EFFECTS OF DRUGS. tique." He calls attention to the fact that Charcot saw a papular eruption appear upon the skin after the long-con- tinued internal use of nitrate of silver, and states that both affections are to be regarded as local irritative effects produced by silver. After the occurrence of arguria, the individual organs manifest the following changes : Neumann, 1 on examining the skin, found the silver most abundant in the papillary layer. A few granules were also found in the other layers of the skin, most plentiful on the external wall of the hair-follicles, sebaceous glands, and sweat-tubes. The epithelial elements, the rete Mal- pighii, and the lining of the root-sheaths were free. In the case of a man who had taken nitrate of silver in large doses for epilepsy, Frommann 2 found, post-mortem, an ulcer between the pyloric and cardiac orifices of the stomach. The duodenum and jejunum looked as if numer- ous little black granules had been scattered over them. These, most thickly crowded together along the tops of the folds, presented the appearance of a dark, striped pig- mentation of the mucous membrane. In the duodenum they formed round spots, about one-half of an inch in diameter, darkest in the centre, and lighter in color around their edges. The intestinal villi contained groups of intensely black bodies, which were readily soluble in cyanide of potassium. Riemer, 3 in the case of a man with tabes dorsalis, who in one year had taken five thousand six hundred and seventy- two pills containing 34.032 grams ( 3 viiiss.) of nitrate of silver, found the surface of the kidneys gray, with numerous dark spots corresponding to the Malpighian bodies, and the mucous membrane of the pelvis grayish-blue in spots. 1 Neumann, Sitzungsberichte d. Gesellschaft Wiener Aerzte, 1 Marz, 1878. 2 Frommann, Virchow's Archiv, Bd. xvii. 3 Riemer, Archiv d. Heilkunde, 1876, xvi., p. 296 u. 385. ASTRINGENTS. 57 Virchow (1. c.) described the changes in the parenchyma of the kidneys produced by arguria, as he found them in a preparation in the collection of the Berlin Pathological Institute. In this, there is seen in the Malphigian bodies, where the transudation of fluid occurs, a blackish-blue dis- coloration of the walls of the vessels, limited to this point, and in a lesser degree to the connective tissue between the straight tubes. Therefore, in the whole kidney, besides those parts from which elimination occurs, only those are affected which correspond to the ultimate capillary distribu- tion in the pyramidal substance. In addition to the parts of the body already mentioned, silver has been found by Riemer and others in many other organs, such as the membranes of the brain, the liver, mesentery, walls of the vessels, the heart, etc. Opinions differ as to the manner of absorption and depo- sition of the metal. Riemer believes that the pigment is taken up as such, i. e., in the form of reduced silver, into the intestinal canal, is here stored up, and soon carried further through the lymphatic glands, being partially de- posited on the way, the greater part being carried into the current of the blood. Thence it passes through the walls of the vessels, being partly deposited in them, the remainder becoming permanently fixed in certain portions* of the tissues. Riemer, therefore, believes that the cause of arguria is dependent upon purely physical laws, as in the case of anthracosis pulmonum, and tattooing of the skin, in which opinion he is supported by the recent inves- tigations of Huet, 1 who found that the particles of silver reached the tissues by a sort of diapedesis. Frommann, Delioux, and others, on the contrary, believe that silver salts can be taken up in the intestinal canal only in a state of solution, and they, therefore, claim that arguria occurs 1 Huet, Journal de l'Anatomie, 1873, p. 10S 58 INCIDENTAL EFFECTS OF DRUGS. in obedience to chemical laws, by precipitation at the affected points. In the differential diagnosis between arguria and Addi- son's disease, the following points are to be considered, according to Gamberini. In the latter, the color varies between bronze and black, while in the former the skin is slaty-gray, with a reddish tinge. When the skin is washed with a solution of iodine, an evident change in color is produced, which is not the case in Addison's dis- ease. The treatment of arguria may be directed either to the gastric symptoms or to the discoloration of the skin. As regards the former, the existing evidences of intestinal irritation should be treated symptomatically. In order to produce a clearing up of the color of the skin, it is advisa- ble, after the successful process of Gamberini, to try the internal administration of the iodide of sodium or potas- sium, and the long-continued use of warm baths. As regards prophylaxis, care must be taken that the silver is not used longer than three months, and to the extent of at most fifteen grams ( § ss.) Plumbi Acetas. In view of the recognized poisonous nature of the ace- tate, as well as of most of the other preparations of lead, and the extensive internal and external employment of the agent in relatively large doses, it is remarkable that inju- rious incidental effects are not more frequently seen from its use than is really the case. Attention must, neverthe- less, be directed to the fact that, in the cases of saturnism which arise in consequence of the technical use of lead or its introduction with the food, the consumption of the metal has usually been going on for a relatively much longer time than is the case with even the most prolonged use of the drug for therapeutic purposes, and that the majority of the functional disturbances in the lead disease ASTRINGENTS. 59 are produced by the extremely gradual deposition of mi- nute quantities of the metal in the organs and its subsequent cumulative action. That there are exceptions to this mode of origin of lead poisoning is proved by the fact, particu- larly insisted upon by Romberg, 1 that certain persons, who are for a long time in contact with preparations of lead, nevertheless remain healthy, while others quickly suffer from its effects. A few cases have been collected by Wibmer, 2 in which hurtful incidental effects followed the use of medicinal doses of the acetate of lead, probably owing to individual causes, such as diminished elimination of the lead by the intestines, the kidneys, etc. Baker 3 observed in a man who, to cure a hematuria, took for four days, morning and evening, 0.06 gram (gr. i.) of the acetate of lead, loss of appetite, pain in the stomach, constipation, and paralysis of one hand, lasting three weeks. In another case, after the use for three days of 0.24 gram (gr. iv.) daily, there oc- curred attacks of colic extending over several months. Tanquerel des Planches, 4 who was the first to study and carefully describe the action of lead, warns against the too extensive internal use of its preparations, on the ground that it readily produces unpleasant symptoms. The external application of lead, in the form of solutions and ointments, is also said to be sometimes followed by unpleasant results. Those cases in which a discoloration of the skin of longer or shorter duration is caused by lead, are here first to be mentioned. Foucaud de l'Espagne 5 reports the case of a lady who, on the order of a physician, 1 Romberg: Lebrbuch der Nervenkrankheiten, i., p. 167, 2 Wibmer, 1. c, Bd. iv., p. 23. 3 Baker, London Med'cal Transactions, i. and ii. 4 Tanquerel des Planches: Traite des maladies de plomb, ubers. von Franken- berg. ii., p. 343. 5 Foucaud de l'Espagne, Gazette des Hopitaux, 1863, No. 153, p. 611. 6o INCIDENTAL EFFECTS OF DRUGS. used a solution of the acetate of lead as an astringent eye- wash. In consequence of the simultaneous use of sulphur baths for rheumatism, on the order of another physician, a black discoloration of the edges of the eyelids ensued, which spread over the cheek-bones and was only removed after six days by washing the parts with infusions of aro- matic herbs. Berenger-Ferand 1 reports a similar observa- tion. In this case, in spite of the use of various acid, alka- line, and alcoholic lotions and cosmetics, the black color persisted for thirty months. The application of solutions of lead upon mucous mem- branes and the surfaces of wounds seems in very rare cases to produce poisonous effects. Such a case was observed by Tanquerel des Planches after the application of lead- water compresses to the eye. Percival, 2 after the frequent application of the acetate of lead as a lotion to a contused shoulder, witnessed the ap- pearance of gastric pains, which ceased with the discontin- uance of the remedy and reappeared when it was again used. The washing of a large ulcer of the leg with lead, water, and the application of lead-plaster was followed four days later by attacks of colic and paralysis of the extremi- ties, which soon passed off after the discontinuance of the drug. In another case, observed by Werdermann, after the application of lead- water upon an ulcer, there appeared a sweetish styptic taste in the mouth and stiffness of the neck. In this case also, the symptoms ceased and reap- peared in accordance with the abandonment or renewed use of the drug. From a physiological stand-point, there are no reasons for doubting the possibility of the occurrence of such effects of lead. Since it has been definitely proved that under certain circumstances an absorption of lead into the 1 Berenger-Ferand, Gazette des Hop., 1864, p. 62. 2 Percival, on the Poison of Lead, London, 1774, in Wibmer, Bd. vi., p. 237. ASTRINGENTS. 6 1 system may take place even through the normal skin, the penetration of lead, particularly the caustic preparations which form precipitates with albumen, is comprehensible. Of course, only small quantities can be absorbed in this man- ner, nevertheless so much may be taken up, that after a few applications of the drug it may be demonstrated in the urine. The reason why injurious incidental effects so sel- dom follow this method of using the drug is unknown. Similar individual conditions, however, prevail with the majority of drugs, and are not dependent upon the manner of absorption. ZlNCI OXIDUM. The oxide of zinc, as well as all other zinc combinations (except the sulphate) which, during the last few decades, have been much employed in the treatment of affections of the central nervous system, such as epilepsy, eclampsia, and chorea, produce, not infrequently, like other metallic salts, undesirable incidental effects, pertaining principally to the digestive tract. The doses after which they may appear range between as low as 0.2 and 0.3 gram (gr. iv.-v.). In many persons, there then occur nausea and a feeling of op- pression in the epigastrium, differing in degree with the individuality of the person, and the amount of food in the stomach. For the irritating effect upon the gastric mucous membrane becomes 'more intense in proportion as the zinc salts have the opportunity, either directly or after their solution in the stomach, to form an albuminate by acting upon the mucous membrane. If there be sufficient food in the stomach to transform all the zinc into an albuminate, the irritating quality of the metal is almost entirely neu- tralized, since the albuminate goes through the regular digestive process, and is then taken up directly into the vascular channels. In any event, the long-continued use of small doses of zinc salts should be avoided, since even with the greatest 62 INCIDENTAL EFFECTS OF DRUGS. care they may produce injurious effects upon different functions. Thus Werneck 1 observed in his own case, after taking repeated 0.24 gram (gr. iv.) doses of the oxide of zinc, oppression in the stomach, eructations, a slight ful- ness of the head, later dizziness and a sense of physical depression, and after the fourth dose intense thirst, pain in the stomach, slight vomiting, and a feeling of tension in the limbs. If the zinc salt reaches the intestines and is able to irritate the mucous membrane, diarrhoea is also associ- ated with these symptoms. Similar effects have been ob- served by other authors, even after small doses taken at long intervals. It should also be stated that, according to Pereira, a zinc dyscrasia, analogous to chronic lead poison- ing, may be produced by frequent use of medicinal doses of the agent, characterized by obstinate constipation, emaciation, and anasmia. From a prophylactic stand-point, the symptoms detailed above may be easily prevented, if the zinc salt is adminis- tered in a soluble form, e. g., as the lactate, and upon a full stomach. If, however, the incidental effects have appeared, milk and fluid albumen may be given, in order that they may combine with any zinc which may be present in the stomach. Every effort must also be made to cause its speedy elimination from the body, by the administration of laxatives and diuretics. Cadmii Sulphas. The sulphate of cadmium was employed internally by Grimaud 2 in the treatment of syphilis, chronic rheumatism, etc. It produces, in a still higher degree than the zinc salts, irritation of the stomach and intestines, which is, however, of a transitory nature. Burdach saw, after 0.06 1 Werneck, Medic, chirurg, Zeitung, 1831, iii., p. 317 ; ref. in Wibmer, 1. c, Bd. v., p. 469. 2 Grimaud, Gazette medicale de Paris, 1851. ASTRINGENTS. 63 gram (gr. i.), salivation, colic, and frequent stools with tenesmus. An ointment of the sulphate of cadmium, according to Grimaud, produces pustules similar to those caused by an ointment of tartar emetic. Barii Chloridum. The chloride of barium, which on the recommendation of Hufeland 1 was formerly employed as a specific in differ- ent forms of scrofula, sometimes causes in certain individu- als, in quantities less than the maximum, 0.12 (gr. ij.) at a dose, 1.5 gram (gr. xxiij.) daily, functional changes in differ- ent organs. According to the experience of Lisfranc, 2 the medicinal action of this drug is very variable, and much larger doses are borne in warm climates than in colder regions. The disturbances to be noticed on the part of the stomach and intestines are nausea and even vomiting, anorexia, colicky pains, oppression in the epigastrium and diarrhoea. Catarrhal irritation of the conjunctiva, the nasal and respi- ratory mucous membranes (that of the last two probably extending from the pharynx) have been a few times ob- served after the use of baryta. After the long-continued use of medicinal doses, the symptoms detailed may, as Hufeland also observed, in- crease to an excessive degree, even to the production of well-marked gastro-enteritis, and with this there may be associated symptoms affecting the central nervous system, such as giddiness, great anxiety, swooning, muscular weak- ness, trembling, and even convulsions. Kohl, 3 in a case in which chloride of barium was employed for twenty-four 1 Hufeland: Ueber die Natur, Kenntniss und Heilart der Scrofelkrankheit, P.erlin, 1819. 2 Lisfranc, by Bernatzik, Encyclopadie der ges. Heilkunde, 1880, Bd. ii , p. 15. 3 Kohl, in llusemann, Toxicologic, p. 945. 64 INCIDENTAL EFFECTS OF DRUGS. days, observed salivation, swelling of the salivary glands,, a bad odor from the mouth, and falling out of the teeth. It is not improbable that this intensification of the symp- toms produced by the long-continued use of baryta is due to a cumulative action of the drug, in consequence of its slow elimination with the urine and faeces. This hypothe- sis finds support in the fact that, as has been proven, the chloride of barium is transformed in the body into the sul- phate, and this, an almost insoluble substance, is deposited at the point of its origin, and is afterwards gradually cast out of the system. In this way it is possible for a more intense action of the drug to occur, and one which lasts long after its use has been suspended. In this manner also, an observation of Schwilgue 1 is ex- plained. He found that when he gave small doses of baryta, the symptoms of irritation of different organs were intensified after the drug was stopped, and lasted at least seven weeks longer. The treatment of the symptoms detailed consists, in the first place, in the suspension of the remedy. The gastric disturbances require symptomatic remedies for the relief of the inflammation. Diuretics are advisable to cause a more rapid elimination of the drug. The use of a direct antidote, such as the sulphate of sodium or magnesium, is indicated only in very bad cases. Acidum Tannicum. Individual susceptibility to the action of tannic acid varies greatly in different persons. Tully, who took daily for a week 0.6 gram (gr. x.) of tannin, experienced nothing more than slight nausea and loss of appetite,, while Hennig, 2 after even 0.2 gram (gr. iij.), experienced in his own case pain in the stomach and intestines, a coated 1 Schwilgue: Matiere medicale, T. i,. p. 409. 2 Hennig, Archiv f. physiol. Heilkunde, Bd. xii., 1853. ASTRINGENTS. 65 tongue, eructations, thirst, tenesmus, and an increase of an habitual hemorrhoidal congestion. After a large dose of tannin, taken for diarrhoea, Roller 1 observed pains in the stomach and abdomen, obstinate vomiting and constipation, lasting fourteen days, besides slight febrile movement. After the constipation was re- lieved, blood and pus were passed with the fasces. This was probably due to a cauterization of the gastric and in- testinal mucous membranes by small particles of tannin. In order to avoid such unpleasant effects and to still be able to take tannin for a long time, L. Lewin 2 recommends the administration of the albuminate of tannin, or of tannin in an alkaline solution. The former is easily prepared by dissolving the desired quantity of tannin in a little water, precipitating it by a solution of albumen, and adding albu- men in excess to the albuminate of tannin thus formed until it is dissolved. For a solution of 2 grams (gr. xxx.) of tannin in 100 grams ( 5 iij.) of water, the white of one egg dissolved in 100 ccm. ( 3 iij.) of water and filtered, is sufficient. Tannin in an alkaline solution may be obtained by adding carbonate of sodium to the desired solution of tannin until the reaction is slightly alkaline, or by adding albumen to it, and again dissolving the tannate of albumen by the addition of carbonate of sodium. Ergotinum. Both the extractum secalis cornuti of Wiggers and that of Bonjean produce now and then in medicinal doses (0.2 to 0.4 gram) (gr. iij. to vij.) a disagreeable taste in the mouth, tickling in the throat, increased flow of saliva, nausea, burning in the stomach, pains in the abdomen, eructation, 1 Roller, Wiener med. Wochenschr., 1865, 97. 2 L. Lewin: Untersuchungen iiber Wirkung und Verhalten des Tannins im Thierkorper. Virchow's Archiv, Bd. 81, 1880. 66 INCIDENTAL EFFECTS OF DRUGS. vomiting, and diarrhoea. With some of these symptoms there may be associated fulness in the head, headache or chilly sensations, giddiness, dilatation of the pupils, and general lassitude, unsteadiness of gait, and irregularity of the pulse. Aside from the individuality of the patient, the differences in the mode of action of the drug are probably to be attributed to variations in its chemical composition. A number of undesirable incidental effects have also been observed after the subcutaneous injection of ergotin, first employed by Von Langenbeck 1 (Extr. secal. corn. Bonjean, 2.5 (gr. xxxviii.) ; spts. vini, glycefini, aa 7.5 (gr. cxiii.). This author, after the injection of 0.3 gram (gr. v.), noticed the occurrence of specks before the eyes, and pain in the shoulder, and Eulenberg 2 saw dizziness and vomiting. More threatening were the general symptoms which appeared in a case reported by Rezek, 3 after the injection of 0.04 gram (gr. -§-) of ergotin. Five minutes afterwards, the patient made a few convulsive movements with the whole body, the pupils became dilated, the eyeballs rolled, unconsciousness occurred, the skin became cool, and the pulse ceased. Cold douches and the internal administration of ether dissipated these symptoms. Hildebrandt 4 witnessed milder symptoms. In the case of a lady, after six injections, there appeared dizziness, un- certainty of motion, spasmodic contractions of the flexors of the upper and lower extremities, nausea, and a sense of constriction of the chest. As soon as the use of the drug was discontinued, these phenomena disappeared, to return when it was again employed. More common than these general manifestations are the 1 V. Langenbeck, Berl. klin. Wochenschr., 1869, p. 117. 2 Eulenberg: Die hypodermat. Injection der Arzneimittel, Berl., 1875, p. 240. 3 Rezek, ref. by Eulenberg, 1, c, p. 244. 4 Hildebrandt, Berl. klin. Wochenschr., 1872, p. 298. ASTRINGENTS. 6j more or less intense local symptoms of reaction. After nearly every injection, a painful, nodular infiltration is formed at the point of puncture, and in its immediate neighborhood, which does not result in suppuration. Hil- debrandt, who used injections of ergotin in the treatment of fibro-myomata of the uterus, believed that the pain caused by the injection of the fluid recommended by Von Langeubeck was due to the alcohol which it contains. He, therefore, used a solution of Extr. sec. corn, aq., 3.0 (gr. xlv.) in glycerine and water, aa 7.5 (gr. cxiii.), and found that it caused less pain, but there remained, after the injection, persistent, somewhat sensitive, nodules. Bengelsdorff, 1 after the injection of ergotin according to Hildebrandt's formula (the ergotin in it is not entirely dissolved, but a large part suspended), often saw decided pain and not infrequently a true phlegmonous, not suppu- rative, inflammation spring up more or less extensively around the point of injection. At the same time there was usually formed a hard nodular swelling, corresponding in size to the quantity of fluid injected, which often remained eight days or longer. Carrying the canula deep down into the tissues and rubbing the skin did not hinder the formation of the nodules. Folia Salvia. The favorite popular remedy, salvia leaves, which are occasionally administered internally in the form of an infu- sion as an astringent, may, under certain circumstances, produce disagreeable effects, as is shown by an experiment of Pidoux upon himself, who, after taking a cold infusion of the drug, experienced profuse sweating, lasting several hours, a bitter taste, and a feeling of dryness in the mouth and throat, obstinate constipation, and increased frequency 1 Bengelsdorff, Berl. klin. Wochenschr, 1874, p. 21. 68 INCIDENTAL EFFECTS OF DRUGS. of pulse. These symptoms represent the combined effects of the tannin and the ethereal oil contained in the plant. Pix LlQUIDA. Tar, which was formerly much used internally in the form of tar-water, in the treatment of skin diseases and bronchial affections, is now usually employed only exter- nally, either pure, as an embrocation for the treatment of eczema, or as an inhalation in the form of tar-water. In either form it is capable of producing- undesirable delete- rious effects, if large quantities of the more active sub- stances which it contains are absorbed. These effects ma)' be general or local. The general manifestations produced by the absorption of small quan- tities, are nausea and inclination to vomit, and, after larger quantities, headache, a feeling of giddiness, vomiting or diarrhoea, associated with abdominal pains. The local symptoms are due to an inflammatory irrita- tion of the normal, and, in a still greater degree, of the morbidly altered skin, probably caused by the carbolic acid and creasote, or the empyreumatic substances con- tained in the tar. In consequence of this local irritation, there is produced, according to Hebra, 1 an acne which appears in the form of hard red nodules, and lasts as long as the influence of the tar is present. A tar-acne, once de- veloped, undergoes involution very slowly, requiring on an average a period of two to four weeks for its disappear- ance, which occurs, however, without leaving scars or pig- mented spots behind. Wilkinson's sulphur and tar oint- ment, modified by Hebra (Sulphur, prase, Pic. liquid., aa 1 80 (|vss.), Cretas, 120 ( 3 iv.), Sapon. vulg., Adipis, aa 500.0 (O.i.), used for the treatment of scabies, also causes eczema, either by being brought in contact with healthy 1 Hebra: Lehrbuch der Hautkrankheiten, i., p. 594. ASTRINGENTS. 69 parts, or in consequence of the great sensitiveness to oint- ments shown by many persons. The urine passed after the application of tar often shows changes which are probably due to the carbolic acid in the tar, and which point to its absorption into the blood. Petters 1 found the urine of an intensely blackish- brown color, with the characteristic odor of tar. Upon distilling it with sulphuric acid, he obtained in the distillate carbolic acid and heavy dark-brown oil-drops, similar to creasote. For the sake of analogy, it should be stated that the dark urine which is occasionally passed after treatment with carbolic acid, contains hydroquinone, an oxidation-product of carbolic acid. Oleum Juniperi Empyreumaticum, or Oleum Cadini. The oil of cade, obtained by dry distillation from Juni- perus oxycedrus, not infrequently excites inflammatory action, when applied to the skin. Kleinhaus, 2 who ap- plied the undiluted oil, as is usually done, directly upon the surfaces affected with acute, chronic, or impetiginous eczema, noticed that even when the skin was but moder- ately inflamed, a tolerably intense redness and swelling, with acute pain, was developed in consequence of the action of the oil, and that soon after the hair-folliclee pro- jected above the skin in the form of nodules of the size of a hemp-seed — an affection which was seen to be identical with tar-acne. Bazin observed in patients who used inunctions of the oil of cade in the treatment of psoriasis, an eruption of isolated or grouped papules, but slightly confluent, hard, of considerable size, surrounded by a halo, most plentiful on those parts co vered with a well-developed growth of hair. 1 Petters, Prager Vierteljahrschr , 1855, Jahrg. xii., Bd. 3. 2 Kleinhaus, Allgem. med. Centralzeit., 1863, No. 24. p. 185. jO INCIDENTAL EFFECTS OF DRUGS. They were seated upon broad nodular bases, and ended in a sharp point, or sometimes a vesicle. A little black point, due to the presence of a hair, was always found at the summit. These nodules almost never suppurate, and even when scratched, only at their apices. The hair-follicles are the seat of the affection. Bazin designated it cade- sycosis (sycosis cadique). In many cases, according to Kleinhaus, the swelling and inflammation extend from the original point of application over a large extent of surface, and may then present the picture of a dermatitis, complicated by erysipelas; in fact, even the lymphatic vessels and, through sympathy, the lymphatic glands, may participate in the inflammatory process. In the milder form of the affection first described, hydro- pathic applications, with soothing ointments and the dis- continuance of the drug, suffice to cause the disappearance of the disease. To diminish the pain in the wide-spread dermatitic form, it is advisable to employ warm baths, in which the patient should remain for from one-half an hour to an hour, and to give small doses of opium internally. An incidental effect of less importance is the brown color of the skin produced by oil of cade, which is very difficult to remove. In order to avoid this inconvenience, the oil may be used in the form of a soap, as Kleinhaus did, acccording to this formula: $. Butyr. Cacao, 12.0 ( 3 iij.); 01. Cadini, 9.0 ( 3 ij. gr. xv.); Ol. Lini, Liq. Ammonii caust., aa 4.0 ( 3 i.). Of this 5 to 10 grams ( 3 1. to 3 ij.) are rubbed in, according to the extent of surface affected. This soap can be easily washed off with water. ACIDA. The dilute inorganic acids, such as sulphuric, hydrochlo- ric, phosphoric, and nitric, and the fruit acids, as citric, ACIDS. 71 tartaric, etc., cause not infrequently, when taken for a long period, disturbances of digestion. The appetite dimin- ishes, the tongue becomes coated, the teeth ache, and pains in the stomach and eructations occur, and sometimes sali- vation and diarrhoea. After the long-continued use of dilute nitric acid, ac- cording to Mitscherlich, 1 the gums and the tongue often become ulcerated ; the former bleed readily and the teeth are loosened — symptoms which must be regarded as purely local effects. Acidum Carbolicum. The fact that in some persons disturbances of the gen- eral nervous system sometimes follow the internal use of carbolic acid in medicinal doses has been recognized since the first employment of the remedy. Declat 2 observed slight headache after its use, lasting from five to fifteen minutes, spreading over the whole head, and returning every time the drug was taken, most intense in some per- sons in the frontal region, in others in the occipital. After the administration of the acid in the form of pills, Neu- mann observed heaviness and fulness of the head, weakness of the legs, dizziness, the appearance of circles before the eyes, horripilation, and profuse sweating. Only during the past few years has the attention of physicians been directed to the exceedingly injurious, even fatal, consequences which may, under certain circum- stances, follow the external employment of carbolic acid in the treatment of wounds. The majority of observers believe that in the production of this result the individual- ity of the patient is a factor, the nature and power of which is unknown to us, but which exerts an immense, if not an exclusive influence in bringing about such injuri- ous incidental effects. 1 Mitscherlich: Lehrbuch d. Arzneimittellehre, Bd. iii., p. 81. 2 Declat: Traite de l'Acide phenique. Paris, 1854. 72 INCIDENTAL EFFECTS OF DRUGS. Thus Busch l regards carbolic acid as one of the drugs which, indeed, act favorably in medicinal doses, but to which certain individuals, for reasons as yet unknown, are so sensitive that quantities harmless to innumerable other persons act poisonously upon them. Carbolic acid may gain entrance into the body after any method of application. The acid can be detected in the tissues, the blood, and the secretions and excretions, as well after its application to the healthy skin as to the sur- faces of wounds and mucous membranes. In each of these methods of application, there may be produced that condi- dition described under the name of "carbolism," by which we understand an abnormal action of carbolic acid pro- duced by one or more medicinal doses. It was formerly believed that the most certain criterion of the existence of carbolism was the emission of urine already brown or greenish when passed, or, if of a lighter color then, becoming blackish-brown or deep-brown after exposure to the air. Bill believed that the carbolic acid was transformed into quinone in the body, and that this substance gave the urine its black color. Quite recently Baumann and Preusse 2 have given the true explanation of this discoloration of the urine. They proved by analy- sis of such urine that, in addition to colored products, it contained hydroquinone in the form of hydroquinone-sul- phuric acid. According to this, a large part of the car- bolic acid introduced into the body is transformed into hydroquinone by oxidation. One portion of this is further oxidized in the system into indefinite colored products which pass into and color the urine, while the larger part appears in this fluid as hydroquinone-sulphuric acid. The dark color seen in many specimens of urine con- taining carbolic acid after standing, is due to the fact that 1 Busch, Berl. klin. Wochenschr., 1880, p. 304. 2 Baumann and Preusse, Archiv f. Anatomie u. Physiol., 1879, p. 245. ACIDS. 73 the eliminated hydroquinone-sulphuric acid is split up, and the hydroquinone thus set free, is oxidized under the influ- ence of the air, to form colored compounds. The more alkaline the urine, the more rapidly this takes place. Careful observations have determined that this carbolic- acid urine does not always appear as a pathognomonic symptom of the occurrence of noxious incidental effects, but that, in a number of cases, it is much rather a series of but little characteristic, although dangerous, symptoms which make up the picture of carbolism, and may lead to a fatal issue. Kuster, 1 who called attention to the poison- ous qualities of carbolic acid particularly in the antiseptic treatment of wounds, maintained that the reason why so few cases of death are recorded in consequence of the employment of carbolic acid is, that the majority of them, on account of the uncertainty of the symptomatology, are concealed under the names of shock, collapse, and similar terms. Of five such cases which he observed, four had a fatal termination. As predisposing to the occurrence of a deleterious action of carbolic acid, he mentions bodily weakness and pre-existing diseases. V. Langenbeck 2 saw a case of severe carbolic-acid poisoning in the treatment with carbolic paste, of abscesses in a boy, and two others, ending fatally, after insignificant operations followed by the application of the dry dressing. Rose 3 also reported a case in which, after the application of carbolized cotton which smelt very strong of carbolic acid and was still moist, gangrene occurred in a finger which was the seat of a wound in full process of healing. A striking illustration of the symptomatology of carbol- ism is furnished by a well-observed case of Busch (1. c). A boy, upon whom an operation for the opening of an 1 Kuster, Berl. klin. Wochenschr. , No. 48. 2 Langenbeck, eod. loco, 1878, No. 48. 3 Rose, Verhandlungen d. Gesellschaft d. Aerzte in Zurich, 19 Dec, 1874. 74 INCIDENTAL EFFECTS OF DRUGS. abscess under the trochanter had been performed, and who was exposed to a two-per-cent spray of carbolic acid during the few minutes necessary for the operation, and afterwards to the action of carbolized gauze, was seized on the same day with vomiting, which was attributed to the chloroform which had been used. After the dressing was opened the next morning under the carbolic spray, an inclination to renewed vomiting appeared, and in the evening carbolic urine was passed, and later symptoms of collapse showed themselves, the pulse becoming small and frequent, and the temperature falling to 35. 5 C. (96.5 F.). The frequent vomiting made it impossible to introduce anything into the stomach, and in spite of the subcuta- neous and external employment of analeptics, the patient died fifty hours after the operation. As an instance of a local organic affection, it may be stated that Liicke 1 observed a nephritis due to the action of carbolic acid, which disappeared when the use of the drug was stopped. E. Wagner 2 studied the changes in the kidneys with greater care. Carbolic acid was applied in a case of gangrene of the leg. The next day, carbolic acid urine was passed, containing casts of medium width, the majority hyaline, and a few fatty, some studded with red blood-corpuscles or renal epithelium. After death, micro- scopic examination showed that the uriniferous tubules were dilated, their epithelia large and very fatty, project- ing far into their cavities, which contained numerous masses of protoplasm and jagged shining bodies. In our opinion, not enough importance has been attrib- uted to the action of the spray in the discussion of the subject of the absorption of carbolic acid during the anti- septic treatment. Olshausen 3 believes that the skin is 1 Liicke, Berl. klin. Wochenschr., 1878, p. 248. 2 Wagner, Deutsches Archiv f. klin. Medicin, 1880, p. 529 3 Olshausen, Berl. klin. Wochenschr., 1878, p. 248. ACIDS. 75 rendered much more capable of absorbing the agent under the influence of the first dressing, and Langenbuch 1 main- tains that absorption by this organ is underestimated in comparison with that from wounds, and believes that per- haps more is taken up by the normal skin than by the surfaces of wounds, during the cleansing process. As favoring absorption, he regards the soaping, shaving, and scraping of the skin, by which the sweat-glands are opened, as well as the literal bathing of the skin by the spray. The latter, however, operates in still another manner. It has been proved by the investigations of Robrig 2 that finely pulverized watery solutions of substances are taken up by the skin, while they are not absorbed when simply laid upon it. The experiments bearing upon this point, which were made with all possible precautions, showed that when watery solutions of the iodide or ferrocyanide of potassium, e. g., were applied to the skin in a finely divided condition, one or the other of these drugs ap- peared in the urine. Animals could also be stupefied or brought into a paralytic condition by solutions of morphia or woorara applied in the same manner. This proves that the act of atomizing introduces substances into the body much more easily and in larger quantities than sim- ple contact. Therefore, the belief is fully justified that a very large portion of the carbolic acid employed in the spray is absorbed by the skin or its sweat glands. It also becomes clear that carbolic-acid poisoning may easily occur under these circumstances in the cases of children, who naturally possess a much more limited power of resistance, since the surface of the skin acted upon by the spray is much larger in proportion to the entire surface of the body than in adults, and therefore, caeteris paribus, much more carbolic acid is taken into the system. Never- 1 Langenbuch, eod. loc , 1878, p. 414. 2 Rohrig : Physiologie der Haut, 1878, p. 116, j6 INCIDENTAL EFFECTS OF DRUGS. theless, the prejudicial influence of soaping, brushing, and shaving (manipulations against which Lister has also spoken) in facilitating the occurrence of hurtful incidental effects, must not be underestimated. After what has been said, it will be readily understood that the introduction of carbolic acid into cavities lined with mucous membrane may also lead to carbolic-acid poisoning. The application of enemata containing car- bolic acid, and the irrigation of the uterus and vagina with this drug, should be considered in this connection. Thus Pratorius, 1 in the case of a woman in whom an irri- gation of the rectum with a weak carbolic acid solution — one-quarter litre (| viij.) of a one-per-cent solution to one- third litre ( 3 x.) of warm water — was employed, noticed, after a third of this solution had been used, ringing in the ears, dizziness, weakness, and fainting fits. Kottmeyer 2 describes exactly analogous phenomena after the use, per enema, of a half-per-cent solution of carbolic acid, in the case of a boy suffering from oxyurides. Olshausen (1. c.) observed severe symptoms of poisoning after washing out the uterus, and Lohlein 3 saw evidences of carbolism appear two days after carbolic-acid injections into the vagina and uterus of lying-in-women. It must finally be mentioned that Edwards, after the introduction into the vagina of tampons of cotton impregnated with carbolic acid, saw singultus, nausea, chilliness, and ana- sarca, with diminution or suppression of urine, delirium, and, finally, death. He attributes these phenomena to an acute nephritis, with ursemia, produced by carbolic acid. The treatment of carbolism should vary with the man- ner in which the acid was taken into the body. A directly antidotal therapeutic proceeding is generally without re- 1 Pratorius, Berl. klin. Wochenschr., 1879, p. 214. 2 Kottmeyer, eod. loc, 1879, p. 501. 3 Lohlein, eod. loc., 1878, p. 25. 4 Edwards, Virchow-Hirsch's Jahresber., 1869, 1, p. 349. ALTERATIVES. yy suit. Husemann and Ummethun recommend the saccharate of lime as an antidote, on the ground that lime forms with phenol an insoluble compound, but slightly poisonous. The sulphate of sodium is also said to act as antidote, by combining with phenol, to form the harmless phenol-sul- phuric acid. If the drug was introduced by enema, it would be well to thoroughly wash out the intestine, if only a short time have elapsed between the injection and the arrival of the physician. In the case of carbolism as ordinarily seen, arising from absorption from the skin or from wounds, a rapid symptomatic treatment of the general symptoms is indicated. The internal or subcutaneous use of stimu- lants, energetic irritation of the skin, sinapisms, frictions, and the faradic current, will aid in this object. For the vomiting, ice-pills and vegetable astringents should be administered. ALTERATIVES. Hydrargyrum. Mercury occupies the first place among the remedies which, from their extensive therapeutical employment, very frequently produce symptoms which cause uneasi- ness to the physician, and much more to the patient. The affections produced by its external or internal employment are of manifold nature. Thev consist both of anatomical lesions of the skin and mucous membranes, and of purely functional disturbances of various organs without demon- strable changes, e. g, of the salivary glands, and also of disturbances in the domain of the peripheral and central nervous systems. This condition has been described under the name of " hydrargyrosis," or " mercurialism." In order to obviate the numerous external accidents, as well as the directly injurious incidental effects which fre- quently occur after the traditional methods of using mer- 78 INCIDENTAL EFFECT S OF DRUGS. cury, several new modes of administration have been recommended during the last few decennia, particularly for the treatment of syphilis. Inunctions of gray ointment, formerly employed in horrible doses — as much as 500 grams ( 3 xvi.) daily — are well known to still frequently produce undesirable results, perhaps for the reason that, while in this manner too small a quantity of the drug is taken into the body to destroy the syphilitic poison in a short time, the mercury absorbed at long intervals, although small in amount, is sufficient to act injuriously when the necessary predisposition thereto is present. The long-continued administration of calomel is also sometimes followed by unpleasant results, owing to the fact demonstrated by Radziejewski, 1 that when the drug re- mains long in the caecum, it is transformed by contact with chloride of sodium or ammonium into corrosive sublimate, and thus may cause corrosion and ulceration. For this reason, the treatment of syphilis with subcuta- neous injections of the bichloride of mercury, introduced by G. Lewin, 2 in which almost all of the drug is carried into the circulation, is to be regarded as an important step forward, even although incidental effects are occasionally observed to follow the use of the drug in this manner also. Quite recently, two other combinations of mercury have been recommended for subcutaneous injection by Bamberger, 3 with a view to avoid the local irritation often produced by corrosive sublimate. One is a solution of the albuminate of mercury, prepared from 100 cubic cm. ( 3 iij.) of a filtered solution of albumen (three to four parts of water to one part of albumen), sixty ccm. ( 3 xv.) of a five-per-cent solution of corrosive sublimate, sixty ccm. 1 Radziejewski, Archiv fur Anatomie und F hysiologie, 1870, p. 22. 2 G. Lewin : Die Behandlung der Syphilis mit Subcutaner Sublimatinjection, Berl., 1869. 3 Bamberger, Wiener med. Wochenschr., 1876, No. 11 and No. 44, p. 1074.' ALTERATIVES. yg ( 3 xv.) of a twenty-per-cent solution of common salt, and eighty ccm. ( J iiss.) of distilled water. One ccm. (gtt. xv.) of this fluid, which becomes clear after filtration and standing for two days, contains o.oi gram (gr. -§-) of the bichloride in combination with albumen. This solution produces no local irritative effect what- ever. This author recommends still more strongly a solu- tion of mercurial-peptone, prepared as follows : one gram (gr. xv.) of commercial meat-peptone is dissolved in fifty grams ( 3 iss.) of water, and the solution filtered. To the filtrate, twenty ccm. (3 v.) of a five-per-cent solu- tion of the bichloride of mercury is added, and also, in order to dissolve the resulting precipitate, fifteen to six- teen ccm. ( 3 ss.) of a twenty-per-cent solution of common salt. The whole quantity of liquid is diluted with water to 100 ccm. (|iij.-), and filtered, after standing for sev- eral days. Each ccm. of this solution then contains 0.01 gram (gr. 1) of mercury, in form of a peptone combina- tion. The elimination of the mercury by the kidneys, when these fluids are injected, is said to be extremely rapid. In any event, great value should be attached to the method, since in this manner a cure is much more rapidly effected, and the organism is not long exposed to the action of mercury. We commence the description of the incidental effects of mercury with the : Changes in the Skin. — The affections of this organ, which show themselves in some persons in consequence of the use of mercury, appear in the shape of erythemata and eczemata (eczema mercuriale). The latter was first observed by Benjamin Bell 1 and also by Pearson, while Alley' 2 furnished the first exact descrip- 1 Benjamin Bell: Treatise on Gonorrhoea violenta and Lues venerea, ii., p. 228. 2 Alley: Observations on the Hydrargyria, or that vesicular disease arising from the exhibition of mercury. Dublin, 1804. 80 INCIDENTAL EFFECTS OF DRUGS. tion of this affection, which he called " hydrargyria." Hebra 1 and also Kussmaul 2 deny that it possesses any characteristic peculiarities as regards its course or symp- toms, and therefore regard it as identical with ordinary eczema, while Bouchardet considers it a disease sni gen- eris. According to the statements of older observers, eczema mercuriale, which is usually seen only after the external employment of mercury, sometimes follows its internal ad- ministration also. Thus Alley (1. c.) saw it in an adult after taking 0.12 gram (gr. ij.), and in a girl after 0.18 gram gr. iij.) of calomel. Ascherson found it in a young man after 0.24 gram (gr. iv.). Fournier has recently reported a similar case, and Engelmann 3 has cited an instance in which, after the use of 0.45 gram (gr. vij.) of calomel in 0.15 gram (gr. iiss.) doses, there appeared, two hours after the last dose, an erythema on the head, attended with febrile movement, swelling of the face, etc. The disease spread in one night over the whole body, with intense burning and itching, and great weakness. Four days later, the fever diminished, and the skin began to desquamate on the face and breast, partly in large scales, as in the case of scarlatina. Appetite and strength returned very slowly. The affected person stated that he had frequently suffered in the same manner after taking mercury internally. In opposition to this view, Hebra denies most positively the occurrence of this eruption from the internal use of any of the preparations of mercury. In an}' event, its appear- ance is extremely rare, and it seems that it can only take place under the influence of some individual predisposition. On the other hand, this eczema not infrequently follows 1 Hebra: Hautkrankheiten, i., p. 452. 2 Kussmaul: Untersuch. uber den constitutionellen Mercurialisums. Wiirzburg, 1861. 3 Engelmann, Berl. klin. Wochenschr , 1S79, p. 647. ALTERATIVES. 8 1 the longer or shorter external application of mercury, most commonly the inunction of gray ointment. In some persons it shows itself after very small doses of mercury, and in many others it fails to appear even after the long- continued use of large doses. Alley found that twice as many men as women suffered from it, which is prob- ably due to the fact that men require the use of gray ointment much more frequently than women. Hebra defines mercurial eczema as a disease of the skin which appears in the form of red papules, vesicles, or small pustules in great number and closely aggregated. Alley distinguishes, according to its intensity and course, three forms of the eczema: i. Hydrargyria mitis ; 2. Hydrargy- ria febrilis; 3. Hydrargyria maligna. Such a divisionis, however, entirely arbitrary, all three forms of the erup- tion being essentially the same. The exanthema sometimes appears after one, but usually after repeated inunction of gray salve, with intense itching and burning, usually on the internal surfaces of the thighs, the scrotum (or vulva), and in the groins, more rarely on the arms, back, and face. In many persons, during the whole course of the eruption, there are present febrile movement, headache, sleeplessness, and gastric disturb- ances. The affected portions of skin are covered with dark-red spots readily disappearing on pressure, varying in size, and soon running together over a large surface, upon which are seated vesicles of pin-head size, and very rarely large bullae, with at first clear, later cloudy con- tents, which may burst or dry up. ' As a rule, after this eruption, which sometimes resembles measles and again scarlatina, has lasted for four or five days, the skin becomes paler and desquamation begins in large masses or small scales. Complete recovery usually takes place in from eight to fourteen days. In many cases the disease is especially annoying to the 6 82 INCIDENTAL EFFECTS OF DRUGS. patient, owing to the fact that large portions, sometimes the whole, of the body are affected by the eruption ; that high fever with angina of the fauces is present, and that from the irritating and bad-smelling contents of the nu- merous pustules, which burst or are scratched open, and which may also undergo relapses, painful excoriations, swelling of the skin deprived of epidermis, and the forma- tion of crusts may occur. In such bad cases of eczema repeated desquamation of the epidermis is sometimes observed, and occasionally, although rarely, falling out of the hair. This latter occur- rence is especially worthy of notice, because in animals which have taken mercury for some time, it is the only evi- dent effect of the drug upon the skin. In addition to these affections of the skin, it is said that mercury may, in rare instances, after its external applica- tion, cause the formation of gangrenous ulcers, or even gangrene. We must, however, agree with Gwalter 1 in regarding the existence of such an effect of mercury as not proven. Nothing positive is known as to the manner of occur- rence of the mercurial eruption after inunctions of gray salve. Two possibilities are here to be considered, accord- ing to either of which it may be supposed that the absorp- tions occurs. According to one theory, the preparation of mercury, applied by inunction, unfolds its action by being vaporized by the heat of the body, and thus gaining an entrance into the lungs and the system at large. From this point of view, the above-described affections must occur secondarily, after the circulation of the drug in the organism, and its transformation into corrosive sublimate or an oxide of mercury. If, however, we adopt the other view, according to 1 Gwalter: Ein Fall von Quecksilbervergiftung. Inaug. Dissert., Zurich, 1877. ALTERATIVES 83 which the oleate of mercury, which is constantly being formed by rubbing the drug with fat, is absorbed as such by the skin, we must suppose that the eruption is due to the directly irritating effect of the mercury upon this organ. This irritation, if long continued, may lead to a hyperaemia of the dermal capillaries, swelling of the epi- dermis and sebaceous follicles, and consequently to exu- dation and the formation of papules and vesicles. The latter is probably the most common, if not the only mode of origin of the skin affection. This seems all the more probable, because the oleic combinations of mercury may exert a corrosive action, like the bichloride, and also because when mercurial preparations, even corrosive sub- limate, are suddenly introduced into the circulation, e.g., by subcutaneous injection, neither erythemata nor ecze- mata are ever observed. There, therefore, seems neces- sary for the production of the latter affections, a long- continued action of a soluble salt of mercury upon large portions of the skin, such as is furnished by repeated inunctions of gray salve, containing combinations of mer- cury with a fatty acid. This, however, does not preclude the possibility of the occurrence of skin changes from the internal use of mercury, which, in view of recent obser- vations on this point, seems likely. In opposition to the view held by the so-called anti-mer- curialists, concerning the specific character of affections of the skin which follow the use of mercury, attention need only be called, without entering into subtle deductions, to the numerous eruptions mentioned in this work, produced by the most heterogeneous substances. These present a complete analogy among themselves, and the only specific element which they manifest is a direct or reflex action upon the skin. The treatment of mercurial eczema consists in the imme- diate suspension of the drug, and the local application of soothing oils, salves, or vaseline. 34 INCIDENTAL EFFECTS OF DRUGS. A second incidental effect of the use of mercury, which occurs in about thirty or forty per cent of all cases, is sali- vation or stomatitis. Usually only twenty-four or forty- eight hours, in rarer cases two or three hours after the internal or external use of preparations of mercury in me- dicinal doses, there appears either alone or simultaneously with redness, swelling, softening, and sensitiveness of the gums, or before these symptoms, a sometimes quite exces- sive secretion of saliva, even as much as five kilos (eleven pounds) in twenty-four hours, which may last all night, and prevent the patient from sleeping. It persists usually for from three to ten days, or longer, and is attended with an offensive odor from the mouth and a subjective metallic taste. The saliva itself offers nothing especially characteristic. Its specific gravity may rise in the com- mencement of the salivation to 1.059, but later falls again. After some time it smells bad, has a strongly alkaline reac- tion, and irritates the soft parts over which it flows. The gums, the mucous membrane of the cheeks and palate, the tongue, the soft palate, and also the tonsils, experience changes varying in degree according to the individuality of the patient, the length of time during which the mer- cury was employed, and the amount of the drug used. The changes embrace ail stages, from simple hyperaemia to the formation of ulcers and necrosis of tissue. In the milder grades of mercurial stomatitis, the edges of the readily-bleeding gums are covered with a stinking yellowish, greasy mass. The teeth may even become loose. The ulcers, which are present in the severer forms, show a tendency to spread in depth and extent. They generally have smooth, jagged edges, and a base covered with a thin yellowish secretion. Not infrequently swell- ing of the lymphatic glands of the neck is also observed. The subjective general disturbances which accompany these affections are exceedingly annoying, even in the milder forms. The constant flow of saliva causes sleeplessness, in ALTERATIVES. 85 consequence of the necessity of either expectorating or swallowing it. To this is added pain, whenever articles of food come in contact with the inflamed or ulcerated parts. The swelling of the tongue, which frequently occurs, interferes with speech, and slight fever, which is often present, loss of appetite, headache, and bodily weak- ness, render the condition of the patient a very unpleasant one. After the affection has lasted for several days, if the use of the drug has been meanwhile suspended, the flow of saliva becomes less profuse, the changes in the mucous membrane of the mouth begin to disappear, and the ulcers which may be present, to heal, leaving star-like cicatrices behind. If more extensive destruction of tissue be pres- ent, many weeks and months elapse before complete re- storation occurs. The observation has been made that there are two fac- tors which predispose to the occurrence of the affection of the mouth, and particularly the salivation. These are : 1, uncleanliness of the mouth ; and 2, a weak anaemic con- dition of the body, or previous severe diseases. The affections considered above may also be produced by subcutaneous injections of mercury. This fact, com- bined with the circumstance that mercury may be found in the saliva, where it probably exists in an organic com- bination, proves among other things that the elimination of the metal occurs through the salivary glands, no matter what the manner of its use. In this way are explained the salivation and the tissue-changes in the mouth, since we must believe that, in the first instance, the irritating action of the eliminated mercury upon the tissues of the parotid or submaxillary gland, or their nerves, must cause, by a reflex action, the increased secretion of saliva, and that, further, the thus eliminated saliva, which contains mercury, if it act long enough, and contain a sufficient quantity of the drug, must produce inflammation or ero- 86 INCIDENTAL EFFECTS OF DRUGS. sion of those parts of the buccal cavity with which it comes in contact. The treatment of a mercurial affection of the mouth must, in the first place, be prophylactic. For this purpose, patients must attend to cleanliness of the teeth, especially removing all products of decomposition contained in cari- ous ones. Attention must also be paid to nutrition, in view of the predisposition shown by badly nourished indi- viduals to the development of such affections. In pro- phylactic and curative therapeutics, the first place, after the discontinuance of mercury, is still occupied by the chlorate of potassium, first recommended by Herpin. This acts most safely and speedily upon the affections of the mouth. It should be prescribed in a two to three per cent solution as a gargle, and also internally to the extent of two to three grams (gr. xxx.-xlv.) daily. In cases of pure sali- vation, a solution of astringents (sol. Acid. Tannici, 1.0-3.0 : 150.0) (gr. xv.-xlv. : § iv.) renders good service when used for washing the mouth. Besides chlorate of potas- sium, alum in one to one and a half per cent solution is also used for the same purpose. Sigmund uses tar for paint- ing the gums during treatment by inunction, both for the prevention of mercurial stomatitis, as well as for curing it when already present. Gums which bleed easily, may be pencilled to advantage with Tinct. Myrrhas, or equal parts of Tinct. Myrrhas and Tinct. Kino, or with Tinct. Rhatanae. These last remedies should also be used for the cleansing of foul ulcers of the mouth, if it be not preferred to employ pure disinfectants, such as carbolic acid (0.5-1 : 150) (gr. viij.-xv. : | ivss.) or thymol (0.5 : 500) (gr. viij. : O. i.). The incidental effects of mercury hitherto described are by far the most common, and occur as well after large and medium as after small doses. Although their duration is relatively short, they are included in the collection of symptoms designated as mercurialism. They only prove that the mercury has been absorbed, is circulating ALTERATIVES. 87 through the body, and causing certain functional or ana- tomical changes at one of its points of entrance or exit. True constitutional mercurialism, however, i. e., the dis- turbances of nutrition, sensation, and even motion, which seriously affect the animal economy, arises most frequently after the loner-continued use of small doses of mercury, disappears less speedily, and is probably due to an elimina- tion and deposition of the metal in different organs. These symptoms are observed in their most pronounced forms in workmen who use quicksilver in their occupations, and have been described in a classical manner by Kussmaul (1. a). They appear more rarely after the medicinal employment of mercury, and in the following remarks only the positively established facts bearing upon this point shall be detailed, without considering the exaggera- tions of the enemies of the drug. The disturbances of nutrition are always attended with alterations of the general condition, and are due almost ex- clusively to a direct action of mercury upon the gastro- intestinal canal and its secreting glands, and not, as was formerly believed, to its mythical faculty of melting the organs and drying up the blood. The direct involvement of the stomach and intestines is proved by several facts. G. Lewin (1. c.) saw, even after the subcutaneous use of mercury, especially when the proper doses were exceeded, the symptoms of a gastro-enteritis, pain, and burning in the region of the stomach, particularly upon pressure, and diarrhceic stools, sometimes tinged with blood. In keeping with this, the patients felt badly generally ; they were pale, and complained of a tired feeling, weakness, and troubled sleep. The explanation of this action upon the intestinal tract is furnished by the fact that, even after subcutaneous injection, mercury is eliminated by this organ. In agreement with this stand the changes in the digest- ive canal experimentally produced in animals and also observed in man, which present the picture of catarrhs of 88 INCIDENTAL EFFECTS OF DRUGS. different degrees of intensity, even of ulceration, par- ticularly in the ileum and caecum. In this simple man- ner are explained the anorexia, emaciation, vomiting, the pains in the stomach and abdomen, and the failure of the bodily forces, observed in the cases of many persons treated for a long time with small doses of mercury, par- ticularly when one considers that the casting-out of the drug into the intestinal canal, together w T ith the above- described physical anatomical changes in the stomach and intestines, destroys the activity of the digestive fluids. In such persons there occurs, therefore, in consequence of the gradual diminution or loss of appetite, not only a lessened assimilation of food, but this process, when the canal is in a catarrhal condition, is much retarded, under certain cir- cumstances, to such a degree, that, in order to preserve the continuity of the nutritive processes, the body is forced to live upon itself. This view of the matter is well borne out by the result of the investigations of the nutritive processes made by V, Boeck, in a man who was treated for syphilis by mercurial inunctions. He found no changes in the decomposition of albumen during treatment. In this case, however, the action of the mercury had lasted only sixteen days — a period in which the intestinal changes above described do not usually appear. It must be especially remembered that, for the appearance of disturbances of nutrition, there is necessary either a certain predisposition or a prolonged action of mercury upon the digestive tract. An alteration in the urine which permits us to draw a conclusion as to the condition of the kidneys sometimes occurs, usually in company with the nutritive disturbances, more rarely alone. It not unfrequently contains albumen, but in small quantities. Since the kidneys, as has been proved, are the organs which eliminate a portion of the mercury, the presence of albumen in the urine is most probably to be attributed to the irritating action of the ALTERATIVES. 89 drug upon these organs, particularly the uriniferous tu- bules. The view that this albumen is not due to an altera- tion of the kidneys, but belongs to the metal which is eliminated in the form of an albuminate, is proven to be unwarranted, by the fact that the urine of persons using the drug always contains mercury and but rarely albumen. The latter always appears when toxic doses are adminis- tered, and then substantial alterations can also be found in the urinary passages. In addition to albumen, sugar may also be found in the urine after the use of mercury. This was. proven by experiments upon animals made by Saikowski ' and Rosenbach. 2 In this respect, mercury bears a certain analogy to other poisonous substances, such as morphia, carbonic oxide, etc. The treatment of the general disturbances of nutrition consists essentially in a removal of the injurious agent and a suitable dietetic regimen. In addition to improving the hygienic relations of the patient, the effort must be made, by the administration of appropriate non-irritating articles of food, to correct any changes which may be present in the intestinal canal, and also to cause a rapid and as com- plete an elimination of the drug from the body as is possi- ble. The latter end may be reached by producing active diuresis, by means of vapor and sulphur baths, and espe- cially by iodide of potassium, as recommended by Melsens 3 after the use of which a larger amount of mercury is said to leave the body by the kidneys than under ordinary cir- cumstances. These disturbances of nutrition and the general condi- tion, as is also observed in cases of chronic poisoning with other metals, are frequently only the forerunners of func- tional disturbances of the general nervous system. Occa- 1 Saikowsk', Virchow's Archiv, p. 346. 2 Ros-nbach, Zeitschr. f. naturw. Medicin, 3 Reihe, xxxiii., p. 36. 3 Melsens, Annal. de Physique et de Chimie, III. S., T. 26. 9 small doses may produce incidental effects, which are usu- 1 Rilliet, Bullet, de l'Academie de Medec, i860, p. 382. ALTERATIVES. 105 ally seen only after large doses, and vice versa. It is, therefore, evident that, for unknown reasons, sometimes one organ and sometimes another is affected in its func- tions, or experiences material changes through the action of iodine. We are not, however, in a position to construct laws from this circumstance, because we are ignorant of the conditions necessary for the production of these affec- tions. We must, therefore, content ourselves with study- ing in detail the various effects produced by iodine upon individual organs. After taking iodide of potassium, man)' persons experi- ence, particularly after waking in the morning, an astrin- gent metallic and bitter taste on the tongue. This quickly disappears, as Laroche 1 states, after washing the mouth with cold water, to which a dessert-spoonful of spirits of horse-radish has been added. In very sensitive persons, there is also occasionally observed, after small doses, tickling and burning, and a sensation of dryness and con- striction of the pharynx. In rare cases, disturbances of the power of swallowing are observed.- The sensation of burning may extend from the throat down the sternum to the region of the stomach. With this there is frequently associated increased flow of saliva, in consequence of the peculiar power of iodide of potassium to excite the secre- tion of nearly all the glands. Although the function of the stomach is not affected by one or more small or medium doses of iodide of potassium, even an increase of the appetite to intense hunger being sometimes noticed, there is occasionally observed, in the case of persons who have a pronounced antipathy to this drug, nausea and vomiting, and in others, as Ricord 2 states, a pain seated at the fundus of the stomach, not increased by pressure, and without influence upon diges- 1 Laroche, Canstatt's Jahresbeiicht f. d. ges. Medicin, 1844, IV., p. 195 2 Riccrd, Bulletin generale de Therapeut., 1842, p; 161. 106 INCIDENTAL EFFECTS OF DRUGS. tion. Rabuteau attributes these phenomena to adultera- tion of the iodide of potassium (IK) with the iodate of potassium (KI() 3 ). He claims that, in this case, in conse- quence of the influence of the gastric acid, free iodine is formed in the stomach, and attacks the mucous mem- branes. Although the hypothesis is not altogether satis- factory, in view of the fact that these symptoms occasion- ally show themselves after taking the pure iodide of potassium, it is nevertheless possible that in some cases the freshly-liberated iodine may favor their occurrence. Therefore, in case doubts arise as to its purity, the iodide of potassium should be tested for the presence of the iodate, in the manner to be described later. Digestive disturbances occur only after the long-con- tinued use of large doses of the iodide of potassium. The irritative effects of the drug upon the mucous membranes of the air-passages, on the other hand, take place so readily, that perhaps a majority of those who take it suffer from them in a greater or lesser degree. This action is prima- rily exerted upon the mucous membrane of the nose, but it often occurs simultaneously upon that of the larynx, and the bronchial tubes and their ramifications. Since the affection first became known, the changes in the nose have been called " iodine-cold." It manifests it- self in the form of a catarrhal inflammation of the mucous membrane of varying intensity, and may spread over its whole surface, invading the choanse, the frontal sinuses, and the antra of Highmore. The membrane in such cases is softened and swollen, secretes freely, and the subjective symptoms, which often begin with a burning sensation in the nose, take the form, later on, of a feeling of oppression and occlusion, sneezing, etc. If the olfactory region is particularly affected, loss of smell also occurs. The whole affection ends soon after the discontinuance of the drug. In the description of the acute pathological symptoms produced by the external application of iodine, the occur- ALTERATIVES. \oy rence of oedema of the glottis has already been mentioned. The tendency of the preparations of iodine to excite catar- rhal conditions of mucous membranes makes it probable that this oedema is due to a sudden swelling of the mem- brane of the affected parts, with a subsequent infiltration of the submucous connective tissue. The irritation of mucous membranes of parts more deeply situated which occurs in many persons after the use of small doses of iodide of po- tassium renders this view more probable. Thus Ricord (1. c.) often observed in such cases a bronchitis which could be physically demonstrated, attended with labored respira- tion, cough with oppressed breathing, pains in the breast and tolerably free expectoration, which, however, never became putrid. These respiratory disturbances have been by some authors 1 needlessly designated as " iodine asthma," in analogy to those previously described as asth- matic, occurring after the use of lead, mercury, and other metals. But even true oedema of the glottis, as has been proven by the observations of Petitjean,' 2 may be pro- duced by medicinal doses of iodide of potassium, but only in persons already suffering with laryngeal affections before taking the drug. In the case of an individual who died from such an oedema of the glottis, there were found smail ulcers in the larynx, as well as oedema of the epiglottis. That pre-existing organic changes may be made worse in this manner is proved by a case reported by Rodet, 3 of a man suspected to have tuberculo- sis, who every time he took iodide of potassium had a more or less profuse haemoptysis. From an extension of the catarrhal irritation to the vocal cords there occurs in very exceptional cases difficulty in phonation, without deeper lesions. 1 Sant'us, Deutsche Klinik, 1856, p. 18. 2 Pet tjean: Accidents du cote de la peau et des muqueuses determines par l'administration de l'jodure de potassium. Paris, 1879, p. 29. 3 Rodet, Gazette medicale de Paris, 1849, p. 946 IG 8 INCIDENTAL EFFECTS OF DRUGS. Analogous to the pathological changes on the mucous membrane previously named, are those which appear with tolerable frequency on the eyes and their appendages after the use of iodide of potassium. These rarely appear en- tirely alone, but are usually attended with nasal or bron- chial catarrh, and occur suddenly in one or both eyes, and manifest themselves immediately, in part as a catarrhal irritation of the conjunctiva and the lining membrane of the lachrymal gland and duct. The vessels of the palpe- bral and bulbar conjunctiva are greatly injected, the mucous membrane itself is swollen and softened, the flow of tears is increased, but photophobia occurs but rarely ; on the other hand chemosis and oedema of the eyelids some- times take place. The subjective symptoms vary with the degree of the affection. The patients usually complain of burning and itching, and have a feeling as if a foreign body were in the eye. In some cases, a painful sensation of weight is experienced in the supra-orbital region, at the point of exit of the supra-orbital nerve. These incidental effects of iodide of potassium may, ac- cording to the specific disposition of the individual, appear after either one or repeated doses. They usually show themselves after the frequent use of small doses, and dis- appear spontaneously a few days after stopping the drug, without leaving after-effects, and still more quickly if mildly astringent lotions are used. Many cases have been described in which the above-mentioned symptoms ap- peared after 0.5 gram (gr. viiss.) and even less, of iodide of potassium. Thus Mecklenburg, 1 among others, witnessed after 0.5 gram (gr. viiss.) of this drug, in the course of a few hours, intense pains in the eyes, abundant flow of tears, burning in the nose and throat, as well as swelling and livid discoloration of the upper eyelids, particularly in the tarsal region. Twenty-four hours later, all these 1 Mecklenburg, Berl. klin. Wochenschr., 1866, p. 262. ALTERATIVES. 109 phenomena had disappeared. When only 0.25 gram (gr. iv.) of iodide of potassium was again taken, the same symptoms, with the exception of the swelling of the eye- lids, reappeared in four hours. In addition to the purely external phenomena already described, it is said that there sometimes appears, although very rarely, a limitation of the power of accommodation, as well as diminution of the sharpness of sight, symptoms of presbyopia. Corlieu 1 reports such a case. He observed, in addition to other abnormal effects of iodine, presbyopia with dilatation of the pupils and a suddenly-occurring hy- permetropia, symptoms which passed away a few days after stopping the iodine. Dorval 2 also observed diplopia with dimness of sight, and Brera 3 the latter symptom as- sociated with orbital pain. Which of the possible factors Avas instrumental in causing these disturbances of function has not yet been positively determined. The already-described irritative effects upon the skin, occurring upon distant parts of the body after the external application of iodine, also show themselves in many cases after the internal administration of the iodide of potassium, under widely-varying conditions as regards the dose and length of time during which the drug was used. In the latter case, however, the multiformity of the eruptions is much more marked than in the former. This particular incidental effect of the iodide of potassium has been well known ever since its introduction into the materia medica, and one therefore finds almost innumerable observations on this subject in literature. They all go to establish as a fact that the iodide of potassium often produces eruptions, from simple erythema to petechias, with or without fever, occurring either alone or in combination with other ab- 1 Corlieu, Gazette des hopitaux, Juin, 1856. 2 Dorval, eod. loco. 3 Brera, eod loco. II0 INCIDENTAL EFFECTS OF DRUGS. normal effects of iodine, and disappearing, as a rule, very soon after the use of the remedy is suspended. These eruptions, according to Fischer, 1 are divisible into four principal forms. I. The erythematous form. — The skin, particularly on the forearms, and also on the face, is reddened, either dif- fusely or on circumscribed spots, and its temperature elevated. After discontinuing the drug, this symptom disappears in a few hours, but if its use be persisted in, the eruption may pass into that which is most common, II. The urticaria-like form. — Usually on the abdomen and extremities, but also on other parts of the body, there ap- pear, without fever, intensely red wheals, but slightly raised, surrounded by an areola, generally collected into groups, only distinguishable from a genuine urticaria by their more intense color, which is usually described as rose-red, and which become pale on pressure. They dis- appear after the use of iodine is stopped, without desqua- mation. III. The no dulo -pustular form. — This is more rarely ob- served, and occurs most frequently in scrofulous individu- als, usually upon the upper half of the body. An itching spot forms, of a deep-red color, which is soon transformed by exudation into a papule, or a bluish-red nodule, with or without an areola. This may persist, but as a rule there is developed upon it a colored vesicle filled with clear fluid, or a pustule, which may burst or dry up, while the papule, after the cessation of the use of the iodide of po- tassium, slowly disappears with desquamation, often leav- ing behind a bluish-red or marbled pigmentation of the skin. As intermediate forms pure vesicles, acne-like pustules (iodine-acne), and even furuncles are observed. Thus Brshesinsky 2 witnessed, in the case of a woman who took 1 Fischer, Wiener medic. Wochenschr., 1859, No. 29, p. 470'. 2 Brshesinsky, Canstatt's Jahresber. f. d. ges. Medicin, 1843, iv. , p. 32. ALTERATIVES. IIT three times daily thirty drops of the tincture of iodine, the development of large furuncles with intense surrounding inflammation, on the breast and between the shoulder- blades. After warm applications they fell off in the form of lumps, leaving large ulcers behind. IV. The eczematous form. — This is very rare, and appears especially on the hairy scalp and in the neighborhood of the scrotum. The differential diagnosis between syphilis of the skin and this affection is easily made, especially in view of the fact that the latter disappears soon after the discontinuance of the drug. In this connection, for the sake of completeness, mention should be made of a form recently described, viz.: V. The petechial form. — Fournier 1 describes this eruption, which he calls iodine purpura (jodisme petechiale) as very rare. He saw the eruption, which has also been mentioned by Ricord, in the majority of the cases during the first three days after the use of iodide of potassium, more rarely from the third to the sixth day. In some individuals it always appeared as soon as iodine was administered, and in the case of one patient a new eruption occurred every time the dose was increased. It appeared in every case exclusively on the legs (once only on the trunk) more pro- fusely on the extensor than on the flexor surfaces. It never attacked the knees or the feet. There are usually as many as one hundred discrete patches on each leg. They are miliary, usually of pin-head size, rarely as large as a bean, and cause no general disturbances of any kind. The eruption usually reaches its height in two to three days, and lasts at most two to three weeks, and then disappears. Petitjean 2 confirms these details in the main, but describes a case in which the eruption also occupied the dorsal surface of the foot. 1 Fournier, Revue mens, de Medecine, 1877, p. 653. Vierteljahrsch. f. Der. u. Syph., 1878, p. 294. 2 Petitjean, 1. c., p. 35. 112 INCIDENTAL EFFECTS OF DRUGS. Ausspitz 1 saw a similar eruption in a patient who had taken twenty -five iodide of potassium pills, each containing 0.2 gram (gr. iiss.) or in all five grams (gr. lxxv.) The best explanation of the occurrence of the above de- scribed incidental effects of iodide of potassium is found in the view that they are all due to a direct influence of the drug (or its products of decomposition) upon the affected parts, which it reaches through the blood. The hypothesis of " a saturation of the body with iodide of potassium," for- merly held by the majority of authors, of which these symptoms were considered as the expression, is both so obscure and inexact, and so easily refuted by the fact that these affections may occur after quite insignificant doses, that it is unworthy of further discussion. The results of chemical analysis also speak in favor of the local origin of these phenomena. It has long been known that iodine can be found in various secretions, e. g., the urine, saliva, sweat, milk, and tears, a short time after taking iodide of potassium. Adamkiewicz 2 also succeeded in demonstrating its presence in the nasal mucus and in the contents of the sebaceous glands in cases of iodine acne, thus showing that the dif- ferential diagnosis between this affection and ordinary acne may be made by chemical means. In view of this discovery, Adamkiewicz attributes iodine acne to the action of iodine upon the sebaceous glands. He believes that the disease is due to the fact that the salt of iodine which is taken into the body forms free iodine in combina- tion with the nitrate of ammonium present in the stagnant secretions of the skin, and this may irritate the glands and the surrounding tissues. The iodine which is discharged with the sweat does not produce this affection, as is shown by the well-known fact, that the palms of the hands 1 Ausspitz, Vierteljahrsch. f. Dermatolog. u. Syphilis, 1878, p. 294. 2 Adamkiewicz, Charite-Annalen, iii., 1876. ALTERATIVES. H3 and soles of the feet are not affected by iodine acne. That iodide of potassium should choose these unusual channels of exit from the body, instead of the ordinary ones, may be due to individual peculiarities, or to the fact that the urinary passages, although in a physiological condition, perform less work than usual, as in summer, or that they are diseased. Thus Johnson 1 saw in many cases of Bright's disease, in which small doses of iodide of potassium were given, pus- tular iodine eruptions, and Rose, 2 after the injection of preparations of iodine into an ovarian cyst, found a large quantity of the drug in the fluids which were vomited soon afterwards. In the latter case, there probably occurred an elimination of the drug into the stomach, in consequence of a diminished secretion of urine. The fact observed by Simon and Regnard (1. c.) that al- buminuria sometimes results from the external use of iodine, goes to prove that this substance may exert a direct action upon the urinary passages. Iodide of potassium is said to produce a similar effect in some persons. Rodet (1. c.) and Petitjean (1. c.) have reported cases in which vesical tenesmus, dysuria, retention of urine, and evert hsematuria, followed the use of this salt. The old and familiar experience that iodine possesses the power of reducing hyperplasia of glandular tissue,, finds a physiological analogy in the effect of long-continued medicinal doses of iodide of potassium upon the testicles, ovaries, and mammae. Many authors claim to have wit- nessed under its use the occurrence of varying degrees of atrophy in these organs, although they were previously in a normal condition. It is probable that a direct localized action of the iodine salt or iodine upon the cellular ele- ments of the gland is largely instrumental in producing such results. 1 Johnson, British Medical Journal, Jan., 1859. 2 Rose, Virchow's Archiv, Bd. 35, 1864, p. 32. H4 INCIDENTAL EFFECTS OF DRUGS. As regards the genital system, it is said that increase of the sexual appetite, a discharge of semen, and in women more abundant menstruation, may result from the pro- tracted use of the iodide of potassium. Mention must finally be made of the disturbances of the general nervous system and of nutrition which occur in some persons after the use of iodine — that group of symp- toms which Rilliet has designated constitutional iodism. This condition, according to him, may follow the pro- tracted use of even minimal doses of the iodide of potas- sium. The patients present a peculiar cachectic color of the skin, and become much emaciated, although their ap- petite is usually good. This condition shows itself in the face and about the hips, breast and scrotum, and is asso- ciated with a feeling of lassitude and physical weakness, and a kind of cerebral confusion which has been called " ivresse iodique " by French authors. The patients also suffer from derangements of hearing, lancinating pains in the extremities, slight spasms of the tendons, and nervous palpitation of the heart. Although the facts detailed prove that iodide of potas- sium often fails to act in a normal manner, causing instead undesired incidental effects in the most different organs, this circumstance would not justify us in limiting the use of this drug, as Rodet proposed, to a small number of dis- eases. For these phenomena are observed in only an in- significant number of persons, and in the large majority of instances they are of merely temporary duration. This fact does not exclude the necessity of observing a certain amount of caution in administering this remedy, especially in cases which already suffer from diseases of the larynx or kidneys, and the discontinuance of its use on the first appearance of undesirable incidental effects. If disorders of the intestinal tract, such as vomiting, diarrhoea, etc., appear immediately or a short time after taking the drug, it would be advisable to test the purity ALTERATIVES. U5 of the solution used, for which purpose it should be de- composed with hydrochloric or sulphuric acid. If the iodate of potassium be present, a precipitate is thrown down, and free iodine is formed. Brominum. On account of its disagreeable physical qualities, bro- mine is but seldom employed therapeutically. It is, how- ever, occasionally used by inhalation, and in watery solu- tion as a gargle in infectious diseases, such as diphtheria, etc. Besides, on the recommendation of Liebreich, living- rooms, which are suspected of being infected, are some- times purified by spontaneously volatilizing bromine — a method which is certainly preferable to all others, when the apartments can be closed and allowed to remain unoc- cupied for a long time. For bromine, which, in solution, acts as a caustic upon the skin and mucous membranes, in the form of a gas irritates the mucous membranes with which it comes in contact, exciting changes varying from slight redness to violent inflammation. On this account, one not unfrequently observes conjunctivitis, coryza, sali- vation, a feeling of suffocation, and slight bronchitis with cough in those who have inhaled bromine for therapeutic purposes, or accidentally, in rooms filled with the vapor. The internal use of bromine-water also frequently causes coryza, lachrymation, bronchial catarrh, salivation, and diarrhoea. In the experiments of Glover 1 upon himself with this agent, there appeared only occasionally pains in the stomach, and, after larger doses, nausea, hiccough, burning in the mouth, oppression over the stomach, etc. Experiments of other authors showed that bromine-water used in small quantities for a short time, exerts a depress- ing influence upon the central nervous system. Those who took it experienced a feeling as if ants were crawling 1 Glover, Edinb. Med. and Surg. Journ., 1842, p. 120. Il6 INCIDENTAL EFFECTS OF DRUGS. over the skin, drowsiness, apathy, confusion of ideas, and weakness of the power of thought and memory. These symptoms disappeared immediately after stopping the drug. POTASSII BROMIDUM. In strong contrast with those affections, insignificant in number and intensity, which may develop after the use of bromine, are a number of incidental effects, produced by the internal administration of bromine salts, particu- larly the bromide of potassium (and what is true of this, applies also to the bromides of sodium and ammonium). They present, on the whole, a certain resemblance to the symptoms produced by the use of the iodide of potassium, but are not of so manifold a nature, and persist, as a rule, for a longer time. The mucous membranes are very frequently affected, but in a lesser degree than by iodide of potassium, while, on the other hand, in many cases, the influence upon the skin, and to a still greater extent upon the central nervous system, far exceeds in intensity and duration that of iodine. The fact mentioned in discussing iodide of potassium, that the individuality of the affected person is of vital importance in determining the occurrence of incidental effects, applies also to bromide of potassium. For, while they show themselves in some persons after one or more small doses, others manifest a certain tolerance for even toxic quanti- ties of the agent. In favor of the existence of this want of susceptibility, speaks, among others, in a characteristic manner, a case reported by Schweig l of a patient who manifested no reaction after taking thirty-one grams ( 3 i.) of bromide of potassium in seven hours, and after ninety- three grams ( 3 iij.) in forty-eight hours, experienced only a diminution in the amount of urine excreted, with saliva- 1 Schweig, Virchow-Hirsch's Jahresber , 1S76, p. 401. ALTERATIVES. 117 tion and somnolence. Arthaud also states that, in fourteen cases in which he prescribed doses of from ten to twelve grams ( 3 iiss. to 3 iij.) daily, he never saw any affection of the skin. Bromide of potassium produces, a short time after it is taken, a salty, according to others, a bitter after-taste in the mouth, and sometimes an increased flow of saliva, due to irritation of the buccal mucous membrane and a reflex hypersecretion from the salivary glands. In sensitive per- sons, there also occur burning in the throat, sometimes slight nausea, eructation, and, when it is taken upon an empty stomach, pains in the epigastric region, or a sensation of oppression, or warmth and fulness. A genuine catarrh of the stomach is a rarity, if the drug is not habitually taken in an improper manner, upon an empty stomach. One now and then observes eructation and vomiting, and more rarely diarrhoea, in some patients a short time after tak- ing bromide of potassium. On the other hand, as Hutte 1 first showed, there occur, after long-continued small doses, or after larger quantities taken for a short time only, a blunting of the sensibility as well as the reflex action of the soft palate, the root of the tongue, the uvula, and the posterior wall of the pharynx. Gatumeau, 2 after three grams (gr. xlv.) of the drug had been taken, observed a complete analgesia of the pharynx and epiglottis, so that touching the posterior wall of the throat excited no reflex movements of swallowing. Krosz 3 also observed in his own person, after large doses of the bromide of potassium, such a lessening of the reflex excitability of the parts mentioned that no reflex nausea could be produced by irritating the velum. No less a diminution of sensibility is also experienced by the respiratory mucous membrane. 1 Hutte, Gazette medicare de Paris, 1850, Juin 28. 2 Gatumeau: These, Montpeilier, 1869. 3 Krosz, Arch. f. exper. Pathologie u. Pharmakol., Bd. vi., p. 15. Il8 INCIDENTAL EFFECTS OF DRUGS. This fact, in connection with the not-uncommonly observed appearance of bronchial catarrh with copious secretion, after the use of bromide of potassium, must not be lost sight of during the prolonged treatment of patients with this agent, particularly epileptics, maniacs, etc. Stille x called attention to the fact that the catarrhs of the air-pas- sages, which occur during treatment with bromide of potassium, may threaten life, if the use of the agent be continued, in consequence of the fact that the diminution of the reflex excitability of the respiratory mucous mem- brane prevents the occurrence of fits of coughing, which might remove the collected mucus. The bronchial catarrh is sometimes attended, as Horing 2 found in his own case, with pain in the larynx, paroxysms of coughing, and hoarseness of voice. According to older authorities, haemoptysis also occurs in a large number of patients who use this drug, and disappears after its use is abandoned. No confirmation of this statement is, however, to be found in modern literature. Another accessory symptom of the already described effects of bromide of potassium which is often noticed, is a foetid odor of the expired air, which Veiel 3 has recently called attention to. This cannot be due to pathological changes in the mouth, such as occur, for instance, after the use of mercury, for bromide of potas- sium produces but insignificant alterations in this locality. It is probable that the bromine is temporarily separated from the potassium in the body, and that the elimination of a portion of it by the lungs is the cause of the bad odor of the breath. This explanation is not intended to convey the idea that the bromine, as such, produces the catarrhal changes in the mucous membranes, for even if a small part 1 Stille, Virchow-Hirsch's Jahresber., 1878, i., p 384. 3 Horing: Ueber die Wirkung des Broms und seiner Praparate auf den thie- rischen Organ'smus. Tubingen, 1838. 3 Veiel, Vierteljahrsch. f. Dermatol, u. SyphiL, 1875, p 17. ALTERATIVES. II 9 of it does leave the body in the form of a vapor, the greater part, immediately after its separation from the potassium, finds enough of the alkaline metallic salts in the blood to be enabled to act upon the different mucous membranes in its original character of a bromine salt. The mucous membranes of the nose and eyes may also be attacked, as is shown by the occasional occurrence of coryza, conjunctivitis, lachrymation, etc., after the use of bromide of potassium. Dilatation of the pupil is almost always noticed after repeated doses. Laborde 1 witnessed the occurrence, one or two hours after taking it, of dimness of vision and in some cases anaesthesia of the scleral con- junctiva. Hiitte (1. c.) stated that myopia, amblyopia and diplopia could be produced by bromide of potassium. This was also believed by Martin Damourette and Pelvet, 2 while Nicol and Mossop claim to have observed dilatation of the retinal vessels after its use. These statements are opposed to the experiments of Krosz 3 upon himself and others, which always gave negative results as regards these pathological phenomena. It has been demonstrated that the urino-genital appara- tus is affected in an extensive degree by this drug. In addition to a real increase in the quantity of urine excreted, there sometimes occurs, in certain persons, strangury , -a constant feeling of fulness of the bladder, and also a diminution of the sensibility of the urethral and vaginal mucous membranes. The sexual appetite, as Rabuteau 4 stated, is diminished by the long-continued use of the bromide of potassium. This effect of the drug had previously been utilized by Thielmann, 5 who prescribed it 1 Laborde, Gazette medicale de Paris, 1869. 2 M. Damourette et Pelvet, Bullet, de Therap., lxxiii., 1867, p. 241. 3 Krosz, 1 c., p 21. 4 Rabuteau: Gazette medicale de Paris, 1869, p. 312. 5 Thielmann, Medic. Zeitung f. Russland, 1854. j 20 INCIDENTAL EFFECTS OF DRUGS. in doses of 0.18 gram (gr. iij.) as an antaphrodisiac. On the other hand, after one large dose, Laborde (1. c.) ob- served in himself, sexual excitement, erections and pollu- tions. Voisin 1 reports the same^ result as occurring after ordinary doses, but very rarely. Sometimes a diminution of the catamenial flow occurs in women. The irritating effect which bromide of potassium is capable of producing upon the skin deprived of epidermis, as well as upon mucous membranes, is also manifested in a large number of cases after the internal administration of the agent, by the production of eruptions of various kinds. Their existence has been recognized for a long time, and they are usually collectively designated as " bro- mine acne," although they occupy a different place in the dermatological system. Berenguier 2 observed the eruptions in fifty-three per cent, Clark and Amory 3 in sixty-six per cent, and Voisin in seventy-five per cent of all patients treated with bromide of potassium. Some authors, as Bedford Brown, 4 wit- nessed their occurrence attended with local or general ele- vation of temperature ; while Veiel (1. c.) lays stress upon the fact that the acne-like eruption develops very gradu- ally, without fever. Voisin found this complication only once, in a case of general bromine acne. Falret 5 states that he has always found the eruption when four grams (3i.) of the salt were taken, but it is certain that it may occur after much smaller doses. Children are, as a rule, less frequently attacked by it. The eruptions produced by this agent are differently described by different authors. They are. however, in 1 Voisin, Bulletin gene'rale de Therapeut , lxxxiii , 1867, p. 241. 2 Berenguier, Des eruptions provoque'es par l'ingestion des medicaments, Paris, 1874, p 14. 3 Clark and Amory, Virchow-Hirsch's Jahresber., 1872. 4 Bedford Brown, Virchow-Hirsch's Jahresb., 1873, p. 358. 5 Falret, Annales Medico-psychologiques, 1871. ALTERATIVES. 121 great part due to affections of the sebaceous glands and their consequences, and since the different stages of devel- opment are usually represented at the same time in one individual, they closely simulate various dermatoses. Voisin (1. c.) has given a classification of all the skin-affec- tions which occur after the use of bromide of potassium. In view of more recent observations by other authors, however, his classification may be advantageously in- creased by the addition of a few varieties, so that the following arrangement may be regarded as comprising all the changes of the skin which may be produced by bromide of potassium. There appear, therefore, in certain individuals, according to their specific disposition, independently of sex and previous condition of health, at different periods during the administration of this drug, and under the widest vari- ation as regards dose, various affections of the skin, such as: i. The erythematous form. — This was observed by Veiel (1. c.) as the sole symptom produced by the drug, attended with fever, and diffusely spread over the lower extremities. The erythema caused the patient great pain. Brown (1. c.) also describes this eruption as an effect of bromide of potassium. In children he witnessed the occurrence of roseola under the same circumstances. 2. Acne. — This is by far the most frequent form of bro- mide of potassium eruption. According to Veiel a thick- ened skin, having a greasy look from the free secretion of sebaceous matter, as well as the presence of comedones or a pre-existing acne, especially predispose to the occurrence of this eruption. It appears under different modifications which, as regards their seat and their external behavior, present a complete analogy to ordinary acne. The first step in its formation is usually an erythematous condition of the skin of varying extent, attended with pricking and 122 INCIDENTAL EFFECTS OF DRUGS. burning. In this disease also, it is advantageous to distin- guish two varieties, acne punctata, and acne pustulosa. a. Acne punctata. — This usually precedes the pustular form. There appear red elevations, of barley-corn to pea size, on a more or less indurated base, surrounded by an areola, seated by preference on the face, the eyebrows, the hairy scalp, more rarely on the breast and back, and almost never on the lower extremities. Veiel found that the majority of the nodules were perforated by hairs. After a longer or shorter duration, this form may disappear with desquamation, or develop into : b. Acne pustulosa. — This may be regarded either as the result of disintegration of the papules or as an independ- ent form of eruption. The pustules are at first of pin-head size, of a yellowish-white color, and surrounded by an areola. They afterwards increase in size, and in rare cases, according to Voisin, may present the aspect of ecthyma- pustules. After a few days or weeks, the pustule empties out its contents and a firm nodule or a red spot remains behind. The number of the pustules varies greatly, the whole face being sometimes covered and disfigured by them. They may remain for days, or one or more months, and if the use of the drug be not stopped, even several years ; but they usually disappear in from one to three weeks after the discontinuance of the bromide. Voisin (1. c.) also noticed that the number of the pustules increased or diminished with the increase or diminution of the dose. After healing, they often leave depressed, irregularly- rounded scars or spots behind. They form on the same locations as the nodules previously described, and become confluent in some cases, being usually covered with scabs on the scalp. Veiel sought in vain for bromine in the contents of the acne pustules, but could find it only in the urine. Guttmann, 1 in the case of a man who, after using 1 Guttmann-, Virchow's Archiv, Bd 74, p 540. ALTERATIVES. 123 for one year, at first four grams ( 3 L), later twelve grams ( 3 iij.) of the bromide of potassium daily, developed a pus- tular acne, succeeded in demonstrating the presence of bromine in the pustules by the usual method, viz., separat- ing the bromine from the potassium by the addition of chlorine water to the diluted and filtered pus, and extract- ing the bromine by chloroform. 3. The urticaria-like form was observed a few times by Veiel. Wheal-like elevations, varying in size from one- quarter to one-half an inch, showed themselves on erythe- matous portions of skin. The) 7 were exceedingly sensitive to touch, and gradually assumed a wart-like appearance, and took on suppurative action. The ulcer thus formed became deeper, and had an unhealthy aspect, but disap- peared as soon as the bromide was discontinued. This form is without doubt identical with the tumor-like variety described by Voisin, which consists, according to his description, in the appearance of oblong or rounded tumors or elevations of the skin, with hard bases, two to five centimetres (one and a half to two inches) in diameter, and of a rosy-red or cherry color. They show themselves only on the legs or calves, and are covered with small yel- lowish prominences which, on careful examination, are seen to be agminated acne-like pustules, which empty their contents in the form of a creamy mass, either spontane- ously or when punctured. They are very painful when touched, and may be transformed, if the use of the drug is continued, into foul atonic ulcers, which last three or four months, but if the agent is stopped, disappear in a few days. Neumann 1 observed the same affection. He proved that these tumors are, produced by an inflammation of the glands of the skin, attended with an increase of their cellu- lar elements and consecutive cell-growth in the cutis, 1 Neumann, Wiener medic. Wochenschr , 1873, p. 124. 124 INCIDENTAL EFFECTS OF DRUGS. with enlargement of the papillae. During this process the hair-follicles are dilated, and appear either as long tubes or globular bodies, containing pus, epithelial cells, and masses of smegma. 4. Erythema nodosum. — In two cases out of ninety-six, treated for a long time with bromide of potassium, Voisin witnessed the appearance on the arms and legs, as well as on the body, of patches slightly elevated above the skin, of different forms, sometimes having smooth and some- times irregular edges. They attained a size of four milli- metres to six centimetres (one-fifth to two and a half inches), were of a pale-red color in the centre and cherry- red in the periphery. They formed and disappeared very quickly, and presented the shape, color, and hard base of erythema nodosum, but resembled urticaria in reappearing when rubbed. Veiel states that he has seen such an erythema nodosum a few times, but only on the lower extremities. After large doses of bromide of potassium, Smith 1 also saw patches of the size of a half-dollar, somewhat elevated above the surface of the skin, of a bluish-red color, seated upon both arms. They bled readily, were indolent, and disap- peared soon after the drug was discontinued. 5. The vesicular form. — Voisin saw in a single case, that of a patient who had taken bromide of potassium for more than a year, a moist eczema on the thighs. This observa- tion stands alone in literature. 6. TJie fur uncular form. — The coincidence of the use of bromide of potassium with the appearance of furuncles has been asserted by so many authors that there can be no doubt that the two things may stand in the relation of cause and effect. Voisin, Smith, and Neumann saw furun- cles occur in widely varying numbers, on many different 1 Smith, Virchow-Hirsch's Jahresbericht, 1879, p. 384. ALTERATIVES. 125 parts of the body. The latter observed them on the hairy portions of the face, and on the forehead and neck. It should finally be mentioned that Veiel (1. c.) witnessed the appearance of numerous warts on the face and legs of a boy, a short time after beginning the use of bromide of potassium. Various opinions prevail as to the manner in which the above-described changes in the skin are produced after the internal administration of the bromine salts. Thus Clarke and Amory regard bromine-acne as a tropho-neurosis, and not as an effect of the eliminated bromide of potas- sium, and Veiel, also, does not believe that it is due to an irritation of the sebaceous glands produced by the depo- sition of bromine in them, having failed to find it there. Martin, Damourette, and Pelvet, on the other hand, believe the cause of the affection to be the irritation produced upon the skin in consequence of the elimination of the salt by this channel. The demonstration by Guttmann of bromide of potassium in the contents of the pustules, ele- vates into a certainty the a priori already probable hypothe- sis, that, under certain circumstances, an elimination of the salt by the skin may take place. In this way, on the one hand, an analogy is established with the similar changes in the skin which are excited by the salts of iodine, and, on the other, the view is supported that it is the bromine in the bromide of potassium which causes the affection, and not the potassium, as has been claimed by various authors. This is rendered more probable by the fact that other bromine combinations exert a similar influ- ence. Thus Gowers 1 showed that similar eruptions appear after the use of bromide of ammonium, and Stark 2 saw acne occur in seventy-five per cent of all cases of epi- lepsy treated with bromide of sodium, which lasted longer 1 Gowers, Lancet, 1878, p. 866. 2 Stark, Zeitschr. f. Psychiatrie, xxxii., p. 148. I2 6 INCIDENTAL EFFECTS OF DRUGS. than that produced by bromide of potassium, and resulted much more frequently in suppuration. He never found affections of the skin after a similar administration of chlorate of potassium. The main treatment of these disorders consists in the suspension of the drug. Gowers (1. c.) used Fowler's solu- tion in the treatment of bromine-acne, and found that five drops daily sufficed to cause the pustules to disappear in two weeks. This result was largely imaginary, however, since experience teaches that recovery usually occurs in this time without treatment. Distinct from the previously mentioned transitory inci- dental effects of bromide of potassium are a group of functional disturbances in the sphere of the central and peripheral nervous system, which may be associated with one of the affections already described, may persist after the use of the drug has been suspended, and may, indeed, cause permanent injury to the health of the affected per- son. These phenomena constitute the condition known as "bromism." Voisin distinguishes a chronic and an acute bromism and a bromine-cachexia. Intense frontal headache /is usu- ally present in all forms of the affection (a symptom occasionally observed after the use of bromide of potas- sium, without the production of cachectic conditions), and bronchial catarrh and cough may also complicate the situ- ation. Acute bromism may show itself suddenly, even when the drug has been well borne for years, and is marked by a staggering gait, mental apathy, a dull expres- sion of the eyes, and somnolence, while the chronic form is characterized by a sallow color of the face, dryness of the mouth, and an unpleasant odor of the breath, emacia- tion, diarrhoea, failure to preserve the usual bodily car- riage, and trembling of the hands, with weakness of the memory and loss of will-power. It may also find expres- sion in symptoms affecting the cerebro-spinal system, such ALTERATIVES. I2 y as delirium, hallucinations, and motor and sensory distur- bances. Bromine-cachexia, according to Voisin (1. a), begins with loss of appetite, emaciation and somnolence, and the condition of weakness associated with it leads, if the use of the drug be continued, to the formation of car- buncles, or the occurrence of pneumonia, which may prove fatal. Although this classification is open to the objection of being too dogmatic, the fact is nevertheless established that all the phenomena which have been described, in their most varied modifications, may be produced by the use of bromide of potassium. The question as to which of the component parts of this preparation is to be regarded as the cause 01 these peculiar effects, has, in this case also, been differently answered at different times. It may, how- ever, be accepted as proven, that they are due to the com- bined action of the bromine and the potassium, for Stark has shown, by a series of careful observations, that patients treated with chlorate of potassium also suffer from certain symptoms pertaining to the cerebral sphere, such as con- fusion of ideas, diminution of the reflex excitability of the throat, uncertainty of motion, etc. Krosz (1. c.) regards the bromine as the sole cause of bromism, as far as this affects the cerebral and nervous elements, and the potas- sium as the cause of the anaemia and the motor distur- bances. The treatment of bromism should be directed to the dis- continuance of the use of the drug, the furthering of its speedy elimination from the body, and the ordering of an appropriate diet. The physical powers of the patient should be strengthened, and change of climate recom- mended for the psychical lesions. The rapid elimination of the bromide is most readily effected through the kid- neys, which are the regular channels for the elimination of the halogen salts, and diuretics are, therefore, indicated. 128 INCIDENTAL EFFECTS OF DRUGS. POTASSII CHLORAS. Jacobi : has recently called attention to the dangers which may attend the use of chlorate of potassium in too large doses, and has reported a number of cases in which dangerous transitory symptoms occurred, as well as fatal results. These observations were confirmed later by Marchand, 2 Baginsky, 3 Hofmeier, 4 and Wegscheider. 5 On the ground of these facts, Marchand, whose cases, as has been shown by Klister, 6 cannot all stand criticism as re- gards correctness of diagnosis, demands that chlorate of potassium should be entirely abandoned in practice, par- ticularly among children. But, if all drugs which pro- duce hurtful effects when given in unsuitable quantities, or which, when given in ordinary doses, occasionally act abnormally, were treated in this manner, the materia med- ica would soon be reduced to a minimum. Instead of being so ready to dispense entirely with a drug, it would be well to exactly determine the doses suitable for different ages, and to carefully study the physical conditions which may predispose to the occurrence of unpleasant effects. Ever since Lacombe ' published a case of the kind, the fact has been recognized that chlorate of potassium in too large doses may cause fatal poisoning. Isambert, 8 who used it for several days in increasing doses of from eight to twenty grams ( 3 ij. to 3 v.), afterwards observed a 1 Jacobi, Gerhardt's Handbuch der Kinderkrankh., ii., p. 764, and the Med. Record, 1879, iii., 112. 2 Marchand, Virchow's Archiv, Bd. 77, p. 456. 3 Baginsky, Arch. f. Kinderheilkunde, nach einem Vortrage vom 10. Novem- ber, 1878. 4 Hofmeier. Deutsche medicin. Wochensch , 1880, Nos. 38 and 39. 5 Wegscheider, eod. loco, No. 40. 6 Kuster Berlin, klin. Wochenschr , 1880, No. 40. 7 Lacombe, Jour, de Medecine de Bruxelles, 1856. 8 Isambert: Etudes chimiques, physiol. et cliniques sur l'emploi the'rap. de Clor. de Potasse. Paris, 1856. ALTERATIVES. i2 q greenish color of the stools and an increased flow of urine, with a feeling of oppression and pain over the kidneys. Ten minutes after it was taken, he could find it in the urine, the elimination lasting one or two days. The cases of poisoning reported by these authors pre- sent a number of analogous symptoms, equalling in dan- ger those caused by the most active poisons. These are : obstinate choking and vomiting, icteric discoloration of the skin, pains in the stomach and over the kidneys, and occasionally epistaxis, and diminution in quantity and even suppression of urine, lasting from one day to a day and a half, hematuria and albuminuria. With these symp- toms may be associated sleeplessness, a feeling of alternate cold and heat without demonstrable fever, a small rapid pulse, and violent hiccough, and death may occur in a comatose condition. In the case reported by Wegschei- der, there appeared, on the seventh day after the poison- ing, at first only on the arms and forehead, a few red, not elevated spots, of the size of a pea, which became momen- tarily somewhat paler under pressure, and spread in the course of the next three days over the whole body, becom- ing larger, and of a copper-red color. These observations should be contrasted, however, with the fact that hitherto no case has been recorded in litera- ture, in which the administration of chlorate of potassium in medicinal doses was followed by injurious incidental ef- fects similar to those just described, with the exception of the digestive disturbances. As medicinal doses we regard those proposed by Falck, 1 0.1-0.5 gram (gr. ij.-viij.) at once, or five grams (gr. lxxv.) daily, or those of Jacobi (1. a), for a child of from one to three years of age, one to two grams (gr. xv.-xxx.) daily, and for adults six to eight grams (3 iss.-ij.). Of course we leave out of consideration, in this connec- 1 Falck: Uebersicht der Normalgaben der Arzneimittel. Marburg, 1875, p. 10. 9 130 INCIDENTAL EFFECTS OF DRUGS. tion, those cases in which no positive opinion can be formed as to whether a pre-existing dipththeritis or the chlorate of potassium prescribed for it has caused the threatening symptoms, or the death. Whenever the doses exceed the usual limit, a number of incidental effects may be produced, such as Marchand describes in his second observation. A boy from three to four years of age, suf- fering from stomatitis, who took at least ten grams ( 3 iiss.) of chlorate of potassium in one day, was attacked by drowsiness, vomiting, diarrhoea, and delirium. He also suf- fered from epistaxis, and passed bloody albuminous urine, containing a granular brownish sediment. Recovery took place in fourteen days. The treatment of such cases can be only symptomatic. Emptying the stomach of any of the poison which it may contain, quieting the vomiting by ice-pills, champagne, etc., the administration of demulcent drinks, in order to act upon the affected kidneys, constitute the therapeutic measures to be employed. Potassit Chloridum. The chloride of potassium, which Sander 1 considers of equal value with the bromide of potassium, is said by him to have the advantage over it of producing no incidental effects. Further investigations have not confirmed either statement. For Stark 2 found, as has already been stated, that chloride of potassium has no effect whatever upon epileptic attacks, and that, on the other hand, it may, in certain individuals, in medicinal doses, produce a series of hurtful incidental effects in the same way as bromide of potassium. These consisted of a mild degree of confusion of ideas, drowsiness, torpidity, pains in all the limbs, di- minished power of motion, difficulty of speech, loss of 1 Sander, Centralbl. f. d. median. Wissenschaften, 1808, No. 52. 2 Stark, Zeitschrift f. Psychiatrie, xxxii., p. 159. EXCITANTS. 131 appetite, and in one case also a complete suspension of the reflex excitability of the pharynx. While these symptoms lasted, the frequency of the pulse was much diminished. Potassii Sulphas. The external application of the alkaline sulphates, partic- ularly the sulphate of potassium, in the form of ointments, lotions and baths, causes not infrequently, in certain per- sons especially predisposed thereto, an irritation of the skin whose intensity is in proportion to the quantity of the salt used. According to Bazin 1 small, intensely painful, confluent vesicles are formed upon a reddened base, which become filled with a serous or purulent fluid, and are surrounded with an areola two or three times as large as their diame- ter. This affection disappears in a few days. More serious symptoms may also be produced by the inunction of sulphate of potassium. Thus Bazin, 1 after four or five applications to the lumbar region of a solution of four grams ( 3 i.) of sulphate of potassium in thirty grams (fl. 3 i.) of water, witnessed the occurrence of a vio- lent phlegmonous inflammation, with the formation of pustules and abscesses. Strange to say, the skin of the thighs and buttocks, upon which the remedy was applied in the same manner, was affected by the inflammation in only a slight degree. EXCITANTS. Camphora. Upon the mucous membrane of the mouth camphor produces a biting, later a burning taste, and a subsequent feeling of coldness extending down to the stomach. If it is held in the mouth for some time, there appear symp- 1 Bazin, Lecons sur les affections cutane'es artificielles. Paris, 1862, p. no. 132 INCIDENTAL EFFECTS OF DRUGS. toms of irritation of the mucous membrane, such as pain, swelling, etc. The power of the drug to cause pain is also exerted when it is applied to the surfaces of wounds. The effects produced by the internal administration of camphor in medicinal doses, differ, as Jorg 1 discovered, according to the individuality of the person. While some persons experience no abnormal sensations after 0.3-0.5 gram (gr. v.-viij.), in others there appear, even after doses of 0.03-0.06 gram (gr. j^-i.), headache, dizziness, slight confusion of ideas, redness of the face, dryness of the mouth, and thirst. The alcoholic solution of camphor is said to act more powerfully than the drug in substance. Purkinje 2 ob- served in himself, after doses of 0.5 gram (gr. viij.) a pleas- ant excitement and liveliness, similar to intoxication, a desire for active motion, and a slight pricking in the skin. While these symptoms rapidly disappear, as a rule, without leaving any unpleasant after-effects, the phenom- ena which not unfrequently follow the administration of camphor per enema are more serious, last longer, and de- mand therapeutic interference. There occur vomiting of masses smelling of camphor, strangury, heat, clammy sweating (the sweat also smelling of the drug), increased frequency of the pulse, and a condition of psychical exal- tation, which may result in delirium. In such cases, enemata of senna and sulphate of sodium, sinapisms to the neck and body, cold applications to the head and cold douches, are indicated. Moschus. The statements concerning the incidental effects of musk are to a certain extent contradictory. After doses 1 Jorg: Materiallen zu einer Arzneimittellehre. Jena, 1827, p. 230. 2 Purkinje, Neue Breslauer Samml., 1829, I., p. 428. EXCITANTS. 133 of 0.06-0.25 gram (gr. i.-iv.), Jorg 1 observed, in those upon whom he experimented, slight headache, particularly in the frontal region, confusion of ideas, giddiness, and oppres- sion in the orbital fossae. As regards the digestive canal, Jorg himself, after 0.18 gram (gr. iij.) experienced oppres- sion in the stomach, and eructation with a penetrating odor of musk, and other observers noticed burning and dryness in the throat. Trousseau and Pidoux, 2 on the other hand, after the same dose, felt only a peculiar sensa- tion of warmth in the stomach and abdomen, which after- wards changed into a decided sensation of hunger. Some time later they experienced pains in the temples and occipital region, dizziness, and excitement of the sexual organs. According to the observations of Mitscherlich, 3 vomiting without digestive disturbances occasionally occurs after small doses of musk. This is probably due to a subjective aversion to the drug. Diarrhoea has also been observed after its use. Radix Valerianae. The root of Valeriana officinalis, by many regarded as inert, is capable, as shown by the experiments of Jorg (1. c.) of producing unpleasant symptoms in some individuals, even in small doses. This author sometimes observed the following symptoms, either alone or combined, after the administration of four to twelve grams (3 i. to 3 iij.) of an infusion of valerian root : tickling in the throat, eructation, nausea, headache, especially in the frontal and parietal re- gions, a feeling of constriction of the pharynx, rumbling in the abdomen, diarrhoea, colicky pains, and anorexia. 1 Jorg, 1. c. p. 285. 2 Trousseau et Pidoux: Traite de Therap., III. Edit., II., p. 193. 3 Mitscherlich: Lehrbuch der Arzneimittellehre. Berlin, 1849, Bd. II., p. 369. 134 INCIDENTAL EFFECTS OF DRUGS. Barbier 1 witnessed the occurrence of hallucinations of sight in a person treated with this agent. Flores Arnice. Tinctura Arnic.e. In some persons, irrespective of the mode of employment, even small quantities of arnica may cause disagreeable ac- cidents. Infusions of 0.3 to 1.0 : 120.0 grams of water (gr. iv.-xv.: fl. \ iv.) not infrequently produce burning and tickling in the throat and mouth, pains in the stomach and abdomen, eructation, and occasionally rectal tenesmus and diarrhoea. There also occur oppressive headache, a sen- sation of fulness, giddiness, and unquiet sleep. Wilkinghoff 2 has recently shown that when arnica is kept for some time, its active principle may grow weaker and finally become inert. This fact explains the differ- ences which have been observed, in the action of the drug. It seems that the symptoms detailed, affecting the primse viae, are due to a local irritant action of the drug, and that the nervous disturbances are of a reflex nature. This view is sustained by the fact that if the tincture of arnica is applied to the healthy human skin, there may appear, in accordance with the strength of the preparation, either itching and burning, and later redness of the affected parts, or miliary or pea-sized vesicles may develop upon a red- dened base, or even well-formed bullae. These changes are followed by corresponding general symptoms. NARCOTICS. Opium. In the case of no other medicinal agent are the individ- ual relations of the patient so influential in determining 1 Barbier: Matiere medic, 1824, II., p. 83. 2 Wilkinghoff: Median. Be ; trage zur Kenntniss der Arnica montana. Jnaug. Diss., Bonn, 1880. NARCOTICS. I3 5 the occurrence of an abnormal mode of action as in that of opium. Among the more important of these relations are the nature of the disease, the age and sex of the patient, and, according to Charvet, 1 even the climate in which he lives, and the race to which he belongs ; in short, that peculiar ready susceptibility to the unusual action of a certain drug which is dependent upon definite physical -considerations, and which, in a given case, is very difficult of detection. As regards the age of the patient, it should be stated that, in the cases of many children, injurious, and some- times even fatal incidental effects may very readily follow the administration of opium. A knowledge of this fact has, therefore, for a long time caused it to be held as an axiom, that opiates should be but sparingly used in the treatment of children. In recent times, however, this teaching of experience has been frequently ignored, the dangers said to result from the use of such agents being regarded as exaggerated, even if not absolutely destitute of foundation. Nevertheless, that this warning is well grounded, and that a cautious use of these agents is indi- cated in such cases, is proved by the large number of accidents of this nature found in literature, occurring after moderate, and even the very smallest doses. Sobotka, 2 among others, reports several cases in which serious symp- toms of poisoning appeared after almost minimal doses of opium, and one case of death after the administration of a few dessert-spoonfuls of a mixture containing three drops of laudanum and fifteen grams (fl. 3 ss.) Syrup. Papaver. alb., diluted to one hundred and eighty grams (fl. § vi.). After still smaller doses, 0.0006 to 0.0003 gram (gr. yi to -j^o), Edwards, 3 and also Smith, 4 saw fatal results occur. 1 Charvet : Die Wirkung des Opiums auf die thier. Oekonomie. Leipzig, 1872. 2 Sobotka, Journ. f. Kinderkrankh., Dec., 1845. 3 Edwards, in Taylor : Die Gifte. 4 Smith, Medical Times and Gaz., 1854, April 15th, p. 386. 136 INCIDENTAL EFFECTS OF DRUGS. A large number of similar observations has been collected by Taylor. 1 In women also, in consequence of their greater sus- ceptibility to irritation, abnormal effects are much more easily produced by opium than in men, caeteris paribus. Gastric disturbances and cerebral hyperasmia are also fac- tors which may exercise a favoring influence upon the occurrence of incidental effects. But constitutional bod- ily conditions, above all other things, are capable of modifying the normal effects of opium, or of producing undesirable symptoms. The incidental effects hitherto described may show themselves after any manner of using opium. They seem to occur most readily, however, after its administration per enema, for numerous observations have been reported of cases in which threatening symptoms, or even death, occurred after enemata containing very small quantities of opium. Whether, as Dupuytren believed, a more rapid and complete absorption of opium takes place in the intes- tines than in the stomach, and, therefore, a more intense action of the drug occurs, has not yet been experimentally determined. The central nervous system is first to be considered among the points of attack of opium. There not unfre- quently occur in some persons, even after doses of 0.015 to 0.05 gram (gr. ^-f), a feeling of excessive fulness of the head, dizziness, and headache, lasting several hours or even a number of days, seated sometimes in the frontal and sometimes in the occipital region. These symptoms were known to physicians of antiquity, such as Scribonius Largus and others. Tralles, 2 who reported such an obser- vation upon a man, says in not very classical Latin : . . . per multos dies ponderosissimum caput circumgestasse." 1 Taylor: Die Gifte, iibersetzt von Seydeler. Coin, 1863, Bd. iii , p. 31. 2 Tralles : Usus opii salubris et noxius, Vratislav., 1774. NARCOTICS. 137 Convulsions are also said to have been produced by medi- cinal doses of opium. After larger doses, but still less than the maximum, there have been noticed buzzing and ringing in the ears, confusion of ideas, dimness of vision, disturbances of hearing, and partial or complete uncon- sciousness. The motor sphere may also be affected, there occurring in some cases, as Albers a stated, spasm of ten- dons, particularly of the extensor muscles, tremor of the hands, jerking, weakness, and even temporary paralysis, of the legs. Disturbances in the digestive apparatus may also appear, either simultaneously with these symptoms or as independent effects of the action of opium. The mouth and throat become dry, nausea and vomiting occur, and the appetite is lost. The latter, however, occurs in many cases only after repeated doses of the drug. The changes which sometimes occur in the skin, after the use of opium, are especially worthy of study. Aside from the sometimes very profuse sweating which takes place, the face is congested, intensely reddened, and the rest of the skin feels hot to the touch. Annoying itch- ing, without eruption, may also be present. This " pruritus opii " was mentioned by Dioscorides, 2 Paulus ^Egineta, 3 and also by authors of the last century, and described as a tormenting and unbearable affection. In rare cases, an eruption, with or without pruritus, is noticed after th'e use of opium. The first recorded obser- vations on this subject emanated from Tralles; 4 who believed that the eruption bore a certain relation to the sweating which appeared simultaneously with it. The presence of the latter symptom is, however, not essential to the production of the exanthema. Duclos 5 lays spe- 1 Albers, Virchow's Archiv, Bd. 26, p. 225. 2 Dioscorides : De noxiis venenis, Cap. xxiii. Venetiis, 1516, p. 124. 3 Paulus ^Egineta : Opera. Lugduni, 1551, lib. v., cap. xliii., p. 355. 4 Tralles, 1. c, p. 137 and 138. 5 Due os, Journ. de Medec, Septem., Novembre, 1846. Ref. in Schmidt's Jahrb., Bd. 64, 1849, p. 74. 138 INCIDENTAL EFFECTS OF DRUGS. cial stress upon the fact that this may occur without aug- mentation of the secretion of the skin. The eruption produced by opium consists usually of small, red, isolated spots, resembling in form that of mea- sles. According to an observation of Rieken, 1 these spots may spread diffusely over the whole body, and thus pre- sent the appearance of scarlatina. Even the mucous membrane of the mouth and throat, this author states, maybe attacked by this ''erythematous inflammation." He witnessed the occurrence of such an eruption on a man every time he took opium internally, and even after the employment of ointments and collyria containing it. According to Berenguier, 2 the erythematous spots show themselves shortly after taking the drug, on the face, neck, arms, and breast, and disappear without leaving traces of their presence behind. Behrend 3 has also recently stu- died an opium eruption. It appeared after taking a few powders containing 0.015 gram (gr. £) of opium with 0.5 gram (gr. viij.) of sugar, accompanied with violent itching, on the chest from the clavicles to the lower end of the sternum, on the inner surfaces of both upper arms, the flexor surfaces of the forearms, and over the wrist-joints, spreading down the thighs, from the neighborhood of the adductors to the popliteal spaces, and the posterior and inner aspects of the legs, terminating at the ankle in a stripe of livid color, about three fingers in width. It ap- peared as a pale scarlatina-like redness, which spread dif- fusely over the surrounding healthy skin, and, on closer examination, was seen to be composed of papules of pin- head size, lying close together. Several days after the eruption had passed away, there occurred a fine branny 1 Rieken, Schmidt's Jahrbucher, Bd. cvii., p. 22. 2 Berenguier : Des eruptions provoquees par l'ingestion des medicaments. Paris, 1874. 3 Behrend, Berl. klin. Wochensch. , 1879, P- 626. NARCOTICS. 139 desquamation of the epidermis. Brand ' also observed an eruption which spread over the trunk and flexor surfaces •of the body, was attended with intense itching and high fever, and presented the appearance of a diffuse redness* made up of innumerable small points. In this and a simi- lar case, there appeared, after eight days, a desquamation in the form of flakes of various sizes, which lasted nearly ten days. The mode of occurrence of this exanthema is probably the same as that of all other drug eruptions. In the pres- ent instance, also, we may regard a direct action of the drug upon the affected portions of skin, or upon its tro- phic nerves, as the cause of the disease. This view, at least, aids us in forming an opinion as to the ultimate cause of the affection, although we are still unable to ex- plain why only certain persons, and only certain portions of the bodies of those persons, are attacked. Although Behrend (1. c), in describing the case of disease already alluded to, states that the occurrence of the opium erup- tion in consequence of a possible elimination of the drug by the skin, or even as an effect of its presence in the vessels of this organ, is to be excluded " with absolute certainty," this assertion must be regarded as absolutely unproved, its only force lying in the positiveness with which it was made. His supposition, that eruptions from opium and other drugs occur in consequence of some mysterious change produced in the blood by these agents, leads to absolutely untenable hypotheses, and would, even if it were correct, be likewise ultimately dependent upon a local action of the " dyscrasic blood " upon the skin. As regards the therapeutics of the incidental effects of opium, recovery occurs spontaneously, as a rule, on the stoppage of the drug. If threatening symptoms, such as sopor, etc., have occurred, external excitants, stimulants, 1 Brand. Berl. klin. Wochenschr , 1879, p. 718. I40 INCIDENTAL EFFECTS OF DRUGS. ice, cold baths, sinapisms, etc., should be employed. Ac- cording- to Da Costa, 1 bromide of potassium possesses the power of preventing the incidental effects of opium, par- ticularly the fainting, headache, dizziness, and nausea, and also of lessening the itching of the skin, when taken in doses of two to three and a half grams (gr. xxx. to 1.), a few hours before the opium. Morphia. What has been said of opium applies in the main to its most active constituent, morphia, and its salts. After its use also, headache, stupor, and particularly nausea and vomiting are observed. Thus Billroth, 2 in the case of a lady who took small doses, 0.007 gram (gr. ■£), and even 0.003 gram (gr. J^-), saw such anxiety, nausea, and vomit- ing, that, although suffering intense pain, she refused to take the remedy again. Laborde attributes the vomiting to the bad quality of the morphia, which after a time becomes partially transformed into apomorphia. How- ever, no careful chemical investigation of this subject has yet been made. Wernick 3 has called attention to the occurrence of a parsesthesia of taste after the use of morphia, which,, according to his observations, is especially liable to occur in patients much reduced in health, and in robust persons after prolonged inanition, and is probably due to a centraL irritation analogous to that set up by santonin. The affected persons, shortly after the injection, complain of an intensely bitter or sour taste in the mouth, which usually ends simultaneously with the cessation of the morphia action. The incidental effect which morphia sometimes pro- 1 Da Costa, Virchow-Hirsch's Jahresb., 1871, i., p. 307. ' 2 Billroth, Wiener medicin. Wochenschr. , 1868, p. 763. 3 Wernick, Archiv f. Psychiatrie, Bd. ii., p. 174. NARCOTICS. I4I duces on the eyes has been carefully described by v. Graefe. 1 There occurs, particularly in very irritable per- sons, a spasm of the accommodation, the result of the stimu- lating influence of the drug upon the ciliary muscle. The focal point approaches so near that the range of accommo- dation is much limited, and myopia therefore occurs. Sommerbrodt also observed spasm of the accommodation lasting only thirty seconds, after the injection of o.oi gram (gr. -J-) of morphia. The outlines of the faces and heads of persons standing around the bed seemed to the patient to suddenly run together, so that he was unable to recognize any one. Although, according to v. Graefe, this condition usually appears thirty to forty-five minutes after the injection, in this case it presented itself immedi- ately after it. The skin may also be affected by morphia, as is shown by the occurrence of itching and eruptions after its use. Thus Apolant 2 saw in the case of a man who took several times twelve to fifteen drops of a solution of Morphias mur., 0.08 (gr. ij), in Aquae Amygdalar., 10.0 (fl. 3 iiss.), an urticaria-like eruption, which the patient, without know- ing what he had taken, at once attributed to morphia, having already discovered that he was specially suscepti- ble to its incidental effects. The eyelids were swollen, the whole face cedematous, and red, wheal-like prominences appeared on the hands and other parts of the body. After five days, desquamation set in, during which large, coher- ent pieces of epidermis could be pulled off. A distinction should be made between the true inci- dental effects of morphia already mentioned, and the symptoms which frequently appear without their cause being clear, after the direct intra-venous injection of the drug, in consequence of the canula being accidentally c ~ f 1 V. Graefe, Archiv f. Ophthalmologic, Bd. ix., 2, p. 62. 2 Apolant, Berl. kMn. Wochenschr., 1877, p. 361. T 4 2 INCIDENTAL EFFECTS OF DRUGS. thrust into a vein. In such a case, there occur, as Chouppe 1 states, redness of the face, heaviness and a feel- ing of fulness of the head, increase in frequency of the pulse to ioo, great anxiety, and cold sweating. These symptoms last but a few minutes, and can be prevented by withdrawing the canula a little after introducing it r and by making the injection only when no blood flows from its opening. In this connection we shall consider that pathological condition produced by the habitual use of opium or mor- phia, which has been made the subject of such thorough study, and is so frequently discussed in modern literature. Opium Eating and the Morphine Habit. The phenomena which manifest themselves after the prolonged use of opium in increasing doses, are analogous to those produced by the internal or subcutaneous em- ployment of morphia. The quantities which can be taken for a long time without injury by some persons must be regarded as simply enormous, when we consider how little of the drug is necessary to produce dangerous or even fatal poisoning in a normal system, and the state- ments as to their amount would be received with incredu- lity, if we were not forced to accept them as absolutely proven. The tolerance for such otherwise certainly fatal doses is produced by habituation to the action of the poison, and can be established only by beginning with small doses, and gradually increasing them. The opinion is justifiable that, in this manner, those cell-groups, whose functions are usually only temporarily affected by opium, are deprived of their energy by the chemical or physical influence continually brought to bear on them, or, in other words, that they constantly require a fresh stimulus of 1 Chouppe, Gazette hebdomad, de Medecine et de Chirurg., Mars, 1876, p. 162. NARCOTICS. 143 increasing strength, in order to manifest the same func- tional capacity as formerly, and, at the same time, are pro- tected against the danger of a poisonous action of the drug causing the irritation. A point must, however, be finally reached, at which the quantity administered no longer suffices to excite or restrain the functions of certain organs, and when a still further increase of the dose causes such profound changes in the organ itself, or in others, by a reflex or sympathetic action, that the symptoms of poi- soning and its consequences appear. These affections may be developed by the frequent therapeutic employment of opium or morphia. The patient, who has learned to appreciate its power of reliev- ing pain, has recourse to the drug whenever opportunity offers, even in insignificant bodily ailments, in order to relieve conditions for which another would hardly seek medical aid. Thus the first step is taken upon the road which leads unalterably to the vicious use of these nar- cotics. For when unpleasant bodily conditions which might furnish an occasion for their use are lacking, there appear at first psychical emotions, such as sorrow or care, and later slight mental disturbances, anger, vexation, etc., take their place (for opiates in suitable doses produce happy forgetfulness, lasting for hours, or an agreeable alienation of consciousness). When even these induce- ments are lacking, the constantly diminishing capacity for work, the neglect of social and family duties, as well as numerous other alterations of the emotional nature and the bodily functions, furnish an excuse for still further increasing the dose, until bodily and mental marasmus, or natural or violent death, puts an end to the wicked prac- tice. Before the more rapidly and powerfully acting morphia came into such extensive employment as at present, the above-described phases of the abuse of narcotic drugs 44 INCIDENTAL EFFECTS OF DRUGS. were observed, either singly or collectively, after the use of opium. Flemming 1 furnishes a striking description of the moral condition and the physical sufferings of opium eaters. He shows how a confession of their vice can be drawn from such persons only by strategy, that they are lost to every feeling of shame, and how social and family ties are loosened by this passion. In advanced degrees of this vice, there occur depression or excitement of spirits, childish impatience, incapacity for thought or inability to fix the attention upon a certain object, a want of sympathy for the affairs of daily life, clouding of the memory, and Aveakening of the power of judgment. At the same time, bodily disturbances appear, among others, inability to sleep, gnawing pains in the stomach, loss of appetite, a feeling of chilliness with sweating, and not infrequently derangements of the sexual activity. The same symptoms are produced by morphia taken internally. In a case reported by Samter, 3 it was taken for three years, and during a period of three hundred and twenty days, in which the patient was constantly under careful observation, he consumed 79.5 grams ( f iiss.) of the agent. Eder 3 saw still larger doses taken. The patient observed by him took laudanum for six years, in increas- ing doses to thirty grams (fl. 3 viiss.) daily, for eighteen months pure opium, at first one gram (gr. xv.), later as much as nine grams (3ij. gr. xv.) daily, and for six months morphia, beginning with 0.4 gram (gr. vi.) and increasing to 2.6 grams (3 ij.) daily. The introduction of the practice of injecting morphia subcutaneously, and the habit of intrusting the syringe to the control of the patient, his friends, or the nurse, has undoubtedly largely contributed to the spread of the mor- 1 Flemming, British Medic. Journal, Feb. 15th, 1868, p. 177. 2 Samter, Deutsche Klinik, 1864, 16, 17. 3 Eder, Oesterreichische Zeitschrift f. pr. Heilkunde, 1864, No. 33. NARCOTICS. 145 phine habit, although we have not yet gone so far as to justify us in saying with Bouchardat, 1 "que le morphi- nisme fait a Berlin de tels progres qu'il y a des maisons de sante speciales pour en recueillir les victimes." Observations on this subject have greatly increased in number during the past few years. From America, Mat- tison 2 has called attention to the abuse of morphia which prevails in that country. In Germany, Lahr 3 and Fiedler 4 were the first to raise their voices against the spread of this vice and to attribute the blame for it, in part at least, to physicians. At the same time with Fiedler, L. Lewin 6 described a case of morphinism. More recently Levin- stein 6 has treated this condition most exhaustively, basing his remarks upon a large number of observations, and after him Burkart 7 communicated his views upon the subject. All cases present in an equal degree a gradual continu- ous decline of the psychical life, and also a series of bodily disturbances similar to those which we have described in connection with opium, and as incidental effects of mor- phia. As exceptional symptoms, there appear in some cases slight, transitory albuminuria or glycosuria, such as occurs in other conditions of chronic intoxication. The morphia habit should be regarded as such a condition, and we cannot share the opinion of those who are inclined to con- sider as diseases sui generis, either single groups of symp- toms, or the sum of all the pathological phenomena which this condition presents. For it is plain that arsenicism, 1 Bouchardat, Annuaire de Therapeut. de Matiere medic. Paris, 1879, p. 13. 2 Mattison, Schmidt's Jahrbiicher, 1875, No. i., p. 21. 3 Lahr, Zeitschr. f. Psychiatrie, 1872, H. 3. 4 Fiedler, Deutsche Zeitschr. f. pr. Medicin, 1874, No. 27. 5 L. Lewin, eod. loco, 1874, No. 28. 6 Levinstein, Die Morphiumsucht, berlin, 1876, and Berl. klin. Wochenschr., 1875, No. 48. 1 Burkart, Die chron. Morphiumvergiftung, etc. Bonn, 1877. IO I4 6 INCIDENTAL EFFECTS OF DRUGS. alcoholism, the saturnine affections, and others, conditions in which the mental and bodily attributes are seriously and extensively disordered, can be regarded from a clini- cal stand-point only as intoxications, each of which has received a special stamp only because a series of second- ary phenomena have rendered the pathological picture more complicated, in consequence of the long duration of the condition. The treatment of opium-eating and the morphine-habit consists, of course, in the withholding of the particular drug. Opinions differ as to the manner in which this should be done, whether suddenly or gradually. The discussion of this question, as regards pure opium, was already carried on at a time when the morphine-habit was still unknown. Christison first practised the sudden with- drawal of the drug, in the year 1850. According to Flemming (1. a), the mental and physical sufferings of the patient are much increased by this method of treatment. He becomes sleepless, irritable, anxious, despairing, and begs and prays for opium. With this condition are asso- ciated thirst, neuralgic pains, diarrhoea, sweating, attacks of chilliness, etc. But, on the other hand, the sudden stoppage of the drug puts the moral and physical powers of the patient to a less severe test than the method of gradual diminution of the quantity taken, in which the same unpleasant reaction takes place at every dose, no matter how small it may be. In recent times both meth- ods have found defenders, as regards the morphine-habit also. During the course of the withdrawal, when the patient is completely isolated, and has no opportunity to procure the drug for himself, there frequently occur con- ditions of collapse, for counteracting which stimulants must be freely employed, since otherwise a fatal result may easily take place. Just as much to be dreaded are the conditions of excitement which appear soon after the NARCOTICS. 47 withdrawal of the morphia, in which attempts at suicide are by no means uncommon. To determine whether, •during- the withdrawal, morphia has been secretly admin- istered, nothing- can be done except to study the subjective condition of the patient. If this be very good, a suspicion that such is the case would be justifiable. The demon- stration of the presence of the alkaloid in the urine gener- ally fails, since it rapidly decomposes in the blood, as Landsberg 1 has shown. Only a very insignificant minority of these patients succeed in really and permanently weaning themselves from the drug. The large majority fall back again into the old vicious habit sooner or later after the withdrawal. The employment of substitutes for morphia, such as can- nabis indica, hyoscyamus, etc.. is attended with no practi- cal benefit. The use of atropia, valerianate of zinc, qui- nine, and bromide of potassium as symptomatic remedies is not indicated, because as long as the exciting cause is at work, the temporary relief of this or that pathological phenomenon is of no practical value. Cannabis Indica. In accordance with the good quality of the preparation and the individuality of the patient, unexpected results of varying intensity appear after the use of the preparations of hemp. Unlike the phenomena produced by the inges- tion of opium, these are relatively rare and speedily pass away, leaving no unpleasant after-effects. A number of observations bearing upon this subject were communi- cated by Schroff. 2 He generally noticed in those upon whom he experimented, a blunting of the tactile sensi- bility, a feeling as if the lower extremities were asleep, dizziness, visual hallucinations, and slight delirium. 1 Landsberg, Pfluger's Archiv, Bd. xxiii., 1880, p. 432. 2 v. Schroff: Lehrbuch der Pharmakologie, 1855, p. 536. T4 8 INCIDENTAL EFFECTS OF DRUGS. Husemann, 1 in experimenting upon himself, once pro- duced a condition of tearful joyfulness, while, on another occasion, his mental condition was sorrowful — a state which was in exact correspondence with the hallucina- tions and illusions which he experienced at the time. Caffeinum. Caffe'in, which is so much used in the treatment of migraine, seems to produce different effects upon different persons. Husemann, 2 who took only 0.24 gram (gr. iv.), afterwards observed intense congestion of the head and difficulty of respiration; while Albers, 3 after 0.18-0.3 gram (gr. iij.-v.) of the citrate of caffeiin, felt no effects whatever ; and Frerichs, even after two grams ( 3 ss.) of pure caffeiin, noticed only congestion of the head and one attack of vomiting. Folia Hyoscyami— Extr. Hyoscyami. The incidental effects which show themselves after the use of preparations of henbane correspond in many re- spects to those produced by belladonna. The first, as regards importance, is an affection of the skin, which pre- sents itself in many persons as an erythema. Thus, Cabot 4 describes the case of a man who took tincture of hyoscy- amus to relieve pains in the abdomen. A short time afterwards, his nose began to swell, and gradually the whole body became similarly affected, and the seat of itching and burning. The face was red and shining, and the redness gradually spread as far as the umbilicus, below which there appeared only isolated red patches. This 1 Husemann: Handbuch der Toxikologie, 1862, p. 430. 2 Husemann, 1. c, p. 544. 3 Albers, Deutsche Klinik, 1853, 34. 4 Cabot, Amer. Jour, of Med. Sciences, Oct., 1851. NARCOTICS. I49 erythema began to grow paler an hour and a half later, and had entirely disappeared by the second day. Bes- sieres, 1 in the case of a lady who was accustomed to use vaginal injections of a decoction of hyoscyamus, also observed an erythema on the face after she used the same preparation per enema. Picard 2 also reports the case of a woman who, after an injection into the rectum of a medicinal dose of hyoscyamus, was attacked by an intense erythema of the face. Golding 3 saw a pustular eruption several times after the repeated internal use of small doses of henbane. Functional disturbances in other organs may appear simultaneously with this affection. In this category belong an excessive dilatation of the pupils, a feeling of dizziness, weakness, and collapse. Paralytic conditions of the upper and lower extremities have been also occasionally ob- served. If the use of the drug be persisted in, it is said that swelling of the parotids, salivation, and catarrhal inflammation of the nasal mucous membrane may also occur. Therapeutical interference is necessary only on the appearance of symptoms of weakness, in which case stimu- lants should be administered. Atropia. Atropice Sulphas. Daring the external employment in ophthalmological practice of atropia in the ordinary doses, there appear in some persons, in addition to its physiological mydriatic effect, certain abnormal local and general symptoms, due to the absorption of the agent. 1 Bessieres: Abeille medicale, Novembre, 1853. 2 licard, Ref. in Fodere: Traite de Medec. lega^ et d'hygiene publ , T. iv., P- 25. 3 Golding, in Wibmer: Wirkungen der Arzneimittel und Gifte. Munch en, 1842, Bd iii , p. 1219. 150 INCIDENTAL EFFECTS OF DRUGS. As regards the local phenomena, v. Graefe 1 made the observation that the at first unirritating mydriatic could not be long borne by some individuals. " An anatomical change is produced, as a result of the repeated action of the agent, which modifies the normal susceptibility of the conjunctiva to further medicinal influences. When the membrane is once saturated with atropia, there therefore occurs, after each new instillation, blepharo-conjunctival irritation, lachrymation, oedema of the lids, and even eczematous eruptions. This antipathy of the conjunctiva to atropia sometimes persists for months after the suspen- sion of its use, during which time the mucous membrane may present an entirely normal appearance. In the most pronounced cases, granulations of a peculiar kind appear,, somewhat similar to the ordinary vesicular lymph-follicles of the lower lid, and only distinguishable from them by their somewhat more consistent and more yellowish con- tents, and the altered condition of the vascular supply of the mucous membrane." Graefe recommends, in order to be able to employ atropia again in such cases, the inter- mittent use of solutions of the acetate of lead or nitrate of silver. In addition to these local changes, Graefe 2 sometimes noticed permanent dilatation of the pupils, after the use of atropia, particularly in cases of syphilitic iritis. The symptoms due to absorption of the agent, which occur after its application to the eye, point to a central action of atropia, such as ordinarily occurs only in cases of poisoning by it. They are, as a rule, but rarely observed after instillation of atropia or the use of collyria containing it, and are not dependent upon the quantity of the drug absorbed by the eye, but are due to the action of that portion which is taken up by the lachrymal ducts, and 1 v. Graefe, Archiv f. Ophthalmol., Bd i., 2, p. 242, and Bd. x., 2, p. 200. 2 v. Graefe, eod. loco, Bd. ii. NARCOTICS. 5 reaches the throat and stomach. Susceptibility to this mode of action of atropia stands, therefore, in direct pro- portion to the width of the tear-passages. Proof of this statement is furnished, according to R. Liebreich, 1 by those who have impermeable tear-ducts, whose general condition is never affected by even the largest doses, used for a long period. According to an observation of Chas- saignac, in a case of double cataract with adhesions of the iris to the capsule, in which three or four drops of a solu- tion of atropia (0.06 gram to ten grams of water; gr. i.- fl. 3 iiss.) were instilled into the eye, there occurred in thirty minutes dizziness, and later, turgescence of the face, tickling in the throat, and hallucinations of the senses. These symptoms disappeared spontaneously three or four days later. Laborde 2 saw fulness of the head and marked delirium occur after its use by adults, while Galezowski observed convulsive phenomena in children only. This statement of Laborde finds interesting confirmation in an observation of Kowalewski. 3 After the application of a considerable quantity of atropia to the eye of a man, there appeared great excitement as well as hallucinations of hearing, sight, and feeling, which the patient described as the embodiment of abstract ideas. On the fifth day, dryness of the mouth, spasm of the throat, etc., also appeared, and complete recovery took place only after ten days. Especially worthy of notice in this connection is an observation of v. Graefe, 4 that in consequence of the pro- longed use of atropin collyria, there not infrequently occur symptoms which are recognizable as erethisti'c weakness and interruption of assimilation. It is difficult 1 R. Liebreich, Berl. klin. Wochenschr., 1864, p. 457. 2 Laborde, Gazette medicale de Paris, 1878, p. 606. 3 Kowalewski, Allgemeine Zeitsch f. Psychiatrie, Bd. 36. Heft 4. 4 v. Graefe, Archiv f. Ophthalmologic, Bd. ix., 1864. 15: INCIDENTAL EFFECTS OF DRUGS. to recognize this condition and refer it to its real cause, on account of the fact that other symptoms of the action of atropia are lacking. It is unnecessary to attempt curative treatment of these affections, because the above-described symptoms usually cease soon after suspending the use of the drug. If they become very urgent, small doses of morphia should be administered (0.005-0.01 gram — gr. -^— J-). Prophylactic measures are, however, indicated. Accord- ing to the advice of R. Liebreich (1. c), patients should be recommended to bend the head forwards during instilla- tion of atropia, not to swallow the tears or the fluid which drops from the eyes, to blow their noses frequently, and to gargle, or to press a finger into the corner of the eye and draw the tear-duct downwards. Since this manoeuvre does not always succeed, when the patient is awkward or in a reclining position, Liebreich employs a small forceps similar to a serre-fme, with which the lid at the angle of the eye is grasped in such a manner as to produce a slight degree of ectropium, and tarn the puncta lachry- malia downwards and outwards. It usually suffices to treat only the lower lid in this manner; when large doses are used, and in the cases of sensitive persons, the upper lid must also be included. Incidental effects are more rarely observed after the internal administration of atropia. When they do appear, they are generally limited to dryness of the mouth, a feeling of rawness in the throat, slight fulness of the head, the appearance of rings before the eyes, and some- times diplopia, and redness of the face. Only after large doses do threatening symptoms show themselves, on the part of the circulatory system, the motor and psychical spheres, and the general sensibility. An affection of the skin is occasionally observed after NARCOTICS. 153 small medicinal doses. Thus Lusanna 1 reports a case, in which fifteen minutes after taking a small dose of atropia the skin became intensely red, and presented the appear- ance of having been exposed to the intense heat of the sun. This erythema lasted from one-half to one hour, and appeared every time the drug was taken. Belladonna. Folia — Radix — Extr actum — Unguentum Belladonna?. After the external or internal employment of bella- donna, various authors have observed an exanthema, which, like most drug-eruptions, is of a very transitory nature. The affection is sometimes general and some- times localized, and appears, as Guerard 2 states, especially in children, even after very small doses. Tt usually as- sumes the form of extensive erythematous patches, or a scarlatinous exanthema. The spots disappear on pres- sure, but return immediately when this is removed. They affect, by preference, the face and neck, and appear with- out itching, and speedily pass away. They may show themselves a very short time after the administration of the drug, and may pass through the various stages of development in a few hours. In some cases, as if to ren- der perfect the apparent likeness to scarlatina, there follow redness and painful swelling of the throat. Fever is not present, and no desquamation occurs. Traube 3 gives it as a result of his experience that such an eruption may occur after taking belladonna. Beren- guier 4 observed a diffuse scarlatinous redness, which ap- 1 Lusanna, L' Union me'dicale, 1854. 2 Guerard: Des eruptions medicamenteuses pathogenetiques. Paris, 1S62, p. 26. 3 Traube : Beitrage zur Pathologie und Physiologic Berlin, 1871, ii., Abth. 1, p. 163. 4 Berenguier, 1. c, p. 31. 154 INCIDENTAL EFFECTS OF DRUGS. peared after taking a mixture containing belladonna, lasted eight hours, and then suddenly disappeared. In the cases of two lying-in women, who had used for several days a belladonna liniment, to relieve swelling of the mammary glands, Wilson 1 witnessed the occurrence of a scarlatina-like exanthema, which disappeared without des- quamation after three or four days. Kobner 2 also found well-marked hyperaemia, particularly of the face, after the introduction into the vagina of a suppository containing extract of belladonna. It will be readily understood from what has been said about atropia, that belladonna, after its external or inter- nal use, may also excite other abnormal somatic symptoms which are identical with the phenomena produced by the action of atropia. Two cases reported by Golden 8 are worthy of notice, in which the inunction of belladonna ointment upon the breast suppressed the secretion of milk. . DUBOISINUM. Duboisia is the yellow alkaloid, in the form of an extract, prepared by Gerrard, and at the same time by Petit (1878) from a plant which grows in Australia, the Duboisia myo- poroides, belonging to the family of Solanaceae. It is sparingly soluble in water (1 : 120) but dissolves readily in alcohol, chloroform, etc. The watery solution has a slightly alkaline reaction. Its sulphuric acid compound is crystalline. The main effect of duboisia is to produce dilatation of the pupils, in which respect it equals atropia, or even far surpasses it, as some investigators found. Wecker 4 states that it is less irritating to the conjunctiva than atropia. A 1 Wi'son, Virchow-Hirsch's Jahresbericht f. d. ges. Medicin, 1872, i., p. 380. 2 Kobner, Berl. klin. Wochensch., 1877, p. 328. 3 Golden, Lancet, 1856, No. 6. 4 Wecker, Bulletin de Therapeutique, 1879. NARCOTICS. 55 solution of o.ooi gram (gr. -fa) in water, subcutaneously injected, prevents or lessens the colliquative night-sweats of phthisical patients. Gubler, on the other hand, after the subcutaneous injec- tion of 0.0005 gram (gr. y^) of this substance, observed dryness of the throat and visual disturbances, and after 0.001 gram (gr. ^l), thirst, increased frequency of the pulse, redness of the skin, and sometimes collapse. Sidney Rin- ger found that three drops of a solution of duboisia 1 : 4 parts of water, subcutaneously injected at the height of the action of pilocarpin, made the skin perfectly dry in seven minutes, and after ten minutes produced such a sensation of dryness in the mouth that the patient com- plained of it. Incidental effects have already been observed after the external application of this drug to the eye also. Thus Davidson 1 reports eight cases, in which, after the instilla- tion of duboisia into the conjunctival sac, pathological symptoms of varying intensity appeared, such as dizziness, restlessness, and excitement increasing to violent delirium. Dryness of the throat was also observed in some cases. Scholer 2 used the sulphate in a solution of 0.05 : 5.0 (gr. f : lxxv.) without producing symptoms of general intoxication. On the other hand, in three or four cases, after the em- ployment of this agent, he observed a well-marked con- junctivitis follicularis, and in two or three cases pain during the instillation, redness of the conjunctiva, and failure of the effect upon the pupils. ACONITIA. Tuber a — Extract. — Tinct. A coniti. The effects of the different kinds of aconitia prove that the mode of preparation of the alkaloids is capable of 1 Davidson, Lancet, September 6th, 1879. 2 Scholer, Jahresbericht iiber s Augenklinik fur 1878. Berlin, 1879. 1 56 INCIDENTAL EFFECTS OF DRUGS. modifying- their action. While German aconitia is by no means to be regarded as relatively one of the most poison- ous of substances, this claim is made by nearly all English experimenters for English aconitia (Morson's napelline or pure aconitine) which is probably prepared by a secret process from Aconitum ferox. While the largest permissible dose of German aconitia, according to the Pharmacopcea Germanica, is 0.004 gram, (gr. -J^.), Pereira 1 saw almost fatal consequences ensue from the use of 0.0015 gram (gr. -fo) of English aconitia. Al- though it is true that the individuality of the persons using these powerful agents plays a certain role, the differences in the mode of action of the two kinds of aconitia, which have been demonstrated by Schroff also, are too great to be left out of consideration by physicians in their observa- tions of the injurious incidental effects of the drug, such as have been observed in different degrees after both preparations. According to Pereira, English aconitia, even in very small doses, produces a sensation of heat and itching on the surface of the body. After its external employment, Turnbull 2 observed pricking, of the parts to which it was applied, and Schroff, 3 after painting a weak alcoholic solu- tion of this aconitia upon the forearm, experienced prick- ing and formication, without the appearance of inflamma- tory changes. Cases of poisoning, which occurred in consequence «of the administration of English instead of German aconitia, are frequently met with in literature. The English prep- aration should, in our opinion, be entirely abandoned for internal use. 1 Pereira, Refer, in Husemann, Pflanzenstoffe, i87i,p. 226. 2 Turnbull, Refer, in Husemann, Pflanzenstoffe, 1871, p. 226. 3 Schroff, Jour. f. Pharmakodynamik, Toxikologie und Therapie, Bd. i., 1857, P- 365. NARCOTICS. 157 German aconitia and the other pharmaceutical prepara- tions made from the Wolfsbane, cause, as Dworzak and Heinrich 1 found in their own cases, a biting, burning feel- ing upon the lips and tongue, and salivation. An eruption of white vesicles has also been occasionally observed on these parts. A vague drawing sensation in the face also occurs not infrequently, which may pass into a persistent pain involving the distribution of the trigeminal nerve, and be accompanied by an intensely annoying feeling of pricking, usually on the chin and cheeks, but also appear- ing on the body and extremities. The gastric and intesti- nal mucous membranes are also irritated by this drug. Nausea occurs, and even vomiting and rumbling in the abdomen. If the use of the aconite be continued, more remote effects are produced, such as headaches, more or less intense fulness of the head, buzzing in the ears, and general weakness, symptoms which disappear a short time after the administration of the agent is suspended. Although as a rule no symptoms which threaten life are to be expected from the use of medicinal doses of German and other preparations of aconitia, direct therapeutical interference may become necessary when cardiac lesions or other causes predisposing to a more intense action of the drug are present. Contrary to the view formerly entertained, it has been shown by L. Lewin 2 that aconitia belongs to that class of cardiac poisons whose fatal action may be long deferred, or even absolutely prevented, by long-continued artificial respiration. This procedure must therefore be- resorted to whenever symptoms of dyspnoea and anomalous heart-action (interruption and irregularity of rhythm) show themselves. When milder effects of aconitia appear, the usual stimulants and diuretics may 1 Dworzak u. Heinrich, Prager Vierteljahr. , Bd. 42, p. 153, et seq 2 L. Lewin: Experimentelle Untersuchungen uber die Wirkung d. Aconitin auf d. Herz. Berlin, 1870. l$% INCIDENTAL EFFECTS OF DRUGS. also be employed to produce a more rapid elimination of the drug. No direct antidote for aconitia is known. Veratria. Rhizoma — Tinct. Veratri. The alkaloid prepared from white hellebore as well as the roots of the plant produce not infrequently, when used therapeutically, a few pathological phenomena which were known even to physicians of the middle ages. They may occur with more or less intensity after any mode of administration of the drug. A mere trace of the powder, accidentally brought in contact with the nasal mucous membrane, causes violent sneezing lasting for a considerable period, which may re- sult in profuse epistaxis. The conjunctiva is affected with equal violence when veratria in solution or in the form of an ointment is applied to it. The relatively extensive ex- ternal use of this agent in the treatment of neuralgias of various nerve-tracts has furnished abundant opportunity for becoming familiar with the symptoms which it pro- duces. An ointment of 0.6-1.0 gram (gr. x.-xv.) of ve- ratria, thirty grams ( 1 i.) of simple cerate, soon produces prickling and a feeling of increased heat, not only at the point of application, but also on remote parts of the body. This sensation, according to Reiche, 1 gradually increases to burning, and if the application be long continued, a feeling of restlessness and anxiety appears. These phenomena may become permanent, if the use of the drug be not dis- continued, and deprive the patient of sleep. An itching petechial or vesicular eruption, which soon disappears after the use of the drug is stopped, is occasionally ob- served on different parts of the body. More intense incidental effects may be produced by the 1 Reiche, Medic. Zeitung d. Vereins f. Heilkunde, 1839, 23. NARCOTICS. 159 internal use of the drug. Owing to its power of reducing the frequency of the pulse, the blood-pressure and the temperature, and of slowing the respiration, veratria was and is still employed in acute febrile affections, particu- larly in pneumonia. In such cases, it is usually adminis- tered several times daily, in doses of from 0.003-0.0005 gram (gr. ^V~rio)' an( ^ even beyond the maximal limit of 0.01 gram (gr. £). But even the small normal doses usu- ally excite dryness in the mouth, burning thirst, difficulty in swallowing, nausea, choking, and vomiting, and some- times also salivation, colicky pains, and diarrhoea, in which the stools may be tinged with blood. Children often vomit, as Forcke 1 states, even after the first dose, adults more rarely. During the prolonged use of medicinal doses of the drug, there occurs a pricking or burning feeling on remote parts of the body, particularly the extremities. In some individuals there appear dizziness and dimness of sight, and also trembling and unsteadiness of gait. In others, well-marked collapse may take place. Cerebral symptoms occur not infrequently in children after the administration of tincture of veratrum viride. Thus, Fleischmann 2 reports that, after the hourly administration to a boy of a teaspoonful of the following mixture : Tinct. Veratri virid. gtt. vi., Mucilag. acac. 60 grams (fl. § ij.), there appeared dryness of the throat, great thirst, and, after a while, convulsive movements of the hands and fingers lasting but a short time, foolish talking, and mild delirium. Forcke, in a few cases, saw a pustular eruption on the face, most marked around the mouth. After the subcutaneous injection of the drug in alcoholic 1 Forcke: Physiologisch-therapeutische Untersuchungen iiber d. Veratrin. Hannover, 1837. 2 Fleischmann, Prager medic. Wochenschr. , 1876, No. 10. l6o INCIDENTAL EFFECTS OF DRUGS. solution, in doses of o.ooi 2-0.001 5 gram (gr. gL— ^), Eulen- burg * witnessed the formation of an abscess in one case, and usually the appearance around the point of puncture of a slight, sometimes spotted, redness and swelling. The feeling of burning lasted several hours after the injection. Hiffelsheim also noticed pain and erythema after the hypo- dermic use of veratria. Sometimes the toxic action was so much intensified as to lead to prostration. The treatment of these incidental effects, besides the immediate suspension of the use of the drug, should con- sist in the administration of analeptic substances, particu- larly the aromatic spirits of ammonia, in*twenty to sixty drop doses, 2 or, according to Reiche, of black coffee with lemon juice. In cases where gastric catarrh is present, the drug, according to Trotzscher, 3 should never be prescribed. EXTRACTUM FAB.E CALABARIOE. Eserina s. Physostigmia. The incidental effects which show themselves after the application of preparations of Calabar bean to the eye have been clearly described in the classical investigations of A. v. Graefe. 4 According to this author, the drug passes through the cornea, is dissolved in the fluids of the eye, and acts directly upon the iris and ciliary muscle. He found that immediately after the instillation of a solution of the alcoholic extract in glycerin, there appeared an itching feeling in the conjunctival sac, with a corresponding reflex action upon the orbicularis muscle and the lachrymal secretion, varying in degree with the in- dividuality of the patient and the concentration of the pre- paration employed. Afterwards, when the contraction of 1 Eulenburg: Die hypodermatischen Injectionen. Berlin, 1875, p. 278. 2 Husemann: Pflanzenstoffe. Berlin, 1871, p. 510. 3 Trotscher: Wiener Medicin. Halle, 1863, p. 487. 4 A. v. Graefe, Archiv f. Ophthalmologic, Bd. ix., 1863, III., p. 87. NARCOTICS. l6i the pupil and the accommodative changes begin, the sub- jects of experiment complain of a painful tense sensation, partly along the equator of the globe, and partly in front of it, in the region of the ciliary body. Other observers describe a nervous aching pain in the whole globe, which may, after the manner of ciliary neuroses, spread along the supraorbital nerves, and, like migraine, may extend over the corresponding side of the head. Graefe leaves it undecided whether spasm of the tensor or of the sphincter is more involved in the production of these pains. He failed to observe any more remote effects. If such should appear, they would be most easily explained by the passage of the drug along the tear-ducts. After the administration of small doses of the extract of Calabar bean, as it is sometimes employed in the treat- ment of neuralgias, tetanus, and epilepsy, and also in cases of poisoning by atropia and strychnia, Fraser 1 noticed a painful feeling in the epigastrium, as well as giddiness and weakness of the muscles of the extremities. The last symptom may pass into a condition resembling paralysis, which, however, lasts but a short time. After small doses of physostigmia, Leven 2 witnessed the occurrence of nausea and general discomfort. Amygdalae Amar^:. Aqua Amygdal. Amararum — Aqua Laurocerasi. Stille 3 states that bitter almonds, in medicinal doses, sometimes produce an abundant eruption resembling urti- caria. Gregory also noticed such an eruption upon him- self after eating a bitter almond. This effect is due to the presence of hydrocyanic acid in the almond, as is proven 1 Fraser: Transactions of the Royal Society of Edinburgh, xxiv., 1867, 73. 2 Leven, Jour, de Pharmac. et Chimie, I., 70. a Stille: Therapeutics and Materia Medica. Philadelphia, 1874, i-» P« I75« \§2 INCIDENTAL EFFECTS OF DRUGS. by the fact that solutions containing this acid, such as bitter-almond and cherry-laurel water, very easily pro- duce the same incidental effects. Small doses (ten drops) of cherry-laurel water may excite tickling in the throat and increased flow of saliva. If this dose be somewhat increased, as is so commonly done in practice, or if small doses be frequently repeated, nausea, vomiting, dizziness, and headache appear not infrequently, as Coullon 1 has stated. With the sensation of giddiness may be associated buzzing in the ears, diffi- culty of respiration, and great weakness. Upon the ground of these facts, and in view of the greatly varying strength of waters containing prussic acid, and also the great differences in the susceptibility of indi- viduals to the action of this agent, Kohler 2 justly protests against its employment in large doses as an antispasmodic, a practice usually regarded as devoid of danger. It has been best described by Trousseau and Pidoux, who said of it that it is often dangerous, nearly always useless, and very rarely beneficial. Semen Colchici. Tinctura — Vinum Colchici. The activity of the preparations of colchicum depends upon the proportion of colchicia which they contain. This, however, varies with the season in which the plant is gathered. According to Aschoff and Bley, 3 colchicum root is richest in colchicia during the months of July and August. It is not impossible that this circumstance is influential in determining the abnormal phenomena which 1 Coullon : Recherches et considerat. medic, sur l'acide hydrocyan. Paris, 1819. 2 Kohler: Handbuch der physiolog. Therapeutik. Gottingen, 1876, p. 1233. 3 Aschofl und Bley, Archiv d. Pharmacie, Januar, 1857. NARCOTICS. ^3 sometimes follow the therapeutical employment of the drug. After small doses, 0.1-0.3 gram (gr. iss.-ivss.) of the seed, a burning sensation in the throat and stomach, ptya- lism, distressing nausea, and watery stools, with rectal tenesmus, are frequently observed. Some, or all these phenomena appear in some cases only after the long-con- tinued use of the agent, but, in others, they may occur soon after taking it. With them are not infrequently asso- ciated, but with greater rarity, a feeling of fulness of the head, dizziness, and headache. The secretion of urine may also be attended with pain. The symptoms which originate in the stomach, intes- tines, and kidneys should be regarded as the result of a local irritation set up by the drug. This statement is substantiated by the fact, which has been established tox- icologically, that, in both man and animals, intense inflam- matory changes in the mucous membranes of these organs may be found after large poisonous doses of this drug. The above-described incidental effects of colchicum are most frequently observed after the use of the wine of col- chicum seed, the dose of which is usually given as two gr,ams (fl. 3 ss.), or six grams (fl. 3 iss.) daily. This is cer- tainly too large, if the preparation is made from the fresh active plant. The action on man of colchicia (which is officinal in the Pharmacopoeia Austriaca) has been studied by Schroff. 2 After taking 0.0 1 gram (gr. ■$•), there appeared at first a bitter taste, later, a tickling sensation in the mouth, and soon afterwards eructation, nausea, inclination to vomit, and salivation. After 0.02 gram (gr. -J), besides these symptoms, vomiting and diarrhoea occurred, with tenes- mus, and also a feeling of chilliness, and sleeplessness. 1 Monneret, Archive ge'ner. de Medecine, 1844. 2 Schroff, Oesterreich. Zeitschr. f. pr. Heilkunde, 1856 ii., 22. ^4 incidental effects of drugs. Folia Digitalis. Extr actum — Tinctura — Infusum Digitalis. Digitalis, in common with only a small number of other drugs, possesses the peculiar faculty (which is probably due solely to an unusually slow elimination through the kidneys) of unfolding its action in the body during a rela- tively long period, and, therefore, of developing cumula- tive effects when repeated doses are administered. These may, under certain circumstances, produce threatening phenomena, or even symptoms of poisoning, among which are headache, dryness of the throat, nausea, and a sensa- tion of choking, and, in well-marked cases, buzzing in the ears, disturbances of vision (manifested by the appear- ance of sparks before the eyes, amblyopia, or diplopia), also dizziness, swooning, vomiting, diarrhoea, sleeplessness, a thready, scarcely appreciable, and sometimes arhyth- mical pulse, and a very great fall in the bodily tempera- ture, a result of the slowing of the circulation. A headache, which appeared after even 0.03 to 0.09 gram (gr. ss.-iss.) was a prominent symptom in many cases. In a large number of patients, even 0.15 gram (gtt. iij.) of the tinc- ture sufficed to produce the above-mentioned phenomena. In the absence of a true antidote for digitalis, the treat- ment of these symptoms consists in the administration of symptomatic remedies, stimulants, irritants to the skin, etc. From a prophylactic stand-point, special attention should be paid to the cumulative power of the drug, which may sometimes cause sudden death from paralysis of the heart, particularly when the agent is to be taken for some time, and its use must be stopped on the first appearance of abnormal subjective symptoms. An observation of Traube 1 on an affection of the skin 1 Traube, Charite-Annalen, Jah-g. i., p. 622 u. Jahrg. ii., p. 19. Beitrage zur Pathologie u. Physiologie, Bd. ii., I. Abth., pp. 130, 136, 164. NARCOTICS. 165 after the use of digitalis, should be mentioned as a very rare occurrence. In a case of pleuritis and pericarditis, the patient took, from the fourth to the sixth day of his illness, 3.75 grams (gr. lvii.) of digitalis in an infusion. Four days after the last dose,, there appeared, while the bodily temperature was normal, an erysipelatoid affection of the face, which resulted, five days later, in an excessive ragged desquamation. In a second case of pleuro-pneu- monia, 4.08 gram (gr. lxi.) of digitalis were taken in five days in the form of an infusion. Four days after taking the last dose, the patient, who had hitherto been free from fever, experienced a rise in temperature, and, on the fifth day, there appeared on the body, the supinator surfaces of the forearms, and the backs of the hands, a papular ex- anthema, made up of quite prominent, carmine-red, round- ed spots, disappearing on pressure, the majority of which united to form large patches elevated above the surface of the skin. On the next day, desquamation began on the face in tolerably large masses, while new eruptions showed themselves on the upper arms and neck. Four days later still, the exanthema had almost entirely disappeared, and not until some time afterwards, during the course of a newly-developed typhoid affection, did desquamation, in large flakes, occur on the body and extremities. A similar exanthema, spreading over the whole body, was observed by Schuchardt, 1 in the case of a young robust man who had taken digitalis for a long time for the relief of endocarditis. When the same patient took digi- talis again, one year later, the same eruption appeared with equal intensity. It is perhaps not unimportant, in order to facilitate the comprehension of the manner of occurrence of this affec- tion, to call attention to the fact that an ointment prepared from fresh digitalis leaves with lard may excite slight 1 Schuchardt: Elandbuch der Arzneimittellehre. Braunschweig, 1858, p. 553. l66 INCIDENTAL EFFECTS OF DRUGS. inflammation and the eruption of a papular exanthema, when several times rubbed upon the healthy skin. More intense inflammation is produced upon the skin deprived of epidermis. In view of this fact, one can readily imagine that, when a certain individual disposition is present, the collection of a large quantity of the active principle of digitalis in the vascular channels may produce the same irritative effect upon the skin as the external application of the drug. This explanation is also supported by the fact that, in Traube's cases, the exanthema first appeared after the use of digitalis had been suspended. Worthy of notice is a statement of Reil, that cumula- tive effects are very rarely observed after the adminis- tration of digitalin, on account of the appearance of certain forerunners of intolerance of this agent, which often render its abandonment absolutely necessary. These are a sensation of weakness in the epigastrium, inclina- tion to vomit, exhaustion, dimness of vision, and heavi- ness of the head. Chloralum Hydratum Crystallisatum. The occurrence of incidental effects after the internal use of the hydrate of chloral is, in view of the very ex- tensive employment of the agent, by no means common. Even its habitual employment, which is very common, particularly in England and America, leads, as Richard- son 2 states, to no habituation of the drug, even in " chloral- drinkers," and produces no deleterious effects, as long as the permissible doses are not exceeded. Liebreich 3 has made the same statement upon the basis of reports from insane asylums, and has at the same time called attention 1 Reil: Materia Medica der reinen Pflanzenstoffe. Berl ; n. 1857, p 155. 2 Richardson, Medical Times and Gazette, February, 1871. 3 Liebreich, Deutsche medic. Wochenschr., 1877, No. 27, und Berlin, klin. Wochenschr., 1874, p. 50. NARCOTICS. 167 to the fact that, when a pure preparation is used to pro- duce an hypnotic effect, even during long periods, no in- crease in the dose is necessary, and that unpleasant effects are not observed, in which respects this drug differs from opium and its alkaloids. He also says that an impure chloral presents a constantly increasing acid reaction and exerts perverse therapeutic effects, in consequence of the formation of noxious chlorine compounds. The bad quality of the drug, which is usually the case with those preparations which are not well crystallized, is probably one of the causes of those cases of death after one or more medicinal doses, which are recorded in the literature of the subject. It is a significant fact, in this connection, that, during the early years of the employ- ment of chloral, many such cases were reported, while, on the other hand, in recent times, when improved methods of preparation have been employed, such accidents are very rarely described. When they do occur, it is natural to regard the impurity of the preparation used as their cause, particularly in view of the fact that we are familiar with several organic chlorine compounds which are cap- able of exerting deleterious effects, even in small doses. At the same time, individual predisposition to the occur- rence of such phenomena also plays a role, and the condi- tion of the absorbing organs should by no means be left out of consideration. It is characteristic of the cases of death after chloral, reported by various authors, that they occurred almost immediately or a short time after taking the drug, and usually during an attack of anxiety. Such cases have been reported, among others, by Notel, 1 after four grams ( 3 i.) of chloral; Jolly, 2 of two insane persons after five grams (gr. lxxv.) each ; Marsh, 3 of four persons, the major- 1 Notel, Virchow-Hirsch's Jahresbericht f. d. ges. Medicin, 1872, ii., p. 11. 2 Jolly, Bair. arztl. Intelligenzblatt, 1872, No. 13, 14. 3 Marsh, Virchow-Hirsch's Jahresb., 1875, 1., p. 479. l68 INCIDENTAL EFFECTS OF DRUGS. ity drunkards, after three grams (gr. xlv.), and Fiirstner, 1 that of a girl, after two grams ( 3 ss.). The published results of autopsies give no information as to the causes of death. According to Kern,' 2 disturbances of the respiratory processes are excited in rare instances, which may increase from a feeling of anxiety, terror, and shortness of breath, to attacks of dyspnoea, and even asphyxia. Shaw 3 also, after about one gram (gr. xv.) of chloral, observed spas- modic breathing with irregular action of the heart. Marsh states that after an ordinary dose of chloral he has found changes in the mucous membrane of the respiratory appa- ratus, as shown by the occurrence of acute bronchitis. Much more common than the above-mentioned phenom- ena is the occurrence of conjunctival irritation after one or repeated doses of chloral. Redness and swelling of the membrane are observed, disappearing on the discontinuance of the administration of the drug. Steinheim 4 treated a lady suffering from asthmatic attacks, who on three occa- sions experienced a severe disorder of vision every time she took chloral. It appeared in the form of dimness of sight, or complete blindness. The condition described by Schiile 5 as chloral-rash y which is characterized by flashes of heat, and cerebral congestion with injection of the conjunctivas, occurs only when alcoholic beverages have been taken after the ad- ministration of chloral. Among other incidental effects, Curschmann 6 reported swelling of the epiglottis and false vocal cords, and Reimer 7 1 Fiirstner, Arch. f. Psychiatric Bd. vi., 1876, p. 344. 2 Kern, Allgem. Zeitschrift f. Psychiatrie, 1872, p. 316. 3 Shaw, Virchow-Hirsch's Jahresber., 1871, i., p. 334. 4 Steinheim, Berlin, klin. Wochenschr., 1875, p. 77. 5 Schiile, Zeitschrift f. Psychiatrie, Bd. 28, p. 4. 6 Curschmann, Deutsches Archiv f. kl. Medicin, Bd. viii., p. 151. 7 Reimer, Zeitschrift f. Psychiatrie, Bd. 28, p. 316. NARCOTICS. 169 the occurrence of decubitus. The ^etiological connection of the latter with the use of chloral is, however, very doubtful. According to Reimer, bed-sores produced by the use of chloral are distinguished from the ordinary variety caused by long-continued pressure, by the fact that the former develop under very slight external pressure, while the epidermis is still intact, and spread deep down into the subcutaneous cellular tissue. Here and there in the literature of chloral, cases are re- ported in which icterus is said to have occurred after the use of this agent. Thus Wernich 1 reports four observa- tions, in which, after the use of chloral, a pre-existing jaun- dice became intensified, and also the case of a drunkard, in which a fresh icterus appeared after four grams of hydrate of chloral were taken. Arndt 2 also witnessed the occur- rence of this condition in a paralytic, after he had taken the drug for fourteen days. The icterus passed off when the medicine was stopped, and reappeared when it was again used. Somewhat hazardous is an opinion of Gell- horn, 3 that, among others, atrophic affections of the liver of a very peculiar nature, may appear as the expression of an idiosyncratic action of chloral. This observation stands alone in literature. Besides the phenomena already cited, eruptions upon the skin, either polymorphous or simple, have been ob- served in some persons either immediately or some time after the use of chloral in varying doses. They may be classified as the erythematous, the urticaria-like, and the eczematous forms. I. The erythematous form is relatively the most common. In it the semblance of a diffuse hyperaemia is usually ob- served upon the face and neck. In other parts of the 1 Wernich, Deutsches Archiv f. klin Medic, Bd. xii., p. 32. 2 Arndt, Archiv f. Psychiatrie, Bd. iii., Heft 3. Gellhorn, Zeitschrift f. Psychiatrie, Bd. 28, p. 625. 170 INCIDENTAL EFFECTS OF DRUGS. body, the erythema generally appears in the form of roseola- like or dark-red spots with irregular outlines, which bear a striking resemblance to purpura. According to Schulle (1. c), it seems to follow by preference the course of the larger nerve-trunks. It disappears when the use of the drug is suspended. In one case, Brown 1 observed an in- flammatory redness which spread uniformly over the whole body, while Husband, 2 in the case of a female patient, who for eight days took each day two doses of 1.3 gram (3t.) each, and for five days two doses daily of two grams each ( 3 ss.) each, witnessed the occurrence of a scarlatina- like exanthema, attended with high fever and increased sensitiveness of the skin, after the disappearance of which abundant desquamation occurred. Kobner 3 also reports a case in which, after the long-continued use of chloral, there appeared not a simple hyperaemic redness, but an erythema exsudativum which spread over nearly the whole of the body. It bore a very close resemblance to scarlatina, but the skin was much more swollen and infil- trated than in this disease. The eruption burned and itched, and, as the use of chloral was persisted in, ended in desquamation only after four or five weeks. II. The urticaria-like form has been observed by Gau- chet 4 and Chapman 5 among others. The latter saw it occur in the case of a lad) 7 ' who for fourteen days took one gram (gr. xv.) of chloral each evening. After this time an erythema showed itself, which passed off when the use of the drug was stopped, and when it was again administered wo days later, the skin over the whole body quickly be- came covered with wheals, and the seat of a feeling of heat. Hypersecretion of the conjunctivae appeared at 1 Brown, Lancet, 1871, Vol. i., p. 440. 2 Husband, eod. loco, 1871, No. 25. 3 Kobner, Berl. klin. Wochenschrift, 1877, p. 327. 4 Gaucher., Bulletin gener. de Therapeut., 1S71, p. 429. 5 Chapman, Lancet, 1871. NARCOTICS. 171 the same time. With this urticaria-like form must also be classed those eruptions which have been described as a papular exanthema, which appear under the same circum- stances. Thus Arndt (1. a), after the use of chloral for eight days, found a papular exanthema which covered at first the extensor surfaces of the upper extremities, and later the entire body. It came and went, in accordance with the use or abandonment of the drug. Kern (1. c.) ob- served a similar eruption located upon the arms. 3. If the administration of the chloral be persisted in, the nodules may develop into vesicles with serous or puru- lent contents, and these, when they burst, may present a complete resemblance to eczema. This occurrence is, how- ever, very rare, and seems to be represented in literature by only one case, which was studied by Kern. This is, however, not a typical case, because during the existence of the eruption, quinine was administered hypodermically, a drug which is itself capable of producing a variety of dermatoses. On the person of a robust woman, the subject of puerperal mania, there appeared on the ninth day of the administration of chloral, an exanthema attended by fever, and at the same time swelling of the face, the cheeks, eyelids, and ears. After a while the eruption grew paler, but reappeared when chloral was again taken, and the skin now presented, in a widely-varying manner, the ap- pearance at one time of an impetiginous, at another of a moist, and at still another that of a squamous eczema or an ichthyosis, on account of the fact that the process of desquamation was not limited, as in the acute exanthemata, to a short period, but lasted for many weeks, during which time large masses of epidermis were cast off from all parts of the body. In a later period of the disease, the disturb- ances of the skin were marked by 'an extensive falling out of the hair of the head, and by a gradual casting-off of all the nails of the upper and lower extremities. Schiille and others regarded a paralysis of the vasomotor 172 INCIDENTAL EFFECTS OF DRUGS. nerves, produced by chloral P- 437- 2 Sanger, Archiv f. Gynakolog., Bd. xiv., H. 1. 220 INCIDENTAL EFFECTS OF DRUGS. which are formed under its influence, and their entrance into the lungs. Expectoration cannot be performed, be- cause unconsciousness and loss of reflex activity are pro- duced by the eclamptic attacks. The fact that these abnormal phenomena were observed by a number of investigators, although they employed the same preparation, excludes the hypothesis that they were due to the quality of the drug. It seems probable that a certain disposition of the affected persons, and, perhaps, in some cases, also the improper doses of the agent em- ployed, are responsible for their occurrence. As regards the latter factor, both Leyden 1 and Curschmann 2 state that the occurrence of collapse may be prevented by a very gradual increase of the dose. In view of previous experi- ence, it must be confessed that it is beyond our power to prevent the occurrence of hurtful incidental effects, and we must, therefore, content ourselves with combating them as soon as they appear. Atropia occupies the most important position as an appropriate remedy for this purpose, because it puts an end to both the sweating and the salivation, and also to the painful sensations, and arrests the vomiting. It should be administered either subcutaneously — five or ten drops of the following solution : Atropine sulphat., o.i ; Aquas dest., 20.0 (gr. iss. : fl. 3 v.) — or internally, twenty to thirty drops every two hours of this solution : Atropiae sulph., o.oi ; Aquae dest., 20.0 (gr. 1 : fl. 3 v.) until the symptoms are relieved. Collapse should be prevented by the adminis- tration of stimulants. Demme (1. c.) says that he avoids the majority of the hurtful incidental effects by giving brandy before making the injection. It is, as a rule, advisable to administer the pilocarpia before rather than after the principal meal, and, in view of the numerous 1 Leyden, Berliner klin. Wochenschrift, 1878, No. 27 u. 28. 2 Curschmann, eod. loco, No. 25. EMOLLIENTS. 221 observations of collapse occurring in patients with cardiac valvular lesions, to regard diseases of the heart as contra- indications to the use of the drug. Ohms 1 also regards pilocarpia as contra-indicated in cases of gastric ulcer and in typhoid fever, because hemorrhages may be easily ex- cited, in consequence of the great dilatation which the vessels experience under the influence of the drug. EMOLLIENTS. Glycerinum. The healing powers of glycerin upon wounds, which were particularly demonstrated by the experiments of Demarquay, 2 frequently fail to show themselves, or are even supplanted by directly opposite effects. This failure on the part of the agent is attributable to the impurity of the preparation employed. If it is placed in an impure condition upon wounds, upon eruptions on the skin, etc., there occurs a burning sensation at the point of applica- tion, lasting several hours, and a feeling of increased heat. At the same time, the affected part becomes swollen. Moist eruptions secrete more freely, and new pustules are formed under certain circumstances. Absolutely pure glycerin applied to wounds produces only temporary burning, which is probably due to its hygroscopic powers. In using this agent, care must be taken that its specific gravity lies between 1.23 and 1.25, as prescribed by the Pharmac. Germanica. More highly concentrated preparations should not be used therapeuti- cally, on account of their irritating properties. Oleum Jecoris Aselli. The peculiarly offensive odor and taste of cod-liver oil 1 Ohms, Petersburger medic. "Wochenschrift, 1878, No. 6, p. 50. 2 Demarquay : De la Glycerine, Paris, 1867. 222 INCIDENTAL EFFECTS OF DRUGS. produce at first, in different persons, usually adults, nausea, and even vomiting, during and after its administration, which are not repeated, however, if it is used for a long time. If too large doses are taken, diarrhoea occurs. Cod-liver oil sometimes produces eczema also, when used for several days. This observation of S. Bennett 1 is explained by the fact that, after large doses of the oil, the skin emits the peculiar odor of the volatile fatty acids in the oil. These, during their circulation in the body, reach the skin also, and there produce eruptions, probably by direct irritation. These are, according to Duclos, 2 always of a vesicular nature, and spread over the entire body. RUBEFACIENTS AND VESICANTS. Chlorinum. Chlorine gas is irrespirable. Even when highly diluted with atmospheric air it is an energetic irritant to the mu- cous membrane of the air-passages, causing increased se- cretion of these parts, nasal catarrh, cough, oppression of the chest, and symptoms of genuine bronchitis. If the gas acts upon the skin, there soon occurs an ery- thema, with itching, which disappears in a short time, with desquamation. Even in a diluted condition it pro duces pricking and itching of the skin ; according to Schu- chardt, 3 this organ is rendered more sensitive, and a papular eruption may appear, which ends in branny des- quamation. Cantharides. After the internal administration of cantharides or its tincture, in medicinal doses, a number of incidental effects 1 Bennett : Treatise on the Oleum Jecoris Aselli, London, 1841, pp. 16 arid 47. 2 Duclos, Journal de Medecine, Sept.-Novembre; 1846. 3 Schuchardt: Arzneimittellehre. Braunschweig, 1858, p. 198. RUBEFACIENTS AND VESICANTS. 223 manifest themselves, varying in intensity according- to the individuality of the affected person. A burning sensation is experienced in the primae viae. After a time there oc. cur urgent desire to urinate, a burning feeling in the urethra, and frequent and painful erections. The last phenomena may develop into dangerous symptoms, after prolonged use of small doses, or after their increase with- out exceeding the ordinary limits. The mucous mem- branes of internal organs become the seat of more or less violent inflammation, and the consecutive symptoms of these changes show themselves, on the part of the stomach and intestines, in the form of nausea, vomiting, and diar- rhoea, and on the part of the urinary passages as increased frequency of micturition, attended with the discharge of urine, sometimes containing blood, or albumen or morpho- logical constituents, and on the part of the genital organs in the form of painful chordee. The skin also sometimes manifests exanthematic disor- ders, in the form of erythematous or papular eruptions. Of more importance than these effects of the internal administration of cantharides is a knowledge of those which appear after its external application. These changes, which correspond to those already described, may be produced by the application of a Spanish-fly blister, in consequence of the absorption of the active principle of cantharides. Thus Ledelius, 1 among others, noticed vom- iting, strangury, and fever, after the application for three hours of a blister. These symptoms produced by absorp- tion are the more intense, the more the portion of skin to which the agent is applied deviates from its normal condi- tion. The treatment of these symptoms consists in the imme- diate removal of the plaster, and cleansing the skin with soap. Mucilaginous beverages should be administered, 1 Ledelius, Refer, in Wibmer, Wirkungen der Arzneimittel, Bd. iii., p. 252. 224 INCIDENTAL EFFECTS OF DRUGS. to counteract the phenomena of irritation of internal organs. Faba Anacardii. The Anacardium bean, popularly known as Cashew nut, contains within its pericarp a reddish-yellow substance, cardol, soluble in ether, alcohol, etc., which was recom- mended by Frerichs as a vesicant, under certain circum- stances preferable to cantharides. The cardol prepared from Anacardium occidentale is known as cardoleum vesi- cans, that from Semecarpus anacardium as cardoleum pruriens. The latter is unfit for use on account of its property of producing dermatitis and even erysipelas. But after the application of anacardium occidentale also, the effect is often not a limited one, extensive inflammatory oedema and eczema being produced on remote parts of the body, e. g., the face. While this agent is but seldom employed by physicians, the anacardium bean is much used among the laity, and therefore frequently produces diseases of the skin. Thus E. Schwerin 1 found in the person of a woman who had placed one-half of a bean in her ear, to relieve toothache and pain in the face, an erysipelas of enormous extent. The face was bloated, both eyelids infiltrated, and the ear, the cheek, and the front of the neck, as low down as the clavicle, swollen and reddened. The external auditory canal, the external ear, and the adjacent portions of skin were covered w T ith vesicles. Recovery took place in a few days. In another case, in order to relieve pains in the chest, an anacardium bean was perforated longitudinally, placed upon a string and hung around the neck in such a manner that it lay over the manubrium sterni. Two days later, an 1 According to a previously unpublished observation which was kindly placed at my disposal. RUBEFACIENTS AND VESICANTS. 225 erysipelas had developed, which covered the whole front of the chest, the mammae, and the region of the shoulder as far up as the lower jaw, and presented a large number of vesicles upon its surface. According to Bazin, 1 the oil expressed from the pericarp of the bean, when applied to the skin, also sometimes produces, within from six to twenty-four hours, one or more vesicles, the contents of which soon become purulent. Cortex Mezerei. Mezereon, which still occasionally finds employment as a vesicant, or for the application of superficial issues, produces vesicles upon the skin which may develop into ulcers. These are very painful, heal with extreme slow- ness, and are often accompanied by a pustular eruption around their edges. After the appearance of the inflammatory phenomena, symptoms of systemic poisoning or even death may occur in consequence of the absorption of the drug. Such a case was studied by Pluskal. 2 Headache, dryness of the throat, cough, and fever appeared, and finally death took place, at- tended with loss of consciousness and convulsions. SUMMITATES SABINE. The use of the powdered tops of savine for the cauteri- zation of condylomata, sometimes causes such intolerable pain that the use of the remedy must be abandoned. After the internal administration of small and medium doses (0.3 to 0.8 grams) (gr. ivss.-xiiss.) as an emmenagogue, there occur di'gestive disturbances, and sometimes also vomiting and diarrhoea, strangury, and during menstrua- tion, excessive loss of blood. In pregnant women, the too 1 Baz n, 1. c, p. 119. 2 Pluskal, Oesterreichische medic. Wochenschrift, 1842, No. 18, and 1S44, No. 50. J 5 226 INCIDENTAL EFFECTS OF DRUGS. prolonged use of small or of too large doses may induce abortion. The action of Oleum Sabinae is more intense than that of the tops. Chrysarobinum. Goa-Powder. A secret remedy, " Araroba-powder, or Goa-powder," has long been employed in the treatment of skin diseases in England, Brazil, and the East Indies. The tree which furnishes the powder is most common in the province of Bahia. The araroba, in the form of a sulphur-yellow powder, is found in the crevices and cavities which traverse the tree in the direction of its transverse diameter. 1 Ac- cording to a previous analysis, the powder should contain eighty-four per cent of chrysophanic acid. Liebermann 2 showed, however, that the substance obtained from goa- powder by extracting it with benzole, was not chrysopha- nic acid, but a body of different chemical composition, which he called chrysarobin. It may be transformed into chrysophanic acid by the addition of potash-lye and the admission of air. Balmanno Squire 3 first employed this agent in the form of an ointment, in the treatment of psoriasis, and after- wards of eczema, acne, etc., with good results. Numerous therapeutical experiments were afterwards made in Ger- many with chrysarobin. The ointment is usually applied upon the skin after the psoriatic scales are removed, either mechanically or by chemical means (green-soap, etc.). All the experimenters who used chrysarobin report unpleasant incidental effects after its application, which appeared as local and general symptoms. These have 1 Vierteljahrschrift f. Dermatolog. u. Syphilis, vi., 1879, p. 385. 2 Liebermann, Berichte der deutsch. chem. Gesellschaft, Jahrg. xi., p. 1603. 3 Balmanno Squire, British Medical Journal, May and November, 1877. RUBEFACIENTS AND VESICANTS. 227 been best described by Kaposi. 1 If chrysarobin is rubbed upon psoriatic patches, there appears, early in some persons, later in others, an inflammation at the point of application, which may spread over a large extent of the healthy skin. Many individuals seem especially predisposed to this accident, and in such cases the inflam- mation increases inordinately in intensity and extent. The face and the genitals seem to possess a peculiar sensitive- ness to chrysarobin ointment. Three forms of inflammation occur, according to Ka- posi : 1. A diffuse inflammatory redness and swelling. In many cases this appears as a halo of varying breadth around each patch of psoriasis, after from four to six in some, in others after from eight to fifteen applications. If no more inunctions are made, this redness disappears after from ten to fourteeen days, with desquamation of the epidermis. But in spite of the cessation of the applications, the inflam- mation and swelling often spread still further, and cause pain, fever, sleeplessness, glandular swelling, etc., in short,, the general symptoms which are usually observed after a diffuse dermatitis. 2. The inflammation may also manifest itself by the ap- pearance of pin-head sized, reddish-brown, firm papules, some of which also present vesicles and pustules. They correspond to the openings of the follicles. The patient complains of annoying itching and burning. 3. Painful furuncles may also be developed. For the relief of the pain and the inflammation, the ap- plication of cold-water compresses has been recommended. In order to prevent these irritations of the skin, Neumann advised the protection of the parts around the diseased patches by strips of adhesive plaster. Others believe that the unpleasant effects of the drug may be avoided by 1 Kaposi, Wiener medicin. Wochenschrift, 1878, No 44. 228 INCIDENTAL EFFECTS OF DRUGS. gradually increasing- the proportion of chrysarobin in the ointment. Kaposi advises against the use of the agent on the face, and directs that it be employed on the genitals only after careful isolation of the adjoining folds of skin, and that the application be suspended, as soon as inflam- matory areola? have formed around the patches of psoria- sis. A discoloration of the tissues which come into contact with the drug nearly always occurs as an accessory symp- tom of the above-mentioned incidental effects. The nor- mal skin, as well as the nails, take on a reddish or violet- brown appearance, and the hair becomes of a golden-yellow or of a variegated greenish color. If soap is used upon parts thus deprived of their normal color, the reddish- brown color is changed into dark violet, in consequence of the action of the potash upon the chrysarobin. This trans- formation of color is most marked on the inflammatory ring which forms around the psoriatic patches. The under- clothing of the patients, like the skin, becomes covered with spots of a more or less purple-brown or violet color, which are very hard to remove. Acidum Pyrogallicum. Pyrogallic acid was introduced into the treatment of skin diseases by Jarisch. 1 Only insignificant incidental effects show themselves after its employment. Applied to psoriatic patches or the normal skin, it produces a brown discoloration. On the extremities it excites localized in- flammation, which may lead to epidermic desquamation and the formation of vesicles. When applied to hard, in- filtrated patches, the ointment produces deep losses of tissue, reaching down to the corium. The scars left behind, after cauterizing lupus nodules with pyrogallic acid, are smooth, white, and flexible. Jarisch, after the use of the 1 Jarisch, Wiener medic. Jahrbiicher, 1878, H. iv. RUBEFACIENTS AND VESICANTS. 229 acid in eczema marginatum, observed pain lasting several days, and increasing when the dressings were changed. Instigated by the success obtained by Jarisch, Neisser 1 also tried pyrogallic acid in the case of a man afflicted with psoriasis universalis. For purposes of comparison the right arm and leg, and the back, were energetically rubbed with unguentum Rhei (Extr. Rhei spirit, in the form of a twenty-per-cent ointment), the left side and the breast with pyrogallic acid, and finally smeared with a thin layer of the ointment, and then the whole body was covered with rubber paper, which was secured by roller bandages. A few hours after this operation there appeared rigors, diar- rhoea, and vomiting, which lasted three days, until death occurred in collapse. The urine contained the coloring matter of the blood. The autopsy revealed as the causes of death, decomposition of the blood, nephritis hsemoglo- binica, and a disseminated fatty degeneration of the mus- cular tissue of the heart. The majority of the symptoms observed in this case were undoubtedly due to the arrest of the bodily perspira- tion, because the effect of so extensive an application must be the same as that of varnishing the whole body. 1 Neisser, Zeitschr. f. klin. Medicin, Bd. i., Heft 1. INDEX OF AUTHORS. Adamkiewicz, 112 yEgenita, Paulus, 93 Albers, 137, 148 Alley, 79, 80 Amory, 120, 125 Apolant, 141 Arndt, 169, 171 Arnold, 205 Arthaud, 117 Ascherson, 80 Aschoff, 162 Auspitz, 112 Badin, 102 Baginski, A., 128 Bailly, 36 Baker, 59 Balmanno Squire, 226 Bamberger, 78 Barbier, 44, 51, 134 Bardenhewer, 216 Barella, 96 Bartscher, 178 Bauer, 90 Baumann, 72 Bazin, 48, 69, 95, 131, 204, 225 Beau, 202 Begin, 51 Behrend, 28, 138 Bell, Benjamin, 79 Bengelsdorff, 67 Bennet, S., 222 Berenger Ferand, 60 Berenguier, 47, 50, 120, 138, 153 Bergeron, 96 Berghmann, 179 Bernard, 45 Bessieres, 149 Bianchi, B., 213 Bill, 72 Billroth, 140, 174, 181, Binswanger, 54 Binz, 37, 93, 96, 190 Bley, 162 Boeck, 204 Boeck, von, 88 Bouchardat, 80, 145 Bouchut, 52 Bouisson, 187 Bourneville, 195 Bouvier, 199 Brand, 139 Brera, 109 Bretet, 24 Brieger, 42 Briquet, 36, 37 Brochin, 47 Brown, 120, 170 Brshesinsky, no Buckell, 103 Burdach, 62 Burkart, 145 Busch, 72 Cabot, 148 Carnot, 52 Chapman, 170 Charcot, 56, 98 Charvet, 21, 135 Chassaignac, 151 Chatin, 96 Chevallier, 31 C^ievandhr, 46 Chouppe, 142 Chrestien, 98 Christison, 146 Clark, 120, 125 Clemens, 181, 182 232 INDEX OF AUTHORS. Clover, 175, 1S0 Cogliesi, 213 Corlieu, log Coullon, 162 Curschmann, 108, 220 Fothergill, 38 Fournier, 80, 111 Fraser, 161 Frerichs, 148, 224 Freudenberg, 41 Frommann, 56 Fiirstner, 168 Da Costa, 140 Damourette, 119, 125 Dauboeuf, 33 Davidson, 155 Declat, 71 Delioux, 57, 205 De'marquay, 221 Demme, 218, 220 Denk, 34, 35 Denonvilliers, 181 Devergie, 98 Dioscorides, 137 Dorval, 109 Duclos, 137, 222 Dujardin-Beaumetz, 99 Dupuytren, 136 Duroy, 180 Dworzak, 157 Eder, 144 Edwards, 76, 135 Englemann, 80 English Chloroform Committee, 175, 179 Esmarch, 175 Eulenburg, 160 Ewald, 93 Faginoli, 37 Falck, 94, 129, 203 Fallopius, 197 Falot, 202 Falret, 120 Federschmidt, 218 Fiedler, 145 Fischer, no Feischmann, 47, 159 Flemming, 144, 146 Fonssagrives, 103 Forcke, 159 Foucaud de l'Espagne, 59 Galezowski, 151 Gamberini, 55, 58 Garraway, 33 Gatumeau, 117 Gauchet, 33, 37, 170 Gellhorn, 169 Gerrard, 154 Girl, 43 Glover, 115 Gohlius, 203 Golden, 154 Golding, 149 Goltdammer, 40 Gowers, 125 Graefe, A. von, 35, 141, 150, 160, 161 Gregory, 161 Grimaud, 62 Grissac, 32, 35 Gubler, 48, 155 Guerard, 153 Guisson, 55 Guttmann, 122, 125 Guyochin, 37 Gwalter, 82 H Hager, 30 Hardy, 48 Harles, 97 Hebra, 48, 68, 80, 201 Hegar, 192 Heiberg, 187 Heim, 97 Heinlein, 4T Heinrich, 157 Helbert, 204 Hemming, 33 Hennig, 64 Hermann, 16, 204, 213 Herpin, 86 Heusinger, 34 Hjaltelin, 100 INDEX OF AUTHORS. 233 Hiffelsheim, 160 Hildebrandt, 66 Horing, 118 Hoffmeier, 128 Hollander, 191 Holmgreen, 179 Huet, 57 Huter, 179, 189 Hiitte, 117, 119 Hufeland, 63 Husband, 170 Husemann, 77, 148 Imbert-Gourbeyre, 94, 95, 97, 203 Isambert, 28 Itzstein, 212 Jacobi, 201 Jacobi, A., 128 Jacquot, 207 Jarisch, 228 Johnson, 113 Jolly, 167 J6rg, 132 K Kaltenbach, 192 Kaposi, 227 Kappeler, 174, 183 Kidd, 183 King, 30 Kern, 168, 171 Kleinhau-s, 69 Koch, 92 Kobner, 33, 154, 170 Kohler, 43, 162 Kohl, 63 Kottmeyer, 76 Kowalewski, 151 Krosz, 117, 119, 127 Kiistner, 73, 128 Kussmaul, 80, 90 Laborde, 119, 140, 151 Lacombe, 128 Ladendorff, 196 Lahr, 145 Laennec, 203 Lallemand, 180 Landsberg, 147 Langenbeck, M., 200 Langenbeck, von, 66, 73, 175 Langenbuch, 75 Laroche, 105 Ledelius, 223 Lefort, 184 Legrand, 98 Lemattre, 96 Leube, 41 Leven, 161 Levinstein, 145 Lewin, G., 78, 87, 91 Lewin, L., 65, 90, 145, 157, 207, 212 Leyden, 220 Lichtheim, 42 Liebermann, 226 Liebreich, 115, 151, 166, 192 Lightfoot, 38 Lisfranc, 21, 63 Lister, 76 Litten, 26 Loffler, 51 Loehlein, 76 Lohrisch, 216 Losch, 218 Lvicke, 74 Lurmann, 40 Lusanna, 1 53 M Macnal, 94 Maestri, 50 Magitot, 55 Marchand, 128, 130 Marsh, 167 Martin, 125, 211, 213 Martindale, 217 Mattison, 145 Mayer, 24 Mecklenberg, 108 Melsens, 89 Merat, 210 Mialhe, 11, T3, 212 Mitscherlich, 71, : Mogling, 208 Monneret, 37, 52, Morganti, 97 Mossop, 119 33 163 234 INDEX OF AUTHORS. Miiller, 39 Mund, 31 Munk, J., 2ii N Neisser, 229 Nelaton, 103 Nicol, 119 Neumann, 56, 71, 123, 227 Notel, 167 Oberlander, 190 Odier, 53 Ohms, 221 Olshausen, 74 Orfila, 53 Reiche, 158 Reil, 166 Reiner, 168 Rezek, 66 Richardson, 44, 166, 191 Riche, 52 Richet, 186 Ricord, 105, 107 Riegel, 39, 215 Rieken, 138 Riemer, 56 Riess, 39 Rilliet, 104, 114 Ringer, Sidney, 155 Rodet, 107 Rohrig, 75 Roser, 100 Roller, 65 Romberg, 59 Ronchard, Simon de, 37 Rose, 73, 113, 212 Rosenbach, 89 Rossbach, 47 Paget, 182 Pearson, 79, 90 Pelvet, 119, 125 Percival, 60 Pereira, 62, 94, 156 Perrin, 180 Petit, 154 Petitjean, 107, in, 113 Petters, 69 Picard, 149 Pick, 194 Pickel, 92 Pidoux, 50, 133, 162 Piorry, 37 Pleische, 92 Plouviez, 188 Pluskal, 225 Pratorius, 76 Preusse, 72 Purkinje, 46, 132 Rabuteau, 106, 119 Radziejewski, 78, 202 Ranneft, 219 Rayer, 48 Recklinghausen, von, 175 Regnard, 101, 103, 113 Sanger, 219 Saikowski, 89 Samelsohn, 195 Samter, 144 Sander, 130, 194 Sansom, 183 Santlus, 107 Scheinesson, 184 Schlothauer, 46 Scholer, 155 SchrOter, 194 Schroff, 23, 147, 156, 163 Schweig, 116 Schwerin, E., 224 Schuchardt, 165, 222 Schulle, 168, 170 Schiitz, 15 Schuhmacher, 39 Schulz, 93, 96 Schultze, M., 2r3 Schwilgue, 64 Scribonius Largus, 136 Sedillot, 176 Seitz, 215 Senator, 10 Shaw, 168 Sieveking, 214 Sigmund, 86 INDEX OF AUTHORS. 235 Simon, A., 101, 103, 113 Simpson, 214 Skinner, 33, 43 Smith, 124, 135 Sobotka, 135 Sommerbrodt, 141 Sonnenburg, 176 Spencer Wells, 212 Spoerer, 189 Stark, 125; 130, 197 Steinheim, 168 Stille, 161 Strieker, 39 Unna, 209 Urbantschitsch, 195 V Veiel, 118 Vepan, 32 Veyrieres, 195 Virchow, 1, 6, 21, 54, 57 Voisin, 120 W Tanquerel des Planches, 59 Taylor, 136 Thielmann, 119 Tralles, 136 Traube, 153, 164, 166 Trotzscher, 160 Trousseau, 29, 97, 162 Tully, 64 Turnbull, 156 Wade, 38 Wagner, 74 Weber, 218 Wecker, 154 Wegscheider, 128 Werdermann, 60 Werneck, 53, 62 Wernich, 140, 169 Wibmer, 44, 59, 98, 199 Wilkinghoff, 134 Wilkinson, 68 Wilson, 154 Wyss, 95 U Ummethum, 77 Yvonneau, 17b INDEX OF SUBJECTS. Acid, arsenious, 27, 92 boracic 54 carbolic, 71 citric, 70 chrysophanic, 226 copaivic, 49 hydrobromic, 38 hydrochloric, 70 hydrocyanic, 161 nitric, 70 picric, 215 phosphoric, 70 pyrogallic, 228 salicylic, 38 sulphuric, 70 tannic, 64 tartaric, 70 Acids, 70 Acne from bromide of potassium, 121 iodide of potassium, no, 112 iron, 29 Aconitia, 155 ^Ether, sulphuric, 192 yEthylidene chloride, 192 Aloes, 22, 197 Alteratives, 77 Alum, 51 Ammonium chloride, 207 Amygdalae amarae, 161 Amyl nitrite, 194 Antimony, tartarized, 27, 200 sulphuretted, 13, 207 Apomorphia, 24 Aqua amygdal amar., 161 calcis, 50 chlorini, 222 laurocerasi, 161 Arguria, 55 Arnica, 134 Araroba, 226 Arsenic, 92 in bismuth, 52 Atropia, 27, 149 Auri chloridum, 98 et sodii chloridum, 98 B Balsam of copaiba, 47 of Peru, .208 Barium chloride, 63 Belladonna, 153 Benzole, 214 Berberin, 44 Bismuth subnitrate, 12, 52 Boracic acid, 54 Bromine, 121 acne, 126 cachexia, 126 Bromism, 126 Cade, oil of, 69 Cadmium sulphate, 62 Caffein, 148 Calabar bean, 160 Calomel, 13, 15, 78 Camphor, 131 Cannabis Indica, 147 Cantharides, 222 Carbolic acid, 71 spray, 74 urine, 74 Carbolism, 72 Cardol, 224 Castor oil, 196 Chelidonium, 44 Chloral hydrate, 166 Chlorate of potassium, 128 Chloride of gold, 98 238 INDEX OF SUBJECTS Chlorine, 222 Chloroform, 2, 20, 173 death from, 174 Chrysophanic acid, 226 Chrysarobin, 226 Citric acid, 70 Cod-liver oil, 221 Colchicum, 23, 162 Colocynth, 198 Colombo-root, 43 Constitution, 2 epidemic, 21 Creasote, 44 Cubebs, 50 Eruptions from sulphur, 199 veratria, 159 Excitants, 131 Fowler's solution, 24, 94 Gamboge, 14 Gold chloride, 98 and sodium chloride, 98 Digitalin, 166 Digitalis, 23, 164 Duboisia, 154 H Habituation, 17 Hydrargyrum, 77 Hydroquinone, 8 Hyoscyamia, 23 Hyoscyamus, 148 Eczema mercuriale, 81 Elaterium, 14 Ergotin, 65 Eserin, 160 Eruptions from anacardium, 224 antimony, 200 arsenic, 94 atrjpia, 152 balsam of Peru, 209 belladonna, 153 benzole, 2 1 5 bitter almonds, 161 bromide of potassium, . 120 cantharides, 223 chloral hydrate, 169 chlorine, 222 chrysarobin, 227 cod-liver oil, 222 croton oil, 200 digitalis, 164 hyoscyamus, 148 iodine, 109 ipecac, 204 mezereon, 225 morphia, 141 opium, 137 pyrogallic acid, 228 quinine, 3 [ santonin, 214 Idiosyncrasy, 5, 20 chemical, 11 idiopathic, 11 Immunity, 16 Individuality, 6 Iodine, 27, 99 acne, 109 Iodism, 106 Iodoform, 190 Iron, 29 Jaborandi, 215 Lead, acetate of, 58 cachexia, 16 Lime-water, 50 M Mercury, albuminate of, 78 Mercurial peptone, 79 INDEX OF SUBJECTS. Mercurial tremor, 91 Mercury, 77 Methylene bichloride, igi Morphia, 5, 24, 140 habit, 142 Musk, 132 Quassia, 44 Quinine, 30 2 39 N Narcotics, 134 Napelline, 56 Nitrate of silver, 54 Ointments, 8 Opium, 1, 20, 26, 134 eating, 142 eruptions, 137 Resorcin, 4i Salivation, mercurial, 84 Salvia leaves, 67 Santonin, 211 Saturnism, 16 Secale cornutum, 23 Silver nitrate, 54 Skin, changes in, 28 Sodium chloride, 13 Strychnia, 42 Styrax, 209 Sulphur, 199 Phloroglucin, 8 Phosphoric acid, 70 Phosphorus, 99 Physostigmia, 160 Pilocarpin, 5, 217 Picric acid, 215 Pix liquida, 69 Pomegranate root, 23 Potassium bromide, 27, 116 chlorate, 128 chloride, 130 iodide, 27, 104 sulphate, 131 Predisposition, transitory, 15 Pruritus opii, 137 Pyrocatechin, 8 Pyrogallic acid, 228 Tannin, 25 Temperaments, 7 Tonics, 29 Turpentine oil, 45 Valerian, 133 Veratria, 158 Zinc oxide, 61 lactate, 61