New York State College of Agriculture At Cornell University Ithaca, N. Y. Library ,..„,...versity Library An experimental research on the Physiolo 3 1924 003 149 337 Cornell University Library The original of tiiis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924003149337 AN EXPERIMENTAL RESEARCH PHYSIOLOGICAL ACTIONS OF DRUGS SECRETION OF BILE PA' WILLIAM EUTHERFORD, M.D., F.R.«. PROFESSOR OF THE INSTITUTES OF MEDICINE (pHYSror bile ; a/yw, to drive away) have been administered to man for over 2000 years, there has always been much uncertainty as to those which are really to be regarded as cholagogues j and even in the case of any agent which increases the discharge of bile, he has been quite unable to determine whether this effect is due to a stimulation of the hUe-secreting or of the hile-expelling mechanism. The reasons for these uncertainties are not difficult to find. The bile, when it enters the intestinal canal, mingles with other secretions, and with alimentary substances, whose quantities are variable. The physician roughly estimates the amount of bile discharged, by observing the colour of the dejections'-^a method which is of necessity so inaccurate that it is often difficult, sometimes indeed impossible, to say whether or not the dis- charge of bile is increased, diminished, or unchanged. Thus, when rhubarb is administered, it gives; a colour to the dejections similar to that communicated by the bile, and the physician is VIU PEOF. EUTHEEFOKD AND M. TIGNAL. therefore puzzled to say whether or not rhubarb affects the liver ; yet, by another method of research, it can be shown that rhubarb increases the secretion of bile. Where the substance, as in the case of sodium sulphate, stimulates the intestinal glands, and thus occasions copious dejections of a watery character, whereby their colour is diluted, the physician has found it difficult to say whether or not there is a variation in the quantity of bile discharged ; yet, by another method, it can be shown that this substance certainly stimulates the liver as well as the intestinal glands. Again, iu the case of such substances as magnesium sulphate and castor oil, which stimulate the intestinal glands but not the Uver, the physician, although he certainly did not suppose that they increase the flow of bile, nevertheless failed to observe the fact — which may be shown by another method, — ^that they diminish the production of Hie. Again, when a substance excites the liver to produce more bile but does not excite the intestinal glands to pour forth their watery secretion, and as it were to wash out the bile discharged into the canal, the clinical observer has in the case of benzoic acid and its compounds, sodium salicylate and other substances, failed to observe that they are cholagogues. But again, the clinical observer is unable to say whether or not any cholagogue actually stimulates the hepatic cells to produce more bile, or merely excites the muscular fibres of the gall-bladder and bile-ducts to expel their contents. Yet rational medicine imperatively requires that the first of these questions at all events shall receive a definite answer. There are two methods — the clinical and the physiological — by which the actions of medicinal agents are investigated. On the clinical method, experiments are made on men and animals in a state of disease, with a view to cure the diseased condition ; whereas, on the physiological method, experiments are made with drugs on animals and sometimes also on man in a state of health, with a view to determine how they affect the bodily system when its action is not distorted by the influence of disease. The clinical method is as old as medicine itself, but the physiological mode is of comparatively recent date, and has grown out of the fact that the clinical method Las proved to have very seriously failed — and nowhere more signally than in the case of the liver — to furnish the physiciali with that EXPBKIMENTS on the biliary secretion of the dog. IX definite knowledge which is required to bring therapeutics even within sight of the pale of exact science. Of necessity the influence of a drug upon a diseased condition is the ultimatum of pharmacology, and every experiment upon a healthy bodily system, whether of man or animal, is merely ancillary to experiments with the drug in disease. Therefore, if we discover that a drug stimulates the healthy liver of such an animal as a dog, we do not infer that it must also stimulate the human liver in health, and stiU less do we conclude that it must also act thus in disease. The experiments on the healthy liver of the dog, on the normal, and on the abnormal human liver, are three sets of experiments closely related, but still distinct. The facts derived from any one of the three cannot be substituted for those of the other two. Each set of facts has its own proper place, and must be carefully kept there. When, therefore, we show by the physiological method that such substances as sodium benzoate, sodium salicylate, ammonium phosphate, and others, powerfully stimulate the liver of a dog, we do not for a moment say to the clinical observer, you will find that these things have a similar action in man. We merely say it is likely that they also act thus in man ; experi- ment with them in his case, and tell us if you find that they have on him a similar action, and tell us also in what diseased states you find the employment of this or of that substance most advantageous. All are agreed that medical science has much to gain from the attainment of a precise knowledge of the physiological actions of medicinal agents. The action of ipecacuan in dysen- tery is an apt illustration of this fact. On asking a highly experienced Indian physician how he explained the appearance of a large amount of bile in the dejections after the administra- tion of sixty grains of ipecacuan in cases of dysentery, he at once replied, " My theory is that it relieves a spasm of the bile- ducts, and thus allows of the escape of pent-up bile." But, when we give sixty grains of ipecacuan to a healthy dog, it never faUs to cause the Kver to secrete a greatly increased quantity of bUe. Probably, therefore, no one will now be inclined to doubt that in dysentery, ipecacuan affects the liver in a similar manner, and that the increased discharge of bile is due to its increased secretion, and not to the relief of an imaginary spasm of the bile- X PROF. KUTHEEFORD AND M. VIGNAL. ducts. It must be admitted that the attainment of this precise knowledge regarding the action of ipecacuan does not reveal to us the true pathology of dysentery, but it places us one step nearer to a knowledge of it ; for, once we know the action of a drug in a healthy state of the body, and find that a diseased state is cured by that action, our knowledge of the nature of the diseased state is necessarily advanced. While aU have admitted the limited and unsatisfactory character of our knowledge of the effects of drugs on the liver, several investigators have attempted to advance the subject by the physiological method of experimenting with drugs on animals. Nearly all the observations have been made on the dog — that being the animal best suited for the purpose. The method resorted to by the earlier experimenters was that of continuously collecting the bile from a permanent biliary fistula, and observing how its amount and composition were affected by drugs. A permanent biliary fistula is established by occluding the common bile-duct, and establishing a communication between the fundus of the gall-bladder and the exterior of the abdomen. When the wound in the abdominal wall has completely healed, and nothing remains but the fistulous opening into the gall- bladder, through which all the bile is necessarily discharged, a cannula is placed in the fistulous opening, and the bile collected either in a bag attached to the cannula, or in a large sponge placed in a tin box and secured to the abdomen of the animal. The difficulty of perfectly collecting the bile continuously by day and night, while allowing of such freedom of movement on the part of the animal as is necessary for the maintenance of its health, is so serious that few investigators have succeeded in accomplishing the task. By this method ISTasse (1852, Op. i.), Kolliker and Miiller (1855, Op. ii.), and Scott {Op. iv.), severally made observations on a single dog with reference to the effect of calomel on the biliary secretion, and the results of their experi- ments will be detailed under the action of mercury. Beinw in some measure contradictory, the subject was in 1866 taken up by a committee, of which the late Professor Hughes Bennett was ehaimian and reporter. Professor Arthur Gamgee and the author were the two junior members of the committee upon whom devolved the task of performing the experiments. The investigation was laborious, and lasted two years. Very great EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. XI difficulty was experienced in making a constant collection of the bile extending over a number of days, and it was repeatedly observed, that although the animals were kept on a fixed diet, remarkable variations took place in the amount of bile secreted daily, when no cause could be assigned. This circumstance rendered the method of experiment one from which it was difficult to arrive at just conclusions ; never- theless the experiments seemed to warrant the statement that " spontaneous diarrhoea, dysentery, and purgation produced by pilula hydrargyri, calomel, corrosive sublimate, and podophyllin diminished the soUd constitutents of bile, and, with one excep- tion, the fluid portion of the bile also" (British Association Reports, 1868, p. 229). These are indeed meagre results, considering the great labour which their attainment entailed, and it must be admitted that they were to some extent misleadiag ; not because of any inac- curacy of observation, but because the method of experiment was not adapted to supply, at brief successive periods of time, information regarding the state of the secretion of bile. On that account it failed to show that in the case of such a substance as podophyllin — which certainly increases the biliary secretion, but which also stimulates the intestinal glands — if too large a dose be given, the effect on the liver may be overcome by its effect on the intestine, and a diminished secretion of bile result. (See Experiment 9 in the sequel.) In 1873 Ebhrig (Op. vi.) reopened the investigation of this subject. He observed the rate of biliary flow from temporary fistulse in fasting curarised dogs before and after the injection of purgative agents into the stomach or intestine. He found that large doses of croton oil greatly increased the secretion of bile, and that a similar effect, though to a less extent, was produced by colocynth, jalap, aloes, rhubarb and senna, and sulphate of magnesia — the potency of these agents as stimulants of the liver being in the order mentioned. He found, moreover, that castor 9il had little effect, and that calomel, while it seldom recalled the biliary secretion after it had ceased, nevertheless somewhat augmented it when it was taking place slowly. Ebhrig's statement with regard to calomel does not much differ from that made by Hughes Bennett's committee, but nejverthieless he did find that certain purgative agents, when Xll PROF. RUTHBfiFOKD AND M. VIGNAL. given to fasting animals with temporary biliary fistulae, increased the biliary secretion, while the committee found that in non-fasting animals with permanent fistulse, purgative action, induced by podophyUin, calomel, &c., diminished the amount of bile secreted in the twenty-four hours. It appeared to me that this important subject could not be allowed to remain in a position so unsatisfactory. I therefore entered on the following research, but ere I had proceeded very far I found its labours so excessive, that I- was glad to avail myself of the very valuable assistance of my pupils. Monsieur W. Vignal, and latterly of Dr William Dodds, in performing the experiments. Method of Experiment. All the experiments recorded in the following pages were performed on dogs. The dog was selected — 1. Because the size of its common bile-duct renders it possible to introduce a cannula with an orifice sufficiently large to prevent its being blocked up by particles of inspissated mucus from the gall-, bladder. 2, For the reason that its digestion resembles that of man, inasmuch as its stomach becomes empty when the process is completed. It is very different in the case of a rabbit, whose stomach is never empty. 3. As Eohrig had performed his experiments on dogs, it was necessary that we should compare our results with his. The selection of the dog has proved fortunate, for the results of our experiments are in complete harmony with every perfectly ascertained fact regarding the actions of medicinal agents on the human liver, and prove that the liver of this animal is affected in the same sense — although it may not be to the same degree — by substances that act on the human liver. All the experiments having been performed on animals of the same species, placed as nearly as possible under similar conditions, the results are fairly comparable ; although it must be borne in mind that just as no two members of the human species can even in their normal condition be regarded as equally susceptible to the influence of any medicinal agent, neither can any two members of the canine species be held to possess identical susceptibilities. AU the animals had a full meal of lean meat at three or four o'clock in the afternoon, and the experiment was begun between nine and ten o'clock on the EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 1 following morning, so that the digestion and absorption of the food were completed, and the animal was therefore in a fasting condition. This was an essential preliminary ; for, as is well known, the secretion of bile is accelerated during the process of digestion, and had we taken the amount of bile secreted per hour during digestion, as an index of the activity of the liver previous to the administration of a drug, our experiments would necessarily have been worthless. The disturbing effect of irregular muscular movements upon the biliary flow was prevented by injectiag into a vein small doses of curara, repeated at intervals, when the motor paralysis which it induces became too slight. In consequence of the curara palsy, artificial respiration was had recourse to, and maintained at regular intervals throughout the whole experiment. Chloro- form was used during the preliminary operation in two cases, but the stimulation of the liver which it induced rendered the experiments worthless.^ On the other hand, we have abun- dantly proved that the doses of curara administered in the following experiments have no influence on the biliary secretion, and do not interfere with the effects of hepatic stimulants. It is therefore an exceedingly valuable auxiliary in a research of this nature. The method of experiment we adopted was always that of a tem/porary biliary fistula. Through an opening in the linea alba a glass cannula was inserted into the common bile- duct near to its junction with the duodenum, and tied therein. To the end of the cannula projecting from the abdomen a short caoutchouc tube was attached, and to the free end of this a short glass tube drawn to a narrow aperture so that the bile might drop from it, as Eohrig (flp. vi.) had recommended. The gall-bladder was then compressed, in order to fill the whole tubing with bile, and the cystic duct was clamped to prevent its return to the gall-bladder, and so compel all the bile secreted ' It may be well to state, however, that in all the operations for the previous experiments on the action of chnlagogues performed by me twelve years ago, at a time when there was no antiphysiological excitement prevailing, chloroform was fully administered to every animal, because in those experiments the biliary fistula was of a permanent nature, and observations were not begun on the biliary secretion until some days after the operation — when of course the effect of the chloroform had completely passed off. The biliary fistula being of a temporary character in the present research, and the whole time taken up by each experiment being not more than a few hours, the use of anaesthetics was inadmissible. R. 1 ^ PROF. RUTHERFORD AND M. VIGNAL. by the liver to flow througli the cannula. The wound in the abdominal wall was then carefully closed, and in all save the earliest experiments the animal was thoroughly covered with cotton wool, in order to quickly restore it to its normal temperature ; and, guided by a thermometer in the abdominal cavity, great care was taken to keep the temperature normal, — a matter of no small importance, — for if the temperature fall several degrees, the liver secretes more slowly. The respiration requires to be maintained with regularity, otherwise the bUiary flow is rendered somewhat unequal by irregular diaphragmatic compression of the liver. Moreover, if the respiration be deficient, the secretion of bile is always diminished. Some of the slight oscillations observable in the charts of the biliary secretion in these experiments are probably owing to variations in the respiration; for in the earlier experiments we were obliged to have the respiratory bellows moved by the hand, and this is never so regular as a machine. Notwithstanding this, however, the main results of these experiments are perfectly clear. Until it is attempted, one might suppose that this mode of experiment is extremely simple, but it is by no means so simple as it appears. It is needful to manipulate the abdominal viscera with great care, and to avoid all dragging at the bile-duct, other- wise the secretion of bile becomes so irregular that the experi- ment may be useless. The cannula must be very carefully retained in a position which will permit of its moving with the diaphragm, but will prevent it from twisting the duct, and thus impeding the exit of the bile by forming a valve at its orifice. Eohrig estimated the velocity of the biliary secretion by counting" the seconds that elapsed between the fall of the drops from the orifice of the tube. A single trial convinced us that this method is extremely laborious, and leads to inaccurate results, because it does not permit of continuous observation for any length of time. Variations in secretion often occur inde- pendently of the administration of any substance, and it is impossible to estimate their significance, and make due allow- ance for them, unless the method of continuous collection of the bile be adopted. Moreover, we saw that the degree of viscosity of the bile caused a variation in the size of the drops. EXPEUIMENTS ON THE BILIARY SECRETION OF THE DOG. 3 and, therefore, in the intervals between their fall. We therefore abandoned this for the more accurate method of allowing the bile to flow into a fine cubic centimeter measure, and recording the quantity secreted every quarter of an hour. In addition to constant collection of the bile, this method has the great advan- tage of permitting a graphic representation of the results. It is evident from the method of experiment that all our observations relate exclusively to the effects of substances on the hile-secreting mechanism. We have made no observations regarding their effects on the bile-expelling mechanism. Nor do we intend to prosecute the latter part of the inquiry, for the question, what substances stimulate the liver to secrete more bile, is of infinitely greater importance. We shall be able to give to it a precise answer, and thus for the first time to furnish the physician with definite knowledge for his guidance in the treatment of hepatic disorder. In several instances we analysed the bile secreted before and after the administration of a drug ; but although valuable facts were thus ascertained, we found that in consequence of the excessive labour of this research it was impossible to analyse the bile in all cases. We therefore discontinued the analyses, after observing that even when a hepatic stimulant renders the bile more watery, the increased velocity of secretion always more than compensates the diminution of the solids, and thus compels the liver to produce in a given time a larger amount of the biliary constituents proper. We were also at the pains to make in most cases post-mortem examinations of the small and sometimes of the large intestines and stomach, in order to compare the effect of the drug on the liver with its effect on the intestine. The results are valuable, because — 1. They furnish for the first time a systematic account of the effects of well-known and also of many new drugs upon the intestinal mucous membrane; 2. By separating the secretion of the liver from that of the intestinal glands, a more exact knowledge of the effects of substances on the latter is obtained, and a very important generalisation regarding the effect on the secretion of the bile, produced by stimulating the intestinal glands, has been arrived at, as wiU be shown in the sequel. It ought to be observed that some of the substances may pierhaps 4 PEOF. RUTHERFOED AND M. VIGNAL. have stimulated the pancreas, and as the pancreatic duct was never tied, the fluid in the intestinal canal may have been a mixture of int^estinal and pancreatic juices. But as the liver viras the primary object of our investigations, it would have been alto- gether unjustifiable to have set up more irritation at the duodenum, by cutting down on the pancreatic duct and placing a cannula in it — always a difficult thing to do in the dog, and apt to involve a good deal of haemorrhage. Although by such a procedure, definite knowledge might have been arrived at with regard to what substances affect the pancreas, yet our results as regards the liver — a gland of greater importance in the economy, — might have been vitiated. Probably in most cases the fluid found in the intestine was chiefly intestinal juice, but for the reason mentioned no conclusive statement is_permissible with regard to this point. The small doses of curara given to the animals were injected into the jugular vein, in order that their effect might be speedy ; but nearly all the drugs given for the purpose of affecting the liver or intestine were injected into the duodenum, because the animals being curarised could not swallow, and the penetration of the duodenal wall by the sharp nozzle of a small syringe was a much simpler operation than the introduction of a tube down the oesophagus into the sjtomach. Moreover, the stomach in a dog that has fasted for many hours usually contains a large quantity of mucus that must have retarded the absorption of the substance if given by the mouth. To avoid this delay was a matter of great importance, both on the animal's account, and also because of the impossibility of continuing the experiment for more than a few hours. Moreover, it has been alleged that the action of a cholagogue may be due to a reflex excitement of the liver proceeding from the duodenal mucous membrane ; therefore by always injecting the substances into the duodenum we ensured its action — if any — on this portion of the intestine. It must of course be borne in mind, that when a drug is placed in the duodenum directly, and a certain effect on the liver ensues, it by no means follows that the same effect will accrue, if the drug be placed in the stomach and thus come in contact with the gastric juice. But the general harmony of the results of our injecting substances into the duodenum, with those EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 5 observed in man when the drugs are taken by the mouth, con- vinces us that our method is reliable. In only one instance indeed — that of calomel — did it seem probable that its having escaped the influence of the gastric juice was vitiating the result, for the hydrochloric acid of the juice can convert calomel into corrosive sublimate, and we have discovered that while calomel does not, corrosive sublimate does, stimulate the liver. A dis- cussion of that case will be found under the action of mercury, and we think it the only one that needs special consideration. Secretion of Bile in a Curakised Fasting Dog. It was of course necessary — as a preliminary step — to observe the amount of bile secreted in the course of a day by a dog that had fasted about eighteen hours, and to which nothing but curara was administered. The solution of curara employed in all the experiments was a filtered aqueous solution, every minim of which contained one milligramme of the poison. The solution was always injected into the jugular vein. In aU the woodcuts the numbers under the abscissa indicate the hours during which the secretion of bUe was observed, while those to the left of the ordinate indicate in cubic centi- meters the amount of bile which flowed from the cannula; the dots in the curve indicate the quantities of bile collected every quarter of an hour. The vertical dotted lines that cross the curves in the illustrations indicate that something was given to the animal. In all such experiments the amount of bUe first collected is usually much greater than that at sub- sequent periods. This apparently results from the sudden diminution in the resistance to the exit of the bile consequent upon opening of the duct. The first one or two collections are therefore not reliable indices of secretion, and they are therefore omitted from some of the charts. Experiment 1. Dog that had fasted 18 hours. Weight 7"6 kilogrammes. — Twentj' milligrammes of curara were in- jected into jugular vein (at a, fig. 1). The abdomen was then opened, and the cannula placed in the common bile-duct, as above indicated. The wound in • the abdomen was closed, the 6 PROF. RUTHERFOKD AND M. VIGNAL. animal enveloped in cotton wadding, and the bile collected. As the experiment proceeded, the effect of the curara gradually Fis. 1. 8 hours. Secretion of bile by a fasting dog with nothing hut curara administered. a. 20 mill. ; J. 2 mill. ; e. and d. i mill, ; e,f, g. 3 mill, curara injected into jugular vein. wore off, owing to its elimination, and it was necessary to inject from two to four milligrammes from time to time (b, c, d, e, /, g, Fig. 1). If the curve be examined, it will be observed that these doses had no apparent effect on the biliary secretion, which was in this case tolerably regular. After falling until the middle of the third hour, it increased for a time and then fell somewhat. At the eighth hour it was slightly below what it had been at the close of the first. Experiment 1a. Dog that had fasted 17 hours. Weight 18.7 kilogrammes. (Fig, Ia.) Fig. 1a. Secretion of bile by * fasting dog with nothing but curara administered, 20 mill, given at c, 4 mill, given at c', c", c'", c^, c=, 3 mill, given at <^. KXPKRIMENTS ON THE BILIARY SECRETION OF THE DOG. 7 As it is evident from these two experiments that doses of curara such as those given above do not apparently affect the biliary secretion, the times at which they were given are not indicated in any of the subsequent charts, for in all cases curara was given, as above indicated. The great value of this substance in this connection is, that while not obviously affecting biliary secretion, as chloroform does, it paralyses voluntary movement, and thus prevents the irregular outflow of the bile that ensues when the abdominal muscles contract. The analysis of the bile in such a case as the above having been omitted, another experiment was performed for the pur- pose of supplying the want. Experiment 2. Dog that had fasted 19 hours. "Weight 15 kilogTammes. — Nothihg was given but curara in doses similar to those above mentioned. (Fig. 2.) The biliary flow was not so regular in this as in the previous cases. The mean has been taken, and triangles with dotted lines are superadded in the Fig. for the purpose of indicating the probable position of the dots had the secretion been regiilar. Fig. 2. 12 3 4 5 6 7 Secretion of bile in a fasting dog with nothing but curara administered. This was done on the supposition — entertained until more experience was gained — that these irregularities in the curve were due, not to variation in secretion, but to irregularity of outflow, owing to a variation in the facility with which the bile could enter the cannula. It was in time ascertained, how- ever, that an irregular curve generally ensued when there was much difficulty in inserting the cannula into the duct, and the latter had to be a good deal pulled about, in consequence of 8 PEOF. EUTHERFOED AND M. VIGNAL. which the liver probably suffered somewhat from nervous irritation. Composition of Bile in a Fasting Dog. Analyses were made of the bile secreted by the second dog during the first, fourth, and last hours of the experiment. The following are the results : — Table I. — Composition of Bile secreted by a Dog paralysed by Curara after fasting nineteen hours. Experiment 2. Bile secreted during First Hour. Fourth Hour. 1 Last Hour. Water Bile-acids, pigments, choleste- rin, fats Mucus Ash 89.53 8.73 0.71 1.03 89.58 8.68 0.72 1.02 89.55 8.71 0.72 1.02 Total 100.00 100.00 100.00 It therefore appears that in the progress of the experiment the composition of the bile remained almost precisely the same. This is remarkable, seeing that the animal had been deprived of water for so long a time, and, moreover, seeing that the entrance of the bile into the intestine had been cut off. It should be mentioned that in taking the bile secreted near the beginning of such experiments for aijalysis, we were always careful to eliminate that which had been expressed from the gall-bladder into the cannula. Segeetion of Bile pee Kilogeamme of Body-weight in a Fasting Condition. The absolute quantity, of bile secreted by different individuals varies with the size of the animal ; therefore, in order to ascertain the amount of work that is really done by the liver in any case, it is necessary to know the quantity of bile secreted per kilogramme weight of the animal in a imit of time. In all these experiments, therefore, the animals were EXPEKIMENTS ON THE BILIAKY SECRETION OF THE DOG. » weighed, so that the secretion of bile per kilogramme might be determined. Experiment 1. Secretion of bile per kilogramme of dog : per hour. Secretion of bile per 15". cc. 1.0 0.85 e.7 0.75 0.75 0.75 0.75 0.65 0.6 0.45 0.65 0.55 0.75 0.75 0.85 0.8 0.77 0.77 0.75 0.8 0.7 0.65 0.55 0.65 0.6 0.65 0.6 0.7 0.5 0.55 0.47 0.6 > 0.394 .0.309 .0.381 .0.393 .0.355 .0.328 .0.292 0.351 CO. Experiment lA. Secretion of bile per kilogramme of dog : per hour. Seeietion of bile per 15". cc. 1.5 1.47 1.5 1.4 1.5 1.35 1.5 1.4 1.42 1.4 1.4 1.5 1.47 1.45 1.42 1.4 1.52 1.37 1.42 1.42 1.37 1.45 1.4 1.3 1.27 1.32 1.5 1.3 1.25 1.3 1.15 1.05 1.2 .0.307 .0.3 ■ 0.312 .0.305 .0.301 .0.288 • 0.267 0.254 00. Experiment 2. Secretion of bile per kilogramme of dog : per hour. Secretion of bile per 15". CO. 1.1 0.85 0.55 0.6 0.75 0.6 0.6 0.45 1.0 0.75 0.65 0.7 0.45 0.65 0.8 0.4 0.45 0.45 0.5 0.45 0.55 0.5 0.5 0.62 0.55 0.6 0.75 0.65 0.4 0.15 0.65 • 0.17 0.19 • 0.177 ■ 0.12 • 0.133 • 0.168 ■0.123 Mean, 0.164 cc. In the three curara experiments detailed above, the mean secretion per kilogramme weight of the animal was 0.351 cc. in Exp. 1, 0.254 cc. in Exp. 1a, and 0.154 ,cc. in Exp. 2. In the first case, the secretion was, from some unknown cause, unusually high : the last two figures will be found a mach nearer indication of what is usual in the fasting animal, but in subsequent experiments it will be seen that the secretion is frequently below even the small figure in Exp. 2. 10 PROF. RUTHERFORD AND M. VIGNAL. Undoubtedly, the true test of hepatic work is the amount of hile-soUds secreted per unit of animal weight, in a unit of time. Any one may calculate this from the analyses, but inasmuch as these were not made in every case, and seeing that we have found that whenever a substance increases the biliary secretion, it augments the excretion of bile-sohds by the liver, even although the bile be rendered more watery, we have thought that a statement of the amount of fluid bile secreted per kilo- gramme of dog will be sufficiently refined for the purpose of this research, because the question we have set ourselves to answer is principally this : What substances have the power of exciting the secreting apparatus of the liver ? a question which cannot be answered by the ordinary observations on man, for there it is impossible to determine whether an increased amount of biliary matter in the dejections is due (1) To contraction of the gall-bladder, and larger bile-ducts. (2) To the relief of some possible spasm of the larger bile-ducts, or (3) To an increased secretion by the liver. A second question before us is the relative powers as hepatic stimulants of the various substances employed. Our answer to this can only be approximative, for it would require a considerable number of experiments with any one substance to ascertain the most effective dose in the dog. This would entail an amount of suffering and of labour that seems altogether unwarranted by the result to be attained. We therefore believe that we do enough if we give a definite answer to the first of our questions, and an approximative answer to the second. The latter will be fairly well given by determining the amount of bile secreted per kilogramme weight of the animal per hour. Action of Croton Oil. Rohrig has placed croton oil at the head of his list of hepatic stimulants, with the statement that in doses from eighteen drops to a " teaspoonful" it has an exciting effect on the biliary secretion even under the most unfavourable circumstances (Op. vi. p. 250). This substance was therefore made the subject of our first experiments with cliolagogues. EXPERIMENTS UN THE BILIARY SECRETION OF THE DOG. 11 Experiment 3. Dog weighing 7.3 kilogrammes. — Consideriug the small size of this dog, the secretion of bile was unusually great. This probably resulted from digestion being incomplete ; for, although the animal was fed seventeen hours before the experiment, at death a quantity of elastic tissue, and a greyish fluid resembling chyme, were found in the stomach. After the secretion had fallen very low, fifteen grains (about thirty drops) of croton oil, in sixty minims of almond oil, were injected directly into the duodenum (at c, Fig. 3). The dose was a large one, but not so large nor yet so small as the quan- Fig. 3. Secretion of bile when digestion was incomplete. Fifteen grains croton oil injected into duodenum at c. tities given by Eohrig. After half-an-hour, the fall in the bile-secretion was arrested, and a slight rise took place. To- wards the close of the experiment, the pulse became extremely weak. Autopsy.^ — The mucous membrane of the upper three- fourths of the small intestine was intensely red, especially in the duodenum, the colour of which resembled that of claret. ^ In all cases, unless otherwise stated, the autopsy was performed immediately at the close of the experiment. 12 PROF. EUTHERFOED AND M. VIGNAL. There was evidence of impending purgation in the small intestine. The weak pulse at the close of this experiment, together with the violent intestinal irritation, suggested that the collapse had been occasioned by the drug, and that a smaller dose should be given in the next experiment. Hxperiment 4. Dog weighing 5.9 kilogrammes. — This animal had refused almost all food for nearly' two days. Six grains of croton oil in sixty minims of almond oil were injected into the duodenum (c, Fig. 4). No increase of the biliary secre- tion followed. The pulse became so weak that the experi- ment was ended two hours and a half after the oil was given. Fig. 4. Secretion of bile before and after six grains of croton oil were injected into duodenum at c. Neceopsy. — The oil had found its way into the stomach. The gastric mucous membrane was of a claret colour. There was slight redness of the duodenum, but no evidence of pur- gative action. Experiment 5. Dog that had fasted 18 hours. Weight 3.1 kilogrammes. — In this experiment, only three grains croton oil in sixty minims almond oil were injected into the duodenum. A decided increase in the biliary secretion began within an hour after the injection. The secretion soon reached a maxi- mum, and then fell in the course of two hours to the same level as before the injection. (Fig. 5.) Neceopst, — A portion of the oil was found in the stomach, and another portion half way down the small intestine. The gastric mucous membrane was intensely red. There were patches of slight redness here and there in the duodenum. No evidence of purgative action. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 13 These experiments were undertaken simply to test the accuracy of Eohrig's conclusion arrived at by his method of Fig. 5. The secretion of bile before and after three grains of croton oil were injected into the duodenum at c. counting the drops of bile. Our method, which, as we have explained, is more reliable, gives no evidence that croton oil is to be regarded as a potent cholagogue, and, seeing that it has no reputation as such in practical medicine, we deemed further experimentation with it uncalled for. That there was no purgation from these doses of croton oil is a singular fact, which has been laid hold of by some persons as evidence that medicines affect the dog and man very differently, and that therefore the results seen in the one cannot be applied to the other. It is well known, however, that a difference in action is quite exceptional, and certainly the following experiments fully bear out this opinion. The only explanation of the non-purgative action of the oil in the above cases that suggests itself is, that possibly too great a dose of this violent irritant was introduced into the intestine, and that a paralysis of Lieberkiihn's follicles was the result. The large doses were given in imitation of Eohrig's experiments. Action of Podophylline, Experiment 6. Dog that had fasted 19 hours. Weight 15.3 kilogrammes. — The secretion of bile fell very gradually (Fig. 6). Ten cubic centimeters of water were injected into the duodenum at w. There being no apparent effect, 100 cc. were injected at w'. The slight jise in secretion that ensued at the end of an hour may have been owing to this ; but it is not likely, seeing that water is absorbed with rapidity. At p, ten grains 14 PROF. EUTHEKFOED AND M. VIGNAL. podophylline, suspended in 10 cc. water, were injected into the duodenum ; and it is probable that the rise in secretion two hours afterwards was due to the podophylline. Negeopsy. — The mucous membrane of the duodenum, and to a slight extent below it, was very vascular, and this part of the Fig. 6. Secretion of bile before and after water and podophylline. w. 10 cc. water ; «/. 100 cc. water ; p. 10 grains resina podophylli in 10 cc. water injected into duodenum. intestine contained a considerable quantity of a slightly brown fluid, thereby affording evidence of a purgative effect. Experiment 7. SmaU dog that had fasted 19 hours. — Eight grains podophylline in 25 cc. water injected into duodenum (p. Fig. 7). The subsequent increase in the biliary secretion Fig. ?. Secretion of bile before and after eight grains of resina podophylli in 25 cc water were injected into duodenum at^. was most marked about four hours after administration, but by the end of the sixth hour the effect had greatly diminished. EXPERIMENTS ON THE BILIARY SECKETION OF THE DOG. 15 Necropsy. — Upper part of small intestine contained a viscous brownish fluid. As the small quantity of water injected had probably been absorbed, the intestinal contents were regarded as distinct, though not abundant, evidence of purgative action. The mucous membrane, to the extent of about eighteen inches below the pylorus, was extremely vascular. The remainder of the intestine was pale. A small quantity of mucus was found in the stomach, the mucous membrane of which was pale. Experiment 8. Dog that had fasted 18 hours. Weight 6.6 kilogrammes. — Six grains podophylline in 9 cc. water injected into duodenum {p, Fig. 8). The subsequent rise in the bile- secretion is very evident. The secretion attained its maximum between three and four hours after the administration of the podophylline. As in the previous case, the effect on the liver had very greatly diminished by the end of the sixth hour after administration. Necropsy. — Distinct, though not abundant, evidence of purgative action in small intestine, and decidedly increased vascularity of the mucous membrane in its upper two-thirds. Nothing remarkable in stomach or large intestine. Fig. 8. Secretion of bile before and after six grains of resina podophylli in 9 cc. water, were injected into duodenum at^. Probably every one will be struck by the slowness and the small extent of the purgative action in these experiments, not- withstanding the large doses of podophylline. That this was owing to the insolubility of podophylline in water is probable, from the two following experiments. Zwicke, Hagentorn, and Kohler having shown {Op. vii.) that convolvulin, elaterin, and some other substances have no purgative action unless they come in contact with bile — which, therefore, appears to be a 16 PllOF. EUTHEKFOED AND M. VIGNAL. solvent for them — it occurred to us that the tardy action of the podophylline might be owing to the non- entrance of the bile into the intestine. Accordingly in the next experiment the podophylline was suspended in bile. Experiment 9. Dog that had fasted 18 hours. Weight 11 kilogrammes. — 12.2 cc. bile injected into duodenum {b, Fig, 9). Unfortunately, there is a hiatus in the curve immediately before the injection, owing to a loss of the bile; nevertheless it is Fig. 9. Secretion of bile before and after podophylline. h. 12.2 cc. bile ; p, nine grains resina podophylli in 12 cc. bile injected into duodenum. evident that increased bile-secretion followed the injection when the biliary flow had become fairly constant. Nine grains podophylline, triturated in a mortar with 12 cc. bile, were injected into the duodenum (p). A rapid increase in the bile- secretion ensued ; but it soon diminished, and three hours after the injection it was lower than it had ever been. In , this remarkable experiment, therefore, the diminution of bile- EXPERIMENTS OX THE BILIARY SECRETION OF THE DOG. 17 secretion after podophylline was far more remarkable than its increase ; indeed, the increase might possibly have been owing to the injected bile, and not to the podophylline. Towards the close of the experiment the pulse became weak, but not exces- sively so. Autopsy. — Mucous membrane of stomach and whole length of small intestine intensely red. The small intestine contained a large quantity of fluid. The large intestine contained a con- siderable quantity of liquid faecal matters. There was, therefore, abundant evidence that excessive purgation was imminent. In this experiment, the intestinal irritation and the pur- gative effect were far greater than they were in any of the previous experiments with podophylline, and it is evident that the principal change in the bile-secretion was diminution. It therefore appeared that, with a powerful solvent such as the bile, nine grains of podophylline produced a too violent effect upon the alimentary canal. The previous experiments having shown that, with a slighter action on the intestine, there was a more powerful action on the liver, suggested that with a smaller dose of podophylline given in the biliary solvent, an action on the liver would be evident, and that this would follow the injection more speedily than it had done in the experi- ments where the podophylline was not given in a state of solution. The next experiment realised this anticipation in a very striking manner. Experiment 10. Dog that had fasted 19 hours. Weight 17.1 kilogrammes.— The bile-secretion was about 2 cc. per fifteen minutes before injection into the duodenum of 6 cc. bile and 6 cc. of water, b, Fig. 10. The subsequent increase of secretion was trivial. An hour after this, four grains podo- phylline, in-tlie same quantity of bile and water, were injected {p). About half an hour afterwards a great acceleration of the biliary flow began, and lasted about an hour. In one of the periods of fifteen minutes, no less than ."i.S cc. of bile were secreted; a quantity never noticed in any other experiment, even on larger dogs. When this great hepatic excitement had disappeared, 6 cc. of bile and 6 cc. of water were again injected {b'), as in the first instance. The fall in the secretion was for a time arrested ; but within three hours after the administration B. 2 18 PROF. EUTHEEFOKD AND M. VIGNAL. Fig. 10. =.. Secretion of bile before and after podophylline. 6 cc, bile and 6 cc. water injected into duodenum at b. and '6', Four grains podophylline in the same fluids injected at p, . EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 19 of the podophylline, the action of the liver had almost entirely ceased. The pulse was weak, but not extremely so. Autopsy. — The mucous membrane of the duodenum was intensely vascular, but that of the remainder of the small intestine did not show an increased vascularity nearly so great as in the previous experiment. The upper three-fourths of the small intestine contained very decided evidence of purga- tive effect. The gastric mucous membrane had a dull red appearance. Expeiioient 8. | Experiment 9. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog : per hour. hour. ce. cc. cc, cc. 0.3 3.05 0.1 3.2 0.07 2.6 0.05 lost. 0.1 lost. 0.15 6 0.12 1.5 0.1 J 2.4 0.1 0.05 i 0.042 2.2 2.2 ■ 0.836 0.03 ) 2.4 I 0.32 %.8 1 0.15 0.2 2.8 2.4 > 0.927 ) 0.27 2.2 0.52 1.9 ) 0.52 2.6 V 0.645 0.57 1.3 0.52 1.3 ) o.e 1.5 ) 0.75 0.6 1.2 1.1 I 0.427 0.75 0.9 ) 0.8 0.4 0.75 \ 0.5 0.8 0.8 l 0.477 0.8 ) 0.75 0.75 0.02 0.52 0.42 0.35 0.35 Experiment 10. Secretion of bile per kilogramme of dog : per hour. Secretion of bile per 15". cc. 8.6 a.6 2.3 1.7 1.9 2.1 lost. 2.2 » ■ 2.1 2.4 2.2 2.3 2.1 2.2 3.8 5.8 4.1 8.6 2.2 1.9 1.9 2.6 0.2 CO, 0.526 } 1.01 2—2 20 PROF. RUTHERFORD AND M. VIGNAL. Composition of Bile befoi-e and after Podophylline. The next question to be answered was evidently this, is the increase in the quantity of bile after podophylline merely due" to an increase of water, or are the bile-solids also increased? The bile secreted by dog 10, between the second hour and a half and the third hour, and that secreted an hour and a quarter after the administration of podophylline, were analysed with the following results. (Table II.) Table II. — Podophylline. Experiment 10. Before. After. . Water .: Bile-acids, pigments, cholesteriue, fats Mucus .,. ■. Ash 90.83 7.75 1.00 0.42 91.07 7.84 0.€0 0.49 100.00 100.00 Velocity of secretiofn per half -hour 4.6 CO. 9.6 CO. It thus appears that, notwithstanding the great velocity of bile-formation, the special bile-solids were not diminished ; the only: noteworthy diminution being in the amount of mucus. This remarkable result was confirmed by the following analysis of the bile in another case. (Table III.) Table ISI.^-PodopkylUne, Experiment 10 a. Before. After. Water Bile-acids, pigments, fats, cholesterine Mucus Ash 94.26 4.66 0.73 0.35 94.28 4.68 0.70 0.34 100.00 100.00 Velocity of secretion per half -hour 1.86 cc. 2.47 CO. Eesults of the Experiments with Podophylline. — 1. Podo- phylline, when injected into the duodenum of a fasting dog, increases the secretion of bile. It is inferred that the increased biliary flow in the preceding experiments was due to increased EXPERIMENTS ON THE BILIARY SECRETION. OP THE DOG, 21. secretion, and not merely to expulsion, because the gall-bladder had been wellnigh emptied by compression, and the cystic duct had been clamped: moreover, the increased flow was far. too prolonged in some of the experiments to be attributable to spasm of the larger bile-ducts ; therefore, an increase in sepre- tion must have been the cause. 2. When the bile is prevented from entering the intestine, podophylliiie acts less powerfully and less quickly than when bile is introduced. 3. Augmenta- iion of. the biliary secretion is most marked when the purgative effect is not severe ; indeed, if the purgative effect be very decided {Experiment 9), diminution and not augmentation of the biliary secretion may be the chief result. 4. Podophylline purgation is apparently due to a local action, for the irritation of the intestinal mucous membrane extends gradually from above downwards. 5. The bile secreted under the influence of podophylline, although it may be in increased quantity, contains as much of the special biliary matter as bUe secreted under normal conditions. These results are in exact accordance with clinical expe- rience of the action of podpphylline in man, but in addition they show that this substance actually increases tha secretion of biliary matter, and that the liver is stimulated to secrete bile of the normal composition. They therefore supply infor- mation of a precise and important character, which the observa- tions on the human subject have failed to give. In the experiments with podophylline, performed by Hughes Bennett's committee above referred to, it was found that podo- phylline diminishes the secretion of bile. How is that state- ment to be reconciled with the above ? The principal expla- nation is probably this, that in the experiments of the committee the doses given were large and generally produced profuse pur- gation. We see that in experiment 9 of this series diminished bile-secretion was the chief result of a dose that was too large, knd it may be repeatedly observed in the following experi- ments. 1. That when a substance produces purgation, but does not stimulate the liver, it diminishes the secretion of bile. 2. That when a substance stimulates the liver as well as the intestinal glands, a moderate dose increases both the hepatic and the intestinal secretion, the effect on the former being 22 PEOF. EUTHEBFOED AND M. VIGNAL. most marked in the- earlier part of the experiment, and di- minishing as the purgative effect increases; but an excessive dose, by producing a violent purgative effect early in the ex- periment, may occasion nothing but diminished secretion of bile. Action of Aloes, Although aloes has been found by Rohrig to accelerate the biliary secretion, we were anxious to compare its action, as ascertained by our method, with that of other substances ; and we also desired to know the composition of the bile secreted before and after its administration. Eoffperiment 11. Dog that had fasted 18 hours, weight 8.6 kilogrammes, — Sixty grains of aqueous extract of Socotrine aloes in 12 cc. of water were injected into the duodenum (a, Fig. 11)'. A decided increase in the biliary secretion was perceptible within half-an-hour thereafter. After attaining a maximum about an hour and a half after the administration of Fig. 11, Secretion of bile before and after sixty grains extract of Socotrine aloes in 12 cc. water were injected into the duodenum at a. ^ This dose was probably much larger than need have been given, but when these earlier experiments were performed, we were under the impression that the dog requires larger doses than man. Further experience convinced us that this is exceptional. In many subsequent experiments we found that doses of various substances similar to those given to man act on the hepatic and intestinal glands of the dog. EXPERIMENTS ON THE BILIARY SECRETION OF THE EOG. 23 the drug, the secretion gradually fell; but although the ex- periment was continued for seven hours after the aloes \vas given, the effect had not disappeared. Autopsy. — The aloes had extended along two-thirds of the small intestiue, which contained about an ounce and a half of viscous fluid as the only evidence of purgation. There was a decided increase in the vascularity of the mucous membrane in this part of the intestine. The stomach contained a little mucus. Its mucous membrane was pale. Experiment 12. Dog that had fasted 18 hours. Weight 5 kilogrammes. — Sixty grains of extract of Soeotrine aloes in 12 cc. water were injected into the duodenum (at a. Fig. 12). As in the previous experiment, the biliary secretion was in- creased within half an hour, and it became very strongly marked. Autopsy. — The aloes had extended half way down the small intestine. This portion of the intestine contained about two ounces of viscous fluid ; and its mucous membrane, together with that of the stomach, was intensely red. Fig. 12, Secretion of bile before and after sixty grains extract of Soeotrine aloes in 12 cc, water were injected into the duodenum at a. Composition of the Bile before and after Aloes. It is evident from Tables IV. and V. that, under the influ- ence of aloes, the bile became more watery ; nevertheless, the amount of bile-solids secreted per unit of time increased. 24 PROF. BUTHEBEOED AND M. VIQNAL. Table IV. — Aloes. Experiment 11. Before. After. Water ■ Bile-acids, pigments, cholesterine, tats Mncua Ash 84.11 12.45 1.77 1.67 91.44 7.53 0.38 0.65 100.00 100.00 Veloc'ty of secretion per half-hour 1.5 cc. 2.65 ce. Table V. — Aloes. Experiment 12. Water Bile-acids, pigments, cholesterine, fat Mucus Ash Velocity of secretion per half-hour Before. 83.93 12.30 2.74 1.03 100.00 0.66 cc. After. 86.75 .10.79 1.49 0.97 100.00 2.2 cc. Eesalts of Experiments ioith Aloes. — 1. Sixty grains of the extract of Socotrine aloes, when placed in the duodenum, powerfully stimulated the liver. 2. Under its influence the liver excreted a greater quantity of biliary matter in a given time, although the bil© was rendered more watery. 3. Coin- cident with the marked action on the liver there was only slight purgation. Action of Bhubabb. The following experiments show that rhubarb is also an undoubted hepatic stimulant. The ordinary infusion of the British Pharmacopoeia was made with Indian rhubarb ; it was then filtered and concentrated until 5 cc. contained the active part of seventeen grains of rhubarb. This was the dose em- ployed. Experiment 13. Dog that had fasted 15 hours. Weight 22-2 kilogrammes.— 5 cc. of the above infusion of rhubarb were injected into the duodenum four times in succession EXPERIMENTS ON THE BILIAEY SECRETION OP -THE DOG. ^ {r, r', r", r'", Fig. 13). Within half-an-hour after every dose there was an increase in the biliary secretion. Fig. 13. 12 3 4 5 Secretion of bile before and after 5 co. of a concentrated infusion of rhubarb lyere injected into duodenum at r, r', r", ir"'. f Autopsy. — The rhubarb had extended along about a third of the small intestine. There was no unusual redness of the Pig. 14. Secretion of bile before and after rhubarb. Artificial respiration improved at a, 5 cc. concentrated infusion of rhubarb injected into duodenum at r, /, and r". 26 PROF. RUTHERFORD ANJD M. VIQNAL. mucous membrane, and there was only slight evidence of purgative action. Experiment 14. Dog that had fasted 18 hours. Weight 13.4 kilogrammes. — The artificial respiration, which was defi- cient at the commencement of this experiment, was improved at a. Fig. 14. This was followed by an increase in the secre- tion of short dtiration : 5 cc. of the same infusion of rhubarb as that used in, the previous experiment were injected into the duodenum three times in succession (r, •/•', r", Fig. 14). The biliary secretion was augmented within half-an-hour after each injection. AUTOPSY.^The rhubarb had extended along four-fifths of Experir aenlj 11. Experiment 12. | Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilggramme of bile per kUogramme 15". of dog : per 15", of dog : per hour. hour. CO. CO. cc. cc. 0.85 ) 0.65 0.9 0.7 \ 0.348 0.42 0.37 1 0.55 a ■ ) 0.3 0.35 I 0.264 0.75 0.3 1 1.05 a 1.4 0.35 1.15 J 0.97 1.75 1.55 \ 0.697 0.87 0.85 1.55 ) 1.1 1.4 1.2 1 1.3 1.05 1.45 1.05 >0.93 1.45 1.35 1 1.25 0.8 1.25 1.15 1.4 1.1 1.25 1.15 1.25 1.05 1.2; 1.05 1.05 1.15 1.15 0.9 1.1 1.2 i.o: 0.65 0.9' 0.9 0.85 0.8 Experiment 13. Secretion Secretion of bile per of bile per kilogramme 15", of dog : per hour. cc. cc. 1.15 1 0.95 0.95 \ 0.173 0.80 1 0.95 1.3 1.15 r' 1.5 I 0.27 1.65 1.45 1.4 r" 1.55 \ 1.8 1.45 \ 0.279 1.4 ) /" 2.0 \ 1.85 1.9 I 0.322 1.4 1 1.45 1.15 1,4 EXPERIMENTS ON THE BILIARY SECRETION OP THE DOG. 27 the small intestine. There was no unusual redness of the mucous membrane. The portion of intestine through which the rhubarb had extended contained 120 cc. of a thick yellowish fluid : there was, therefore, decided evidence of purgatiye action. The amount of water given with the rhubarb in these experiments was so trivial that it may be entirely disregarded. Composition of the Bile before and after Rhubarb, Table VI. — Rhubarb. Experiment 13. Before. After the second dose. At the close of the experiment. Water Bile-acids, pigments, cholesterine, " fat Mucus Ash 88.80 9.60 1.00 0.60 89.28 9'.60 0.60 0.52. 88.93 9.60 0.80 - 0.62 100.00 100.00 100.00 Velocity of secretion per half-hour 1.0 CO. 2.95 CO. 2.55 CO. Table YH.— Rhubarb. Experiment 14. Before. After. Water Bile acids, pigments, cholesterine, fat Mucus , Ash 85.47 11.59 1.87 1,07 86.23 11.08 1.72 1.02 100.00 100.00 Velocity of secretion per half -hour 1.45 cc. 3.95 cc. It therefore appears that rhubarb, lilke podophylline, excites the liver to secrete bile, having a composition similar to that secreted under normal conditions. Remits of Experiments with Rhvharb. — 1. An infusion of seveateen grains of Indian rhubarb, when placed in the duo- denum, never failed to increase the secretion of bile within half-an-hour after it was given, 2. The bile, although secreted in increased quantity, had the composition of normal bile as 28 PEOF.. EUTHEEFOED AND M. VIGNAL, regai'ds the biliary constituents proper. 3. The doses which excited the liver had in one case no marked purgative effect,, but in another case the purgative effect was considerable. Notwithstanding the fact that rhubarb has been given to man for an indefinitely long period, there has alwaj's been consider- able doubt as to its being a cbolagogue, possibly because the colouring matter of the rhubarb increases the colour of the dejections in a rnanner similar to an increased discharge of bile. But by this method of investigation this source of fallacy is eliminated, and the action of rhubarb as a cholagogue proved in the case of the dog, and there seems no longer any reason to doubt that it has a similar action in man. If the amount of bile secreted per kilogramme of dog under the influence of rhubarb be compared with the results of the action of podo- phylline, it will be seen that rhubarb is a less powerful chola- gogue ; a conclusion that is quite in accordance with observa- tions on man. Action of Senna. Senna excites the liver, but not so powerfully as rhubarb. The ordinary infusion of senna of the British Pharmacopoda was prepared and concentrated until 5 cc. contained the active part of forty-five grains of senna ; a small dose for a man. Experiment 15. Dog that had fasted 19 hours. Weight 8 kilogrammes. — 5 cc. of the above-mentioned concentrated infusion of senna were injected into the duodenum five times in succession {s,s',s", s"',s^\ Fig. 15). The secretion of bile Fig. 15. Secretion of bile before and after s^nna. 5 cc. concentrated infusion of senna injected into duodenum at s, s', s", s'", s''. experiments' on the biliary secretion of the dog. 29 rose rapidly after the second dose, as in the previous experi- ment, but it soon fell again; and the third, fourth, and fifth doses did not increase it. Autopsy. — The senna had extended along three-fourths of the small intestine, which contained 80 cc. of liquid. Seeing that the amount of fluid injected was 25 cc, considerable pur- gation had been produced. There was a considerable increase in the vascularity of the duodenal mucous membrane, but else- where there was no unusual redness.' Experiment 16. — Dog that had fasted 18 hours. Weight 23.1 kilogrammes. — ^cc. bile and 5cc. water injected into duodenum at e (Fig. 16) and ^ cc. bile with 5 cc. infusion of senna of the stren^h above mentioned were injected at 8, s', s", s"'i There was only a slight increase in the biliary secretion. Autopsy. — ^The senna had passed through the whole length of the smajl and had entered the large intestine. The amount of fluid in the small intestine was 103 cc, showing that a very considerable purgative efi'ect had been produced. Fig. 16. Secretion of bile before and after senna. J cc. bile and 5 ce. water injected. J cc. bile and 5 cc. concentrated infusion of senna injected into dnodennm at s, s', s", and «'". It appears from this analysis and from the velocity of secretion, that although senna causes the liver to excrete more biliary matter, its power is below that of rhubarb, as may be further seen by comparing the amount of bile secreted per 30 PROF. EUTHEEFORD AND M. VIGNAL. kilogramme of dog, under the influence of senna and of rhubarb. It is extremely probable that the greater purgative influence of senna as compared with rhubarb is one cause of its less powerful action as a cholagogue (see p. 21). Experiment 14. Experiment 15. | Secretion Secretion Secretion of bUe per Secretion of bile per of bile per kilogramme of bile per kilogranmie 15". of dog : per 15", of dog : per hour. hour. cc. cc. cc. cc. 0.37 0.55 0.37 0.30 \ 0.35 0.45 0.35 0.25 \ 0.175 0.65 0.5 ) 1.15 s 0.7 0.5 1.6 0.55 1.3 s' 1.2 1.0 1 1.0 1.05 0.75 0.9 > 0.456 ' 6.95 ) 1.0 ) 0.75 0.85 > 0.227 0.5 0.75 0.5 ) «'■ r 0.6 0.8 0.65 2.0 0.55 !■' 0.6 1.6 s'" 2.2 j 0.62 j 2:05 1.9 I 0.604 0.52 0.55 \ 0.298 1.95 ) 0.7 ) 1.5 0.5 1.55 s" 1.72 0.67 1.37 0.55 r" 0.45 1.1 0.6 1.75 0.6 1.07 Experiment 16. Seci;etion of bile per kilogramme of dog : per hour. Secretion of bile per 15". cc. 1.2 1.2 1.3 1,2 1.2 1.1 1.15 1.2 1.2 1.2 1.2 1.1 1.3 1.4 1.2 1.5 1.3 1.2 1.2 1.3 1.2 1.5 1.3 1.17 1.2 1.3 1.4 1.5 1.3 1-2;. 1.1 1.2 1.0 0.212 • 0.238 EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 31 Table VIII.— Senno. Experiment 15. Before. After. Water Bile-acids, pigments, cholesterine, fat Mucus Ash 90.63 7.20 1.30 0.87 91.31 6.75 1.20 0.74 100.00 100.00 Velocity of secretion per half -hour 0.82 cc. 1.136 cc. Results of the Experiments with Senna. — 1. Senna is a hepatic stimulant of feeble power. 2. It renders the bile more watery. Action of Colchicum. Colchicum has been recommended as a cholagogue in cases of gout, but its action on the liver has not hitherto been tested by direct experiment. Experiment 17. Dog that had fasted 16 hours. Weight 23.5 kilogrammes. — Sixty grains of the aqueous extract of colchicum of the British Pharmacopoeia in 10 cc. of water were injected into the duodenum (c, Fig. 17). In an hour the biliary secretion began to increase, and five hours after the injection it was nearly five times more than before the drug was given. The secretion then fell, and just at the close of the experiment a large quantity of liquid faeces was discharged. The rise in the curve in Fig. 17 suggests a very powerful stimulation of the liver, but it must be remembered that the animal was of large size, and the table of numbers shows that the secretion per kilogramme of dog never went higher than 0.453 cc. Autopsy. — There was great vascularity of the upper four- fifths of the mucous membrane of the small intestine. The vascularity of the duodenum was intense. The mucous mem- brane of the large intestine was also unusually vascular. The gastric mucous membrane was pale. There was evidence of considerable hydrocatharsis in the small intestine. The large intestine was empty, owing to the recent discharge of fsecal matter. 32 PEOF. EUTHEEFORD AND M. VIGNAL. Fig. 17. Secretion of -bile before and after sixty grains extract of colchicum in 10 cc. water were injected into the duodeuuiu at c. Experiment 18. — Dog that had fasted 18 hours. Weight 23.6 kilogrammes. — Sixty grains of aqueous extract of colchicum in 10 cc. of water were injected into the duodenum (c, 'Fig. 18). Although the biliary flow thereafter varied much, a decided Fig. 18. Secretion of bile before and after sixty grains of aqueous extract of colchicum in 10 CO. of water were injected into duodenum at c. EXPEBIMEHTS- ON THE BILIARY SECEETION OF THE DOG. 33 increase was evident an hour and a half after the administra- tion of the drug. The increase lasted about four hours, after which the secretion gradually fell. The liver was certainly excited, but not powerfully, for the secretion of bile per kilo- gramme of dog did not rise above 0.205 cc. Autopsy. — There was increased vascularity of the mucous membrane of the upper three-fourths of the small intestine. The whole small intestine contained evidence of powerful cathartic action. Experiment 17. Experiment 18. Secretion Secretion Secretion of bile per Secrption of bile per of bile per kilogramme of bUe per kilogramme 15". of dog : per 15'- of dog : per hour. hour. cc. CO. ce. cc. 1.07 1.42 0.92 0.5 \ 0.138 0.75 0.47 u.. 0.77 0.5 c 0.72 > 1.02 c — ^ 1.0 0.7 1.15 > 0.207 1.35 0.95 1.55 > 0.186 1.25 . 0.55 J 1.1 1.05 > 0.227 0.62 1.02 0.95 1.3 1.25 1.02 j 1.65 1.45 > 0.216 1.15 1.22 > 0.205 1.45 1.47 i 1.7 1.1 2.25 2.22 [ 0.371 1.1 0.75 2.55 1,35 2.65 1.0 2.7 2.5 > 0.453 0.95 0.85 i.8 0.85 1.36 0.8 2.0 1.0 1.5 0.75 0.75 0.7 0.55 0.5 ■: 0.4 ' 0.37 ■;; These experiments show that the aqueous extract of col- chicum in large doses increases the biliary secretion. R. 3 S4 PBOF. RUTHERFOKD AND M. YIGNAL. Table IK..—Compositicm of the Bile before and after Colchicunt. ■ Experiment 18. . Before. After. Water Organic Bile-solids Ash ... 88.434 10.616 0.950 90.63 8.75 . 0.62 100.00 100.00 Velocity o£ bile-secretion per half-hour 1.2 CO. 2.24 cc. It appears from the above analysis that colchicum rendered the bile more watery; nevertheless, owing to the increased velocity of secretion, more biliary matter is excreted by the liver under under its influence. Results of Experiments vdih Colchicum. — 1. Sixty grains of the aqueous extract of colchicum powerfully excited the liver, and produced hydroeatharsis, although tl^ absolute amount of bile secreted per kilogramme of dog was never very high. 2. Colchicum, although it increases the amount of biliary matter excreted by the liver, renders the bile more watery. AicTION OF TaBAXACTIM. Experiment 19. Middle-sized dog tha^ had fasted 24 hours. — One hundred and eighty grains of solid, extract of taraxacum in 25 cc. of water were injected into the duodenum (f, Fig. 19) ; Fig. 19. Secretion of bile before and after taraxacum, t, 180 grains; t*, 120 grains of solid extract of taraxacum in 25 cc. of water were injected into the duodenum. 0.0708 cc. 1.1 0.95 1.7 0.3 ) 1.0 1.2 « 1.0 1.8 0.95 > 0.2578 cc. 0.6 0.35 1.15 0.95 1 2.4 1.12 e 2.35 1.0 2.6 2.9 } 1.15 1.5 1.5 2.4 3.1 1 0.4678 CO. 1.25 1.4 1.6 2.5 1 1.6 2.95 j 2.8 1.25 1.7 1.75 1 0.4789 CO. 2.45 2.25 2.22 2.0 \ 2.7 1 1.75 2.0 1.1 2.25 2.2 > 0.3039 CO. 1.5 1.6 2.22 ) 1.4 1.85 1.85 1.1 1.6 2.2 1.5 1.2 1.45 1.1 2.2 2.2 2.0 1.25 1 Table X. — Compositian of Bile lefore and after " Sajigulnarin." Ezpetimeut 29, Before. After. Water 90.09 91.41 Bile-acids, pigments, cholesterin, fata 7.38 6.67 Mucus 1.04 0.90 Ash 1.49 1.12 100.00 100.00 Velocity of secretion per half -hour 2.4 00. 4.25 CO. m PROF. KTJTHEEFOKD AND M. VIGNAL, It appears from this analysis that under the influence of " sanguinarin " the bile becomes more watery, nevertheless the velocity of secretion having been nearly doubled by this agent, it is evident that the liver secreted more biliai^ matter. Experiment 30. Dbg- that had fasted 17 hours. 20 kilogrammes. (Fig. 30.) Weight Fig. 30. Secretion of bile teJore and aiter "sanguinarin." 2ec. bile and 3cc. water injected into the duodenum at 6. 1 grain "sanguinarin" in the same fluid injected at s. Autopsy. — ^Vascularity of the mucous membrane of upper half of small intestine somewhat increased. Considerable evidence of purgative action in upper half of small intestine. Contents of a viscid mucous character. Results of Experiments with " Sangidnarin" — 1.- In one experiment three grains, in another experiment one grain, of " sanguinarin " when mixed with a small quantity of bile and water and placed in the duodenum powerfully stimulated the EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 4<9 liver. 2. It rendered the bile more watery, nevertheless it caused the -liver to secrete more biliary matter in a given time. 3. The: secretion of the intestinal glands was slightly increased by these doses. These, results show that the statements of Tully and Mothershead ought not to be treated with indiffer- ence and neglect, as they at present appear to be, in practical medicine. Action of "Iridin." The root of the Iris Versicolor, or American Blue Flag, is said by Wood and Bache (lib. cit. p. 487) to possess cathartic, emetic and diuretic properties. The American " Eclectics " have used, under the name of "iridin" or irisin, an oleo- resin obtained by precipitating a tincture of the root with water and mixing the precipitate with an equal weight of some absorbent powder. The dose of this is 1 — 5 grains as a purgative. "It is thought to unite cholagogue and diuretic with aperient properties" (Wood and Bache, loc. cit.). An anonymous writer in the Lancet (August 30, 1872) states that "it is gentler in its action than podophyllin, and more reliable when a slight cholagogue action is required for a lengthened period." This statement however has been generally neglected;^ and the substance appears to be unknown to most persons. The substance employed by us is a resin prepared in the same way as euonymin (see p. 42). Experiment 31. Dog that had fasted 17 hours. Weight 22.7 kilogrammes. (Fig. 31.) AuT-OPSY.— Stomach normal. Mucous membrane of upper two-thirds of small intestine rather more vascular than usual. This portion of the intestine contained 63 cc. of fluid, thus affording evidence of a decided purgative effect. Experiment 32. Dog that had fasted 18 hours. Weight 5.4 kilogrammes, (Fig. 32.) R 4 50 PROF. RUTHERFORD AND M. VIGNAL. Fig. 31. Secretion of bile before and after "iridin." 2 oc. bile andScc. watet injected into the duodenum at b. 5 grains " iridin " in the same fluid injected at i. Fig. 32. Secretion of bile before and after into the duodenum at 6. 5 at i. " iridin." 2 eo. bile and 2 cc. water injecteJT grains " iridin " in the same fluid injected EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 51 Experiment 30. Experiment 81. Experiment 32. Secretion Secretion Secretion Secretion of bile per Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme of bile per kilogramme 15". of dog: per 15". of dog: per 15". of dog: per hour. hour. hour. CO. cc. oc. 0.41 1.8 0.32 0.49 1.1 0.3 0.52 1.25 0.2 0.45 » 1.0 0.25 6 1.15 0.2 0.65 i 0.12 cc. 6 0.25 0.65 1.5 1 6 0.65 s 1.16 1.3 V 0.227 cc. 0.25 0.2 ) 1.25 1.2 ) 0.26 > 0.166 cc. 2.15 \ i 0.25' 1 2.65 1.55 I 0.401 cc. 1.4 1.25 0.2 i 1 1.7 ) 1.45 0.2 1.45 1.3 0.15 1.8 1.55 0.2 1.9 1.55 0.25 2.02 2.75 0.45 1.7 2.45 0.3 1.3 2.8 ) 0.4 2.0 4,0 > 0.537 cc. 0.55 1.05 2.65 1 0.55 1.05 2.75 0.6 1.35 2.4 0.55 2.0 2.5 0.7 1.05 2.1 0.85 1.4 2.4 0.9 I 1.1 2.6 0.8 > 0.638 cc. 0.8 2.3 1.5 1.3 0.85 0.9 0.7 0.75 ) Autopsy. — Stomach normal. There was increased vascu- larity of the mucous membrane of nearly the whole length of the small intestine. The redness was not very marked, but it was greater than in the previous experiment. There was decided purgation, the small intestine containing 87 cc. of fluid with abundant mucous flecculi. Results of Experiments with Iridin. — 1. Five grains of iridin when mixed with a little bile and water and placed in the duodenum very powerfully stimulated the liver. It is not so powerful as large doses (four grains) of podophyllin, but it is more powerful than euonymin, as is shown by the 4—2 62 PROF. EUTHERFOBD AND M. VIGNAL. amount of bile secreted per kilogramme of dog; the frac- tions for the two euonymin experiments being 0.4789 cc. and 0.4678 cc, whereas in the "iridin" experiments they are 0.587 cc. and 0.638 cc. The high fraction in the second iridin experiment probably resulted from a much smaller dog getting the same dose as in the first experiment, the smaller liver being thereby stimulated to do a proportionally greater amount of work'. [ 2. Iridin is also a decided stimulant of the intestinal glands. Judging from these experiments its irritant effects on the intestinal mucous membrane are decidedly less than those of podophyllin, while the purgative effects are greater than in the case of euonymin. The statement of the writer in the Lancet (above quoted) that in man "it is gentler in its action than podophyllin" is fully supported by these experiments, and there seems every reason why this substance should be removed from its present obscurity and placed in a prominent position in practical medicine. Action of " Leptandria." "Leptandria" or "Leptandrin" is a resin prepared from the root of the American plant Leptandra Virginica or Veronica Virginica in the same manner as euonymin (see p. 42). It is a remedy that has been much lauded by the " Eclectics " as a cholagogue and tonic. As this remedy is now a good deal emiployed, it seemed desirable to obtain more precise information regarding its mode of action. The dose for a man is I — 3 grains three or four times daily. Experiment 33. Dog that had fasted 18 hours. Weight 20.4 kilogrammes. (Fig. 33.) ' The analyses of the bile secreted before and after " iridin " were lost. EXPERIMKNTS ON THE BILIARY SECRETION OF THE DOG. 53 Fig. 33. Secretion of bile before and after " leptandria." 3cc. bile and 3cc. water injected into the duodenum at b. 6 grains " leptandria " in the eame fluid injected at e. 12 grains "leptandria" in 2 cci rectified spirit' and 8cc. water injected at e'. Table XI. — Composition of the Bile before and after "Leptandria.'" Experiment 33. Before. After. Water ... Bile-acids, pigments, cholesterin, fats Mucus Ash 91.34 6.64 0.95 1.07 91.41 6.60 0.92 1.07 100.00 100.00 Velocity of secretion per half-hour 1.9 cc. 2.5 cc. It appears from this analysis that the bile secreted under the influence of leptandria retained its normal composition. Ejrperimmt 34. Dog that had fasted 18 hours. Weight 13.1 kilogrammes. (Fig. 34.) Autopsy. — Slightly increased vascularity of the mucous membrane of the upper half of the small intestine. There was slight purgation; — the upper half of the small intestine containing 37 cc. of a viscous fluid. Results of Experiments with " Leptandria." — 1. " Leptandria " when mixed with bile and placed in the duodenum undoubtedly ' We have a 0.0839 CO. 6 6 0.3 ) 0.3 i 0.113 CO. 1.2 > 0.191 ce. g 0.4 0.95 0.55 0.5 0.95 J 0.4 0.5 e 0.45 i 1.4 0.35 0.8 1.3 0.55 2.0 1 1.45 1.45 ) 0.4 1.1 1.4 > 0.4 cc. 1.35 > 0.272 cc. 0.55 1.5 ) 1.3 ) 0.55 1.1 1.2 0.5 1.0 1.2 e" 0.9 e' 0.5 1.2 1.45 0.7 1.3 1.3 j 0.85 1.5 1.45 1.5 I 0.274 cc. 1.2 0.9 1.0 1.0 1.35 1 0.9 1.0 1.2 1.05 0.5 1.1 1.0 1.0 1.4 1.05 1 1.0 1.25 1.2 0.95 1.1 1.05 >■ 0.3167 cc. 1.0 1.05 1.1 0.8 0.7 56 PROF. KUTHEBFOED AND M. VIGNAL. Experiment 36. Dog that had fasted IS hours. Weight 27.2 kilogrammes. (Fig. 36.) Fig. 36. Secretion of bile before and after ipecacuan. 2 cc. bile and 5 cc. water injected into the duodenum at 6. The game fluid with 60 grains ipecacuan powder injected at t. Autopsy. — Stomach normal. The ipecacuan extended along the upper two-thirds of the small intestine, the mucous mem- brane of which exhibited a slight increase of vascularity, and was covered with thick mucus, but there was no purgation. Even in much smaller doses, however, ipecacuan excites the liver, as is shown by the two following experiments. EXPEEIMENTS ON THE BILIABY SECRETION OF THE DOG. 57 Experiment 37. Dog that had fasted 18 hours. Weight 6.1 kilogrammes. (Fig. 37.) Fig. 37. Secretion of bile before and after ipecacnan. 1.5 oc. bile and 2 oe. water injected into the duodenum at 6. The same fluid with 3 grains of ipecacuau powder injected at i. Autopsy. — Thick mucus covering the mucous membrane of upper fourth of small intestine. No purgation. Experiment 38. Dog that had fasted 17 hours. Weight (Fig. 38.) 6.8 kilogrammes. Secretion of bile before and after ipecacuan. 1.5 cc. bile and 2 cc. water injected into duodenum at h. 3 grains ipecacuan powder in the same fluid injected at i. Autopsy. — The appearances of the intestine were similar to those observed in the preceding experiment. Results of E,cperiments with Ipecacuan. — 1. Sixty grains of powdered ipecacuan mixed with a small quantity of bile and placed in the duodenum powerfully stimulated the liver. Even three grains had an effect on a dog weighing 6.8 kilo- grammes very nearly as great as the effect of sixty grains on a dog weighing 27.2 kilogrammes ; the amount of bile secreted 58 PKOF. EUTHERFOED AND M. VIGNAL. Experiment 36. | Experiment 37. | Experiment 38. Secretion Secretion Secretion Secretion of bile per Secretion of bUe per Secretion of bile per of bile per kilogramme of bile per kilogramme of bile per kilogramme 15". of dog: per hour. 15". of dog: per hour. 15". of dog: per hour. cc. cc. CO. 1.9 0.2 0.3 1.7 0.2 0.2 1.5 0.2 0.25 1.7 ' 0.25 0.25 i O.B 0.25 1.65 ■ 0.24 cc. 0.25 & 1.55 0.3 0.3 ) 1.65 / 0.3 0.35 > 0.186 CO. i • 0.2 0.32 1.6 b 0.3 1.9 25 J- 0.18 CO. i 1.8 0.25 0.45 1.7 0.3 0.6 1.85 0.3 0.9 2.4 i 0.6 2^.6 0.4 0.6 3.3 0.25 0.9 ) 3.05 0.3 1.0 \ 0.506 cc. 3.75 0.7 ) 0.8 ) 2.02 3.0 \ 0.7 0.45 I 0.385 cc. 1.15 0.55 4.25 4.0 I 0.555 cc. 0.5 0.7 ) 0.45 0.5 " 3.85 1 0.7 0.35 3.42 0.35 0.4 2.6 0.45 0.3 2.8 0.5 2.35 0.45 2.3 0.4 1.7 Composition of the Bile before and after Ipecacuan. Table XII. Experiment 36. Before. • After. Water Bile-acids, pigments, cholesterin, fats Mucus Ash 89.631 e.l3 1.01 1.229 89.77 8.129 0.87 1.231 100.000 100.000 Velocity of secretion per half -hour 3.2 cc. 6.35 cc. EXPERIMENTS ON THE BILIAKY SECRETION OF THE DOG. 59 Table XHI. Experiment 38. Before. After. Water Bile-acids, pigments, cholesterin, fats Mucus Ash 91.32 6.73 0.98 0.97 91.51 6.73 0.79 0.97 100.00 100.00 Velocity of secretion per half -hour 0.65 cc. 1 1.9 cc. These analyses show that, notwithstanding the accelera- tion of secretion by ipecacuanj the percentage amount of the special biliary constituents remains unchanged. per kilogramme of dog being nearly the same in both cases. 2. The bile secreted under its influence was of normal composi- tion as regards the biliary matter proper. 3. No purgative effect was produced, but there was an increased secretion of mucus in the small intestine. The composition of the bile did not afford any evidence of an increased secretion of mucus having taken place from the glands of the bile-ducts. The increased biliary flow that followed ipecacuan could not in these experiments be ascribed to any relaxation of " spasm of the bile-ducts," for that no such thing existed was clearly shown by the free flow of the bile before the substance was given. Nor could it be owing to contraction of the gall- bladder, for the cystic duct was clamped. Nor can it be ascribed to contraction of the bile-ducts, for the increased flow was far too prolonged to be attributable to any such cause. It is therefore certain that this substance, like the others, has the power of stimulating the secreting apparatus of the liver. This being now proved as regards the dog, it can scarcely be doubted that the modus operandi is the same in man. The results of these experiments will therefore lead to new specu- lations regarding the pathology of dysentery ; for every step towards greater accuracy of knowledge regarding the modus operandi of any therapeutic agent is certainly calculated to advance our knowledge of the true nature of the pathological condition that is relieved or cured by it. 60 PROF. EUTHERFOED AND M. VIGNAL. Action of Ooloctnth. Colocynth and jalap are substances whose action on the biliary secretion of the dog has already been investigated by Kohrig (Strieker's Jahrbucher, 1873, p. 240). According to that observer croton oil is a powerful cholagogue, and colo- cynth and jalap stand near it in importance. We have already pointed out the faultiness of Ebhrig's method, and have shown (this Journal, Vol. X. p. 259) that croton oil is scarcely worthy of being classed amongst cholagogues. It seemed therefore desirable that we should experiment with colocynth and jalap in order to have results comparable with our experi- ments on other substances. Experiment 39. Dog that had fasted 16 hours. Weight 26.3 kilogrammes. (Fig. 39.) Fig. 39. Secretion of bile before and after colocynth. 2 ce. bile and 2 cc. water injected into the duodenum at- 6. The same fluid with 7 grains of powdered colo- cynth pulp injected at c. The same dose repeated, at c'. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 61 Autopsy. — Gastric raucous membrane very vascular. The mucous membrane of the small intestine was intensely vas- cular throiighout its entire length. There was evidence of powerful purgation, — ^the small intestine containing 82 cc. of fluid. Experiment 40. Dog that had fasted 16 hours. Weight 16.3 kilogrammes. (Fig. 40.) Fig. 4Q. Secretion of bile before and after colocynth. 3 co. bile and 3 cc. water injected into the duodenum at c. The same repeated at c'. Autopsy. — There was increased vascularity throughout the whole length of the mucous membrane of the small intestine, especially marked in the upper part. There was considerable evidence of purgation. Composition of the Bile before and after Colocyrith, Table XIV. Experiment 89. Before. After. Water Bile-acids, pigments, cholesterin, fata Mucus Ash 92.99 5.49 0.90 0.62 94.13 4.70 0.70 0.47 100.00 100.00 Velocity of secretion per half- hour 3.4 cc. 6.35 cc. 62 PROF. RUTHERFORD AND M. VI6NAL. Table XV. Experiment 40. Before. After. Water Bile-acids, pigments, cholesterin, fats Mucus Ash 91.48 6.85 0.83 0.84 91.72 6.69 0.77 0.82 100.00 100.00 Velocity of secretion per half -hour 1.15 cc. 2.35 cc. These analyses show that colocynth renders the bile more watery, although it at the same time increases the secretion of the special biliary matters. In Exp. 40, the pulse became very weak towards the close of the experiment, and it may be that this weakness rendered the effect of the colocynth upon the liver less than it other- wise might have been. Be this as it may, we did not think it necessary to perform another experiment, for the first experiment with this substance may be regarded as sufficient. Eesults of the Experiments with Colocynth. — 1. Colocynth is a hepatic stimulant of considerable power. It renders the bile more watery but nevertheless increases the secretion of biliary matter. 2. It is also a powerful stimulant of the intes- tinal glands. Action of Jalap. Experiment 41. Dog that had fasted 17 hours. Weight 25 kilogrammes. (Fig. 41.) Autopsy. — The jalap had extended along about four-fifths of the small intestine, the mucous membrane of which was more vascular than usual, especially so at the lower part of the duodenum. The purgative effect was considerable — there being 64 cc. of fluid in the intestine. The fluid was of a very watery character. KXPEBIMENTS ON THE BILIARY SECRETION OF THE DOG. 63 ■Fig. 41. 1 Z J 1 6 D 7 Secretion of bile before and after jalap. 2.5 co. bile and 2.5 cc. water injected into the duodenum at b. 30 grains of jalap powder in the same fluid injected atj. Experiment 39. Experiment 40. Experiment 41. Secretion Secretion Secretion Secretion of bile per Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog : per 15". of dog : per hour. hour. hour. CO. CO. CO. 2.3 0.6 1.1 1.6 0.6 1.1 1.8 0.55 1.0 h 0.6 1.0 1.7 0.55 b 2.2 \ b 0.165 ec. 0.95 > 0.16 CO. 1.75 0.8 1.0 2.2 > 0.2908 CC. 0.75 1.05 1.5 1 c 1.0 c 0.9 j • 1.4 1.15 J 1.0 2.3 1.3 1.1 1.95 1.05 > 0.279 00. 1.15 2.0 1.05 ) 1.4 2.2 0.8 1.45 c' 1.1 1.6 2.55 1.15 1.5 2.2 1.1 1.65 2.5 C^ 1.4 2.5 \ 1.0 1.8 3.2 0.95 1.9 3.15 V 0.452 CC. 0.65 1.9 ) 3.05 2.45 I 0.6 0.8 1.8 1.9 > 0.296 CO. 1.5 1.05 1.8 ) 1.4 0.85 0.65 1.6 1.2 1.4 1.1 64) PROF. BUTHERFOED AND M. VIGNAL. Experiment 42. Dog that had fasted 20 hours. Weight 11.8 kilogrammes. (Fig. 42.) Fig. 42. Secretion of bile before and after jalap. 3 co. water and 2 cc. bile injected into tbe duodenum. 20 grains jalap powder in the Bame fluid injected at j, and again at /. Autopsy. — Profuse purgative action throughout the whole extent of intestine. Vascularity of mucous membrane of small intestine somewhat increased, most marked in the duodenum. The rapid fall in tbe bile-secretion towards the close of this experiment probably resulted from the purgation. It is to be noted that in Exp. 42, a, larger dose of jalap was given (40 grains) to a dog less than haK the size of the subject of Exp. 41. This is doubtless the cause of the greater effect on the liver and on the intestinal glands in Exp. 42. The effect of a still larger dose in a dog of nearly the same weight as No. 42 is instructive. (See Fig. 43.) Experiment 43. Dog that had fasted 22 hours. Weight 12.3 kilogrammes. (Fig. 43.) Autopsy. 20 cc. of fluid had been injected into the duodenum, much of which had probably been absorbed ; the small intestine, however, contained in its upper third 117 cc. of watery fluid, showing that a profuse purgative action was taking place. The jalap had extended along only a third of the small intestine. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 65 Fig. 43. e.s Secretion of bUe before and after jalap. 2 oc. bile and 3 oo. water injected into duodenum at 6. 20 grains jalap powder in the same fluid injected at j, f, and/'. The fall of the bile-secretion towards the close of the experiment is only another illustration of the fact often witnessed by us — that severe purgation diminishes the secretion of bile. Composition of the Bile before and after Jalap. Table XVI. Experiment 41. Before. After. Water Bile-acids, pigments, cholesterin, fats Mucus Ash 89.31 8.41 0.93 1.35 89.75 8.05 0.87 1.33 100.00 100.00 Velocity of secretion per half-hour 2.1 ec. 3.7 cc. Table XVII. Experiment 42. Before. After. Water Bile-acids, pigments, cholesterin, fats Mucus Ash 87.91 9.94 0.73 1.42 88.19 9.87 0.52 1.42 100.00 100.00 Velocity of secretion per half -hour 1.4 cc. 2.55 00. B. 66 PROF. BUTHEEFORB AND M. VIGNAL. EXPERIMENTS, &C. Experiment 42. | Experiment 43. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of (log : per 15". of dog : per hour. hour. cc. CC. 1.0 0.6 1.0 0.55 0.95 0.6 0.45 0.75 0.75 0.5 ^ 0.7 6 0.65 0.5 ■ 0.178 cc. b 0.6 0.65 0.6 0.85 J 0.55 \ 0.65 0.6 0.9 I 0.254 cc. 0.85 0.8 0.95 1 0.6 j 0.9 1.25 / 1.35 1.0 0.95 1.35 j 0.95 1.65 » 1.05 1.05 I 0.357 cc. 0.95 1.5 > 0.436 CO. ) 0.95 1.0 I 1.05 1.05 0.95 0.55 / r — 0.95 0.75 1.75 0.5 0.55 0.75 0.6 0.75 0.55 0.25 0.25 0.25 0.35 \ 0.4 0.35 I 0.113 cc. 0.3 ) Results of Experiments with Jalap. — 1. Jalap is a hepatic stimulant of considerable power. It renders the bile more 'watery, but at the same time increases the secretion of biliary matter. 2. Its effect on the liver is however far less notable than its effects on the intestinal glands. Its hydrogogue cathartic effects on these were fully manifested in these ex- periments. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. By Prof. Rutherfoed and M. ViGNAL. third series. Action of Sodium Sulphate. Works on Therapeutics generally make no mention of any cholagogue action of this substance. In the fourth edition of Garrod's Materia Medica, however, it is stated, that in addition to its action as a saline purgative it "probably influences the biliary secretion." Eayperiment 44. Dog that had fasted 19 hours. Weight 19,5 kilogrammes. (Fig. 44.) Fig. 44. Secretion of bile before and after sodium sulphate. 21 cc. water injected into duodenum at w. 60 grains sodium sulphate in 12 cc. water injected at s, and again at s'. Autopsy. Evidence of decided purgative action in small intestine, the mucous membrane of which exhibited a con- siderably increased vascularity. 5—2 68 PEOF. RUTHERFORD AND M. VIGNAL. Experiment 45. Dog that had fasted 20 hours. Weight 15.7 kilogrammes. (Fig. 45.) Fig. 45. 0.5 Secretion of bile before and after sodium sulpbate. 3 eo. bile and 5 cc. ■water — heated to ST'O. — ^injected into duodenum at b. 608 grains sodium sulphate — in the same fluid heated to ST'C, injected at s. Autopsy. Mucous membrane of whole length of small in- testine slightly reddened. The small intestine contained 147 cc. of clear fluid with greenish flakes ; thus affording evidence of a decided purgative effect. Results of Experiments with Sodium Sulphate. — Doses of 60 grains twice repeated (Experiment 44), and a single dose of 508 grains (Experiment 45), increased the biliary secretion Sodium sulphate is undoubtedly, therefore, a hepatic stimulant, but not of great power, for even in the second case the hourly secretion of bile per kilogramme of body- weight did not rise higher than 0.388 cc. per hour. The positive character of this result is important, because it is well known that the waters of Carls- bad have a cholagogue action, and although they contain in addition to sodium sulphate, sodium carbonate, sodium chloride, potassium sulphate, and small quantities of other substances, sodium sulphate is the principal salt, and to it the cholagogue action is doubtless chiefly due. Sodium sulphate, however, has for a considerable time been — in practical medicine — almost entirely superseded by magnesium sulphate, on account of its " more agreeable taste" EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 69 (Garrod) : we therefore performed the two following experiments to determine whether or not this substance is a cholagogue. Action of Magnesium Sulphate. Experiment 46. Dog that had fasted 17 hours. Weight 5.4 kilogrammes. (Fig. 46.) Fig. 46. 0.5 Secretion of bile before and after magnesium sulphate. 60 grains in 6 oc. water injected into duodenum at m, m' and m" (180 grains given in aU). Autopsy. Great purgative action in upper half of small intestine. Mucous membrane intensely reddened. Experiment 47. Dog that had fasted 17 hours. Weight 8.2 kilogrammes. (Fig. 47.) Fig. 47. Secretion of bile before and after magnesium sulphate. 60 grains in 12 co. water at m. 60 grains in 6 oc. water at m', m", m'", and 120 grains in la cc. water at m"", all injected into duodenum (360 grains given in all). Autopsy. Small intestine contained 90 cc. of fluid, whereas only 42 cc. had been injected. There was, therefore, evidence of decided purgation, and there was intense irritation of the mucous membrane in the upper half of the small intestine. 70 PROF. RUTHERFORD AND M. VIGNAL. Results of Experiments with Magnesium Sulplmte. — Experi- ment 46 — but especially experiment 47 — clearlyshow that, unlike sulphate of soda, magnesium sulphate has no cholagogue action. The curve in experiment 47 exhibits remarkably well the effect on the secretion of bile, produced by a substance that stimu- lates the intestinal glands, but not the liver. In such a case the biliary secretion is simply diminished. Experiment 46. Experiment 44. { Experiment 45. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog: per 15". of dog: pet hour. hour. cc. cc. 0.25 1.00 0.25 0.95 0.30 0.95 0.40 0.95 0.55 1 h 0.50 0.95 \ 0.50 w > 0.107 cc. 1.05 0.95 I 0.251 cc. 0.55 ' 1.00 ) 0.80 1.00 1.00 j 1.10 1.05 1.65 J. 0.266 cc. 1.05 1.15 1.50 I 1.25 0.65 1.40 1.00 1.45 s' 1.50 \ 0.60 1.30 j 1.60 1.55 y 0.388 cc. 1.40 1.50 > 0.279 cc. 1.45 1.55 I 1.25 I 1.45 1.35 1.50 1.45 1.55 1.35 • Secretion Secretion of bile per of bile per kilogramme 15". of dog: per hour. cc. 0.70 0.45 j 0.70 0.95 > 0.564 cc. 0.95 I 1.20 1.20 1.00 m 0.90 0.55 0.40 0.40 m' 0.30 0.40 0.45 0.65 \ 0.50 0.40 1 0.342 cc. 0.80 ) Action of Potassium Sulphate. Potassium sulphate is sometimes employed as a purgative agent, but no mention is made in the books, of its having any action on the liver. Dr "Wade of Birmingham, however, in- formed us that he finds this substance a cholagogue in man, EXPEUIMENTS ON THE BILIARY SECRETION OF THE DOG. 71 and at his request we tested by our method its action on the liver of the dog. Sxperiment 47. Secretion of bile per kilogramme of dog : per hour. Secretion of bile per 15". CO. 0.50 0.60 0.55 0.60 0.55 0.50 0.50 0.50 0.50 0.50 0.40 0.40 0.35 0.30 0.35 0.35 0.30 r 0.40 0.25 0.25 ■ 0.28 cc. 0.146 cc. Ssperiment 48. | Secretion Secretion of bile per of bile per kilogramme 15". of dog: per hour. ce. 1.45 1.40 1.35 1.40 1.32 6 1.32 1 1.32 1.40 I 0.315 cc. 1.32 1 1.40 1.32 1.40 1.42 1.20 1.52 1.42 1.35 1.40 1.42 1.35 1.42 1.20 1.35 1.20 145 1.27 1.37 1.17 1 1.22 1.10 \ 0.266 cc. 1.02 1 Experiment 49. Secretion Secretion of bile per of bile per kilogramme 15". of dog: per hour. cc. 1.80 1.90 1.70 ) 1.65 1.65 > 0.31C cc. 1.70 ) V 1.80 1.70 1.90 1.80 1.90 2.05 2.07 2.10 2.25 2.37 2.45 2.40 2.45 2.50 2.47 2.55 2.55 2.57 1 I 0.47 ec. 2.45 1 2.40 2.30 2.40 2.40 1 2.20 1.95 \ 0.352 cc. 1.20 1 Experiment 48, Dog that had fasted 17 hours. Weight 17 kilogrammes. (Fig. 48.) Autopsy. Small intestine contained 137 cc. greenish fluid with mucous flakes. The mucous membrane exhibited in- creased vascularity with small ecchymoses in its upper fourth. In this case, therefore, this substance irritated the intestine and produced purgation, but did not excite the liver. It was decided to give in the next case a larger dose. 72 PROF. RUTHERFORD AND M. VIGNAL. Fig. 48. Secretion of bile before and after potasBinm sniphate. 2 J cc. bile and 16 cc. ' water injected into duodenum at b. The same with 124 grains potassium sniphate heated to SfoC. injected at p. Experiment 49. Large dog that had fasted 17 hours. •weight unfortunately was not recorded. (Fig. 49.) Fig. 49. Its 0.6 Secretion of bile before and after potassium sulphate. 2| cc. bile and 35 cc. water injected into duodenum at b, the same with 142 grains potass, sulph. injected at s and again at i'. EXPERIMENTS ON THE BILIARY SECRETION OP THE DOG. 73 Autopsy. Small intestine contained 143 cc. watery fluid. The vascularity of the mucous membrane in the whole length of the small intestine was slightly increased. There being in this case evidence of a slight increase of the biliary secretion, another experiment was thought desirable. Experiment 50. 21.5 kilogrammes. Dog that had fasted 17 hours. Weight (Fig. 50.) Fig. 50. 0.6 Secretion of bile before and after 232 grains potassium sulphate dissolved in 32 cc. water at ZT>C and injected into duodenum at p. Autopsy. Increased vascularity of mucous membrane in whole length of small intestine. The small intestine contained 90 cc. clear brownish fluid with numerous mucous flakes. There was, therefore, evidence of considerable purgative action. Results of Experiments with Potassium Sulphate. — Experi- ment 50 clearly shows that potassium sulphate is undoubtedly a hepatic stimulant. The dose of 232 grains, given in this case to a full-sized dog, was just the maximum dose for a man. The negative effect of 124 grains in experiment 48, and the slight effect of 142 grains twice repeated in experiment 49, 74 PEOF. EUTHEEFORD AND M. VIGNAL. suggest that this substance is uncertain in its action on the liver. Regarding its action on the intestinal glands, however, there was no uncertainty, for its purgative effect was pronounced in all the three experiments. Possibly the sparing solubility of the salt may render its absorption into the portal vein uncer- tain. The bile given along with the salt in experiments 5 and 6 had probably nothing whatever to do with the result. The result of experiment 60 completely supports Dr Wade's opinion, that potassium sulphate is a cholagogue. Indeed, the amount of bile secreted per kilogramme of body-weight under its influ- ence in experiment 50 was greater than in either of the experi- ments with sodium sulphate (44 and 45). The apparent uncer- tainty, however, in the action of potassium sulphate must not be lost sight of. Action of Sodium Phosphate. Sodium phosphate is described in the text-books as a mild saline purgative; nothing being said about its action as a cholagogue. Professor Stephenson of Aberdeen, however, has found it specially useful for children when there is a deficiency of bile in the discharges {Edinburgh Medical Journal, 1867, Vol. XIII. p. 336). The dose as a purgative for a man is 120—480 grains. Experiment 51. Dog that had fasted 20 hours. Weight 26.9 kilogrammes. (Fig. 51.) Autopsy. Somewhat increased vascularity of mucous membrane of small intestine. Evidence of a very decided purgative effect: the contents of the small intestine being of a very watery character. Table XYIIL Composition of the Bile before and after Sodium Phosphate. Experiment 51. Before. After. Water Bile-acids, pigments, oholesterin, fats Mucus Ash 84.69 13.23 1.01 1.07 85.15 12.91 0.93 1.01 100.00 100.00 Velocity of secretion per half-hour 3.6 cc. 5.5 oc. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 75 Fisr. 51. o.s Secretion of bile before and after sodium phosphate. 77 grains in 15 cc. water injected into duodenum at s, and 124 grains in 25 cc. water injected at s'. Results of Experiments with Sodium Phosphate. — 1. This substance is undoubtedly a hepatic stimulant of very consider- able power. 2. Although it renders the bile more watery, it increases the amount of biliary matter secreted per unit of time. 3. While acting as a purgative, it irritates the intesti- nal mucous membrane very slightly. The results of experiment 51 were so satisfactory — both doses of the substance producing an effect — ^that it was thought needless to repeat it, as it confirms Dr Stephenson's observa- tions on the human subject, adding to these, however, the defi- nite knowledge that it has the power of actually increasing the flow of the bile, and that it does so by stimulating the hepatic cells. 76 PROF. RUTHERFOBD A^ND M. VIGNAL. Action of Rochelle Salt. Nothing is stated in the hooks regarding anj' cholagogue action of this substance. Its dose as a purgative for a man is from 120 to 240 grains. Eorperiment 52. Dog that had fasted 17 hours. Weight 5.2 kilogrammes. (Fig. 52.) Fig. 52. 1 0.6 Secretion of bile before and after tartrate of potash and soda. 10 cc. water injected into duodenum at w. The same with 60 grains Bochelle salt in- jected at r, )■', r", and r"' (2iO grains given in all). No autopsy. Considering the small size of this animal, the exciting effect of the salt on the liver was very remarkable, the secre- tion of bile per kilogramme of body-weight per hour being raised to 0.653 cc. The fall in the secretion towards the close of the experiment was doubtless owing to purgative action taking place. Experiment 53. Dog that had fasted 20 hours. Weight 12.5 kilogrammes. (Fig. 53.) Autopsy. Small intestine contained 130 cc. of a clear mucous fluid. Mucous membrane of small intestine exhibited a slightly increased vascularity. Results of Experiments with Rochelle Salt. — It is certainly a hepatic stimulant. Experiment 52 shows what a rapid secretion of bile it called forth in a liver that was nearly passive before it was given. The effect was by no means so remarkable in EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 77 Fig. 53. Secretion of bile before and after Bocbelle salt. 3 ec. bile and 55 cc. water heated to ST'G. injected iato duodenum at b. The same with 463 grains Bochelle salt heated to ST'G. injected at r. experiment 53, where the liver was relatively more active before the substance was given. Probably the latter affords a better general indication than the former, of the power of this substance as a cholagogue, and it must be remembered that in both cases, considering the size of the animals as com- pared with man, the doses were large ; so that, on the whole, it may be anticipated that observations on man— now that we specially direct attention to the matter — will show that this substance is a cholagogue, but not a powerful one. Action of Sodium Chloride. Sodium chloride is a cathartic when given in doses of 120 to 240 grains. It is not known to be a cholagogue, but as it is contained in considerable quantity in the mineral waters of Carlsbad, Ems, Friedrichshalle, that have a reputation in abnormal conditions of the liver, we thought it desirable to test its action on this organ. Escperiment 54. Dog that had fasted 18 hours. Weight 25 kilogrammes. (Fig. 64.) Autopsy. The small intestine contained 203 cc. of fluid, with numerous mucous flakes. As only 50 cc. of fluid had been 78 PUOF. RUTHERFORD AND M. VIGNAL. Kg. 54. 0.5 Secretion of bile before and after sodium chloride. 10 cc. water injected' into duodenum at w. The same with 120 grains sodium chloride injected at s, s', s", s'" (480 grains given in aU). injected, decided purgative action had taken place. The vas- cularity of the mucous membrane was slightly increased. Result of Experiment with Sodium Chloride. — Inasmuch as the first three doses of sodium chloride, amounting in the aggre- gate to 360 grains, produced scarcely any effect on the secretion of bile, it may be concluded that this substance is a very feeble hepatic stimulant. Another experiment did not appear to be required. Action of Sodium Bicarbonate. Experiment 55. 16.3 kilogrammes. Dog that had fasted 18 hours. (Fig. 55.) Weight Autopsy. The vascularity of the mucous membrane of the small intestine was slightly increased. The viscus contained 60 cc. of a greenish mucous fluid. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 79 Fig. 55. 1.6 Secretion of bile before and after sodium bicarbonate. 5 co. water and 2 cc. bile injected into duodenum at 6. The same with 31 grains sodium bicarbonate injected at s, s' and s". 15 cc. water with 2cc. bile and 124 grains sodium bicarbonate injected at s"' (217 grains given in all). Eayperiment 56. 19.9 kilogrammes. Dog that had fasted 18 hours. Weight (Fig. 56.) 0.5 Fig. 56. ■■H 9BH ^^■1 Secretion of bile before and after sodium bicarbonate. 5 cc. water and 2.5 cc. bile injected into duodenum at 6. The same with 64 grains sodium bi- carbonate injected at s, s', and s" (192 grains given in all). Result of Eosperiments with Sodium Bicarbonate. — ^la expe- riment 55, the amount of bile secreted per kilogramme of bodj- •weight during the first hour was 0.294 cc, during the seventh hour it was 0.287 cc; and during the last hour — after 217 80 PROF. EUTHEEFORD AND M. VIGNAL. grains sodium bicarbonate had been given, it was 0.341 cc. In experiment 56 the secretion during the first hour was 0.23 cc. per kilogramme of body- weight; during the fifth hour, when the secretion was at its height, it was 0.28cc. per kilo- gramme, 128 grains of sodium bicarbonate having been given. It is, therefore, evident, that this substance has scarcely any effect on the secretion of bile. Nevertheless, the slight effect perceptible in experiment 56 more especially, indicates an ex- citing influence on the liver, although an extremely feeble one. Experiment 51. Secretion of bile per kilogramme of dog: per hour. Secretion of bile per 15". cc. 2.05 2.07 1.90 1.90 1.80 1.80 1.70 1.90 1.80 1.95 2.07 2.15 2.17 2.17 2.20 2.27 2.25 2.40 2.40 2.30 2.60 lost. 2.70 2.80 2.90 2.95 3.15 3.05 2.30 2.57 ■ 0.278 cc. 0.448 CO. Experiment 52. Experiment 53. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog: per 15". of dog : per hour. hour. cc. cc. 0.25 ■v 0.75 0.15 0.70 w i 0.115 cc. 0.70 0.15 0.70 0.05 ) b r 0.75 1 0.25 0.30 0.80 0.70 ■ 0.236 cc. 0.35 0.70 r- r 0.35 0.75 0.50 0.70 0.60 0.70 r" 0.80 0.80 \ 0.90 1.00 0.85 r"' } 0.653 cc. 0.90 1.00 I 0.95 0.60 J 0.85 0.50 0.85 0.50 1.00 ) 0.55 0.35 1.05 1.00 1.10 1.00 0.90 1.00 0.90 0.70 V 0.332 cc. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 81 Action of Potassium Bicarbonate. Eocperhnent 57. Dog that had fasted 18 hours. Weight 19.3 kilogrammes. (Fig. 57). Secretion of bile before and after potassium bicarbonate. 31 grains in 8 cc. water injected into duodenum at p, p', and p". 108 grains in 8 cc. water injected at p'". (201 grains given in all. ) Autopsy. — 53 cc. of a clear brownish fluid, with numerous mucous flakes in small intestine. Vascularity of mucous mem- brane considerably increased. Result of Eocperiment with Potassium Bicarbonate. — 201 grains of this substance increased the secretion of bile but not to a great extent, for the bile-secretion per hour did not rise higher than 0.384 cc. per kilogramme of body-weight. Seeing that 31 grains produced no effect, it may be safely inferred that the dose of 10 or 15 grains often taken by a man does not appre- ciably affect his biliary secretion. Action op Iodide of Potassium. Potassium iodide is sometimes administered in hepatic affections, in the hope that it may produce an "alterative" 82 PEOF. RUTHERFORD AND M. VIONAI,. effect. On that account it seemed desirable to ascertain whether or not it affects the biliary secretion. Experiment 58. Dog that had fasted 18 hours. "Weight 17 kilogrammes (Fig. 58). — 10 grains of potassium iodide in 3 cc. of water were injected into the duodenum at^, 20 grains atp', and 30 grains at p". There was no increase of secretion, but, Fig. 58. Secretion of bile before and after potassium iodide. At jj 10 grains, at p' 20 grains, and at p" 30 grains in 3 cc. of water injected into the duodenum. on the contrary, a rather greater fall than is usually observed in a normal case. A repetition of the experiment was therefore necessary. Necropsy. — 54 cc. of a thick yellowish mucous fluid found in the small intestine, thus affording evidence of a slight purgative action. Experiment 68a. Dog tha;t had fasted 19 hours. Weight 16.9 kilogrammes (Fig. 58a).— 6 grains of potassium iodide in 2 cc. of water were injected into the duodenum at p, 10 grains in 2 cc. of water atp', 20 grains in 5 cc. of water aty, 30 grains in 5 cc. of water at p'", and 40 grains in 8 cc. of water at/'". The trifling increase of secretion after the second and fourth doses may be discarded, and the fall of secretion as the experiment advanced might very probably have been equally marked had nothing been given. Necropsy. — Small intestine contained 25 cc. of a clear mucous fluid, indicating a slight purgation ; for, though 22 cc. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 83 of water had been injected, much of it had doubtless been absorbed. Residt, of Experiments with Potassium Iodide. — This substance does not appear to affect the biliary secretion. Fig. 68a. Secretion of bile before and after potassium iodide. At ^ 5 grains in 2 cc. of water, at p' 10 grains in 2 cc. of water, aty 20 grains in 5 cc. of water, at p'" 30 grains in 5 cc. of water, and at p"" 40 grains in 8 cc. of water, injected into the duodenum. Action op Ammonium Chloride. According to Garrod {Op, viii. p. 51), chloride of ammonium is " by some considered a cholagogue." The most valuable evidence which we have regarding the action of this substance is that furnished by Dr Stewart of Brecon {Op. ix.). The large experience in the treatment of hepatic affections acquired by Dr Stewart in India has led him to regard ammonium chloride as an invaluable agent in the treatment of active hepatic congestion, chronic hepatitis, and in " torpor of the liver," associated with congestion of the organ and lithsemia. Many such cases he has seen cured by from ten to twenty grain doses, given twice or thrice daily, with attention to diet, rest, and such other general indications. The drug produces diuresis, a sensation of warmth beginning in the epigastrium and 84 PEOF. KUTHEKFOED AND M. VIGNAL. gradually extending over the whole body, diaphoresis, exhilar- ation of the nervous system, and an undoubted effect on the liver, as shown, not only by gradual disappearance of the symptoms referable to hepatic congestion, but by other and more immediate signs, "peculiarly and directly referable to the liver and related parts." Thus, within from five minutes to half an hour after a dose of the salt, the patient may experience one or more " shocks " as of " something giving way," or a " pricking " or " gnawing " sensation in the hepatic region. In addition to these symptoms a full dose increases intestinal peristalsis, " as evidenced by the twisting and other movements experienced in the situ- ation of the duodenum, or all over the abdomen, and which, at times, are more sensibly felt in the situation of the umbilicus, or in the inguinal region. The abdominal muscles may also be thrown into tonic contractions, which are perceptible at times to both sight and touch." " Torpor of the liver," and functional derangements attended by Hthsemia (Murchison), associated with congestion of the liver, want of sleep, and depression of spirits, are benefited in a remarkable manner by a course of ammonium chloride, with careful attention to diet and regimen. In such cases, he has known a few twenty-grain doses of the salt " remove symptoms of disordered liver, restore sleep, and revive the drooping spirits, after the failure of other remedies." Dr Stewart, however, nowhere says that he ever observed any cholagogue effect of this remedy. Experiment 59. -Dog that had fasted 18 hours. Weight 7 kilogrammes (Fig. 59). Fig. 59. Secretion of bile before and after ammonium chloride. 6 cc. water injected into duodenum at w. The same with 6 grains ammonium chloride, injected at a, and again at a' and a" (18 grains given in all). Necropsy. — Small intestine, in nearly its whole length EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 85 contained a large quantity of a very watery fluid. The vascu- larity of the mucous membrane was only slightly increased. Experiment 59a. Dog that had fasted 20 hours. Weight 13.7 kilogrammes (Fig. 59a). Necropsy. — Somewhat increased vascularity of the mucous Fig. 59a. Secretion of bile before and after ammonium chloride. J cc. bile and 5 cc. water injected into duodenum at J. The same with 10 grains ammonium chloride injected at a. At a' the same with 20 grains, at a" the same with 40 grains, at a'" the same with 60 grains. membrane of the upper three-fourths of the small intestine. There was evidence of a moderate purgative effect. Result of Experiments with Ammonium Chloride. — The two experiments with this substance show that doses capable of stimulating the intestinal glands did not excite the liver. The effect on the biliary secretion is comparable to that of sulphate of magnesia (p. 69), or other substances having a stimulant effect on Lieberkiihn's glands, but not on the liver. In proportion to the body-weight, the doses we gave to the dog were greater than those given to man, and therefore it need not be expected that, in the doses recommended by Dr. Stewart, a purgative effect should be observed in man. Inasmuch, therefore, as these experiments give no evidence of any stimulant action of this substance on the liver, and seeing that in the human subject also there is no certain evidence of its having any direct cholagogue action, one is led to ask whether the effects observed by Dr Stewart, in cases of chronic hepatic torpidity, may not have been the result of some indirect action on the liver, due to a slight but prolonged increase of the intestinal secretion, or to some effect on the system generally. Our experiments supplement Dr Stewart's observations, and plainly narrow the range of speculation in searching for a rational theory of the action of the drug in hepatic congestion. 86 PKOF. BUTHBKFOKD AND M. VIGNAL. Action of Niteo-hydeochloric Acid. The dilute nitro-hydrochlorio acid employed by us was pre- pared by mixing 3 cc. nitric acid with 4 cc. hydrochloric acid, and, after an interval of twenty-four hours, adding 25 cc. water {British Pharmacopoeia). The dose for a man is from 5 to 20 minims. The employment of this substance in hepatic disorder was first recommended by Dr Scott of Bombay, who used it largely in congestion of the liver. It was administered as a foot-bath, and also internally. Its effects, however,, were by some held to be so doubtful, that its use appears to have been abandoned for a time (Christison, Op. xii. p. 41). Annesley, Martin, and others — experienced in the diseases of India— have, however, supported the opinion held by Scott. Wood (Op. xi, p. 88) maintains, from his own observation, that it increases the flow of the bile. Bxperiment 60. A small dog (weight not ascertained) that had fasted 17 hours (Fig. 60). — 20 cc. water injected into Fig. 60. Secretion of bile before and after nitro-hydroehlorio acid. 20 cc. water injected into duodenum at a. The same with 20 minims dilute nitro-hydrochloric acid injected at b, c, d, and e. duodenum at a. The same with 20 minims dilute nitro-hydro- chloric acid injected at b, o, d, and e. Neceopsy. — The duodenal mucous membrane was slightly congested. There was no evidence of purgation. Experiment 60a, Dog that had fasted 17 hours. Weight 17-7 kilogrammes (Fig. 60a). — 40 minims dilute nitro-hydro- chloric acid in 8 cc. water injected into duodenum at a, and again at a'. EXPERIMENTS ON THU BILIARY SEOKETION OF THE DOG. 87 Neceopsy. — There was slight congestion of tlie upper part of the small intestine to the extent of about 10 inches. lu the Experiment 60a. Secretion Secretion Secretion of bile ])er Secretion of bile per of bile per kilogramme of bile per kilogramme 15" of dog ; per 15". of dog : per hour. hour. ce. oc. 0.55 \ 1.60 0.40 0.50 [ 0.117 cc. 1.40 1.50 . 0.65 a ' 2.20 1.72 V 0.392 cc. 1.00 1.62 ) 0.95 c 1.45 1.05 a' 1.10 1.50 1.40 1.35 1.45 0.95 1.55 FiK 60a. Secretion of bile before and after nitro-hydrochlorio acid. 40 minims dilute uitro-hydrochloric acid in 8 cc. of water injected into duodenum at a, and again at a'. duodenum the mucous membrane had a yellowish-grey appear- ance, as if it had been slightly corroded by an acid. There was no evidence of any purgative effect. 88 PROF. RUTHERFOUD AND M. VIGNAL. Results of Experiments with Nitro-hydrocMoric Acid. — The positive effect of the acid in Experimeut 60a is in remarkable contrast to the negative result observed in Experiment 60. In consequence of the positive result in the former case, and seeing that it completely agrees with observations on man, we did not think it necessary to perform another experiment. In view of the positive effect in 60a, we do not attach any importance to the negative result of Experiment 60 ; for the animal was a small one, and in such cases we have found that undoubted cholagogues sometimes faU to act, probably because of the effect of the shock of the operation on the liver. Strong dogs of con- siderable size should always be selected for such experiments. Experiment 60a shows that dilute nitro-hydrochloric acid is a hepatic stimulant of considerable power. EXPERIMENTS ON THE BILIAEY SECEETION OF THE DOG. By Prof. Eutherfoed, assisted by W. J. Dodds, M.B., D.Sc. fourth series. Action of Physostigma. Since the well-known researches of Sir Eobert Christison and Professor Eraser, the physiological actions of Calabar bean have been made the subject of extensive inquiry ; its action on the liver has not, however, hitherto been investigated, owing to the want of a reliable method of experiment. As stated by Pro- fessor Eraser, this agent excites the salivary, intestinal, and lachrymal glands ; and at his request we performed the follow- ing experiments on the liver. The extract of Calabar bean of the British Pharmacopoeia was the preparation employed, the maxi- mum dose of which for the human subject is a quarter of a grain. Experiment 61. Dog that had fasted 18 hours. Weight 26.7 kilogrammes (Fig. 61). — 1 grain extract of Calabar bean triturated with half cc. of bile, half cc. of rectified spirit, and 5 cc. of water, was injected into the duodenum at c, and the same dose was given again at c'. The increased secretion of bile was decided and prolonged after the second dose. The bile and alcohol were employed merely to promote absorption of the active principle ; and it may be safely assumed that none of the effect was directly due to either, for it has been already stated that 2 cc. or 3 cc. of bile introduced into the duodenum does not notably affect the biliary secretion ; and it will be shown that a much larger quantity of alcohol than was given in this case has also no effect (Experiments 74a and 74b). Although the antagonism between the atropia and physo- stigma has been abundantly proved by Eraser, Arnstein, Heiden- hain, and others, it was nevertheless deemed desirable to definitely ascertain whether or not, in the case of the liver, this antagonism also obtains ; accordingly, four-fifths of a grain of atropia sulphate, dissolved in 3 cc. of water, was injected into the duodenum at a. The effect being somewhat doubtful, three- fifths of a grain dissolved in 3 cc. of water was injected into the 90 PROF. KUTHEEFOED AND DE. DODDS. Fig. 61. Secretion of bile before and after Calabar bean anil atropia. 1 grain extract Calabar bean witb J ec. bile, J cc. rectified sp'rit, and 5 cc. water, injected into duodenum at c, and again at c' ; ftlis grain atropia sulphate injected into duodenum at a ■ f tils grain into jugular vein at a'. Experiment 61. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogi-amme of bile per kilogramme 15"; of dog : per 15". of dog : per hour. hour. cc. cc. 0.70 2.50 . 0.90 2.40 I 0.305 cc. 0.65 0.55 V 0.098 cc. 2.16 2.40 0.70 0.60 2.20 1.75 0.80 2.00 c a 0-75 1.90 0.65 1.80 0.85 1.90 1.10 1.65 1.60 a' — — 1.30 1.20 1.35 0.60 li.90 0.90 •\ 0.75 c' 0.50 0.70 1 0.098 cc. 1,95 0.55 ) 2.05 EXPEKIMEWTS ON THE BILIAKY SECRETION OF THE DOG. 91 jugular vein. The bile-secretion speedily fell, and it is evident from the chart that within half an hour after the administration of the second dose the effect of the physostigma had entirely disappeared. Necropsy. — There was decided irritation of the duodenal FiL'. 6lA. Secretion of bile before and after Calabar bean, atropia, and lead acetate. 2 grains extract of Calabar bean with 1 cc. of bile and 5 cc. of water injected into the duodenum at c; ^i grain extract, with same, at c' ; 2 gi-ains extract, with same, at c"; ^ths of a gi-ain of atropia sulphate in 4 cc. of water injected into the jugular vein at a ; |ths of a grain at a'; 8 grains of lead acetate in 20 cc. of water injected into the duodenum at I. mucous membrane to the extent of 8 inches below the pylorus. Evidence of only slight purgative action was found in the small intestine. Experiment 61a. Dog that had fasted 18 hours. Weight 92 PROF. EUTHEEFORD AND DR. DODDS. 13.6 kilogrammes (Fig. 61a).— Two grains of the extract of Calabar bean, triturated with 1 cc. bile and 5 cc. water, were injected into the duodenum at c. The stimulating effect on the Experiment 61a. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog : per hour. hoar. cc. 00. 0.35 1 0.65 \ 0.45 0.50 1 0.138 CO. 0.50 0.15 1 0.121 cc. 0.60 j 0.35 3 L c c' 1.10 1.35 2.00 0.85 1.75 1 0.753 CO. 0.75 1.90 1.05 2.70 1.10 c" 1.30 4.00 3.05 1.15 1.95 1.25 1.45 1.10 1.00 I 0.95 1.35 1.05 0.25 a' 0.00 liver was rapid and very powerful. Four-fifths of a grain of atropia sulphate, dissolved in 4 cc. water, was injected into the jugular vein at a. This was done just five minutes before the next reading of the bile. It is, therefore, certain that much of the bile that formed the highest reading in the experiment was secreted previous to the injection of the atropia; and, as atropia did not increase the secretion in the preceding experi- ment, it follows that the very high reading of the bile immedi- ately subsequent to the atropia administration is to be attributed to the action of the physostigma not yet antagonised. Ere long, however, the atropia asserted its influence and antagonised the physostigma. At a', three-fifths of a grain of atropia sulphate was again injected into the jugular vein, and it is evident from the chart that the physostigma was completely antagonised thereby. A continuation of the experiment was, perhaps. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 93 scarcely necessary ; still a grain and a half of Calabar extract triturated with 1 cc. bile and 5 cc. water, was injected into the duodenum at c', and two grains of the extract similarly treated were injected at c". The exciting effect was not very marked; nor need this be wondered at, considering how powerfully the liver had been previously stimulated, and its partial exhaustion induced not merely owing to the above cause, but also owing to the duration of the experiment. As the action of acetate of lead on the liver was to be investi- gated, eight grains of that substance, dissolved in 20 cc. of water, were injected into the duodenum at /, and the secretion of bile soon thereafter came to a standstill. Subsequent experi- ments show that this effect was unusual and attributable to the depressant effect of the lead on a liver already well-nigh exhausted. Necropsy. — Great irritation of the mucous membrane of the small intestine to the extent of about fifteen inches below the pylorus. The viscus contained only slight evidence of purgative action. Result of Experiment with Physostigma. — The relation of the dose to the size of the animal, and the coefficients of the secretion before and after its administration, are stated in Table XIX. Table XIX. Physostigma. Total Dose in Grains. Grains per Kilogramme of Body-weight. Secretion of Bile per Kilogramme of Body- weight per hour. Before. After. Experiment 61, . Experiment 6lA, . 2 with bile 2 „ 0,0074 0,0147 0,098 cc. 0,138 cc. 0.365 cc. 0.753 cc. It is interesting to observe that in Experiment 61a the dose, which, in relation to the size of the animal, was twice as great as in Experiment 61, raised the coefficient of secretion to a little more than twice the figure attained in Experiment 61, showing 94 PROF. RUTHERFORD AND DR. DODDS. forcibly the precision of the experimental method employed. The high coefficient in Experiment 61a indicates a very powerful effect ; yet, since the dose employed was four times the maximum dose for a man, and seeing that one grain produced only a trifling effect in Experiment 61, it may be inferred that, in the human subject, physostigma will probably be found to have, in the relatively small doses administered, an insignificant effect on the liver ; for many of the preceding experiments have demonstrated that, when the same dose of a substance that powerfully excites the human liver is given to an average-sized dog, it powerfully excites its liver. It is an error to suppose that the dog requires much larger doses of all drugs than are necessary for the human subject. The effect of physostigma on the liver is completely antagonised by atropia svilphate. Prevost of Geneva, in a communication to the Paris Academy of Sciences (August 3, 1874), states that muscaria increases the biliary secretion, and that atropia checks the hypersecretion due to muscaria. Action of Atropia. It is known that atropia causes purgation and diuresis in dogs {Op. viii. p. 322). On the other hand, it paralyses the chorda tympani and the secretory nerves of the sweat and milk glands, and thereby arrests their secretions. It therefore seemed desirable to give atropia previous to the administration of any other substance, in order to determine its influence on the liver. Experiment 62. Dog that had fasted 18 hours. "Weight 16.1 kilogrammes (Fig 62). — In this experiment the secretion of bile rose at the end of the first hour, although no drag had been administered. Our previous experiments have convinced us that this is due to reaction, which is apt to ensue unless great care is taken to pull as little as possible at the bile-duct during the operation for inserting the cannula. Half a grain of atropia sulphate, dissolved in twenty minims of water, was injected into the jugular vein at a, a\ a", and a'" ; and one grain was injected at a"". Thus three grains were given in all. The fall of secretion after the first dose may be EXPERIMENTS ON THE BILIARY SKCRliTION OF THE DOG. 95 discarded, as it would probably have taken place had no atropia been given. It is evident that the atropia does not arrest the secretion of bile as it does that of saliva, sweat, and milk. Nor Fig. 62. Secretion of bile before and after atropia sulpliate, lead acetate, and sodium salicylate. -^ grain of atropia sulphate in 20 minims of water in- jected into jugular vein at«, a!, a", and a"'; 1 gr.ain injected into vein at a'"'; 10 grains of lead acetate in 20 cc. of warm water injected into the duodenum at Z ; 25 grains of sodium salicylate in 25 oc, of water injected into the duodenum at s. can it be said to augment it; for the increased secretion that followed the third dose is trivial, and may be discarded in view of the sequel to the second dose in Experiment 61a. Ten grains of acetate of lead, dissolved in 20 cc. of tepid water, were injected into the duodenum at /, without producing any notable effect. Having, in other experiments — mentioned in the sequel — discovered that the alkaline salts of benzoic acid are powerful hepatic stimulants, I suspected that the alkaline salts of salicylic acid would be found to have a similar action. Accordingly, twenty-five grains of sodium salicylate, dissolved in 25 cc. of 96 PEOF. EUTHllRFORD AND DR. DODDS. water, were injected into the duodenum, and within half an hour a very rapid secretion of bile had begun ; and this, notwith- Experiment 62. Secretion '\ Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15." of dog : per 15". of dog : per hour. hour. CO. cc. 0.65 0.75 0.50 0.80 0.60 0.90 0.60 a!" 1.00 1.05 1.30 1.00 1.55 a"" 1.45 1.00 1.50 1.00 1.35 1.10 I 0.95 a, 1.20 0.70 1.05 ~\ 0.55 0.60 1.10 0.95 I 0.260 cc. 0.60 1.10 3 0.65 s a' 1.50 0.60 2.75 1 0.70 a" 2.90 2.60 2.45 1 0.664 cc. standing the previous administration of lead acetate and three grains of atropia sulphate. Result of Eoaperiments with Atropia — Atropia sulphate does not paralyse the hepatic cells, neither does it appear to excite them. Whether or not it possesses the power of paralysing the hepatic secretory nerves is doubtful ; but, seeing that it antago- nises the effect of physostigraa on the liver, and remembering the actions of these substances on the nerves of the heart and salivary glands, the suspicion is entertainable that physostigma stimulates the hepatic cells through a nervous apparatus that is affected in an opposite sense — possibly paralysed — by atropia ; while the hepatic cells, and perhaps some nervous mechanism like the motor ganglia of the heart in close relation to them, are unaffected by atropia. EXI'ERIMENTS ON THE BILIARY SECRETION OF THE DOG, 97 Action of Eesina Menispermi or " Menispermin." The substance termed menispermin by Keith & Co. of 41 Liberty Street, New York, is derived from the root of the yellow parilla {Menispermum canadense). Messrs Keith have informed me that the crude root of the plant is dried, crushed, and perco- lated with alcohol. The alcohol is then evaporated or distilled off, leaving the active principles in the form of an extract, which is then " freed from impurities," dried, and pulverised. How it \a freed from impurities is not stated. This is also the manner in which they prepare baptisin, phytolaccin, hydrastin, and jug- landin — substances whose actions are described in the sequel. Menispermin is stated by Keith (Op. xiv.) to be " alterative, tonic, laxative, diuretic, stimulant, and resolvent, and to be useful in hepatic torpor, indigestion," &c. On this account, we experimented with it on the liver ; but we probably would not Expeiiment 63. Secretion of bile per 15". cc. 1.65 2.00 1.95 1.80 1.55 1.45 1.40 1.30 1.25 1.05 1.30 Secretion of bile per kilogramme of dog : per hour. .0.311 cc. 0.233 cc. Secretion of bile per 15". cc. 1.40 1.35 1.35 1.50 1.65 1.95 2.10 3.00 2.05 1.95 1.75 Secretion of bile per kilogramme of dog : per hour. 0.233 cc. • 0.394 cc. have taken the trouble had we at the time been aware of the account given of its effects by Wood and Bache (Op. x. p. 1555). In that account the root is said to be a gently stimulating tonic, probably very closely allied to calumba, which also belongs to the Menispermaceae. The medium dose of Keith's menispermin for a man is two grains. Experiment 63. Dog that had fasted 18 hours. Weight 7 R. 98 PHOF. RUTHEEFOED AND DE. DODDS. 23.1 kilogrammes (Fig. 63).— Seven grains of menispermin, triturated with 1.5 cc. of bile and 3 cc. of water, were injected Fig. 63. Secretion of bile before and after menispermin and baptisin. 7 grains of menis- permin in 1-5 cc. of bile and 3 cc. of water injected into the duodenum at m ; 7 grains of baptisin in 2 cc. of bile and 3 cc. of water injected at b. into the duodenum at m; and, as no obvious effect ensued, seven grains of baptisin, similarly treated, were injected into the duodenum at b. The secretion of bile thereafter speedily rose. The result was evidently somewhat equivocal, and therefore another experiment, in which menispermin was alone given, was performed. Necropsy. — The duodenal mucous membrane showed only one slightly reddened patch. There was but scanty evidence of purgative action, for the upper part of the small intestine con- tained only 35 cc. of fluid ; but whether due to a purgative action of the menispermin, or of the baptisin, could not be apparent from this experiment. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 99 Experiment 63a. Dog that had fasted 17 hours. "Weight 15.7 kilogrammes (Fig. 63a).— Two cc. of bile and 2 cc. Experiment 63a. Secretion Secretion of bile per kilogramme of Secretion Secretion of of bile per 15". of bile per 15". bile per kilogramme of dog : per hour. dog : per hour. cc. cc. 1.4 m' 1.4 1.30 1.3 1.25 1.4 ^ 1.15 \ b 1.4 0.34 cc. 1.25 1.30 [ 0.315 cc. 1.3 1.25 \ 1.25 J m" m 1.30 *■ , 1.25 1 15 1.20 1.16 \ 1.25 1.30 1.25 1.05 [ 0.287 cc. 1.15 1.05 ' of water were injected into the duodenum at h. This producing no perceptible effect on the secretion, five grains of menisperniin Fig. 63a. Secretion of bile before and after menispermin. 2 cc. of bile and water injected into the duodenum at b ; the same, with 5 grains of menispermin, injected at TO, and again at m' ; the same, with 10 grains injected at m". were triturated with the same amount of bile and water, and injected into the duodenum at m ; and the same dose was 100 PROF. RUTHEEFOED AND DR. DODUS. repeated at m'. The secretion remaining unaffected, ten grains with bile and water, as before, were injected at m". The bile- secretion was remarkably constant, and the experiment clearly proved that this substance, even in large doses, does not excite the liver ; and that the rise of secretion observed in Experiment 63 could not be ascribed to the menispermin. Indeed, the chart of this experiment (Fig. 63a) simply shows the normal curve of bile-secretion in a fasting animal. Necropsy. — ^The mucous membrane of the upper third of the small intestine was slightly reddened, and there was evidence of decided purgative action ; for, while only 16 cc. of fluid had been injected, the small intestine contained 170 cc. of yellowish fluid containing much mucus. Result of Experiments with Menispermin. — This substance is an intestinal, but not a hepatic, stimulant. Action of.Eesina Baptisi^?? or "Baptisin." The substance termed "baptisin" is an impure resin prepared from the root of the wild indigo plant (Baptisia tiToctoria) after the same manner as menispermin. The specimen employed in these experiments was obtained from Keith & Co. of New York. The root of this plant is said to bea powerful emetic and cathartic in large, and a mild laxative in small, doses. Stevens of Pennsylvania recommends a decoction of the root in epidemic dysentery. It is said to have proved useful in scarlatina, typhus fever, and in that state of the system that attends morti- fication (fip. X. p. 1469). Tlie physiological actions of this plant have apparently not been investigated, and it is nowhere stated that it is a cholagogue. The dose of baptisin for a man is from one to five grains. In Experiment 63 it has already been shown that baptisin increases the biliary secretion ; but, as in that experiment its administration followed that of menispermin, it was desirable to give baptisin first in another experiment. Experiment 64. Dog that had fasted 17 hours. "Weight 18.7 kilogrammes (Fig. 64).— Seven grains of baptisin triturated with 2 cc. of bile and 5 cc. of water were injected into the duo- EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 101 denum at 6. In half an hour its stimulating effect on the liver was perceptible, and in the course of an hour it became very evident. Experiment 64. Secretion of bile per Secretion of bile per kilo- Secretion of bile per 15". Secretion of bile per kilo- 15" gramme of gramme of dog: per hour. dog: per hour. nc. cc. 0.75 1.30 0.296 cc. 0.80 1.25 0.55 I 0.60 1.15 0.75 \ 1.15 0.65 0.45 [o.l20ce. 0.95 0.75 0.40 ) 0.85 b 0.65 0.45 V 0.50 - 0.55 0.75 0.50 \ 1.35 ) 0.45 1.45 > 0.296 cc. 0.40 > 0.098 cc. 1.45 i 0.50 ) As this result confirmed the observation made in Experiment 63 no more baptisin was given. Fig. 64. Secretion of bile before and after baptisin and lead acetate. 7 grains of baptisin, with 2 cc. of bile and 5 cc. of water, injected into the duodenum at ft ; 8 grains of lead acetate in 15 cc. of water injected at ^ ; 12 grains in 25 cc. of warm water at V. With a view to follow up the observations made with lead acetate in Experiments 61a and 62, eight grains of lead acetate 102 PROF. HUTHEKFOKD AND DE. DODDS. dissolved in 15 cc. of water were injected into tlie duodenum at I, and 12 grains of the same in 25 cc. of tepid water were injected at I' into the lower part of the small intestine. The result was equivocal, in so far as the secretion of bile would doubtless have diminished had no lead been given. The experi- ment is, therefore, decisive as regards the action of baptisin, but inconclusive as regards that of lead. Necropsy. — Considerable redness of the mucous membrane of about 15 inches of upper part of small intestine. Slight evidence of purgative action. Bssult of Experiments with Baptisin. — The two experiments with this substance prove it to be a hepatic stimulant, and Table XX. indicates its power as such. Table XX. Baptisin. Total Dose in Grains. Grains per Kilogramme of Body- weight. Secretion of Bile per KUogramme of Body-weight per hour. Before. After. Experiment 63, . Experiment 64, . 7 with bile, 7 ,. 0.303 0.374 0.233 CO. 0.120 cc. 0.394 cc. 0.296 CC. Taking into account the fact that in Experiment 64 the coefficient of bile-secretion did not rise higher than 0.296 cc, when nothing but baptisin had been administered, and at the same time the dose being relatively larger than in Experiment 63, it may be concluded that this substance is a hepatic and also an intestinal stimulant of moderate power, and it may pos- sibly be found of service as a hepatic stimulant in cases of torpid liver with a depressed condition of the system tending to gangrene. We commend it to the attention of the physician. Action of Eesina Phytolacca or " Phytolaccin." The poke-plant {Phytolacca decandra) grows abundantly in the United States. The root is the part employed; and in small KXPEKIMENTS ON THE BILIARY SECKETION OF THE DOG. 103 doses it is said to act as an alterative, and has been highly recommended in chronic rheumatism. In large doses it pro- duces excessive vomiting and purging, with great prostration of strength, and sometimes with convulsions {Op. x. p. 646). The preparation employed by us was a substance termed " phyto- laccin," prepared from the root of the plant by Keith & Co. of New York, after the same manner as menispermin (p. 97). The dose for a man is from one to three grains. The physiological actions of the phytolacca have not hitherto been investigated. Hxperitmnt 65. Dog that had fasted 18 hours. Weight Experiment 65. Secretion of bile per 16" Secretion of bUe per kilogramme of Secretion of bile per 15". Secretion of bile per kilogramme of dog: per hour. dog: per hour. cc. cc. 1.10 2.00 { 0.244 cc. 0.85 a 0.90 1.80 1.10 ^ 2.25 1.30 1.20 •0.144 cc. a' 1.90 P J 2.20 1.45 2.30 1.55 a" 1.65 2.40 1.85 2.35 ~ 1.85 1.90 a'" 2.35 U.299 cc. 1.90 1.90 0.244 cc. 2.30 31.1 kilogrammes (Fig. 65.) — Two grains of phytolacciu triturated with 2 cc. of bile and 4 cc. of water were injected into the duodenum at p. The subsequent excitement of the liver was unequivocal. When the increase of secretion was well declared, one-tenth of a grain of atropia sulphate dissolved in ten minims of water was injected into the jugular vein at a, and again at a', a", a'" — in all four-tenths of a grain ; but the stimulating effect of the phytolaccin was not antagonised thereby. Had this experiment been performed after instead of before Experiment 61, a larger dose of atropia would have been given. Eemember- 104 PROF. RUTHEEFOKD AND DR. DODDS. ing the non-exciting effect of atropia on the liver, the high secretion at the close of the experiment may be safely referred to the continued action of the phytolaccin. Fig. 65. 0..5f Secretion of bile before and after phytolaccin and atropia. 2 grains of phytolaccin in 2 CO. of bile and 4 cc. of water injected into the duodenum at p ; 1-lOth of a grain of atropia sulphate injected into the jugular vein at a, a', a", and a'". Necropsy. — The duodenal mucous membrane was slightly reddened, but there was no evidence of purgative action worthy of mention. Experiment 65a. Dog that had fasted 17 hours. Weight 19.2 kilogrammes (Fig. 65a). — Two cc. of bile and 2 cc. of water were injected into the duodenum at h, and 2 grains of phytolaccin triturated with the same fluids were injected at p. A consider- able increase of bile-secretion ensued. Owing to the high secretion previous to the administration of the drug, the result is less striking than in the preceding experiment; yet, in this case the coefficient of secretion was much higher than in the former experiment (Table XXI), a circumstance which was pro- bably largely due to the fact that, while the same dose was given in both cases, the subject of Experiment 65a was much smaller EXPEKIMENTS ON THE BILIARY SECRETION OF THE DOG. 105 than that of Experiment 65. The liver of dog 65a was, there- fore, more powerfully affected than that of dog 65. Experiment 65a. Secretion of bile per 15". Secretion of bile per kilogramme of Secretion of bile per 15". Secretion of bile per kilogramme of dog : per hour. dog : per hour. CO. cc. 1.65 2.30 1.60 2.20 1.60 \ 2.15 1.65 2.25 6 y 0.338 cc. 2.15 1.60 ( 2.30 [-0.471 cc. 1.65 P ; 2.20 2.25 1.55 2.30 1.75 2.15 1.90 2.10 1.80 1.60 1.80 1.95 2.15 Fig. 65a. Secretion of bile before and after phytolaccin. 2 cc. of bile and 2 cc. of water injected into the duodenum at 6 ; 2 grains of phytolaccin with 2 cc. of bile and 2 cc. of water injected at p. Necropsy. — The small intestine contained 40 cc. of liquid, indicating a mild purgative effect. 106 PROF. EUTHERFORD AND UK. DODDS. Besult of Uxperiments with Phytolaccin. — It is a mild intestinal, but a powerful hepatic, stimulant, as is shown by Table XXI. Table XXI. Phytolaccin. Total Dose in 6rain.s. Grains per kilogramme of Body-weight. Secretion of Bile per kilogramme of Body-weight per hour. Before. After. Experiment 65, Experiment 65a, 2 with bile, 2 „ 0.064 0.104 0.144 cc. 0.338 cc. 0.299 cc. 0.471 cc. Considering the small dose that was given, the high coefficient of secretion in Experiment 65a is probably to be regarded as a nearer indication than that in Experiment 65 of the power of phytolaccin as a hepatic stimulant. This substance appears to be eminently worthy pf the attention of the physician. Action of Eesina Hydrastis or " Hydrastin." The root of the Hydrastis canadensis has had various medicinal properties claimed for it. It is admitted by all to be tonic, and by some it is said to be aperient, cholagogue, diuretic, antiseptic, &c. " It has been employed in dyspepsia and other affections requiring tonic treatment, in jaundice and other functional disorders of the liver, as a laxative in constipation and haemor- rhoids, and as an alterative in various diseases of the mucous membranes, such as catarrh, chronic enteritis, &c. By some it is used as one of the best substitutes for quinia in intermittents." These and other statements regarding it are made by "Wood and Bache {Op. x. p. 458), who further aver that a " more precise investigation of its physiological and therapeutic properties is necessary before we can venture to decide its place among medicines." It contains an alkaloid, hydrastia or hydrastin, which has been found to be identical with berberina {Op. x. p. 457), found in the Berberis vulgaris and in calumba. The " hydrastin " EXPERIMENTS ON THE BILIAKY SECRETION OF THE DOG. 107 employed in the following experiments was not the alkaloid, but a resinous substance prepared from the root of the plant, in the same manner as menisperim (p. 97) by Keith & Co. of New York. The dose for a man of this preparation is from one to two grains. ExperimeTti 66. Dog that had fasted 17 hours. Weight Experiment 66. Experiment 66a. Secretion Secretion Secretion of bile per of bile per kilo- Secretion of bile per of bile per kilo- 15". gramme 15". gramme of dog : of dog : per hour. per hour. cc. CO. 1.40 ^ 0.7 1.60 1.65 V 0.230 cc. 0.35 0.60 1.45 J 0.35 h 0.30 0.60 0.40 \ 0.95 1.60 0.30 0.35 V0.09 CC. 2.15 h ) 1.90 0.17 1.75 0.17 K- 0.15 1.40 0.10 0.85 0.30 1.70 0.20 3.55 \ 0.15 2.45 2.30 > 0.386 cc. 0.30 0.35 1.70 ) 0.55 2.15 h! 1.00 0.60 1.-30 0.80 s 0.80 1.95 0.90 ] 1.40 3.95 1.10 1.15 V 0.323 CC 3.45 1.05 1.10 0.95 1.05 ) 25.9 kilogrammes (Fig. 66). — Two grains of hydrastin triturated with 2 cc. of rectified spirit, 1 cc. of bile, and 2 cc. of water were injected into the duodenum at h, and the same dose was repeated at h'. A wave, as it were, of increased bile-secretion followed both doses, the second being higher than the first. It 108 PROF. EUTHERFOED AND DR. DODDS. is notable that the periods of excitement after both doses were of the same length — an hour and a half. Twenty grains of sodium salicylate in 10 cc. of water were then injected into a Fig. 66. Secretion of bile before and after hydra-stin and sodium salicylate. 2 grains of ' hydrastin in 2 co. of rectified spirit, 1 cc. of bile, and 2 cc. of water injected into the duodenum at h and A'; 20 grains of sodium salicylate in 10 cc of water injected into the lower portion of the intestine at s. lower part of the small intestine (s), and it produced a higher bile-secretion than had resulted from the hydrastin. Necropsy. — Decided redness of mucous membrane in the upper 12 inches of the small intestine; but there was only scanty evidence of purgation where the hydrastin had been injected^ EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 109 Experiment 66a. Dog that had fasted 17 hours. Weight 13.6 kilogrammes (Fig. 66a).— Two grains of hydrastin, Fig. 66a. Secretion of bile before and after hydrastin. 2 grains of hydiastin in 2 cc. of bile, 1 CO. of rectified spirit, and 6 cc. of water injected into the duodenum at h and h'. triturated with 2 cc. of bile, 1 cc. of rectified spirit, and 6 cc. of water, were injected into the duodenum at h, and the same dose was again given at h'. Before the experiment was begun, it was observed that the animal was somewhat unhealthy, which accounts for the result being less definite in this than in the previous case: yet, ere the second dose was given, the bile- secretion had begun to rise, and after the second dose the increase was decided. Necropsy. — Slightly increased redness of duodenal mucous membrane. Very slight evidence of purgative action. Besult of Experiments with Hydrastin. — It is a hepatic Table XXII. Hydrastin. - Total Dose in Grains. Grains per kilogramme of Body-weight. Secretion of Bile per kilogramme of Body-weight per Hour. Before. After. Experiment 66, Experiment 66a, 2 with bile, 2 „ 0.077 0.U7 0.23 cc. 0.09 cc. 0.386 cc. 0.323 cc. stimulant of considerable power, and a feeble intestinal stimu- lant. The fact shown in Table XXII. that in Experiment 66a a dose relatively larger in proportion to the size of the animal 110 PROF. RUTHERFORD AND DR DODDS. than in Experiment 66 produced a smaller effect on the liver — seems only explicable by the fact that the subject of the former experiment was, as already stated, in an abnormal condition. Altogether, hydrastin appears to be a substance eminently worthy of the attention of the physician. Action of Resina Jtjglandis or " Juglandin." The juglandin employed in the following experiment was not an alkaloid, but an impure resin prepared by Keith & Co. of New York, from the bark of the root of the butternut or white walnut {Juglans cinerea), after the same manner as menispermin (p. 97). Regarding the properties of the bark of the butternut, Wood and Bache {Op. x. p. 492) state that it is a mild cathartic, operating without pain or irritation, and resembling rhubarb in the property of evacuating withoat debilitating the alimentary canal. It was much employed during the late American civil war by Dr Eush and other army physicians,. It is especially useful in habitual costiveness and dysentery. Nothing is stated regarding any influence on the liver. An extract of the bark is officinal in the United States. The dose of Keith's juglandin — the substance used in the following experiment — is from two to five grains. Experiment 67. Dog that had fasted 18 hours. Weight 21.1 kilogrammes (Fig. 67V — Five grains of juglandin, triturated with 2 cc. of bile, 2 cc. of rectified spirit, and 5 cc. of water, were injected into the duodenum at j, and the same dose was repeated at j'. Both doses were followed by increased bile- secretion, which lasted four hours, and would probably have lasted even longer. Twenty grains of sodium salicylate in 10 cc. of water were injected into a lower part of the small intestine at s, and speedily caused a much greater hepatic excitement. Before any drug was given, the coefficient of secretion was 0.104 cc. of bile per kilogramme of body- weight per hour. After the first dose, it rose to 0.286 cc. and after the second to 0.327, showing that juglandin is a hepatic stimulant of moderate power. Indeed, it occasions a coefficient of secretion almost pre- cisely the same as rhubarb (0.32 cc.) and leptandria (0.31 cc). EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. Ill Necropsy. — Slightly increased redness of the duodenum, and slight purgation. Experiment 67. Secretion of bile Secretion of bile Secretion of bile per kilogramme Secretion of bile per kilogramme per 15". of dog : per per 15". of dog : per hour. hour. cc. cc. 0.75 1.30 0.65 y — 0.45 1.45 0.45 1.75 0.40 1.65 \ 0.45 0.45 0.45 1-0.104 00 1.65 1.85 1.55 1 0.327 cc. 0.65 1.60 0.65 1.70 3 1.65 0.60 g 0.85 1.95 0.95 3.40 1.80 ^ 3.75 1.40 1.55 [- 0.286 cc. 1.30 i Result of Eoaperiment ivith Juglandin. — It is a mild hepatic stimulant and a mild purgative, and seems eminently worthy of the attention of the physicians of this country. Action of Benzoic Acid and its Compounds. Benzoic acid is said to act as a stimulant of the system generally, and particularly of the kidneys, mucous membrane of the bladder, and bronchial glands. It is nowhere stated to be a cholagogue. Yet it is sometimes used empirically in hepatic affections. Tanner, in his Practice of Medicine, recommends ammonium benzoate in hepatic congestion with deficient urine, and benzoic acid in suppressed action of the liver and uraemia. Dr Wade of Birmingham employs benzoic acid in cases of catarrh of the bile-ducts ; and we owe to the deep interest which he has taken in this research the valuable suggestion that we should endeavour to furnish a rational theory for the use of 112 PROF. RUTHERFORD AND DR DODDS. this agent in hepatic affections, by ascertaining whether or not it has the power of stimulating the liver. For a man, the dose Fig. 67. Secretion of bile before and after juglandin and sodium salicylat?. 5 grains of juglandin in 2 oo. of rectified spirit, 2 co. of bile, and 5 cc. of water injected into the duodenum at j' and /; 20 grains of sodium salicylate in 10 cc. of water injected ii;to the lower portion of the intestine at s. of benzoic acid is from ten to thirty grains ; that of benzoate of ammonia, from ten to twenty grains. Benzoate of soda has been employed by Socquet and Bonjean (Wood and Bache Op. X. p. 1471) as a remedy for gout and rheumatism ; but we have not been able to ascertain the dose given. Probably the dose of the sodium is similar to that of the ammonium salt. Experiment 68. Dog that had fasted 17 hours. Weight 14.3 kilogrammes (Fig. 68). — Fifteen grains of benzoic acid, partially dissolved in 20 cc. of water, were injected into EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 113 the duodenum at 6. A slight increase of the bile-secretion ensued ; but it was not thought judicious to repeat the benzoic Experiment 68. Secretion of bile Secretion of bile Secretion of bile per kilogramme Secretion of bile per kilogramme per 15". , of dog : per per 15". of dog : per honr. hour. CC. CC. 0.75 ^ 6s 0.80 0.90 V 0.223 CC 1.05 1.60 0.75 J 2.35 b 2.80 0.85 2.50 ) 1.20 2.35 1.05 2.35 > 0.646 cc. 1.25 A 2.05 0.80 2.10 1.30 V 0.332 CC. 1.40 J Fi£t. fifi. Secretion of bile before and after benzoic acid and sodium benzoate. 1 5 giains of benzoic acid in 20 cc. of water injected into the duodenum at 6 ; 20 grains of sodium benzoate in 10 co. of water injected at 6s. lU PiROF. RUTHERFOKD AND Dli DODDS. acid, owing to the fallacy that would have arisen from the effect of the large quantity of water required for its solution. Accord- ingly, twenty grains of sodium henzoate — an extremely soluble suhstance — dissolved in 1 cc. of water, were injected at bs, and a very powerful stimulation of the liver was the result, the coefficient of secretion rising as high as 0*646 cc. of bile per kilogramme of body-weight per hour. Necropsy. — Very slight increase of redness of the duodenal mucous membrane. No purgation. Experiment 68a. Dog that had fasted 18 hours. Weight Experiment 68a. Secretion of bile Secretion of bile Secretion of bile per kilogi'amme Secretion of bile per kilogramme per 15". of dog: per per 15". of dog : per hour. hour. cc. cc. 1.40 2.80 1.35 2.55 1.85 2.55 1.55 2.45 1.55 ) 2.50 \ 1.65 1.70 V 0.247 cc. 2.50 2.50 lo.37cc. 1.80 ) 2.50 J 2.65 / 1.55 2.35 3.63 \ a 4.05 I 2.45 4.00 y 0.544 cc. a' 3.10 j 2.25 3.30 2.30 3.20 a" 2.90 2.40 2.66 2.25 27.1 kilogrammes (Fig. 68a). — Twehty grains^ of ammonium benzoate, dissolved in 25 cc. of water, were injected into the duodenum at h. Within half an hour a powerful stimula- tion of the liver ensued that lasted five hours, and would probably have continued still longer had the experiment been continued. One-fifth of a grain of atropia sulphate, injected into the jugular vein at a, a', and a" — three-fifths of a grain iu all — did not antagonise the action of the benzoate. Necropsy. — There was no purgation, * the intestine being KXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. IIT) perfectly dry ; but the mucous membrane of the small intestine was considerably reddened to the extent of 3 feet below the pylorus. Fig. 68a. Scivetion of bile before and after ammonium beiizoate and atropi.". 20 grains of ammonium benzoate in 25 cc. of watia' injected into the duodenum at l ; one-fiftli of a grain of atropia sulphate injected into tlie jugular vein at ii^ a', and ri". A repetition of experiments so entirely satisfactory was unnecessary ; nevertheless, in Experiment 72a there was a reason for giving sodium benzoate, and hepatic excitement again resulted from it. 116 PROF. RUTHERFORD AND DR. DODDS. Table XXIII. Total Dose in Grains. Grains per kilogramme of Body-weight. Secretion of Bile per kilogramme of Body-weight per hour. Before. After. Sod. benzoate. — Ex. 68, Ammon. „ ,, 68a, 20 20 1.320 0.737 0.223 CO. 0.247 cc. 0.646 CO. 0.544 cc. Result of Experiments with the Benzoates. — Sodium benzoate and ammonium benzoate are both very powerful stimulants of the liver, but are not stimulants of the intestinal glands. It appears from the above experiments that the salt of sodium is a more powerful stimulant than that of ammonium ; but the experiments are inconclusive on this point, because in Experi- ment 68 the sodium salt wbs assisted in its action by the previous administration of benzoic acid, and in addition the dose of the salt was greater in proportion to the size of the animal than in Experiment 68a. Now that we have proved this action of these substances on the liver of the dog, a similar action on the human liver will doubtless be found; and probably the reason why it has hitherto escaped the attention of physicians is, that these substances, being hepatic but not intestinal stimu- lants, the hypersecretion of bile induced by them has not been revealed so as to attract attention. But probably, if a dose of sodium or ammonium benzoate were given at night, and a purely intestinal stimulant, such as magnesium sulphate, given in the morning, clear evidence would be found of the increased secretion of bile. These results, therefore, furnish a rational theory for the employment of the benzoates in congestion and some other affections of the liver. In view of the above discovery, we would ask the practical physician to consider the propriety of testing the effect of the benzoates in dysentery, for while they, like ipecacuan, powerfully stimulate the liver, and not the intestinal glands, they, unlike ipecacuan, induce no sickness or depression, but on the contrary, are nerve stimulants. EXFEUIMENTS ON THE BILIAKY SECRETION OF THE DOG. 117 Both the sodium and ammonium salts should be tried. It may also be well to observe that it would be perhaps advisable to more frequently administer the benzoates in ordinary bronchial catarrh, for they stimulate the liver as well as the bronchial glands, and the action of the liver in a common cold generally becomes somewhat defective. One cannot leave the subject of benzoic acid without recalling Wohler and Keller's well-known discovery, that when benzoic acid is introduced into the economy, it is eliminated by the kidneys entirely in the form of hippuric acid. The fact that the latter, when treated with boiling hydrochloric acid, splits up into benzoic acid and glycin, suggested that the hippuric acid consequent upon the ingestion of benzoic acid arises from the union of that substance with glycin. Seeing that the two bile- acids — glycocholic and taurocholic acids — are conjugates of cholalic acid with glycin and taurin respectively, the thought naturally arose that the formation of hippuric acid by the conjugation of benzoic acid with glycm probably takes place in the liver. This theory of the seat of its formation was supported by Kiihne and Hallwachs {Op. xv.) ; but, on the other hand, Meissner and Shepard {Op. xvi.) maintained that the trans- formation of the benzoic acid takes place more in the kidneys than in the liver, and this opinion is supported by Schmiedeberg and Bunge {Op. xvii.). The evidence adduced by Kiihue in favour of the liver as the exclusive seat of formation, or that by the other observers in favour of the kidney, need not here be entered into, for no light would thereby be thrown on the fact that, while benzoic acid is allying itself with glycin and carrying this substance into the urine, the hepatic cells are stimulated to produce more bile. In reviewing this subject, \w& have to express our regret that the bile was not analysed in the last two experiments, for the purpose of ascertaining whether or not its percentage amount of glycocholic acid was diminished, and to find out whether or not hippuric acid is excreted by the liver as well as by the kidney.* * Since the above was written we have ascertained that M osier {Op. iii. p. 46) found, from several experiments on a dog with a permanent fistula, that when 60 and even 90 grains of benzoic acid are administered by the mouth, no hippuric acid is found in the bile. It is singular that he did not collect and measure the bile secreted daily, otherwise he would doubtless have anticipated our discovery of the stimulating effect of benzoic acid on the liver. 118 PROF. RUTHEEFORD AND DR. DODDS. Action of Sodium Salicylate. Scarcely anything is known regarding the physiological actions of salicylic acid. Bertagnini (quoted in Op. xviii. p. 696) took 100 grains within two days in 4-grain doses, and felt nothing but ringing in the ears and some degree of deafness. He observed that the acid was excreted in the urine in the form of salicyluric acid. It is known that this is a conjugate of salicylic acid and glycin. The formula of benzoic acid is C^HgOj ; that of salicylic acid, CjHgOj. Their near chemical alliance and their similar behaviour towards glycin rendered it probable that salicylic acid, like benzoic acid, excites the hepatic cells. This substance has been lately much employed as a remedy in acute rheumatism. The dose for a man is from 15 to 20 grains. Experiments 62, 66, and 67, already detailed, furnish abundant evidence of the remarkable powers of sodium salicylate as a stimulant of the liver, and other experiments yet to be described. Experiments 69, 70a, 73a, and 74a, furnish evidence still more striking ; indeed, this substance is a certain hepatic stimulant, never failing, when placed in the duodenum, to excite the liver within half an hour. Owing to its certain and speedy action, it has been repeatedly used in the later experiments merely to furnish an effect which might be readily compared with that produced by some other substance. Table XXIV. gives the coefficients of bile-secretion under its influence. Table XXIV. Sodium Salicylate. Total Dose in Grains. Grains per kilogramme of Body-weight. Secretion of Bile per kilogramme of Body-weight per hour. Before. After. Experiment 74a, . 62, . 69, 20 25 20 1.00 1.55 2.16 0.178 cc. 2.260 CO. 0.329 cc. 0.665CC. 0.664 cc. 0.890 cc. KXPEllIMKNTS ON THE BILIARY SECRETION OF THE DOG. 119 Result of JEosperiments with Sodium Salicylate. — It is a very powerful hepatic stimulant in the dog. Its slight action on the intestine is probably the reason why its effect on the human liver has passed unobserved by the physician. We have given to a man 30 grains of sodium salicylate at night, and next morn- ing a purely intestinal stimulant, such as magnesium sulphate, and we feel convinced that there was an increased discharge of bile. We commend this point to the attention of physicians. Action of Ammonium Phosphate and of Tannic Acid. The similar effects produced on the liver by the sodium and ammonium salts of salicylic acid, led us to think again of the stimulating effect of sodium phosphate, and induced us to test the action of ammonium phosphate. It is employed in cases of chronic gout, and in urinary affections where uric acid calculi exist or threaten. Nothing has been hitherto known regarding its action on the liver, probably because it is not an intestinal stimulant ; and, therefore, the increased secretion of bile — which it probably induces in man as it certainly does in the dog — has passed unobserved. The dose for a man is from 5 to 20 grains. The first experiment with this substance yielded a negative result ; but it has been thought right to discard it, because the ammonium phosphate was injected after liquor bismuthi into the same part of the intestinal canal. Eoq)eriment 69. Dog that had fasted 17 hours. Weight 9.7 kilogrammes (Fig. 69).— 20 grains of ammonium phosphate dissolved in 22 cc. of water, were injected into the duodenum at a. The subsequent increased bile-secretion was decided and prolonged. Since tannin is employed as an astringent in cases of diarrhoea, 20 grains, dissolved in 20 cc. of warm water, were injected into a fresh portion of the small intestine {t) ; but, a^ it did not affect the bile-secretion, it was not thought worth while to repeat the dose. 20 grains of sodium salicylate, in 10 cc. of water, were then injected into a fresh portion of the small intestine (s), and, within half an hour, its never-failing effect was evident. Obviously it stimulated the liver much more powerfully than ammonium phosphate. At the beginning 120 PROF. KUTHEKFOKD AND DR. DODDS. of the experiment, the coefficient of secretion was 0.19 cc. per kilogramme of body- weight per hour ; a fair average for a fasting Experiment 69. Secretion of Secretion of Secretion of bile per Icilo- Secretion of bile per kilo- bile per 15". grammeofdog; bile per 15". gramme of dog per hour. per hour. cc. cc. 0.35 1.20 0.50 1 1.05 0.45 0.40 V0.19CC. 1.00 0.90 0.50 J t, a 0.90 0.75 0.85 1 (^80 1.10 0.80 0.80 V0.329cc. 1.25 0.75 j 1.10 s — — 1.25 1.25 ^ 1.30 1.50 2.50 2.65 |-0.89cc. 1.50 ^ 2.25 j 1.55 1.60 lo.634cc. 1.50 ) dog. After the ammonium phosphate, it rose to the unusually high figure of 0.634 cc. ; but after the sodium salicylate, it rose still higher to 0.89 cc. The result of this experiment being apparently so unequivocal it was not thought necessary to repeat it. Nevertheless, considering the small size of the animal (9.7 kilos.), and that the dose was the maximum dose for a man, it seems reasonable to regard the effect of the ammonium phosphate in this case as perhaps unduly exaggerated. NECROPSY.^Nothing notable observed in the intestine. Result of Experiment with Ammonium Phosplmte and Tannic Acid. — Ammonium phosphate is a powerful hepatic stimulant, but not so powerful as sodium salicylate. It is not an intestinal stimulant. Probably now that we have directed attention to the matter, it will be found to be a stimulant of the human liver also. Tannin does n«^t appear to affect the liver. EXPEltlMENTS ON THE BILIAKY SECEETION OF THE DOG. 121 Action of Acetate of Lead. The well-kuown astringent effect of lead acetate in cases of diarrliooa renders it desirable to know wiiether or not it has the power of diminishing the secretion of bile. Eobrig {Op. vi. p. 270) experimented with acetate of lead, and found that 0.6 gramme (9.2 grains), dissolved in 4 ounces of warm water, and injected into the small intestine of a dog, diminished the secre- tion of bile. The erroneous nature of some of Eohrig's results, due to his very imperfect mode of experiment — as pointed out Fig. 69, Secretion of bile before and after ammonium phosphate, tanniu, and sodium salicylate. 20 grains of ammonium phosphate in 22 cc. of water injected into the duodenum at a ; 20 grains of tannin in 20 cc. of water injected at i ; 20 grains of sodium salicylate in 10 cc. of water injected at s. in the introduction — rendered necessary a re-investigation of the effects of lead acetate. It has already been stated that, in Experiment 61a the administration of 8 grains of lead acetate was followed by a diminution of the bile-secretion, but that the result was of an equivocal nature. In Experiment 62 ten grains produced no 122 PROF. RUTHERFORD AND DR. DODDS. effect. In Experiment 64, a first dose of 8 grains, with a second dose of 12 grains, was indeed followed by a diminished bile- secretion ; but, as stated in the description of that experiment, the result was entirely equivocal, and therefore other experi- ments were obviously required. Experiment 70. Dog that had fasted 17 hours. Weight not ascertained (Fig. 70). — Owing to great difficulty in intro- Fig. 70. Secretion of bile before and after lead acetate. 2 grains in 15 cc. of water in- jected into the duodenum at I and l^; 4 grains in 32 cc. of water at Z,; 4 grains in 15 cc. of water at Zj; 8 grains in 15 cc. of water at l^; and 10 grains in 15 cc. of water at l^ (30 grains given in all). ducingthe biliary cannula, and consequent serious disturbance of the bile-duct and its surroundings, the secretion of bile became, as mostly happens in such a case, very irregular ; so much so, indeed, that the record of the first three hours is omitted from the chart. Two grains of lead acetate in 15 cc. of water were injected in the duodenum at I and Z^ ; 4 grains in 32 cc. of water z,t l^; 4: grains in 15 cc. of water at Zj; 8 grains in 15 cc. of water at l^; and 10 grains in 15 cc. of water at Zg. Thirty grains were given in all. The irregularity of secretion rendered the experiment unsatisfactory, and the discovery that the acetate of lead used in this and the previous experiments was impure, necessitated another experiment. EXl'ERIMKNTS ON THE BILIARY SECRETION OF THE DOG, 12." Experiment 70a. Dog that had fasted 18 hours. Weight 14.6 kilogrammes (Fig. 70a). — Ten grains of pure lead acetate, Experiment 70a. Secretion of Secretion of Secretion of bile per kilo- Secretion of bile per kilo- bile per 15". gramme of bile per 15". gi-amme of dog: per hour. dog: pc-r hour. CO. cc. 1.8 0.75 .1.15 0.90 1.25 1," 1.80 0.95 1.55 0.95 1.70 0.95 1.40 0.80 1.85 0.70 1.55 r — 1.20 0.60 1.60 0.80 1.15 \ 0.70 1.25 1.25 1.2 V 0.331 cp. I"" 0.75 0.65 I 0.171 cc. I 0.55 j 1.2 0.55 1.15 s 1.10 0.55 ^ 0.90 1.05 1.55 2.10 I 0.452 cc. 1.00 2.40 J V dissolved in 10 cc. of distilled water, were injected into the duodenum at I, I', I", I'", and I"" ; 50 grains in all being given. The decided fall in secretion towards the close of this experiment is abnormal, and may fairly be ascribed to a depressant effect of the lead; but it is obvious that the first doses did not produce the effect which might have been antici- pated from Eohrig's experiments. That the liver was not exhausted, however, and was capable of increased action, was proved by inject! ng|^into the duodenum 20 grains of sodium salicylate dissolved in 10 cc. of water. Although it was the ninth hour of the experiment, the biliary secretion became greatly accelerated, and reached a point decidedly higher than it had been at the beginning of the experiment. All the more, therefore, may the previously diminished secretion be ascribed to the depressant action of the lead ; while it is obvious that an 124 PROF. EUTHERFOKD AND DR. DODDS. ordinary dose of sodium salicylate can excite the liver thus poisoned and depressed. Fig. 70a. SL'cretion of bile before and 'after lead acetate and sodium salicylate. 10 grains of lead acetate in 20 cc. of water injected into the duodenum at I and V; 10 grains in 10 cc. of water at I", V", and I""; 20 grains of sodium salicyate ia 10 cc. of water injected into the duodenum at s. Result of Experiments with Lead Acetate — In large doses, it has a depressant effect on the secretion of bile. Sodium salicylate can overcome that effect. The obstinate constipation observed in cases of lead-poisoning may, to some extent, be owing to the depressant effect of lead on the liver ; but it is probably chiefly owing to a depressant action on the intestinal glands ; for, in view of the astringent effect of a dose of from 1 to 4 grains in diarrhoea, it seems likely, from the above experiments, that it affects the intestinal canal more than the liver. It is a remark- able fact that, of all the substances employed in this research, lead acetate is the only one which depresses the action of the liver without producing purgation. It seems to be a direct hepatic depressant. As previously explained, every purely intestinal purgative agent depresses hepatic action, in a manner which is probably, however, purely indirect, and to which allusion will again be made in the sequel. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 125 Action of Jaborandi. Jaborandi being a powerful stimulant of the salivary and sweat glands, we thought it desirable to ascertain its influence on the liver. The mean dose for a man is a watery infusion of sixty-four grains of the leaves. Experiment 71. Experiment 71 A. Secretion Secretion of bile of bile Secretion per kilo- Secretion per kilo- of bile per gramme of of bile per ' gramme of 15". clog: per 15". dog: per hour. hour. cc. cc. 1.40 1.80 1.42 1.70 1.40 1.67 b 1.70 1.40 I 1} 1.45 V 0.265 cc. 1.70 -) 1.40 j 1.72 1.65 I 0.314 cc. 1.40 1.70 ) 1.40 i — s 1.70 1.40 1.60 1.50 s 1.50 1.60 1.55 1.70 1.50 1.60 1.60 1.75 1.45 1.80 / 1.75 1.50 1.90 1.50 1.95 1.60 2.00 \ 1.70 \ 1.80 t 0.365CC 1.60 1.72 V0.310CC 2.00 2.05 1.55 j 1.85 1.80 1.72 1.55 1.60 1.65 / 1.50 1.50 1.40 1.62 1.70 1.62 1.50 1.67 1.35 1.70 1.75 Experiment 71. Dog that had fasted 18 hours. Weight 21.5 kUogrammes (Fig. 71).— Eight cc. of water with 2 cc. of bile 126 PKOF. EUTHEEFOUD AND DE. DODDS. were injected into the duodenum at h, and 8 cc. of a concentrated aqueous infusion containing the active principle of 64 grains of Fig. 71. Secretion of bile before and after jaborandi. 2 cc. of liile and 8 cc. of water in- jected into the duodennm at J ; 8 cc. of infusion of jaborandi with 2 cc. Of bile injected at / and/ ; salivation began at s. jaborandi leaves were injected at/, and the same dose was again given at/. Powerful salivation began half an hour after the first dose (at s), and it is to be observed that shortly afterwards Fig. 71 A. Secretion of bile before and after j.iborandi. At b, 2 cc. of bile and 10 cc. of water ; at^ and/ the same fluid, with 10 cc. infusion of 75 grains of jabor- andi leaves, injected into the duodenum. Salivation began at s. EXPEKIMENTS ON THE BILIARY SECRETION OF THE DOG. 127 the bile-secretion also underwent a slight increase, that became more marked after the second dose. NiCGROPSY. — Ninety-seven cc. of liquid in the small intestine (30 cc. had been injected), but whether most of it had been secreted by the pancreas or by Lieberkiihn's follicles was undetermined. There was no unusual redness of the intestinal mucous membrane. Experiment 7lA. Peg that had fasted 18 hours. Weight 21.5 kilogrammes (Fig. 71a). — Ten cc. of water with 2 cc. of bile were injected into the duodenum at 6, and the same fluid, with 10 cc. of aqueous infusion of jaborandi, was injected aty and again at j'. As each cubic centimeter of the infusion contained the active principle of 7^ grains of the leaves, 150 grains had been given. Salivation began half an hour after the first dose, and soon thereafter the bile-secretion rose, but to no great extent. It was observed in this experiment that the bronchial glands were much stimulated by the jaborandi, the respiratory cannula being completely obstructed by a watery mucus, which must have been secreted in the bronchi and trachea. Necropsy. — The jaborandi had traversed the whole length of the small intestine, which contained 107 cc. of a clear greenish fluid without mucous flakes. Thirty-six cc. of fluid had been injected ; but how much of the remainder had been secreted by the pancreas and how much by Lieberkiihn's follicles could not be determined. Result of Experiments with Jaborandi. — In doses that were much more than sufficient to excite the salivary glands, jabor- andi produced only a slight increase in the biliary secretion. It is therefore to be regarded as a very feeble hepatic stimulant. Action of Sulphate of Manganese. It is stated by Pareira {Op. xix. I. p. 636) that " C. G. Gmelin tried the effect of the sulphate of the protoxide of manganese on animals; and found that it caused vomiting, paralysis with convulsions, and inflammation of the stomach, small intestines, liver, spleen, and heart. He notices as a remarkable fact, the extraordinary secretion of bile produced by it, and which was 128 PROF. RUTHERFORD AND DR. DODDS. SO considerable that nearly all the intestines were coloured by it, and the large intestines had a wax-yellow colour communi- cated to them." At the suggestion of Pareira {loc. cit), its effects on the human subject were tested by Mr Ure, who found that, in doses of from 60 to 120 grains, it acts as a purgative and cholagogue. In a recent communication to the Lancet (1878, i. 882), Dr E. H. Goolden states that he has been in the habit of using the substance as a cholagogue for more than thirty years. He finds that, in doses of from ten to twenty grains, it prodiices large bilious evacuations. Ten grains he regards as a sufficient dose for ordinary purposes. This he dissolves in a tumbler of water, and adds some citrate of potash or magnesia. These statements rendered it desirable for us to test the action of this substance by our method of experiment. JExjperiment 72. Dog that had fasted 18 hours. Weight 15 kilogrammes (Fig, 72). — Thinking, from Pareira's statement of Fig. 72. Secretion of bile before and after sulphate of manganese. 60 grains of manganese sulphate in 30 cc. of water injected into the duodenum at m. the amount given to the human subject by Ure, that 60 grains of manganese sulphate would not be too large a dose for a dog, we injected that amount in 30 cc. of water into the duodenum at m. So far from any increase of the bile-secretion resulting, there was a decided fall, the secretion coming nearly to a stand- still. The weak pulse of the animal suggested that collapse had been occasioned by the drug, and the necropsy fully confirmed the idea that too much had been given. The fall of secretion, EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 129 however, was in the first instance indirectly due to the efifects of the powerful purgation that was induced, though the very low secretion at the close was, in all probability, due to collapse. Necropsy. — Evidence of powerful purgation in the upper third of small intestine. Very violent irritation of the mucous membrane of this region of the gut, the surface of which was covered with a yellowish- white pulpy matter, as if the epithelium had been dissolved by a caustic alkali. Experimetii 72a. Dog that had fasted 18 hours. Weight 17.7 kilogrammes (Pig. 72a).— As the dose in the previous Fig. 72,4. Secretion of bile before and after manganese sulphate and sodium benzoate. 20 grains of manganese sulphate in 15 cc. of water injected into the duodenum at m; 21 grains of sodium benzoate in 15 cc. of water injected at s. case had evidently been too large, only 20 grains of manganese sulphate were given, in the same manner as before, in this instance (m). But there was not the slightest rise in the bile- secretion ; on the contrary, there was a decided fall, as is the rule under the influence of a substance that produces purgation without exciting the liver. It now came to be the question. Would the bile-secretion rise in spite of the purgative drain from the portal vein, if a hepatic stimulant were administered ? To determine this, 21 grains of sodium benzoate in 15 cc. of water were injected into the duodenum at s ; and, in spite of the disadvantageous circumstance of its being introduced into a R. 9 130 PROF. EUTHEKFORD AND DR. DODDS. column of intestinal juice actively being secreted, it excited the liver to secrete more bile, showing that the liver could be excited by a substance possessed of the property of so doing. NBCROPSY.^Copious watery purgation throughout the whole length of small intestine, whose mucous membrane was, how- ever, scarcely at all reddened. The dose had, therefore, been efficient as an intestinal, but not as a hepatic, stimulant. Mesults of Experiments with Manganese Sulphate. — Experiments 72 and 72a entirely bear out the statement that manganese sulphate is an intestinal stimulant, but lend no support to the idea that it is a hepatic stimulant. The effect on the biliary secretion is, indeed, similar to that of magnesium sulphate (p. 69), or any other purely intestinal stimulant; that is, it diminishes the biliary secretion, probably by draining the portal system. Yet Dr Goolden's statements are explicitly to the effect (J,ih. cit.) that the same result was not produced by sul- phate of magnesia as by sulphate of manganese. We cannot, of course, from the above experiments, deny that the manganese salt is a cholagogue in man ; but, looking to the general harmony between our observations on the dog and those on man, we think we are entitled to throw very grave doubts upon the idea that manganese sulphate excites the human liver. It might, indeed, be maintained that it has the power of inducing con- tractions of the gall-bladder and larger bile-ducts, and of thus increasing the amount of bile in the dejections; but we can only commend to the attention of physicians Dr Goolden's positive observations as to the increased amount of bile in the dejections of man, and our negative results as to any stimulating effect on the bile-secreting mechanism of the dog. Action of Morphia. As morphia has the well-known power of arresting diarrhoea and of producing constipation, it is desirable to know whether this is to be ascribed to its effect on the intestine alone, or also to a power of diminishing the secretion of bile. Experiment 73. Dog that had fasted 18 hours. "Weight 33 kilogrammes (Fig. 73). — -One grain of morphia hydrochlorate EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 131 in 3 cc. of bile and water was injected into the duodenum at m, m', m", and m'", 4 grains being given in all. The first two Fig. 73. Secretion of bile befoi-e and after morphia hydrochlorate. 1 grain with 2 co. of bile and 1 cc. of water injected into the duodenum at m, m', m", and m'". doses had no obvious effect on the bile-secretion ; but it began to fall after the third, and continued to do so after the fourth, doses. As it was impossible to know, from this single experi- ment, whether or not this fall in the secretion was due to the morphia, a second experiment was performed. Necropsy. — The mucous membrane of the small intestine was almost dry. Experiment VSa. Dog that had fasted 18 hours. Weight 19.9 kilogrammes (Fig. 73a). — One grain of acetate of morphia in 5 cc. of water was injected into the duodenum at m, and 2 grains in 10 cc. of water were injected at m'. The morphia did not appear to affect the secretion. As it seemed desirable to know whether or not the liver of an animal so narcotised could be excited by an appropriate stimulant, 20 grains of sodium salicylate in 10 cc. of water were injected into the duodenum at s. Powerful and prolonged excitement of the liver was the result. Necropsy. — Slightly increased redness of the duodenal mucous 132 PROF. EUTHEEFOED AND DE. DODDS. membrane. Evidence of slight purgative action in the upper part of the small intestine. Experiment 73a. Secretion -Secretion ■ Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog : per hour. hoar. cc. cc. 1.15 s 0.85 1.05 0.80 \ 3.05 \ 0.70 0.70 V0,15cc. 3.35 2.45 |-0.565cc. 0.80 ) 2.40 ) m 2.15 0.95 2.30 1.10 2.30 0.95 2.30 to' 2.60 0.90 2.60 0.85 to.l78cc. 0.75 1.05 0.90 Results of Experiments with Morphia. — Three grains of morphia acetate did not affect the secretion of bile. Action of Hyoscyamus. As extract of hyoscyamus is often administered with chola- gogue substances, it is important to know whether or not it diminishes the secretion of bile. The dose of this substance for a man is from 5 to 10 grains. Etxperiment 74. Dog that had fasted 18 hours. Weight 21 kilogrammes (Fig. 74). — Two grains of aqueous extract of hyoscyamus in 3 cc. of water were injected into the duodenum at h, h', h", and h'", 8 grains being given in all. It was im- possible, from this single experiment, to say whether or not the fall in the secretion was due to the hyoscyamus; but the unusually high coefficient of secretion in the earMer part of the experiment (0.311 cc. per kilogramme per hour) favoured the conclusion that the fall was not due to the drug. EXPEEIMENTS ON THE BILIAEY SECRETION OF THE DOG. 133 Neokopsy. — Mucous membrane of small intestine pale and dry. Kg. 73a. Secretion of bile before and after morphia and sodium salicylate. 1 grain of morphia acetate in 5 co. of water injected into the duodenum at m ; 2 grains in 10 cc. of water at m'; 20 grains of sodium salicylate in 10 cc. of water injected into the duodenum at s. Eonperiment 74a. Dog that had fasted 18 hours. Weight 16.8 kilogrammes (Fig. 74a.). — To decide the point left in doubt by the previous experiment, larger doses of the drug were administered. Eight grains of the extract of hyoscyamus triturated with 1 cc. of bile and 10 cc. of water were injected into the duodenum at h, and the same dose was injected into a lower part of the intestine at h'. It is difficult to account for the slight rise of secretion that followed both doses. It may be safely assumed that it was due neither to the bile nor to the water. At all events, there was no fall of secretion, notwith- standing the administration of sixteen grains of the drug. 134 PKOF. EUTHEEFOKP AND DE. DODDS, As the experiment was entirely conclusive regarding the effect of hyoscyamus, it was proposed to investigate the action Experiment 74. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog : per hour. hour. cc. cc. IJJ 1.45 1.75 1.55 1.55 h" 1.65 1.60 1.65 \ 1.45 1.65 ) 1.30 1.65 > 0.311 cc. 1.20 1.60 f 1.35 1.65 J 1.25 h K" 1.60 1.20 1.65 1.10 1.70 0.90 1.65 0.80 'V h' 1.65 0.90 0.80 lo.l76cc. 1.60 0.90 J 1.55 of pure alcohol ; accordingly 5 cc. of absolute alcohol, diluted with 32 cc. of water, were injected into a fresh portion of the Fig. 74. Secretion of bile before and after hyoscyamus. 2 grains of extract of hyoscyamus with 3 cc. of water injected into the duodenum at h, K, li", and h'". EXPEEIMENTS ON" THE BILIARY SECRETION OF THE DOG. 135 small intestine, and, as there was no notable effect, 8 oc. of absolute alcohol in 32 cc. of water were injected into another Fig. 74a. Secretion of bile before and after hyoscyamus and absolute alcohol. 8 grains of extract of hyoscyamus in 10 cc. of water and 1 cc. of bile injected into the duodenum at h ; the same, injected into a lower part of the small intestine, at A' ; 5 cc. of absolute alcohol in 20 cc. of water injected into the small intestine at a ; 8 cc. of absolute alcohol in 32 cc. of water injected into the small intestine at a' ; 20 grains of sodium salicylate in 10 cc. of water injected into the duodenum at s. part of the gut. Notwithstanding the administration of 13 cc. of alcohol (219 minims), the bile-secretion was virtually unaf- 136 PROF. RUTHERFORD AND DR. DODDS. fected. It was now sought to determine what such a liver could do if stimulated. Twenty grains of sodium salicylate in Experiment 74a. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : 15". of dog : per hour. per hour. CO. cc. 1.30 1.30 1.10 1.25 1.10 1.20 0.90 1 a 0.85 0.90 [-0.214 cc. 0.80 0.95 0.95 h ) 1.00 1.00 ) 1.10 a' y 0.231 CO. 1.25 ■) 1.00 I 1.25 1.25 V 0.288 CO. 1.00 0.90 ; 1.10 J s 1.00 0.85 K 2.05 1.15 4.50 10 cc. of water were injected into the duodenum at s, and speedily thereafter the bile-secretion was enormously iucreased, and that so late as the ninth hour of the experiment. Result of Experiments with Hyoscyamus. — Sixteen grains of extract of hyoscyamus, prepared according to the British Fharmacopaia, did not notably affect the biliary secretion, and did not prevent such a stimulant as sodium salicylate from aug- menting it. From- observations on the human subject, we are also able to state that hyoscyamus does not seem to interfere with the stimulating effect of euonymin on the liver, and very probably it may be safely given with all hepatic stimulants that are also intestinal stimulants, and happen to cause griping. Action of Alcohol. It is a matter of common opinion that alcoholic drinks affect the action of the liver ; but, whether their hepatic effects may be ascribed to the alcohol, ethers, or other substances they contain, EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 137 no one has hitherto sought to determine. The results of the pre- ceding experiment already go far to determine the question as regards pure alcohol ; but as hyoscyamus had in that experiment been previously administered, it was desirable to perform another experiment in which nothing but pure, diluted alcohol should be administered. Experiment 74b. A small dog (not weighed) that had fasted 18 hours (Fig 74b). — Fifteen cc. of water were injected Fig. 74b. Secretion of bile before and after alcohol. At w 15 cc. of water; at a, a', a", a'", 5 00. of absolute alcohol with 15 cc. of water injected into the stomach through an cesophagas tube. into the stomach through an oesophagus tube {w) ; then 5 cc. of absolute alcohol diluted with 15 cc. of water were injected into the stomach in the same manner at a, a', a", a!", 20 cc. (338 minims) being given in all. Result of Experiments with Alcohol. — In Experiment 74a, 13 cc. of absolute alcohol, and in Experiment 74b, 30 cc. of abso- lute alcohol, moderately diluted and introduced into the alimen- tary canal, did not produce any apparent effect on the biliary secretion. These experiments, however, furnish no evidence of what might be the effects of the prolonged action of alcohol on the liver ; and, in consideration of the great labour and length of this research, we could not undertake experiments designed to show the effects of various sorts of alcoholic drinks, or of the substances other than alcohol which they contain. Such research could scarcely be of great practical importance, for we already know that certain alcoholic drinks — such as ale, stout, &c. — tend to produce "biliousness;" and, by experiments on the human subject, we have ascertained that the condition, thus induced, may be cured by giving iridin or euonymin, substances which powerfully stimulate the liver. As far as they go, how- ]-38 PROF. RUTHERFORD AND DR. DODDS. ever, our experiments show that pure alcolwl has, at all events, no immediate action on the liver of the dog. Action of Mercurial Salts. Calomel, and mercury in the form of blue pill, are the two preparations of mercury commonly employed for the purpose of inducing purgative action. The most generally received opinion regarding the action of calomel as a cholagogue is thus expressed by Christison {Op. xii. p. 505) : — " The cathartic action of calomel and other mercurials is uncertain, unless other cathartics are united with them. Their action on the bowels is believed to be always attended by an increased discharge of bile from the gall-bladder." But, although this has long been the prevalent opinion, some physicians have doubted the cholagogue property of calomel, and on that account several attempts have been made to determine its action by experiments on animals. Nasse {Op. i. p. 158) seems to have been the first to make the attempt. He established a permanent biliary fistula in the manner already indicated (p. x), and he found that calomel increased the absolute quantity of fluid bile, but diminished its solid constituents. By a similar method KoUiker and Miiller {Op. ii.) found that 4 grains of calomel given to a dog diminished the secretion of bile. Hosier (Op. iii.), adopting also the method of permanent fistula, found, that even when large doses of calomel were administered, not a trace of mercuiy was found in the bile. Scott {Op. iv.) gave to a dog with a permanent biliary fistula 3 grains, 6 grains, and 12 grains of calomel on separate occasions. He collected the bile continuously before, during, and after each dose of the mercurial, and he found but one result, viz., a diminution in the amount of bile and bile- solids secreted after the administration of these doses. Scott's experiment appears to have been very carefully conducted. Its result was so much at variance with the prevalent opinion regarding the action of calomel in man, that some authorities alleged that there i;nust be some difference between the action of mercurials on man and on the dog. Impressed with EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 139 the necessity for obtaining precise information with regard to this point and others, Hughes Bennett organised the committee to which reference has already been made. The committee settled beyond all possibility of doubt that mercury produces in the dog the same general effects as in man (Op. v. p. 201). When small but increasing doses of corrosive sublimate were injected under the skin for several days in succession, salivation occurred, the breath became fcetid, the gums ulcerated, emaciation ensued, and in dogs without biliary fistulee (when therefore the bile was discharged into the intestine) the drug set up profuse diarrhoea, while in dogs with biliary fistula; there was no diarrhoea. The significance of this fact struck ao one at the time, but the experiments hereafter to be detailed (p. 149) suggest that the diarrhcea was probably bilious. The com- mittee further found (Op. v. p. 214) that when calomel was administered to dogs with permanent biliary fistulae in doses of one-twelfth of a grain given from six to fourteen times daily, and in doses of 2 grains from two to six times daily, it did not increase the biliary secretion, nor did it produce purgation ; but when given in doses of 10 grains once a day, it produced purgation and diminished the biliary secretion. More recently experiments were performed by Eohrig {Op. vi. p. 254), who found by the method of temporary fistula, that when " calomel was administered to dogs in large doses (20 grains), it rarely happened that the secretion of bile was recalled after it had come to a standstill, although it increased the secretion when it was only dimbiishing." The imperfections of Ebhrig's method render such a statement of very little value. Our method of experiment being better adapted to afford accurate data, we performed the following experiments : — Experiment 75. Dog that had fasted 18 hours. Weight 19.6 kilogrammes (Fig. 75). — 10 grains of calomel in 7 cc. water were injected into the duodenum at c, and the same dose was repeated at c'. Necropsy. — There was evidence of a profuse purgative effect, the small intestine containing a large quantity of a thick greyish fluid with greenish flakes. The mucous membrane was pale throughout the greater part of its extent, but at intervals in the duodenum there were limited areas of redness. The post- 140 PROF. RUTHERFORD AND DR. DODDS. mortem examination in this case was not made until fourteen hours after death. Fig. 75. Secretion of bile before and after calomel given without bile. 10 grains calomel in 7 cc. water injected into duodenum at c, and again at d. '- In Experiment 75 the administration of 20 grains of calomel in two doses of 10 grains was followed by, a powerful purgative effect and by a slight increase in the bile-secretion ; but, consider- Experiment 75. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog : per hour. hour. cc. cc. 0.30 0.45 ^ 0.32 ^ 0.45 0.35 0.60 1 0.103 cc. 0.45 c' Vo.091cc. ) 0.76 3 0.45 0.50 ^ 0.72 1 0.17 0.35 lo.067oc. 0.97 0.45 V0.133cc. 0.30 j 0.47 ) c 0.60 ) 0.40 0.60 0.50 ~ Iq.102cc. 0.57 0.56 0.57 V 0.116 CO. 0.50 0.60 ) 0.80 0.45 0.40 lo.ll4cc. 0.72 0.65 0.40 V0.12cc. 0.60 J ino' that the coefficient of secretion never rose above 0.133 cc, it is evident that the increased activity of the Uvef was very trifling. Yet one would be apt to be misled by such an experi- ment as this, had we, after the manner of Eohrig, failed to show EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 141 the amount of bile secreted ia , relation to the weight of the animal. Judging from subsequent experiments, it can scarcely be doubted that the trifling increase of secretion in this experi- ment had nothing to do with the calomel. Eayperiment .75a. Dog that had fasted 18 hours. Weight 7 kilogrammes (Fig. 75a). — 10 grains of calomel in 3 cc. water Experiment 75a. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : per 16". of dog : per hour. hour. CO. cc. 0.57 0.60 \ 0.65 0.70 . 0.40 0.65 J-0.31CC. 0.85 0.75 V0.43CC. 0.57 e' J 0.75 J 0.75 \ 0.75 0.52 0.60 V0.36cc. 0.65 0.60 j 0.87 0.45 \ 0.62 0.67 0.50 0.55 |-0.27cc. 0.60 0.45 J were injected into the duodenum at c, and again at 0.29 cc. 1.65 0.62 1.45 0.54 J 1.42 d 0.97 0.20 2.05 0.28 1.00 \ 0.28 cc. 0.32 0.94 0.62 1.12 0.50 0.30 0.40 lo.l2cc. 0.36 3 12.9 kilogrammes (Fig 75b).— The secretion of bile was unfortu- nately very irregular in the early part of the experiment. Ten grains of calomel in 9 cc. water were injected into the duodenum at c, and again at c' ; 20 grains being given in all. A profuse purgative action was the result, but the bile- secretion was only lowered. ISTeokopsy.— Stomach contained a colourless mucous fluid, with here and there a green patch of calomel that had entered it through the pylorus. The upper half of the small intestine contained a large quantity of a greyish fluid with green patches. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 143 thus affording evidence of powerful purgative effect. The mucous membrane in this region of the intestine was very- vascular. Fig. 75b. Secretion of bile before and after calomel given without bile. 10 grains calomel in 9 cc. water injected into duodenum at c, and the same dose repeated at c'. The general result of the three preceding experiments is that calomel did not stimulate the liver, although it did not fail to stimulate the intestinal glands. But it is to be observed that the calomel was introduced into the duodenum suspended in water, it could not come into contact with bile in the intestine, for, owing to the fasting condition of the animal previous to the establishment of the fistula, there was no bile there. Calomel is insoluble in water, and as Headland (Op. xx. p. 380) had pointed out that it is to a slight extent soluble in bile, we were led to suppose that possibly its non-action on the liver in these cases might have resulted from the absence of bile from the intestinal canal. And it was apparent that this source of fallacy had also vitiated every experiment that had been per- formed by previous observers. We accordingly performed the two following experiments, in which the calomel was mixed with bile, and then injected into the duodenum, and we gave smaller doses than in the preceding experiments. Experiment 76. Dog that had fasted 17 hours. Weight 14.7 kilogrammes (Fig. 76). — 2.5 cc. water and 0.5 cc. bile 144 PKOF. EUTHEKFOED AND DE. DODDS. were injected into the duodenum at b, and 2 grains of calomel in the same fluid at c, c', c", and d, 8 grains being given in all. Unfortunately, the secretion of bile was very irregular. The main result of the experiment was diminished biliary secretion, still the slight increments of secretion that followed the first, second, and fourth doses, rendered a repetition of the experiment desirable. Experiment 7S. Experiment 76a. Secretion Secretion Secretion of bile per Secretion of bUe per of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog: per hour. hour. ec. cc. 1.05 1.80 0.85 1.90 0.65 1.80 0.80 1.70 • 0.65 1.70 0.55 1.65 ■ b J ft 0.55 0.35 [o.l25cc. 1.65 1.70 ■ 0.258 cc. 0.40 ) 1.65 , c c 0-65 \ 1.70 0.60 0.80 ( 0.196 CO. 1.70 , 1.65 0.75 ) 1.62 0.45 c" c' 1.60 \ 0.35 0.50 •j 1.62 1.57 ( 0.248 oc. 0.55 0.55 [.0.129 cc. 1.62 o" ' 0.30 J 1.62 c" 1.60 0.15 1.55 0.25 1.60 0.20 c-" 0.10 1.50 0.15 1.40 d 1.50 ,. 0.65 \ 1.40 0.40 0.25 1 0.108 cc. c* 1.40 0.20 J 1.30 0.30 1.40 1.30 1.25 0.204 cc. Neceopsy. — The upper half of the small intestine contained evidence of decided purgation. Its mucous membrane was con- siderably congested. KXPEKIMENTS ON THE BILIAEY SECRETION OF THE DOG. 145 Hxperiment 76a. Dog that had fasted 17 hours. Weight 25.7 kilogrammes (Fig. 76a). — 2.5 cc. water and 0.5 cc. Fig. 76. Secretion of bile before and after calomel given with bile. 0.5 cc. bile and 2. 5 cc. water injected into duodenum at b. 2 grains calomel in the above fluid injected into duodenum at c, c', c", and d, respectively. bile were injected into the duodenum at 6, and-1 grain of calomel in the same fluid was injected at c, c', c", c'" and c* : 5 grains being given in all. The bile-secretion was never in- creased. Fig. 76a. Secretion of bile before and after calomel given with bile. 0.5 ec. bile and 2.5 cc. water injected into duodenum at 6. 1 grain calomel in the above fluid in- jected into duodenum at c, d, c", c"', c*, respectively. Neceopsy. — The upper half of the small intestine contained 187 cc. of a viscous fluid with grey flakes ; thus affording evi- dence of strong purgation. The vascularity of the mucous membrane was decidedly increased. 10 146 PROF. EUTHERFOKD AND DR. DODDS. Result of Experiments with Calomel mixed with Bile. — The biliary secretion in Experiment 76a was so regular, and the doses of calomel so graduated, that its result may "be regarded as conclusively showing that calomel, when mixed with bile and placed in the duodenum, does not excite the liver, although it powerfully stimulates the intestinal glands. The addition of bile to the calomel made therefore no difference in the result. As is well known, Miahle (Chimie Appliquie) ascribed all the effects of calomel, and other mercurial preparations, to the pro- duction of mercuric chloride, by the action of the alkaline chlorides in the secretions of the alimentary canal, more especially in the gastric juice. This theory has, however, been strongly opposed by Buchheim, CEtinger, and Winckler (referred to by Wood in Op. xi. p. 330), on the grounds that, at a temper- ature so low as that of the body, calomel undergoes no trans- formation into mercuric chloride in a solution of alkaline chlorides. Nevertheless, one must remember that the gastric juice contains free hydrochloric acid. The amount is only 0.02 per cent, in the juice of man, mixed with saliva ; in that of the dog, the amount is 0.031 per cent. (C. Schmidt). When Miahle wrote, the free acid of the gastric juice was thought to be lactic ; therefor^the effect of very dilute hydrochloric acid on calomel, at the body temperature, has not hitherto been investigated. As no conclusion could be legitimate in the absence of definite in- formation on this point, we performed the following experi- ment : — Experiment 77. — Calomel was washed with ether, the filtrate tested with caustic potash, and proved to contain no mercuric chloride. Of the calomel — thus ascertained to be pure — we placed three grammes in 500 cc. distilled water containing 0.02 per cent, anhydrous hydrochloric acid, and submitted the whole to a constant temperature of 100° Fahr. — the temperature of the stomach — for thirty-six hours. The fluid was then filtered, concentrated, and tested with sulphuretted hydrogen. A dis- tinct precipitate — first white, then changing to yellow, and finally to black — was obtained, thus proving the presence of corrosive sublimate. Judging from the precipitate, the amount was con- siderable ; but a large quantity of calomel had been employed, and it had been acted on by the acid for a lengthened period. EXPEKIMENTS ON THE BILIARY SECKETION OF THE DOG. 147 We repeated the experiment, using the same amount of calomel and acid fluid, but keeping it only seventeen hours at the temperature of the body. The fluid was then filtered, the filtrate evaporated, the residue dried and weighed, and it was found that three grammes of calomel had yielded 17 milli- grammes of mercuric chloride. Under similar circumstances, 5 grains of calomel — the ordinary dose for a mau — would, if digested seventeen hours with about 50 cc. acid fluid, have yielded ^ grain mercuric chloride. Whether or not so minute a quantity of the latter substance is likely to affect the human liver will be considered in the sequel. Calomel is usually taken at bed-time on an empty stomach. We do not know if it can call forth a secretion of gastric juice sufficient to exert an a;ppreciable influence upon it ; but in any case, it probably does not remain in the stomach more than five or six hours at the utmost. We however postpone for the present the further con- sideration of this point. Obviously, our next duty was to ascertain whether or not corrosive sublimate has the power of stimulating the liver. Experiment 78. Dog that had fasted 17 hours. Weight 8.8 kilogrammes (Fig. 78). — Into the duodenum there were Fig. 78. Secretion of bile before and after mercuric chloride (corrosive sublimate) given without bile, a A grain, h xV grain, c tV grain, i^ -in g™in, e yV g™in./fir grain mercuric chloride in 3 cc. water injected into duodenum (f grain in all). injected the following fractions of a grain of corrosive sublimate dissolved in a cc. water : ^^ at a, j^ at 6, -^ at c, -^q at d, -^^ at e^ ^ at/; two-fifths of a grain being given in all. Necropsy. — The mucous membrane of about 14 inches of the upper portion of the small intestine was much congested. In the upper part of the duodenum there were minute hsemorrhagic 148 PROF. RUTHERFORD AND DR. DODDS. extravasations. There was evidence of a very slight purga- tive effect. The increase of secretion that followed the fourth dose of mercuric chloride was so slight, that on the whole the result must be regarded as negative. Considering the solubility of mercuric chloride in water,~and the striking contrast between it and calomel in this respect, — it is not at all probable that the negative result in Experiment 78 was due to the non-absorption of the mercurial salt. Possibly it was simply owing to the Secretion of bile per 15". Experiment 78a. Secretion of bile per kilogramme of dog : per hour. cc. 0.60 0.80 0.80 0.95 0.80 0.80 0.70 0.90 0.85 0.65 0.65 0.65 0.80 1.1 1.45 1.60 2.10 1.80 1.95 2.20 1.70 >0.171 CO. } 0.472 cc. circumstance that, in small — somewhat weak — dogs, such as that employed in the above experiment, the most certain cholagogues sometimes fail to stimulate the liver, probably because of the depressing eifect of the preliminary operation adopted in these experiments. At the same time, we resolved in the next experi- ment to add some bile to the mercuric chloride solution, in case its presence might facilitate absorption, or, at any rate, in order that the conditions encountered in the intestine in a normal case, might be more exactly imitated. EXPBKIMENTS ON THE BILIARY SECKETION OF THE DOG. 149 Experiment 78a. Dog that had fasted 19 hours. "Weight 16.2 kilogrammes (Fig. 78a). — 2.5 cc. water and 0.5 cc. bile were injected into the duodenum at I, and y'-g grain corrosive subli- mate in the same fluid was injected at c, and the same dose was repeated at c'. At the end of two hours the bile-secretion began to rise, and rose still higher after the second dose. Necropsy. — The mucous membrane of the upper 10 inches of the small intestine was decidedly reddened, and there was evidence of a very slight purgative action in this portion of the intestine. Fig. 78a. Secretion of bile before and after mercuric chloride given with bile. 0.5 cc. bile and 2. 5 cc. water injected into duodenum at J. The same fluid with tV grain mercuric chloride injected into duodenum at c and again at c' (\ grain given in all). Eooperiment 78b. Dog that had fasted 19 hours. Weight 17.5 kilogrammes (Fig. 78b). — In this experiment the same doses were given and in the same manner as in the preceding experi- ment. The result was similar, a decided increase of secretion following the second dose. Necropsy. — The state of the duodenum and its contents was precisely similar to that described in the preceding experi- ment. Experiments 78a and 78b prove conclusively, and in a very striking manner, that mercuric chloride is a hepatic stimulant ; 150 PROF. RUTHERFORD AND DR. DODDS. and that it is a powerful one is shown by the fact that in Experiment 78a, ^ grain raised the bile secretion per kilogramme of body-weight to 0.472 cc. per hour ; while in Experiment 7Sb. it raised the secretion to 0.557 cc. per kilogramme per hour. Experiment 78b. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 16". of dog ; per 15". of dog : per hour. honr. cc. cc. 0.85 c'- 0.80 1.70 0.80 -| 1.70 b 2.10 1.05 y 0-202 cc. 2.15 0.90 2.55 0.80 J 2.15 f 2.40 0.95 2.35 1 1.00 1.10 2.80 2.20 i- 0.557 cc. 1.20 2.40 J 1.30 The contrast between the last two experiments with mercuric chloride and those with calomel is remarkable, both as regards the effect on the liver, and on the intestine ; for, while the mer- curic chloride powerfully excited the liver, but scarcely affected the intestinal glands, notwithstanding its immediate contact with the latter, the calomel did not stimulate the liver, but did powerfully excite the intestinal glands. This startling result, so clearly established by these experi- ments, is a striking proof of the value of this method of investi- gation as an auxiliary to clinical observations on man. To render these experiments still more complete, we in the next two cases injected into the duodenum a minute dose of mercuric chloride along with calomel and bile. These experi- ments are valuable in showing the very remarkable stimulation of the liver that followed an unusually small dose of the mercurial. Experiment 78c. Dog that fasted 17 hours. Weight 9.9 kilogrammes (Fig. 78c). — 0.5 cc. bile and 2 cc. water were EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 151 injected into the duodenum at h, and ^^ grain of corrosive subLi- mate and 1 grain of calomel in the same fluid were injected at m. Fig. 78b. Secretion of bile before and after mercuric chloride given with bile, h, c, and c' indicate precisely the same as in fig. 78a. Experiment 7Sc. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog : per 15". of dog : per hour. hour. cc. cc. 1.2 "4 1.65 1.2 1.80 \ b 1.1 >0.48cc. ) 1.75 1.85 VO.72 CO. 1.3 1.75 ) m 1.50 1.4 1.35 1.65 1.15 1.50 1.15 Necropsy. — Slightly increased vascularity of mucous mem- brane of duodenum. No purgation. 152 PROF. RUTHERFORD AND DR. DODDS. In the above experiment, the bile-secretion per hour rose to 0.72 CO. per kilogramme of body-weight, but the secretion was Fig. 78c. Secretion of bile before and after mereurio chloride and calomel given with bile. 0. 5 cc. bile and 2 co. water injected into dnodenum at b. ^ grain mercuric chloride and 1 grain calomel in the same fluid injected into duodenum at m. Experiment 78d. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 15". of dog: per 15". of dog : per hour. _ hour. cc. cc. ~ 0.7 2.0 0.7 \ m' 1.2 2.4 1.2 V0.228cc. 1.8 1.1 1.4 m 1.3 1.8 1.7 lost m" 1.9 1.45' 2.3 ^ 1.4 3.2 6.0 > 0.85 CO. 1.4 5.2 ) so high — 0.48 cc. — before the drug was given, that it was diffi- cult to know exactly how to regard the very high figure first mentioned, Another experiment was therefore desirable.. EXPERIMENTS ON THE BILIAHY SECRETION OF THE DOG. 153 Eocperiment 78d. Dog that had fasted 17 hours. Weight 18.4 kilogrammes (Fig. 78d). — -^ grain of corrosive subli- Fig. 78d. Secretion of bile before and after mercuric chloride and calomel given with bile. jV grain mercuric chloride with 1 grain calomel in 0.5 cc. bile and 2 cc. water injected into duodenum at m, to', and m" respectively. 1 54 PROP. BUTHEKFORD AND DR. DODDS. mate and 1 grain of calomel mixed with 2 ec. water and 0.5 cc. bile were injected into the duodenum at m, and the same dose was repeated at m' and at m". Necropsy. — Considerable irritation of the mucous membrane of the upper fourth of small intestine. The contents of this portion of the canal indicated considerable purgative action. The increase of bile-secretion in Experiment 78d is very remarkable, not only for its absolute extent, but also because of the smallness of the dose that occasioned it. The amount of bile secreted per kilogramme of body-weight rose to the very high figure of 0.85 cc. per hour. The effect of so small a dose as ^'o grain of corrosive sublimate in this experiment is very remarkable, for the animal was rather larger than those employed in Experiments 78a and 78b, where -^ and even J grain had not so powerful an effect. Considering the result of Experiment 76a, it is not in the least likely that the addition of one grain of calomel to the dose of the mercuric chloride had anything to do with the difference in the result. We can only suggest, by way of explanation, that possibly in some cases the liver is more susceptible to a mercurial stimulus than it is in others. With the mercuric chloride we had given bile in every case save in Experiment 78, and that was the only instance where the result was negative ; we therefore thought it desirable to perform another experiment with mercuric chloride given with- out bile. MxperiTiient 78e. Dog that had fasted 17 hours. Weight 1114 kilogrammes (Fig. 78e). — ^ grain corrosive sublimate in 6 cc. water was injected into the duodenum at c,' and the same dose was repeated at c' and c". The liver was stimu- lated, the coefficient of bile-secretion rising as high as 0.5 cc But the experiment is inconclusive, for a reason mentioned in the necropsy- Nbcropsy.— The upper fourth of the small intestine contained a considerable quantity of somewhat dark fluid, looking as if bile had been injected. Possibly some bile had, in this case, escaped from the bile-ducts into the intestine during the per- formance of the operation. The presence or absence of bile would have been determined by testing the fluid for bile- EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 155 pigment, but unhappily a portion set aside for that purpose was lost. Experiment 78e. Secretion Secretion Secretion of bile per Secretion of bile per of bile per kilogramme of bile per kilogramme 16". of dog : per 15". of clog : per hour. honr. Of. cc. 1.80 1.35 1.70 1.50 1.50 1.50 1.85 1.55 1.45 I 0.388 cc. 1.75 1.35 1.30 1.30 1.65 1.10 1.70 c 1.50 1.15 1.30 0.80 c" 1.45 1.90 ■\ lost 1.25 1.70 1.65 \ 0.50 cc. 1.30 1.45 J 1.55 1.50 1.10 1.45 c' 1.60 This experiment therefore is inconclusive as regards the point at issue, viz., whether or not mercuric chloride is absorbed from Fig. 78e. Secretion of bile before and after mercuric chloride given without bile. \ grain mercuric chloride in 6 cc. water injected into duodenum at c, c', and c" (f grain given in all). 156 PllOF. EUTHEKFORD AND DE. DODDS. the intestine without the preseiice of bile. But we felt that it would scarcely be justifiable to perform yet another experiment to settle the point ; for it is to the last degree improbable that bile is necessary, and probably no one will feel inclined to maintain that it is. Table XXV. Mercury. Total Dose in Grains. Grains per kilogramme of Body-weight. Secretion of bile per kilogramme of Body-weight per hour. Before. After. Experiment 78a, Mercuric Chloride, Experiment 78b, Mercuric Chloride, Experiment HgCl, 780, HgCl Experiment I HgCl^ 78d, ( HgCl J with bile, i 1 A „ 1 0.0077 0.0071 0.005 ) 0.101 ( 0.0027 0.054 0.17 cc. 0.20 cc. 0.48 cc. 0.22 cc. 0.47 cc. 0.55 cc. 0.72 cc. 0.85 cc. Result of Experiments with Mercuric Chloride. — These experi- ments conclusively prove that mercuric chloride is a powerful hepatic stimulant in the dog. Probably — now that attention is specially directed to the subject — it will also be found to stimulate the liver of man ; for the experiments already referred to {Op. v.), that were carried out by the author for Bennett's committee, showed that the general effects of mercuric chloride on the dog are similar to those observed in man. Doubtless the converse will be found to hold. In the series of experiments just referred to, on the pro- duction of mercurialism in the dog, the mercuric chloride was always injected subcutaneously, and in two experiments on the action of this substance on the biliary secretion, performed for that committee, the drug was given in the same manner. This mode of administering a substance for the purpose of acting on the liver was faulty, and its results are not fairly comparable with those of the ordinary method, where the substance is EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 157 placed in the alimentary canal, from which its molecules are absorbed into the radicles of the portal vein, and so pass to the liver in a much more concentrated stream than they possibly can when the substance passes first into the general and then into the portal circulation. With regard to these two experiments, Hughes Bennett stated in the report {Op. v. p. 221) " that corrosive sublimate when given " [suhcutanemisly] " in small doses, gradually increased in strength, does not augment the bUiary secretion, but that it diminishes it the moment the dose reaches a strength sufficient to deteriorate the general health," The latter part of the state- ment was warranted by the results of both experiments. But the first part, though true as regards one of the experiments, was certaiiily untrue as regards the other (Op. cit. p. 212, Table XIII.), where an unequivocal increase of bile-secretion took place when the dose of mercuric chloride, given subcutaneously, was raised from one-sixth grain once a day to one-sixth grain twice a day (loc. dt. June 9th and 10th). The reporter of the experiments on that occasioa overlooked the important fact here stated, and deduced the above general conclusion from mis- leading results, arrived ab by taking the daily average quantity of bile secreted during too prolonged a period. Results of Hxperiments with Calomel. — With regard to calomel, we have proved the following : — (1.) That calomel in doses of 10 grains, 5 grains, or 2 grains, several times repeated, when placed, withoiit bile, in the duodenum of a fasting dog, produces a purgative effect, varying with the dose; but, so far from increasing the secretion of bile, usually diminishes it, just as happens when any other substance that is not a hepatic stimu- lant — e.g. magnesium sulphate — is administered. (2.) That when calomel is mixed vnth bile, and then introduced into the duodenum, there is no difference in the result, even when, as in Experiment 76a, the calomel is given in 1 grain doses several times repeated, and the chance of acting on the liver, previous to supervention of the depressing effect of purgation, thus allowed. (3.) That if 5 grains of calomel.be subjected at 100° Fahr. for seventeen hours to the action of dilute hydrochloric acid, of the same strength as that of the human gastric juice, not more than ^g grain of mercuric chloride is produced. 158 I'EOF. RUTHERFORD AND DR. DODDS. The question now arises, seeing that calomel does not usually remain in the human stomach for . more than a night, probably not more than from five to six hours, is it likely that even so much as -^ grain of mercuric chloride is produced from the ordinary dose of 5 grains, and if it is, What effect may it be supposed to have on the human liver ? It must be borne in mind, however, that we are here on dangerous ground, for we are inclining to reason about the action of the gastric juice itself from experiments on the action of dilute hydrochloric acid, and a solution of alkaline chlorides. It would clearly be more conclusive if we could substitute direct experiment for mere inference. We are in a position to do this. As regards the dog, it is evident that the only link wanting to complete our chain of evidence is, that we should place the calomel in the stomach instead of the duodenum, and thus render the case analogous to that of the human subject as regards the administration of this drug. With regard to the eases of calomel, we did indeed seriously think for a time that the negative effect of the calomel on the liver might possibly have been due to the circumstance that the drug was introduced directly into the duodenum, and thus escaped the action of the gastric juice. Experiment 78f. — Into the stomach of a eurarised dog, that had fasted the usual time, we injected 5 grains of calomel in water. The injection was made with a fine syringe, through the gastric wall, in order that the whole of it might certainly reach the interior of the viscus. Injection through an oesophagus tube was avoided, because a substance so insoluble as calomel would certainly have clung to the interior of the tube, and would thus have been partly lost. The result of the experiment was entirely negative, both as regards the liver and the intestinal glands. This was readily explained by the fact, that at the necropsy the calomel was found apparently unchanged, enveloped in the mucus of the stomach. The saliva of the dog is peculiar in containing a very large quantity of mucin. As previously stated (p. 41), the accumulation of this viscous saliva in the stomach during fasting is calculated so seriously to interfere with absorption, that we, on this account, in nearly all these experiments, injected the various drugs directly into the duodenum. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 159 We would not, however, have attempted the preceding experi- ment, had we at the moment recollected that the question at issue had already received a satisfactory answer from the previous experiments of KoUiker and Miiller, Scott, and Bennett's Committee. In those experiments the calomel was given by the mouth in the usual way, and the animals had their usual diet. Every opportunity was therefore afforded for a transformation of the calomel into mercuric chloride — probably indeed a better opportunity than is afforded in the human subject, for the gastric juice of the dog is, as previously stated, (p. 146), more acid than that of man, — and yet we find that the action of the calomel, when placed in the stomach of the dog, was just the same as when introduced directly into the duodenum. We have proved that -^ grain corrosive sublimate with 1 grain of calomel when placed in the duodenum (Experiment 78d) can powerfully stimulate the liver of the dog, but we find no reason for entertaining the idea that the amount of mercuric chloride produced by the gastric juice from 5 grains of calomel has any appreciable effect on the liver, for in one of the experiments for Bennett's Committee the amount of calomel placed in the stomach was 10 grains, and it occasioned no increased secretion of bile.* But it may be said, Although these facts render it impossible to entertain the idea that the action of calomel is due to the mercuric chloride produced from it by the gastric juice, is it not possible that the entire absence of the bile from the intestine in the case of the experiments of Bennett's Committee interfered with the absorption of the drug, so that, while it excited the intestinal glands with which it came directly in contact, it failed to excite the liver because it could not reach it ? This objection cannot be entertained — (1.) Because Experiments 76 and 76a of the present series prove that when calomel mixed with bile is placed in the duodenum it does not stimulate the liver. (2.) In the experiments of Bennett's Committee, although the calomel could not possibly encounter bile in the alimentary canal, a part of it must have been absorbed, because, when given ^ The dose of calomel was 10 grains given on three successive days. On the first it produced "slight" and on the other two days "decided" purgation, but on all the days the fluid and the solid bile was diminished. 160 PROF. EUTHEEFOED AND DR. DODDS. in small doses, frequently repeated, the animal speedily lost its appetite and became extremely unwell, although the doses were too small to produce purgative action. The conclusion is inevitable, that vyhile corrosive sublimate does — calomel does not — stimulate the liver of the dog, and that when calomel is placed in the stomach of the dog, there is — if the dose be sufficient — the characteristic action on the intestinal glands, but no excitement of the liver. There is therefore no evidence that a purgative dose of calomel, when acted on by the gastric juice, gives rise to mercuric chloride sufficient to exert any appreciable effect on the liver. Seeing that in these observations we have submitted to direct experiment on the liver of the dog, every substance that has any reputation as a cholagogue in the case of man, and seeing that we have found that, with the exception of calomel, they all increase the biliary secretion in the dog, it appears to us that the remarkable harmony between the vast majority of our results and those of clinical experience, entitles us to maintain that our experiments with calomel are not to be set aside by the clinical observer, merely because he is of the opinion that calomel in some way or other increases the discharge of bile in man. There has been on the part of one or two physicians — who, in their lamentable ignorance and narrow-mindedness, imagine that physiological pharmacology studied on a dog cannot help them to know the action of a drug on man — a tendency to altogether set aside the results of previous experiments with calomel, because they do not harmonise with their previously entertained opinions. These physicians appear to imagine that they can end the discussion by simply saying " the liver of a dog is not that of a man." That truism cannot be disputed, and we are perfectly willing to admit that it is possible that the human liver may be more or less susceptible than the liver of the dog to the influence of various substances, but we maintain that up to this time there is really rbo proven discord between our results and those arrived at by observations on man. All our experiments have had reference to the secretion and not the expulsion of bile. For the purpose of arriving at definite knowledge, we intentionally — in the manner described at the outset of these experiments — threw out of action the Hle-eoypelling EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 161 mechanism, in order that we might have to deal with the Ule- secreting apparatus only. We do not profess to have ascertained anything regarding the action of any drug on the bile-expelling mechanism. The clinical observer has supplied most valuable information regarding the power of various substances to increase the amount ot bile in the dejections. He observes dejections of a clay colour, he gives five grains of calomel, and further observes that in some cases the dejections thereafter assume their natural appearance. He cannot be certain of the manner in which this result is brought about. Tor anything he knows, it might be occasioned (1) by stimulation of the hepatic secreting apparatus ; or (2) by stimulation of the muscular fibres of the gall-bladder and larger bile-ducts — to wit: — the bile-expelling apparatus ; or (3) by removing a catarrhal or congested state of the orifice of the common bile-duct, or of the general extent of the larger bile- ducts ; or (4) by removing from the intestine substances which had been passing therefrom into the portal vein and depressing the action of the hepatic cells ; or (5) by stimulating the intestinal glands, and thus producing drainage of the portal system, whereby the " loaded " liver might possibly be relieved. Yet, notwithstanding the inability of clinical observers to unravel this complicated web, and supply us with any definite statement, one of them ^ has felt inclined to think the results arrived at by Bennett's Committee of no value, because they proved by direct experiment that calomel does not in the dog stimulate the hepatic secreting apparatus. Seeing that calomel stimulates the intestinal glands in the dog as in man ; seeing that mercury produces salivation, ulceration of gums, and other characteristic phenomena in the dog as in man, the obvious inference is that the reputed cholagogue action of calomel in the human subject is probably not owing to stimu- lation of the bile-secreting apparatus. And why should we, in ' Vide Dr Moxon, HwUerian Oration, 1877, Medical Press and Circular, March 1877. In that remarkable "oration" Dr Moxon, while adopting an un- becoming style of supercilious criticism of the experimehts of Bennett's Com- mittee, showed his ignorance of their object, of the experimental method employed, and of the conclusions drawn. His ignorance of the subject is reprehensible enough in a Hunt^rian orator, but much more so in a Lecturer on Materia Medica and Therapeutics in such a school as Guy's Hospital, London. R 11 162 PROF. RUTHEEFORD AND DR. DODDS. the face of our experiments, believe the opposite until the clinical observer substitutes — for vague conjecture — definite proof of that opposite, by experimenting in a case of biliary fistula in the human subject, when it happens that no bile enters the intestine, and where the amount secreted may be measured by collecting it as it flows from the fistula. Our experiments therefore suggest that the cholagogue action of calomel in the human subject is to be sought for, not in any supposed power of stimulating the bile-secreting mechanism, but in some one or more of the last four modes of action above indicated. Calomel undoubtedly excites the intestinal glands, and for anything we know there may be something peculiar in the nature of its action thereon. For anything we know, it may also have some special influence on the mucous glands and mucous membrane generally of the larger bile-ducts, whereby a catarrhal condition of these ducts may be relieved, and the pent-up bile thus permitted to escape. There is evidently still abundant room for conjecture, but our experiments plainly narrow its range, and thus contribute to the attainment of definite knowledge. The practical physician would, however, do well to observe our discovery, that when a small dose of corrosive sublimate is combined with calomel, stimulation of the liver, as well as of the intestinal glands, is the result. He may probably find it of advantage to apply this combination in the case of man. SUMMAEY OF EESULTS., 1. In a curarised dog that has fasted eighteen hours, the secretion of bile is tolerably uniform during the first four or five hours after the commencement of the experiment, but falls slightly as a longer period elapses. Its composition remains constant. 2. Croton oil is a, hepatic stimulant of very feeble power. The high place assigned to it by Eohrig was probably the result of his imperfect method of experiment. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 163 3. Podophyllin is a very powerful stimulant of the liver and of the intestinal glands. During the increased secretion of bile, the percentage amount of the special bile-solids is diminished. If the dose be too large, the secretion of bile is not increased. 4. Aloes in very large doses is a powerful hepatic stimulant. It renders the bile more watery, but at the same time increases the secretion of biliary matter by the liver, 5. Ehubarb is a certain, though not a powerful, hepatic stimulant. The bile secreted under its influence has the normal composition. 6. Senna is a hepatic stimulant of very feeble power. It renders the bile more watery. 7. Colchieum in very large doses is a po^verful stimulant of the liver and intestine. It renders the bile more watery, but increases the secretion of biliary matter proper. 8. Magnesium sulphate stimulates the intestinal glands, but not the liver. 9. Castor oil stimulates the intestinal glands, but not the liver. 10. Gamboge stimulates the intestinal glands, but not the liver, 11. Ammonium chloride stimulates the intestinal glands, but not the liver. 12. Scammony is a powerful intestinal but feeble hepatic stimulant. 13. Euonymin is a powerful hepatic but a feeble intestinal stimulant. 14. Iridin is a powerful hepatic stimulant. It also stimulates the intestine, but not so powerfully as podophyllin. 15. Leptandria is a hepatic stimulant of moderate power. It is a feeble intestinal stimulant. 16. Sanguinarin is a powerful hepatic but a feeble intestinal stimulant. 17. Ipecacuan is a powerful hepatic stimulant. It increases slightly the secretion of intestinal mucus; but has no other apparent stimulant effect on the intestine. The bile secreted under the influence of ipecacuan has the normal composition. 18. Colocynth is, in large doses, a powerful hepatic as well as intestinal stimulant. It renders the bile more watery, but increases the secretion of biliary matter. 164 PROF. EUTHERFOKD AND DR. DODDS. 19. Jalap is a moderately powerful hepatic, and a powerful intestinal stimulant. 20. Taraxacum is a very feeble stimulant of the liver. 21. Dilute nitro-hydrochloric acid is a hepatic stimulant of considerable power. 22. Sodium chloride is a very feeble hepatic stimulant. 23. Eochelle salt is a feeble hepatic but a powerful intestinal stimulant. 24. Sodium phosphate is a powerful stimulant of the liver, and a moderately powerful stimulant of the intestine. 25. Sodium sulphate is a moderately powerful stimulant of the liver, and a powerful stimulant of the intestine. 26. Potassium sulphate is a hepatic and intestinal stimulant of considerable power. Its action on the liver is, however, uncertain, probably owing to its sparing solubiKty. 27. Sodium bicarbonate has scarcely any appreciable effect as a stimulant of the liver, even when given in very large doses. 28. Potassium bicarbonate does not excite the liver unless it be given in very large doses. 29. Potassium iodide has no notable effect on the biliary secretion. 30. Calabar bean stimulates the liver, but not powerfully, unless it be given in very large doses. 31. Atropia sulphate antagonises the e£fect of Calabar bean on the liver, and thereby reduces the hypersecretion of bile pro- duced by that substance. It does not, however, arrest the secretion of bile, and, when given alone, does not notably affect it. 32. Menispermin does not stimulate the liver. It slightly stimulates the intestinal glands. 33. Baptisin is a hepatic and also an intestinal stimulant of considerable power. 34. Phytolaccin is a powerful hepatic stimulant. It also slightly stimulates the intestinal glands. 35. Hydrastin is a moderately powerful stimulant of the liver and a feeble stimulant of the intestine. 36. Juglandin is a moderately powerful hepatic and a mUd intestinal stimulant. ■ 37. Sodium benzoate is a powerful hepatic stimulant. It is not an intestinal stimulant. EXPEKIMENTS ON THE BILIARY SECRETION OF THE DOG. 165 38. Ammonium benzoate stimulates the liver, but not quite so powerfully as the sodium salt of benzoic acid. It does not stimulate the intestinal glands. 39. Benzoic acid stimulates the liver, but, owing to its insolu- bility, its action is less rapid and much less powerful than that of its alkaline salts. 40. Sodium salicylate is a very powerful stimulant of the liver, but a very slight stimulant of the intestinal glands. 41. Ammonium phosphate is a powerful stimulant of the liver. It does not stimulate the intestinal glands. 42. Tannic acid does not affect the secretion of bile. 43. Acetate of lead, in large doses, somewhat lessens the secretion of bile, probably by a direct action on the liver. 44. Jaborandi is a very feeble hepatic stimulant. 45. Sulphate of manganese does not excite the liver, but it is a powerful stimulant of the intestine. 46. Morphia has no appreciable effect on the secretion of bile, and does not prevent the stimulating effect of such a substance as sodium salicylate. 47. Hyoscyamus does not affect the biliary secretion to any noteworthy extent, and does not interfere with the stimulating effect of sodium salicylate. 48. Pure diluted alcohol does not affect the biliary secretion. 49. Calomel stimulates the intestinal glands, but not the liver. 50. Mercuric chloride (corrosive sublimate) is a powerful hepatic, but a feeble intestinal stimulant. When mercuric chloride and calomel are administered together, both the liver and the intestinal glands are stimulated. 51. The injection of 100 cc. (1543 grains) of water into the duodenum gives rise to only a trifling increase of the bile-secre- tion (Experiment 6). 52. The injection of 3 cc. (46.2 grains) bile into duodenum does not affect the bile-secretion (Experiments 25, 26) ; 6 cc. (92.4 grains) increase the secretion slightly (Experiment 10). 53. Purgation produced by purely intestinal stimulants, such as magnesium sulphate, gamboge, and castor oil, diminishes the secretion of bile. 54. When a substance— «.5'., podophyllin — which powerfully 166 PBOF. RUTHERFOED AND DR. DODDS. stimulates the intestine as well as the liver is given in too large a dose, the bile-secretion may never be increased (Experiment 9), and though it should be increased in the first instance, it is soon diminished as the excitement of the intestinal mucous membrane extends downwards and implicates a larger and larger number of its glands (Experiment 10). All the above conclusions are based on experiments performed on the dog, and have no reference to any observations made on the human subject. Although the hourly coefficients of secretion per kilogramme of body-weight before and after the administration of the principal hepatic stimulants have been already given in detail, it will facilitate a comparison of the effects of the different substances if the results be thrown together as in Table XXVI. As already explained, the coefficients of bile-secretion under the influence of hepatic stimulants cannot be regarded as an absolute index of the relative powers of the stimulants, even in the case of the dog, because in some instances — e.g., those of aloes, podophyllin, colchicum, and physostigma — the doses were exces- sive. It would be unfair to compare the effects of such doses with those of moderate doses of other substances. And, as also has been previously stated, young dogs secrete, in proportion to their size, more bile than old dogs ; therefore, a higher coefficient is the rule in their case. We have, as far as possible, taken these points into consideration, and the summary of results above given, contains the conclusions at which we have arrived. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 167 Table XXVI. Secretion of Bile per kilogramme Substance Given. of Body-weight Experi- ment. per hour. Name. Total Dose in Grains. Grains per Kilogramme of Body-Weight. Before. After. ( Normal secretion of bil( '- ) cc. cc. 1 < during the influence o ( small doses of curara I [ 0.35 lA >) i> tt 0.25 3 0.15 8 Podophyliin, 6, without bUe o.'g 0.04 0.47 10 Podophyllin, 4, with bile 0.23 0.62 1.01 11 Aloes, 60, without bile 6.9 0.34 0.69 12 Aloes, 60, 12.0 0.26 0.93 13 Rhubarb, . 68, 3.06 0.17 0.32 17 Colchicum, 60, 2.5 0.13' 0.45 18 Colchicum, 60, ,, 2.5 0.10 0.20 27 Euonymin, 5, with bile o;26 0.25 0.47 28 Euonymin, 5, 0.21 0.07 0.46 29 Sangainarin, 1, 0.05 0.16 0.30 30 Sanguinarin, 3, 0.11 0.12 0.40 31 Iridjii, 5, 0.22 0.22 0.53 32 Iridin, 5, 0.92 0.16 0.63 34 Leptandria, 18, 1.10 0.08 0.31 33 Leptandria, 18, 0.88 0.19 • 0.27 36 Ipeoacuan, 60, 2.2 0.24 0.55 37 Ipecacuan, 3, 0.49 0.18 0.38 39 Colocynth, 14, 0.53 0.29 0.45 40 Colocynth, 7, 0.4 0.16 0.27 41 Jalap, 30, 1.2 0.16 0.29 43 Jalap, 40, 3.2 0.17 0.35 60 Dilute Nitro -hydro- chloric Acid, . 36.4, without) bile i 2.0 0.11 0.39 53 EocheUeSalt, . 463, with bile 37.2 0.23 0.33 51 ' Sodium Phosphate, . 201, without bile 7.4 0.27 0.44 44 Sodium Sulphate, 120, 6.1 ■ 0.10 0.27 45 Sodium Sulphate, 508, with bile 32.3 0.25 0.38 50 Potassium Sulphate, . 232, without bile 10.7 0.32 0.47 61 Extract of Physostigm 1 2, with bile 0.0074 0.09 0.36 6lA Extract of Physostigm 1 2, 0.0147 0.13 0.75 63 Baptisin, . 7, 0.303 0.23 0.39 64 Baptisin, . 7, 0.374 0.12 0.29 65 Phytolaccin, 2, 0.064 0.144 0.29 65a Phytolaccin, 2, 0.104 0.338 0.47 66 Hydrastin, 2, 0.077 0.23 0.38 66A Hydrastin, 2, 0.147 0.09 0.32 I 5 0.236 0.10 0.28 67 Juglandin, I 10, 0.472 0.10 0.32 68 Sodium Benzoate, 20, without bile 1.320 0.22 0.64 68a Ammonium Benzoate, 20, 0.737 0.24 0.54 74a Sodium Salicylate, . 20, 1.000 0.17 0.56 62 Sodium Salicylate, . 25, 1.550 0.26 0.66 69 Sodium Salicylate, . 20, 2.150 0.32 0.89 78a Mercuric Chloride, . J, with bile 0.0077 0.17 0.47 78b Mercuric Chloride, . h „ 0.0071 0.20 0.55 780 HgCP, . . . HgCl, . . . 1, „ 0.005 0.101 0.48 0.72 78d HgCP, HgCl, . 1, 0.0027 0.054 0.22 0.85 168 PROF. RUTHKRFORD AND DR. DODDS. Mode of Action of Hepatic Stimulants. Although we have definitely proved that a large number of substances stimulate the liver to secrete more bile, we do not profess to have absolutely shown in what manner they do this. It may be asked — 1. Do they excite the mucous membrane of the duodenum or other part of the small intestine, and thereby induce reflex excitement of the liver? One would be readily disposed to entertain this idea from the fact that stimulation of the oral mucous membrane so readily induces secretion in the salivary glands ; yet we are obliged to reject the idea that this likewise . holds true of the liver, because such substances as gamboge and magnesium sulphate powerfully irritate the intestinal mucous membrane, while they do not in the least increase the secretion of bUe. On the other hand, such substances as ipecacuan, sodium benzoate, and ammonium benzoate, powerfully excite the liver without inducing any notable excitement of the intestine. 2. Do these substances stimulate the hepatic cells by merely increasing the stream of blood through the liver ? Whatever be the state of the hepatic vessels during increase of the biliary secretion, it is quite certain that increased secretion of bile does not necessarily follow dilatation of the intestinal capillaries, the effect of which, if it be not carried to excess, may with reason be supposed to increase the stream of blood through the portal vein, and thence through the liver. But castor oil greatly dilates the intestinal capillaries, yet the bile-secretion does not rise in the least. 3., We therefore believe that the effect of hepatic stimulants is to be assigned to a direct action of their molecules upon the hepatic cells or their nerves. The effect of physostigma and atropia rather points to an action on the latter — in their instance at all events — as has been already indicated (p. 96). But we do not think it advisable at present to pursue this difficult subject, which, as far as we can see, is of little importance com- pared with knowing what does and what does not stimulate the liver. It is particularly to be observed that all our experiments con- EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 169 cern the influence of substances on the lUe-secreting mechanism. The nature of our method has forbidden any observations on the action of drugs on the hile-ex/pelling mechanism. Seeing that the acid chyme, by irritating the duodenal mucous mem- brane, effects a reflex expulsion of bUe, it may be that many substances which stimulate the duodenum have a similar effect. Yet we cannot but think that to bring about an expulsion of bile by muscular contraction of the gall-bladder and bile-ducts is, in all probability, a small thing when compared with increasing the secretion of. bile. One might expect that such powerful intestinal irritants as magnesium sulphate and gamboge would be likely to bring about a reflex expulsion of bile ; yet no one has attributed any cholagogue power to these. But, without attempting to reason out a question that can only be determined by experiment, we would merely add, that we leave the investi- gation of the action of drugs on the hile-escrpelling mechanism to those who care to enter upon such an inquiry. We are satisfied to have shown that every substance supposed to be a cholagogue has, with the exception of calomel (p. 157) and sulphate of man- ganese (p. 127), the power of exciting the bile-secreting mechan- ism ; and, as our estimate of their powers, from an observation of the bile-secretion only, so closely agrees with observations on the human subject, where actions on the bile-secreting and on the bile-expelling mechanisms cannot be distinguished from one another, we cannot but infer that surely their actions on the human subject must be chiefly on the bile-secreting mechanism. The term cholagogue is of necessity a vague one, and is applicable to any substance that increases the biHary flow, whether by augmenting bile-secretion or by exciting contraction in the walls of the bile-passages. We have, therefore, applied the more definite term hepatic stimulant to those substances which we have proved to increase the secretion of bile. Hepatic Depressants. It cannot fail to strike the reader as a remarkable fact that while in the long lists of drugs whose hepatic effects we have 170 PROF. EUTHEEFOED AND DE. DODDS. investigated, we have found so many that stimulate the liver, there is only one — acetate of lead (p. 121) — which appears to have a directly depressant eifect. We have, however, found several drugs that have an indirectly depressant action; thus, when the intestinal glands are excited to secrete, there is an indirectly depressant effect on the liver, whereby the bile-secre- tion is lessened. This we have seen to happen when magnesium sulphate, castor oil, gamboge, and calomel are given, and doubt- less other purely intestinal irritants have a similar effect. We invariably observed that, while slight purgation — by a purely intestinal irritant — scarcely, if at all, depressed the secretion of bile, powerful purgation produced a very marked effect. Why is the action of the liver thus depressed ? In our experiments, we had to deal with fasting animals, whose intestinal canals contained neither bile nor food. Under such conditions, mag- nesium sulphate could not depress the bile-secretion by dimin- ishing the absorption of substances that augment the formation of bile. Its depressant effect seems, therefore, attributable either to a drain from the portal blood of bile-forming sub- stances, or to an excessive lowering of the blood-pressure in the liver, as in the system generally, by a large dilatation of intes- tinal and mesenteric vessels. But when such a purely intes- tinal stimulant as magnesium sulphate is given to an individual under ordinary circumstances, it doubtless depresses the secre- tion of bile, not only in the manner just indicated, but also by hurrying out of the intestinal canal substances which would otherwise have been absorbed, and would have assisted in the formation of bile. Thus it cannot be doubted that, when the bile is prevented from entering the intestinal canal, less bile is secreted by the liver ; and there is ample reason for believing that about |ths of the sulphur daily secreted by the liver is re-absorbed from the intestinal canal by the portal vessels — in the form of some sulphur-containing substance derived from the decomposition of taurocholic acid — the sulphur-containing acid of the bile. Aiid it may he that, in abnormal states of the intes- tinal contents, various deleterious matters may he ahsorhed, and hamper hepatic action. Therefore, it is reasonable to suppose that a purely intestinal stimulant, such as magnesium sulphate, although it does not stimulate the liver, may nevertheless in EXPERIMENTS ON THE BILIAKY SECRETION OF THE DOG. 171 some abnormal conditions exercise an important influence on that organ, by removing deleterious matters from the intes- tinal canal, and by draining the portal system. We believe, then, that by the discovery of the depressant effect on hepatic action of purely intestinal purgatives, we have furnished the physician with a fact which will not fail to be of service in rational therapeutics. Concluding Observations. In the introduction we pointed out what had been ascertained regarding the actions of drugs on the secretion of bile by our predecessors. We showed that, for want of a proper method of experiment, the definite knowledge arrived at was very meagre, and to some extent erroneous; and, if the statements in that introduction be compared with our summary of results, some idea may be formed of the extent of our labour, which we have striven to render as complete and as free from error as possible. We claim that, by means of a novel and precise method of investigation, we have been the first to place the whole subject of the physiological actions of drugs on the bile-secreting function of the liver upon a sound footing, and thus to lay a real foundation for the rational — that is, scientific — treatment of many diseased conditions of this important organ ; and it is gratifying to know that, in consequence of this research, many physicians have been led to use new remedies to which we have specially directed attention. We have indeed occasioned, by our experiments, a considerable amount of pain to a number of dogs; but, considering that our discoveries are calculated to relieve much suffering, not only of men, but also of dogs, for all time to come, we believe that we have spared infinitely more suffering in the future than we have occasioned in the present. In conclusion, I have to tender my warm thanks to my former pupils, M. Vignal and William J. Dodds, M.B. D.Sc, for their valuable assistance in the performance of the experi- ments, and for their company during the long and weary hours through which they daily extended. I have very cordially to thank the Scientific Grants Committee of , the British Medical Association for having voted upwards of £200 from the funds 172 PROF. RUTHERFORD AND DR. DODDS. of the Association to defray the very heavy expenses incurred for the materials for the research, and for their energetic and powerful support at a time when the clamour of blind ignorance and silly prejudice seriously menaced and almost arrested the progress of this research. Having personally devoted not less than 1400 hours of severe labour to the accomplishment of this work, and having (as, of course, every medical man thinks himself bound to do for the alleviation of suffering) communi- cated to all every fact calculated eventually to cure affections so common as those of the liver, it is, to say the least, ungrateful, that a certain section of the public should have rewarded our unselfish efforts to cure their hepatic derangements by a flood of abuse ; because, like most of- our medical brethren, we believe that to be penny-wise and pound-foolish as regards pain is a policy as short-sighted, as narrow-minded, and as reprehensible here as elsewhere. Though profuse with their ingratitude, I doubt not that one and all of them will be very ready and eager to profit by the results of our labour ; for I suspect that most of them are scarcely willing to refuse all medical aid, and to thus push their logic to its practical issue. Desiring, as I think most of them do, to continue in receipt of all the medical assist- ance they can obtain, it may possibly satisfy their conscientious scruples to vainly attempt to make it appear that "nothing worth knovnng " in medicine has been learned from experiments on animals. It is not difficult, by misrepresentation and by a multiplicity of words, to deceive a public ignorant of the machinery of life and of the processes by which its movements are studied and remedies found for its disorders ; biit they cannot thus deceive any moderately well-informed and right- minded medical practitioner. The discoiirtesy, misrepresentation, and injustice that we have suffered at the hands of those who should have acted otherwise, has not, however, induced us to prove false to the interests of suffering humanity. We are conscious of having faithfully done our utmost to advance the scientific treatment of diseases of the liver, and, while steadily pursuing this great object, we have been most careful to avoid the infliction of all pain that was not absolutely necessary. EXPERIMENTS ON THE BILIARY SECRETION OF THE DOG. 173 REFERENCES. 1. H. Nasse : " Commentatio de bills quotidie a cane secreta copia et indole," Abstract in GanstatVs Jahresbericht, 1858, Heft. i. p. 155. 2. KoLLiEER and Muller : " Beitrag zur Leiire von der Gallen," Wiirz- burg Verbandlungen, 1855, Band v. p. 231. 3. MosLER : " Untersuchungen iiber den Ubergang von Stoffen aus dem Blute in die GaUe," Virchow's Archm, 1858, Band. xiii. p. 29. 4. Scott : " On the Influence of Mercurial Preparations on the Secretion of Bile," Beale's ArcMves of Medicine, vol. i. p. 209. 5. Hughes Bennett : " Keport on the Action of Mercury on the Biliary Secretion,'' British Association Reports, 1868. 6. 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